Difficult Decisions in Thoracic Surgery An Evidence-Based Approach
Mark K. Ferguson (Editor)
Difficult Decisions in ...
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Difficult Decisions in Thoracic Surgery An Evidence-Based Approach
Mark K. Ferguson (Editor)
Difficult Decisions in Thoracic Surgery An Evidence-Based Approach Second Edition
Editor Mark K. Ferguson, MD Professor, Department of Surgery Head, Thoracic Surgery Service The University of Chicago Medical center Chicago, IL, USA
ISBN 978-1-84996-364-0 2nd edition ISBN 978-1-84628-384-0 1st edition DOI 10.1007/978-1-84996-492-0
e-ISBN 978-1-84996-492-0 2nd edition e-ISBN: 978-1-84628-470-0 1st edition
Springer Dordrecht London Heidelberg New York A catalogue record for this book is available from the British Library © Springer-Verlag London Limited 2011 First edition 2007 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licenses issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers The use of registered names, trademarks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that may be made Cover design: eStudioCalamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
To Phyllis, a decision that I would repeat in a heartbeat.
Preface to the First Edition
Why do thoracic surgeons need training in decision making? Many of us who have weathered harrowing residencies in surgery feel that, after such experiences, decision making is a natural extension of our selves. While this is no doubt true, correct decision making is something that many of us have yet to master. The impetus to develop a text on evidence-based decision making in thoracic surgery was stimulated by a conference for cardiothoracic surgical trainees developed in 2004 and sponsored by the American College of Chest Physicians. During that conference it became clear that we as thoracic surgeons are operating from a very limited fund of true evidence-based information. What was also clear was the fact that many of the decisions we make in our everyday practices are not only uninformed by evidence-based medicine but often are contradictory to existing guidelines or evidence-based recommendations. The objectives of this book are to explain the process of decision making, both on the part of the physician and on the part of the patient, and to discuss specific clinical problems in thoracic surgery and provide recommendations regarding their management using evidence-based methodology. Producing a text that will purportedly guide experienced, practicing surgeons in the decision making process that they are accustomed to observe on a daily bases is a daunting task. To accomplish this it was necessary to assemble a veritable army of authors who are widely considered to be experts in their fields. They were given the unusual (to many of them) task of critically evaluating evidence on a well-defined topic and provide two opinions regarding appropriate management of their topic: one based solely on the existing evidence, and another based on their prevailing practice, clinical experience, and teaching. Most authors found this to be an excellent learning experience. It is hoped that the readers of this book will be similarly enlightened by its contents. How should a practicing surgeon use this text? As is mentioned in the book, wholesale adoption of the stated recommendations will serve neither physician nor patient well. The reader is asked to critically examine the material presented, assess it in the light of his or her own practice, and integrate the recommendations that are appropriate. The reader must have the understanding that surgery is a complex, individualized, and rapidly evolving specialty. Recommendations made today for one patient may not be appropriate for that same patient in the same situation several years hence. Similarly, one recommendation will not serve all patients well. The surgeon must use judgment and experience to adequately utilize the guidelines and recommendations presented herein. To produce a text with timely recommendations about clinical situations in a world of rapidly evolving technology and information requires that the editor, authors, and publisher work in concert to provide a work that is relevant and up-to-date. To this end I am VII
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grateful to the authors for producing their chapters in an extraordinarily timely fashion. My special thanks go to Melissa Morton, Senior Editor at Springer, for her rapid processing and approval of the request to develop this book, and to her staff for the rapid processing of the manuscripts. My thanks go to Kevin Roggin, MD, for sharing the T.S. Eliot lines and the addendum to them. Finally, the residents with whom I have had the opportunity and privilege to work during the past two decades continually reinforce the conviction that quality information is the key to improved patient care and outcomes. Mark K. Ferguson, MD Chicago, IL March 27, 2006
Preface to the Second Edition
Since the publication of the first edition of this book, considerable progress has been made in the fields of risk assessment, decision analysis, and evidence-based medicine. That this has occurred during a challenging period in our history is testament to the importance of these fields in the advancement of medical and surgical sciences. The recent world wide financial crisis, which, at the time of this writing has only just begun to reverse its course, has focused considerable attention on health care as a source of increasing financial burden, especially in the United States. Those seeking to reduce costs are looking more closely at innovative means for making therapeutic recommendations and use of objective measures of outcomes in assessing appropriateness of care. The term “comparative effectiveness,” which until recently was unknown by the general public, has become a catch phrase that represents something good to some and everything evil to others, depending on their stance on health care reform. In compiling the second edition of this book, I’d like readers to know that I don’t have a dog in the fight over healthcare reform. The recommendations in this book were sought on topics that are clinically important in the daily lives of surgeons and for which there appeared to be lack of a standard approach to assessment and management. Possible reasons for such failure of consensus may be absence of suitable data, lack of access to such data, inability to apply innovations owing to cost or other constraints, or simple unwillingness to change. This book will hopefully define for each clinical question that is posed whether data of sufficient quality exist to permit recommendations regarding appropriate care, and certainly can serve as a source of clinical information for surgeons and other interested readers to consider. It is not intended to influence current constraints to proper care, and it unlikely to alter attitudes of surgeons who believe that their opinions and experience trump the dictums of quality data. This book is intended as a resource for clinical surgeons and other interested readers who wish to understand how experts in the field assess existing knowledge. The authors were asked to identify relevant publications in their selected topics, grade the quality of the evidence offered by those reports, apply that knowledge to objective management recommendations in an idealized world, and then comment on how they personally use the information in their own clinical practices. The book is not intended to be used as a recipe for management of patients in a rote manner. As with all clinical care, consideration must be given to the individual needs of patients as well as the clinical, institutional, and societal milieu in which the care is provided. Why create a second edition of this book? The primary reason is that there has been considerable enthusiasm for an approach of this type, and it’s necessary to create new IX
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recommendations periodically as the fields of medicine in general, and thoracic surgery in particular, evolve. That having been said, this is not just an update of the first edition. More than 50% of the clinical questions posed in this book are new, and of the questions that remain as holdovers from the prior edition, virtually all have been rewritten by new authors. In addition, the grading system used for evidence quality and strength of recommendations has been changed from the systems used in the previous text to make the summaries clearer and more user friendly. To enable the reader access to up-to-date information, authors were asked to provide their chapters within five months of the inception of this edition, an extraordinarily brief period of time for busy clinical surgeons who also carry considerable additional academic and administrative roles. That they were almost universally able to comply is evidence of the commitment of each to the advancement of the art and science of surgery and to the welfare of their patients. These surgeons were also asked to do something that is typically quite difficult for individuals who are considered experts in their selected fields and have gained international reputations for their opinions. They were asked to look critically at the body of evidence, reexamine their opinions and practice patterns, and objectively arrive at what was sometimes a new approach to their area of expertise. Having worked with the authors through several iterations of some of their chapters, I know how challenging this process was for many, and applaud all for taking on this role. My hope is that readers will find the information and recommendations in this book insightful, and that the summaries and recommendations will stimulate them to read the original source material, consider the data, and make their own objective assessments. Only in this way will we progress from the time honored traditional training format of “see one, do one, teach one,” which stifles insight, objectivity and creativity. Instead, I encourage critical evaluation of information and innovation based in established principles (rather than patterns) of clinical care to improve the outcomes in our surgical patients. Producing a book of this size in a short time requires the help of a number of individuals. I thank the residents and fellows with whom I work, who, through our daily clinical activities and teaching exercises, stimulate identification of the controversial questions found herein. My gratitude goes to the authors, their co-author residents, fellows, and students, and their administrative assistants for all of the hard work required to produce succinct and meaty chapters, and for putting up with my endless requests for revisions. I am indebted to Melissa Morton, Senior Editor at Springer, for fast-tracking the concept and expediting the production of this volume. I also am grateful to Denise Roland and Nadine Firth at Springer for keeping my colleagues on track and ushering the manuscripts through to the finished product. Mark K. Ferguson, MD Chicago
Contents
Part 1 Background 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mark K. Ferguson 2 Evidence-Based Medicine: Levels of Evidence and Evaluation Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sean C. Grondin and Colin Schieman
3
13
3 Decision Analytic Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anirban Basu and Amy Lehman
23
4 Decision Making: The Surgeon’s Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . Thomas K. Varghese, Farhood Farjah, and David R. Flum
39
5 Decision Making: The Patient’s Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dawn Stacey and France Légaré
45
Part 2 Lung 6 PET for Mediastinal Restaging of Patients with Non Small Cell Lung Cancer after Induction Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James R. Nitzkorski, Veeraiah Siripurapu, and Walter J. Scott
61
7 Optimal Initial Pathologic Mediastinal Staging of Lung Cancer: EUS, EBUS, Mediastinoscopy . . . . . . . . . . . . . . . . . . . Varun Puri and Bryan F. Meyers
67
8 VATS vs. Open Lobectomy for Early Stage Non-Small Cell Lung Cancer . . . . Shawn S. Groth and Michael A. Maddaus
77
9 N2 Disease Discovered at Thoracotomy: Resect or Abort? . . . . . . . . . . . . . . . . Frank C. Detterbeck
89
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10 Pulmonary Function Alterations After Induction Therapy for Lung Cancer: Preoperative Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gabriel Loor and Mark K. Ferguson
Contents
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11 Lobectomy After Induction Therapy for Stage IIIA NSCLC in the Presence of Persistent N2 Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gaetano Rocco
111
12 Pneumonectomy After Induction Therapy for Stage IIIA Non-small-cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alessandro Brunelli and Majed Refai
119
13 Segmentectomy Versus Lobectomy for Stage I Lung Cancer in Patients with Good Pulmonary Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brendon M. Stiles and Nasser K. Altorki
125
14 Optimal Therapy for Patients with Marginal Lung Function and Peripheral Stage I Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gonzalo Varela and Marcelo F. Jiménez
135
15 VATS Versus Thoracotomy for Major Lung Resection After Induction Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mark F. Berry and Thomas A. D’Amico
145
16 Chest Tube Management After Lung Resection . . . . . . . . . . . . . . . . . . . . . . . . . Melissa J. Ruiz and Mark K. Ferguson
155
17 Management of the Pleural Space Early After Pneumonectomy . . . . . . . . . . . K. S. Rammohan, Vasudev B. Pai, and Tom Treasure
161
18 Perioperative Prophylaxis Against Venous Thrombo-Embolism in Major Lung Resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tom Treasure, Lee-Yee Chong, and Carlos E. Sharpin
165
19 Perioperative Arrhythmia Prophylaxis for Major Lung Resection . . . . . . . . . Daniela Molena, David Amar, and Bernard J. Park
171
20 For Whom Is Lung Volume Reduction Surgery Effective? . . . . . . . . . . . . . . . . Keith S. Naunheim
179
21 Support Therapy for Lung Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James E. Lynch and Joseph B. Zwischenberger
187
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Contents
Part 3 Esophagus 22 Optimal Management of Barrett Esophagus with High Grade Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jennifer S. Chennat
197
23 Induction Therapy for Resectable Esophageal Cancer . . . . . . . . . . . . . . . . . . . Richard G. Berrisford and Marcello Migliore
203
24 Optimal Surgical Approach to Esophagectomy for Cancer . . . . . . . . . . . . . . . Brechtje A. Grotenhuis, Bas P.L.Wijnhoven, and Jan J.B. van Lanschot
213
25 Extent of Lymph Node Dissection in Esophageal Cancer . . . . . . . . . . . . . . . . . Thomas W. Rice and Eugene H. Blackstone
223
26 Salvage Esophagectomy for Persistent Disease After Definitive Chemoradiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wayne Hofstetter
233
27 Barrett Mucosa in the Cervical Remnant After Esophagectomy for Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xavier Benoit D’Journo and André Duranceau
241
28 Partial or Total Fundoplication for GERD in the Presence of Impaired Esophageal Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David I. Watson
249
29 Surgical Management of Non-acid Reflux Unresponsive to Medical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alexander J. Greenstein, James P. Dolan, and John G. Hunter
257
30 Prophylactic Antireflux Surgery in Lung Transplantation . . . . . . . . . . . . . . . . Michael S. Griffin and Andrew G. N. Robertson
263
31 Optimal Initial Therapy for Achalasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lars Lundell
269
32 Stenting for Esophageal Perforation and Anastomotic Leak . . . . . . . . . . . . . . Jessica M. Leers and Arnulf H. Hölscher
279
33 Lengthening Gastroplasty for Managing GERD and Giant Paraesophageal Hernia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lee L. Swanstrom and Trudie A. Goers
287
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Contents
34 Optimal Therapy for Cricopharyngeal Diverticula . . . . . . . . . . . . . . . . . . . . . . Giovanni Zaninotto and Christian Rizzetto
293
35 Management of Distal Esophageal Pulsion D iverticula . . . . . . . . . . . . . . . . . . Andrew C. Chang
303
Part 4 Diaphragm 36 Giant Paraesophageal Hernia: Optimal Surgical Approach . . . . . . . . . . . . . . . Kelly M. Galey and Thomas J. Watson
315
37 Diaphragm Pacing for Acute Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . Raymond P. Onders
329
38 Synthetic Reinforcement of Diaphragm Closure for Large Hiatal Hernia Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brant K. Oelschlager and Eelco B. Wassenaar
337
Part 5 Airway 39 Stents for Benign Airway Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jon O. Wee and Scott J. Swanson
347
40 Tracheal Reconstruction with Autologous and Engineered Tissues . . . . . . . . Etienne Grunenwald, Emmanuel Moss, and Moishe Liberman
353
41 Optimal Management of Malacic Airway Syndromes . . . . . . . . . . . . . . . . . . . . Cameron D. Wright
363
42 Carinal Resection for Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Federico Venuta and Erino A. Rendina
367
Part 6 Pleura and Pleural Space 43 Use of Sealants to Reduce Air Leak Duration and Hospital Stay After Lung Resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antonio D’Andrilli, Federico Venuta, and Erino A. Rendina 44 Optimal Initial Therapy for Pleural Empyema . . . . . . . . . . . . . . . . . . . . . . . . . . Curtis J. Wozniak and Alex G. Little
375
385
45 Management of Malignant Pleural Effusion: Sclerosis or Chronic Tube Drainage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leslie J. Kohman and Todd L. Demmy
395
46 The Role of VATS Pleurodesis in the Management of Initial Primary Spontaneous Pneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John C. Kucharczuk
401
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47 Malignant Pleural Mesothelioma: Patient Selection for Pleurectomy . . . . . . Raja M. Flores and Naveed Z. Alam 48 Malignant Pleural Mesothelioma: Patient Selection for Extrapleural Pneumonectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David A. Waller
409
417
Part 7 Mediastinum 49 Thymectomy for Myathenias Gravis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Joshua Sonett
425
50 Optimal Surgical Approach and Extent of Resection of the Thymus in Patients with Myasthenia Gravis . . . . . . . . . . . . . . . . . . . . . . Mitchell J. Magee
433
51 The Optimal Approach for Resection of Encapsulated Thymoma: Open Versus VATS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shaf Keshavjee and Christian Finley
439
52 Management of Residual Disease After Therapy for Mediastinal Germ Cell Tumor and Normal Serum Markers . . . . . . . . . . . Heather D. Riggs, Lawrence H. Einhorn, and Kenneth A. Kesler
445
53 Symptomatic Malignant Pericardial Effusion: Surgical or Percutaneous Drainage? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M. Blair Marshall
453
54 Bronchogenic and Pericardial Cysts: Resect or Observe . . . . . . . . . . . . . . . . . . Kemp H. Kernstine and Peace Eneh
461
55 Patient Selection and Optimal Extent of Surgery for Hyperhidrosis . . . . . . . Stephen R. Hazelrigg, Ibrahim Bulent Cetindag, and Melita L. Viegas
471
Part 8 Chest Wall 56 Pectus Excavatum in the Adult: Current Treatment Modalities . . . . . . . . . . . . Dawn E. Jaroszewski, Jason D. Fraser, and David M. Notrica
481
57 Traumatic Rib Fracture: Conservative Therapy or Surgical Fixation? . . . . . . John C. Mayberry and Paul H. Schipper
489
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
495
Contributors
Naveed Z. Alam MD FRCSC Department of Surgery, St. Vincent’s Hospital Melbourne, Melbourne VIC Australia
Alessandro Brunelli MD Department of Thoracic Surgery Ospedali Riuniti, Ancona, Italy
Nasser K. Altorki MD Department of Cardiothoratic Surgery Weill-Medical College of Cornell University New York NY, USA
Ibrahim B. Cetindag MD Department of Surgery Southern Illinois University Springfield IL, USA
David Amar MD Anesthesiology and Critical Care Medicine Memorial Sloan-Kettering Cancer Center New York NY, USA
Andrew C. Chang MD Department of Surgery Section of General Thoracic Surgery The University of Michigan Medical Center Ann Arbor MI, USA
Anirban Basu PhD Department of Medicine The University of Chicago Chicago IL, USA Richard G. Berrisford ChM FRCS(CTh) FETCS Department of Cardiothoracic Surgery Derriford Hospital Plymouth Devon, UK Mark F. Berry MD Department of Surgery Duke Universal Medical Center Durham NC, USA Eugene H. Blackstone MD Department of Thoracic and Cardiovascular Surgery Cleveland Clinic Cleveland OH, USA
Jennifer S. Chennat MD Section of Gastroenterology The University Chicago Chicago IL, USA Lee-Yee Chong Phd BDc Pharm(Hons) National Clinical Guidelines Centre Royal College of Physicians London, UK Thomas A. D’Amico MD Department of Surgery Duke University Medical Center Durham NC, USA Antonio D’Andrilli MD Department of Thoracic Surgery Sant Andrea Hospital Rome, Italy
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Contributors
Xavier B. D’Journo MD FETCS Department of Thoracic Surgery Hopitaux de Marseille Marseille, France
Raja M. Flores MD Division of Thoracic Surgery Mount Sinai School of Medicine New York NY, USA
Todd L. Demmy MD Department of Thoracic Surgery Roswell Park Cancer Institute Buffalo NY, USA
David R. Flum MD MPH Department of Surgery University of Washington Seattle WA, USA
Frank C. Detterbeck MD Department of Thoracic Surgery Yale University School of Medicine New Haven CT, USA
Jason D. Fraser MD Department of General Surgery Mayo Clinic Arizona Phoenix AZ, USA
James P. Dolan MD Department of Surgery Oregon Health & Science University Portland OR, USA
Kelly M. Galey MD Department of Surgery University of Rochester School of Medicine and Dentistry Rochester NY, USA
André Duranceau MD Department of Surgery Université de Montréal Centre Hospitalier de l’Université de Montreal Montreal QC, Canada Lawrence H. Einhorn MD Department of Medicine – Hematology/Oncology Indiana University Indianapolis IN, USA Peace Eneh Concordia College Moorhead MN, USA Farhood Farjah MD MPH Department of General Surgery University of Washington Seattle WA, USA Mark K. Ferguson MD Department of Surgery The University of Chicago Chicago IL, USA Christian Finley MD MPH Division of Thoracic Surgery University Health Network Toronto, Ontario, Canada
Trudie A. Goers MD Department of Surgery Minimally Invasive Fellowship Legacy Health Center Portland OR, USA Alexander J. Greenstein MD MPH Department of Surgery Oregon Health & Science University Portland OR, USA Michael S. Griffin MB BS MD FRCS(Ed) FRCS Northern Oesophago – Gastric Unit Royal Victoria Infirmary Newcastle Upon Tyne, UK Sean C. Grondin MD MPH Department of Surgery Foothills Medical Centre University of Calgary Calgary AB, Canada Brechtje A. Grotenhuis MD Department of Surgery Erasmus Medical Center University of Rotterdam Rotterdam, The Netherlands
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Contributors
Shawn S. Groth MD MS Department of Surgery University of Minnesota Minneapolis MN, USA
Shaf Keshavjee MD FRCSC FACS Division of Thoracic Surgery University Health Network Toronto, Ontario, Canada
Etienne Grunenwald MD Division of Thoracic Surgery University of Montreal Montreal QC, Canada
Kenneth A. Kesler MD Department of Cardiothoracic Surgery Indiana University School of Medicine Indianapolis IN, USA
Stephen R. Hazelrigg MD Department of Cardiothoracic Surgery SIU School of Medicine Springfield IL, USA
Leslie J. Kohman MD Department of Surgery Upstate Medical University Syracuse NY, USA
Wayne Hofstetter MD Department of Thoracic and Cardiovascular Surgery The University of Texas M.D. Anderson Cancer Center Houston TX, USA
John C. Kucharczuk MD Department of Surgery University of Pennsylvania School of Medicine Philadelphia PA, USA
Arnulf H. Hölscher MD Department of General Visceral and Cancer Surgery University Hospital of Cologne Cologne, Germany John G. Hunter MD Department of Surgery Oregon Health and Science University Portland OR, USA Dawn E. Jaroszewski MD MBA Division of Cardiothoracic Surgery Mayo Clinic Arizona Phoenix AZ, USA Marcelo F. Jiménez MD PhD FETCS Department of Thoracic Surgery Salamanca University Hospital and Medical School Salamanca, Spain Kemp H. Kernstine MD PhD Division of Thoracic Surgery City of Hope National Medical Center and Beckman Research Institute Duarte CA, USA
Jessica M. Leers MD Department of General Visceral and Cancer Surgery University Hospital of Cologne Cologne, Germany France Légaré MD PhD CCFP FCFP Department of Family and Emergency Medicine Laval University Research Center of Centre Hospitalier Universitaire de Quebec St François d’Assise Hospital Quebec, Canada Amy Lehman MD MBA Founder and Director Lake Tanganyika Floating Health Clinic Chicago IL, USA Moishe Liberman MD PhD Division of Thoracic Surgery University of Montreal Montreal QC, Canada Alex G. Little MD Department of Surgery Wright State University Boonshoft School of Medicine Dayton OH, USA
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Contributors
Gabriel Loor MD Department of Thoracic and Cardiovascular Surgery Cleveland Clinic Cleveland OH, USA
Emmanuel Moss MD Division of Thoracic Surgery University of Montreal Montreal QC, Canada
Lars Lundell MD PhD Department of Surgical Gastroenterology Karolinska University Hospital Stockholm, Sweden
Keith S. Naunheim MD Department of Thoracic Surgery St. Louis University School of Medicine St. Louis MO, USA
James E. Lynch MD Department of Surgery University of Kentucky College of Medicine Lexington KY, USA
James R. Nitzkorski MD Department of Surgical Oncology Fox Chase Cancer Center Philadelphia PA, USA
Michael A. Maddaus MD Department of Surgery University of Minnesota Minneapolis MN, USA Mitchell J. Magee MD MS Department of Cardiothoracic Surgery Director of Minimally Invasive Thoracic Surgery and Surgical Oncology Medical City Dallas Hospital Dallas TX, USA M. Blair Marshall MD Department of Surgery Georgetown University Hospital Washington DC, USA John C. Mayberry MD Department of Trauma/ Critical Care/Acute Care Surgery Oregon Health & Science University Portland OR, USA Bryan F. Meyers MD MPH Division of Cardiothoracic Surgery Washington University School of Medicine St. Louis MO, USA Marcello Migliore MD PhD FECTS Department of Thoracic Surgery University of Catania Catania, Italy Daniela Molena MD Department of Surgery Memorial Sloan-Kettering Cancer Center New York NY, USA
David M. Notrica MD FACS FAAP Department of Surgery University of Arizona College of Medicine Phoenix AZ, USA Brant K. Oelschlager MD Department of Surgery University of Washington Seattle WA, USA Raymond P. Onders MD Division of Minimally Invasive Surgery University Hospitals of Cleveland Case Western Reserve University Cleveland OH, USA Vasudev B. Pai MBBS MS MCh MRCS Department of Cardiothoracic Surgery Heart Hospital University College Hospitals NHS Trust London, UK Bernard J. Park MD FACS Department of Surgery Memorial Sloan-Kettering Cancer Center Newy York NY, USA Varun Puri MD Department of Surgery Washington University St. Louis MO, USA K. S. Rammohan MBBS MS FRCS Department of Minimal Access Thoracic Surgery Royal Alexandra Hospital and University of Alberta Edmonton AB, Canada
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Contributors
Majed Refai MD Department of Thoracic Surgery Ospedali Riuniti Ancona Ancona, Italy
Paul H. Schipper MD Department of General Thoracic Surgery Oregon Health & Science University Portland OR, USA
Erino A. Rendina MD Department of Thoracic Surgery Sant Andrea Hospital Rome, Italy
Walter J. Scott MD Department of Surgical Oncology Fox Chase Cancer Center Philadelphia PA, USA
Thomas W. Rice MD Department of Thoracic and Cardiovascular Surgery Cleveland Clinic Cleveland OH, USA
Carlos E. Sharpin BSc MSc Department of National Clinical Guideline Centre Royal College of Physicians London, UK
Heather D. Riggs MD Department of Hematology and Oncology, Indiana University Simon Cancer Center Indianapolis IN, USA Christian Rizzetto MD Department of Surgical and Gastroenterological Sciences University of Padova Padova, Italy Andrew G.N. Robertson BSc (Hons) MBChB (Hons) Department of Northern Oesophago-Gastric Unit Royal Victoria Infirmary Newcastle Upon Tyne, UK Gaetano Rocco MD FRCS (Ed) Department of Thoracic Surgery and Oncology National Cancer Institute Pascale Foundation Naples, Italy Melissa J. Ruiz MD Department of Surgery University of Chicago Chicago IL, USA Colin Schieman MD Department of Surgery Foothills Medical Centre University of Calgary Calgary AB, Canada
Veeraiah Siripurapu MD Department of Surgical Oncology Fox Chase Cancer Center Philadelphia PA, USA Joshua Sonett MD Department of Surgery Columbia University New York Presbyterian Hospital New York NY, USA Dawn Stacey RN MScN PhD Faculty of Health Sciences School of Nursing University of Ottawa Ottawa ON, Canada and Clinical Epidemiology Program Ottawa Hospital Research Institute Ottawa ON, Canada Brendon M. Stiles MD Department of Cardiothoracic Surgery Weill Cornell Medical College New York Presbyterian Hospital New York NY, USA Scott J. Swanson MD Division of Thoracic Surgery Brigham and Women’s Hospital Boston MA, USA Lee L. Swanstrom MD Department of Surgery Oregon Health Sciences University Portland OR, USA
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Contributors
Tom Treasure MD MS FRCS FRCP Clinical Operational Research Unit University College London London, UK
David I. Watson MB BS MD FRACS Department of Surgery Flinders University Adelaide, Australia
Jan J.B. van Lanschot MD PhD Department of Surgery Erasmus Medical Center Rotterdam, The Netherlands
Thomas J. Watson MD FACS Department of Surgery University of Rochester School of Medicine and Dentistry Rochester NY, USA
Gonzalo Varela MD PhD FETCS Department of Thoracic Surgery Salamanca University Hospital and Medical School Salamanca, Spain Thomas K. Varghese Jr MD MS Department of Surgery University of Washington Seattle WA, USA Federico Venuta MD Department of Thoracic Surgery University La Sapienza Umberto I Policlinic Rome, Italy
Jon O. Wee MD Dana-Farber Cancer Center Brigham & Women’s Hospital Boston MA, USA Bas P.L. Wijnhoven MD PhD Department of Surgery Erasmus Medical Center University of Rotterdam Rotterdam, The Netherlands Curtis J. Wozniak MD Department of Surgery Wright State University Boonshoft School of Medicine Dayton OH, USA
Melita L Viegas MD Department of Surgery SIU School of Medicine Springfield IL, USA
Cameron D. Wright MD Department of Thoracic Surgery Massachusetts General Hospital Boston MA, USA
David A. Waller BM BS BMedSci FRCS (CTh) Department of Thoracic Surgery Glenfield Hospital Leicester, UK
Giovanni Zaninotto MD FACS Department of General Surgery Hospital SS Giovanni e Paolo Venice, Italy
Eelco B. Wassenaar MD PhD Department of Surgery University of Washington Seattle WA, USA
Joseph B. Zwischenberger MD Department of Surgery University of Kentucky College of Medicine Lexington KY, USA
Part 1 Background
1
Introduction Mark K. Ferguson
Dorothy Smith, an elderly and somewhat portly woman, presented to her local emergency room with chest pain and shortness of breath. An extensive evaluation revealed no evidence for coronary artery disease, congestive heart failure, or pneumonia. A chest radiograph demonstrated a large air-fluid level posterior to her heart shadow, a finding that all thoracic surgeons recognize as being consistent with a large paraesophageal hiatal hernia. The patient had not had similar symptoms previously. Her discomfort was relieved after a large eructation, and she was discharged from the emergency room a few hours later. When seen several weeks later in an outpatient setting by an experienced surgeon, who reviewed her history and the data from her emergency room visit, she was told that surgery is sometimes necessary to repair such hernias. Her surgeon indicated that the objectives of such an intervention would include relief of symptoms such as chest pain, shortness of breath, and postprandial fullness, and prevention of catastrophic complications of giant paraesophageal hernia, including incarceration, strangulation, and perforation. Ms. Smith, having recovered completely from her episode of a few weeks earlier, declined intervention, despite her surgeon’s strenuous encouragement. She presented to her local emergency room several months later with symptoms of an incarcerated hernia and underwent emergency surgery to correct the problem. The surgeon found a somewhat ischemic stomach and had to decide whether to resect the stomach or just repair the hernia. If resection was to be performed, an additional decision was whether to reconstruct immediately or at
the time of a subsequent operation. If resection was not performed, the surgeon needed to consider a variety of options as part of any planned hernia repair: whether to perform a gastric lengthening procedure; whether a fundoplication should be constructed; and whether to reinforce the hiatal closure with non-autologous materials. Each of these intraoperative decisions could importantly affect the need for a subsequent reoperation, the patient’s immediate survival, and her long-term quality of life. Given the dire circumstances that the surgeon was presented with during the emergency operation, it would have been optimal if the emergent nature of the operation could have been avoided entirely. In retrospect, which was more correct in this hypothetical situation, the recommendation of the surgeon or the decision of the patient? Decisions are the stuff of everyday life for all physicians; for surgeons, life-altering decisions often must be made on the spot, frequently without what many might consider to be necessary data. The ability to make such decisions confidently is the hallmark of the surgeon. However, decisions made under such circumstances are often not correct or even well reasoned. All surgeons (and many of their spouses) are familiar with the saying “…often wrong, but never in doubt.” As early as the fourteenth century physicians were cautioned never to admit uncertainty. Arnauld of Villanova wrote that, even when in doubt, physicians should look and act authoritative and confident.1 In fact, useful data do exist that could have an impact on many of the individual decisions regarding elective and emergent
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_1, © Springer-Verlag London Limited 2011
3
4
management of the giant paraesophageal hernia scenario outlined above. Despite the existence of these data, surgeons tend to make decisions based on their own personal experience, anecdotal tales of good or bad outcomes, and unquestioned adherence to dictums from their mentors or other respected leaders in the field, often to the exclusion of objective data. It is believed that only 15% of medical decisions are scientifically based,2 and it is possible that an even lower percentage of thoracic surgical decisions are so founded. With all of our modern technological, data processing, and communication skills, why do we still find ourselves in this situation?
Early Surgical Decision Making Physicians’ diagnostic capabilities, not to mention their therapeutic armamentarium, were quite limited until the middle to late nineteenth century. Drainage of empyema, cutting for stone, amputation for open fractures of the extremities, and mastectomy for cancer were relatively common procedures, but few such conditions were diagnostic dilemmas. Surgery, when it was performed, was generally indicated for clearly identified problems that could not be otherwise remedied. Some surgeons were all too mindful of the warnings of Hippocrates: “…physicians, when they treat men who have no serious illness, … may commit great mistakes without producing any formidable mischief … under these circumstances, when they commit mistakes, they do not expose themselves to ordinary men; but when they fall in with a great, a strong, and a dangerous disease, then their mistakes and want of skill are made apparent to all. Their punishment is not far off, but is swift in overtaking both the one and the other.”3 Others took a less considered approach to their craft, leading Hunter to liken a surgeon to “an armed savage who attempts to get that by force which a civilized man would get by stratagem.”4 Based on small numbers of procedures, lack of a true understanding of pathophysiology, frequently mistaken diagnoses, and the absence of technology to communicate information quickly, surgical therapy until the middle of the nineteenth century was largely empiric. For example, by that
M.K. Ferguson
time fewer than 90 diaphragmatic hernias had been reported in the literature, most of them having been diagnosed postmortem as a result of gastric or bowel strangulation and perforation.5 Decisions were based on dogma promulgated by word of mouth. This has been termed the “ancient era” of evidence-based medicine.6 An exception to the empiric nature of surgery was the approach espoused by Hunter in the mideighteenth century, who suggested to Jenner, his favorite pupil, “I think your solution is just, but why think? Why not try the experiment?”4 Hunter challenged the established practices of bleeding, purging, and mercury administration, believing them to be useless and often harmful. Theses views were so heretical that, 50 years later, editors added footnotes to his collected works insisting that these were still valuable treatments. Hunter and others were the progenitors of the “renaissance era” of evidence-based medicine, in which personal journals, textbooks, and some medical journal publications were becoming prominent.6 The discovery of x-rays in 1895 and the subsequent rapid development of radiology in the following years made the diagnosis and surgical therapy of a large paraesophageal hernia such as that described at the beginning of this chapter commonplace. By 1908 x-ray was accepted as a reliable means for diagnosing diaphragmatic hernia, and by the late 1920s surgery had been performed for this condition on almost 400 patients in one large medical center.7,8 Thus, the ability to diagnose a condition was becoming a prerequisite to instituting proper therapy. This enormous leap in physicians’ abilities to render appropriate ministrations to their patients was based on substantial new and valuable objective data. In contrast, however, the memorable anecdotal case presented by a master (or at least an influential) surgeon continued to dominate the surgical landscape. Prior to World War II, it was common for surgeons throughout the world with high career aspirations to travel to Europe for a year or two, visiting renowned surgical centers to gain insight into surgical techniques, indications, and outcomes. In the early twentieth century Murphy attracted a similar group of surgeons to his busy clinic at Mercy Hospital in Chicago. His publication of case reports and other observations evolved into the Surgical Clinics of North America.
1. Introduction
Seeing individual cases and drawing conclusions based upon such limited exposure no doubt reinforced the concept of empiricism in decision making in these visitors. True, compared to the strict empiricism of the nineteenth century there were more data available upon which to base surgical decisions in the early twentieth century, but information regarding objective short-term and longterm outcomes still was not readily available in the surgical literature or at surgical meetings. Reinforcing the imperative of empiricism in decision making, surgeons often disregarded valuable techniques that might have greatly improved their efforts. It took many years for anesthetic methods to be accepted. The slow adoption of endotracheal intubation combined with positive pressure ventilation prevented safe thoracotomy for decades after their introduction into animal research. Wholesale denial of germ theory by US physicians for decades resulted in continued unacceptable infection rates for years after preventive measures were identified. These are just a few examples of how ignorance and its bedfellow, recalcitrance, delayed progress in thoracic surgery in the late nineteenth and early twentieth centuries.
Evidence-Based Surgical Decisions There were important exceptions in the late nineteenth and early twentieth centuries to the empiric nature of surgical decision making. Among the first were the demonstration of antiseptic methods in surgery and the optimal therapy for pleural empyema. Similar evidence-based approaches to managing global health problems were developing in non-surgical fields. Reed’s important work in the prevention of yellow fever led to the virtual elimination of this historically endemic problem in Central America, an accomplishment that permitted construction of the Panama Canal. The connection between the pancreas and diabetes that had been identified decades earlier was formalized by the discovery and subsequent clinical application of insulin in 1922, leading to the awarding of a Nobel prize to Banting and Macleod in 1923. Fleming’s rediscovery of the antibacterial properties of penicillin in 1928 led to its
5
development as an antibiotic for humans in 1939, and it received widespread use during World War II. The emergency use of penicillin, as well as new techniques for fluid resuscitation, were said to account for the unexpectedly high rate of survival among burn victims of the Coconut Grove nightclub fire in Boston in 1942. Similar stories can be told for the development of evidence in the management of polio and tuberculosis in the midtwentieth century. As a result, the first half of the twentieth century has been referred to as the “transitional era” of evidence-based medicine, in which information was shared easily through textbooks and peer-reviewed journals.6 Among the first important examples of the use of evidence-based medicine is the work of Semmelweiss, who in 1861 demonstrated that careful attention to antiseptic principles could reduce mortality associated with puerperal fever from over 18% to just over 1% (Semmelweiss). The effective use of such principles in surgery was investigated during that same decade by Lister, who noted a decrease in mortality on his trauma ward from 45% to 15% with the use of carbolic acid as an antiseptic agent during operations. However, both the germ theory of infection and the ability of an antiseptic such as carbolic acid to decrease the risk of infection were not generally accepted, particularly in the United States, for another decade. In 1877 Lister performed an elective wiring of a patellar fracture using aseptic techniques, essentially converting a closed fracture to an open one in the process. Under practice patterns of the day, such an operation would almost certainly lead to infection and possible death, but the success of Lister’s approach secured his place in history. It is interesting to note that a single case such as this, rather than prior reports of his extensive experience with the use of antiseptic agents, helped Lister turn the tide towards universal use of antiseptic techniques in surgery thereafter. The second example developed over 40 years after the landmark demonstration of antiseptic techniques and also involved surgical infectious problems. Hippocrates described open drainage for empyema in 229 BC, indicating that “when empyema are opened by the cautery or by the knife, and the pus flows pale and white, the patient survives, but if it is mixed with blood and muddy and foul
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6
The Age of Information These surgical efforts in the late nineteenth and early twentieth centuries ushered in the beginning of an era of scientific investigation of surgical problems. This was a period of true surgical research characterized by both laboratory and clinical efforts. It paralleled similar efforts in nonsurgical medical disciplines. Such research led to the publication of hundreds of thousands of papers on surgical management. This growth of medical information is not a new phenomenon, however. The increase in published manuscripts, and the increase in medical journals, has been exponential over a period of more than two centuries, with a compound annual growth rate of almost 4% per year (Fig. 1.1).10 In addition, the quality and utility of currently published information is substantially better than that of publications in centuries past. Currently there are more than 2,000 publishers producing works in the general field of science, technology, and medicine. The field comprises more than 1,800 journals containing 1.4 million peer-reviewed articles annually. The annual growth rate of health science articles during the past two decades is about 3%, continuing the trend of the past two centuries and adding to the difficulty of identifying useful information (Fig. 1.2).10 When confronting this large amount of published information, separating the wheat from the chaff is a daunting task. The work of assessing such information has been assumed to some extent by
1000 Journals
smelling, he will die.”3 There was little change in the management of this problem until the introduction of thoracentesis by Trusseau in 1843. The mortality rate for empyema remained at 50–75% well into the twentieth century.9 The confluence of two important events, the flu pandemic of 1918 and the Great War, stimulated the formation of the US Army Empyema Commission in 1918. Led by Graham and Bell, this commission’s recommendations for management included three basic principles: drainage, with avoidance of open pneumothorax; obliteration of the empyema cavity; and nutritional maintenance for the patient. Employing these simple principles led to a decrease in mortality rates associated with empyema to 10–15%.
100
1 1665
1765
1865
1965
Year
Figure 1.1. The total number of active refereed journals published annually (Data from Mabe [10]).
experts in the field who perform structured reviews of information on important issues and meta-analyses of high quality, controlled, randomized trials. These techniques have the potential to summarize results from multiple studies and, in some instances, crystallize findings into a simple, coherent statement. An early proponent of such processes was Cochrane, who in the 1970s and 1980s suggested that increasingly limited medical resources should be equitably distributed and consist of interventions that have been shown in properly designed evaluations to be effective. He stressed the importance of using evidence from randomized controlled trials, which were likely to provide much more reliable information than other sources of evidence.11 These efforts ushered in an era of high quality medical and surgical research. Cochrane was posthumously honored with the development of the Cochrane Collaboration in 1993, encompassing multiple centers in North America and Europe, with the purpose of “helping healthcare providers, policy makers, patients, their advocates and carers, make well-informed decisions about human health care by preparing, updating and promoting the accessibility of Cochrane Reviews.”12 Methods originally espoused by Cochrane and others have been codified into techniques for rating the quality of evidence in a publication and for grading the strength of a recommendation based on the preponderance of available evidence. In accord with this, the clinical problems addressed in this book have been assessed using a modification of a single relatively new rating system (GRADE) that is outlined thoroughly in chapter 2.13 Techniques such as those described above for synthesizing large amounts of quality information
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1. Introduction 55000
Health sciences publications 50000
Articles
45000 40000 35000 30000 25000
3% annual growth rate
20000 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Publication Year
Figure 1.2. Growth in the number of published health science articles published annually (Data from Mabe [10])
were introduced for the development guidelines for clinical activity in thoracic surgery, most commonly for the management of lung cancer, beginning in the mid-1990s. An example of these is a set of guidelines based on what were then current standards of care sponsored by the Society of Surgical Oncology for managing lung cancer. It was written by experts in the field without a formal process of evidence collection.14 A better technique for arriving at guidelines is the consensus statement, usually derived during a consensus process in which guidelines based on published medical evidence are revised until members of the conference agree by a substantial majority in the final statement. An example of this iterative structure is the Delphi process.15 The problem with this technique is that the strength of recommendations, at times, is sometimes diluted until there is little content to them. Some organizations that appear to have avoided this pitfall in the general of guidelines of interest to thoracic surgeons include The American College of Chest Physicians, the Society of Thoracic Surgeons, the European Society of Thoracic Surgeons, the European Respiratory Society, the American Thoracic Society, the National Comprehensive Cancer Network, the Society of Clinical Oncology, the British Thoracic Society, and the Society of Surgical Oncology, to name but a few.
Despite the enormous efforts expended by professional societies in providing evidence-based algorithms for appropriate management of patients, adherence to these published guidelines, based on practice pattern reports, is disappointing. Focusing again on surgical management of lung cancer, there is strong evidence that standard procedures incorporated into surgical guidelines for lung cancer are widely ignored. For example, fewer than 50% of patients undergoing mediastinoscopy for nodal staging have lymph node biopsies performed. In patients undergoing major resection for lung cancer, fewer than 60% have mediastinal lymph nodes biopsied or dissected.16 Only one-third of physicians routinely assess diffusing capacity in lung cancer patients who are candidates for lung resection in Europe, and in the United States fewer than 60% of patients who undergo major lung resection for cancer have diffusing capacity measured.17,18 There are also important regional variations in the use of standard staging techniques and in the use of surgery for stage I lung cancer patients, patterns of activity that are also related to race and socioeconomic status.19,20 Failure to adhere to accepted standards of care for surgical lung cancer patients results in higher postoperative mortality rates,21,22 and the selection of superspecialists one’s lung cancer surgery confers an overall long-term survival advantage.23
8
The importance of adherence to accepted standards of care, particular those espoused by major professional societies, such as the American College of Surgeons, The Society of Surgical Oncology, the American Society of Clinical Oncology, the American Cancer Society, the National Comprehensive Cancer Network, is becoming clear as the United States Centers for Medicare and Medicaid Services develops processes for rewarding adherence to standards of clinical care. This underscores the need for surgeons to become familiar with evidence-based practices and to adopt them as part of their daily routines. What is not known is whether surgeons should be rewarded for their efforts in following recommended standards of care, or for the outcomes of such care? Do we measure the process, the immediate success, or the longterm outcomes? If outcomes are to be the determining factor, what outcomes are important? Is operative mortality an adequate surrogate for quality of care and good results? Whose perspective is most important in determining success, that of the patient, or that of the medical establishment?
The Age of Data We have now entered into an era in which the number of data available for studying problems and outcomes in surgery is truly overwhelming. Large clinical trials involving thousands of subjects render databases measured in megabytes. As an example, for the National Emphysema Treatment Trial (NETT), which entered over 1,200 patients, initial data collection prior to randomization consisted of over 50 pages of data for each patient.24 Patients were subsequently followed for up to 5 years after randomization, creating an enormous research database. The size of the NETT database is dwarfed by other databases in which surgical information is stored, including the National Medicare Database, the Surveillance Epidemiology and End Results (SEER; 170,000 new patients annually), Nationwide Inpatient Sample (NIS; 7 million hospital stays annually), and the Society of Thoracic Surgeons (STS) database (1.5 million patients).
M.K. Ferguson
Medical databases are of two basic types: those that contain information that is primarily clinical in nature, especially those that are developed specifically for a particular research project such as the NETT, and administrative databases that are maintained for other than clinical purposes but that can be used in some instances to assess clinical information and outcomes, an example of which is the National Medicare Database. In formation is organized in databases in a hierarchical structure. An individual unit of data is a field; a patient’s name, address, and age are each individual fields. Fields are grouped into records, such that all of one patient’s fields constitute a record. Data in a record have a one-to-one relationship with each other. Records are complied in relations, or files. Relations can be as simple as a spreadsheet, or flat file, in which there is a one-to-one relationship between each field. More complex relations contain many-to-one, or one-to-many, relationships among fields, relationships that must be accessed through queries rather than through simple inspection. An example is multiple diagnoses for a single patient, or multiple patients with a single diagnosis. In addition to collection of data such as those above that are routinely generated in the process of standard patient care, new technological advances are providing an exponential increase in the amount of data generated by standard studies. An example is the new 64 slice computed tomography scanner, which has quadrupled the amount of information collected in each of the x–y–z axes as well as providing temporal information during a routine CT scan. The vast amount of additional information provided by this technology has created a revolutionary, rather than evolutionary, change in diagnostic radiology. Using this technology, virtual angiograms can be performed, three dimensional reconstruction of isolated anatomic entities is possible, and radiologists are discovering more abnormalities than clinicians know what to do with. A case in point is the use of CT as a screening test for lung cancer. Rapid low-dose CT scans were introduced in the late 1990s and were quickly adopted as a means for screening high risk patients for lung cancer. The results of this screening have been mixed. Several reports suggest that the number of radiographic abnormalities identified is
1. Introduction
high compared to the number of clinically important findings. For example, in the early experience at the Mayo clinic over 1,500 patients were enrolled in an annual CT screening trial, and in the 4 years of the trial, over 3,100 indeterminate nodules were identified, only 45 of which were found to be malignant.25 Similar results have been reported by others during screening or surveillance activities.26 Many additional radiographic abnormalities other than lung nodules were also identified. In addition, the increase in radiation exposure owing to more complex exams and more frequent exams has led to concerns about radiation-induced neoplasms, an unintended consequence of the good intentions of those performing lung cancer screening.27,28
What Lies in the Future? What do we now do with the plethora of information that is being collected on patients? How do we make sense of these gigabytes or terabytes of data? It may be that we now have more information than we can use or that we even want. Regardless, the trend is clearly in the direction of collecting more, rather than less, data, and it behooves us to make some sense of the situation. In the case of additional radiographic findings resulting from improved technology, new algorithms have already been refined for evaluating nodules and for managing their follow-up over time, and have yielded impressive results in the ability of these approaches to identify which patients should be observed and which patients should undergo biopsy or surgery.29 What, though, of the reams of numerical and other data than pour in daily and populate large databases? When confronting this dilemma, it useful to remember that we are dealing with an evolutionary problem, the extent of which has been recognized for decades. Eliot aptly described this predicament in The Rock (1934), lamenting: Where is the wisdom we have lost in knowledge? Where is the knowledge we have lost in information?
To those lines one might add: Where is the information we have lost in data?
9
One might ask, in the presence of all this information, are we collecting the correct data? Evidence-based guidelines regarding indications for surgery, surgical techniques, and postoperative management are often lacking. We successfully track surgical outcomes of a limited sort, and often only in retrospect: complications, operative mortality, and survival. We don’t successfully track patient’s satisfaction with their experience, the quality of life they are left with as a result of surgery, and whether they would make the same decision regarding surgery if they had to do things over again. Perhaps these are important questions upon which physicians should focus. In addition to migrating towards patient-focused rather than institutionally-focused data, are we prepared to take the greater leap of addressing more important issues requiring data from a societal perspective, including cost-effectiveness and appropriate resource distribution (human and otherwise) and utilization? This would likely result in redeployment of resources towards health prevention and maintenance rather than intervention. Such efforts are already underway, sponsored not by medical societies and other professional organizations, but by those paying the increasingly unaffordable costs of medical care. Insurance companies have long been involved, through their actuarial functions, in identifying populations who are at high risk for medical problems, and it is likely that they will extend this actuarial methodology into evaluating the success of surgical care on an institutional and individual surgeon basis as more relevant data become available. The Leapfrog Group, representing a consortium of large commercial enterprises that covers insurance costs for millions of workers, was founded to differentiate levels of quality of outcomes for common or very expensive diseases, thereby potentially limiting costs of care by directing patients to better outcome centers. These efforts have three potential drawbacks from the perspective of the surgeon. First, decisions made in this way are primarily fiscally based, and are not patient focused. Second, policies put in place by payors will undoubtedly lead to regionalization of health care, effectively resulting in de facto restraint of trade affecting those surgeons with low individual case volumes or comparatively poor outcomes for a procedure, or who work in
M.K. Ferguson
10
low volume centers. Finally, decisions about point of care will be taken from the hands of the patients and their physicians. The next phase of this process will be requirements on the part of payors regarding practice patterns, in which penalties are incurred if proscribed patterns are not followed, and rewards are provided for following such patterns, even if they lead to worse outcomes in an individual patient. Physicians can retain control of the care of their patients in a variety of ways. First, they must make decisions based on evidence and in accordance with accepted guidelines and recommendations. This text serves to provide an outline for only a fraction of the decisions that are made in a thoracic surgical practice. For many of the topics in this book there are preciously few data that can be used to formulate a rational basis for a recommendation. Practicing physicians must therefore become actively involved in the process of developing useful evidence upon which decisions can be made. There are a variety of means for doing this, including participation in randomized clinical trials, entry of their patient data (appropriately anonymized) into large databases for study, and participation in consensus conferences aimed at providing useful management guidelines for problems in which they have a special interest. Critical evaluation of new technology and procedures, rather than merely adopting what is new to appear to the public and referring physicians that one’s practice is cutting edge, may help reduce the wholesale adoption of what is new into patterns of practice before its value is proven.
Conclusion Decisions are the life blood of surgeons. How we make decisions affects the immediate and longterm outcomes of care of individual patients. Such decisions will also, in the near future, affect our reimbursement, our referral patterns, and possibly our privileges to perform certain operations. Most of the decisions that we currently make in our surgical practices are insufficiently grounded in adequate evidence. In addition, we tend to ignore published evidence and guidelines, preferring to base our decisions on prior training,
anecdotal experience, and intuition as to what is best for an individual patient. Improving the process of decision making is vital to our patients’ welfare, to the health of our specialty, and to our own careers. To do this we must thoughtfully embrace the culture of evidencebased medicine. This requires critical appraisal of reported evidence, interpretation of the evidence with regards to the surgeon’s target population, and integration of appropriate information and guidelines into daily practice. Constant review of practice patterns, updating management algorithms, and critical assessment of results is necessary to maintain optimal quality care. Documentation of these processes must become second nature. Unless individual surgeons adopt leadership roles in this process and thoracic surgeons as a group buy into this concept, we will find ourselves marginalized by outside forces that will distance us from our patients and discount our expertise in making vital decisions.
References 1. Kelly J. The Great Mortality. An Intimate History of the Black Death, the Most Devastating Plague of All Time. New York, NY: Harper Collins; 2006. 2. Eddy DM. Decisions without information. The intellectual crisis in medicine. HMO Pract. 1991;5: 58–60. 3. Hippocrates. The Genuine Works of Hippocrates. C.D. Adams, ed., trans. New York, NY: Dover; 1868. 4. Moore W. The Knife Man: The Extraordinary Life and Times of John Hunter, Father of Modern Surgery. New York, NY: Broadway Books; 2005. 5. Bowditch HI. A treatise on diaphragmatic hernia. Buffalo Med J Monthly Rev. 1853;9:65–94. 6. Claridge JA, Fabian TC. History and development of evidence-based medicine. World J Surg. 2005;29: 547–553. 7. Hedblom C. Diaphragmatic hernia. A study of three hundred and seventy-eight cases in which operation was performed. JAMA. 1925;85:947–953. 8. Harrington SW. Diaphragmatic hernia. Arch Surg. 1928;16:386–415. 9. Miller JI Jr. The history of surgery of empyema, thoracoplasty, Eloesser flap, and muscle flap transposition. Chest Surg Clin N Am. 2000;10:45–53. 10. Mabe MA. The growth and number of journals. Serials. 2003;16:191–197. 11. Cochrane AL. Effectiveness and Efficiency. Random Reflections on Health Services. London: Nuffield Provincial Hospitals Trust; 1972. 12. Cochrane Collaboration website. Available at http:// www.cochrane.org/ accessed April 5, 2010.
1. Introduction 13. Guyatt G, Gutterman D, Baumann MH, AddrizzoHarris D, Hylek EH, Phillips B, Raskob G, Zelman Lewis S, Schunemann H. Grading strength of recommendations and quality of evidence in clinical guidelines: Report from an American College of Chest Physicians Task Force. Chest. 2006;129:174–181. 14. Ginsberg R, Roth J, Ferguson MK. Lung cancer surgical practice guidelines. Society of Surgical Oncology practice guidelines: lung cancer. Oncology. 1997;11:889–892, 895. 15. The Delphi Method: Techniques and Applications. H.A. Linstone and M. Turoff, eds. A Comprehensive Book on Delphi Method. http://www.is.njit.edu/ pubs/delphibook/ Accessed April 5, 2010. 16. Little AG, Rusch VW, Bonner JA, Gaspar LE, Green MR, Webb WR, Stewart AK. Patterns of surgical care of lung cancer patients. Ann Thorac Surg. 2005;80: 2051–2056. 17. Charloux A, Brunelli A, Bolliger CT, Rocco G, Sculier JP, Varela G, Licker M, Ferguson MK, Faivre-Finn C, Huber RM, Clini EM, Win T, De Ruysscher D, Goldman L; European Respiratory Society and European Society of Thoracic Surgeons Joint Task Force on Fitness for Radical Therapy. Lung function evaluation before surgery in lung cancer patients: how are recent advances put into practice? A survey among members of the European Society of Thoracic Surgeons (ESTS) and of the Thoracic Oncology Section of the European Respiratory Society (ERS). Interact Cardiovasc Thorac Surg. 2009;9:925–931. 18. Ferguson MK, Gaissert HA, Grab JD, Sheng S. Pulmonary complications after lung resection in the absence of chronic obstructive pulmonary disease: the predictive role of diffusing capacity. J Thorac Cardiovasc Surg. 2009;138:1297–1302. 19. Shugarman LR, Mack K, Sorbero ME, Tian H, Jain AK, Ashwood JS, Asch SM. Race and sex differences in the receipt of timely and appropriate lung cancer treatment. Med Care. 2009;47:774–781. 20. Coburn N, Przybysz R, Barbera L, Hodgson D, Sharir S, Laupacis A, Law C. CT, MRI and ultrasound scanning rates: evaluation of cancer diagnosis, staging and surveillance in Ontario. J Surg Oncol. 2008;98:490–499. 21. Birkmeyer NJ, Goodney PP, Stukel TA, Hillner BE, Birkmeyer JD. Do cancer centers designated by the National Cancer Institute have better surgical outcomes? Cancer. 2005;103:435–441.
11 22. Goodney PP, Lucas FL, Stukel TA, Birkmeyer JD. Surgeon specialty and operative mortality with lung resection. Ann Surg. 2005;241:179–184. 23. Farjah F, Flum DR, Varghese TK Jr, Symons RG, Wood DE. Surgeon specialty and long-term survival after pulmonary resection for lung cancer. Ann Thorac Surg. 2009;87:995–1006. 24. Naunheim KS, Wood DE, Krasna MJ, DeCamp MM Jr, Ginsburg ME, McKenna RJ Jr, Criner GJ, Hoffman EA, Sternberg AL, Deschamps C. National Emphysema Treatment Trial Research Group. Predictors of operative mortality and cardiopulmonary morbidity in the National Emphysema Treatment Trial. J Thorac Cardiovasc Surg. 2006;131: 43–53. 25. Crestanello JA, Allen MS, Jett JR, Cassivi SD, Nichols FC 3rd, Swensen SJ, Deschamps C, Pairolero PC. Thoracic surgical operations in patients enrolled in a computed tomographic screening trial. J Thorac Cardiovasc Surg. 2004;128:254–259. 26. van Klaveren RJ, Oudkerk M, Prokop M, Scholten ET, Nackaerts K, Vernhout R, van Iersel CA, van den Bergh KA, van ’t Westeinde S, van der Aalst C, Thunnissen E, Xu DM, Wang Y, Zhao Y, Gietema HA, de Hoop BJ, Groen HJ, de Bock GH, van Ooijen P, Weenink C, Verschakelen J, Lammers JW, Timens W, Willebrand D, Vink A, Mali W, de Koning HJ. Management of lung nodules detected by volume CT scanning. N Engl J Med. 2009;361:2221–2229. 27. Smith-Bindman R, Lipson J, Marcus R, Kim KP, Mahesh M, Gould R, Berrington de González A, Miglioretti DL. Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med 2009;169:2078–2086. 28. Berrington de González A, Mahesh M, Kim KP, Bhargavan M, Lewis R, Mettler F, Land C. Projected cancer risks from computed tomographic scans performed in the United States in 2007. Arch Intern Med. 2009;169:2071–2077. 29. MacMahon H, Austin JH, Gamsu G, Herold CJ, Jett JR, Naidich DP, Patz EF Jr, Swensen SJ; Fleischner Society. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology. 2005;237: 395–400.
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Evidence-Based Medicine: Levels of Evidence and Evaluation Systems Sean C. Grondin and Colin Schieman
Introduction Evidenced-based medicine (EBM) is a philosophic approach to clinical problems introduced in the 1980s by a group of clinicians at McMaster University in Canada with an interest in clinical epidemiology. The concepts associated with EBM have been widely disseminated. While many feel EBM represents a paradigm shift,1,2 others have debated the usefulness of this approach.3 In this chapter we will provide a definition and rationale for an evidence-based approach to clinical practice. The central role of systems that grade clinical recommendations and levels of evidence will be outlined, including a review of the Oxford Centre for Evidencebased Medicine Grades of Recommendations and Levels of Evidence. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group system and the modified GRADE approach used by authors in this textbook will also be described.
What Is Evidence-Based Medicine? Evidence-based medicine is a philosophic approach to clinical problems that has arisen from the physician’s need to offer proven therapies to patients. In 1996 Sackett et al. more formally defined EBM as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients”.2 The goal of this approach is to be aware of the evidence supporting a particular approach to a clinical problem, its
soundness and the strength of its inferences. More recently, the term evidence-based clinical practice (EBCP) has been used instead of EBM to indicate that this approach is useful in a variety of disciplines. In this chapter the terms are used interchangeably. Two fundamental principles of EBM have been proposed.1 The first is that evidence alone is never enough to guide clinical decision making. Clinical expertise is required to place the evidence in context and advise individual patients while considering their unique values and preferences. The second principle is that a hierarchy of evidence exists which is determined by the soundness of the evidence and the strength of the inferences that can be drawn from it. It has been recognized that clinicians can embrace the philosophy of EBM either as practitioners of EBM or as evidence users. A practitioner would adhere to the following five steps: 1. Form clinical questions so that they can be answered. 2. Search for the best external evidence for its validity and importance. 3. Clinically appraise that evidence for its validity and importance. 4. Apply it to clinical practice. 5. Evaluate your performance as a practitioner of evidence-based medicine. The evidence user searches for preappraised or preprocessed evidence in order to use bottom line summaries to assist patients in making decisions about clinical care.
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_2, © Springer-Verlag London Limited 2011
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Why Use an Evidence-based Approach? Proponents of EBCP report that the advantages to the physician who use an EBCP approach are that the practitioner acquires the ability to obtain current information, is able to perform a direct review of the evidence, and utilizes a interactive form of continuing medical education.4
Obtaining Current Evidence The traditional method of acquiring information has been the review of traditional textbooks and ongoing review of medical journals. Unfortunately, it has been shown that traditional texts go out of date quickly. In one study, for example, the delay in the recommendation of thrombolytic therapy for myocardial infarction was up to 10 years from when the published literature suggested it was advisable.5 Due to the huge number and variety of journals, however, it is challenging even for the most diligent practitioner to stay current. With the development of modern technology which allows easy and rapid access to MEDLINE and other full-text rapid internet access sites, an increasing number of busy practitioners have been able to obtain current evidence.
Direct Review of Evidence Developing and maintaining critical assessment skills is essential in order to have an EBCP. The ability to perform a direct review of the evidence by the individual practitioner is felt to be a superior method for appraising the literature compared to traditional review articles by experts.6 In many instances, reviews by experts have been revealed to be of low scientific quality and felt to be influenced unfavorably by potentially unsystematic hierarchal authority. Given the time required to critically appraise the literature, however, pre-processed sources of EBM have been necessary for most surgeons to incorporate EBM into their practice.
Interactive Learning Many consider an evidence-based approach to clinical practice an interactive form of learning designed to improve physician performance.
Studies designed to examine the effectiveness of continuing medical education have found that traditional didactic approaches are inferior to interactive forms of learning at changing physician performance.7 Once the learner has acquired the necessary skills for EBCP, interactions with students and fellow learners reinforce the active process of learning and become the starting point for self-appraisal.8 Ironically, the evidence that EBM works is from observational studies which have suggested that recommendations arising from an evidence based approach are more consistent with the actual evidence than traditional approaches.5 The second piece of evidence suggested to demonstrate the effectiveness of EBM is gathered from studies that show that those patients who get the treatment supported by high quality evidence have better outcomes than those who do not.9,10
Levels of Evidence Proponents of an evidence-based approach define evidence very broadly as any empirical observation about the apparent relation between events. Thus, sources of evidence can range from unsystematic clinical observations of individual clinicians to systematic reviews of multiple randomized clinical trials (RCT). The different forms of evidence may each provide recommendations that result in good outcomes for patients, but it is clear that some forms of evidence are more reliable than others in giving guidance to clinicians and their patients. It is for this reason that a hierarchy of the strength of evidence has been used to further guide decision making. The assumption is that the stronger the evidence the more likely the proposed treatment or diagnostic test will lead to the predicted result. However, one must always be cautious because strong recommendations may arise from low quality evidence and high quality evidence does not imply a strong recommendation.11 The hierarchy of strength of evidence for treatment decisions (as opposed to diagnostic tests) is shown in Table 2.1. This hierarchy represents a combination of reasoning and the study of different methodologies used to study treatments. The highest level of evidence will not be familiar
2. Evidence-Based Medicine: Levels of Evidence and Evaluation Systems Table 2.1. Hierarchy of Strength of Evidence for Treatment Decisions. N of 1 randomized controlled trial Systematic reviews of randomized trials Single randomized trial Systematic review of observational studies addressing patient-important outcomes Physiologic studies (studies of blood pressure, cardiac output, exercise capacity, bone density and so forth) Unsystematic observations
to most thoracic surgeons, and is called “N of 1” RCT. N of 1 trials were developed to address the finding that no single treatment is always effective for every patient. These trials involve a patient and his/her physician, usually treating a stable chronic illness, being blinded to randomized periods of taking a placebo or an active medication in random sequence and then deciding if the drug was or was not effective. Clearly, N of 1 trials have no relevance for patients having surgical procedures. Given that N of 1 RCTs are not feasible for thoracic surgical procedures, the fundamental underpinning of the hierarchy is the superiority of well done RCTs as compared to observational studies, physiologic studies, and unsystematic observations. The majority of surgical and thoracic surgical research consists of observational or physiologic studies or unsystematic observations. The superiority of randomized trials as compared to observational studies is still debated by some methodologists and some thoracic surgeons, as seen in debates regarding the National Emphy sema Treatment Trial (NETT) for Lung Volume Reduction Surgery.12–15 The supporters of evidence-based clinical practice would define the observations of an experienced clinician as unsystematic observations. They acknowledge that profound clinical insights can come from experienced colleagues but that these are limited by small sample size and “deficiencies in human process of making inferences”.1 Physiologic studies are defined as studies in which the measured outcome is a physiologic parameter such as blood pressure, forced expiratory volume in one second (FEV1) and exercise capacity rather than patient important endpoints such as quality of life, freque ncy of hospitalizations, morbidity and mortality. Why do evidence-based advocates place such emphasis on RCTs for selecting treatment for patients? First, patients in observational studies
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are not chosen randomly, thus leading to an unavoidable risk of selection bias. The selected patients may, therefore, have systematic differences in outcome that are due not to the given treatment but rather the selection process.12 Second is the observation that the results of RCTs are not necessarily predicted by prior observational or physiologic studies. We would like to outline examples in which RCTs provided surprising results in relation to both the general medical literature and to studies of adjuvant treatments of lung cancer. The classic example often given to demonstrate the potentially misleading conclusions drawn from studies with physiologic endpoints is the study of the anti-arrhythmic drugs flecainide and encainide in which non-randomized studies were shown to decrease the physiologic end point of frequency of ventricular arrhythmias in patients after myocardial infarction. The RCT subsequently carried out using a patient important endpoint of cardiac deaths and arrests found a RR of 2.64 (95%CI, 1.60–4.36), indicating a substantially increased risk among patients on the active drug versus those on placebo.16 An example drawn from thoracic surgery demonstrates the limitations of lower forms of evidence and highlights the important contributions thoracic surgeons have made toward proving the importance and power of RCTs and validating the evidence hierarchy. The studies of adjuvant intrapleural bacillus Calmette-Guerin (BCG) for stage I NSCLC demonstrate the limitations nicely. The initial studies suggesting that an infectious immune stimulant would improve survival in the treatment of lung cancer came from observational studies that suggested that postoperative empyema improved survival in lung cancer.17 An elegant pathophysiologic mechanism of immune stimulant was proposed. This was followed by supportive animal physiologic studies and a small randomized trial in which a sub group analysis suggested that immune stimulation via BCG would confer a survival advantage as adjuvant therapy for lung cancer.18 Unfortunately, this was not shown to be the case when the theory was tested in a well conducted RCT by the Lung Cancer Study Group.19 The evidence-based approach to surgery implies that physiologic rationale or observational studies
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usually predict the results of RCTs, and accordingly the hierarchy of evidence has ranked RCT above other forms of study. The evidence-based approach hierarchy is, however, not proposed as an absolute. For example, in the case where observational studies show an overwhelming advantage for treatment, such as insulin for the treatment of ketoacidosis, RCTs are not required. The majority of treatments, however, do not demonstrate an overwhelming advantage for a particular form of treatment, and major treatment decisions of common problems therefore require evidence from RCTs in order to provide the best advice to patients. In the GRADE system of recommendation, explicit definitions of quality of evidence are given to increase the degree of transparency and to be practical for clinicians. Table 2.2 illustrates the four categories of evidence (high, moderate, low, and very low) with their explanations.20 Like other systems for assessing the quality of evidence, GRADE begins by assessing the study design where RCTs usually provide the strongest evidence, followed by well-designed cohort and case-control studies, and subsequently uncontrolled case series. Clinicians using the GRADE system must also consider additional factors that might increase or decrease the quality of the evidence (Table 2.3).20,21 Criteria for assigning grade of recommendation based on these factors as well as the type of evidence are listed in Table 2.4.22
Systems of Recommendation Organizations and authors have used various systems to grade the levels of evidence and strength of recommendations. Shortcomings and differences in these grading systems have led to confusion and poor communication. To be useful, grading systems should be simple, explicit, and systematic with respect to judgments regarding the quality of evidence and the strength of recommendation.23,24 Because judgments about evidence may be complex, a single classification has not been universally accepted. We will focus this chapter on the Oxford Centre for Evidence-based Medicine Grades of Recommendations as well as the GRADE system of recommendations.
Oxford Centre for Evidence-based Medicine Grades of Recommendations The proliferation of classifications that are slightly different from each other led to the formation of an international working group whose mandate was to reach agreement on a standardized classification, this being the Oxford Centre for Evidencebased Medicine Grades of Recommendations and Levels of Evidence.25 This system was updated in March 2009 and is available at http://www.cebm. net. The strengths of this classification are that it was developed by leaders in the field of EBM, it allows assignment of studies for not only therapy but diagnostic tests, and it has been used
Table 2.2. GRADE quality of evidence and explanation of the categories. 20 Rank
Explanation
High
Further research is very unlikely to change our confidence in the estimate of effect
Moderate
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Any estimate of effect is very uncertain
Low Very low
Examples Randomized trials without serious limitations Well-performed observational studies with very large effects (or other qualifying factors) Randomized trials with serious limitations Well-performed observational studies yielding large effects Randomized trials with very serious limitations Observational studies without special strengths or important limitations Randomized trials with very serious limitations and inconsistent results. Observational studies with serious limitations. Unsystematic clinical observations (e.g. case series or case reports)
Reproduced with permission from Brozek JL, Akl EA, Alonso-Coello P, Lang D, Jaeschke R, Williams JW, Phillips B, Lelgemann M, Lethaby A, Bousquet J, Guyatt GH, Schunemann HJ GRADE Working Group. Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions. Allergy. 2009;64:669–677.
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2. Evidence-Based Medicine: Levels of Evidence and Evaluation Systems Table 2.3. Factors that impact on the quality of evidence for the GRADE system.20,21 A. Study Design (experimental vs. observational) B. Factors that might decrease the quality of evidence Study limitations Major limitations, such as lack of allocation concealment, lack of blinding, large loss of follow-up, no intention-to treat analysis, and a study terminated early for benefit Inconsistency of results Widely differing estimates of the treatment effect (variability in results or heterogeneity) Indirectness of evidence Population: e.g., differences in age, gender, medical condition Intervention: e.g., similar but not identical intervention Comparison: e.g., no head-to head comparison of two interventions Outcomes: e.g., use of surrogates, short-term vs. long-term Imprecision Wide confidence intervals/small sample size/few events that make the result uninformative Publication bias High probability of failure to report studies (likely because no effect was observed) C. Factors that might increase the quality of evidence Large magnitude of effect Two or more observational studies, direct evidence, no plausible confounders, no threats to validity, sufficiently precise estimate Plausible confounding Unaccounted, plausible biases from observational evidence that moves the result in the direction of underestimating the apparent treatment effect Dose-response gradient Presence of a dose–response gradient, (e.g., between INR and risk of gastrointestinal bleeding)
INR international normalized ratio, RR relative risk. Adapted from Brozek JL, Akl EA, Alonso-Coello P, Lang D, Jaeschke R, Williams JW, Phillips B, Lelgemann M, Lethaby A, Bousquet J, Guyatt GH, Schünemann HJ; GRADE Working Group. Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions. Allergy. 2009;64(5):669–677 (permission pending) and Falck-Ytter Y, Kunz R, Guyatt GH, Schünemann HJ. How strong is the evidence? Am J Gastroenterol. 2008;103:1334–1338 (with permission).
Table 2.4. GRADE quality assessment criteria.22 Quality of evidence High
Study design
Lower ifa
Randomized trial
Study quality -1 serious limitations -2 very serious limitations -1 important inconsistency Directness -1 some uncertainty -2 major uncertainty -1 sparse data -1 high probability of reporting bias
Moderate Low Very low
Higher ifa Strong association +1 strong, no plausible confounders, consistent and direct evidenceb +2 very strong, no major threats to validity and direct evidencec +1 evidence of a dose response Gradient +1 all plausible confounders would have reduced the effect
Observation study
Move up or down one grade (for example from high to intermediate); Move up or down two grades (for example from high to low), A statistically significant relative risk of >2 (<0.5), based on consistent evidence from two or more observational studies, with no plausible confounders; c A statistically significant relative risk of > 5 (<0.2) based on direct evidence with no major threats to validity From Schünemann HJ, Fretheim A, Oxman AD. Improving the use of research evidence in guideline development: 9. Grading evidence and recommendations. Health Res Policy Syst. 2006;4:21 (with permission). a
b
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in studies exploring methodology in thoracic surgery.26,27 The limitations are that it is detailed and may appear complex to those not familiar with the field. A number of aspects of the Oxford Centre for Evidence-based Medicine Grades of Recom mendations and Levels of Evidence are worthy of highlighting. The bottom-line for an evidencebased user is the grades of recommendation A-D. In the clinical setting, the levels of evidence of applicable studies are determined and then examined to assign the grade of recommendation. An A level recommendation is the strongest possible. For those surgeons who have an interest in a deeper understanding, the initial step is to determine the methodologic nature of the clinical question. Thoracic surgeons will likely be interested in questions with regard to choice of therapy or diagnostic test. For example, a surgeon may wish to advise a patient regarding the role of adjuvant chemotherapy following lung cancer resection. The surgeon would then examine existing studies and use the Oxford Centre for Evidence-based Medicine Grades of Recommendations and Levels of Evidence table (http://www.cebm.net/index.aspx?o = 1,025) to assign the appropriate level of evidence. The surgeon will note that level 1a is assigned to systematic reviews with homogeneity of RCTs. It is critical to understanding the table that surgeons appreciate that systematic reviews are not the same as traditional narrative reviews. Systematic reviews of published and unpublished data are carried out in an explicit fashion. The criteria for locating articles, assigning methodologic criteria and combing data are explicitly stated and are repeatable by another investigator. Following the location of evidence regarding adjuvant chemotherapy for lung cancer, a level of evidence is assigned to each paper and then a grade of recommendation determined. Given a secure understanding of the soundness of the proposed treatment, the thoracic surgeon can use his/her clinical expertise to determine if the proposed treatment is appropriate for an individual patient after due consideration of factors such as local expertise, patient value’s and preferences. Depending on the nature of the clinical question, the surgeon may find high levels of evidence and grades of recommendation. Many thoracic surgical procedures only have level 4 or 5 evidence.27 This
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does not invalidate the process but rather allows the surgeon to be aware of limitations of the data and potentially to identify critical areas where further higher level studies could be performed.
GRADE and Modified GRADE Systems of Recommendation In 2004, the GRADE Working Group proposed a different approach to patient management that was based on previous systems and was created to be highly structured, transparent, and informative.23 The advantages of the GRADE system over other grading systems are that it uses explicit definitions and sequential judgements during the grading process, provides a detailed description of the criteria for the quality of evidence for single outcomes and for the overall quality of evidence, weighs the relative importance of outcomes, considers the balance between health benefits versus harms, burdens and cost, and develops evidence profiles and summaries of findings.22,28 The GRADE approach has fostered wide interna tional support including endorsement from the World Health Organization (WHO), the American Thoracic Society (ATS), and the American College of Chest Physicians (ACCP). The GRADE system of recommendation is based on two factors.29 The first factor is grading recommendations based on the methodologic quality of the evidence. As discussed earlier, the GRADE system takes into account study design and quality, consistency and directness in judging the quality of evidence for each outcome. The second factor is based on the knowledge that most clinicians will offer a treatment to patients if the benefits outweigh risks, harms, and costs. The confidence or uncertainty with which a clinician views the trade-offs between risks and benefits will determine the strength of recommendation. Factors that panels should consider in deciding the strength of recommendation in the GRADE system are listed in Table 2.5.24,25 To address the main limitation of the GRADE system, its complexity, the ACCP task force modified the GRADE approach.30 Their modifications were based on the following criteria in order of importance: separation of grades of recommendations from quality of evidence, simplicity and transparency for clinical consumers, sufficient (but not too many) categories, explicitness of methodology for
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2. Evidence-Based Medicine: Levels of Evidence and Evaluation Systems Table 2.5. Factors that affect the strength of recommendation for GRADE system.22,24 Factor Quality of evidence
Explanation
Examples of strong recommendations
Examples of weak recommendations
Uncertainty about the size of the (relative) effects (benefits and harms)
Many high quality randomized trials Only case series have examined the have shown the benefit of inhaled utility of pleurodesis in steroids in asthma pneumothorax Uncertainty about the balance Uncertainty about the baseline risk, prevalence Aspirin in myocardial infarction Warfarin in low risk patients with atrial between desirable and undesirable of the problem or health status, which reduces mortality with minimal fibrillation results in small stroke effects could affect the size of the of the (absolute) toxicity, inconvenience, and cost reduction but increased bleeding effects risk and substantial inconvenience Uncertainty or variability in values Uncertainty about the relative importance of Young patients with lymphoma will Older patients with lymphoma may not and preferences the benefits and downsides to those invariably place a higher value on place a higher value on the life affected, or differences in how important the life prolonging effects of prolonging effects of chemotherapy they are to different people, which could chemotherapy than on treatment than on treatment toxicity affect the balance between the benefits toxicity versus harms and burdens Uncertainty about whether the Uncertainty related to lack of information The low cost of aspirin as prophylaxis The high cost of clopidogrel and of intervention represents a wise use about the cost or whether the resource against stroke in patients with combination dipyridamole and of resources expenditure is justified by the anticipated transient ischemic attacks aspirin as prophylaxis against stroke benefit in patients with transient ischemic attacks
Adapted from Schünemann HJ, Fretheim A, Oxman AD. Improving the use of research evidence in guideline development: 9. Grading evidence and recommendations. Health Res Policy Syst. 2006;4:21 and Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ. GRADE: an emerging consensus on rating quality of evidence and strength of recommendation. BMJ. 2008;336(7651):924–926 (with permission).
guideline developers, simplicity for guideline developers, consistency with general trends in grading systems, and explicit approach to different levels of evidence for different outcomes. In the modified GRADE system, the quality of the evidence is classified as high, moderate, low, or very low. Recommendations are classified as strong (grade 1) or weak (grade 2) based on the balance between benefits, risks, burdens, costs and the degree of confidence of estimates of benefits, risks and burdens. Table 2.6 summarizes the ACCP modified GRADE system that is used throughout this textbook.30 By using a binary classification a clear decision pathway is provided to patients and clinicians as well as policy-makers. A strong recommendation would imply that most patients in this situation would want the recommended course of action and that clinicians should provide the intervention. A recommendation with a strong strength of recommendations can usually be adopted as policy in most situations. For weak recommendations the majority of patients in this situation would want the suggested course of action, but some may not. Clinicians should examine the evidence or a summary of the evidence for weak recommendations to formulate their own opinion. Policy-making for
intervention with weak recommendations usually requires substantial debate and involvement of key stakeholders.21 Using a system of recommendation such as GRADE enables more consistent judgements about quality of evidence and strength of recommendations and better communication of these judgments allowing informed choices in health care. For the clinician, understanding and participating in an approach such as GRADE provides a tool for systematic reviews and health technology assessments as well as the foundation to develop evidence-based clinical practice guidelines.20,31 Further research and modifications of systems of recommendations such as GRADE will allow a better balance between incorporating the complexity of evidence and maintaining clarity for guideline users and healthcare policy-makers.21
Limitations of EBCP and Pre-processed Evidence Most health care providers have embraced the principles of EBM. However, discussions persist among doctors as to whether or not EBM represents a time consuming “cookbook” approach to
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20 Table 2.6. Modified GRADE – grading recommendations.30 Grade of recommendation/description
Benefit vs. risk and burdens
Methodological quality of supporting evidence
Implications
RCTs without important limitations or overwhelming evidence from observational studies RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies Observational studies or case series
Strong recommendation, can apply to most patients in most circumstances without reservation Strong recommendation, can apply to most patients in most circumstances without reservation
1A/strong recommendation, high-quality evidence
Benefits clearly outweigh risk and burdens, or vice versa
1B/strong recommendation, moderate quality evidence
Benefits clearly outweigh risk and burdens, or vice versa
1C/strong recommendation, low-quality or very low-quality evidence
Benefits clearly outweigh risk and burdens, or vice versa
2A/weak recommendation, high-quality evidence
Benefits closely balanced with risks and burden
RCTs without important limitations or overwhelming evidence from observational studies
2B/weak recommendation, moderate-quality evidence
Benefits closely balanced with risks and burden
RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies Observational studies or case series
2C/weak recommendation, low-quality or Uncertainty in the estimates of benefits, very low-quality evidence risks, and burden; benefits, risk, and burden may be closely balanced
Strong recommendation but may change when higher quality evidence becomes available Weak recommendation, best action may differ depending on circumstances or patients’ or societal values Weak recommendation, best action may differ depending on circumstances or patients’ or societal values Very weak recommendations; other alternatives may be equally reasonable
From Guyatt G, Gutterman D, Baumann MH, Addrizzo-Harris D, Hylek EH, Phillips B, Raskob G, Zelman Lewis S, Schunemann H. Grading strength of recommendations and quality of evidence in clinical guidelines: Report from an American College of Chest Physicians Task Force. Chest. 2006;129:174–181 (with permission) Order Total: $78.00
patient care that ignores patient values.3 Although EBCP has a number of limitations, we feel these limitations are outweighed by the advantages of an evidence-based approach. One of the biggest concerns among busy practicing surgeons is the large amount of time required to develop and maintain an EBCP. Increasingly, surgeons must juggle a significant operative workload, clinical visits, hospital patient care, on call responsibilities, research and administrative duties. Adding the time and cost to acquire a variety of new skills such as critically appraising the literature and grading current evidence can seem overwhelming. A potential solution is to become a knowledgeable user of EBM using pre-processed evidence such as the evidence-based summaries in this textbook. This text combines the selected authors’ individual clinical expertise with an evidence-based summary of the literature to provide the reader with
information on the management of complex thoracic surgery problems. Another limitation to EBCP is that it places less weight on hierarchical authority and non-systematic clinical observations; a concept which is counter- intuitive to traditional surgical training and practice. This observation, combined with the fact that many surgeons do not embrace the best evidence because of their personalities (self-confidence, the need for rapid clinical decisions and decisive actions during surgery), may lead to a diminished willingness to incorporate EBM principles into their practice.32 Although the limitations that have been discussed are significant, we believe they can be overcome. Improving the number and quality of available research trials and teaching the principles of EBM in undergraduate and graduate medical training will be important for establishing the widespread use of EBM.
2. Evidence-Based Medicine: Levels of Evidence and Evaluation Systems
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orbidity in patients receiving encainide, flecainm ide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781–788. 17. Ruckdeschel JC, Codish SD, Stranahan A, McKneally MF. Postoperative empyema improves survival in lung cancer. Documentation and analysis of a natural experiment. N Engl J Med. 1972;287:1013–1017. 18. McKneally MF, Maver C, Kausel HW. Regional immunotherapy of lung cancer with intrapleural BCG. Lancet. 1976;1(7956):377–379. 19. Mountain CF, Gail MH. Surgical adjuvant intrapleural BCG treatment for stage I non-small cell lung cancer. Preliminary report of the National Cancer Institute Lung Cancer Study Group. J Thorac Cardiovasc Surg. 1981;82:649–657. 20. Brozek JL, Akl EA, Alonso-Coello P, Lang D, Jaeschke R, Williams JW, Phillips B, Lelgemann M, Lethaby A, Bousquet J, Guyatt GH, Schünemann HJ; GRADE Working Group. Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions. Allergy. 2009;64: 669–677. 21. Falck-Ytter Y, Kunz R, Guyatt GH, Schünemann HJ. How strong is the evidence? Am J Gastroenterol. 2008;103:1334–1348. 22. Schünemann HJ, Fretheim A, Oxman AD. Improving the use of research evidence in guideline development: 9. Grading evidence and recommendations. Health Res Policy Syst. 2006;4:21. 23. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henryn D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton, P, Mrukowicz J, O’Connell D, Oxman AD, Phillips P, Schünemann HJ, Edejer TT, Varonen H, Vist GE, Williams JW Jr, Zaza S; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490. 24. Guyatt GH, Oxman AD,Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendation. BMJ. 2008;336(7651):924–926. 25. Schünemann HJ, Best D, Vist G, Oxman AD. Letters, numbers, symbols and words: how to communicate grades of evidence and recommendations. CMAJ. 2003;169:677–680. 26. Graham AJ, Gelfand G, McFadden SD, Grondin SC. Levels of evidence and grades of recommendations in general thoracic surgery. Can J Surg. 2004; 47:461–465. 27. Lee JS, Urschel DM, Urschel JD. Is general thoracic surgical practice evidence based? Ann Thorac Surg. 2000;70:429–431. 28. Guyatt GH, Oxman AD, Vist GE, Falck-Ytter Y, Schünemann HJ; GRADE Working Group. GRADE: What is “quality of evidence” and why is it important to clinicians. BMJ. 2008;336(7651):995–998.
22 29. Guyatt G,Schunëmann H,Cook D,Jaeschke R,Pauker S, Bucher H. Grades of recommendation for antithrombotic agents. Chest. 2001;119(1 suppl):3S–7S. 30. Guyatt G, Gutterman D, Baumann MH, AddrizzoHarris D, Hylek EH, Phillips B, Raskob G, Zelman Lewis S, Schünemann HJ. Grading strength of recommendations and quality of evidence in clinical
S.C. Grondin and C. Schieman g uidelines: report from an American College of Chest Physicians Task Force. Chest. 2006;129:174–181 31. Ricci S, Celani MG, Righetti E. Development of clinical guidelines: methodological and practical issues. Neurol Sci. 2006;27(suppl 3):S228–S230. 32. Slim K. Limits of evidence-based surgery. World J Surg. 2005;29:606–609.
3
Decision Analytic Techniques Anirban Basu and Amy Lehman
Introduction Over the last decades, growth in biomedical and associated social sciences research has resulted in the accumulation of a large body of new and more reliable information on human health.1 This research has certainly played a key role in the unprecedented improvement of health throughout the world. It has also complicated decision making, both at the individual and at the policy level, by presenting clinicians and policy makers with an increasing number of choices of medical technologies and strategies for the management of a given medical situation. A fundamental concern in medical decision making is how to synthesize information about the effect of a medical intervention on patients with specific characteristics. An additional challenge, relevant mostly to clinical decision making, involves integrating population level evidence about outcomes with patient-level values for these outcomes in order to produce individualized care. Such individualized decisions for patients demand a systematic approach to sort through the evidence and to incorporate patients’ and their family members’ values and preferences into the decision making processes. In this context, the decision analytic model (DAM) has proven to be a successful tool that can provide a systematic approach for decision makers,2–4 so that it can combine the much-acclaimed evidence-based approach to medicine5 with the pragmatism of shared-decision making.6 These models enable the clinicians to apply a systematic, quantitative approach called decision analysis, and thereby assess the relative value of one or more
options or strategies to approach a particular medical problem. Furthermore, they allow them to pool evidence from a variety of settings including randomized clinical trials, as well as incorporate patients’ preferences to inform the final decision. There are several published reviews and text books that are entirely devoted to this topic. Interested readers are pointed to these references.4–8 This chapter is intended to provide a succinct description of the fundamental theory and methods of decision analysis to clinicians, and to illustrate a stylized example of building a decision analytic model based on a clinical choice problem in thoracic surgery.
Theoretical Foundations The goal of a decision analytic model (DAM) is simple – it compares two or more treatment decisions or strategies for dealing with the same problem, and applies a set of rules to identify the preferred decision that would produce the maximum benefit or the minimum loss. Expected utility theory is the most commonly used rule to calculate the final outcome in terms of benefits (or loss).9 Under this theory, the final outcome resulting from a treatment decision is given by B = ∑ l=1 pl · bl L
(3.1)
where payoff values or utilities bl are associated with each level (l =1,2,.., L) of success (or failure). The expected outcome is then calculated using the product of the probability of a specific level of
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_3, © Springer-Verlag London Limited 2011
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s uccess ( pl ) with its corresponding payoffs, summed over all levels. Expected utility theory suggests that the preferred treatment decision is the one with the maximum expected benefit (or minimum expected loss). Although almost all DAM perform under the auspices of this simple theoretical intuition, any DAM that attempts to model a practical clinical situation can become complicated very quickly. Each level of success depends on a sequence of chance outcomes and various intermediate decisions that, in turn, may depend on further chances and decisions. Therefore, understanding, defining, and structuring the decision process is essential for clinical decision analysis. In this pursuit, a fundamental decision tool is a decision tree that helps the clinician to systematically display the temporal and logical structure of the decision problem and to thus carry out the analysis. In order to facilitate explanation of each part of this process in more detail, we begin with a stylized example of clinical decision making in thoracic surgery.
A Motivating Example Let us begin with a common problem in thoracic surgery − that of the solitary pulmonary nodule – which can illustrate the basic principles of decision analysis. Suppose we have a patient referred to a thoracic surgery clinic. She is a 65 year old woman who presents with an incidentally found solitary pulmonary nodule discovered on chest X-ray taken in an emergency room after a minor motor vehicle collision. She has a 35 pack-year smoking history, but quit smoking 6 years ago. She has well-controlled hypertension, no heart disease, and no diabetes. She has no previous chest X-ray with which to compare to this new abnormal one. The patient underwent a CT scan scheduled by her primary care doctor, and this scan shows an 8 mm peripheral nodule with no enlarged lymph nodes. Let us further specify that due to the size of her lesion, PET scan is non-diagnostic, and that due to the location and size of her nodule, she is not a candidate for biopsy via bronchoscopy, fine needle aspiration, or VATS. How shall we advise this patient? We are now faced with a choice in recommendations: watchful waiting, or perform open
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diagnostic thoracotomy. For the sake of simplicity, other options such as proceeding to lobectomy via thoracotomy or VATS are not included in this example. There are several considerations which inform our decision that have been discussed in detail elsewhere10; namely, we must consider the pre-test probability of cancer, the risk of surgical complications, and whether the appearance of the nodule on CT suggest benign or malignant disease. Finally, what are the patient’s preferences given the possibility of adverse outcomes of open surgery? A decision analytic model can help in the systematic integration of all this information in order for the surgeon to make an individualized and informed decision. A simple, stylized decision tree to address this clinical decision is illustrated in Fig. 3.1. We now discuss in detail each part that goes into making up this decision tree and how one would arrive at the final result.
Elements of the Decision Analytic Approach Identify and Bound the Decision Problem The first step in decision analysis is to understand the decision problem at hand and the particular issues associated with making that decision. To do this, one must define the set of alternative actions under consideration and the primary outcome measure based on which decision will be made, determine the perspective and the time frame of the analysis, and consider several factors, such as the clinical characteristics of the patient, which may influence the primary outcome measure. These considerations can be broadly classified into the following: Define the set of alternative actions Decision analysis always presumes that there is more than one action for the same decision problem. If this were not the case, there would be no decision to make. Note that one of these alternative actions may, and often does, include the option to “do nothing”. In our stylized example, the alternatives are watchful waiting versus intervention.
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3. Decision Analytic Techniques Dead (1%)
Comorbidities (Th) (19%)
Thoracotomy
Stage I (54%)
Cancer (37%)
Stage II
Alive
Lobectomy
Dead (3% + 12%)
with Comorbidities (Lb) (25%) Alive
with no Comorbidities (Lb)
0.5xq1 0.5x (q1+q2) 0.5x (q1+q1)
Dead
Lobectomy
0.5xq1 (5% + 12%) with Comorbidities (Lb) (25%) 0.5x (q1+q2) Alive with no Comorbidities (Lb) 0.5x (q1+q1) Dead
No Cancer
Payoff (QOL) 0
(12%)
0.5xq1
Alive No Comorbidities (Th)
Stage I Cancer (37%)
q1
Same as Comorbidities (Th) branch (Outcomes depend on only comorbidties due to Lobectomy)
(54%)
Dead (18%)
0.5xq3
Alive
q3
Dead
Watchful Waiting Stage II
No Cancer
(36%)
0.5xq3
Alive
q3
Dead (12%)
0.5xq3
Alive
q3
Figure 3.1. A decision-tree to model the clinical decision between thoracotomy and watchful waiting
Perspective The most common perspective taken in clinical decision making is that of the patient, whose welfare is often the primary outcome for the decision at stake. This is also the perspective we take in our example. Chapter 4 explores the implications of the patient perspective in greater detail. Nevertheless, it is easy to foresee that a clinical decision based on a patient’s perspective will be integrally tied with the preferences of that individual patient. Comprehending an individual patient’s preferences and incorporating them in the decision process is essential for optimal decision making. However, in certain acute conditions, where the patient’s preferences are unknown, alternative preferences of those of family members or sometimes those of clinicians may be used as proxies. More broadly, depending on the types of questions asked, perspectives of different stake-
holders – for example, the hospital, the healthinsurance company, and even society at large – may become relevant in the analyses.11 For example, from the hospital’s perspective, reducing inpatient mortality may be more important than a patient’s potentially diminished quality of life due to sideeffects of treatments. Outcomes such as costs and cost-effectiveness may be more relevant to health insurance companies than to individual patients. Clinical conditions and demographics of patient(s) Several risk factors affect patient outcomes and therefore are important to consider when choosing between alternative therapies. A patient’s past medical history and current clinical condition perhaps can provide the most important source of information for appropriate medical care. For example, surgeons require clinical information on
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the stage, and often grade, of a cancer before performing a surgical resection. Often, information on comorbidities, such as genetic susceptibilities to malignancy, becomes critical for prescribing appropriate treatment. Demographics also play a key role in determining outcomes. For example, pre-test probability of cancer would depend on a patient’s gender, smoking history, age, and possibly many other factors. Time frame of analysis The time frame of analysis should reflect the time over which the consequences of the clinician’s choices have the potential to influence the patient’s survival and quality of life. In some acute conditions, the time frame may be the time until the patient is sent home from inpatient care. In chronic conditions, the time frame may extend up to the patient’s remaining life expectancy. In the clinical choice problem that we illustrate, the ideal time frame should be the lifetime of the patient since both the disease process as well as the potential complications of surgery influence the patient’s quality of life over her entire lifetime. However, since our analysis is a mere illustration of the concepts and not a substantive analysis, we will use a time frame of 1 year. Primary outcome of interest The optimal clinical decision may vary depending on what type of benefits the patients and/or the clinicians want to maximize. Identifying the primary outcome based on which the final decision is made is perhaps the most crucial issue in decision analysis. Is the primary concern the survival of the patient over the next few months, or is the overall quality of life for the patient over his/her remaining life expectancy the most relevant measure to dwell on? Answering this question often involves incorporating the patient’s preference and perspective, as well as determining the overall goal of medical treatment. It also uniquely determines what type of analysis the clinician is interested in. The types of analyses can be broadly classified into four categories based on the types of outcomes being evaluated: (a) clinical outcomes; (b) patient’s values about the clinical outcomes; (c) costs and (d) both costs and outcomes.12
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Outcomes analysis: In such analysis, neither costs nor patient preferences are incorporated in the primary outcome measure. Instead, the focus is entirely on one of the clinical outcomes (e.g. survival or length of hospital stay), which is used to make decisions. The optimal treatment is selected based on the most beneficial clinical outcome (e.g. lowest mortality or shortest length of hospital stay). Utility analysis: In these analyses, costs are not incorporated in the decision making process; however, patient’s preferences are included, in conjunction with the relevant clinical outcomes. Most clinical decisions have an effect not only on life and death, but also on the quality of life of patients, mediated through a variety of health states. In utility analyses, the value of any particular health state to the patient, popularly known as utility or quality of life (QOL) weight, is measured using either a time-tradeoff or standard gamble method.11,13,14 The utility for any health state is constructed to lie between 0 (representing death) and 1 (representing perfect health). In timetradeoff methods, patients are asked to trade-off a longer time in a particular health state for a shorter time in perfect health. In standard gamble methods, patients are asked to choose between living with a particular health state and a gamble between perfect health and death. The utility for the health state under consideration is obtained at the point of indifference between the choices in either method. These utilities, multiplied with the duration of time that the patient remains in that health state under a specific decision choice, forms the quality-adjusted life-years (QALYs) corresponding to that decision. The decision producing the maximum QALYs is chosen to be the optimal one. The advantage of utility analyses over outcomes analyses is that a variety of outcomes that influence the patient’s overall quality of life can be summarized using one generic measure such as the QALYs, and therefore the effects of a decision on multi-dimensional outcomes can be simultaneously determined and compared to other decisions. We use QALYs as the primary outcome of interest in our analysis. Cost analysis: In these analyses, only the costs of alternative treatments form the primary outcome of interest and the least costly treatment is recognized as the optimal choice.15 Such analyses
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are carried out when the clinical outcomes of the alternative treatments is not a contentious issue – a situation that is becoming increasingly less common in clinical practice. Direct medical costs include both the price of the treatment and also all other concomitant costs of medical care during the time period of evaluation. It is often difficult to separate related (to the primary medical condition being studied) versus unrelated costs of care, and therefore overall or total cost is used as the main outcome measure. A broader (e.g. societal) perspective of analysis can also look at indirect costs, which include items such as productivity losses, caregiver’s time costs and legal costs. Cost-effectiveness analysis: Cost-effectiveness analysis (CEA) compare both the resources used (costs) and the health benefits achieved (e.g., QALYs or simply life years) among alternative treatments, making these trade-offs explicit to both the clinician and to the patient so that together they can make the optimal decision for the patient.16,17 The practice of cost-effectiveness analysis when comparing two interventions, e.g. a new treatment versus standard care, can be summarized as follows: the first step is to calculate the mean costs incurred and the mean benefits produced by each intervention; next, an incremental cost-effectiveness ratio (ICER) is formed by dividing the difference in the mean costs over the difference in the mean benefits between the new and standard interventions. The ICER represents the additional costs required by the new intervention in producing one extra unit of benefit over that produced by the standard intervention. The ICER is then compared with the threshold value that represents the maximum a decision maker is willing to pay for an additional unit of benefit.18 If the ICER is lower than this threshold value then the new intervention is deemed to be cost-effective. Since, in most cases, a substantial portion of the costs of health care is often borne by health insurance and not the patient, several interesting normative issues arise when an attempt is made to compare both costs and benefits simultaneously. A widely debated question revolves around whose perspective is most appropriate to consider when the burden of costs is distributed amongst patients, health care providers and third-party payers. Furthermore, obtaining a threshold value that represents the maximum willingness-to-pay for an
additional unit of benefit is difficult to ascertain at the individual patient level. However, in order to preserve some notion of fairness, one can uniformly apply a societal threshold to all patients. Such discussions are beyond the scope of this chapter but interested readers are encouraged to explore this important literature.5,6 Other considerations Several other considerations may influence treatment choices. They include information on how much weight patients place on outcomes that will arise in the future compared to those at present time (this is popularly summarized by the concept of the discount rate),11,12 whether consideration of the effects of patients outcomes on the family members are important,19 and how patient demographic characteristics, health insurance status and out-of pocket payments influence the primary outcome of interest.20,21 Many of these factors are essential to appropriately model patient behavior, which in turn determines effectiveness of a therapy in a practical setting.
Structure the Decision Problem over Time Although choosing between alternative actions is the primary goal of a decision analysis, often the decision problem will involve a temporal sequence of choices that inevitably influence the final choice of action. Moreover, these choices may themselves depend on certain chance outcomes that may or may not be controlled by previous decisions. Therefore, the second step in decision analysis is to identify the components of the decision problem. To do this, one defines a structure for the temporal and logical sequence of choices, chances and outcomes, as well as their interactions that would lead to the final outcome of interest as defined in the previous step. A decision tree helps to structure this temporal decision problem in a systematic format. An excellent primer for building decision trees is given by Detsky et al.22 Figure 3.1 illustrates the decision tree for our simple example on the choice between proceeding to open thoracotomy and watchful waiting. Each point in the decision tree that leads to multiple outcomes or decisions is called a node. There are two types of nodes – (1) a decision node is indicated by
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a square box, and (2) a chance node is indicated by a circle. A decision node represents the alternative choices that are available to the clinician. A chance node represents the alternative outcomes and patient’s responses that are possible. Each chance node is associated with a probability with which a specific outcome is realized, thereby accounting for the inherent uncertainties in such processes. The rightmost column of the decision tree illustrates the final payoffs or outcomes associated with each possible branch of the decision tree. Each branch can be visualized as a level of success given the initial choice of treatment, and is defined by the sequence of events starting with the initial treatment choice and leading up to the final outcome. In our example, we assume that the clinician makes a decision aiming to maximize the patient’s quality-adjusted life-year (QALYs) over the next 1 year period after considering the potential risks and benefits of each choice. If the patient undergoes open thoracotomy, the benefits will include definitive diagnosis (cancer or no cancer), as well as pathologic staging and a potential curative resection (lobectomy) with or without adjuvant therapy if the nodule is indeed malignant. The risks include possible morbidity and mortality from both thoracotomy and lobectomy (if needed). These outcomes generally depend on a number of issues including the experience of the surgeon and the patient’s other medical comorbidities, as well as the risk of development of other chronic problems such as a post-thoracotomy chronic pain syndrome that would affect the patient’s quality of life. If the patient undergoes watchful waiting, she avoids the comorbidities associated with thoracotomy. However, the patient is then subjected to a higher mortality risk if the nodule is indeed malignant; she may also suffer from the anxiety of not knowing whether she has cancer, and therefore a reduced quality of life. Please note that the time frame of 1 year does not permit the increased risk of mortality associated with a cancer diagnosis and the choice of watchful waiting to become fully realized in the real world. We have arbitrarily chosen this time frame to simplify our tree and facilitate the model. Therefore, the reader should be cautioned to not use this model for actual clinical decision making, as it is not clinically accurate. The non-cancer yearly mortality risk applies irrespective of the choice. The associate payoffs
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include the quality of life weights of the patient. Death from thoracotomy happens at the beginning of the period and so is assigned a QOL value of 0. Death from lobectomy or natural death is assumed to occur at the middle of the year; so half year of life is weighted by the patient’s QOL during that time. Under the thoracotomy arm, if the patient stays alive for the year, her QOL depends on the presence or absence of comorbidities. Under watchful waiting, death from cancer or natural death is also assumed to occur at the middle of the year. If the patient stays alive, then her quality of life is determined by her level of anxiety about cancer. Note again, that the model in Fig. 3.1 is illustrative and uses a very simplified and stylized version of an actual decision making process. Several additional factors such as the sensitivity and specificity of detecting cancer through thoracotomy, differences between clinical staging and the true pathological stage and recurrence of cancer post lobectomy, to name a few, must be considered for developing a comprehensive model that can appropriately represent this clinical situation.
Characterize the Information to Fill in the Structure Once the clinician has identified the sequence of choices to be made and the sequence of chances nodes and their associated outcomes determined by these choices, the next step is to obtain information on these chances and outcomes. Choices at each step of the decision process can be made based on this information. This is the critical part of the decision model, since the quality of information that goes into these chance nodes entirely determines the credibility of the decision model and the decision it generates. Incorporating all relevant evidence into the model is accomplished by a detailed search on the published and possibly unpublished research literature that point to evidence for the specific parameters in the model. Information gathering for decision analysis almost always uses one or more of the following: literature review, metaanalysis, primary data collection, and consultation with experts.5,6 Evidence pooling, such as metaanalyses, often weights evidence by its quality as defined by sample size of the study, study design and use of other robust analytic methods.
3. Decision Analytic Techniques
Chance nodes are always associated with probability parameters. These probability estimates are based on current evidence. Often there are multiple sources of evidence which must be integrated to inform the probability parameter relevant to the decision model. The classic example of this situation is the interpretation of results from a diagnostic test. In the decision tree, if a patient has a positive test, one must determine the probability of the patient having the disease given test is positive (i.e. the positive predictive value) so that one can model the progression of this patient accordingly. However, estimates available in the literature may only report that the diagnostic test correctly detects a clinical problem 90% of the time (specificity – a measure of prior belief) and correctly detects the absence of a clinical problem 85% of the time (sensitivity – also a measure of prior belief). Moreover, another source of evidence provides an estimate for the prevalence of the disease in the patient population that is being considered in the analysis. To recover the probability that the patient has the problem (posterior belief about success in diagnosis) given a positive or negative test result (evidence), one must rely on the Bayes’ formula,23,24 which generally says Pr (Success | Evidence ) =
Pr(Evidence | Success) × Pr (Success) (3.2) Pr (Evidence )
where “Pr(x|y)” represents probability of x conditional on or given y. To interpret this formula in the context of determining the positive predictive value, one can replace “Success” with having the “Disease”, and “Evidence” with the result of the diagnostic test. Therefore, Pr(Disease | Test + ve) Pr(Test + ve | Disease)× Pr(Disease) Pr(Test + ve) (3.3) Specificity × Prevalence = {Specificity × Prevalence =
+ Sensitivity × (1 − Prevalence)}
with the denominator determined via standard conditional probability arguments.
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Note that this exposition of Bayes formula can also be used to represent a prospective process of updating beliefs and information about specific parameters in the model, as new evidence become available. Often, there will be uncertainty regarding the true success rates and there may be more than one prior belief. However, once new evidence (e.g. observed data in clinical trials) is revealed, likelihood of that evidence, (Pr(Evidence | Prior belief)), under a variety of prior beliefs becomes known. This likelihood will be smaller under certain prior beliefs, thereby making those beliefs weaker than before; the likelihood will be stronger under other prior beliefs, thereby making those beliefs stronger than before. Consequently, one can feel more confident to restrict the beliefs on success rates to those ranges that correspond to the highest likelihood for the evidence. These new updated (posterior) beliefs then form the evidencebased posterior beliefs based on which that particular chance node in the model can be informed. Thus, the role of evidence is important since more evidence would tend to strengthen the posterior beliefs and dispel a larger part of uncertainty associated with prior beliefs. The relevant information for our model and their sources are outlined in Table 3.1. Because we are using a stylized example, we will use point estimates for our model parameters that reasonably lie within the widely disparate ranges that are reported in the literature concerning morbidity and mortality from thoracic procedures. In a more formal treatment of this problem, one has to pay considerable attention to pooled and meta-analyzed available evidence so as to obtain estimates that more closely reflect true values and also properly account for uncertainties from multiple sources. We discuss these sorts of issues further in the Advanced Models section. Attention should also be paid to the timeliness of information. For example, estimates given in Table 3.1 do not account for the fact that published literature shows a consistent trend over time toward lower morbidity and mortality from thoracic procedures, probably resulting from a combination of improved technique, improved anesthesia, and improved performance by dedicated thoracic surgeons, as well as the vast improvements in adjuvant chemotherapy therapy now available to patients.
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30 Table 3.1. Information on parameters for the choice between thoracotomy and watchful waiting. Description
Value
Pr (Death due to Thoracotomy) Pr (Cancer| Patient Characteristics) Pr (Stage I| Cancer, Patient Characteristics) Pr (Death| Lobectomy, Stage I Cancer)a Pr (Co-morbidities | Lobectomy, No Death) Pr (Death| Lobectomy, Stage II Cancer)a Pr (Co-morbidities | Thoracotomy, No Death) Pr (Death| Watchful Waiting, Stage I Cancer) Pr (Death| Watchful Waiting, Stage II Cancer) Pr (Death| Watchful Waiting, No Cancer, Patient Characteristics) QOL (Alive with no co-morbidity & no cancer) QOL (Co-morbidities due to Lobectomy) = q2 QOL (Co-morbidities due to Thoracotomy) = q1 QOL (Alive with the anxiety of knowing that cancer might be present ) = q3 QOL (Death)
1% 37% 54% 3% + 12% 25% 5% + 12% 19% 18% 36% 12%
45
1 = 0.9aq1 0.90 0.80
Standard Assumed Assumed Internal data
0
Standard
Sources 46 47 48 49 48 50 51,52 51,52 53–55
We model this probabilities as inclusive of the probability of natural death given no cancer, i.e. Pr(Death| Lobectomy, Stage I Cancer) = Pr(Death due to Lobectomy) + Pr(Death| Watchful Waiting, No Cancer, Patient Characteristics)
a
Apply Decision Analysis The final step is to synthesize the information gathered and the choices made in the process of decision making. This will allow us to obtain estimates of the primary outcome of interest that can be directly compared, in order to choose among alternative actions. This is accomplished by working backwards, i.e. from right to left, on our decision tree for which we have filled in probability values for nodes. At decision nodes, we “roll back” (alternatively, the term “fold back” is also used5) along the best choices – in effect, the choices that maximize gain or minimize harm. At chance nodes, we “average out” along all branches, yielding an expected value, such as QALYs, expected number of days of hospital stay, or expected risk of post-operative survival, etc. Consider the expected QALYs of lobectomy for the patient after she survives thoracotomy with comorbidities and is detected with Stage I cancer and undergoes lobectomy. Let the q1 and q2 be utility weights for comorbidities due to thoracotomy and lobectomy respectively. As mentioned previously, we also assume that death occurs on average at the middle of the year. The levels of outcomes possible are (1) death from lobectomy
(payoff = 0.5*q1); (2) survive with comorbidities from lobectomy (payoff = (0.5*q1) + (0.5*q2)); and (3) survive without comorbidities from lobectomy (payoff = q1). The overall expect payoff is then calculated using the formula in equation (3.1) by multiplying the corresponding probability of each level of outcome (Table 3.1) with its corresponding payoffs. This process is repeated for each possible level of outcome under thoracotomy and under watchful waiting. Based on the parameter estimates in Table 3.1, thoracotomy produces an expected QALY of 0.899 while watchful waiting produces an expected QALY of 0.731. This is our baseline result, which reveals that thoracotomy may be the optimal decision for this patient.
Sensitivity Analysis Clinical decision making using a DAM is usually followed by an assessment of the strength of the final decision that can be accomplished by quantitatively assessing the sensitivity of the final decision to the structural assumptions of the models and feasible alternative information sets. This is done by substituting a range of values for those parameters which are believed to be the most variable in practice. If the conclusions of the model are robust over a range of values for each node, then one can feel very comfortable with the decision that the model suggests. If the decision changes as values are varied, then one must be pay closer attention to those parameters and try to get a better sense of the parameters for the case at hand. This exercise will produce a threshold value where two decisions stand at equipoise. In this latter case, the strength of the data used to generate the parameter estimates becomes exceedingly important. In our case, we vary the QOL of the patient anxiety and that of the comorbidities of thoracotomy to see how our baseline result change. Figure 3.3 shows the phase diagram for this sensitivity analysis. In the diagram, the Y-axis represents different levels of QOL for anxiety while the X-axis represents different levels of QOL for thoracotomyrelated comorbidities. The area in the graph identifies the regions where, conditional of the respective QOL weights, either thoracotomy or watchful waiting is more beneficial. As evident
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from Fig. 3.3, a patient with high levels of anxiety (i.e. low QOL(Anxiety)) would benefit from thoracotomy. A patient with low anxiety (i.e. high QOL(Anxiety)) but low QOL(complications of thoracotomy) would benefit from watchful waiting. Such phase diagrams can help clinicians identify where their patient lie in this graph so that they can make an informed decision about treatment choices. Phase diagrams, as in Fig. 3.3, can be produced based on several other parameters in the model. However, multiple phase diagrams can easily make the decision as complicated as it was to begin with, and hence lose the utility of DAMs. Such scenarios, where there are considerable uncertainties and heterogeneity in several parameters in the model, can be addressed using probabilistic analysis, which we discuss in the Advanced Techniques section.
Clinical Decision Analysis in Thoracic Surgery Heretofore, DAMs have been used to address a number of issues and/or problems in thoracic surgery. Many of these issue and controversies will be more thoroughly explored in the context of this book. Some examples of models that have been published in the past include those that evaluate different surgical techniques,25 whether or not to proceed to more invasive and/or aggressive treatments given a common problem in thoracic surgery,26,27 and appropriate management of certain types of metastases,28 to name a few. The perspectives that have been used include: the patient’s (as we have, and is most common in clinical DAMs); the treating hospitals; and the government, via Medicare and Medicaid programs. Many DAMs use clinical conditions of patients that have been somewhat simplified, although this may change as older, sicker patients undergo thoracic procedures, and new data are generated about their outcomes. Time frames tend to be dominated by traditional markers of success or failure in surgery; i.e. 30-day morbidity and mortality or 1–5 year survival. There are centers,29 however, that have published long term data. Such information will become increasing relevant and important as outcomes of interest
expand to include measures like QALYs and costeffectiveness ratios that usually require long time frames for appropriate conclusions to be drawn. These longer term time-horizons are more commonly found when a DAM incorporates data from sources like the Surveillance, Epidemiology and End Results database or the VA Hospitals extensive database where patients are followed for many years. Several different primary outcomes of interest have been measured, including mortality, particular morbidities for certain operations, and length of hospital stay, as well as QOL, cost-effectiveness, and patient satisfaction. The chief problem with many of the published DAMs revolves around the fact that almost all point estimates are generated from a few retrospective studies or blinded, prospective, randomized trials, mostly comprised of a handful of patients. The robustness of these estimates can be greatly improved by meta-analyzing the data across studies and properly accounting for the uncertainties arising out of different sources. For example, one DAM compares three choices concerning optimal management for patients undergoing esophagectomy for carcinoma of the esophagus30 and bases all probabilities on a single, randomized, prospective trial that compared the use of pyloroplasty with non-use.31 However in the 72 patients enrolled, there was no statistically significant difference demonstrated between populations. In addition, there was little exploration of the potential negative side-effects of both procedure non-use and use from the patient’s perspective; i.e. which might decrease quality of life more: delayed gastric emptying or dumping syndrome? Though the model is very insightful, it is also quite hypothetical – just as our example is in this chapter. Therefore, to overcome these sorts of limitations, one can employ more advanced techniques that have been developed by practitioners of decision analysis.
Advanced Issues in Decision Analytic Techniques The discussions below are an attempt to provide a general understanding of the advanced issues in modeling and analysis. It does not in any way
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serve to provide a comprehensive review of these topics. More importantly, we recommend that clinicians interested in taking advantage of these advanced techniques consult with professionals who are well-versed with the nuances of these methods.
over time, and therefore are critical in evaluating the costs and outcomes of any intervention at a particular point in time. We refer interested readers to some of the applications of Markovian processes in decision models available in the literature.32–36
Markov Models
Probabilistic Analysis
Although decision trees provide intuitive re presentation of the disease process and the consequences of choice over a short time period, they can get extremely complicated when extended over long periods of time. To address this situation, one can use a Markov process that is a modeling technique based on matrix algebra. The fundamental idea behind these models is that, instead of considering health state transitions over a short period of time, as in decision trees, a Markov process is concerned with transitions during a series of short time intervals or cycles. For example, consider the watchful waiting arm of the decision tree in Fig. 3.1. One can revise the model to include a bi-annual followup for detecting whether the lesion is growing or not. The probability that the clinician would find an advanced lesion in the next follow-up will be based on the natural progression of cancer over time. In order to model the progression of cancer, the cancer can be delineated into mutually exclusive health states based on its stage and grade. An example of such a model, borrowed from our colleague David Meltzer’s work in prostate cancer, is shown in Fig. 3.2 – also known as a bubble diagram. Each health state, defined by a combination of stage and grade, is represented by a bubble. The figure represents progression of cancer by stage and grade leading up to cancer-related death. The patient begins in one of these bubbles and in every cycle, with some transition probabilities, either stays in that bubble or moves to another bubble representing an advanced health state. The sum of all transition probabilities in a cycle must add up to one because, by definition, a patient has to be in one of the mutually exclusive health states. The transition probabilities can vary with time (or number of cycles) and also with patient characteristics such as age of diagnosis. The transition probabilities determine the progression of the disease
Uncertainty remains an integral part of any analysis. Although a part of this uncertainty is reflected in the probability estimates used in decision models (e.g. such as those in Table 3.1), they do not reflect the overall uncertainty for an outcome. For example, if we say that Mrs. X has a 40% change of having cancer, we make a statement about a population comprised of millions of Mrs. X-clones in which 40% of them will have cancer and 60% will not. When the clinician is faced with one Mrs. X from that population, her true cancer status is not known with certainty. But by incorporating the point estimate of 40%, the clinician can characterize the uncertainty that she might fall in the part of the population who has cancer. In other words, it is the patient’s risk of having cancer. This type of model, as the one we illustrate above, is called a deterministic model as one uses predetermined point estimates for probabilities to reflect the risks. However, we seldom know how many patients in that population truly have cancer; instead, we rely on a random sample from the population to determine how many patients in that sample have cancer. If we find 40% of patients in the sample have cancer, it gives us a reasonable estimate for the population, but not the exact estimate. That is, 35% of patients in the population may truly have cancer, while in the random sample we have chosen, 40% show up with cancer. The bigger the sample size, the closer will be the sample estimate to the population estimate. Hence, there remains a degree of uncertainty about the true value of the population parameter since we almost always infer based on a fraction of that population. The traditional way to deal with this uncertainty (technically known as second-order uncertainty) is to a perform sensitivity analysis by varying the parameter of interest across a range of values and observing the changes in outcome associated with
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Stage I Low Grade
Stage I Mod. Grade
Stage I High Grade
Stage II Low Grade
Stage II Mod. Grade
Stage II High Grade
Metastatic Low Grade
Metastatic Mod. Grade
Metastatic High Grade
Death from Cancer
Figure 3.2. Structure of a Markov model for cancer progression
1 Watchful Waiting
.9
QOL (Anxiety)
.8 .7 .6 .5 .4 .3 .2 Thoracotomy
.1 0 0
.1
.2
.3
.4
.5
.6
.7
.8
.9
1
QOL (Thoracotomy Comorbidities)
Figure 3.3. Sensitivity analysis of the baseline QALY result with respect to QOL weights for patient’s anxiety and of thoracotomy-related comorbidities. The shaded and the blank areas in the graph identify the values of QOL weights for which thoracotomy or watchful waiting produces the maximum expected QALY respectively
it, as we have shown in our stylized example. However, there are several limitations to this method. One-way or two-way sensitivity analysis may severely undermine the effect of uncertainty in a multi-parameter model. Multiple-way sensitivity analysis can easily become sufficiently complicated as to prevent straightforward interpretation. Even
in the absence of complicated analysis, traditional sensitivity analysis can identify the optimal decision if only the true values of the parameters are known, as, for example, in case of patient’s preferences that can be directly measured. This poses problems for the clinicians, who may often find it hard to use sensitivity analysis results in clinical decision making due to lack of guidance and uncertainty about the true value of many clinical parameters. Probabilistic analyses help to characterize these uncertainties in the model parameters and to arrive at the final decision by simultaneously averaging out the uncertainties in multiple parameters. In these models, instead of specific point estimates of different parameters in the model, one specifies distributions for these input parameters where these distributions might center on the point estimates. Using Monte Carlo techniques, a patient is then propagated through the model several times (iterations), each time with random values of a parameter drawn from its respective distribution. The costs and outcomes are then averaged over all iterations and compared across treatment options. A good example of a probabilistic analysis can be found Andrew Brigg’s work on gastroesophageal reflux disease.37
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Bayesian Meta-analysis
Value of Information Analyses
Bayesian meta-analysis is a sophisticated hierarchical modeling approach that utilizes the concept of Bayes’ theorem discussed earlier. It summarizes and integrates the findings of research studies in a particular area. One can obtain the posterior distribution of Pr(Success| Evidence), that is the current distribution of belief about success rates given all the past evidence, and directly use it as an input in a probabilistic analysis. Such an approach provides a combined analysis of studies that indicate the overall strength of evidence for a success while properly accounting for multiple sources of uncertainty. For example, suppose there are four studies with varying sample sizes indicating that a woman with a smoking history similar to that in our example has a pre-test probability of cancer of 60%, 45%, 30% and 75%, respectively. Perhaps we also know, from even bigger studies, that women are 1.5 times more likely than men to have a lung cancer unrelated to their smoking, while a person with a significant smoking history is 9 times more likely to have cancer than a never-smoker. A Bayesian meta-analysis can combine this prior information on the effects of gender and smoking history with the data from the four samples to produce the posterior distribution of the pre-test probability of cancer for this female patient given all relevant evidence. With the advent of the Society of Thoracic Surgeons General Thoracic Surgery Database, these methods will be most relevant for the field of thoracic surgery in order to synthesize information arising out of a large number of prospectively collected data. Several books on Bayesian estimation and metaanalysis have been written and several examples of Bayesian meta-analysis can be found in the literature. Interested readers are encouraged to explore Peter Congdon’s book on this topic.38 Of interest to the readers of this book may be the work by Tweedie et al., who perform a Bayesian meta-analysis of the published literature to determine the association between incidence of lung cancer in female never smokers and exposure to environmental tobacco smoke.39 Bayesian metaanalysis can be most conveniently implemented using freely available software called the WinBUGS (http://www.mrc-bsu.cam.ac.uk/bugs).
As we discussed earlier, probabilistic models often can provide a more efficient way to address uncertainty in decision models. It provides the clinician with a sense of the strength of evidence for an optimal decision after accounting for multiple sources of uncertainty. It also provides the basis for conducting value of information analysis on specific parameters. In these analyses, uncertainties in parameter estimates that translate into uncertainties surrounding the outcome of interest can be used to establish the value of acquiring additional information by conducting further research. Information is valuable because it reduces the expected costs of uncertainty surrounding a clinical decision. The expected costs of uncertainty are determined by the probability that a treatment decision based on existing information will be wrong and by the consequences (or costs) if the wrong decision is made. The expected costs of uncertainty can also be interpreted as the expected value of perfect information (EVPI), since perfect information (an infinite sample) can eliminate the possibility of making a wrong decision. It is also the maximum a decision maker should be willing to pay for additional evidence to inform this decision in the future. Such analyses can identify research priorities by focusing on those parameters where more precise estimates would be most valuable.40–42 Additionally, an analogous type of calculation may be done on heterogeneous parameters such as quality of life weights and patient’s preferences and attitudes towards treatment. Knowing this information can help clinicians make individualized decisions by incorporating patients’ values and preferences into the process of making treatment decisions. Concretely, clinicians might pursue this approach using a variety of decision aids that are designed to facilitate transmission of information on patients’ values and preferences to physicians. These decision aids are often expensive in terms of program development and implementation as well as in time costs for patients and physicians.43 Therefore, in order to decide how to best allocate limited resources towards decision aids and similar approaches to implementing individualized care, it is important to have information on the potential social value of such
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endeavors and which dimensions of patient preference are most valuable to elicit. This is accomplished by the Expected Value of Individualized Care (EVIC) analysis.44 EVIC represents the expected costs of ignorance of patient-level heterogeneity. It is the potential value of research, as compared to optimal population level decision making, to elicit information on heterogeneous parameters so that individualized information about each patient can be conveyed to the physician.
Conclusions Decision analytic modeling (DAM) is a systematic approach to integrate information about a variety of different aspects of clinical decision making. It helps the clinician to make an objective decision by incorporating both the population level evidence on outcomes and also the individual level preferences in the decision making process. It is worthwhile to issue a reminder at this point that the sole purpose of DAM is to provide information in a systematic way so as to facilitate decision making based on best and comprehensive evidence. DAM, although viewed by some clinician and researchers as prescriptive, only prescribes the consideration of a decision to be optimal and should not be viewed as the final prescription for the patient. DAM in no way serves to make a decision for the clinician, who must utilize his/her own expertise to interpret the evidence placed in front him/her and determine the relevance of this evidence in the context of an individual patient’s case. The tension inherent in any DAM lies between the desire to create a model that is conceptually rich – to more accurately reflect the complexity of real-world decision-making – that is also somewhat data-poor, versus creating a more simple model which utilizes few, highly reliable estimates. However, if real world decision making does demand a richer model, we believe that it is more appropriate to develop such a model, even if subjective decisions and estimates inform some parts of this model. We say this because, often in real world clinical practice, such subjective decisions and estimates do play a part in clinical decision
making. DAM helps to translate these subjective estimates into a formal statement about uncertainty and help clinicians understand the implications of these uncertainties in the decision process. It also helps clinicians to identify priorities in research areas and patient preferences that are most critical for patient outcomes. Most DAMs in thoracic surgery have focused on information from clinical data. Such information is certainly crucial and forms the backbone of a DAM. However, any attempt to translate efficacy information available from clinical trials and other studies into effectiveness for a given patient requires a careful examination of patient preferences and behavior. Therefore, creating models that accurately reflect the choices at hand requires a fusion of several types of information. This information can be crudely divided into two categories – information that is derived from biological science, and that derived from social science. As we learn more about the genetic behavior and cell biology of tumors, as well as genetic information about individual patients, clinical decision making will most certainly be impacted. But this sort of information must be contextualized within the study of actual human behaviors – information that is captured by fields as diverse as be havioral and classical economics to statistics to political science to epidemiology. Consequently, it is imperative that surgeons and practitioners in these other fields collaborate if DAMs are to function as nuanced, effective tools to improve the clinical outcomes, and indeed the lives, of patients. Acknowledgements We are grateful to Caleb G. Alexander and William Dale at the University of Chicago for helpful comments and suggestions.
References 1. Meltzer D. Can medical cost-effectiveness analysis identify the value of research? In: Murphy KM, Topel RH, eds. Measuring the Gains from Medical Research: An Economic Approach. Chicago, IL: University of Chicago Press. 2003:206–247. 2. Pauker SG, Kassirer JP. Decision analysis. N Engl J Med. 1987; 316:250–257. 3. Weinstein MC, Fineberg HV. Clinical Decision Making. Philadelphia, PA: WB Saunders Company. 1980.
36 4. Petitti DB. Meta-analysis, Decision Analysis and Cost-Effectiveness Analysis. New York, NY: Oxford University Press; 1994. 5. Sackett DL, Rosenberg WM, Gray JA. Evidence based medicine: what it is, what it isn’t. BMJ. 1996;312:71–72. 6. Coutler A. Partnerships with patients: the pros and cons of shared clinical decision-making. J Health Serv Res. 1997;2:112–121. 7. Detsky AS, Naglie G, Krahn MD et al. Primer on medical decision analysis: getting started. Med Dec Making. 1997; 17:123–125. 8. Eddy D. Clinical Decision Making: From Theory to Practice. Boston, MA: Jones & Bartlett Publishers, 1996. 9. von Neumann J, Morgenstern O. Theory of Games and Economic Behavior. 1953 ed. Princeton, NJ: Princeton University Press; 1944. 10. Ost D, Fein A. Management strategies for the solitary pulmonary nodule. Curr Opin Pulm Med. 2004; 10:272–278. 11. Gold MR, Siegel JE, Russell LB, Weinstein MC. CostEffectiveness in Health and Medicine. New York, NY: Oxford University Press; 1996. 12. Drummond M, Stoddard G, Torrence G. Methods of Economic Evaluation of Health Care Programmes. Oxford: Oxford University Press; 1987:6–26. 13. Torrence GW. Utility approach to measuring healthrelated quality of life. J Chron Dis. 1987;40:593–600. 14. Torrence GW. Measurement of health state utilities for economic appraisal: a review. J Health Econ. 1986; 5:1–30. 15. Lowson KV, Drummond MF, Bishop JM. Costing new services: long-term domiciliary oxygen therapy. Lancet. 1981;ii:1146–1149. 16. Weinstein MC, Stason WB. Foundation of cost-effectiveness analysis for health and medical practices. N Eng J Med. 1977;296:716–721. 17. Garber A, Phelps C. Economic Foundations of costeffectiveness analysis. J Health Econ. 1997;16:1–32. 18. Weinstein M, Zeckhauser R. Critical ratios and efficient allocation. J Pub Econ. 1973;2:147–158. 19. Basu A, Meltzer D. Implications of spillover effects within the family for medical cost-efectiveness analysis. J Health Econ. 2005;24:751–773. 20. Alexander GC; Casalino LP; Meltzer DO. Patientphysician communication about out-of-pocket costs. JAMA. 2003;290:953–958. 21. Alexander GC; Casalino LP; Meltzer DO. Physician strategies to reduce patients’ out-of –pocket prescription costs. Arch Intern Med. 2005;165:633–636. 22. Detsky AS, Naglie G, Krahn MD et al. Primer on medical decision analysis: Building a tree. Med Dec Making. 1997;17:126–135. 23. Bayes T. An Essay towards solving a problem in the doctrine of chances. Philos Transact Roy Soc. 1763;330–418. Reprinted, with biographical note by GA Barnard in Biometrika. 1958;45:293–315. 24. Pratt JW. Bayesian interpretation of standard inference statements (with discussions). J R Stat Soc B. 1965;27:169–203.
A. Basu and A. Lehman 25. Ferguson MK, Lehman AG. Sleeve lobectomy or pneumonectomy: optimal management strategy using decision analysis techniques. Ann Thorac Surg. 2003;76:1782–1788. 26. Morimoto T, Tsuguya F, Koyama H et al. Optimal strategy for the first episode of primary spontaneous pneumothorax in young men. J Gen Intern Med. 2002;17:193–202. 27. Falcoz PE, Binquet C, Clement F et al. Management of the second episode of spontaneous pneumothorax: a decision analysis. Ann Thorac Surg. 2003;76:1843–1848. 28. Porter G, Cantor S, Walsh G et al. Cost-effectiveness of pulmonary resection and systemic chemotherapy in the management of metastatic soft tissue sarcoma: A combined analysis from the University of Texas M.D. Anderson and Memorial Sloan-Kettering Cancer Centers. J Thorac Cardiovasc Surg. 2004;127:1366–1372. 29. Martini N, Rusch V, Bains, MS et al. Factors influencing ten-year survival in resected stages I to IIIa nonsmall cell lung cancer. J Thorac Cardiovasc Surg. 1999;117:32–36. 30. Olak J, Detsky A. Surgical decision analysis: esophagectomy/esophagogastrectomy with or without drainage? Ann Thorac Surg. 1992;53:493–497. 31. Cheung HC, Siu KF, Wong J. Is pyloroplasty necessary in esophageal replacement by stomach? A prospective, randomized controlled trial. Surgery. 1987;102:19–24. 32. Goldie SJ, Kuntz KM, Weinstein MC et al. Costeffectiveness of screening for anal squamous intraepithelial lesions and anal cancer in human immunodeficiency virus-negative homosexual and bisexual men. Am J Med. 2000;108:634–641. 33. Goldie SJ, Weinstein MC, Kuntz KM et al. The costs, clinical benefits, and cost-effectiveness of screening for cervical cancer in HIV-infected women. Ann Intern Med. 1999;130:97–107. 34. Goldie SJ, Kuhn L, Denny L et al. Policy analysis of cervical cancer screening strategies in low-resource settings: clinical benefits and cost-effectiveness. JAMA. 2001;285:3107–3115. 35. Zeliadt SB, Etzioni RD, Penson DF et al. Lifetime implications and cost-effectiveness of using finasteride to prevent prostate cancer. Am J Med. 2005;118:850–857. 36. Manser R, Dalton A, Carter R et al. Cost-effectiveness analysis of screening for lung cancer with low dose spiral CT (computed tomography) in the Australian setting. Lung Cancer. 2005;48:171–185. 37. Briggs AH, Goeree R, Blackhouse G et al. Probabilistic analysis of cost-effectiveness models: choosing between treatment strategies for gastroesophageal reflux disease. Med Dec Making. 2002;22:290–308. 38. Congdon P. Bayesian Statistical Modeling. Chichester, England/New York: Wiley; 2001. 39. Tweedie RL, Scott DJ, Biggerstaff BJ et al. Bayesian meta-analysis, with application to studies of ETS and lung cancer. Lung Cancer. 1996;14(suppl 1): S171–S194.
3. Decision Analytic Techniques 40. Meltzer D. Addressing uncertainty in medical costeffectiveness analysis: Implications of expected utility maximization for methods to perform sensitivity analysis and the use of cost-effectiveness analysis to set priorities for medical research. J Health Econ. 2001;20:109–129. 41. Claxton K. The irrelevance of inference: a decision making approach to the stochastic evaluation of health care technologies. J Health Econ. 1999;18: 341–364. 42. Claxon K, Neumann PJ, Araki S. et al. Bayesian value of information analysis: An application to a policy model of Alzheimer’s disease. Int J Tech Ass Health Care. 2001;17:38–55. 43. Kennedy AD, Sculpher MJ, Coulter A et al. Effects of decision aids for menorrhagia on treatment choices, health outcomes, and costs: a randomized controlled trial. JAMA. 2002;288:2701–2708. 44. Basu A. Value of information on preference heterogeneity and individualized care. Med Dec Making. 2007;27:112–127. 45. Dominioni L, Imperatore A, Rovera F et al. Stage I non small cell lung carcinoma, analysis of survival and implications for screening. Suppl Cancer. 2000;89:2334–2344. 46. Swensen SJ, Silverstein MD, Ilstrup DM et al. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med. 1997;157:849–855. 47. Wisnivesky JP, Yankelevitz D, Henschke CI. Stage of lung cancer in relation to its size. Chest. 2005;127: 1136–1139.
37 48. Ginsberg RJ, Hill LD, Eagan RT et al. Modern thirtyday operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg. 1983;86: 654–658. 49. Stéphan F, Boucheseiche S, Hollande J et al. Pulmonary complications following lung resection: a comprehensive analysis of incidence and possible risk factors. Chest. 2000;118:1263–1270. 50. Barrera R, Shi W, Amar D et al. Smoking and timing of cessation: impact on pulmonary complications after thorocatomy. Chest. 2005;127:1977–1983. 51. Chadha AS, Ganti AK, Sohi JS et al. Survival in untreated early stage non-small cell lung cancer. Anticancer Res. 2005;25:3517–3520. 52. McGarry RC, Song G, des Rosiers P et al. Observationonly management of early stage, medically inoperable lung cancer: poor outcome. Chest. 2002;121: 1155–1158 53. U.S. Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. 54. Arias E. United States Life Tables, 2002. National Vital Statistics Reports. Hyattsville, MD: National Center for Health Statistics; 2004:53(6). 55. English DR, Holman CDJ, Milne E et al. The Quantification of Drug Caused Morbidity and Mortality in Australia. Canberra: Commonwealth Department of Human Services and Health; 1995
4
Decision Making: The Surgeon’s Perspective Thomas K. Varghese, Farhood Farjah, and David R. Flum
Introduction An examination of surgical trends before the National Emphysema Treatment trial (NETT) demonstrates the importance of nonclinical determinants of care. The number of lung volume reduction surgery (LVRS) claims increased dramatically after 1994 despite the fact that there was considerable uncertainty in the available literature.1 Favorable media reports and testimonials from patient advocacy groups influenced both patient and surgeon attitudes about LVRS.2 Some surgeons felt that investigations prior to the NETT demonstrated clear and dramatic improvements in quality of life sufficient to justify Medicare reimbursement for the procedure.3 Accordingly, they believed the NETT was a form of coercion because patients who refused to enroll in the study would not have financial coverage of their LVRS or receive the operation from a NETT surgeon. Furthermore, even if patients enrolled, the study deprived half of them of a procedure with “established” benefits. Surgeons less comfortable with this level of scientific uncertainty may have decided against performing the procedure. Nonsurgeon observers proposed that surgeons were motivated by financial gains, as the procedure was relatively inexpensive and reimbursement was generous.2 In addition to potential patient and surgeon influences, third-party coverage had an effect on decision making as evidenced by a dramatic decrease in the number of operations upon suspension of Medicare reimbursement in December 1995.4 Because many third-party payers based their coverage plans on Centers for Medicare and
Medicaid Services (CMS) guidelines, this policy likely affected many non-Medicare patients and providers as well. Whether surgeons stopped performing the operation because of lack of reimbursement or as an acknowledgement of scientific uncertainty is unclear. It is clear, however, that the sharp decline in the number of procedures was temporally related to CMS intervention.Subsequent CMS policy partly limited surgical decision-making because reimbursement was limited to eligible patients and surgeons. Delivery of medical advice is characterized by a process of weighing, prioritizing and structuring information given to a patient into a decision. In the ideal world, this is evidence-based. There is a growing expectation of patients to participate in their medical care and about informed choice in treatment decision making. The case of LVRS is an example of how many non-clinical factors can also influence the surgical decision-making process.
Models of the Surgeon–Patient Relationship Several models of the surgeon-patient relationship have been proposed, with each varying by how much decisional authority is conferred or assumed by patients. They include the surgeon as agent, informed decision-making, and shared decisionmaking models. The surgeon as agent is one in which the physician is the expert adviser who incorporates the values of the patient when making a treatment recommendation. The surgeon
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can elicit or assume these values from the patient, and clearly has total command over the decisionmaking process. As patient participation is limited, autonomy is minimal, and patients may be subjected to biased treatment options when limited options are given, or in the delivery of the same. Informed decision-making is on the opposite end of the spectrum. Here also the surgeon is recognized as one who has technical expertise, but patients are the ones who elicit and understand information about the treatment choices. The surgeon in this instance does not give his opinion, but rather presents the patient with the various options, allowing patients to arrive at their own conclusions. In between these two is the shared decision model. Here surgeons and patients are equal partners in the interaction. Each is required to freely exchange information and preferences about treatment options so that a mutually acceptable decision can be achieved. In the surgical field, situational decision-making is often the norm, where patient autonomy and participation can be influenced by medical condition, surgeon factors, patient education level, and availability of evidencebased literature on the condition. The focus of the current chapter is on those factors that influence the decision-making process from the surgeon’s perspective. A subsequent chapter will focus on issues from the patient side.
Methodology for Evaluating DecisionMaking Factors Studies of nonclinical factors influencing clinical decision-making have used qualitative or semiquantitative research methodologies – surveys, case vignettes, and decision-analytic modeling – all of which have important methodological limitations.5 There is a paucity of these types of studies in the field of thoracic surgery. Clinicians often find qualitative research (i.e. focus groups and key informant interviews) difficult to interpret because the question of generalizability is more problematic, and because this approach does not test hypotheses. Rather, qualitative research helps develop hypotheses that may then be evaluated using semiquantitative evaluations such as surveys. Surveys are difficult to interpret because of their
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limited generalizability to those who respond, the degree to which the question being asked is understood by the respondent, and, in the case of physician surveys, the extent of socially normative responses. Socially normative responses occur when members of a group provide “acceptable” answers to questions when the “real” answer would generate negative social judgments. These socially normative answers can also occur in the setting of anonymous surveys but are more common when the individuals are identified. In quantitative evaluations of these issues, such as in a prospective cohort that includes data on beliefs and attitudes of the surgeon and patient, the number of variables of interest and potential for confounding may be overwhelming. Methods less familiar to surgeons, such as the factorial experimental design, may partly overcome these obstacles. Factorial design allows comparison of differential groupings of categorical variables. For example, five dichotomized variables have 32 (25) unique groupings that one can analyze using hierarchical logistic regression. In essence, factorial design can estimate the individual and combined effects of many variables, allowing some control of confounding, and may facilitate studies trying to quantify the influence of clinical and nonclinical variables. The complexity of the calculations rises with the number of variables and combinations of variables, and thus even this study design has practical limits in terms of the number of variables it can analyze. Of greatest importance to the surgeons interested in assessing this complicated line of research is the need to collaborate with behavioralists and biostatisticians with relative knowledge and experience in alternative research designs.
Surgeon Factors Related to Clinical Decision-Making As demonstrated in the LVRS example, the clinical decision-making process appears to be influenced by non-clinical factors from the surgeon’s perspective. These factors include the surgeon’s tolerance of uncertainty, how willing they are to take risks in clinical care, the demographic characteristics of the surgeon, and their level and type of training.
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Impact of Risk-Taking Attitude on Clinical Decision Making Because clinical decisions are made under conditions of uncertainty, reactions to uncertainty and attitudes towards risk taking may have important implications on clinical decision-making. There is a limit in our understanding of the degree to which this issue influences surgical care.6 Several investigators have developed instruments to assess risk taking among physicians. Nightingale and colleagues7–9 developed a two-question test that has been frequently used to assess the degree to which physicians view themselves as risk seeking or risk averse (Table 4.1). In Nightingale’s study, respondents’ willingness to gamble for their patients in both the face of gain and in the face of loss is measured. Those who refuse to gamble in the face of loss are considered risk averse. In three different studies that Nightingale conducted, a significant correlation was found between resource utilization and risk preference in the face of loss. The more often physicians chose the second gamble, the more likely they were to utilize additional resources to rule out uncertain outcomes, as compared to those who chose the certain outcome. Thus, physicians in the setting of certain loss would rather minimize loss and fail in half of these attempts, than accept a certain loss. This fear of failure in risk taking has been found to be less consistent in other studies,10 and varies based on mode of testing and across different cultures.11
Impact of Surgeon Age There is little data looking at the impact of surgeon age on clinical decisions. In a study by Nakata and colleagues12 the relationship between risk attitudes and demographic characteristics of surgeons and anesthesiologists were explored. The authors distributed a survey on clinical decision-
making and expected life years to 122 physicians in Japan. Participants were asked their responses to two situations – one where they envisioned themselves as the patient, and one where they made the decision as the provider. Both asked about the willingness to undergo a treatment with 80% success rate, with the assumption that success would result in living for 20 years, and failure would be immediate death. Additionally, if the treatment was not chosen, the patient would live for 18 years. The questions were repeated with 2-year differences in longevity. Based on the responses, participants were classified as risk averse, risk neutral, and risk seeking. Of the 93 physicians who participated in the study (38 anesthesiologists, 55 surgeons), there were no differences in the number and percentage of risk takers between the groups. Gender, specialty and the role played during the decision (physician or patient) also did not demonstrate any differences. The only positive finding was with regards to age – the older the physician, the more risk averse they were. The study concluded that older physicians may shy away from risk, while younger physicians may be more willing to gamble.
Impact of Surgeon Gender As only 2.2% of all thoracic surgeons are women,13 there haven’t been any significant studies looking at this aspect in the field. However, there have been studies looking at the varying communication styles between male and female physicans.14 Female doctors are more likely to actively facilitate patient participation on medical decisions by practices such as partnership building, positive talk, question asking, and information giving.12–16 Female doctors also tend to be less dominant verbally during clinic visits than male physicans14 and engage in discussions more with patients than male doctors.16
Table 4.1. Questions used to assess relative risk preferences of surgeons. 1. In a choice between two therapies for an otherwise healthy person (a) Treatment A: 100% chance of increase in survival by 5 years as compared to the average person, 0% chance of no increase in survival (b) Treatment B: 50% chance of increase in survival by 10 years as compared to the average person, 50% chance of no increase in survival 2. In a choice between two therapies for a sick person (a) Treatment A: 100% chance of decrease in survival by 5 years as compared to the average person, 0% chance of decrease in survival by 10 years as compared to the average person (b) Treatment B: 50% chance of no difference in survival, 50% chance of decrease in survival by 10 years as compared to the average person
T.K. Varghese et al.
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Impact of Specialty Training Surgeon specialty has been shown to be associated with better post-operative outcomes among highrisk operations.17 Goodney and colleagues18 demonstrated that board-certified thoracic surgeons have lower rates of operative mortality with lung resection compared to general surgeons, although they noted that surgeon and hospital characteristics, especially volume, also influenced a patient’s operative risk of mortality. In a study conducted by our group in the SEER-Medicare population,19 we found that board-certified general thoracic surgeons had higher long-term survival rates than those treated by general surgeons. General thoracic surgeons were found to have performed preoperative and intraoperative staging more often than generalsurgeons or cardiothoracic surgeons (those who performed both cardiac and thoracic procedures). Dimick and colleagues20 found that specialty board certification in thoracic surgery was independently associated with lower operative mortality rates after esophageal resection in the national Medicare population. Although some of this effect may be influenced by provider volume, process-of-care variables are often different in specialty-trained surgeons. Training and specialization thus impact decisionmaking by physicians. As there is a trend towards increasing specialization, thoracic surgeons in general may be more recently trained, and hence may include more recently developed evidencebased protocols in their decision-making. There is also a trend towards multi-disciplinary participation in tumor boards amongst specialists, with additional influence in the decision-making process. It is unknown if subspecialty-trained physicians are more risk seeking in their treatment options in light of their additional training experience.
Healthcare System Factors Related to Clinical Decision Making Impact of Practice Environment The large shift from fee-for-service to managed care payment systems has created a whole new set of conflicts for surgeons who are making decisions
for their patients. An awareness emerges for surgeons in these managed care systems that their medical decisions can potentially negatively influence their income. This is not necessarily unethical, as cost containment has been recognized as an important circumstance in good decision-making.21 In some health maintenance organizations (HMOs) there are rigid guidelines for the treatment of patients that may limit individual surgeon decisionmaking. In other systems the types of devices surgeons use are limited. Hospitals have also been expanding the use of guidelines, treatment pathways, and care plans. All of these are attempts at limiting variation in care, decreasing lengths of stay, and reducing use of resources. Surgeons in the Veterans Administration hospitals have participated for more than a decade in a systematic data-gathering and feedback system of outcomes after major surgery. The National Surgical Quality Improvement Project (NSQIP)22 works to decrease variation in clinical outcomes by demonstrating to surgeons when their center is an “outlier” in performance. This system allows hospitals to target QI activities that may influence components of care and may also influence surgeon decision-making.
Impact of Political Environment Professional organizations can also play a role in decision making by effectively regulating surgeondirected clinical practice in the setting of clinical uncertainty. For example, through educational and advisory statements, the American Society of Colorectal Surgeons strongly influenced its membership to avoid performing laparoscopic procedures for colorectal cancer despite the use of these interventions by many surgeons for benign disease. There was no similar “prohibition” by thoracic surgical professional organizations in 1994, and these circumstances may have “permitted” surgeon-level, non evidence-based decision making to flourish with LVRS. The reporting of surgeon-specific outcome data is another example of the influence of the political environment. Outcome data were rarely reported prior to the mid-1980s.23 The first release of hospital risk-adjusted mortality rates in December 199024 and the first formal public release published in December 1992,25 marked the
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4. Decision Making: The Surgeon’s Perspective
start of a new era. These performance reports, or physician report cards, have become more prevalent in recent years.26,27 Advocates of this form of reporting believe they provide information about quality of care that consumers, employers, and health plans can use to improve their decisionmaking and to stimulate quality improvement among providers.27 They may also appropriately promote regionalization of medical centers and consolidation of services. However, surgeons are concerned that risk adjustment strategies in these reports are not adequate. Without this confidence, publication of procedural mortality rates may cause physicians to withhold procedures in highrisk patients. In a recent study by Narin and colleagues,26 the attitudes and experiences of cardiologists were surveyed about the influence of the New York Percutaneous Coronary Intervention (PCI) report card on their decision-making process. Of those responding, 83% agreed or strongly agreed that patients who might benefit from PCI may not receive the procedure as a result of public reporting of physician-specific mortality rates. Overall, 79% agreed or strongly agreed that the presence of a scorecard influences whether they treat a critically ill patient with a high expected mortality rate. The authors concluded that, while scorecards were developed to improve healthcare outcomes, their unintended consequence may be to adversely affect healthcare decisions for individual patients, especially those with high-risk. Scorecards may also impair the development of new treatments because of the more restrictive clinical practice environment.23 As a result, many have proposed revamping the current system to facilitate rapid and accurate access to outcome data in the local practice environment so that improvement in practice occurs on a voluntary basis rather than in response to punitive restrictions. Examples of such grass-roots initiatives on a state level that are surgeon-led include those in the states of Michigan28 and Washington.29,30 On a national level, The Society of Thoracic Surgeons (STS) was a leader in the development of a societybased, publicly reported, volunteer registry database that has made a tremendous impact on risk-stratification and outcomes in cardiac surgery.31 Based on the widespread acceptance and success of the cardiac database, the STS
General Thoracic Surgery Database has also seen increased participation and growth. A recent study identified predictors of prolonged length of stay, a surrogate morbidity marker after lobectomy for lung cancer.32 Surgeons who participate in such database initiatives can utilize these riskstratified models to better inform their decisionmaking process.
Impact of the Medico-Legal Environment Fear of lawsuits has had a dramatic effect on many specialties such as obstetrics and neurosurgery. In states where insurance rates have soared, many of these surgeons have left their practices. Surgeons may also be influenced by medicolegal risks in terms of their decision-making with certain operations in high-risk populations. The exact extent of this influence in unclear in the field of thoracic surgery. However, as a specialty that deals with a significant proportion of highrisk patients, it is certain that the cardiothoracic surgeon will face such a challenge in their career.33
Summary Although in the ideal world we believe that evidence-based medicine is practiced at all times, there are many non-clinical factors that influence the care that we provide. For nearly every procedure performed, there is significant variability in operative and periprocedural care, and associated outcomes between hospitals. Often this variability occurs as a result of lapses in quality. Non-clinical factors may contribute to this, and although the research methodologies used to understand these effects are limited, further investigation into these factors may help to explain and control variability in clinical care and outcomes. Areas of non- clinical influences include surgeon factors (such as risk-taking attitudes, age, gender, specialty training), and healthcare system factors (practice, political and medicolegal environment). Better assessment and control of these factors can lead to rational, consistent and appropriate care for our patients.
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References 1. Cooper JD, Trulock EP, Triantafillou AN et al. Bilateral pneumonectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg. 1995;109:106–119. 2. Ramsey SD, Sullivan SD. Evidence, economics and emphysema: Medicare’s long journey with lung volume reduction surgery. Health Aff (Millwood). 2005;24:55–66. 3. Cooper JD. Paying the piper: the NETT strikes a sour note. National Emphysema Treatment Trial. Ann Thorac Surg. 2001;72:330–333. 4. Huizenga HF, Ramsey SD, Albert RK. Estimated growth of lung volume reduction surgery among Medicare enrollees: 1994 to 1996. Chest. 1998;114: 1583–1587. 5. Clark JA, Potter DA, McKinlay JB. Bringing social structure back into clinical decision making. Soc Sci Med. 1991;32:853–866. 6. Tubbs EP, Broeckel Elrod JA, Flum DR. Risk taking and tolerance of uncertainty: implications for surgeons. J Surg Res. 2006;131:1–6. 7. Nightingale SD. Risk preference and laboratory use. Med Decis Making. 1987;7:168–172. 8. Nightingale SD. Risk preference and admitting rates of emergency room physicians. Med Care. 1988;26: 84–87. 9. Nightingale SD. Risk preference and decision making in critical care situations. Chest. 1988;93: 684–687. 10. Holtgrave DR, Lawler F, Spann SJ. Physicians’ risk attitudes, laboratory usage, and referral decisions: the case of an academic family practice center. Med Decis Making. 1991;11:125–130. 11. Zaat JOM. General practitioners’ uncertainty, risk preference, and use of laboratory tests. Med Care. 1992;30:846–854. 12. Nakata Y, Okuno-Fujiwara M, Goto T, Morita S. Risk attitudes of anesthesiologists and surgeons in clinical decision making with expected years of life. J Clin Anesth. 2000;12:146–150. 13. Hartz RS. “The XX files”: demographics of women cardiothoracic surgeons. Ann Thorac Surg. 2001; 71(suppl 2):S8–S13. 14. Roter DL, Hall JA. Why physician gender matters in shaping the physician-patient relationship. J Womens Health. 1998;7:1093–1097. 15. Roter D. Lipkin M Jr, Korsgaard A. Sex differences in patients’ and physicans’ communications during primary care medical visits. Med Care. 1991;29:1083–1093. 16. Van den Brink-Muinen A, Bensing JM, Kerssens JJ. Gender and communication style in general practice. Differences between women’s health care and regular health care. Med Care. 1998;36:100–106. 17. Cowan JA Jr, Dimick JB, Thompson BG et al. Surgeon volume as an indicator of outcomes after carotid endarterectomy: an effect independent of specialty practice and hospital volume. J Am Coll Surg. 2002;195:814–821.
T.K. Varghese et al. 18. Goodney PP, Lucas FL, Stukel TAA, Birkmeyer JD. Surgeon specialty and operative mortality with lung resection. Ann Surg. 2005;241:179–184. 19. Farjah F, Flum DR, Varghese TK Jr et al. Surgeon specialty and ling-term survival after pulmonary resection for lung cancer. Ann Thorac Surg. 2009;87: 995–1006. 20. Dimick JB, Goodney PP, Orringer MB, Birkmeyer JD. Specialty training and mortality after esophageal cancer resection. Ann Thorac Surg. 2005;80: 282–286. 21. Devettere RJ. Making health care decisions. In: Devettere RJ, ed. Practical Decision Making in Health Care Ethics. Washington, DC: Georgetown University Press; 2000:94. 22. Itani KM. Fifteen years of the National Surgical Quality Improvement Program in review. Am J Surg. 2009;198(5 suppl):S9–S18. 23. Topol EJ, Califf RM. Scorecard cardiovascular medicine. Its impact and future directions. Ann Intern Med. 1994;120:65–70. 24. Hannan EL, Kilburn H Jr, O’Donnell JF et al. Adult open heart surgery in New York State. An analysis of risk factors and hospital mortality rates. JAMA. 1990;264:2768–2774. 25. Epstein A. Performance reports on quality – prototypes, problems, and prospects. N Engl J Med. 1995;333:57–61. 26. Narins CR, Dozier AM, Ling FS, Zareba W. The influence of public reporting of outcome data on medical decision making by physicians. Arch Intern Med. 2005;165:83–87. 27. Schneider EC, Epstein AM. Use of public performance reports: a survey of patients undergoing cardiac surgery. JAMA. 1998;279:1638–1642. 28. Prager RL, Armenti FR, Bassett JS et al. Cardiac surgeons and the quality movement: the Michigan experience. Semin Thorac Cardiovasc Surg. 2009;21: 20–27. 29. Flum DR, Fisher N, Thompson J et al. Washington State’s approach to variability in surgical processes/ outcomes: Surgical Clinical Outcomes Assessment Program (SCOAP). Surgery. 2005;138:821–828. 30. Aldea GS, Mokadam NA, Melford R et al. Changing volumes, risk profiles, and outcomes of coronary artery bypass grafting and percutaneous coronary interventions. Ann Thorac Surg. 2009;87: 1828–1838. 31. Clark RE. The STS Cardiac Surgery National Database: an update. Ann Thorac Surg. 1995;59: 1376–1381. 32. Wright CD, Gaissert HA, Grab JD et al. Predictors of prolonged length of stay after lobectomy for lung cancer: a Society of Thoracic Surgeons General Thoracic Surgery Database risk-adjustment model. Ann Thorac Surg. 2008;85:1857–1865. 33. Mayer JR Jr. Ethical, legal and health policy challenges in contemporary cardiothoracic surgery: Introduction. Semin Thorac Cardiovasc Surg. 2009;21:1–2.
5
Decision Making: The Patient’s Perspective Dawn Stacey and France Légaré
Introduction There are major gaps in the quality of decisions about treatment options that involve making tradeoffs between benefits and harms.1 Following standard counseling, patients score ‘D’ on knowledge tests and ‘F’ on their understanding of the probabilities of benefits and harms. Moreover, there is a mismatch between the benefits and harms that patients value most and the option that is chosen. Patients participate in decision making less than they prefer and some have high levels of decisional conflict, which is an independent predictor of downstream dissatisfaction, regret and the tendency to blame their doctor for bad outcomes.2–4 Decisional conflict is defined as personal uncertainty about a course of action when options involve risk, loss, regret or challenge to personal values.5 The underlying mechanisms explaining poor decision quality are patients’ difficulties recalling facts and understanding the probabilistic nature of evidence regarding each available option (benefits and harms), and surgeons’ difficulties judging the values that patients place on benefits versus harms. There is a clear need to improve the way patients are prepared to participate in decision making and the way surgeons counsel patients about options. The goal of evidence-based medicine is to integrate clinical expertise with patient’s preferences using the best available evidence.6 Some decisions are straightforward because there is strong scientific evidence that the benefits are large and the risks are minimal. Others are more difficult because:
(a) the probabilistic nature of the diagnosis makes it difficult for both the physician and the patient to choose the best course of action; (b) there is insufficient scientific evidence on the benefits, risks, and side effects; (c) the probabilistic aspect of the evidence that is drawn from populations implies uncertain outcomes for the individual; and/ or (d) patients differ on how they value the benefits, risks, and scientific uncertainties. These decisions are said to be ‘preference sensitive’ or ‘values sensitive’.7 For example, patients with similar demographic and clinical characteristics who become informed about treatment options might differ on their preferred treatment for diseases such as breast cancer (mastectomy vs. breast conserving therapy) or thoracoabdominal aneurysm (corrective surgery vs. watchful waiting). In the past, when patients faced these difficult decisions, surgeons acted as agents in the best interest of their patients by deciding whether the benefits outweighed the harms.8 Today, surgeons are still considered experts in problem-solving: diagnosing, identifying treatment options, and explaining the probabilities of benefits and harms.9,10 However, patients are increasingly recognized as the best expert for judging the personal value of benefits versus harms.1,8,11 The principles of passive ‘informed consent’ are evolving into active ‘informed choice’ or ‘shared decision making’ (SDM).12,13 For example, in 2007 the consent legislation in Washington State, USA was changed to require demonstration of SDM for elective surgical decisions. SDM is defined as a decision making process jointly shared by
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_5, © Springer-Verlag London Limited 2011
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patients and their health care providers.14 It aims at helping patients play an active role in decisions concerning their health15 to reach the ultimate goal of patient centered care.16,17 SDM rests on the best evidence of the risks and benefits of all available options.18 Thus, communication techniques that enable the patient to adequately weight the risks and benefits associated with their choices are essential skills in SDM.19 SDM takes account of patients’ individual circumstances in which their values/preferences are sought and their opinions valued. SDM does not completely exclude a consideration of the values and preferences of the physician or other health professionals involved in the decision.14,18,20 It occurs through a partnership in which the responsibilities and rights of each of the parties are explicit and the benefits for each party are made clear. Therefore, with growing patient interest to participate in decision making about options, evidence-based decision aids have been developed to supplement (not replace) surgeons’ counseling.21 These tools prepare patients to discuss options that the clinician has judged as clinically appropriate by helping them to: (a) understand the probable benefits, risks, and scientific uncertainties of options; (b) consider and clarify the value they place on the benefits, risks, and scientific uncertainties; and (c) participate in decision making with their surgeons. This chapter discusses evidence-based methods to help patients become involved in SDM. Specific questions include: (a) should patients participate in decision making? (b) what is the quality of the decisions in current practice? (c) what is the quality of the current decision making process? (d) what approaches support patients making decisions? (e) do decision aids improve the quality of decisions and the decision making process? (f) what are strategies for using patient decision aids (PtDA) in clinical practice?
Search Methods To our knowledge, the decisional needs and decision making behavior of patients facing specific difficult thoracic surgery decisions have not been studied. For other surgical decisions, the best
Table 5.1. Criteria for considering randomized controlled trials for this review. Participants
Intervention
Comparison Outcomes
People making decisions about screening or treatment options for themselves, for a child, or for an incapacitated significant other PtDAs defined as interventions to help people make specific choices among options (including the status quo) by providing (at a minimum) information on the options and outcomes relevant to a person’s health status and including implicit methods to clarify values PtDAs compared to no intervention, usual care, alternative interventions, or a combination Primary outcomes included attributes of the decision (e.g. knowledge, accurate risk perceptions, value congruence with chosen option) and attributes of the decision making process (e.g. decisional conflict, patient-practitioner communication, participation in decision making, satisfaction)
evidence comes from the Cochrane systematic review of randomized trials of patient decision aids (PtDA) when patients were randomized to receive ‘usual counseling’.1 The obvious limitation of the data is that trial participants may not be similar to non-trial participants. Nevertheless, until data from more representative cohorts are published, data from trials provide some insight into patients’ decision making behavior when facing diverse surgical decisions. Table 5.1 describes the criteria used for selecting trials to be included in the Cochrane review of PtDAs.1
Primary Data Sources The Cochrane systematic review of 55 trials of PtDAs found 12 trials of patients who were facing major elective surgical treatment options: coronary artery disease (2); benign prostate hypertrophy (2); breast cancer (3); menorrhagia (2); prostate cancer (1); orchiectomy (1); and herniated disc or spinal stenosis (1). The Cochrane review is based on contact with known developers and evaluators of decision aids in December 2006 and a search from 1966 to July 2006 of the following electronic databases: MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, and PsycINFO. These data are supplemented with evidence from other systematic reviews4,22,23 and several non-randomized controlled trial studies.
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5. Decision Making: The Patient’s Perspective
Findings Should Patients Participate in Decision Making? Patients want to be involved in making decisions about their health. The majority of patients in the United States (US), Canada, United Kingdom (UK), South Africa, Japan, and Germany want to participate in decision making, with few preferring physicians make the decision on their behalf (e.g. passive role ranged from 10% in South Africa to 3% in Germany).24 However, there was wide variation in the proportion of patients who report that surgeons made the decision in the Cochrane Review of PtDAs: 8% for decisions about prostate surgery in the UK,25 33% for decisions about prostate cancer surgery in Canada,26 42% for adults deciding about cardiac revascularization in the US,27 and 73% for patients deciding about prostate cancer treatment in Finland.28 These findings are consistent with a multi-country comparison (Canada, Australia, New Zealand, Germany, UK, US) in which just over half of participants reported having been exposed to healthcare professionals who involved them in treatment choices.29 Intention to engage in SDM is a modifiable behavior in both physicians and patients.30 Although its determinants differ between physicians and patients, patients with low literacy are less willing to engage in SDM principally because they do not feel that they have the needed self-efficacy to do so. However, engagement of such patients in decision making is modifiable.1 Moreover, patients who participate in decision making have better outcomes. A review of 22 studies found that 34–80% (median 60%) of patients experienced a role in decision making that matched their preferred role and, when mismatches occurred, patients had wanted more active roles.4 Furthermore, when there was a match between their preferred and perceived level of involvement, patients were more satisfied and less depressed. In contrast, mismatches resulted in poorer outcomes for patients (e.g. depression, fatigue, less satisfaction, anxiousness after consultation). Regardless of their preferred role in decision making, two studies found that patients do better when they are actively engaged in the decision making process.31,32 Unfortunately, at the time
of diagnosis and without decision support resources, patients may be less likely to participate in decision making.
What Is the Quality of the Decisions in Current Practice? The current quality of decisions is inadequate based on patients receiving standard counseling in the Cochrane review of PtDAs. According to the International PtDA Standards Collaboration (www.ipdas.ohri.ca),33 decision quality is defined as: (a) informed (knows key facts about options and has realistic perceptions of the probabilities of positive/negative outcomes); and (b) based on patients’ values (option chosen matches the benefits/risks that the patient values most).5,34–38 In the three trials of PtDAs that evaluated how informed the patients were, those who received a usual discussion about surgical options only scored 54–62% on knowledge tests.27,39,40 For example, the accuracy of patient perceptions of the chances of benefits/harms was 58% in the trial of a PtDAs for the surgical decision about breast cancer,41 while other trials not involving surgical decisions indicated an accuracy ranging from 27% to 66%. None of the surgical decision making trials measured the agreement between values and choice. However, in 3 trials of hormonal therapy, agreement between values and choice was poor in the control arms of the trials.42–44
What Is the Quality of the Current Decision Making Process? The current quality of the process of decision making is limited as indicated by using measures of decisional conflict and satisfaction with the process. Three trials of decision aids that measured decisional conflict in patients receiving usual counselling about surgical options indicated that the degree of decisional conflict was 40% for men with benign prostatic hypertrophy, 28% for adults with coronary artery disease, and 16% for women with breast cancer.25,27,41 Furthermore, for every one unit increase in decisional conflict, patients were: 3 times more likely to fail a knowledge test; 23 times more likely to delay their decision; 59 times more likely to change their mind
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about the chosen option; 5 times more likely to regret their decision; and 19% more likely to blame their doctors for poor outcomes.2,3 Overall, patients were satisfied with the usual counselling when considering surgical options; satisfaction scores ranged from 70% to 77% across three trials.27,39,40 This satisfaction could be due to their satisfaction being strongly influenced by the relationship with the practitioner and/or patients unaware of the decision support they did not receive. To date, research findings suggest that physicians and patients who consult them have not adopted SDM processes45–49 and that they experience difficulty doing so.47,50 For example, in an analysis of 271 videotaped clinical encounters, Makoul et al. observed that in less than 20% of the consultations, the patient had the opportunity to express their thoughts about a prescription medication.45 During group interviews, general medical residents reported having tried to influence the patient’s decision if they were convinced it was the best decision.50 In an analysis of 186 taped encounters of 22 general practitioners, Elwyn et al. observed a weak performance in SDM: the mean score of physicians = 16.9 ± 7.7 on a scale from 0 (no SDM) to 100 (optimal SDM).48
Summary of Current Practice It is clear that there are serious problems with the current approach to counseling patients about options. The majority of patients have unrealistic expectations of benefits and harms and about a third have high levels of decisional conflict leading to higher regret and tendency to blame others. Most clinical encounters result in patients not being involved in the decision making process. Com plications and poor outcomes are a reality of surgery, and patients’ expectations need to be re-aligned with the evidence. This does not mean that patients should not ‘hope for the best’, but they do need to be ‘prepared for the worst’. From a legal perspective, the biggest predictor of lawsuits is not bad outcomes but a combination of bad outcomes with poor communication.51 More effective methods are needed to improve surgeon-patient communication and deliberation about treatment options.
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What Approaches Support Patients Making Decisions? When there is no clearly indicated “best” therapeutic option, ‘SDM’ is perceived as the optimal process of decision making between practitioners and patients. SDM is the process of interacting with patients to arrive at an informed, valuesbased choice by considering two or more medically reasonable alternatives (which may include ‘status quo’ or ‘watchful waiting’).14,52 SDM programs, also known as PtDAs, are standardized, evidence-based tools intended to facilitate that process. They are designed to supplement rather than replace patient-practitioner interaction.21 PtDAs help prepare patients to discuss the options by providing information, values clarification, and structured guidance in the steps of collaborative decision making. The goal of these interventions is to improve the quality of the decision making process by addressing the suboptimal intermediary modifiable determinants of decision making. This decision making process does not aim at the adoption of a decision determined a priori by the practitioner. It seeks to ensure that the decision made together with the patient is informed by the best evidence and consistent with the patient’s values. PtDA development has been guided by several different decision theory, transactional, and risk communication frameworks from economics, psychology, and sociology.1 They have been delivered using diverse print, video, or audio media, but there is a current shift toward internet-based delivery systems. PtDAs are self-administered or practitioner-administered. Most are designed to prepare patients for personalized counseling; however, the timing of their integration into the process of care depends on practitioners’ usual counseling practices and feasibility constraints. There are three key elements common to their content: 1. Information and Risk Communication. Decision aids include high quality, up-to-date information about the condition or disease stimulating the need for a decision, the available health care options, the likely outcomes for each option (e.g., benefits, harms, inconveniences), the probabilities associated with these outcomes,
5. Decision Making: The Patient’s Perspective
and level of scientific uncertainty. The information is clearly presented as a “choice situation” in a balanced manner so as not to persuade the viewer toward any particular option and in sufficient detail to permit choosing among the options. 2. Values Clarification. Various methods are used to help patients sort out their “values” for outcomes of options (i.e., the personal desirability/undesirability of different features of the available options). For example, patients are better able to judge the value of options when they are familiar and easy to imagine. Therefore, PtDAs describe what it is like to experience the physical, emotional, and social consequences of the procedures involved and the potential benefits/harms. Some PtDAs directly engage patients in explicitly revealing their values using rating techniques such as balance scales or trade-offs. In balance scales, patients use the familiar ‘1- to 5-star’ rating system to deliberate about the degree of personal importance associated with each of the possible benefits and harms. Visual ratings like this also help family members and the practitioner understand ‘at a glance’ which benefits and harms are most/least salient to the patient in the specific decision. 3. Structured Guidance or Coaching in Delibe ration and Communication. PtDAs are desi gned to improve patients’ confidence and skills by guiding them in the steps involved in decision making. This involves helping them become informed, weighing their specific options, and showing them how to communicate values and personal issues to families and practitioners. Personal coaching by nurses or other professionals can also be used to prepare patients to deliberate and communicate with their surgeon.52–54 Once patients understand what is at stake in a “close call” situation and appreciate the importance of clarifying their personal values, they can meaningfully determine a preference and communicate whether they wish to be actively involved in the health care decision. A typical decision aid guides patients to prepare for discussing decisions with their practitioners by assessing their individual decision making
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needs and comparing their options (Appendix A). The steps include: (a) verifying the decision: options, rationale, timing, and stage in decision making; (b) clarifying the patient’s preferred role in decision making; (c) reviewing the options being considered (including relevant pros and cons for each option) and clarifying their values by rating the importance they attach to each outcome using a ‘one to five’ star rating system; (d) assessing current decision making needs and uncertainty using the Decisional Conflict Scale; and (e) planning the next steps. Patients can be encouraged to share their completed Ottawa Personal Decision Guide with their practitioner as a way to communicate knowledge and values associated with a health related decision ‘at a glance’. Alternatively, the guide can be completed together with the practitioner to structure the process of decision making. A similar guide is being used as part of the process of care in nurse call centers and patient information services located in the United States, Australia, United Kingdom, and Canada. However, referrals to these types of services are intended to compliment and streamline the decision making process rather than replace discussion with the patient’s physician. Most patients have made it clear that individual consultation with their practitioner about options is extremely important.11,24 This Decisional Conflict Scale, used within this decision guide (Appendix A), was developed to determine whether a patient is experiencing uncertainty about the best course of action to identify the modifiable factors contributing to decisional conflict (e.g. feeling uninformed, unclear about values, unsupported in decision making).5 Decisional conflict is a state of uncertainty about the course of action to take and is frequently characterized by difficulty in making a decision, vacillation between choices, procrastination, being preoccupied with the decision, and having signs and symptoms of distress or tension. We recently developed a 4-item SURE screening test in English and French for monitoring decisional conflict in patients (Table 5.2).55 In pregnant women, SURE as predicted correlated negatively with the DCS (r = −0.46; p < 0.0001) and in patients considering treatments, it discriminated between those who made a choice and those who had not (p < 0.0001).
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50 Table 5.2. SURE screening test. Acronym
Items
Sure of myself… Uninformed… Risk/benefit ratio…
Do you feel SURE about the best choice for you? Do you know the benefits and risks of each option? Are you clear about which benefits and risks matter most to you? Do you have enough support and advice to make a choice?
Encourage…
Do Decision Aids Improve the Quality of Decisions and the Decision Making Process? The Cochrane Review of 55 randomized controlled trials of PtDAs shows that decision aids facilitate active participation and are more likely to lead to informed values-based decisions.1 When PtDAs are used as adjuncts to counseling, they have consistently demonstrated superior effects relative to usual practices on decision quality and the decision making process (Table 5.3). More specifically, patients exposed to decision aids improve their knowledge, have more realistic perceptions of the chances of benefits and harms, and improved agreement between patients’ values for outcomes
of options and the chosen option. Three of three trials, all focusing on menopause hormone decisions, found that decision aids were better than educational interventions in improving the match between values and choices. A cohort study by Barry et al. also showed that men who were especially bothered by their urinary symptoms are seven times more likely to choose surgery for benign prostate disease than those who are not. Men who were especially bothered by the prospect of sexual dysfunction as a complication of surgery are one-fifth as likely to choose it compared to as those who are not.56 These improvements in decision quality were accomplished without deleterious effects on patient satisfaction or anxiety.1 Moreover, in a more recent study, the amount of time spent by the physician and nurse counselling patients during the initial consultation and/or follow-up visit did not differ between patients who received usual care compared to those who used the PtDA.57 Of the 55 trials in the systematic review, 8 measured rates of different procedures involving major elective surgery (Table 5.4). Six of these 8 trials demonstrated 21–74% reductions in the use of the more invasive surgical option in favor of
Table 5.3. Summary of PtDA effects on decision quality and the decision making process. Outcome
Number of trials
Number of participants
Pooled weighted differences (95% CI)
18
1,261
WMD 15.2 (11.6, 18.7)*
Improves test score by 15 points to ‘B+’
11
2,953
RR 1.61 (1.4, 1.9)*
Improves test score by 39% to ‘D’
3
473
Unable to combine due to different measures used
Improves match between values and choice
Interpretation
Decision quality outcomes Knowledge of options and outcomes (0–100 scale) Realistic expectations of outcomes with and without treatment Match between choice and patients’ values (benefits/harms that matter most)
Decision making process outcomes Decisional conflict – perceived uncertainty and related deficits in knowledge, values clarity, and support (0 to 100 scale) Proportion remaining undecided Participation – practitioner controlled
12
2,333
RR -6.12 (−8.6, −3.6)*
Reduces decisional conflict by 6 points (and feeling uninformed by 8 points)
4 8
1,032 1,277
RR 0.51 (0.3, 0.8)* RR 0.61 (0.5, 0.8)*
Reduces patients who are undecided by 49% Reduces patients passive in decision making by 39%
Surgical choice Surgery over conservative option
8
1,875
RR 0.75 (0.6, 0.9)*
Reduced uptake of surgery by 25%
CI confidence interval, RR relative risk (relative risk of 1 = no difference between proportion (risk) on PtDA and comparator, >1:greater proportion on PtDA. CI above/below 1 implies significant increase/ reduction in ‘risk’), WMD weighted mean difference (Average value on PtDA minus average value on comparator, adjusted for variation in each group. WMD = 0: no difference between PtDA and comparator). *p < 0.05.
51
5. Decision Making: The Patient’s Perspective Table 5.4. Effect of PtDAs on specific decisions about major elective operations. PtDA group Decision (source)
Comparison group
N
% choosing option
94 86 61 253 184 103 103 54
6.4 52.3 41.0 32.4 53.2 58.3 7.7 11.1
N
% choosing option
Weight (%)
Relative risk (95% CI)
24.3 66.3 58.3 41.4 49.2 91.0 13.8 2.1
5.1 17.7 13.3 18.2 19.2 20.1 5.4 1.0
0.26 (0.11, 0.61)* 0.79 (0.62, 1.01)* 0.70 (0.48, 1.03) 0.78 (0.62, 0.99)* 1.08 (0.89, 1.32) 0.64 (0.54, 0.76)* 0.56 (0.25, 1.26) 5.33 (0.67, 42.73)
PtDA versus usual care Breast cancer surgery41 Coronary revascularization27 Coronary revascularization40 Hysterectomy53 Hysterectomy67 Orchiectomy28 Prostatectomy39 Prostatectomy25
107 95 48 244 179 100 116 48
*p < 0.05. Pooled RR 0.75 (0.59, 0.94)*
more conservative surgical or medical options, without adverse effects on health outcomes. For example, the rates of mastectomy declined in favor of breast conserving surgery. The underlying mechanism of this effect is likely in moderating expectations and communicating values. When patients face a major health issue, their first inclination is to ‘cut it out’ or ‘get rid of ’ the offending organ. When they begin to appreciate that there are alternatives and that there are potential harms associated with the aggressive procedures, some decide on the simpler procedure. The remainder stay with their original view, but their expectations are more realistic. They place more value on the peace of mind from removing the organ than the potential complications and side effects. In the case of the hysterectomy study,53 a video decision aid alone did not have an effect on rates of procedures as much as the combination of the video with nurses’ coaching to encourage patients to clarify and communicate to their surgeon: (a) the value they placed on keeping their uterus; and (b) the role they wished to take in decision making. Therefore, in this arm of the study, surgeons’ follow-up counselling about options was enhanced with better communication of what informed women valued most and their preferred role in decision making. Do PtDAs always dampen patients’ enthusiasm for surgery? In Table 5.4, one trial which showed a non-significant trend toward increasing the rates of prostate surgery also had the lowest rate of surgery in the control group (2%). This was a UK study which had low referral rates by general practitioners due to a shortage of urologists. This
observation suggests that PtDAs may promote uptake in surgery when rates are arguably “too low”. Therefore, PtDAs may address both underuse as well as over-use of options, thereby reflecting the true underlying distribution of informed patients’ preferences.7,58
What Are Strategies for Using Patient Decision Aid in Clinical Practice? Practitioners are essential for clarifying the decision, identifying patients in decisional conflict or requiring decision support, referring patients to the appropriate resources including decision aids as part of the process of care, and following up on patients’ responses in the decision aids to facilitate progress in decision making. Patients prefer faceto-face contact with a practitioner to individualize the information and guide them in decision making.59 PtDAs are designed to enhance this interaction rather than replace it. To use decision aids in practice, the following five steps can be followed: Step 1: Clarify the common decisions including specific options the patient needs to consider Step 2: Refer patients to a decision aid. Endorsement of patient information from one’s personal practitioner is highly valued by patients.59 Direct patients to the A to Z inventory of decision aids (www.ohri.ca/decisionaid) to access decision aids quality rated using international standards33 or provide them with copies. If no decision aids exist for specific health decisions, the Ottawa
D. Stacey and F. Légaré
52
Personal Decision Guide can be combined with quality patient education resources. Step 3: Explain how the decision aid is used in your practice. Ask the patient to complete the decision aid in preparation for a follow-up discussion. Some online decision aids have summary forms that provide a succinct report on patient’s understanding of their options, values associated with outcomes of options, preferred option, and remaining questions.60 Step 4: Refer to the decision aid at follow-up discussion. It is important that the practitioner acknowledge patients’ responses to their decision aid. It can serve as a communication tool to focus the patient-practitioner dialogue. At a glance, one can learn how the patients see the decision.60 Step 5: Screen for residual decisional conflict. Based on what is currently known on the downstream effects of patients presenting with decisional conflict, practitioners would benefit from re-screening for any residual decisional conflict and its sources before arriving at a final decision. After using PtDAs, most patients have unresolved needs for advice and continued uncertainty that only get resolved following counselling with their surgeons. These steps can be completed by the individual practitioner or shared among team members. In the absence of staff to help with this process, referral to nurse call centers or patient information services may be an option to prepare patients. Decision aids can also be used by patients when discussing their preferences with important others such as a spouse, family member, or friend. Two systematic reviews have been conducted to better understand barriers and facilitators to providing SDM and interventions to facilitate adoption of SDM in clinical practice.23,61 In a review of 38 studies, the three most common facilitators of SDM including the use of PtDAs were practitioner motivation, having a positive impact on the clinical process, and improving patient outcomes.61 Another systematic review of 19 studies found that interventions to improve adoption of SDM by health professionals was a combination of two or more interventions such as educational meetings, audit and feedback, and the distribution of educational materials.23 Given the fact that care is increasingly planned and delivered through interprofessional teams,62–64 and knowing that most decisions are made by
patients with more than one healthcare professional, a model of SDM will need to acknowledge the involvement of multiple players. Therefore, an interprofessional approach to SDM could help healthcare teams to collaborate in achieving involvement of patients in decision making and might enable patients to reach healthcare choices that are agreed upon by them and their interprofessional team.20 Consequently, an interprofessional approach to SDM has the potential to improve the quality of decisions made by patients and their healthcare teams by fostering integrated healthcare services and continuity of care across health sectors and the continuum of care.65 This, in turn, could increase quality of care, reduce practice variations, and improve the fit between what patients want and receive.
Conclusions Based on a systematic review evidence, patients facing health decisions, as well as their practitioners, need help beyond standard counselling.1,66 Decision aids improve the quality of patient decision making, facilitate the integration of patient values into evidence-based medical practice, and enhance the practitioner-patient interaction. The challenge is developing best practices for implementing decision aids as part of the process of care that will lead to better evidence-based decision making that matches patients’ values. Needless to say, interprofessional approaches to SDM are needed to acknowledge and mobilize a more comprehensive approach to supporting patient involvement in health decisions.
References 1. O’Connor AM, Bennett CL, Stacey D, Barry M., Col NF, Eden KB et al. Decision aids for people facing health treatment or screening decisions. Cochrane Database Syst Rev. 2009;3:1–118. 2. Gattellari M, Ward JE. Men’s reactions to disclosed and undisclosed opportunistic PSA screening for prostate cancer. Med J Aust. 2005;182:386–389. 3. Sun Q. Predicting Downstream Effects of High Decisional Conflict: Meta-analysis of the Decisional Conflict Scale. Ottawa: University of Ottawa, Master of Science in Systems Science, School of Management; 2004.
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53 21. Collins ED, Moore C.P., Clay KF, Kearing SA, O’Connor AM, Llewellyn-Thomas H.A. et al. Can women with early-stage breast cancer make an informed decision for mastectomy? J Clin Oncol. 2009;27:519–525. 22. Legare F, Ratte S, Stacey D, Kryworuchko J, Gravel K, Turcot L et al. Interventions for improving the adoption of shared decision making by healthcare professionals. Cochrane Database Syst Rev. 2007;(3). 23. Interventions for Improving the Adoption of Shared Decision Making by Healthcare Professionals: Preliminary Results from a Cochrane Review. Boston, MA: International Shared Decision Making Con ference; 2009. 24. Magee. Relationship-based Health Care in the United States, United Kingdom, Canada, Germany, South Africa, and Japan. A Comparative Study of Patient and Physician Perceptions Worldwide. FerneyVoltaire, France: World Medical Association Patient Safety in Care and Research; 2003. 25. Murray E, Davis H, Tai SS, Coulter A, Gray A, Haines A. Randomized controlled trial of an interactive multimedia decision aid on benign prostatic hypertrophy in primary care. BMJ. 2001;323:493–496. 26. Davison BJ, Degner L. Empowerment of men newly diagnosed with prostate cancer. Cancer Nursing. 1997;20:187–196. 27. Morgan MW, Deber RB, Llewellyn-Thomas H et al. Randomized, controlled trial of an interactive videodisc decision aid for patients with ischemic heart disease. J Gen Intern Med. 2000;15:685–699. 28. Auvinen A, Maattanen L, Finne P, Stenman UH, Aro J, Juusela H et al. Test sensitivity of prostate-specific antigen in the Finnish randomised prostate cancer screening trial. Int J Cancer. 2004;111:940–943. 29. Coulter A. Engaging Patients in Their Healthcare. How Is the UK Doing Relative to Other Countries? Oxford, UK: Picker Institute Europe; 2006. 30. Légaré F, St-Jacques S, Gagnon S, Njoya M, Brisson M, Frémont P. Prenatal screening for Down syndrome: A survey of willingness in women and family physician to engage in shared decision-making. Pren. Diag. In press. 31. Hack TF, Degner LF, Watson P, Sinha L. Do patients benefit from participating in medical decision making? Longitudinal follow-up of women with breast cancer. Psycho-Oncology. 2006;15:9–19. 32. Gattellari M, Butow PN, Tattersall MHN. Sharing decisions in cancer care. Soc Sci Med. 2001;52: 1865–1878. 33. Elwyn G, O’Connor A, Stacey D, Volk R, Edwards A, Coulter A et al. Developing a quality criteria framework for patient decision aids: online international Delphi consensus process. BMJ. 2006;333(7565): 417–422. 34. Briss P, Rimer B, Reilley B, Coates RC, Lee NC, Mullen P et al. Promoting informed decisions about cancer screening in communities and healthcare systems. Am J Prev Med. 2004;26:67–80.
54 35. Kennedy AD. On what basis should the effectiveness of decision aids be judged? Health Expect. 2003; 6:255–268. 36. IPDAS-2005. International Patient Decision Aid Standards Collaboration. Ottawa: 3rd International Shared Decision Making Conference; 2005. 37. Ratliff A, Angell M, Dow R, Kupperman M, Nease R, Fisher R et al. What is a good decision? Eff Clin Pract. 1999;2:185–197. 38. Sepucha KR, Fowler FJ, Mulley AG. Policy support for patient-centered care: The need for measurable improvements in decision quality. Health Affairs. 2004. 39. Barry MJ, Cherkin DC, Chang Y, Fowler F, Skates S. A randomized trial of a multi-media shared decisionmaking program for men facing a treatment decision for benign prostatic hyperplasia. Dis Manag Clin Outcomes. 1997;1:5–14. 40. Bernstein SJ, Skarupski KA, Grayson CE, Starling MR, Bates ER, Eagle KA. A randomized controlled trial of information-giving to patients referred for coronary angiography: Effects on outcomes of care. Health Expect. 1998;1:50–61. 41. Whelan T, Levine M, Willan A, Gafni A, Sanders K, Mirsky D et al. Effect of a decision aid on knowledge and treatment decision making for breast cancer surgery: a randomized trial. JAMA. 2004;292:435–441. 42. Dodin S, Légaré F, Daudelin G, Tetroe J, O’Connor A. Prise de décision en matrère d hormonothérapie de remplacement: Essai clinique randomisé. Can Family Phys. 2001;47:1586–1593. 43. O’Connor AM, Wells G, Tugwell P, Laupacis A, Elmslie T, Drake E. The effects of an ‘explicit’ values clarification exercise in a woman’s decision aid regarding postmenopausal hormone therapy. Health Expect. 1999;2:21–32. 44. Rothert ML, Holmes-Rovner M, Rovner D et al. An educational intervention as decision support for menopausal women. Res Nurs Health. 1997;20:377–387. 45. Makoul G, Arntson P, Schofield T. Health promotion in primary care: physician-patient communication and decision making about prescription medications. Soc Sci Med. 1995;41:1241–1254. 46. McKinstry B. Do patients wish to be involved in decision making in the consultation? A cross sectional survey with video vignettes. BMJ. 2000;321:867–871. 47. Godolphin W, Towle A, McKendry R. Challenges in family practice related to informed and shared decision-making: a survey of preceptors of medical students. CMAJ. 2001;165:434–345. 48. Elwyn G, Edwards A, Wensing M, Hood K, Atwell C, Grol R. Shared decision making: developing the OPTION scale for measuring patient involvement. Qual Safety Health Care. 2003;12:93–99. 49. Davis RE, Dolan G, Thomas S, Atwell C, Mead D, Nehammer S et al. Exploring doctor and patient views about risk communication and shared decision-making in the consultation. Health Expect. 2003;6:198–207.
D. Stacey and F. Légaré 50. Elwyn G, Edwards A, Gwyn R, Grol R. Towards a feasible model for shared decision making: focus group study with general practice registrars. BMJ. 1999; 319:753–756. 51. Tamblyn R, Abrahamowicz M, Dauphinee D, Wenghofer E, Jacques A, Klass D et al. Physician scores on a national clinical skills examination as predictors of complaints to medical regulatory authorities. JAMA. 2007;298:993–1001. 52. Stacey D, Murray MA, Legare F, Dunn S, Menard P, O’Connor A. Decision coaching to support shared decision making: a framework, evidence, and implications for nursing practice, education, and policy. Worldviews Evid Based Nurs. 2008;5:25–35. 53. Kennedy A, Sculpher MJ, Coulter A, Dwyer N, Rees M, Abrams KR et al. Effects of decision aids for menorrhagia on treatment choices, health outcomes, and costs. A randomized controlled trial. JAMA. 2002;288:2701–2708. 54. Myers RE. Decision counseling in cancer prevention and control. Health Psychol. 2005; 24(4 Suppl):S71–S77. 55. Legare F, Kearing S, Clay K, Gagnon S, D’Amour D, Rousseau M et al. Are you SURE? Assessing patient decisional conflict with a 4-item screening test. Canadian Family Phys. 2010;56:e308–e314. 56. Barry MJ. Watchful waiting vs immediate transurethral resection for symptomatic prostatism: the importance of patients’ preferences. JAMA. 1988;259: 3010–3017. 57. Whelan T, Sawka C, Levine M, Gafni A, Reyno L, Willan A et al. Helping patients make informed choices: a randomized trial of a decision aid for adjuvant chemotherapy in lymph node negative breast cancer. JNCI. 2003;95:581–587. 58. Wennberg JE, Peters PG Jr. Unwarrented variations in the quality of health care: Can the law help medicine provide a remedy/remedies? Sepc Law Dig Health Care Law. 2004;305:9–25. 59. O’Connor AM, Drake ER, Wells GA, Tugwell P, Laupacis A, Elmslie T. A survey of the decision-making needs of Canadians faced with complex health decisions. Health Expect. 2003;6:97–109. 60. Stacey D, Hawker G, Dervin G, Tomek I, Cochran N, Tugwell P et al. Improving shared decision making in osteoarthritis. BMJ. 2008;336:954–955. 61. Legare F, Ratte S, Gravel K, Graham ID. Barriers and facilitators to implementing shared decision-making in clinical practice: Update of a systematic review of health professionals’ perceptions. Patient Educ Couns. 2008;73:526–535. 62. D’Amour D, Oandansan I. Interprofessionality as the field of interprofessional practice and interprofessional education: an emerging concept. J Inter profess Care. 2005;(Suppl) 1:8–20. 63. D’Amour D, Ferrada-Videla M, San Martin Rodriguez L, Beaulieu MD. The conceptual basis for interprofessional collaboration: core concepts and theoretical frameworks. J Interprofess Care. 2005;19(suppl 1): 116–131.
5. Decision Making: The Patient’s Perspective 64. Oandansan I, Reeves S. Key elements of interprofessional education. Part 2: factors, processes and outcomes. J Interprofess Care. 2005;19(suppl 1):39–48. 65. Haggerty JL, Reid RJ, Freeman GK, Starfield BH, Adair CE, McKendry R. Continuity of care: a multidisciplinary review. BMJ. 2003;327(1219):1221. 66. Guimond P, Bunn H, O’Connor AM, Jacobsen MJ, Tait VK, Drake ER et al. Validation of a tool to
55 assess health practitioners’ decision support and communication skills. Patient Educ Couns. 2003; 50:235–245. 67. Vuorma S, Teperi J, Aalto AM, Hurskainen R, Kujansuu E, Rissanen P. A randomized trial among women with heavy menstruation – impact of a decision aid on treatment outcomes and costs. Health Expect. 2004;7:327–337.
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Appendix A: Ottawa Personal Decision Guide Adapted for Early Stage Breast Cancer Surgery Decision Case Situation: Mrs. Jones is a 60 year old woman newly diagnosed with stage 1 breast cancer. Her surgeon has offered her the option of mastectomy or lumpectomy plus radiation therapy. Mrs. Jones’ responses to the decision aid are indicated below.
5. Decision Making: The Patient’s Perspective
57
Part 2 Lung
6
PET for Mediastinal Restaging of Patients with Non Small Cell Lung Cancer after Induction Therapy James R. Nitzkorski, Veeraiah Siripurapu, and Walter J. Scott
Despite significant advancement in the multimodality approach to lung cancer, the optimal management of patients with stage IIIA non-small cell lung cancer (NSCLC) continues to be a challenge. Identifying pathological N2 disease is of importance because it significantly affects outcomes and potential treatment strategies. More widespread utilization of endobronchial ultrasound techniques and refinements in fluorodeoxyglucose positron emission tomography (FDG PET) imaging have considerably increased our ability to accurately stage patients with advanced lung cancer, consequently increasing the number of patients in the IIIA “borderline” resectable category. Improved stratification of patients in this category enables surgeons to select surgery for those most likely to benefit, improving outcomes and eliminating unnecessary thoracic morbidity. Recent phase III clinical trials demonstrate improved survival after surgical resection in patients who had mediastinal node clearance after induction therapy.1–4 These data emphasize the potential utility of a highly accurate test to preoperatively identify those patients who have achieved clearance of their mediastinal nodal metastases after induction therapy. Such a test would allow surgeons to limit resection to those patients with the greatest likelihood of long term benefit. To date, FDG PET with integrated computerized tomographic (CT) scans are the best noninvasive method of evaluating the mediastinal response to induction therapy in the borderline resectable patient. Few publications exist regarding the utility of integrated PET/CT for mediastinal lymph node restaging after induction therapy.
Furthermore, interpretation of the available data is complicated by a lack of standardization in terms of technology and interpretation of radiographic findings. This chapter will summarize the published experience of FDG PET in terms of analyzing mediastinal node response to induction therapy in patients with stage IIIA NSCLC.
Methods A literature search used the matched keywords “positron-emission tomography” and “carcinoma, non-small-cell lung” by the Ovid Medline search utility to identify studies published since 1950. Although early data emerged in the 1990s, the vast majority of studies were published after the year 2000. The literature search was limited to studies published in English, with 384 papers identified. The search was further refined to capture relevant studies by combining the keywords with “induction therapy,” “neoadjuvant therapy,” “chemotherapy,” “radiation,” and “restaging.” This was supplemented by reviewing reference lists from retrieved articles. Fifty studies were identified and further scrutinized. Criteria for inclusion in our analysis required that studies compare post-induction PET/CT imaging with histologic evaluation of nodal basins after surgical resection. Studies considering only the primary tumor without evaluation of the mediastinal nodes were excluded. Although several studies compared survival outcomes after PET restaging, the majority of these were excluded because histologic evaluation of
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_6, © Springer-Verlag London Limited 2011
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lymph nodes was not performed. Studies that failed to define how lymph nodes were classified as either “positive” or “negative” by PET were also excluded. Finally, studies not specifically evaluating the mediastinal lymph node stations were excluded. Twelve papers meeting the above criteria were used for the final analysis (Table 6.1).
Results Study Quality No randomized trials have been performed. The number of patients in these studies varied substantially with Cerfolio et al.5 having the largest series numbering 97 patients, while some other series numbered fewer than 20 patients. We also found significant variability within and among the studies that were included in this analysis with respect to: the type of PET scan used, the definition of a PET-positive lymph node used by the authors, the specific induction therapy regimen that was administered and finally in the timing of post-induction PET.
PET Versus Integrated PET/CT Early studies were performed prior to the general availability of integrated PET/CT technology. Findings on PET in these studies were interpreted by comparing them side-by-side with images from an available chest CT scan (Table 6.1). Only four of the studies used integrated PET/CT technology.
Overall sensitivity for nodal response ranged from 20% to 77% in studies using a stand-alone PET scanner versus 62–89% in studies that used integrated scanners. Specificity ranged from 61% to 99% for stand-alone PET versus 88–92% for PET/ CT. These data must be interpreted cautiously, given the significant differences in the way these studies were performed. In several cases sequential PET scans were performed on different machines throughout the course of treatment. Because many of the studies published are from large referral centers that treat patients from surrounding hospitals, some patients had already undergone staging and started induction therapy prior to study center referral. Standardization of both initial staging and imaging quality within a given center’s experience was therefore impossible. PET/CT images performed prior to induction therapy had to be compared to the study center’s post-treatment images, which expectedly varied in terms of quality, consistency, and interpretation.
Definition of Positive Mediastinal Nodes Using PET Unlike the Response Evaluation Criteria in Solid Tumors (RECIST) system, no standardized definition of what constitutes a positive node on PET exists, thus a standardized definition of treatment response is also lacking (Table 6.1). We focused primarily on reporting data on mediastinal lymph node restaging rather than discussing restaging of the primary tumor. In defining mediastinal node positivity, some studies interpreted a node as positive based on visual appearance alone,6 while others used a standardized uptake
Table 6.1. Comparative view of PET/CT technology utilized by reviewed studies. Reference
Year
PET/CT technology
Definition of nodal response
Restaging interval (weeks)
Ryu Akhurst6 Cerfolio9 Port8 Hellwig7 Hoekstra11 Cerfolio14 De Leyn18 Ohtsuka12 Pottgen13 Cerfolio5 Eschmann10
2002 2002 2003 2004 2004 2005 2006 2006 2006 2006 2007 2007
Side-by-side Side-by-side Side-by-side Side-by-side Side-by-side Side-by-side Integrated Integrated Side-by-side Integrated Integrated Side-by-side
Visual Visual SUV < 3.0 maxSUV < 50% Visual Visual maxSUV < 50% Visual + RECIST on CT Node/cerebellar ratio DSUV analysis Any decrease in maxSUV Visual
2 3 2 2–11 3–4 4–12 3–4 10 <1–13 2
17
SUV standardized uptake value, RECIST response evaluation criteria in solid tumors, CT computerized tomography, D delta
6. PET for Mediastinal Restaging of Patients with Non Small Cell Lung Cancer after Induction Therapy
63
value (SUV) greater than 2.5,7,8 and others used an SUV greater than 3.0.9 Assessment of response was visual in some studies,10 while others used a percentage of change in SUV.11 One study compared side-by-side FDG-PET to conventional CT,12 using region of interest (ROI) ratios between the node in question and cerebellar tissue in a previously validated model. This study concluded that FDG-PET offered no advantage to conventional CT for predicting response to induction therapy. Another study used a more complicated statistical analysis of lesion volume and corrected maximum standardized glucose uptake values. The authors concluded that nodal response could be predicted by using PET/CT with a sensitivity and specificity of 73–89%, respectively.13 A 2003 study by Cerfolio demonstrated a higher sensitivity, specificity and accuracy for restaging N1 and paratracheal nodes than for other N2 nodes.9 This trend was substantiated in a subsequent study by Cerfolio14 that reported finding unsuspected N2 disease at the time of surgical biopsy in station 5, 6, and 7 most frequently. This study found integrated PET/CT to be better than CT alone for predicting nodal response. Receiver operating characteristic (ROC) curve analysis showed a maxSUV decrease of ³50% in a lymph node statistically predicted clearance in that node after induction therapy. This well-designed, prospective trial using integrated scanning technology on nearly 100 patients still found a moderately high rate of false negatives and false positives (20% and 25% respectively).
characteristic (ROC) curves for overall restaging was 88% at 26 days and approached 100% at 29 days for N2 restaging.
Timing of PET Scan
Reported Results of the Ability of PET and PET/CT to Measure the Response of N2 Metastases to Induction Therapy
The length of time between the completion of induction therapy and final restaging with PET varied widely (Table 6.1). Even in a single study it varied from 4 to 12 weeks.14 The other studies also reported a wide range of restaging intervals. Because inflammation occurring as a result of external beam radiation may cause a false-positive PET findings,15,16 Cerfolio designed a study5 to determine the optimal time to re-image with PET after the completion of induction therapy. This study suggested that accuracy can be optimized by waiting 1 month after the completion of a total dose of 60 Gy of radiation with a cisplatin-based chemotherapy protocol. Accuracy based on receiver operating
Induction Therapy Another source of heterogeneity in our analysis was the fact that no standard induction therapy was used in these studies (Table 6.2). Chemotherapy regimens varied,11–13 although most induction therapy protocols included a platinum agent. When treatment was combined with radiotherapy, details regarding the use of sequential or concurrent radiotherapy were rarely mentioned. As an example, Hoekstra et al.11 reported a multicenter study that enrolled patients on different treatments protocols based on whether treatment was initiated in the Netherlands or in Belgium. The treatment of patients in this non-uniform manner limits our ability to analyze the PET response to induction therapy in this broad subset. Radiation therapy was used in the majority of the listed studies. There was however, a wide variation in the dose used, with a range from 30 Gy12 to 68 Gy7 and in the timing with chemotherapy. Three of the studies administered chemotherapy and radiation therapy concurrently,10,13,17 but other studies reported that patients received chemotherapy alone or failed to clearly state the details of induction therapy. The fact that different radiation therapy regimens were used in these studies makes it difficult to assess the accuracy of PET in the post-induction setting.
The sensitivity, specificity, accuracy, positive and negative predictive values (PPV and NPV) reported in the twelve studies are summarized in Table 6.2. In general, PET has a high specificity and negative predictive value. These data are influenced by the baseline prevalence of N2 lymph node metastases in the groups of patient that were studied. The accuracy of PET for restaging mediastinal lymph nodes ranged from 60% when six patients (25% of study group) had mediastinal disease,8 to 69% when 100% of study group had N2 disease.14
J.R. Nitzkorski et al.
64 Table 6.2. Clinical data from studies included for analysis. Reference, year
Design
Patients with N2 or IIIAa
Treatment (n)
Ryu 2002
Prospective
21
Ch + RT: 26
Akhurst 20026
Retrospective
18
Cerfolio 20039
Prospective
11
Port 20048
Prospective
6
Ch: 40 Ch + RT: 11 RT: 5 Ch: 27 Ch + RT: 7 Ch
Hellwig 20047
Prospective
10
Hoekstra 200511
25
Cerfolio 200614 De Leyn 200618
Prospective multicenter Prospective Prospective
Ch + RT: 45 RT: 2 Ch
93 30
Ch + RT Ch
Ohtsuka 200612
–
Pottgen 200613 Cerfolio 20075
Retrospective Retrospective
20 97
Ch: 4 Ch + RT: 18 Ch: RT: 50 Ch + RT: 109
Eschmann 200710
–
29
Ch + RT: 70
17
7
Chemo
RT (Gy)(n) Sens (%) Spec (%)
Acc (%)
PPV
NPV
5-FU, cisplatin, vinblastine –
42
58
93
85
–
–
–
67
61
–
46
79
Carboplatin, taxol
45
50
99
93
81
94
Carboplatin, paclitaxel Platinum
–
20
70
60
14
77
45–68
50
88
79
57
85
Multiple
–
50
71
–
66
67
Carboplatin based cisplatin, gemcitabine Multiple
– –
62 77
88 92
69 83
– 93
– 75
30: 17 60: 1 – £50.4: 16 ³60: 93 45
57
66
64
29
86
89 –
– –
– – 40–100%b –
– –
77
68
73
–
–
60 (20–89)
80 (61–99)
75 (40–100)
56 80 (14–93) (67–86)
Multiple Cisplatinum based Paclitaxel, carboplatin
Mean Range
n number; RT radiotherapy, Gy grays, Sens sensitivity, Spec specificity, Acc accuracy, PPV positive predictive value, NPV negative predictive value, Ch chemotherapy, ‘–’ = not specified a includes only total of number of patient who underwent induction therapy and had complete post surgical histologic analysis b = studying optimal time to restage using PET
Conclusion The best algorithm for assessing the response of patients with stage IIIA NSCLC to neoadjuvant (induction) therapy remains a matter of debate. The goal is to select those patients with N2 disease who have achieved some degree of mediastinal lymph node clearance after induction therapy and who theoretically will benefit the most from subsequent surgical resection. Currently, PET/CT is one of several modalities used to evaluate these patients. Our evidencebased review focused only on the role of PET for restaging mediastinal lymph nodes in patients with initial N2 metastases who underwent induction therapy. Based on our review, we have concluded that the use of PET/CT as the sole method for mediastinal restaging after induction therapy remains problematic for various reasons:
1. Specific data reviewing PET use for restaging the mediastinum are sparse, with only twelve papers meeting our specified criteria. 2. Occurrences of lymph node downstaging as reported in the studies we reviewed varied, probably because different treatment modalities (chemotherapy or chemoradiotherapy) were used. 3. No consensus exists regarding the definition of treatment response as measured by PET (e.g. SUVmax, percent change in SUVmax). 4. No consensus exists to guide clinicians regarding when to order a restaging PET after induction therapy is completed. Based on limited data, integrated PET/CT showed greater accuracy, positive predictive value and negative predictive value than stand-alone PET for evaluating mediastinal lymph node response to induction therapy. Its higher specificity than sensitivity in nodal restaging may help stratify
6. PET for Mediastinal Restaging of Patients with Non Small Cell Lung Cancer after Induction Therapy
those patients who have a complete normalization in response to induction therapy. Potential benefits of PET or PET/CT include identification and targeting of abnormal mediastinal nodes for biopsy. Other potential benefits of PET and PET/CT are beyond the scope of this review, but include improved detection of extrathoracic metastases (advanced or stage IV disease), and also excluding locoregional progression during neoadjuvant treatment. The integration of PET and PET/ CT into a restaging algorithm incorporating EUS– FNA and EBUS–TBNA, cervical mediastinoscopy or video-assisted lymph node evaluation requires further study. Repeating mediastinoscopy after induction therapy is known to be technically challenging and potentially less accurate than pre-induction cervical mediastinoscopy, with sensitivities ranging from 30% to 70%.18 The data do not support the use of PET/CT alone to predict response to induction chemotherapy for mediastinal disease in NSCLC.
Recommendations In patients with IIIA (N2) NSCLC who undergo induction (neoadjuvant) therapy, PET or PET/CT is safe but is not sufficiently accurate to determine the response of N2 nodes to therapy (evidence quality low). We make a weak recommendation against the use of PET/CT for restaging the mediastinum prior to surgical resection after induction therapy for N2 NSCLC (recommendation grade 2B).
A Personal View of the Data In our practice, patients with stage IIIA (N2) NSCLC generally undergo restaging PET/CT within 2–4 weeks of the completion of induction chemoradiotherapy. We feel that PET/CT provides useful information on FDG uptake in mediastinal lymph nodes and throughout the body from the skull base to the mid-thigh. Additional restaging studies include a dedicated chest CT extending through the entire liver and brain MRI. Patients with evidence of a treatment response or stable disease are offered surgery if they are considered fit. Confirmed signs of progression on any of these studies preclude surgery in almost every instance.
65
If surgery is planned, repeat pulmonary function tests including diffusion capacity (DLCO) are also obtained because induction therapy can have a significant impact on pulmonary function. In patients with IIIA (N2) NSCLC who undergo induction therapy, PET is safe but is not sufficiently accurate to determine the response of N2 nodes to therapy (evidence quality low). We make a weak recommendation against the use of PET for restaging the mediastinum prior to surgery after induction therapy for N2 NSCLC (recommendation grade 2B).
References 1. Albain KS, Rusch VW, Crowley JJ et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA(N2) and IIIb non-smallcell lung-cancer - mature results of SouthwestOncology-Group Phase-II Study-8805. J Clin Oncol. 1995;13:1880–1892. 2. van Meerbeeck JP, Kramer GW, Van Schil PE et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst. 2007;99:442–450. 3. Thomas M, Rube C, Hoffknecht P et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III nonsmall-cell lung cancer. Lancet Oncol. 2008;9:636–648. 4. Albain KS, Swann RS, Rusch VW et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374: 379–386. 5. Akhurst T, Downey RJ, Ginsberg MS et al. An initial experience with FDG-PET in the imaging of residual disease after induction therapy for lung cancer. Ann Thorac Surg. 2002;73:259–266. 6. Cerfolio RJ, Bryant AS. When is it best to repeat a 2-fluoro-2-deoxy-d-glucose positron emission tomo graphy/computed tomography scan on patients with non-small cell lung cancer who have received neoadjuvant chemoradiotherapy? Ann Thorac Surg. 2007; 84:1092–1097. 7. Hellwig D, Graeter TP, Ukena D, Georg T, Kirsch C-M, Schafers H-J. Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma. J Thorac Cardiovasc Surg. 2004;128:892–899. 8. Port JL, Kent MS, Korst RJ, Keresztes R, Levin MA, Altorki NK. Positron emission tomography scanning poorly predicts response to preoperative chemotherapy in non-small cell lung cancer. Ann Thorac Surg. 2004;77:254–259.
66 9. Cerfolio RJ, Ojha B, Mukherjee S, Pask AH, Bass CS, Katholi CR. Positron emission tomography scanning with 2-fluoro-2-deoxy--glucose as a predictor of response of neoadjuvant treatment for non-small cell carcinoma. J Thorac Cardiovasc Surg. 2003;125:938–944. 10. Eschmann SM, Friedel G, Paulsen F et al. 18F-FDG PET for assessment of therapy response and pre operative re-evaluation after neoadjuvant radio- chemotherapy in stage III non-small cell lung cancer. Eur J Nucl Med Mol Imaging. 2007;34:463–471. 11. Hoekstra CJ, Stroobants SG, Smit EF et al. Prognostic relevance of response evaluation using [18F]2-fluoro-2-deoxy-d-glucose positron emission tomo graphy in patients with locally advanced non-small-cell lung cancer. J Clin Oncol. 2005;23:8362–8370. 12. Ohtsuka T, Nomori H, Ebihara A et al. FDG-PET imaging for lymph node staging and pathologic tumor response after neoadjuvant treatment of non-small cell lung cancer. Ann Thorac Cardiovasc Surg. 2006;12:89–94. 13. Pottgen C, Levegrun S, Theegarten D et al. Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-smallcell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res. 2006;12:97–106.
J.R. Nitzkorski et al. 14. Cerfolio RJ, Bryant AS, Ojha B. Restaging patients with N2 (stage IIIa) non-small cell lung cancer after neoadjuvant chemoradiotherapy: a prospective study. J Thorac Cardiovasc Surg. 2006;131: 1229–1235. 15. Mawlawi O, Pan T, Macapinlac HA. PET/CT imaging techniques, considerations, and artifacts. J Thorac Imaging. 2006;21:99–110. 16. Hautzel H, Muller-Gartner HW. Early changes in fluorine-18-FDG uptake during radiotherapy. J Nucl Med. 1997;38:1384–1386. 17. Ryu J-S, Choi NC, Fischman AJ, Lynch TJ, Mathisen DJ. FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology. Lung Cancer. 2002; 35:179–187. 18. De Leyn P, Stroobants S, De Wever W et al. Prospective comparative study of integrated positron emission tomography-computed tomography scan compared with remediastinoscopy in the assessment of residual mediastinal lymph node disease after induction chemotherapy for mediastinoscopy-proven stage IIIA-N2 Non-small-cell lung cancer: a Leuven Lung Cancer Group Study. J Clin Oncol. 2006;24: 3333–3339.
7
Optimal Initial Pathologic Mediastinal Staging of Lung Cancer: EUS, EBUS, Mediastinoscopy Varun Puri and Bryan F. Meyers
Introduction Patients with suspected lung cancer require tissue diagnosis and accurate staging to determine opti mal treatment. In the absence of distant meta stases, mediastinal lymph node staging is an important branch point in deciding therapy. The initial clinical evaluation of patients with sus pected lung cancer includes a contrast CT scan of the chest and upper abdomen that provides stag ing information about the T descriptor and usu ally leads to a presumptive clinical staging of the mediastinal lymph nodes. Increasingly, this clini cal CT assessment is being supplemented or replaced altogether in routine clinical practice with a CT-PET scan. The CT portion of the CT-PET examination is performed without intravenous contrast and is of lower resolution than a dedi cated CT scan. One often comes across the caveat describing the CT as “not of diagnostic quality” in the radiologic reports. For the purpose of this dis cussion, we will assume that the patient has known or suspected lung cancer and has undergone a CT scan and CT-PET examination. In most cases, it will be useful to have patho logical data about the mediastinal lymph nodes prior to performing the pulmonary resection. Pathologic mediastinal staging in advance of resection permits consideration of induction ther apy strategies, allows for re-consideration of resec tion in the first place, provides pathological assessment of N3 stations, and may inform the decision about lymph node dissection versus sam pling at the time of resection. Prior to resection or
invasive mediastinal staging, radiological staging with CT and PET scan provides valuable informa tion about the need for mediastinal invasive stag ing and offers guidance for the highest yield targets to be assessed in the mediastinum. The purpose of this chapter is to discuss the optimal initial pathologic mediastinal staging of a patient with lung cancer. The techniques avail able for pathologic staging of mediastinal lymph nodes include cervical mediastinoscopy, EUS-NA (endoscopic ultrasound needle aspirate), TBNA (transbronchial needle aspirate), EBUS-NA (endo bronchial ultrasound needle aspirate), VATS (video assisted thoracic surgery) and less common surgi cal techniques like anterior mediastinotomy (also called the Chamberlain procedure) and extended cervical mediastinoscopy. The chapter will discuss the recent literature and provide recommendations for different clini cal situations.
Review of Published Data On 8.1.2009, separate electronic literature database searches were carried out using Pubmed (http:// www.ncbi.nlm.nih.gov/pubmed/) with the terms: CT scan, PET scan, endobronchial ultrasound, endoscopic ultrasound, cervical mediastinoscopy, and extended cervical mediastinoscopy. The sec ond search term for each of these searches was “Lung cancer”. Generally, studies from 2004–2009 were considered for the evidence presented here.
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_7, © Springer-Verlag London Limited 2011
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Broadly, the patients being evaluated for known or possible lung cancer can be divided into those in whom the probability of mediastinal disease based upon CT and/or CT-PET is low (<10%), intermediate (10–20%), and high (>20%). The approach towards pathologic mediastinal assess ment differs accordingly.
Low Probability of Mediastinal Nodal Involvement on CT or CT-PET (Clinical N0) It is generally ac1cepted that computed tomogra phy (CT) has a sensitivity of 50–76% and specific ity of 55–86% for predicting metastatic involvement of mediastinal lymph nodes when they exceed 1 cm in the short axis.1–3 The false negative rate of CT-PET scan in staging the mediastinum of patients with known or suspected lung cancer var ies from 5% to 15%, but most studies report values in the 4–7% range.4–11 This number has great clini cal importance because of the trend to omit preresection invasive mediastinal lymph node assessment in patients with T1 tumors and nega tive mediastinal and hilar nodes on CT and CT-PET scans. It also becomes apparent that most of the false negative results are in lymph nodes less than 10 mm in size. In these studies, the false positive rates range from 0% to 53%.4–11 These pose a greater clinical concern than the false nega tives, as they may lead to inappropriate withhold ing of surgical resection. For that reason, positive clinical and radiological studies suggesting medi astinal metastases should lead to additional inva sive assessment of the mediastinum. We retrospectively reviewed a cohort of 248 patients deemed clinical stage I by computed tomog raphy and positron emission tomography.12 One hundred seventy-eight patients (72%) underwent mediastinoscopy before resection. A total of 14/248 patients (5.6%) with occult mediastinal lymph node metastases (missed by CT and PET) were identified at final pathology. That number might have been higher had a routine systematic node dissection been part of the lung resection operations. Decision analysis determined that routine mediastinoscopy in this patient cohort would have added 0.008 years of life expectancy at a cost of $250,989 per life-year gained, suggesting that patients with clinical stage I lung cancer staged by CT and PET benefit little from routine mediastinoscopy. The survival advantage it
V. Puri and B.F. Meyers
confers is very small and is dependent on the preva lence of N2 metastasis and the unproven superiority of induction therapy over adjuvant therapy. Similarly, DeFranchi et al.13 retrospectively reviewed 968 patients with pathologic T1 NSCLC and identi fied 59 (6.1%) patients who had pathologic N2 dis ease at post resection analysis. Mediastinoscopy found positive lymph nodes in only 3 of 16 patients (19%) in which it was performed. Thus, there is a low prevalence of occult medi astinal lymph node involvement in patients deter mined to have clinical stage I lung cancer with CT and CT-PET scan, and invasive staging, although safe, has a low sensitivity when the prevalence of N2 disease is so low (quality of evidence moder ate). When the pre-test risk of mediastinal nodal metastases is very low, such as in a small, periph eral T1N0 tumor or an indeterminate pulmonary nodule with a low SUV on CT-PET, we make a strong recommendation against formal patho logic mediastinal staging prior to resection (rec ommendation grade 1B). The mediastinum should, however, be staged by nodal dissection or sam pling at the time of resection, if the lesion turns out to be a primary lung cancer.
Intermediate Probability of Mediastinal Nodal Involvement Based on Imaging Within the subset of patients deemed to have resect able early stage disease, retrospective studies have identified certain risk factors that may predict a higher incidence of occult mediastinal LN involve ment,10,14,15 which are summarized in Table 7.1. The risk factors that are common in the outcomes of these studies are centrally located tumors, CT or PET positive N1 nodes, and high SUV on PET. The cen tral tumor factor stems from the perceived increased risk of mediastinal metastases from such a tumor, plus the concern that is difficult or inaccurate to use PET to assess nodes when a bright central tumor may obscure the ability to detect FDG avidity in the adjacent lymph nodes. Also, retrospective studies have shown that the false negative rate for PET in the mediastinal nodes in patients with central tumors or clinical N1 disease is high (24–83%).16–19 Interestingly, it has also been shown that a high SUVmax of the primary tumor may be associated with a higher incidence of mediastinal lymph node involvement.20
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7. Optimal Initial Pathologic Mediastinal Staging of Lung Cancer: EUS, EBUS, Mediastinoscopy Table 7.1. Predictors of occult N2 disease: factors to consider invasive staging in clinical stage I and II patients. Author
Year
Patients
Design
Predictors of occult N2 disease
Comment
Quality of evidence
Al Sarraf
2008
215
Retrospective
Most common location - subcarinal
Low
Melek14
2008
170
Retrospective
Paul15
2007
224
Retrospective
Centrally located tumors Right upper lobe tumors PET positive N1 nodes Adenocarcinoma histology Central tumors Positive N1 nodes Central tumors Larger clinical T size (esp. > 6cm) Adenocarcinoma Higher SUVmax of the primary tumor
10
When the pretest risk of mediastinal nodal metastases is intermediate, invasive pathological assessment of the nodes is safe and has a moder ate chance of providing additional staging infor mation (quality of evidence low). Examples of intermediate risk will include T2 tumors, central tumors, tumors with very high SUVmax on PET scanning, and tumors with clinically suspected N1 metastases. We make a strong recommendation that patients with an intermediate probability of mediastinal nodal involvement should undergo invasive mediastinal staging prior to resection if the subsequent care will be altered by the detec tion of mediastinal nodal metastases (recommen dation grade 1C).
High Probability of Mediastinal Nodal Involvement on CT or CT-PET (Clinical N2) Gould et al.21 performed a meta-analysis evaluat ing the radiologic diagnosis of mediastinal LN involvement and found that for CT, median sensi tivity and specificity were 61 and 79%, respectively. For FDG-PET, median sensitivity and specificity were 85 and 90%, respectively. De Langen et al.5 published a meta-analysis showing the probability of lymph node metastasis in mediastinal lymph nodes measuring 10–15 mm in the short axis on CT is 29%, and is about 66% when nodes are larger than 15 mm. They found that, in patients with lymph nodes measuring 10–15 mm in the short axis on CT, if PET was negative the probability of N2 disease was 5%. For patients with lymph nodes measuring ³16 mm in the short axis on CT and with a negative FDG-PET result, the probability of
Low
Low
N2 disease was 21%. Although the evidence from these studies is indirect, it indicates a significant false positive rate of 13–14% for mediastinal nodes even in the face of both CT and CT-PET being positive, and higher false positive rates for either study alone. Similarly, they indicate a false nega tive rate of 13–21% for PET when nodes are enlarged on CT scan. These data suggest that patients with either CT scan evidence of node enlargement or PET posi tive lymph nodes have a higher prevalence of N2 disease, and mediastinal sampling is safe and may be worthwhile even when the two studies are dis cordant, i.e. PET positive and CT negative or vice versa (quality of evidence moderate). Many patients in this scenario are not N2 positive, so invasive staging must be done to rule out the high rate of false positives. We make a strong recom mendation that mediastinal lymph node patho logic staging should be performed if either the CT or the CT-PET indicates mediastinal node involve ment ( recommendation grade 1B).
Mediastinal Sampling Techniques Cervical Mediastinoscopy (CM) Cervical mediastinoscopy is performed via a small suprasternal incision and can sample sta tion 2R, 2L, 4R, 4L and 7 lymph nodes. A more radical version of the procedure is the so-called extended cervical mediastinoscopy, in which the mediastinoscope is advanced in between the innominate and left carotid arteries into the pre vascular compartment to sample station 5 and 6
V. Puri and B.F. Meyers
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lymph nodes. The extended procedure is uncom monly performed and there are no publications about it in the last 5 years. A prior study of 106 patients showed that sensitivity was 81.2%, spec ificity 100%, accuracy 93.3%, positive predictive value 100%, and negative predictive value 91%.22 The technical difficulty of the procedure, the absence of widespread use, and the availability of the Chamberlain procedure and VATS to assess station 5 and 6 lymph nodes make this an increasingly less appealing option. Another recently described modification of the transcer vical technique is the transcervical extended mediastinal lymphadenectomy (TEMLA).23 In TEMLA, mediastinal lymph nodes from stations 1 through 8 are formally dissected transcervi cally using a 6 cm incision and videoscopic visu alization. In an RCT comparing 21 patients undergoing TEMLA to 21 patients undergoing standard cervical mediastinoscopy, sensitivity of standard mediastinoscopy was 37.5% and its negative predictive value was 66.7%, compared to 100% and 100% in the TEMLA group.24 The data from the randomized trial are robust, but the procedure is not widely practiced and is technically arduous. Results from other centers need to be reported prior to recommending TEMLA for general use. Cervical mediastinoscopy has been regarded as the gold standard in pathologic staging of the mediastinum and can be performed with low morbidity (<2%) and very low mortality (0.08%).25 The sensitivity of the procedure ranges from 58% to 97%, while the false negative rate is around 10–12% (range 6–41%; Table 7.2).26–31 The sensi tivity is associated with the prevalence of medi astinal nodes, and is thus lower (around 45%) in patients with peripheral T1 lesions.12,26 Because
these patients also have a low prevalence of N2 disease the FN rate is also low at 5–9%. The addi tion of videoscopic technology can further improve the diagnostic yield.27,28 The false nega tive rate of CM also is related to N2 disease in loca tions not accessible by mediastinoscopy17,23 and to operator technique and diligence. In a series by Cerfolio et al., the posterior mediastinal nodes were the site of unsuspected N2 disease in 21/28 (75%) of patients with false negative mediastinos copy.17 While it is possible that use of one modality of mediastinal staging may occasionally miss N2 disease, especially in the intermediate risk group, the impact is not sufficiently great to recommend the routine use of two modalities of mediastinal staging.
Endobronchial Ultrasound Guided Needle Aspiration (EBUS-NA) EBUS-NA can sample lymph nodes in stations 2, 4, 7 and 10. The initial iteration of EBUS involved radial EBUS technology and “blind” needle aspi rate of the area where the node was seen. EBUS now offers real-time ultrasound-guided sampling in which the needle for node aspiration can be seen with ultrasound throughout the process. Only studies that utilize the real-time technology have been considered for this review. Blind TBNA with out any ultrasound assessment will not be reviewed. Table 7.3 summarizes the results from recent stud ies looking at the diagnostic yield of EBUS-NA in patients with known or suspected lung cancer.32–36 With one exception, these studies have looked at patients with a high pre-test probability of N2 dis ease by selecting enlarged or FDG-avid lymph nodes for sampling. The sensitivity is in the 95% range with a false positive rate of zero. The false
Table 7.2. Recent studies of the diagnostic yield of cervical mediastinoscopy for N2 disease in lung cancer.
Author Choi Kimura27 Vennisac28) Detterbeck29 Tournoy30 Ernst31 26
Year
Study
Patients
Prevalence of N2 mediastinal nodal metastases
2003 2003 2003 2007 2008 2008
Retrospective Retrospective Retrospective Review RCT: Med ± EUS RCT: Med vs EUS
291 125 154 6505 27 120
15 36 71 39 58 62
Sensitivity (%)
Specificity (%)
58 85 97 78 73 68
100 100 100 100 100 100
RCT randomized controlled trial; Med mediastinoscopy; EUS endoscopic ultrasonography; Video videomediastinoscopy
Comments Video Video
Quality of evidence Low Low Low Low Moderate Moderate
71
7. Optimal Initial Pathologic Mediastinal Staging of Lung Cancer: EUS, EBUS, Mediastinoscopy Table 7.3. Recent studies of the diagnostic yield of EBUS-NA for N2 disease in lung cancer. Author
Year
Study
Patients
Prevalence of cancer in mediastinal nodes (%)
Sensitivity (%)
Specificity (%)
Comment
Quality of evidence
Herth32
2006
Observational
502
98
94
100
Vincent33
2008
Retrospective
152
74
99
100
Herth34
2008
Observational
100
10
89
100
Bauwens35 Yasufuku36
2008 2005
Retrospective Observational
103 108
58 69
95 95
100 100
Patients with enlarged nodes only 80% LN > 1 cm Limited F/U, thus FN rate not reliable Radiographically negative mediastinum PET positive mediastinal LN LN > 1 cm
Moderate Low Moderate Low Moderate
LN lymph nodes; PET positron emission tomography; FN false negative
negative rate is in the 10% range with the excep tion of a study by Herth.34 This particular paper enrolled 100 clinical stage I patients prospectively and demonstrated excellent results with a sensitiv ity of 89% and a false negative rate of 1%.
the false negative rate was 21% and the prevalence of N2 pathologic disease was 33%.40 EUS-NA has the added potential advantage of assessing direct mediastinal involvement (T4 disease), left adrenal metastases, liver metastases, and the celiac lymph nodes.
Endoscopic Ultrasound Guided Needle Aspirate (EUS-NA) EUS-NA can sample station 5, 7, 8 and 9 lymph nodes and some studies have described the sam pling of station 2 and 4 lymph nodes also. Recent studies evaluating the role of EUS-NA in staging of NSCLC are summarized in Table 7.4.30,37–43 Like the EBUS studies discussed previously, most of these studies look at patients with mediastinal lymph nodes suspicious on CT and/or PET scans. The sensitivity of this technique ranges from 70% to 90% and, with the exception of one study41 early in the EUS experience, the remaining studies have a false negative rate of 10–20% (Table 7.4). In a cohort of patients with normal sized lymph nodes,
Comparative Studies Recent studies have compared the three com monly employed invasive mediastinal sampling techniques: cervical mediastinoscopy, EBUS-NA and EUS-NA. Ernst et al.31 enrolled 66 patients with enlarged lymph nodes in stations 2, 4 or 7 in a prospective observational trial with patients undergoing EBUS-NA and mediastinoscopy. The sensitivity, specificity, and negative predictive value of endobronchial ultrasound were 87, 100, and 78%, respectively. The sensitivity, specificity, and negative predictive value of mediastinoscopy were 68, 100, and 59%, respectively.
Table 7.4. Recent studies of the diagnostic yield of EUS-NA for N2 disease in lung cancer. Year
Study
Patients
Prevalence of cancer in mediastinal nodes (%)
Sensitivity (%)
Specificity (%)
Comment
Quality of evidence
Annema37
2005
Observational
93
35
76
97
Moderate
Caddy38 Eloubeidi39 LeBlanc40
2005 2005 2005
Retrospective Observational Observational
52 104 76
67 38 33
91 93 45
100 100 100
Kramer41
2004
Observational
81
85
72
100
Tournoy30 Larsen42
2008 2005
RCT RCT
19 50
79 57
93 78
100 100
LN enlarged in 50% patients Mean LN size 23 mm Suspicious LN on CT or PET No mediastinal adenopathy on CT Radiographically suspected N2 disease Suspected N2/N3 Decreases futile thoracotomy
Sawhney43
2007
Retrospective
44
NA
NA
NA
Author
LN lymph nodes; CT computed tomography; PET positron emission tomography; NA not available
Low Low Low Moderate Moderate Moderate Low
V. Puri and B.F. Meyers
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Tournoy et al.30 randomized 40 patients with radiologically suspected N2 or N3 disease to EUS-NA or surgical staging. In that trial, patients with no definite diagnosis after EUS-NA crossed over and also underwent surgical staging. EUS-NA provided a diagnosis in 68% of the patients and thus precluded surgical staging in that fraction. Larsen et al.,42 in a randomized trial involving 104 patients (80% stage III/IV by CT, PET performed in 35%), compared routine EUS-NA versus selec tive EUS-NA. They found that routine EUS-FNA diminished the rate of futile thoracotomy. Annema et al.37 noted that the combination of EUS-FNA and mediastinoscopy identified more patients with tumor invasion or lymph node metastases (36%) than either mediastinoscopy alone (20%) or EUS-FNA alone (28%). This indicated that 16% of potentially futile thoracotomies could have been avoided by using EUS-FNA in addition to mediastinoscopy. Surprisingly, 2% of the EUSFNA findings were deemed false-positive. Half of these patients had enlarged lymph nodes on CT scan and PET scan was not performed. In general, these studies enrolled patients from a heteroge neous population with varying levels of suspicion for N2 disease. Wallace et al.44 performed TBNA, EUS-NA and EBUS-NA on 138 patients in a prospective study. In patients with a radiographically positive medi astinum (i.e. N2 suspected on CT or PET), the false negative rate of EUS and EBUS combined was zero, and in those with clinical N0 disease it was 6%. In general, EBUS and EUS-NA appear to be as effective as mediastinoscopy, and combinations of more than one modality increase the diagnostic yield. EBUS and EUS-NA can be performed with minimal risk and mediastinoscopy has a low risk of complications. A recent decision analysis model shows that the cost of EUS-NA, EBUS and medias tinoscopy is comparable at between $18,000 and $20,000.45
Anterior Mediastinotomy Left upper lobe tumors have a predilection for lymphatic spread to station 5 and 6 lymph nodes. Anterior mediastinotomy, or the Chamberlain procedure, provides access to sample both these areas. A recent retrospective analysis by Nechala et al looked at 117 patients with left upper
lobe tumors who did not have enlarged station 5 or 6 lymph nodes. Patients underwent cervical mediastinoscopy and anterior mediastinotomy. The anterior mediastinotomy detected metastases in 5 of 117 patients (4%) and the false negative rate was 4/117 (3%).46 Detterbeck et al.29 summarized prior studies (624 patients total) in a review and found a false negative rate of 0–20%.
VATS Nodal Assessment Video assisted thoracic surgery can be utilized to assess N2 disease. With the recent popularity of VATS resection for lung cancer and the ensuing multitude of publications, it is difficult to accu rately assess the current sensitivity and negative predictive value of VATS for N2 disease. In an older study, Sebastian-Quetglas et al.47 noted a false neg ative rate of 11% in patients who had been deemed N0 by CT scan. In the setting of a planned VATS lobectomy with intermediate risk, one may stage the mediastinum with a frozen section evaluation of mediastinal and hilar nodes prior to com mitting to resection, as opposed to performing a separate mediastinal staging. All techniques for sampling mediastinal lymph nodes provide similar yield and are safe (quality of evidence moderate). The choice of modality for assessing the mediastinal lymph nodes in the intermediate probability situation depends on the skills and the preferences of the practitioner and the subsequent plans for the patient in the event of positive and negative results. We make no specific recommendation for one modality over another - the choice among EBUS, EUS and cervical mediastinoscopy is a personal and local decision. In the setting of a planned VATS lobec tomy with intermediate risk for mediastinal metastases, one may assess lymph nodes with a frozen section evaluation of mediastinal and hilar nodes prior to committing to resection, as opposed to a separate mediastinal staging. In a patient with high likelihood of mediastinal metastases, all modalities appear to have compa rable and high sensitivity and accuracy, and are safe (quality of evidence moderate). We make a strong recommendation for EUS or EBUS as the simplest, safest and most economical choice to confirm the presence of mediastinal metastases in this setting (recommendation grade 1B). If
7. Optimal Initial Pathologic Mediastinal Staging of Lung Cancer: EUS, EBUS, Mediastinoscopy
EBUS or EUS fails to confirm metastases in a patient with clinical N2 disease, strong consider ation for a tissue biopsy via mediastinoscopy or VATS is advised unless the institutional track record demonstrates an extraordinarily low rate of false negative FNAs.
The Authors’ Approach In general, local algorithms for any clinical prob lem follow the available expertise. In our institu tion, the thoracic surgical service performs the surgical approaches to mediastinal lymph node assessment as well as EBUS-NA using a linear ultrasound system. We have a closely allied inter ventional pulmonologist who also performs EBUS in lung cancer patients. All our patients undergo CT scans and the vast majority of patients undergo CT-PET scans. We perform invasive mediastinal staging in patients with enlarged (>1 cm short axis diameter) medi astinal lymph nodes and those with FDG avid mediastinal lymph nodes. We also perform inva sive mediastinal staging if N1 nodes are FDG avid, primary tumors have high SUVmax, or tumors are centrally located. For the remaining patients, the decision is individualized. Larger T2 lesions, e.g. a 5.5 cm tumor, warrant invasive stag ing while a 2.5 cm lesion abutting the visceral pleura will not. In general, all T3 tumor patients (chest wall invasion, more than one nodule in the same lobe, etc.) undergo invasive staging. In an ideal situation, one would have a video-mediasti noscopy setup and have rapid onsite evaluation for EBUS-NA specimens. Our procedure of choice depends upon the pretest probability of N2 dis ease and the location of the suspected lymph nodes. For radiographically suspicious nodes in station 2, 4 or 7 locations, we perform an EBUS-NA as our procedure of choice. For suspicious nodes in station 5 or 6 locations, we perform a Chamberlain procedure or, preferably, a VATS evaluation. When assessing suspicious nodes in stations 8 or 9, we recommend an initial EUS-NA, or a VATS if resection will follow immediately. For patients undergoing invasive assessment for higher risk clinical stage I disease (central tumor, etc.) we perform a cervical mediastinoscopy and,
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if negative, proceed to resection under the same anesthetic. The decision to schedule the medi astinal assessment at the same time as the pulmo nary resection or as a stand-alone procedure prior to the planned resection depends on local factors such as OR availability, frozen section availability and accuracy, probability of a positive result, and convenience to the patient and the surgeon.
In patients determined to have clinical stage I lung cancer with CT and CT-PET scan, invasive staging, although safe, has low sensitivity (qual ity of evidence moderate). We make a strong recommendation against formal pathologic mediastinal staging prior to resection in patients with clinical stage I lung cancer (recommendation grade 1B).
When the pretest risk of mediastinal nodal metastases is intermediate, invasive pathologi cal assessment of the nodes is safe and has a moderate chance of providing additional stag ing information (quality of evidence low). We make a strong recommendation that patients with an intermediate probability of mediasti nal nodal involvement should undergo inva sive mediastinal staging prior to resection (recommendation grade 1C).
In patients with either CT or PET evidence of abnormal mediastinal lymph nodes, mediasti nal sampling is safe and is worthwhile (quality of evidence moderate). We make a strong rec ommendation that mediastinal lymph node pathologic staging should be performed if either the CT or the CT-PET indicates medi astinal node involvement (recommendation grade 1B).
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All techniques for sampling mediastinal lymph nodes provide similar yield and are safe in patients with an intermediate chance of medi astinal nodal involvement (quality of evidence moderate). We make no specific recommenda tion for one modality over another – the choice among EBUS, EUS and cervical mediastinos copy is a personal and local decision.
In a patient with high likelihood of mediasti nal metastases, all sampling modalities appear to have comparable and high sensitivity and accuracy, and are safe (quality of evidence moderate). We make a strong recommendation for EUS or EBUS as the simplest, safest, and most economical choice to confirm the pres ence of mediastinal metastases in this setting (recommendation grade 1B).
References 1. Toloza E, Harpole DL, Mc Crory D. Non-invasive staging of non-small cell lung cancer: a review of the current evidence. Chest. 2003;123:137–147s. 2. Pieterman RM, van Putten JW, Meuzelaar JJ et al. Preoperative staging of non-small-cell lung cancer with positron emission tomography. N Engl J Med. 2000;343:254–261. 3. Yasufuku K, Nakajima T, Motoori K et al. Comparison of endobronchial ultrasound, positron emission tomography, and ct for lymph node staging of lung cancer. Chest. 2006;130:710–718. 4. Billé A, Pelosi E, Skanjeti A et al. Preoperative intrathoracic lymph node staging in patients with non-small-cell lung cancer: accuracy of integrated positron emission tomography and computed tomography. Eur J Cardiothorac Surg. 2009;36: 440–445. 5. de Langen AJ, Raijmakers P, Riphagen I, Paul MA, Hoekstra OS. The size of mediastinal lymph nodes and its relation with metastatic involvement: a metaanalysis. Eur J Cardiothorac Surg. 2006;29:26–29. 6. Cerfolio RJ, Bryant AS, Ojha B, Eloubeidi M. Improving the inaccuracies of clinical staging of patients with NSCLC: a prospective trial. Ann Thorac Surg. 2005;80:1207–1214. 7. Kim BT, Lee KS, Shim SS et al. Stage T1 non-small cell lung cancer: preoperative mediastinal nodal staging with integrated FDG PET/CT--a prospective study. Radiology. 2006;241:501–509.
V. Puri and B.F. Meyers 8. Yi CA, Lee KS, Kim BT et al. Efficacy of helical dynamic CT versus integrated PET/CT for detection of mediastinal nodal metastasis in non-small cell lung cancer. AJR. 2007;188:318–325. 9. Lee BE, von Haag D, Lown T et al. Advances in posi tron emission tomography technology have increased the need for surgical staging in non-small cell lung cancer. J Thorac Cardiovasc Surg. 2007;133:746–752. 10. Melek H, Gunluoglu MZ, Demir A, Akin H, Olcmen A, Dincer SI. Role of positron emission tomography in mediastinal lymphatic staging of non-small cell lung cancer. Eur J Cardiothorac Surg. 2008;33: 294–299. 11. Perigaud C, Bridji B, Roussel JC et al. Prospective preoperative mediastinal lymph node staging by integrated positron emission tomography-comput erised tomography in patients with non-small-cell lung cancer. Eur J Cardiothorac Surg. 2009;36: 731–736. 12. Meyers BF, Haddad F, Siege B et al. Cost-effectiveness of routine mediastinoscopy in computed tomogra phy– and positron emission tomography–screened patients with stage I lung cancer. J Thorac Cardiovasc Surg. 2006;131:822–829. 13. Defranchi SA, Cassivi SD, Nichols FC et al. N2 dis ease in T1 non-small cell lung cancer. Ann Thorac Surg. 2009;88:924–929. 14. Al-Sarraf N, Aziz R, Gately K et al. Pattern and predic tors of occult mediastinal lymph node involvement in non-small cell lung cancer patients with negative mediastinal uptake on positron emission tomogra phy. Eur J Cardiothorac Surg. 2008;33:104–109. 15. Lee PC, Port JL, Korst RJ et al. Risk factors for occult mediastinal metastases in clinical stage I non-small cell lung cancer. Ann Thorac Surg. 2007;84:177–181. 16. Serra M, Gonzalez S, Cicera L et al. Routine positron tomography (PET) and selective mediastinoscopy is as good as routine mediastinoscopy to rule out N2 disease in non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol. 2006;24:371s. 17. Cerfolio RJ, Bryant AS, Ojha B et al. Improving the inaccuracies of clinical staging of patients with NSCLC: a prospective trial. Ann Thorac Surg. 2005;80:1207–1214. 18. Verhagen AFT, Bootsma GP, Tjan-Heijnen VC et al. FDG-PET in staging lung cancer: how does it change the algorithm? Lung Cancer. 2004;44:175–181. 19. Pozo-Rodriguez F, Martin de Nicolas JL, SanchezNistal MA et al. Accuracy of helical computed tomography and [18F] fluorodeoxyglucose positron emission tomography for identifying lymph node mediastinal metastases in potentially resectable non-small-cell lung cancer. J Clin Oncol. 2005;23:8348–8356. 20. Cerfolio RJ, Bryant AS, Ohja B, Bartolucci AA. The maximum standardized uptake values on positron emission tomography of a non-small cell lung can cer predict stage, recurrence, and survival. J Thorac Cardiovasc Surg. 2005;130:151–159.
7. Optimal Initial Pathologic Mediastinal Staging of Lung Cancer: EUS, EBUS, Mediastinoscopy 21. Gould MK, Kuschner WG, Rydzak CE et al. Test per formance of positron emission tomography and computed tomography for mediastinal staging in patients with non–small-cell lung cancer. Ann Intern Med. 2003;139:879–892. 22. Freixinet GJ, García PG, de Castro FR et al. Extended cervical mediastinoscopy in the staging of bronchogenic carcinoma. Ann Thorac Surg. 2000;70: 1641–1643. 23. Kunzdzał J, Zielinski M, Papla B et al. Transcervical extended mediastinal lymphadenectomy— the new operative technique and early results in lung cancer staging. Eur J Cardiothorac Surg. 2005;27:384. 24. Kunzdzał J, Zielinski M, Papla B et al. The transcer vical extended mediastinal lymphadenectomy ver sus cervical mediastinoscopy in non-small cell lung cancer staging. Eur J Cardiothorac Surg. 2007;31: 88–94. 25. Passlick B. Intial surgical staging of lung cancer. Lung Cancer. 2003;4:S21–/5. 26. Choi YS, Shim YM, Kim J, Kim K. Mediastinoscopy in patients with clinical stage I non-small cell lung can cer. Ann Thorac Surg. 2003;75:364–366. 27. Kimura H, Iwai N, Ando S et al. A prospective study of indications for mediastinoscopy in lung cancer with CT findings, tumor size, and tumor markers. Ann Thorac Surg. 2003;75:1734–1739. 28. Venissac N, Alifano M, Mouroux J et al. Videoassisted mediastinoscopy: experience from 240 con secutive cases. Ann Thorac Surg. 2003;76:208–212. 29. Detterbeck FC, Jantz MA, Wallace M, Vansteenkiste J, Silvestri GA. Invasive mediastinal staging of lung cancer. Chest. 2007;132:202S–220S. 30. Tournoy KG, DeRyck F, Vanwalleghem LR et al. Endoscopic ultrasound reduces surgical mediastinal staging in lung cancer. Am J Respir Crit Care Med. 2008:177:531–535. 31. Herth FJF, Eberhardt R, Krasnik M, Ernst A. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologi cally and positron emission tomography-normal mediastinum in patients with lung cancer. J Thorac Oncol. 2008;3:577–582. 32. Herth FJF, Eberhardt R, Vilmann P, Krasnik M, Ernst A. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling medi astinal lymph nodes. Thorax. 2006;61:795–798. 33. Vincent BD, El-Bayoumi E, Hoffman B et al. Realtime endobronchial ultrasound-guided transbron chial lymph node aspiration. Ann Thorac Surg. 2008;85:224–230. 34. Herth FJF, Eberhardt R, Krasnik M, Ernst A. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologi cally and positron emission tomography-normal
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mediastinum in patients with lung cancer. Chest. 2008;133:887–891. 35. Bauwens O, Dusart M, Pierard P et al. Endobronchial ultrasound and value of PET for prediction of path ological results of mediastinal hot spots in lung can cer patients. Lung Cancer. 2008;61:356–361. 36. Yasufuku K, Chiyo M, Koh E et al. Endobronchial ultrasound guided transbronchial needle aspiration for staging of lung cancer. Lung Cancer. 2005;50: 347–354. 37. Annema JT, Versteegh MI, Veseliç M et al. Endoscopic ultrasound added to mediastinoscopy for preopera tive staging of patients with lung cancer. JAMA. 2005;294:931–936. 38. Caddy G, Conron M, Wright G, Desmond P, Hart D, Chen RY. The accuracy of EUS-FNA in assessing mediastinal lymphadenopathy and staging patients with NSCLC. Eur Respir J. 2005;25:410–415. 39. Eloubeidi MA, Cerfolio RJ, Chen VK, Desmond R, Syed S, Ojha B. Endoscopic ultrasound-guided fine needle aspiration of mediastinal lymph node in patients with suspected lung cancer after positron emission tomography and computed tomography scans. Ann Thorac Surg. 2005;79:263–268. 40. LeBlanc JK, Devereaux BM, Imperiale TF et al. Endoscopic ultrasound in non-small cell lung can cer and negative mediastinum on computed tomog raphy. Am J Respir Crit Care Med. 2005;171:177–182. 41. Kramer H, van Putten JW, Post WJ et al. Oesophageal endoscopic ultrasound with fine needle aspiration improves and simplifies the staging of lung cancer. Thorax. 2004;59:596–601. 42. Larsen SS, Vilmann P, Krasnik M et al. Endoscopic ultrasound guided biopsy versus mediastinoscopy for analysis of paratracheal and subcarinal lymph nodes in lung cancer staging. Lung Cancer. 2005;48:85–92. 43. Sawhney MS, Bakman Y, Holmstrom AM, Nelson DB, Lederle FA, Kelly RF. Impact of preoperative endo scopic ultrasound on non-small cell lung cancer staging. Chest. 2007;132:916–921. 44. Wallace MB, Pascual JMS, Raimondo M et al. Minimally invasive endoscopic staging of suspected lung cancer. JAMA. 2008;299:540–546. 45. Harewood GC, Pascual J, Raimondo M et al. Lung Cancer - LUNG-3347. In print. 46. Nechala P, Graham AJ, McFadden SD, Grondin SC, Gelfand G. Retrospective analysis of the clinical per formance of anterior mediastinotomy. Ann Thorac Surg. 2006;82:2004–2009. 47. Sebastian-Quetglas F, Molins L, Baldo X et al. Clinical value of video-assisted thoracoscopy for preopera tive staging of non-small cell lung cancer: a prospec tive study of 105 patients. Lung Cancer. 2003;42: 297–301.
8
VATS vs. Open Lobectomy for Early Stage Non-Small Cell Lung Cancer Shawn S. Groth and Michael A. Maddaus
Lobectomy and Complete Mediastinal Lymphadenectomy: The Gold Standard for Early Stage NSCLC Of the estimated 219,440 people in the United States who will be diagnosed with lung cancer in 2009,1 about 13% (32,900 people) will have early stage (American Joint Committee on Cancer [AJCC] stage I and II) non-small cell lung cancer (NSCLC).2,3 Patients with untreated stage I NSCLC, albeit an early stage neoplasm, have a 5-year survival rate of less than 5%.4 – 6 Radiation and chemotherapy (alone or in combination) offer little survival benefit. Only patients who undergo complete surgical resection are afforded a significant chance at long-term survival.7–9 Because early stage tumors are confined within a focus of lung parenchyma, the goal of pulmonary resection for early stage NSCLC is to obtain local control of the tumor, thereby preventing future tumor dissemination. The current standard of care for treating early stage NSCLC patients with sufficient cardiopulmonary reserve is a lobectomy10,11 and complete mediastinal lymph node dissection.12,13 In the early 1990s, video-assisted thoracoscopic surgery (VATS) lobectomy emerged as a safe, feasible option for treating early stage NSCLC.14,15 A variety of definitions for “VATS lobectomy” have been used in the literature, making interpretation of the results of some studies difficult. Such definitions include: (1) video-assisted mini-thoracotomies (with rib spreading),16 (2) video-assisted lobectomy with en masse stapling of the hilar vessels and bronchus,17 and (3) video-assisted anatomic lobectomy
with individual ligation of the lobar vessels and bronchus using 2 or 3 port sites and a small (£6 cm) access incision without rib-spreading.18 Currently, most minimally invasive thoracic surgeons consider VATS lobectomy to be the latter definition. Attempts at performing well-powered, multiinstitutional, randomized clinical trials to compare outcomes after open and VATS lobectomy for early stage NSCLC were impaired by poor accrual rates. Potential reasons for poor accrual included: (1) a lag in the dissemination of the technical skills necessary to perform VATS lobectomy among practicing surgeons (many of whom did not receive instruction in the VATS approach as part of their fellowship training), (2) poor compliance with the randomization schedule by surgeons who had a preference for a particular approach, and (3) unwillingness of patients to be randomized. A prospective multi-institutional registry study comparing outcomes after VATS and open lobectomy (Cancer and Leukemia Group B (CALGB) 14501) failed to open due to funding limitations. Consequently, the data in the literature is limited to two small, randomized trials, a number of single institution case-series and cohort studies, one prospective cooperative group feasibility study (CALGB 39802), and two systematic reviews and meta-analyses.
Literature Search To identify relevant articles for inclusion in this evidence-based review, we used the MEDLINE database. We began our search by querying for
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_8, © Springer-Verlag London Limited 2011
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non-small-cell lung carcinoma (National Library of Medicine [NLM] Medical Subject Heading) and non-small-cell lung cancer (mapping term). We limited our review to articles written in English, involving humans, and published from January 1, 1992 (the year the first VATS lobectomy was reported), through October 31, 2009. Of the articles we retrieved, we only included those containing pneumonectomy as a NLM Medical Subject Heading or lobectomy as a mapping term. The following NLM Medical Subject Headings were used to limit our search: quality of life, morbidity, mortality, survival, postoperative complications, length of stay, radiotherapy, chemotherapy, drug therapy, lymph node excision, and immunology. References from the articles we retrieved from our MEDLINE query were also examined for inclusion in our review.
Perioperative Outcomes Intraoperative Outcomes There is significant heterogeneity of the data in the literature on intraoperative outcomes; some studies demonstrate better intraoperative outcomes for VATS patients, some favor thoracotomy patients, and other show no significant difference between the two approaches.19 A recent systematic review of the literature by Yan et al. (which included 1,391 VATS patients and 1,250 thoracotomy patients with early stage NSCLC) indicates that the operating room time for VATS lobectomy (median 3.7 h; range 1.3–4.8) and open lobectomy (median 3.6 h; range 1.4–4.9) for early stage NSCLC are similar.19 A prospective, single-arm, cooperative group, feasibility study (CALGB 39802), which included a number of experienced VATS surgeons who underwent rigorous credentialing, indicates that VATS can be performed with a median operating room time of 130 min (range 47–428 min) and with a low rate of major complications (7.4%). The systematic review by Yan et al. also indicates that the estimated blood loss during VATS lobectomy (median 146 mL; range 72–253) is comparable to (or possibly lower than) open lobectomy (median 235 mL; range 82–443).19
Based on data from large series, the conversion rate from VATS to thoracotomy is low (1–18%).18,20–22 Published reasons for conver sion include anatomy, difficulty evaluating the tumor, inadequate visualization, dense lymphadenopathy, adhesions, bleeding, failed lung isolation, obesity, and non-diagnostic pathology findings.18,21,22 These data (evidence quality low) indicate that VATS lobectomy: (1) is feasible, (2) does not expose the patient to an unnecessary duration of general anesthesia, (3) has a comparable risk of intraoperative hemorrhage as open lobectomy, and (4) can be performed with an acceptable conversion rate.
Morbidity Though many intra- and extrathoracic operations are technically feasible through a minimally invasive approach, their efficacy should be evaluated (in part) by whether avoiding the necessary incision for an open approach (i.e., a thoracotomy) reduces perioperative morbidity and mortality without compromising the oncological principles of the open approach. Thoracotomies are invasive procedures that are associated with significant morbidity (overall complication rate 5–60%).23–26 As such, one of the benefits of VATS lobectomy is a lower rate of postoperative morbidity (evidence quality moderate).
Overall Complication Rate A recent systematic review and meta-analysis of the literature by Whitson et al. compared outcomes after VATS and open lobectomy for early stage NSCLC patients.27 Patient characteristics (age and gender) and tumor characteristics (histology, tumor size, and stage) were not significantly different between the two groups. Based on data from 2,149 VATS patients (12 studies) and 981 thoracotomy patients (9 studies), the overall complication rate after VATS lobectomy (16.4%; 95% confidence interval [CI] 12.2–20.6%) was significantly lower (p = 0.018) than after open lobectomy (31.2%; 95% CI 19.7–42.8%). The data from the individual studies in that meta-analysis are listed in Table 8.1.
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8. VATS vs. Open Lobectomy for Early Stage Non-Small Cell Lung Cancer Table 8.1. Overall complication rate: VATS vs. open lobectomy. Lead author Thoracotomy Harpole26 Kirby84 Morandi85 Sugi86 Aoki87 Muraoka88 Okada24 Shigemura89 Whitson25 VATS Kirby15 Kirby84 Kaseda90 Yim91 Solaini92 McKenna93 McVay94 Muraoka88 Onaitis20 Shigemura89 Whitson25
Publication year
Number of patients
Complication rate (%)
Evidence quality
1995 1995 1997 1998 2003 2006 2006 2006 2007
193 31 144 115 49 42 262 55 88
28 51.6 50 13.4 40.8 47.6 7.3 5.1 58
low Moderate Low High Very low Low Moderate Low Low
1993 1995 1998 1998 2001 2005 2005 2006 2006 2006 2007
15 25 62 203 108 1015 153 43 416 50 59
8.7 24 6.5 22 11.6 15.3 18 25.6 23.2 6 34.2
Very low Moderate Low Low Low Moderate Low Low Low Low Low
VATS Video-assisted thoracoscopic surgery
Operative Mortality A number of recent observational studies18,28,29 and one meta-analysis19 found that the operative mortality rates after VATS lobectomy (0.6–2.7%) and open lobectomy (0% to 2.6%)30–35 are similar (RR 0.49; 95% CI 0.06% to 3.76%; p = 0.49).19
Respiratory Complications Due in part to pain, prior tobacco use, and poor pulmonary toilet, pneumonia is a significant source of morbidity after open lobectomy. The meta-analysis by Whitson et al. compared the rate of postoperative pneumonia after VATS lobectomy (based on data from 1,095 patients from seven studies) and open lobectomy (based on data from 245 patients from three studies). Though the VATS patients had a lower rate of postoperative pneumonia (2.7%; 95% CI 0.9–4.6%) than thoracotomy patients (6.0%; 95% CI 0.0–13.2%), the difference did not reach statistical significance (p = 0.33).27 The meta-analysis by Yan et al. also found a nonsignificant (p = 0.09) lower incidence of pneumonia after VATS lobectomy (RR 0.34; 95% CI 0.10–1.16).19
Men36 and older patients37,38 have a significant increased risk for postoperative pneumonia. Though the VATS and thoracotomy patients in the meta-analysis by Whitson et al. had a similar age and gender distribution, the distribution of other risk factors for postoperative pneumonia (preoperative pulmonary function38,39 and use of neoadjuvant chemotherapy38,40) were not assessed. Consequently, the results of that study may be confounded by covariates that were not assessed. A single institution retrospective study used propensity score-based matching based on several risk factors to compare 284 open and 284 VATS lobectomy patients.28 They found that the rate of pneumonia was significantly lower (p = 0.05) among VATS patients (5%) than thoracotomy patients (10%).28 One potential reason for a lower incidence of pneumonia among VATS patients may be improved pulmonary toilet. Indeed, the authors also noted that a significantly (p = 0.006) lower rate of postoperative atelectasis was found among VATS (5%) than thoracotomy patients (12%). Of note, that study also found that the rate of bronchopleural fistula (£1%) and empyema (<1%) were not significantly different between the
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groups,28 suggesting that the technique of dividing the bronchus via a minimally invasive approach is not inferior to the open approach. Both meta-analyses in the literature found a non-significant, lower incidence of prolonged air leak among after VATS lobectomy.19,27 Whitson et al. noted a 5% prolonged air leak after VATS lobectomy (95% CI 3.3–6.8%) and an 8.8% rate after open lobectomy (95% CI 2.4–15.2%), which was not significantly different (p = 0.27).27 Though the incidence of prolonged air leaks was not significantly different, the chest tube duration for VATS patients (mean 4.2; 95% CI 3.2–5.3 days) was significantly shorter than thoracotomy patients (mean 5.7; 95% CI 4.9–6.5 days).27 Variations in practice patterns may have contributed to these differences. Anecdotally, surgeons who perform VATS lobectomies tend to accept a higher volume of output prior to chest tube removal than surgeons who prefer open lobectomies.21,41
Cardiac Complications The meta-analysis by Whitson et al. found a nonsignificant (p = 0.33) reduction in the incidence of postoperative atrial fibrillation after VATS lobectomy (5.2%; 95% CI 2.0–8.4%) as compared with open lobectomy (9.0%; 95% CI 2.1–15.2%).27 This meta-analysis was not designed to elucidate the underlying mechanisms, but data from other studies may provide insight. In a single-institution retrospective study of stage I NSCLC patients who were in sinus rhythm preoperatively and did not receive prophylactic anti-arrhythmics, Park et al. found a lower rate of postoperative atrial fibrillation among 122 VATS lobectomy patients (12%) compared to 122 open lobectomy patients (16%) that were matched on age and gender; this difference did not reach statistical significance.42 It’s possible that the number of patients this study and the aforementioned meta-analysis (fewer than 1,100 in each group) were too small to detect a significant difference. Alternatively, the difference in rate of postoperative atrial fibrillation may have been underestimated, which would reduce the statistical power to detect a significant difference between the groups. Most studies that have reported postoperative atrial fibrillation rates after VATS lobectomy did not place their patients on use continuous
telemetry in the postoperative period. Because of logistical constraints, only 23% of patients were placed on continuous telemetry in the study by Park et al.42 Consequently, it is possible that patients not on continuous telemetry had paroxysmal episodes of atrial fibrillation that went undetected. Indeed, in another single institution retrospective study that used continuous telemetry, the rate of atrial fibrillation was significantly higher (p = 0.01) among open lobectomy patients (21%) than VATS lobectomy patients (13%) after propensity score matching (284 patients in each group).28 Interestingly, in the study by Park et al., there was no significant difference between VATS and thoracotomy patients or between patients who had atrial fibrillation and those that did not with regards to co-morbidities, pre-operative electrolytes values, use of beta-blockers, and use of calcium channel blockers.42 Though age, gender, and co-morbidities are well-known risk factors for atrial fibrillation after noncardiac thoracic surgery,43 this study suggests that other factors likely underlie the difference in the rate of atrial fibrillation between VATS and open lobectomy. One such factor may be differences in the postoperative neurohormonal stress response between VATS and thoracotomy.44 There is little data in the literature on the risk of other postoperative cardiac complications (i.e., acute myocardial infarction) after open vs. VATS lobectomy. Based on single institution data, the risk appears to be similar.22,28
Other Complications Few studies in the literature have compared the incidence of other complications after VATS and open lobectomy. One study found that the rate of renal failure was lower among VATS patients while the rate of stroke and venous thromboembolism was not significantly different that open lobectomy patients.28
Length of Stay The meta-analysis by Whitson et al. indicated that the length of stay was significantly shorter (p = 0.016) after VATS lobectomy (mean 8.3; 95% CI 6.9–9.8 days) than open lobectomy (mean 13.3;
8. VATS vs. Open Lobectomy for Early Stage Non-Small Cell Lung Cancer
95% CI 9.5–17.1 days). Significant regional variation was noted in the meta-analysis, which included data from North American and Asian institutions. In general, the length of stay in Asian studies was longer than North American studies, which could have skewed the weighted averages. However, this variation was noted for both VATS and thoracotomy patients, indicating that this potential source of bias likely had minimal significance. It’s possible that the length of stay comparison in the meta-analysis may be confounded by differences in patient factors that were not assessed and which may be associated with an increased length of stay (such as number of co-morbidities and baseline pulmonary function). However, a recent single-institution study of 313 VATS lobectomy and 313 open lobectomy patients with clinical stage Ia NSCLC that used propensity scoring to match patients on a number of variables (including age, gender, pulmonary function, smoking status, and number of co-morbidities) demonstrated that VATS patients had a 2 day shorter hospital stay than thoracotomy patients.22 In an era in which medical economics have ever-increasing importance in the public and private sectors, shorter hospitals stays have important financial implications. The first cost analyses for VATS vs. open pulmonary resections (which had conflicting findings) are difficult to interpret due to heterogenous patient populations (which raises concern for confounding and selection bias),45 small sample sizes,45,46 and relatively long hospital stays.45,46 However, two recent singleinstitution retrospective reviews have provided insight into the costs associated with VATS and open lobectomies. Park and Flores compared the cost (which included indirect costs, direct costs, and surgeon fees) for open lobectomy (269 patients) and VATS lobectomy (87 patients) over a 12-month period and found that VATS lobectomy was associated with significantly lower average total costs (by $7,969) compared with open lobectomy. Much of the extra cost associated with open lobectomy ($5,098) was attributed to a 2-day increased length of stay as compared with open lobectomy.47 Similarly, another single-institution retrospective cost analysis of open (253 patients) and VATS lobectomy (93 patients) for early stage NSCLC found that the total hospital charges were
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lower for VATS lobectomy. Though the operating room costs were higher for VATS lobectomy, they were offset by cost savings from a 1 day shorter hospital stay.48
Quality-of-Life A number of studies have demonstrated that VATS lobectomy, as compared with open lobectomy, is associated with subjective and objective improvements in surgery-related quality-of-life (evidence quality low). In a retrospective study of 168 patients who underwent VATS (without ribspreading) and 61 patients who underwent open lobectomy for clinical stage I NSCLC, Tajiri et al. demonstrated that VATS lobectomy (as compared with open lobectomy) is associated with lower analgesics requirements and less pain at 1 day, 2 weeks, 4 weeks, 6 months, and 1 year postoperatively.49 Other smaller studies have also found that VATS lobectomy is associated with less acute postoperative pain50–52 and less chronic pain.52 Using a variety of questionnaires, a number of studies have compared quality-of-life after VATS and open lobectomy.53–55 Handy et al. compared Short-Form-36 (SF-36) Health Survey scores before and 6 months after VATS lobectomy (without rib-spreading) and open lobectomy.53 As compared with preoperative scores, postoperative SF-36 scores for the 49 VATS patients were significantly improved in 2 SF-36 categories (pain and general health) and were unchanged in the remaining 6 categories. In contrast, the 192 open lobectomy patients in that study had significantly worse physical function, role-physical, and social function scores.53 With regards to functional capacity, the results of several observational studies indicate that VATS (as compared with thoracotomy) is associated with better preservation of (Eastern Cooperative Oncology Group [ECOG]) performance status,53 greater maintenance of exercise capacity (on a 6-minute walk test),56 and earlier return to preoperative activities.55 VATS is also associated with greater preservation and more expeditious return of respiratory function. In one study of 9 open lobectomy and 13 VATS lobectomy patients, VATS patients
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demonstrated significantly improved and faster recovery rates of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and vital capacity (VC) at 7 and 14 days after lobectomy.51 Other observational studies have confirmed the advantages of VATS with regards to preservation and recovery of pulmonary function at shortterm57 and mid-term (3 months) follow-up.58
High-Risk Patients As compared with open lobectomy, VATS lobectomy is an especially advantageous approach for high-risk patients with early-stage NSCLC (evidence quality low), such as those with marginal pulmonary function (percent predicted forced expiratory forced expiratory volume in 1 s less than 50%),52,59 poor functional status (ECOG performance score of 2 or more),52 co-morbidities,25,52 and elderly patients (age 70 and older).52,60 Such patients may not have the physiologic reserve to tolerate a thoracotomy and its attendant complications. By reducing postoperative pain, VATS lobectomy offers the theoretical advantage of avoiding complications associated with poor pain control (e.g., pneumonia), narcotic analgesic use (e.g., delirium, aspiration, ileus), and impaired mobility (e.g., deep venous thrombosis and deconditioning). Indeed, in matched case-control studies of highrisk NSCLC patients, those who underwent VATS lobectomy had lower morbidity and lower mortality rates,60 shorter hospital stays,52,60 earlier return to preoperative activities,52 and less pain at shortterm (3-week) follow-up as compared with those who underwent open lobectomy.52
Oncologic Efficacy As compared with open lobectomy, VATS lobectomy has demonstrated significant advantages in terms of lower morbidity and improved qualityof-life. Nonetheless, VATS lobectomy, like any cancer operation, should ultimately be judged on the basis of its oncologic efficacy. To this end, the oncologic principles of an open lobectomy should
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not be compromised with a VATS approach. In particular, an anatomic resection (with individual ligation of the vessels and lobar bronchus) and complete mediastinal lymph node dissection should be performed.15,18
Mediastinal Lymph Node Dissection Complete mediastinal lymph node dissection (which should include at least 11 lymph nodes61) is an important adjunct to lobectomy, regardless of the approach. Because patients who undergo mediastinal lymphadenectomy have better survival rates12 than those who undergo lymph node sampling,13 complete mediastinal lymph node dissection should not be supplanted by less thorough techniques. Despite concerns to the contrary, complete mediastinal lymphadenectomy (via a thoracotomy) adds little morbidity,12,13,62 does not increase the postoperative length of stay,62 and adds only 15 min to the operative time.62 A number of retrospective63 and prospective studies64 have demonstrated that a complete mediastinal lymph node dissection is possible with a VATS approach. Watanabe and colleagues performed a retrospective review of 221 patients who underwent VATS lobectomy (without rib-spreading) and 190 patients who underwent open lobectomy, and found that there was no significant difference between the two approaches with regards to the number of mediastinal lymph nodes, regardless of which lobe was removed.63 In a prospective study, Sagawa and colleagues performed a VATS lobectomy and complete mediastinal lymph node dissection in 29 patients with clinical stage I NSCLC. In the same anesthesia setting, a second surgeon then performed a thoracotomy and completion mediastinal lymph node dissection to remove any residual lymph nodes. For both rightand left-sided tumors, a mean of 1.2 residual lymph nodes (about 2% of the total nodal tissue) were identified at thoracotomy. None of the residual lymph node tissue contained metastatic disease.64 These data indicate that a complete mediastinal lymph dissection via a VATS approach can be performed with comparable rigor to an open approach; the number of lymph nodes removed via VATS is not inferior to thoracotomy (evidence quality moderate).
8. VATS vs. Open Lobectomy for Early Stage Non-Small Cell Lung Cancer
Compliance with Adjuvant Therapy Some patients with early-stage NSCLC, especially those with stage II disease, may require adjuvant chemotherapy.65,66 The delivery of a planned adjuvant regimen (without delayed or reduced doses) may be impaired in patients who have a complicated postoperative course. Because patients who undergo VATS lobectomy have a lower risk of postoperative complications as compared with patients who undergo open lobectomy,27 VATS lobectomy may offer the advantage of increase compliance with undergoing a planned adjuvant chemotherapy regimen (evidence quality low). A recent retrospective study by Nicastri et al. compared compliance of planned adjuvant therapy in 100 consecutive patients who underwent lobectomy (57 via VATS; 43 via thoracotomy) for NSCLC and required adjuvant chemotherapy; more than 50% of patients in each group had early stage disease. There were significantly fewer delayed (VATS, 18%; thoracotomy, 58%; p < 0.001) or reduced (VATS, 26%; thoracotomy, 49%; p = 0.02) chemotherapy doses in patients who underwent VATS lobectomy. Furthermore, a significantly higher (p = 0.03) percentage of VATS patients (61%) than thoracotomy patients (40%) received 75% or more of their total planned adjuvant regimen without delayed or reduced doses.67 In another series of 153 consecutive patients (120 with early stage NSCLC) who underwent VATS lobectomy, 73% of patients completed a full course of adjuvant therapy on schedule, and 85% received all of the planned cycles.68 Though a comparison (thoracotomy) group was not included in that study, these results seem comparable to the study by Nicastri et al.
Recurrence After VATS lobectomy, NSCLC may recur locoregionally or systemically. Rarely (0.3% to 0.6%), NSCLC recurrences in VATS incisions and staple lines have been reported (time to recurrence 3–23 months).29,69,70 Surgical technique is imperative to reduce the risk of such recurrences. It is likely that they are the result of tumor dissemination (to the suture line, pleura, and/or skin incision) that occurs during tumor manipulation and removal
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of the lobectomy specimen through a small, unprotected skin incision.71–73 Meticulous technique and use of a specimen retrieval bag are essential. Anecdotally, the authors of one large VATS lobectomy series have not had a trochar site recurrence since they began using laparoscopic specimen bags for tumor retrieval.29 The systematic review and meta-analysis by Yan et al. compared the risk of recurrence after VATS and open lobectomy. They found that a lower risk of locoregional recurrence after VATS lobectomy, but this difference did not reach statistical significance (RR 0.64; 95% CI 0.30–1.35; p = 0.24). They also found a statistically significant lower risk of systemic recurrence after VATS lobectomy as compared with open lobectomy (RR 0.57; 95% CI 0.34–0.95; p = 0.03).19 Therefore, VATS lobectomy can be performed with comparable (or possibly lower) recurrence rates as compared with open lobectomy (evidence quality moderate).
Survival The meta-analysis by Whitson et al. found that patients who underwent VATS lobectomy for early stage NSCLC had a higher overall survival rate at each year of follow-up. This difference, however, did not reach statistical significance until 4 years of follow-up (Table 8.2).27 These results (and others) indicate that survival after VATS lobectomy is not inferior (and may be superior) to open lobectomy (evidence quality moderate). Though VATS lobectomy may offer a survival advantage over open lobectomy, the underlying mechanisms are uncertain. The meta-analysis was comprised primarily of observational studies; only one randomized trial was included. As such, the results are prone to the inherent limitations of observational studies, including selection bias and confounding. Nevertheless, there is growing evidence that immunologic factors may be important.
Immunologic Effects Surgery incites a well-characterized postoperative stress response74; the impact of minimally invasive vs. conventional (open) surgery on this response has been the source of recent research
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84 Table 8.2. Overall survival rates: VATS vs. open lobectomy. VATS
1-Year 2-Year 3-Year 4-Year 5-Year
Thoracotomy
Number of studies
Number of patients
Overall survival rate (95% CI)
9 11 13 8 5
867 1,486 1,623 759 531
98.2% (91.6–100) 91.6% (86.7–96.5) 87.2% (82.0–92.3) 88.4% (81.7–95.1) 80.1% (67.5–92.7)
Number of studies
Number of patients
Overall survival rate (95% CI)
p Value
10 8 12 10 16
914 658 1,223 981 1,975
93.2% (86.9–99.4) 84.9% (77.8–91.1) 81.6% (75.4–87.8) 71.4% (62.4–80.3) 65.6% (56.7–74.4)
0.28 0.12 0.18 0.003 0.06
VATS Video-assisted thoracoscopic surgery 95% CI = 95% confidence interval
interest. Several investigators have demonstrated that VATS, as compared with thoracotomy, is associated with blunted peri-operative interleukin (IL) production. In particular, as compared with open lobectomy, VATS lobectomy is associated with reduced generation of IL-6 (which activates the hypothalamic-pituitary-adrenal axis and is an index of the degree of systemic inflammation) and diminishes IL-6 modulation of the hepatic acute phase protein response (i.e., decreased C-reactive protein production).51,75–78 As compared with open lobectomy, VATS is also associated with decreased generation of IL-8 (a chemokine) and, as a secondary effect, decreased peri-operative reactive oxygen species production by neutrophils (which is normally incited by IL-8).75,77,78 In addition to reducing the acute inflammation associated with the postoperative stress response, VATS is also associated with less immunosuppression, as evidenced by less impairment of peripheral blood mononuclear cell [PBMC] cytotoxicity, and more rapid recovery of immune function as compared with thoracotomy.79–81 This difference may be particularly relevant for cancer-specific outcomes. In particular, natural killer (NK) cells (a PBMC) may be important in scavenging tumor cells that are shed at the time of lobectomy.71–73 Indeed, animal models of colon cancer have demonstrated that open colectomy is associated with increased local progression82 and development of pulmonary metastasis as compared with minimally invasive colectomy.83 The clinical relevance of differences in the postoperative inflammatory response and differential impairment of cellular
immunity after open and VATS for NSCLC, however, has yet to be determined.
Summary and Recommendations Lobectomy with complete mediastinal lymphadenectomy is the gold standard for treating early stage NSCLC. Though traditionally performed through a thoracotomy, VATS has emerged as a safe and effective alternative approach for lobectomy. A growing body of evidence from observational studies and systematic reviews and meta-analyses of those studies suggests that VATS lobectomy is associated with lower morbidity, improved quality-of-life, and improved survival as compared with open lobectomy (evidence quality moderate). Though the mechanisms underlying the potential survival advantage of VATS lobectomy have yet to be definitively determined, differential effects on inflammation and immune function likely play a role. Patients with early stage NSCLC and sufficient cardiopulmonary reserve should undergo lobectomy and complete mediastinal lymph node dissection. We make a strong recommendation for VATS lobectomy as a safe alternative to open lobectomy for early stage NSCLC (recommendation grade 1B). The oncologic principles of an open lobectomy should not be compromised with a VATS approach. In particular, an anatomic resection (with individual ligation of the vessels and lobar bronchus) and complete mediastinal lymph node dissection should be performed without rib-spreading.
8. VATS vs. Open Lobectomy for Early Stage Non-Small Cell Lung Cancer
VATS lobectomy is associated with lower morbidity, improved quality-of-life, and improved survival as compared with open lobectomy (evidence quality moderate). We make a strong recommendation for VATS lobectomy as a safe alternative to open lobectomy for early stage NSCLC (recommendation grade 1B).
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65. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350: 351–360. 66. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005;352:2589–2597. 67. Petersen RP, Pham D, Burfeind WR, Hanish SI, Toloza EM, Harpole DH, Jr. et al. Thoracoscopic lobectomy facilitates the delivery of chemotherapy after resection for lung cancer. Ann Thorac Surg. 2007;83:1245–1250. 68. Nicastri DG, Wisnivesky JP, Litle VR, Yun J, Chin C, Dembitzer FR et al. Thoracoscopic lobectomy: report on safety, discharge independence, pain, and chemotherapy tolerance. J Thorac Cardiovasc Surg. 2008;135:642–647. 69. McKenna RJ, Jr. Complications and learning curves for video-assisted thoracic surgery lobectomy. Thorac Surg Clin. 2008;18:275–280. 70. Downey RJ, McCormack P, LoCicero J, 3rd. Dissemination of malignant tumors after videoassisted thoracic surgery: a report of twenty-one cases. The Video-Assisted Thoracic Surgery Study Group. J Thorac Cardiovasc Surg. 1996;111: 954–960. 71. Okumura M, Ohshima S, Kotake Y, Morino H, Kikui M, Yasumitsu T. Intraoperative pleural lavage cytology in lung cancer patients. Ann Thorac Surg. 1991;51:599–604. 72. Li YN, Shi HZ, Liang QL, Yang HB, Huang GM. Prognostic significance of pleural lavage cytology in patients with lung cancer: a meta-analysis. Lung Cancer. 2008;60:183–192. 73. Shintani Y, Ohta M, Iwasaki T, Ikeda N, Kanou T, Tomita E et al. Intraoperative pleural lavage cytology after lung resection as an independent prognostic factor for staging lung cancer. J Thorac Cardiovasc Surg. 2009;137:835–839. 74. Baxevanis CN, Papilas K, Dedoussis GV, Pavlis T, Papamichail M. Abnormal cytokine serum levels correlate with impaired cellular immune responses after surgery. Clin Immunol Immunopathol. 1994;71:82–88. 75. Yim AP, Wan S, Lee TW, Arifi AA. VATS lobectomy reduces cytokine responses compared with conventional surgery. Ann Thorac Surg. 2000;70:243–247. 76. Craig SR, Leaver HA, Yap PL, Pugh GC, Walker WS. Acute phase responses following minimal access and conventional thoracic surgery. Eur J Cardiothorac Surg. 2001;20:455–463. 77. Raeburn CD, Sheppard F, Barsness KA, Arya J, Harken AH. Cytokines for surgeons. Am J Surg. 2002;183:268–273. 78. Sugi K, Kaneda Y, Esato K. Video-assisted thoracoscopic lobectomy reduces cytokine production more than conventional open lobectomy. Jpn J Thorac Cardiovasc Surg. 2000;48:161–165.
88 79. Leaver HA, Craig SR, Yap PL, Walker WS. Lymphocyte responses following open and minimally invasive thoracic surgery. Eur J Clin Invest. 2000;30:230–238. 80. Ng CS, Lee TW, Wan S, Wan IY, Sihoe AD, Arifi AA et al. Thoracotomy is associated with significantly more profound suppression in lymphocytes and natural killer cells than video-assisted thoracic surgery following major lung resections for cancer. J Invest Surg. 2005;18:81–88. 81. Whitson BA, D’Cunha J, Andrade RS, Kelly RF, Groth SS, Wu B et al. Thoracoscopic versus thoracotomy approaches to lobectomy: differential impairment of cellular immunity. Ann Thorac Surg. 2008;86:1735–1744. 82. Bouvy ND, Marquet RL, Jeekel J, Bonjer HJ. Laparoscopic surgery is associated with less tumour growth stimulation than conventional surgery: an experimental study. Br J Surg. 1997;84:358–361. 83. Carter JJ, Feingold DL, Kirman I, Oh A, Wildbrett P, Asi Z et al. Laparoscopic-assisted cecectomy is associated with decreased formation of postoperative pulmonary metastases compared with open cecectomy in a murine model. Surgery. 2003;134:432–436. 84. Kirby TJ, Mack MJ, Landreneau RJ, Rice TW. Lobectomy--video-assisted thoracic surgery versus muscle-sparing thoracotomy. A randomized trial. J Thorac Cardiovasc Surg. 1995;109:997–1002. 85. Morandi U, Stefani A, Golinelli M, Ruggiero C, Brandi L, Chiapponi A et al. Results of surgical resection in patients over the age of 70 years with non small-cell lung cancer. Eur J Cardiothorac Surg. 1997;11: 432–439. 86. Sugi K, Nawata K, Fujita N, Ueda K, Tanaka T, Matsuoka T et al. Systematic lymph node dissection
S.S. Groth and M.A. Maddaus for clinically diagnosed peripheral non-small-cell lung cancer less than 2 cm in diameter. World J Surg. 1998;22:290–295. 87. Aoki T, Tsuchida M, Watanabe T, Hashimoto T, Koike T, Hirono T et al. Surgical strategy for clinical stage I non-small cell lung cancer in octogenarians. Eur J Cardiothorac Surg. 2003;23:446–450. 88. Muraoka M, Oka T, Akamine S, Tagawa T, Nakamura A, Hashizume S et al. Video-assisted thoracic surgery lobectomy reduces the morbidity after surgery for stage I non-small cell lung cancer. Jpn J Thorac Cardiovasc Surg. 2006;54:49–55. 89. Shigemura N, Akashi A, Funaki S, Nakagiri T, Inoue M, Sawabata N et al. Long-term outcomes after a variety of video-assisted thoracoscopic lobectomy approaches for clinical stage IA lung cancer: a multi-institutional study. J Thorac Cardiovasc Surg. 2006;132:507–512. 90. Kaseda S, Aoki T, Hangai N. Video-assisted thoracic surgery (VATS) lobectomy: the Japanese experience. Semin Thorac Cardiovasc Surg. 1998;10:300–304. 91. Yim AP, Izzat MB, Liu HP, Ma CC. Thoracoscopic major lung resections: an Asian perspective. Semin Thorac Cardiovasc Surg. 1998;10:326–331. 92. Solaini L, Prusciano F, Bagioni P, Di Francesco F, Basilio Poddie D. Video-assisted thoracic surgery major pulmonary resections. Present experience. Eur J Cardiothorac Surg. 2001;20:437–442. 93. McKenna RJ, Jr. New approaches to the minimally invasive treatment of lung cancer. Cancer J. 2005; 11:73–76. 94. McVay CL, Pickens A, Fuller C, Houck W, McKenna R, Jr. VATS anatomic pulmonary resection in octogenarians. Am Surg. 2005;71:791–793.
9
N2 Disease Discovered at Thoracotomy: Resect or Abort? Frank C. Detterbeck
Introduction The reported incidence of finding N2 node involvement at thoracotomy which was not anticipated varies from 2%1 to 25%.2–4 However, with good quality staging, it should be less than 10%.1,5 Nevertheless, when N2 node involvement is found intraoperatively, the decision whether to proceed with resection or abort the procedure is difficult. This is the subject of this chapter. The analysis of this issue is complicated, because different subgroups of N2 involvement are seen that carry a different prognosis.6,7 Additionally, the detection of N2 involvement is affected by the thoroughness of evaluation of mediastinal nodes.8 In fact, the quality of staging has a dramatic effect on outcomes.9,10 This complexity accounts for the confusion about how to manage unanticipated N2 disease. Often data from one situation or cohort is applied erroneously to another setting or cohort. This chapter tries to define, as best as possible, specific settings and cohorts of patients.
Methods This review draws on peer-reviewed papers published in English over the last 20 years (1989– 2009). Many studies that were not designed specifically to focus on surprise N2 disease contain useful data; therefore, it was difficult to define narrow
search terms that did not exclude pertinent studies. In the end, titles were reviewed appearing in PubMed for the search terms non-small cell lung cancer and surgery. References from 2006 through November of 2009 were reviewed, including abstracts and whole articles of any papers that appeared relevant. In addition the reference lists of pertinent articles were reviewed. Publications prior to 2006 were assembled from previous systematic reviews.11–14 Specific inclusion criteria for particular tables are listed in the respective legend. Articles were included if they contained data about outcomes of patients who were discovered to have N2 node involvement at the time of a planned resection of NSCLC. In most of these the outcomes involved patients who were resected; few studies have reported on patients in whom the procedure was aborted. The outcomes of alternative treatment approaches are taken from papers selected on the basis of being relatively recent, and comprising either a large cohort or a review or metaanalysis. No formal metaanalysis was performed. Where averages are presented, they are simple averages without weighting by study size. This is because (a) small studies were excluded as listed in the inclusion criteria; (b) weighting gives undue emphasis to size over multiple other sources of variation among studies; and (c) exploratory analyses of weighted vs. nonweighted averages did not uncover any significant differences that altered the conclusions.
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_9, © Springer-Verlag London Limited 2011
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Results
Short-Term and Functional Outcomes
Alternative treatment Arriving at a treatment recommendation for a patient with N2 disease discovered at thoracotomy involves consideration of the alternatives. One management option is to proceed with resection, followed by adjuvant chemotherapy and possibly radiotherapy (RT).14 Alternatively, one could abort the resection, and treat with either definitive chemoradiotherapy or induction therapy with subsequent plans to attempt resection again. One has to consider the short-term and long-term effects of an exploratory thoracotomy vs. a resection on functional outcomes and quality of life (QOL). One also has to consider the ability to administer the planned treatment. Finally, a crucial factor is the long-term survival, which must be assessed for all patients for whom a particular treatment strategy is chosen, not just a subset (i.e. only those who complete it successfully).
There appears to be little difference in the perioperative mortality of a lobectomy (2–4%)1,5,15–17 vs. an exploratory thoracotomy (average 4%, range 0–7%).15,18–23 A pneumonectomy, on the other hand, has a 6–8% perioperative mortality.5,15 Both short-term and long-term QOL also appear to be quite similar. Most studies of perioperative QOL have suggested that, while short-term QOL is decreased by surgical resection, QOL returns to baseline by 3–6 months (Table 9.1).15,24–31 The slight decrease in QOL at >6 months seen in some studies is considered clinically insignificant; however, one study found a persistent clinically relevant decrease.32 Other studies have associated a persistent significant decrease in QOL with either cancer recurrence26 or pneumonectomy.30,31 On the other hand, many studies have shown that specific symptoms, such as pain, dyspnea, fatigue and cough may persist in a substantial proportion of patients.26,28,32 Persistent pain is likely due to the incision (which should be expected after exploratory thoracotomy),
Table 9.1. Comparison of preoperative and postoperative (³3 months) QOL measures.
Study Schulte30 Balduyck31 Brunelli27 Handy32 Dales24 Mangione119 Kenny26,d Zieren28 Win29 Schulte30 Balduyck31
Evaluable pts
QOL Instrument
131 61 156 139 117 123 111 20 110 28 17
C-30 C-30 SF-36 SF-36 several SF-36 C-30 C-30 C-30 C-30 C-30
(%) (%) Attrition Pneum 7a 17 16 26 32 7a 14e – 25 7a 17
0 0 8 8 13 – 23 25 33 100 100
Interval (mo.) 12 6 3 6 6 12 4–24 12 6 12 6
Overall Compos QOL BL ↑ – – BL – BL BL BL BL BL
Phys Func
phys Role
Emot Func
BL BL BL ↓ BL BL BL ↓ BL (↓) ↓
BL BL BL ↓ – BL BL BL BL ↓ ↓
BL BL BLb BLb BL ↑b BL BL BL ↓ BL
Social Func BL BL BL ↓ BL BL BL BL BL BL BL
Pain
Dyspnea
Fatigue
(↑) ↑ ↑ ↑ – ↑ BL ↑ BL (↑) ↑
(↑) BL – – BL – BL ↑ BL (↑) ↑
– – ↑c BL BL – BL ↑ BL – –
Inclusion criteria: Studies of ³50 patients total reporting QOL after thoracotomy from 1980–2009. Higher scores in QOL parameters indicate a better outcome (minor differences classified as not clinically significant by standard definitions are counted as no change); higher scores in the symptom categories indicate higher rate of symptoms. Values in parentheses indicate a trend that is not statistically significant. ↑, significantly increased; ↓, significantly decreased; BL Baseline (i.e. values are equal to preopeerative baseline); Compos composite; Emot emotional; Func functioning; QOL, quality of life; Phys, physical; Pneum, pneumonectomy; pts, patients a For entire study population; b emotional role; c physical activity; d for patients without recurrence; e at 2 year mark.
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9. N2 Disease Discovered at Thoracotomy: Resect or Abort?
whereas other specific symptoms are probably due to parenchymal resection. Dyspnea is primarily associated with pneumonectomy.26–28,31 The majority of studies demonstrate good longterm functional capacity after resection even in patients with limited pulmonary reserve24,28,33–35 (with few exceptions).32 Lobectomy results in minimal (<10%) loss of exercise capacity, although that loss is 20–25% after pneumonectomy.36–42 Furthermore, data show that poor long-term functional outcomes are not well correlated with limited preoperative reserve but rather with random “unpredictable” events.18 Similarly, the effect of surgery on long-term QOL does not seem to be impacted by marginal preoperative lung function in most studies.27,43,44 QOL after exploratory thoracotomy has not been studied. Given the generally good recovery after resection, it can be expected to occur after an exploration as well. Specific symptoms such as pain are likely similar (presumably due to the incision), whereas dyspnea is likely to be diminished without resection. However, exploration without resection is probably associated with a significant psychological burden. Finally, data shows that definitive RT results in an eventual loss of lung function that is similar to lobectomy (~10% for FEV1 and ~10– 30% for DLCO),45–49 although this effect may be diminished with current RT techniques. In summary, longer-term functional and QOL outcomes appear to be relatively good and similar for lobectomy and exploratory thoracotomy. Perioperative mortality is also similar. Pneumo nectomy, however, carries a higher mortality, results in diminished functional capacity in a substantial proportion of patients and may be associated with worse QOL.
Ability to Deliver the Planned Treatment Too often, data are reported for only select subsets of patients for whom a treatment strategy was chosen, i.e. those who completed the treatment successfully or who responded to induction therapy. In making a decision, however, one must consider all of the patients, because it is not yet clear which subgroup a given patient will fall into. The ability to carry out a complete resection in patients with pathologically documented N2 involvement (pN2) disease is approximately 75–80% in patients who are clinically N2 negative (cN0,1) and 66% in patients who are clinically N2 positive (cN2).11 Post-operative adjuvant chemotherapy has been able to be delivered in approximately 66% of patients as planned among studies of stage I–IIIa patients (Table 9.2).11,50–55 If surgery is aborted with a plan to deliver induction therapy and subsequent resection, only a minority of patients (~30%) will eventually undergo a complete resection.56 This data comes from a prospectively collected large series of 402 cN0,1 patients, who were carefully staged prior to attempted resection, and thought to be good candidates for induction chemoradiotherapy and resection.56 This is the only large series that has tracked patients and reported detailed results for the entire group. Attrition was due to multiple factors (death 8%, lost 10%, induction toxicity 10%, progression 24%, persistent N2 at restaging 11%, R1,2 resection 9%). It is likely that attrition would be greater for cN2 patients due to a higher incidence of progressive disease. There is no information on the ability to administer definitive chemoradiotherapy (chemoRT)
Table 9.2. Alternative treatment approaches. Abort →
Resect →
Parameter
Ind→S
ChRT
Adj Tmt
Adj Tmt
Adj Tmt
Description of patient cohort Delivery of Induction/adjuvant Treatment (%) Rate of complete (R0) resection (%) Delivery of all planned treatment modalities (%) Overall 5-year survival of entire cohort (%) Main References
cN0,1 80 30 30 15
cN2 (65–80) – (65–80) (15–20)
cN0,1 65 75–80 (50) 25–40
cN1 65 75–80 (50) 15–20
cN2 65 65 (40) 10–15
56
59–61
11,50,57
11,50,57
11,50,57
Inclusion criteria: Selected representative studies reporting data on alternative treatments in cohorts that are as comparable as possible to “surprise” N2 patients. Values in parentheses are calculated or estimated and not directly reported. Numbers are rounded to the nearest multiple of 5. Legend: Adj adjuvant (postoperative), ChRT chemoradiotherapy, Ind induction (preoperative), S surgery, Tmt treatment.
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after an exploratory thoracotomy. In general, the ability to deliver adjuvant therapy after a thoracotomy is only about 66%.11,50,57 There may be a slightly greater willingness to carry out the plan in patients who have not been resected, but in the study of induction chemoradiotherapy cited above only 81% completed it.56
Survival of Patients Treated with Alternative Approaches If surgery is aborted with the intent for induction chemoRT and subsequent resection the 5 year survival for all patients is 13%.56 This comes from a large study of carefully preoperatively staged patients, and is due to significant attrition at each step, despite the patients being thought to be good candidates for trimodality therapy. The ability to deliver induction chemotherapy alone may be slightly better due to less toxicity, but may be offset by a lower rate of mediastinal downstaging.58 Data specifically reporting survival of aborted resection and planned definitive chemoradiotherapy are not available. The best estimate probably comes from the chemoRT arms of randomized trials comparing this to trimodality therapy; the overall survival in the chemoradiotherapy arms is approximately 20% (13–30%).59–61 The extent of disease in these studies is probably greater than in patients with unanticipated N2; on the other hand the definitive chemoRT patients were not subjected to thoracotomy. Among studies of chemoradiotherapy in general (for both stages IIIa and IIIb), the 5 year survival is approximately 15–20%.62,63 In summary, if resection is aborted with planned trimodality therapy, the survival achieved is approximately 15% (Table 9.2). The same is true if resection is aborted with planned definitive chemoradiotherapy, although data directly addressing this specific situation is not available.
Categories of N2 Patients Most importantly, long-term survival of patients with pN2 disease (i.e. post-resection N2 disease) varies markedly according to preoperative characteristics and the extent of preoperative staging investigations. On one end of the spectrum are patients with suspicious mediastinal nodes (by CT and/or PET) who nevertheless undergo a
resection (without further staging investigations), and are found to have pN2 involvement. These patients should perhaps be more appropriately called ignored N2. Underappreciated N2 refers to patients with more subtle suspicion of N2,3 involvement who do not undergo an invasive staging procedure – namely those with a central tumor or cN1 involvement, who have a well-documented 20% incidence of N2 involvement despite a normal CT and PET of the mediastinum.7,12,64 Finally, incidental N2 are patients with clinical stage I or II disease after extensive preoperative staging including invasive procedures, but are found to be pN2 postoperatively. In addition, data should be considered relative to specific factors (e.g. involvement of specific node stations, need for pneumonectomy), as these may influence the decision to proceed with resection. However, these data must be viewed with caution. A single factor cannot be viewed in isolation from others, even with multivariate analysis. Furthermore, there are geographic variations in outcomes. Finally, it is unclear how well post-operative criteria that define subgroups with good or poor survival can be extrapolated to factors that can de determined intra-operatively. Each of these issues confounds the ability to define prognosis relative to a single factor accurately enough to dictate how such a patient should be managed when surprise N2 is found.
Ignored N2 Patients who have cN2 disease harbor asymptomatic distant metastases in approximately 30% of cases, and should therefore undergo PET and brain imaging.7,13,64–67 If the clinical suspicion of N2 disease was ignored it is likely that that a similar lack of thoroughness occurred with respect to distant staging. If pN2 is found in a cN2 patient who has not had investigation for distant metastases, the resection should be aborted because of a 30% chance of distant detectable metastases. Furthermore, a negative PET in the mediastinum in patients with cN2 by CT carries a false negative rate (FN) of approximately 25%12,68–71; therefore invasive confirmation of the mediastinal node status is required. The 5-year survival is poor for cN2 patients who are confirmed at resection to be pN2, being
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9. N2 Disease Discovered at Thoracotomy: Resect or Abort?
All % R1,2
40
# of Studies
50
R0
40
30
30
20
20
10
10
Med’ oscopy cN by CT
9
4
0
11
% R1,2 resection
50
5-Year Survival (%)
Figure 9.1. Outcomes of patients with pN2 NSCLC. Inclusion criteria: Studies reporting on ³30 operated pN2 patients in whom preoperative characteristics are well defined by CT, mediastinoscopy, or both (³15 patients for the category of positive mediastinoscopy); published from January 1980 to December 2009 (updated from a prior review).11 Legend: #, number; cN0,1, clinical N0 or N1 by CT; cN2, clinical N2 by CT; Med-, negative results of Mediastinoscopy; Med+, positive results of Mediastinoscopy; Med’oscopy, Mediastinoscopy; R0, complete resection; R1,2, incomplete resection; References: Med+79,101–103; cN284,85,87,89,94,104–107; cN0,12,6,85,87,89,94,105,107–109]; Med-, cN0,12,79,101
3 0
Med+ ?
Selective cN2
Selective cNo,1
MedcNo,1
Only highly selected patients
only 13% to 15% in a recent comprehensive review (Fig. 9.1).11 This holds true whether there was suspicion of N2 disease based on CT or PET, and is the case even for highly selected patients who had a positive mediastinoscopy but were thought to be good candidates for primary resection nevertheless. Therefore, even in the face of careful distant staging, proceeding with resection is debatable because of poor survival. Given such poor outcomes, it is difficult to justify omitting preoperative microscopic investigation of the mediastinal nodes and proceeding directly to thoracotomy with intent to resect regardless of pN2 disease.
Underappreciated N2 Patients with central tumors or with cN1 involvement have a 20–25% chance of mediastinal node involvement, despite a normal mediastinal CT and despite a negative PET in the mediastinal nodes.12,70–73 Therefore, microscopic confirmation of node status is recommended by clinical guidelines.12 Furthermore, imaging for distant disease is also recommended, although the incidence of occult distant metastases is less well defined (estimated at 10–15%).7,13,64,65 The 5-year survival of patients with pN2 found at resection who have central or cN1 tumors is not explicitly defined, but is estimated to be approximately 15–20%. This estimate is obtained from a recent comprehensive review of data for T3 tumors,
cN1, and pN1 (non-skip) patients.11,74 The survival of such patients undergoing alternative treatment strategies also has not been well defined, but is likely slightly better than that of alternative treatment in general, based on speculation that the disease extent is perhaps less than for N2 patients in general. Therefore, the survival with resection or an alternative approach for pN2 patients with cN1 or central tumors appears to be similar. An argument can be made to proceed with resection, given that the morbidity of thoracotomy has already been incurred. This is most applicable for lobectomy; given the higher mortality and worse long-term functional results a pneumonectomy should probably be avoided. However, an argument can also be made for more aggressive preoperative staging, with the speculation that alternative approaches (e.g. neoadjuvant therapy or definitive chemoradiation) would be better tolerated and more successful without the morbidity of thoracotomy.
Incidental N2 Patients with cN0 tumors have a low incidence of occult distant metastases (~5%) and of N2,3 involvement (~10%).7,64,65,67,75–77 The 5-year survival of patients with pN2 found at resection with cN0 tumors is not explicitly defined, but is estimated to be approximately 25–40%, based on limited direct data and extrapolation from similar cohorts.11,74 In addition, if patients have undergone invasive staging
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which was negative, the available data suggests they also have survival of 25–30%, regardless of the cN status by imaging. Therefore, while the outcome of alternative approaches in these patients is undefined, it appears to be well-justified to proceed with resection (including pneumonectomy) if incidental N2 involvement is found.
The clinically relevant issue, however, is not independent prognostic significance, but which factors predict such poor survival that proceeding with resection is relatively futile and an alternative approach is better. This is primarily determined by the long-term survival, given the relative similarity in quality of life and functional outcomes. A reasonable place to set a threshold might be to recommend an alternative approach if the 5-year survival with resection is <10%, and to proceed if it is >15%. An analysis of all larger series reporting survival data on particular patient subgroups is shown in Fig. 9.2 and Tables 9.4, 9.5. This suggests that an incomplete resection is not justified (average 5-year survival of 5%, range 0–10%). This is corroborated by other reviews as well (involving different inclusion criteria).78 The survival is consistently poor, regardless of the definition (i.e. a microscopically positive margin,2,6,79–85 extracapsular mediastinal node involvement,86 or involvement of the most distant (highest) node3,87–89). The most robust definition of an incomplete resection is a positive margin, and this definition has been adopted by official bodies defining the stage classification system.23,90,91
Other Prognostic Factors Specific Characteristics Several studies have performed multivariate analyses of multiple factors, which is the necessary approach when there are multiple interrelated factors (Table 9.3).11 These studies indicate that an incomplete resection, multilevel N2 involvement, clinical N2 stage (by CT), and subcarinal node involvement are independent markers of poor prognosis in over half of the studies. The presence of T3,4 tumors, pN1 disease and older age are less consistent markers of a worse prognosis. The histologic type of NSCLC, which lobe is involved or whether a pneumonectomy or lobectomy is needed has little independent prognostic significance.
Table 9.3. Multivariate analyses of factors predicting poor survival in pN2 patientsa. Node level Study
n Multilevel
Andre Ichinose85 Riquet83 Suzuki89 Miller82 Thomas88 Tanaka87 Inoue106 Cerfolio118 Iwasaki113 Vansteenkiste79 Tanaka107 Ohta116 6
Prognostic Valued
702 406 237 222 167 163 155 154 148 142 140 99 94
<0.0001 <0.0001 <0.05 <0.001 <0.05 <0.02 NS 0.005 0.03 NS 0.03 0.01 – High
cN2
R1,2
N1±
#7
#5
#1,2
<0.0001 NS NS – – <0.05 <0.001 0.02 – NS – – NS 0.001 <0.001 – – – – – 0.04 NS <0.04 – NS –
– <0.03 NS – – – – – – NS – – 0.03
– – NS – <0.05 NS – – – 0.002 NS – £0.001
– – NS – NS – – – – – NS – –
– <0.0001 – <0.05b NS NS – NS (NS)c NS NS NS – 0.03 – NS – NS – NS (NS) c 0.003 – NS NS <0.001
Mod
Mod
Mod
Mod
–
–
T3,4
Low
Larger Size Lower Lobe pneum Adeno/Large Older Age – – NS 0.001 – – – – – – – – NS Low
– – NS – – – – <0.04 – – NS – NS Low
– NS NS NS <0.05 – – – – NS NS – –
NS NS NS NS NS NS NS 0.002 NS NS 0.03 NS NS
–
–
– 0.02 – NS <0.05 – NS 0.007 – NS NS NS NS Low
Inclusion criteria: Studies reporting multivariate analysis of >90 patients with pN2 disease, 1980–2009 Legend: Adeno/Large Adenocarcinoma, in some cases also including large cell carcinoma (not squamous), cN2 clinical N2 by CT; Mod moderate, N1+ N1 nodes involved (non-skip metastasis to N2 nodes), NS not statistically significant, pneum pneumonectomy, R1,2 incomplete resection T3,4 T3 or T4 primary tumor. a Values given are p values by multivariate analysis (Plain: Relative risk >1.0-<2.0; Bold: Relative risk 2.0-<3.0; Bold-underlined: Relative risk >3.0). Factors analyzed by <3 studies are omitted; b T2,3 vs. T1; c Stations 1–4 vs. others; d Scale: High: ³75% positive; Moderate 50–74% positive; Low 25–49% positive (excluding values in parentheses).
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9. N2 Disease Discovered at Thoracotomy: Resect or Abort?
Resection of a T3 tumor with N2 node involvement is very questionable (average 5-year survival of 11%, range 0–15%). Proceeding with resection may be more reasonable with multi-station N2 involvement or with cN2 disease – although the average survival is in the gray zone of 10–15%, the range is broad, with some series reporting survivals of 20–25% (Table 9.4). These data are in close agreement with a previous systematic review (5-year survival 15% and 13% for multilevel N2 and T3 tumors, respectively).78 The International Association for the Study of Lung Cancer (IASLC) staging analysis found a 5-year survival of 20% for multilevel pN2 involvement (other factors such as T stage could not be analyzed).74 Factors associated with a particularly good prognosis include an R0 resection, a T1,2 tumor, single level N2 involvement and patients staged as clinical N0,1 (Fig. 9.2, Table 9.5). Resection in the face of surprise N2 is well justified. Factors with an intermediate prognosis include the histology, extent of resection, upper vs. lower lobe location, and the presence of involved N1 nodes (skip or non-skip).11 #of Factor Studies R1,2 12 T3
10
Multi
9
cN2
8
level 7
7
Pneum
4
Adeno
8
Lobe
4
R0
23
T1,2
11
Single
10
cN0,1
These results are all consistent with other recent analyses.74,78,92 However, a wide range of survival results is seen, likely due to confounding factors. For example, patients with subcarinal node involvement may often also have multilevel involvement (upper lobe cancers involve level 7 primarily when there is multilevel disease). There does not seem to be a mediastinal node station with major prognostic significance. Level 7 is worse by multivariate analysis in about half of the studies, but survival is still good enough to justify resection. In particular, station 5 does not seem to be a particularly favorable, either by multivariate analyses (Table 9.3) or in other reviews and in the IASLC analysis.11,74,78 Survival of patients with only “regional” vs. “non-regional” N2 nodes has shown conflicting and inconsistent results.79,89,93,94
Geographic Variation Across all studies the 5-year survival in series from North America appears to be approximately half
Range
7
0
10
20 30 5-Year Survival (%)
40
50
Figure 9.2. Prognostic factors for patients with pN2 NSCLC. Inclusion Criteria: Studies of ³100 pN2 patients reporting survival by prognostic factor from 1980–2009. Legend: Adeno, adenocarcinoma; cN0,1, clinical N0 or N1 by CT; cN2, clinical N2 by CT; level 7, nodal station 7; lobe, lobectomy; multi, multilevel node involvement; pneum, pneumonectomy; R0, complete resection; R1,2, incomplete resection; single, single level node involvement; T1,2, T1 or T2 primary tumor; T3, T3 primary tumor References: R1,24,6,79–83,87,89,94,104,110; T33,4,6,79–81,87,89,104,110; Multi6,79–81,83,87,89,94,104; cN26,79,80,87,89,104,105,110; Station 72,79,81,82,88,94,104; Pneumonectomy2,79,82,89; Adenocarcinoma2,4,6,79,80,87,89,110; Lobectomy2,79,82,89; R02,4,6,79–83,85,87,89,94,104,106,107,110–117; T1,22–4,6,79–81,87,89,104,110; Single2,6,79–81,83,87,89,94,104; cN0,16,79,80,87,89,105,110
F. C. Detterbeck
96 Table 9.4. Survival of pN2 patients with particular negative prognostic factors. Study Andre6 Naruke4 Maggi81 Régnard104 Riquet83 Suzuki89 Wada3 Watanabe94 Miller82 Thomas88 Tanaka87 Watanabe80 Goldstraw2 Vansteenkiste79 Cybulsky105 Ishida110 Average (all patients)
% 5-year survival, all patients (R0–2) cN2 multi T3 pneum #7
Table 9.5. Survival of pN2 patients with particular positive prognostic factors.
N
R1,2
702 545 278 254 237 222 214 199 167 163 155 153 149 140 124 115
10 8b 0 0c 8 0e –e 0 5 –e 6e 0 – 4 –c 9b
7 – – 18 – 7 – – – – 25 16 – 15 7 16
7 – 15 9 8 19 – 9 – – 25 7 – 22 – –
13a 14 10 11 – 13a 15 – – – 15 15 – 2 – 0
– – – – – 13 – – 18 – – – 21 22 – –
– – 8 18d – – – 23d 13 14 – – 27 14 – –
13 21 – – – 31 – – – – 27 24 4 18 – 19
Andre6 Naruke4 Maggi81 Régnard104 Riquet83 Suzuki89 Wada3 Watanabe94 Miller82 Tanaka87 Watanabe80 Goldstraw2 Vansteenkiste79 Cybulsky105] Ishida110 Detterbeck11,b
4
14
13
11
19
17
20
Average (all)
Ad/Lg
Inclusion Criteria: Studies of ³100 pN2 patients reporting survival by prognostic factor from 1980–2009 Legend: #7 nodal station 7, Ad/Lg Adenocarcinoma, in some cases also including large cell carcinoma (not squamous), cN2 clinical N2 by CT, LL lower lobe, Multi multilevel node involvement, pneum pneumonectomy, R1,2 incomplete resection, defined as microscopic or gross residual except as indicated, T3 T3 primary tumor. a T3 and T4; b defined as positive margin (R1,2) or no complete node dissection performed; c no definition provided; d Single level involvement; e defined as positive margin (R1,2) or highest node positive.
that of European or Asian series (7% vs. 18% vs. 17% for cN2; 14% vs. 28% vs. 30% for cN0,1, respectively, with limited preoperative invasive staging).11 The IASLC staging database corroborates the presence of differences, although in a different order: Europe < North America < Asia (12% vs. 17% vs. 20% 5-year survival for cN2, respectively).74 The reason for the geographic variation is not clear. There are regional differences in lung cancer on different continents (e.g. higher proportion of squamous cancers in Europe, higher proportion of bronchoalveolar carcinoma and EGFR mutations in Asia). There also are regional differences in how specific lymph nodes are classified, and a node near the pleural reflection is more likely to be classified as N2 by Japanese surgeons and N1 by European surgeons.95 A revised node map that seeks to reconcile these continental differences has been developed.96
Study
N 702 545 278 254 237 222 214 199 167 155 153 149 140 124 115 1,443
% 5-year survival, all patients (R0–2) R0 cN0,1 Single T1,2 Lobe
Sq
23 23 18 23 20 36 – 20 24 34 24 20 25 – 26 24
29 – – – – 43 – – – 30 33 – 22 14 24a –
25 – 22 24 26 35 – 35 – 37 35 21 20 – – –
22 21a 20 29a – 31 34 – – 33a 33 14 29a – 23a –
– – – – – 31 – – 31 – – 21 14 – – –
20 31 – – – 21 – – – 27 22 30 22 – 15 –
24
28
28
26
24
24
Inclusion Criteria: Studies of ³100 pN2 patients reporting survival by prognostic factor from 1980–2009 Legend: Ad/Lg Adenocarcinoma, in some cases also including large cell carcinoma (not squamous), cN0,1 clinical N0 or N1 by CT; Lobe lobectomy, R0 complete resection, defined as negative margins, Single single level node involvement; Sq Squamous cell cancer, T1,2 T1 or T2 primary tumor. a Estimated from reported data; b additional studies reporting only on R0 resection.
It is not clear how the geographic differences should affect recommendations for patient management. The overall data presented here represent an average of studies conducted throughout the world. It is reasonable to conclude that perhaps in Asia one can be more aggressive with resection, whereas in Europe and North America caution is advised. Given the somewhat conflicting results for Europe and North America, it is difficult to go any further. Perhaps the recommendations will change as we implement a new stage classification system and node map worldwide.
Discussion What to do when intraoperative N2 disease is found remains a difficult decision, but the overall thrust of these findings is that the key is careful
9. N2 Disease Discovered at Thoracotomy: Resect or Abort?
preoperative assessment. If patients have ignored N2 disease (suspicious nodes that were not investigated) it is probably best to close the patient and do the staging that should have been done in the first place. On the other extreme, if careful imaging and invasive staging has been performed, proceeding with resection in the face of N2 disease is justified (provided a complete resection can be performed). There are good data to support invasive mediastinal staging in patients with a normal mediastinum by CT and PET but a central tumor or cN1 disease (20–25% chance of N2 involvement). If this is negative but N2 disease is found at thoracotomy, there is ample justification to proceeding with resection. However, if invasive mediastinal staging was not done, the long-term survival that can be expected is only 15–20%, and the justification to proceed is significantly weakened. This focus on aggressive preoperative staging in order to make intraoperative decision-making easier if N2 disease is discovered can be criticized as just shifting the question of how to manage the patient to a different setting. What is the best treatment for a patient with a small amount of N2 involvement in a single node station? Some would argue it is primary surgical resection (especially in Europe and Asia). Others would opt for chemoradiation, considering these patients to be in the cohort of N2 patients in the randomized trials that have shown similar outcomes for definitive chemoradiotherapy and a trimodality approach. Others would offer neoadjuvant treatment and then surgery. A full discussion of these approaches is beyond the scope of this review. However, three major points should be noted. First, the published outcomes for primary surgery in highly selected patients with preoperatively identified N2 involvement are poor (5-year survival 10–15%). If selection of patients with a better outcome for primary surgery is possible, it has not yet been substantiated by published results. Second, it is much better to make a decision about how to manage a patient with N2 involvement calmly in a multidisciplinary discussion (i.e. after invasive staging) than under duress intraoperatively because invasive staging was omitted. Finally, if an alternative approach to primary resection is considered, it is much more feasible and successful if the morbidity and mortality of an exploratory thoracotomy are avoided.
97
In general, if careful preoperative staging has been carried out, it is best to proceed with resection unless it is clear this will be incomplete. The influence of specific factors on survival should be viewed with some caution; the results are not really independent of other factors and the exact clinical setting is not clear. However, there is good justification in practically all cases to proceed with resection if there is a T1,2 primary tumor and single station involvement (although this is not really known intra-operatively). Multilevel N2 involvement does not seem to be such a poor prognostic factor to warrant aborting the resection, and the range of reported results is fairly broad.Involvement of a specific node station does not appear to be a factor that should affect decision–making. The histologic type of NSCLC is also not significant, although the range of survival for adenocarcinoma is quite broad. What appears to be most debatable is what to do in the face of a T3N2 tumor. Perhaps in the setting of good preoperative staging, resection should be carried out, whereas if preoperative staging is less extensive or if there are multiple other negative factors (i.e. multimode involvement) an alternative therapy is better. Intraoperative decision-making is primarily determined by the long-term survival that can be expected, both with resection and with alternative therapies. The short-term outcomes are generally quite similar for lobectomy and an aborted resection. However, if a pneumonectomy is needed, perioperative mortality as well as long-term quality of life factor into the decision. The long-term survival, on the other hand, is quite similar for pneumonectomy vs. lobectomy when N2 disease is found (Figs. 9.4, 9.5 and Table 9.3). If the operative risk is assessed to be low (e.g. younger age, left lung, good pulmonary reserve) it is reasonable to proceed. If the perioperative risk is high, definitive chemoradiotherapy may be better, especially if there are other negative prognostic factors (e.g. T3 tumor, multilevel N2). In some ways, however, the assessment of the perioperative risk with a pneumonectomy is more of a general consideration whether the patient should undergo surgery, rather than an alteration of the plan if N2 disease is found. This analysis has focused on patients who are undergoing a thoracotomy for lung resection as opposed to a thoracoscopic (VATS) resection. This is
F. C. Detterbeck
98
because there are more data defining outcomes after thoracotomy. VATS has a lesser impact on patients, with lower perioperative morbidity and mortality31,97–99 as well as higher success in delivering adjuvant chemotherapy.100 These aspects would favor initial surgery and postoperative chemotherapy. On the other hand, the impact of a thoracoscopic exploration should also be lower, which would argue in favor of aborting a resection and planning an alternative treatment. These factors may well balance themselves out, meaning that the recommendations remain the same for thoracotomy and VATS. There are different attitudes in different parts of the world regarding the role of surgery for N2 disease, and the geographic variation in outcomes suggests these may be justified. However, this issue has not been fully analyzed, and the results are somewhat inconsistent. Therefore it is not possible to formulate different recommendations depending on geographic location.
Conclusion A comprehensive review of data regarding N2 involvement with NSCLC found intraoperatively shows that the extent of preoperative staging is the major factor affecting survival. If staging has been poor, resection should be aborted; if the preoperative staging has been extensive, resection is well justified (provided it will be complete). For the most part, specific factors such as which node stations are involved do not have a major impact on the decision. In the face of T3 disease one should be careful that other prognostic factors are favorable; in the face of a pneumonectomy patients need to be selected carefully to have low perioperative risk. The decision in many cases remains a difficult judgment, because many other factors, such as geographic variation, also play a role.
Summary In patients with enlarged or PET positive nodes who have not undergone invasive mediastinal staging (ignored N2), and are found intraoperatively to have
N2 involvement, the long-term outcome of resection is poor, although resection appears to be safe (evidence quality low). A weak recommendation is made that the resection should be aborted and an alternative treatment strategy should be pursued (e.g. induction therapy and subsequent resection or definitive chemoRT) (recommendation grade 2C). Patients with central tumors or cN1 disease who are found intraoperatively to have N2 involvement (underappreciated N2) have reasonable long-term survival after resection and resection appears to be safe (evidence quality low). A weak recommendation is made for proceeding with resection and adjuvant therapy (chemotherapy and possibly RT), provided a complete resection can be achieved and a pneumonectomy is not needed (recommendation grade 2C). Patients with incidental N1 involvement discovered at thoracotomy have moderately good longterm outcomes after resection, and resection appears to be safe (evidence quality low). A weak recommendation is made for proceeding with resection (including pneumonectomy) and adjuvant therapy (chemotherapy and possibly RT), provided a complete resection can be achieved (recommendation grade 2C). In patients found intraoperatively to have N2 involvement, who have T3 disease or multilevel N2 involvement, lobectomy appears to be safe and is associated with acceptable long-term outcomes (evidence quality low). A weak recommendation is made for proceeding with resection if a complete resection can be achieved, a pneumonectomy is not needed, and there are no major other negative prognostic factors or significant comorbidities (recommendation grade 2C).
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101 66. Eschmann SM, Friedel G, Paulsen F, Budach W, Harer-Mouline C, Dohmen BM, Bares R. FDG PET for staging of advanced non-small cell lung cancer prior to neoadjuvant radio-chemotherapy. Eur J Nucl Med Mol Imaging. 2002;29:804–808. 67. Weder W, Schmid RA, Bruchhaus H, Hillinger S, von Schulthess GK, Steinert HC. Detection of extrathoracic metastases by positron emission tomography in lung cancer. Ann Thorac Surg. 1998;66:886–893. 68. Dietlein M, Weber K, Gandjour A, Moka D, Theissen P, Lauterbach KW, Schicha H. Cost-effectiveness of FDG-PET for the management of potentially operable non-small cell lung cancer; priority for a PETbased strategy after nodal-negative CT results. Eur J Nucl Med. 2000;27:1598–1609. 69. Gould MK, Kuschner WG, Rydzak CE, Maclean CC, Demas AN, Shigemitsu H, Chan JK, Owens DK. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a metaanalysis. Ann Intern Med. 2003;139:879–892. 70. Serra M, Cirera L, Rami-Porta R, Bastus R, Gonzalez S, Simo M, Domenech M, Barbeta E, Soler JM, Belda J. Routine positron tomography (PET) and selective mediastinoscopy is as good as routine mediastinoscopy to rule out N2 disease in non-small cell lung cancer (NSCLC). J Clin Oncol. 2006;24(suppl): 371s. 71. Cerfolio RJ, Bryant AS, Ojha B, Eloubeidi M. Improving the inaccuracies of clinical staging of patients with NSCLC: a prospective trial. Ann Thorac Surg. 2005;80:1207–1214. 72. Verhagen AFT, Bootsma GP, Tjan-Heijnen VCG, van der Wilt GJ, Cox AL, Brouwer MHJ, Corstens FHM, Oyen WJG. FDG-PET in staging lung cancer: How does it change the algorithm? Lung Cancer. 2004;44: 175–181. 73. Pozo-Rodriguez F, Martin de Nicolas JL, SanchezNistal MA, Maldonado A, Garcia de Barajas S, CaleroGarcia R, Pozo MA, Martin-Escribano P, Martin-Garcia I, Garcia-Lujan R, Lopez-Encuentra A, Arenas de Pablo A. Accuracy of helical computed tomography and [18F] fluorodeoxyglucose positron emission tomography for identifying lymph node mediastinal metastases in potentially resectable non-small-cell lung cancer. J Clin Oncol. 2005;23: 8348–8356. 74. Rusch VW, Crowley J, Giroux DJ, Goldstraw P, Im J-G, Tsuboi M, Tsuchiya R, Vansteenkiste J. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2007;2:603–612. 75. Farrell MA, McAdams HP, Herndon JE, Patz EFJ. Non-small cell lung cancer: FDG PET for nodal staging in patients with stage I disease. Radiology. 2000;215:886–890. 76. Reed C, Harpole D, Posther K, Woolson S, Downey RJ, Meyers BF, Heelan R, MacApinlac H, Jung S-H, Silvestri GA, Siegel BA, Rusch VW. Results of the
102 American College of Surgeons Oncology Group Z0050 Trial: the utility of positron emission tomography in staging potentially operable non-small cell lung cancer. J Thorac Cardiovasc Surg. 2003;126: 1943–1951. 77. Viney RC, Boyer MJ, King MT, Kenny PM, Pollicino CA, McLean JM, McCaughan BC, Fulham MJ. Randomized controlled trial of the role of positron emission tomography in the management of stage I and II non-small-cell lung cancer. J Clin Oncol. 2004;22:2357–2362. 78. Detterbeck FC, Jones DR. Surgical treatment of stage IIIa (N2) non-small cell lung cancer. In: Detterbeck FC, Rivera MP, Socinski MA, Rosenman JG, eds. Diagnosis and Treatment of Lung Cancer: An Evidence-Based Guide for the Practicing Clinician. Philadelphia, PA: W.B. Saunders; 2001:244–256. 79. Vansteenkiste JF, DeLeyn PR, Deneffe GJ, Stalpaert G, Nackaerts KL, Lerut TE, Demedts MG, and the Leuven Lung Cancer Group. Survival and prognostic factors in resected N2 non-small cell lung cancer: a study of 140 cases. Ann Thorac Surg. 1997;63:1441–1450. 80. Watanabe Y, Shimizu J, Oda M, Hayashi Y, Watanabe S, Tatsuzawa Y, Iwa T, Suzuki M, Takashima T. Aggressive surgical intervention in N2 non-small cell cancer of the lung. Ann Thorac Surg. 1991;51:253–261. 81. Maggi G, Casadio C, Cianci R, Molinatti M, Filosso PL, Nicolosi M, Oliaro A. Results of surgical resection of Stage IIIA (N2) non small cell lung cancer, according to the site of the mediastinal metastases. Intern Surg. 1993;78:213–217. 82. Miller DL, McManus KG, Allen MS, Ilstrup D, Deschamps C, Trastek V, Daly R, Pairolero P. Results of surgical resection of patients with N2 non-small cell lung cancer. Ann Thorac Surg. 1994;57:1095–1101. 83. Riquet M, Manac’h D, Saab M, Le Pimpec-Barthes F, Dujon A, Debesse B. Factors determining survival in resected N2 lung cancer. Eur J Cardio-Thorac Surg. 1995;9:300–304. 84. Martini N, Flehinger BJ, Zaman MB, Beattie Jr EJ. Results of resection in non-oat cell carcinoma of the lung with mediastinal lymph node metastases. Ann Surg. 1983;198:386–397. 85. Ichinose Y, Kato H, Koike T, Tsuchiya R, Fujisawa T, Shimizu N, Watanabe Y, Mitsudomi T, Yoshimura M. Overall survival and local recurrence of 406 completely resected stage IIIa-N2 non-small cell lung cancer patients: questionnaire survey of the Japan Clinical Oncology Group to plan for clinical trials. Lung Cancer. 2001;34:29–36. 86. Mountain CF. Expanded possibilities for surgical treatment of lung cancer: survival in stage IIIa disease. Chest. 1990;97:1045–1051. 87. Tanaka F, Yanagihara K, Ohtake Y, Fukuse T, Hitomi S, Wada H. Time trends and survival after surgery for p-stage IIIa, pN2 non-small cell lung cancer (NSCLC). Eur J Cardiothorac Surg. 1997;12: 372–379.
F. C. Detterbeck 88. Thomas PA, Piantadosi S, Mountain CF. Should subcarinal lymph nodes be routinely examined in patients with non-small cell lung cancer? J Thorac Cardiovasc Surg. 1988;95:883–887. 89. Suzuki K, Nagai K, Yoshida J, Nishimura M, Takahashi K, Nishiwaki Y. The prognosis of surgically resected N2 non-small cell lung cancer: the importance of clinical N status. J Thorac Cardiovasc Surg. 1999;118:145–153. 90. UICC. TNM Classification of Malingnant Tumors. Hoboken: Wiley-Blackwell; 2009. 91. Detterbeck F, Boffa DJ, Tanoue L, Wilson L. Details, difficulties and dilemmas regarding the new lung cancer staging system. Chest. 2010; submitted. 92. Vansteenkiste JF, De Leyn PR, Deneffe GJ, Lerut TE, Demedts MG. Clinical prognostic factors in surgically treated stage IIIA-N2 non-small cell lung cancer: analysis of the literature. Lung Cancer. 1998;19:3–13. 93. Okada M, Tsubota N, Yoshimura M, Miyamoto Y, Matsuoka H. Prognosis of completely resected pN2 non-small cell lung carcinomas: what is the significant node that affects survival? J Thorac Cardiovasc Surg. 1999;118:270–275. 94. Watanabe Y, Hayashi Y, Shimizu J, Oda M, Iwa T. Mediastinal nodal involvement and the prognosis of non-small cell lung cancer. Chest. 1991;100: 422–428. 95. Watanabe S, Ladas GP, Goldstraw P. Inter-observer variability in systematic nodal dissection: comparison of European and Japanese nodal designation. Ann Thorac Surg. 2002;73:245–248. 96. Rusch V, Asamura H, Watanabe H, Giroux D, RamiPorta R, Goldstraw P, Members of the IASLC Staging Committee. The IASLC Lung Cancer Staging Project: a proposal for a new international lymph node map in the forthcoming 7th edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4:568–577. 97. Cheng D, Downey RJ, Kernstine K, Stanbridge R, Shennib H, Wolf R, Ohtsuka T, Schmid R, Waller D, Fernando H, Yim A, Martin J. Video-assisted thoracic surgery in lung cancer resection: a meta-analysis and systematic review of controlled trials. Innovations. 2007;2:261–292. 98. Detterbeck F. Thoracoscopic vs. open lobectomy debate: the pro argument. Thorac Surg Sci. 2009;(accepted). 99. Li WW, Lee TW, Lam SS, Ng CS, Sihoe AD, Wan IY, Yim AP. Quality of life following lung cancer resection: video-assisted thoracic surgery vs thoracotomy. Chest. 2002;122:584–589. 100. Petersen RP, Pham D, Burfeind WR, Hanish SI, Toloza EM, Harpole JDH, D’Amico TA. Thoracoscopic lobectomy facilitates the delivery of chemotherapy after resection for lung cancer. Ann Thorac Surg. 2007;83:1245–1250.
9. N2 Disease Discovered at Thoracotomy: Resect or Abort? 101. Pearson FG, DeLarue NC, Ilves R, Todd TRJ, Cooper JD. Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg. 1982;83:1–11. 102. Coughlin M, Deslauriers J, Beaulieu M, Fournier B, Piraux M, Rouleau J, Tardif A. Role of mediastinoscopy in pretreatment staging of patients with primary lung cancer. Ann Thorac Surg. 1985;40:556–560. 103. Mansour Z, Kochetkova EA, Santelmo N, Ducrocq X, Quoix E, Wihlm J-M, Massard G. Persistent N2 disease after induction therapy does not jeopardize early and medium term outcomes of pneumonectomy. Ann Thorac Surg. 2008;86:228–233. 104. Régnard JF, Magdeleinat P, Azoulay D, Dartevelle P, Deneuville M, Rojas-Miranda A, Levasseur P. Results of resection for bronchogenic carcinoma with mediastinal lymph node metastases in selected patients. Eur J Cardiothorac Surg. 1991;5:583–587. 105. Cybulsky I, Lanza L, Ryan M, Putnam Jr J, McMurtrey M, Roth J. Prognostic significance of computed tomography in resected N2 lung cancer. Ann Thorac Surg. 1992;54:533–537. 106. Inoue M, Sawabata N, Takeda S, Ohta M, Ohno Y, Maeda H. Results of surgical intervention for p-stage IIIA (N2) non-small cell lung cancer: acceptable prognosis predicted by complete resection in patients with single N2 disease with primary tumor in the upper lobe. J Thorac Cardiovasc Surg. 2004;127:1100–1106. 107. Tanaka F, Yanagihara K, Otake Y, Kawano Y, Miyahara R, Takenaka K, Katakura H, Ishikawa S, Ito H, Wada H. Prognostic factors in resected pathologic (p-) Stage IIIA-N2, non-small-cell lung cancer. Ann Surg Oncol. 2004;11:612–618. 108. Daly B, Mueller J, Faling L, Diehl J, Bankoff M, Karp D, Rand W. N2 lung cancer: outcome in patients with false-negative computed tomographic scans of the chest. J Thorac Cardiovasc Surg. 1993;105:904–911. 109. Sakao Y, Miyamoto H, Yamazaki A, Oh T, Fukai R, Shiomi K, Saito Y. Prognostic significance of metastasis to the highest mediastinal lymph node in nonsmall cell lung cancer. Ann Thorac Surg. 2006;81:292–297.
103 110. Ishida T, Tateishi M, Kaneko S, Sugimachi K. Surgical treatment of patients with nonsmall-cell lung cancer and mediastinal lymph node involvement. J Surg Oncol. 1990;43:161–166. 111. Maggi G, Casadio C, Mancuso M, Oliaro A, Cianci R, Ruffini E. Resection and radical lymphadenectomy for lung cancer: prognostic significance of lymphatic metastases. Int Surg. 1990;75:17–21. 112. Rea F, Marulli G, Callegaro D, Zuin A, Gobbi T, Loy M, Sartori F. Prognostic significance of main bronchial lymph nodes involvement in non-small cell lung carcinoma: N1 or N2? Lung Cancer. 2004;45:215–220. 113. Iwasaki A, Shirakusa T, Miyoshi T, Hamada T, Enatsu S, Maekawa S, Hiratsuka M. Prognostic significance of subcarinal station in non-small cell lung cancer with T1 - 3 N2 disease. Thorac Cardiovasc Surg. 2006;54: 42–46. 114. Okada M, Tsubota N, Yoshimura M, Miyamoto Y, Nakai R. Evaluation of TMN classification for lung carcinoma with ipsilateral intrapulmonary metastasis. Ann Thorac Surg. 1999;68:326–331. 115. Conill C, Astudillo J, Verger E. Prognostic significance of metastases to mediastinal lymph node levels in resected non-small cell lung carcinoma. Cancer. 1993;72:1199–1202. 116. Ohta Y, Shimizu Y, Minato H, Matsumoto I, Oda M, Watanabe G. Results of initial operations in non–small cell lung cancer patients with single-level N2 disease. Ann Thorac Surg. 2006;81:427–433. 117. De Leyn P, Schoonooghe P, Deneffe G, Van Raemdonck D, Coosemans W, Vansteenkiste J, Lerut T. Surgery for non-small cell lung cancer with unsuspected metastasis to ipsilateral mediastinal or subcarinal nodes (N2 disease). Eur J Cardiothorac Surg. 1996;10:649–655. 118. Cerfolio RJ, Bryant AS. Survival of patients with unsuspected N2 (Stage IIIA) nonsmall-cell lung cancer. Ann Thorac Surg. 2008;86:362–367. 119. Mangione CM, Goldman L, Orav EJ, Marcantonio ER, Pedan A, Ludwig LE, Donaldson MC, Sugarbaker DJ, Poss R, Lee TH. Health-related quality of life after elective surgery: measurement of longitudinal changes. J Gen Intern Med. 1997;12:686–697.
10
Pulmonary Function Alterations After Induction Therapy for Lung Cancer: Preoperative Considerations Gabriel Loor and Mark K. Ferguson
Introduction Neoadjuvant chemotherapy or chemoradiotherapy prior to surgery offers hope for extended survival in patients with regionally advanced non-small cell lung cancer (NSCLC), particularly those patients with ipsilateral mediastinal nodal involvement. However, neoadjuvant therapies are sometimes associated with pulmonary toxicity. A recent large scale analysis using the Society of Thoracic Surgery (STS) General Thoracic Surgery Database identified induction therapy as an independent predictor of postoperative pulmonary complications.1 The present chapter reviews the effects of neoadjuvant therapy on pulmonary function as well as perioperative morbidity and mortality, and examines whether altering the timing of resection can reduce the risk of complications.
Literature Search Strategy A Pubmed search incorporating the index terms “neoadjuvant,” “lung cancer,” and “pulmonary function tests” was used to review the literature between 1994 and 2009 published in the English language. Studies had to describe complications related to neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy. Most studies included pulmonary function tests in the analysis of perioperative variables. In addition, all studies had to include a cohort size large enough to reach a statistical conclusion about the effect of neoadjuvant therapy on perioperative morbidity.
Role of Neoadjuvant Therapy in the Treatment of Lung Cancer A number of studies have reported that the use of neoadjuvant therapy for non-small cell lung cancer (NSCLC) improves long-term survival in patients with ipsilateral mediastinal nodal involvement. In Roth’s initial report, 60 patients with advanced non-small cell lung cancer were randomized to receive either six cycles of perioperative chemotherapy and surgery or surgery alone.2 Patients treated with preoperative chemotherapy and surgery had an estimated median survival of 64 months compared with 11 months for patients who had surgery alone (p < 0.008). In a follow-up analysis this survival benefit was maintained up to 82 months post randomization.3 In a study by Rosell, 60 patients with stage IIIA (73% N2 positive) NSCLC were randomly assigned to receive either surgery alone or three courses of chemotherapy prior to surgery.4 The median period of survival was 26 months in the patients treated with chemotherapy plus surgery compared with 8 months in the patients treated with surgery alone (p < 0.001). In a follow-up analysis patients with neoadjuvant chemotherapy had a 22 month median survival compared with a 10 month median survival for patients treated with surgery alone (p = 0.005).5 Although these two studies were small and their findings have not been subsequently replicated, they provide high quality evidence that neoadjuvant chemother apy extends survival in patients with stage IIIA NSCLC.
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_10, © Springer-Verlag London Limited 2011
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Effects of Chemotherapy and Radiotherapy on Pulmonary Function Several studies have demonstrated detrimental effects of chemotherapy on the diffusion capacity of the lung for carbon monoxide (DLCO), forced expiratory volume during the first second (FEV1) and forced vital capacity (FVC). Castro evaluated the effects of mitomycin on pulmonary function and demonstrated a 15% average decline in dif fusion capacity after three cycles.6 Pulmonary toxicities attributed to mitomycin included noncardiogenic pulmonary edema, interstitial pneumonitis and pleural effusions. Dimoupoulo evaluated the effects of paclitaxel and carboplatin on pulmonary function and demonstrated a significant decline in DLCO that persisted for 5 months after treatment.7 There were no differences observed in FVC or FEV1. Bhalla evaluated the effects of induction chemotherapy on pulmonary function in breast cancer patients.8 They found that after three cycles of induction chemotherapy the mean DLCO decreased by 12.6%. In addition, delayed pulmonary toxicity syndrome (DPTS) occurred in 72% of patients who went on to receive high dose chemotherapy with autologous bone marrow transplantation versus only 4% in patients who subsequently received standard dose chemotherapy. Rivera evaluated the impact of gemcitabine, paclitaxel, cisplatin, and carboplatin on preoperative pulmonary function in patients with stage I or II NSCLC.9 They showed a mean decrease in DLCO of 8.7% (p < 0.0001) from pretreatment values. Interestingly, there was no statistically significant change in other spirometric values. These studies provide consistent observational evidence that induction chemotherapy results in a decrease in DLCO without necessarily affecting spirometric values (evidence quality moderate). Radiotherapy has also been shown to have an important impact on pulmonary function. Choi studied patients with unresectable lung cancer and found that those with a preoperative FEV1 > 50% had a decrease in FEV1, FVC and DLCO by as much as 22% after radiation therapy.10 This effect was not as pronounced for patients with FEV1 < 50% at baseline. In an analysis by Fan,
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radiation-induced changes in regional perfusion were shown to correlate with impairment in pulmonary function.11 A variety of other studies have shown similar impairments in pulmonary function related to thoracic radiotherapy.12–14
Impact of Neoadjuvant Chemotherapy on Postoperative Complications It is well known that patients with impaired DLCO (predicted postoperative value <40% of normal) are at increased risk for perioperative death and cardiopulmonary complications after major lung resection.15–18 Neoadjuvant chemotherapy may result in interstitial changes in the pulmonary parenchyma that predispose patients to increased postoperative pulmonary complications.19 Several studies suggest that neoadjuvant chemotherapy increases perioperative pulmonary complications. In Roberts’ study, 34 consecutive patients who underwent resection after neoadjuvant therapy with carboplatin and taxol were compared with 67 patients who underwent resection alone.20 Neoadjuvant chemotherapy was associated with a significant increase in pulmonary complications, including the need for tracheostomy and reintubation, compared to patients who did not undergo induction therapy (26.5% vs. 6%; p = 0.0036). Leo’s group studied 30 consecutive patients with stage IIIA (N2) NSCLC treated with cisplatin and gemcitabine followed by resection.21 One patient died after surgery and four patients (13.3%) experienced postoperative respiratory complications. Compared with patients without complications, these four patients had a greater mean decrease in DLCO (-27.8% vs -13.6%; p = 0.03). Four weeks following their last chemotherapy cycle, mean DLCO was significantly decreased from 74% to 65% (p = 0.0006). The impact of a change in DLCO on postoperative respiratory complications was not confirmed by their multivariate analysis, although the study was limited by a small sample size (n = 30) and a small number of events (n = 4) (p = 0.16). Martin retrospectively looked at all patients in their institution who underwent induction chemotherapy from 1993 to 1999. In this large study on a cohort of 470 patients receiving neoadjuvant chemotherapy, they showed that preoperative FEV1 significan
10. Pulmonary Function Alterations After Induction Therapy for Lung Cancer: Preoperative Considerations
tly predicts postoperative pulmonary morbidity. Unfortunately, they were not able to define a specific cutoff value that could be used in clinical practice. The DLCO approached significance by univariate analysis. Other factors independently associated with postoperative complications after neoadjuvant chemotherapy included blood loss and right-sided pneumonectomies.22 Conversely, a study by Brouchet contradicts the notion that neoadjuvant chemotherapy increases perioperative pulmonary morbidity. They perfor med a retrospective review of a large prospective database including 3,888 patients operated on for NSCLC.23 On multivariate analysis, age (older than 65 years), sex (male), presence of comorbidities (two or more), clinical score (moderate), and type of operation (bilobectomy) were associated with increased pulmonary morbidity. Neither preoperative chemotherapy nor clinical stage had a significant influence on postoperative morbidity. However, the fact that this is a retrospective study suggests that patient selection was likely an important factor in who did and did not get induction therapy. This bias may have impaired their ability to detect the effects of neoadjuvant therapy on perioperative morbidity. In addition, the studies by Roth and Rosell do not support the notion that chemotherapy increa ses perioperative pulmonary morbidity. In Roth’s study, the incidence of atelectasis, atrial fibrillation or pneumonia was not different between the group of patients who received chemotherapy and those who did not. Rosell reported only mild effects due to chemotherapy most commonly involving nausea and vomiting. While morbidity was not a primary outcome and respiratory complications were not clearly described, neither study noted a difference in pulmonary morbidity between treatment groups (Table 10.1).2–5
Impact of Neoadjuvant Chemoradiotherapy on Postoperative Complications It is becoming increasingly common to include radiotherapy along with chemotherapy in the neoadjuvant treatment of NSCLC. A recent study evaluated over 7,000 patients from the STS General
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Thoracic Surgery Database and linked induction chemoradiotherapy with increases in postoperative complications.1 Extent of resection, age and decreases in DLCO were also independently associated with increased perioperative morbidity. In particular, a decreasing percent of predicted diffusing capacity was incrementally related to an increased incidence of pulmonary complications (odds ratio 1.12 per 10 point decrease; p < 0.0001). In addition, Matsubara studied the impact of induction chemoradiotherapy on extended resection for 758 consecutive patients who underwent surgery for lung cancer.18 Six hundred and sixtysix patients underwent resection alone while 92 patients received induction therapy. A multivariate analysis showed that neoadjuvant chemoradiotherapy was a strong independent predictor for postoperative pulmonary morbidity (p < 0.0001). A study by Gaissert looked retrospectively at 183 patients who underwent pneumonectomies for lung cancer over a 15 year period in a single institution. They found a significantly greater rate of tracheostomies in the induction chemoradiotherapy group compared with the surgery alone group.24 In a recent retrospective review of a prospective database (n = 132 patients), Cerfolio showed that a decrease in DLCO of > 8% after neoadjuvant chemoradiotherapy is significantly associated with either respiratory or major non-respiratory morbidity.25 This study suggests that chemoradiotherapy-induced decreases in DLCO may be a mediator of, or at least a marker for, postoperative pulmonary morbidity. Similarly, Takeda’s group looked at 66 consecutive patients who underwent pulmonary resection after induction therapy with chemoradiation. A multivariate analysis revealed that predicted postoperative DLCO was a strong independent predictor of postoperative pulmonary morbidity. DLCO dropped by an average of 19% in patients who developed pulmonary complications (p < 0.0001) (Table 10.2).26
Optimal Timing of Operative Intervention It is unclear exactly how chemotherapy leads to changes in lung function. A variety of interesting observations related to cellular and interstitial
G. Loor and M.K. Ferguson
108 Table 10.1. Effects of neoadjuvant chemotherapy on postoperative. Pulmonary complications Study
Design
Roberts
Neoadjuvant agent Carboplatin, taxol
Leo21
Prospective, non-randomized comparison n = 111 Prospective, observational n = 30
Martin22
Retrospective review n = 470
Multiple agents
Brouchet 23
Retrospective review, prospective database n = 3,888 Prospective, randomized controlled trial n = 60 Prospective, randomized controlled trial n = 60
Multiple agents
20
Roth2 Rosell4
Cisplatin, gemcitabine
Cyclophosphamide, cisplatin, etoposide Mitomycin, ifosfamide, cisplatin
Conclusion(s) Increased post-op life-threatening pulmonary complications Increased post-op pulmonary morbidity is not predicted by a decrease in DLCO FEV1, Right pneumonectomy and blood loss are independent predictors of postop complications Neoadjuvant chemotherapy does not increase post-op pulmonary morbidity Neoadjuvant chemotherapy does not increase post-op pulmonary morbidity Neoadjuvant chemotherapy does not increase post-op pulmonary morbidity
Strength of evidence Moderate Low Moderate
Moderate Moderate Moderate
Table 10.2. Effects of neoadjuvant chemoradiotherapy on postoperative. Pulmonary complications Study
Design
Ferguson
Retrospective review, prospective database, n = 7891
Matsabura18
Retrospective review n = 758
Gaissert24
Prospective, nonrandomized comparison n = 183 Retrospective review, prospective database n = 132 Prospective, observational n = 66
1
Cerfolio25 Takeda26
Conclusion(s)
Strength of evidence
Induction chemo-xrt, age, FEV1, extent of resection and decreased DLCO are associated with increased post-op morbidity Induction chemo-xrt is a strong independent predictor for post-op pulmonary complication Increased risk of tracheotomies with neoadjuvant chemo-xrt
Moderate
Decrease in DLCO of >8% is associated with greater post-op pulmonary morbidity Postop predicted DLCO is an independent predictor of post-op pulmonary morbidity
Moderate
changes have been proposed.8,19,27,28 There is scant observational data that patients who have impaired DLCO as a result of these parenchymal changes will recover in a period of 4–6 weeks. This time interval was employed in the Roth and Rosell studies, showing that resections could be safely undertaken after neoadjuvant therapy. In fact most of the studies listed above used a 4–6 week window of time prior to surgical resection. However, whether waiting for pulmonary function to improve decreases postoperative risk has not been specifically addressed in the literature. In general, the timing of surgery should be governed by recovery from side effects of chemotherapy, restoration of blood counts, and return to baseline performance status. There are no data that specifically address the timing of therapy relative to changes in pulmonary function.
Low Moderate
Moderate
Recommendation Neoadjuvant chemotherapy benefits long term survival without having a negative impact on perioperative mortality in patients with N2 NSCLC (strong quality evidence). Chemotherapy and chemoradiotherapy negatively affect preoperative DLCO (moderate quality evidence). The pre ponderance of evidence suggests that induction chemotherapy and chemoradiotherapy increase postoperative pulmonary morbidity, although the results are mixed (low quality evidence). We make a strong recommendation that patients who undergo neoadjuvant chemotherapy or chemoradiotherapy for NSCLC should have their pulmonary function re-assessed after completion of induction therapy, and that resection should be performed a minimum of 4 weeks after
10. Pulmonary Function Alterations After Induction Therapy for Lung Cancer: Preoperative Considerations
completion of therapy (recommendation grade 1C). A meaningful decrease in DLCO (>10%) should alert the physician to the possibility of an increased risk of postoperative pulmonary complications. If surgery is postponed pending an improvement in lung function, no recommendation can be made with regards to the duration of time the postponement should be.
A Personal View of the Data Patients are always evaluated physiologically for their ability to undergo major lung resection prior to beginning induction therapy. Testing includes measurement of spirometry, DLCO, and assessment of predicted postoperative function. If either ppoFEV1 or ppoDLCO is <40%, additional evaluation normally includes a quantitative lung per fusion scan and measurement of peak oxygen consumption during exercise. For patients with either ppoFEV1 or ppoDLCO <40%, the peak oxygen consumption generally must be >15 mL/kg/min for patients to qualify for major lung resection. Patients are evaluated shortly after completion of induction therapy looking at, in addition to performance status and organ system dysfunction, clinical and physiologic evidence of pulmonary dysfunction. If the DLCO shows a clinically important (>10%) decrease from baseline, then they are reevaluated in 4 weeks with repeat PFT’s. If their DLCO remains importantly reduced compared to baseline, then measurement of peak oxygen consumption during exercise is used to make a final decision regarding surgery. It is important to note that there is a trivial risk of progression to unresectable disease during that 4–5 week interval of time. Future areas of research that would be help ful include: (1) prediction of which patients are likely to experience a drop in DLCO after chemotherapy; (2) assessment of the timeframe required for the reversal of pulmonary dysfunction following chemotherapy; (3) potential pharmacological interventions that may prevent or reverse pulmo nary dysfunction; (4) definition of the minimum preoperative PFT parameters following neoadjuvant chemotherapy which would limit perioper ative morbidity. While chemotherapy is clearly
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beneficial for patients with advanced lung cancer, it is important that patients and physicians be aware of the risks of neoadjuvant therapy and that signs and symptoms of pulmonary toxicity must be carefully investigated prior to surgery.
Although neoadjuvant therapy benefits long term survival without having a negative impact on perioperative mortality in patients with N2 NSCLC (strong quality evidence), che motherapy and chemoradiotherapy negatively affect preoperative DLCO (moderate quality evidence), and induction therapy increases postoperative pulmonary morbidity (low quality evidence). We make a strong recommendation that patients who undergo induction therapy for NSCLC should have their pulmonary function re-assessed prior to surgery, and that resection should be performed a minimum of 4 weeks after completion of therapy (recommendation grade 1C).
References 1. Ferguson MK, Gaissert HA, Grab JD, Sheng S. Pulmonary complications after lung resection in the absence of chronic obstructive pulmonary disease: The predictive role of diffusing capacity. J Thorac Cardiovasc Surg. 2009;138:1297–1302. 2. Roth JA, Fossella F, Komaki R et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst. 1994;86:673–680. 3. Roth JA, Atkinson EN, Fossella F et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA nonsmall-cell lung cancer. Lung Cancer. 1998;21:1–6. 4. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med. 1994;330: 153–158. 5. Rosell R, Gomez-Codina J, Camps C et al. Preresec tional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial. Lung Cancer. 1999;26:7–14. 6. Castro M, Veeder MH, Mailliard JA, Tazelaar HD, Jett JR. A prospective study of pulmonary function in patients receiving mitomycin. Chest. 1996;109: 939–944.
110 7. Dimopoulou I, Galani H, Dafni U, Samakovii A, Roussos C, Dimopoulos MA. A prospective study of pulmonary function in patients treated with paclitaxel and carboplatin. Cancer. 2002;94:452–458. 8. Bhalla KS, Wilczynski SW, Abushamaa AM et al. Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous hematopoietic support. Am J Respir Crit Care Med. 2000;161:17–25. 9. Rivera MP, Detterbeck FC, Socinski MA et al. Impact of preoperative chemotherapy on pulmonary function tests in resectable early-stage non-small cell lung cancer. Chest. 2009;135:1588–1595. 10. Choi NC, Kanarek DJ. Toxicity of thoracic radiotherapy on pulmonary function in lung cancer. Lung Cancer. 1994;10(suppl 1):S219–S230. 11. Fan M, Marks LB, Hollis D et al. Can we predict radiation-induced changes in pulmonary function based on the sum of predicted regional dysfunction? J Clin Oncol. 2001;19:543–550. 12. De Jaeger K, Seppenwoolde Y, Boersma LJ et al. Pulmonary function following high-dose radiotherapy of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2003;55:1331–1340. 13. Mehta V. Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: pulmonary function, prediction, and prevention. Int J Radiat Oncol Biol Phys. 2005;63:5–24. 14. Videtic GM, Stitt LW, Ash RB et al. Impaired diffusion capacity predicts for decreased treatment tolerance and survival in limited stage small cell lung cancer patients treated with concurrent chemoradiation. Lung Cancer. 2004;43:159–166. 15. Colice GL, Shafazand S, Griffin JP, Keenan R, Bolliger CT. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 suppl):161S–177S. 16. Deslauriers J, Ginsberg RJ, Dubois P, Beaulieu M, Goldberg M, Piraux M. Current operative morbidity associated with elective surgical resection for lung cancer. Can J Surg. 1989;32:335–339. 17. Ferguson MK, Vigneswaran WT. Diffusing capacity predicts morbidity after lung resection in patients without obstructive lung disease. Ann Thorac Surg. 2008;85:1158–1165.
G. Loor and M.K. Ferguson 18. Matsubara Y, Takeda S, Mashimo T. Risk stratification for lung cancer surgery: impact of induction therapy and extended resection. Chest. 2005;128:3519–3525. 19. Leo F, Pelosi G, Sonzogni A, Chilosi M, Bonomo G, Spaggiari L. Structural lung damage after chemotherapy fact or fiction? Lung Cancer. May 26, 2009. [Epub ahead of print] 20. Roberts JR, Eustis C, Devore R, Carbone D, Choy H, Johnson D. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer. Ann Thorac Surg. September 2001;72:885–888. 21. Leo F, Solli P, Spaggiari L et al. Respiratory function changes after chemotherapy: an additional risk for postoperative respiratory complications? Ann Thorac Surg. 2004;77:260–265. 22. Martin J, Ginsberg RJ, Abolhoda A et al. Morbidity and mortality after neoadjuvant therapy for lung cancer: the risks of right pneumonectomy. Ann Thorac Surg. 2001;72:1149–1154. 23. Brouchet L, Bauvin E, Marcheix B et al. Impact of induction treatment on postoperative complications in the treatment of non-small cell lung cancer. J Thorac Oncol. 2007;2:626–631. 24. Gaissert HA, Keum DY, Wright CD et al. POINT: Operative risk of pneumonectomy--influence of preoperative induction therapy. J Thorac Cardiovasc Surg. 2009;138:289–294. 25. Cerfolio RJ, Talati A, Bryant AS. Changes in pulmonary function tests after neoadjuvant therapy predict postoperative complications. Ann Thorac Surg. 2009;88:930–936. 26. Takeda S, Funakoshi Y, Kadota Y et al. Fall in diffusing capacity associated with induction therapy for lung cancer: a predictor of postoperative complication? Ann Thorac Surg. 2006;82:232–236. 27. Sleijfer S, van der Mark TW, Schraffordt Koops H, Mulder NH. Decrease in pulmonary function during bleomycin-containing combination chemotherapy for testicular cancer: not only a bleomycin effect. Br J Cancer. 1995;71:120–123. 28. Todd NW, Peters WP, Ost AH, Roggli VL, Piantadosi CA. Pulmonary drug toxicity in patients with primary breast cancer treated with high-dose combination chemotherapy and autologous bone marrow transplantation. Am Rev Respir Dis. 1993;147:1264–1270.
11
Lobectomy After Induction Therapy for Stage IIIA NSCLC in the Presence of Persistent N2 Disease Gaetano Rocco
Introduction Involvement of mediastinal nodes by metastatic deposits from non-small cell lung cancer (NSCLC) is characterized by heterogeneous manifestations and diverse clinical scenarios (Table 11.1).1,2 For many of these N2 subsets the therapeutic options are well known and are accepted in the clinical practice.3 Patients with potentially resectable N2 disease detected preoperatively usually undergo induction treatment (chemotherapy and/or chemoradiotherapy) and subsequent resection if they show a clinical or pathological complete response.4 Conversely, patients with technically unresectable NSCLC and N2 disease are treated with definitive chemoradiotherapy.5 When N2 disease is discovered only at final pathology, an adjuvant chemoradiation therapeutic regimen is proposed.4,5 In addition to the above N2 categories, two types of N2 disease often entail a difficult decision- making process.5 The first includes patients with N2 involvement discovered at the time of the scheduled resection (“occult N2”). The second category includes those potentially resectable N2 patients who have an incomplete response to induction treatment (“persistent N2”) and the small group of patients whose disease was resolved at clinical restaging but were found to have microscopic residual disease at final pathology of the surgical specimen (“recalcitrant N2”).6 While “occult” N2 and “recalcitrant” N2 disease categories share the distinctive feature of an unexpected finding at surgery or at final pathology and seem to portend a more favorable
prognostic outlook, “persistent” N2 disease after induction treatment is clinically evident and results after resection are often not encouraging.7 A review of several literature sources (Pubmed search conducted for the period 1966 through 2005) and a metanalysis of available randomized controlled trials (RCTs) of neoadjuvant chemotherapy for IIIA-N2 NSCLC yielded a 6% 5 year survival advantage for chemotherapy followed by surgery compared to surgery alone.8 While several chemotherapy-related factors were analyzed in detail, no evaluation of the methodology and the structure of the surgery alone arms was carried out.8
Considerations and Caveats Emerging from Published Results The American College of Chest Physicians recently published guidelines on the management of stage IIIA-N2 disease,5 which emphasized the need for careful re-evaluation of patients who undergo induction treatment in order to select a surgical option when appropriate. The small, albeit clear, survival advantage for lobectomy after neoadjuvant treatment for N2 NSCLC appears sufficiently supported to the point that it can be recommended as standard therapy. In contrast, whenever pneumonectomy is required in these patients, the recommendation is to avoid surgery and complete treatment with chemotherapy and with the addition of radiation therapy to ensure local disease control.
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_11, © Springer-Verlag London Limited 2011
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112 Table 11.1. Classification of N2 disease from a surgical perspective. 1. N2 disease that is not detected by preoperative imaging or biopsy, including EUS, EBUS, mediastinoscopy, etc., and only is discovered as a result of surgery (unexpected N2 disease) (a) N2 disease diagnosed intraoperatively (b) N2 disease diagnosed postoperatively 2. N2 disease recognized at the time of diagnosis and staging by means of imaging or biopsy (a) Isolated nodal abnormalities amenable to resection (b) Confluent, extracapsular spread of nodal disease not amenable to resection 3. N2 disease recognized initially that has responded completely to induction therapy as assessed by repeat imaging or biopsy 4. N2 disease recognized initially that has not responded completely to induction therapy as assessed by repeat imaging or biopsy (recalcitrant N2 disease)
Published RCTs on surgical resection after induction chemotherapy or chemoradiotherapy reveal a common weakness: a relatively limited numbers of the patients enrolled in the surgical arms.9–12 This may reflect a lack of surgical input in the design and the analysis of N2 trials, especially of phase II trials in which surgical results are analyzed as corollary end-points or at post-hoc evaluation. As an example, in some authoritative RCTs, patients were not offered surgery in the presence of stable N2 disease after chemotherapy. This is not in line with the results from other trials10–12 in which pathology from surgical specimens from resected patients showed a major pathological response that was undetected at postinduction clinical re-staging. Whether postinduction surgery should encompass the original extent of disease when N2 disease is associated with T3 tumors is still a matter of debate. Also, if the upper mediastinal nodes are involved with tumor, it is not clear what extent of parenchymal resection is consistent with the concept of radical surgery.7,11 There is a relative abundance of retrospective information as well as data from prospective, randomized trials focusing on the oncological value and the impact on postoperative morbidity and mortality of pneumonectomy after induction treatment.13–16 From an oncological standpoint, pneumonectomy normally is a suitable operation; however, if pneumonectomy is performed as part of a trimodality treatment regimen, it is endowed with a significant burden of postoperative complications, in addition to high short and medium term operative mortality rates.17 Lung cancer surgery in the absence of induction therapy is associated with mortality rates ranging from 1.3% to 3.7%.18 When these figures are stratified by type of
resection, the mortality rates for lobectomy and pneumonectomy are 1.2–2.9% and 3.2–6.2%, respectively. When the resection is performed after neoadjuvant treatment, the figures increase to 2.4–3.8% for lobectomy and 7.2–12% for pneumonectomy.18 All in all, the surgical literature tends not to consider resection after induction treatment to be associated with substantially increased operative risks.19,20 Kunitoch and Suzuki reviewed the available data on 505 patients undergoing pneumonectomy after chemoradiation, and demonstrated an operative mortality ranging between 7% and 33% – with a mortality rate in one report of 37% after right pneumonectomy.17 Moreover, the reported overall postpneumonectomy morbidity was more than 50%.17 The trend towards improved resection and operative mortality rates of single institutional, compared multinstitutional, series may hint at some variability in surgical outcomes among multicenter studies, raising concerns about standardization of surgical protocols for postoperative care and quality control.21 Compared to the pneumonectomy data, there is a paucity of information on the outcomes of lobectomy after induction therapy. However, available data seem to confirm the findings that mortality and morbidity rates are comparable to those associated with lobectomy without preoperative therapy (Table 11.2).22 Another interesting point for consideration involves the concept of technically unresectable N2 disease. Although there have been scattered reports of acceptable results after trimodality treatment of bulky mediastinal nodal disease, fixed nodes with extracapsular dissemination are considered unresectable and, as a rule, patients with such disease are not considered candidates for postinduction resection, but are instead
CT CT CT CT + RT
CT CT
CT + RT CT/CT + RT
Betticher11 Port7 Garrido12 Uy18
Kappers31 Van Meerbeeck9
Albain10 Girard30
34 96 (surgery arm) NR 78
66 32 27 67.5**
98/54 20/22
19/19 58/72
38/37 36/15 23/18 29/11
Clinical Lobectomy vs. response (%) pneumonectomy
71 91**
79 50
57 90 72 92**
RR (%)
CT in 55% RT in 16%
no RT in 62
RT in 33 no RT in 12 no
Postoperative adjuvant therapy
CR 18% CR 5%
CR 19% CR 3.8% CR 3% CR (17%) + PR (50%) = 67% CR 5% CR + PR 41%
Pathologic response
1 4**
3** 0
3 1.9 8.6 0
Operative mortality (%)
NR 22**
NR NR
17 NR 30 6.9
Overall morbidity (%)
CT chemotherapy; RT radiation therapy; CR complete response; PR partial response; NR not reported; NS not significant; NA not applicable; RR response rate *5 year survival or median survival in months **overall figure.
Induction therapy
Author
Table 11.2. Outcomes of resection for N2 nodal involvement in non-small cell lung cancer.
36% 33.6 mos 30 mos**
35 mos 19% 29.7 mos 36% 36.9 mos 51.7% (all) Not reached 43% 33 mos 27% 25.4 mos
Survival after lobectomy*
22% NR
16%19 mos 12% 13.4 mos
46 mos (right) NR 34% (40.4 mos) NR
Survival after pneumonectomy*
Yes NR
Yes Yes
NS NR NS NS
Survival difference
20% 22.2 mos NA
16.% 14% 17.5 mos
NA NA NA NA
Survival without surgery*
11. Lobectomy After Induction Therapy for Stage IIIA NSCLC in the Presence of Persistent N2 Disease 113
G. Rocco
114
assigned to definitive chemoradiation regimens. The inclusion of such subsets of N2 disease into phase III RCTs reiterates the possibility of a lack of substantial surgical focus in the design of the studies.18 In this context, the issue of heterogeneity of N2 disease in the EORTC 08941 trial was raised23 only to elicit the reply that EORTC investigators, in their study analysis, had not been “especially interested in subdivisions of N2 disease.”24 Despite the fact that N2 NSCLC represents a heterogeneous group of patients, there is a trend towards comparing outcomes of lobectomy to those of pneumonectomy without specifying the extent of the associated T status or the subsets of nodal disease ranging from bulky and extracapsular to occult, persistent, or even recalcitrant. Indeed, parenchyma saving resections (i.e., bronchovascular sleeve lobectomies) are successfully used after induction treatment and sometimes encompass the same primary tumor extent as would a simple pneumonectomy.25,26 This is even more true if one analyzes the more prognostically favorable subsets of N2 disease (i.e., single station N2 disease27). Technically, these patients are usually amenable to lobar resections, either with or without the need for angio/bronchoplasty for reconstruction of the vascular and the bronchial axes. However, even the more widespread use of lobectomy and its technical variations may not eliminate the need for pneumonectomy,10 especially in persistently stable N2 disease (i.e., non responders to induction chemotherapy). Overall, the surgical contribution to planning prospective, randomized studies of definitive multimodality treatment for N2 NSCLC is still limited, with many confounding factors affecting their design. The net result is an overall feeling of unreliability towards the reported outcomes, apart from almost intuitive conclusions (i.e., lobectomy carries better functional prognosis than does pneumonectomy) that arise from the bulk of the published evidence. Surgeons have developed a very selective and somewhat intuitive approach in deciding which N2 patients to operate on. They have identified resected N2 subsets with the most favorable prognoses, and, more importantly, surgeons are the ones who, in the operating room, determine the appropriate extent of resection designed to ensure optimal local control for a disease which, at that stage, can be rightfully
considered systemic. In this setting, RCTs appear to be designed almost ignoring that parenchymal resection is designed to treat the primary tumor – not the extent of mediastinal nodal disease. As a rule, N2 nodes are anatomically distinct from the bronchovascular components of the hilum, usually surrounded by N1 nodes. When the latter are enlarged, bronchoplasty and angioplasty to facilitate lobectomy, alone or in combination, can be used to reduce unnecessary loss of functioning lung. In those relatively rare patients in whom enlarged N2 impinge on any hilar or perihilar (i.e., superior vena cava) structures, the decision to perform an extended pneumonectomy is the rule and the prognosis is almost invariably dismal. This scenario gets even more complicated when prethoracotomy invasive methods of mediastinal exploration, along with induction therapy (especially the combination of chemotherapy and radiation therapy), effect substantial derangements in the surgical field. In conclusion, the value of lobectomy (simple or complex, when associated with bronchoplasty and/or angioplasty) for persistent N2 disease still needs to be fully evaluated in order to define the evidence for a survival advantage of surgery vs radiotherapy as preferred modality for local control – if local control is really the issue.28 In this context, the role of pneumonectomy as an adverse oncologic prognosticator compared to lobectomy is yet to be assessed. Also, the possible need for dedicated resources and expertise for parenchyma sparing resections (sleeve, wedge) to avoid pneumonectomy has to be elucidated along with the impact on treatment of the newly introduced histology type-specific chemotherapy regimens.29,30
Recommendations Many confounding factors prejudice the analysis of the value of surgery for persistent N2 disease after induction chemotherapy or chemoradiation therapy. Several metaanalyses demonstrate a 6–7% 5-year survival advantage for induction therapy followed by surgery compared to no surgery (level of evidence moderate).8 However, recently published RCTs do not confirm these results; instead, they report only a progression-free survival advantage in the surgical arm (level of evidence moderate).9,10
11. Lobectomy After Induction Therapy for Stage IIIA NSCLC in the Presence of Persistent N2 Disease
For selected patients with prognostically favorable N2 disease (i.e., single station, not bulky, with no extracapsular extension), surgery is the best modality to achieve local control of the disease after induction treatment. After induction chemoradiation for stage IIIA N2 disease, pneumonectomy should be avoided due to lack of a survival benefit compared to other multimodality regimens owing to excessive postoperative morbidity and mortality rates.31 Conversely, following neoadjuvant treatment, lobectomy is feasible and safe, and, compared to postinduction therapy pneumonectomy, lobectomy in this setting is not associated with increased morbidity and mortality rates.
Personal View With the currently available data, an analysis of the outcomes of lobectomy after induction therapy should be performed as a post-hoc evaluation of phase III RCTs. In the future, the surgical arms of phase III RCTs will have to focus on the need to consider lobectomy as the ideal extent of resec tion to be considered in the surgical arms. The predominance of T4 in stage IIIB patients may directly affect the proportion of pneumonectomies needed to achieve complete resection. On the other hand, the surgical arm of the INT0139 trial confirms that adequate surgical expertise leads to performing more lobectomies – 89% of the patients randomized to surgery had T1 (25%) or T2 (64%) – than pneumonectomies.10 Nevertheless, in the same study, 45% of T0N0 patients had a possibly unnecessary pneumonectomy, as identified from a post-hoc analysis.10 The concept of resectable NSCLC with regard to the mediastinal nodal stations should be revised.3,28,32,33 Results of the surgical arms should be stratified by the different categories of N2 disease, specifying short and medium term morbidity and mortality rates along with quality of life analyses.8 From the surgical arm of an RCT, patients with bulky, extracapsular N2 disease should be excluded, whereas the inclusion of stable disease detected in prognostically favorable (i.e., single station) N2 patients should be contemplated.7 These subsets are likely to be resectable even before induction treat ment. In addition, standard criteria for complete
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lymphadenectomy after induction therapy should be determined, since radical mediastinal nodal dissection is currently reported in only 35% of the patients.32 The extent of node removal is of paramount importance, especially in light of the prognostic importance of postinduction downstaging and the current difficulties in reliably restaging the N2 compartment in a pre-thoracotomy setting.11 Also, in order to minimize surgeon-dependent variability in practice in multicentric trials,13 technical and functional criteria for parenchyma saving techniques as an alternative to pneumonectomy, and attendant postoperative care protocols should be strictly defined. Finally, patients undergoing postsurgical treatment (i.e., adjuvant radiation therapy) should also be excluded to evaluate the outcomes from the surgical arm without upstaging interference. A close collaboration between surgeons and medical and radiation oncologists will lead to structured design of future trials based on new chemotherapy regimens and a better appreciation of the flaws of already conducted RCTs for N2-NSCLC.3,4,34 In the meantime, clinical practice will be based on individualization of treatment determined by a thorough evaluation of patients with N2 disease.3
Lobectomy after induction therapy in patients with non-small cell lung cancer and favorable N2 disease (single station, non-bulky, without extracapsular extension) is safe and provides a survival advantage (moderate quality evidence). A weak recommendation is made for lobectomy in the absence of disease progression after induction therapy (recommendation grade 2B).
References 1. Andre F, Grunenwald D, Pignon JP, Dujon A, Pujol JL, Brichon PY, Brouchet L, Quoix E, Westeel V, Le Chevalier T. Survival of patients with resected N2 non–small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol. 2000;18: 2981–2989. 2. Johnson DH, Rusch VW, Turrisi AT. Scalpels, beams, drugs, and dreams: challenges of stage IIIA-N2 non–small-cell lung cancer. JNCI. 2007;99:415–418.
116 3. van Meerbeeck JP, Surmont VFM Stage IIIA-N2 NSCLC: a review of its treatment approaches and future developments. Lung Cancer. 2009;65:257–267. 4. Tieu BH, Sanborn RE, Thomas CR. Neoadjuvant therapy for resectable non-small cell lung cancer with mediastinal lymph node involvement. Thorac Surg Clin. 2008;18:403–415. 5. Robinson LA, Ruckdeschel JC, Wagner H, Stevens CW. Treatment of non-small cell lung cancer-stage IIIA: ACCP Evidence-Based Clinical Practice Guidelines, 2nd ed. Chest. 2007;132(suppl 3):243S–265. 6. Cerfolio RJ, Maniscalco L, Bryant AS. The treatment of patients with stage IIIA Non-Small Cell Lung Cancer from N2 disease: who returns to the surgical arena and who survives. Ann Thorac Surg. 2008; 86:912–920. 7. Port JL, Korst RJ, Lee PC, Levin MA, Becker DE, Roger Keresztes, Altorki NK. Surgical resection for residual N2 disease after induction chemotherapy. Ann Thorac Surg. 2005;79:1686–1690. 8. Burdett S, Stewart L, Rydzewska L. Chemotherapy and surgery versus surgery alone in non-small cell lung cancer: a systematic review and meta-analysis of the literature. J Thorac Oncol. 2006;1:611–621. 9. van Meerbeeck JP, Kramer GW, Van Schil PE, Legrand C, Smit EF, Schramel F, Tjan-Heijnen VC, Biesma B, Debruyne C, van Zandwijk N, Splinter TA, Giaccone G. European Organisation for Research and Treatment of Cancer-Lung Cancer Group. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst. 2007;99:442–450. 10. Albain KS, Swann RS, Rusch VW, Turrisi AT, Shepherd FA, Smith C, Chen Y, Livingston RB, Feins RH, Gandara DR, Fry WA, Darling G, Johnson DH, Green MR, Miller RC, Ley J, Sauze WT, Cox JD. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small cell lung cancer.: a phase III randomized trial. Lancet. 2009;374:379–386. 11. Betticher DC, Hsu Schmitz SF, Totsch M, Hansen E, Joss C, von Briel C, Schmid RA, Pless M, Habicht J, Roth AD, Spiliopoulos A, Stahel R, Weder W, Stupp R, Egli F, Furrer M, Honegger H, Wernli M, Cerny T, Ris HB, for the Swiss Group for Clinical Cancer Research (SAKK). Prognostic factors affecting longterm outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study. Br J Cancer. 2006;94:1099–1106. 12. Garrido P, Gonzalez-Larriba JL, Insa A, Provencio M, Torres A, Isla D, Sanchez JM, Cardenal F, Domine M, Barcelo JR, Tarrazona V,Varela A,Aguilo R,Astudillo J, Muguruza I, Artal A, Hernando-Trancho F, Massuti B, Sanchez-Ronco M, Rosell R. Long-term survival associated with complete resection after induction chemotherapy in stage IIIA (N2) and IIIB (T4N0-1)
G. Rocco non small-cell lung cancer patients: the Spanish Lung Cancer Group Trial 9901. J Clin Oncol. 2007;25: 4736–4742. 13. Brunelli A, Charloux A, Bolliger CT, Rocco G, Sculier JP, Varela G, Licker M, Ferguson MK, FaivreFinn C, Huber RM, Clini EM, Win T, De Ruysscher D, Goldman L; European Respiratory Society; European Society of Thoracic Surgeons Joint Task Force on Fitness For Radical Therapy. The European Respiratory Society and European Society of Thoracic Surgeons clinical guidelines for evaluating fitness for radical treatment (surgery and chemoradiotherapy) in patients with lung cancer. Eur J Cardiothorac Surg. 2009;36:181–184. 14. Gudbjartsson T, Gyllstedt E, Pikwer A, Jönsson P. Early surgical results after pneumonectomy for nonsmall cell lung cancer are not affected by preoperative radiotherapy and chemotherapy. Ann Thorac Surg. 2008;86:376–382. 15. Doddoli C, Barlesi F, Trousse D, Robitail S, Yena S, Astoul P, Giudicelli R, Fuentes P, Thomas P. One hundred consecutive pneumonectomies after induction therapy for non-small cell lung cancer: an uncertain balance between risks and benefits. J Thorac Cardiovasc Surg. 2005;130:416–425. 16. Van Schil P. Mortality associated with pneumonectomy after induction chemoradiation versus chemotherapy alone in stage IIIA-N2 non–small cell lung cancer. J Thorac Cardiovasc Surg. 2008;135: 718–719. 17. Kunitoch H, Suzuki K. How to evaluate the risk/benefit of trimodality therapy in locally advanced non-small cell lung cancer. Br J Cancer. 2007;96:1498–1503. 18. Uy KL, Darling G, Xu W, Yi QL, De Perrot M, Pierre AF, Waddell TK, Johnston MR, Bezjak A, Shepherd FA, Keshavjee S. Improved results of induction chemoradiation before surgical intervention for selected patients with stage IIIA-N2 non–small cell lung cancer. J Thorac Cardiovasc Surg. 2007;134:188–193. 19. Siegenthaler M,Pisters K,Merriman K et al.Preoperative chemotherapy for lung cancer does not increase surgical morbidity. Ann Thorac Surg. 2001;71:1105–1112. 20. Perrot E, Guibert B, Mulsant P et al. Preoperative chemotherapy does not increase complications after non-small cell lung cancer resection. Ann Thorac Surg. 2005;80:423–427. 21. Burrows WM. Anatomical lung resection after neoadjuvant chemoradiotherapy. Semin Thorac Cardiovasc Surg. 2007;19:360–365. 22. Venuta F, Anile M, Diso D, Ibrahim M, De Giacomo T, Rolla M, Liparulo V, Coloni GF. Operative complications and early mortality after induction therapy for lung cancer. Eur J Cardiothorac Surg. 2007;31: 714–717. 23. Leo F, De Pas T, Catalano G, Piperno G, Curigliano G, Solli P, Veronesi G, Petrella F, Spaggiari L. Re: Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non small-cell lung cancer. J Natl Cancer Inst. 2007;99:1210.
11. Lobectomy After Induction Therapy for Stage IIIA NSCLC in the Presence of Persistent N2 Disease 24. van Meerbeeck JP, van Schil P, Senan S; EORTC-Lung Cancer Group. Reply: Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small cell lung cancer. J Thorac Oncol. 2007;2:1138–1139. 25. Veronesi G, Solli PG, Leo F, D’Aiuto M, Pelosi G, Leon ME, F. De Braud, L. Spaggiari, U. Pastorino. Low morbidity of bronchoplastic procedures after chemotherapy for lung cancer. Lung Cancer. 2002;36: 91–97. 26. Venuta F, Ciccone AM,Anile M, Ibrahim M, De Giacomo T, Coloni GF, Rendina EA. Reconstruction of the pulmonary artery for lung cancer: long-term results. J Thorac Cardiovasc Surg. 2009:138(5):1185–1191. 27. Ohta Y, Shimizu Y, Minato H, Matsumoto I, Oda M, Watanabe G. Results of initial operations in non– small cell lung cancer patients with single-level N2 disease. Ann Thorac Surg. 2006;81:427–433. 28. Vansteenkiste J, Betticher D, Eberhardt W, De Leyn P, Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small cell lung cancer. J Thorac Oncol. 2007;2:684–685. 29. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543–3551.
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30. Girard N, Mornexa F Douillardb J-Y, Bossardd N, Quoixb E, Beckendorfb V, Grunenwald D, Amourb E, Milleron B. Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial. doi.org/10.1016/j.lungcan. 2009.10.003 31. Kappers I, van Sandick JW, Burgers SA, Belderbos JSA, van Zandwijk N, Klomp HM. Surgery after induction chemotherapy in stage IIIA-N2 non-small cell lung cancer: why pneumonectomy should be avoided. Lung Cancer. 2009; doi 10.1016/j.lungcan. 2009.07.001 32. Wright G, Manser RL, Byrnes G, Hart D, Campbell DA. Surgery for non-small cell lung cancer: systematic review and meta-analysis of randomised controlled trials. Thorax. 2006;61:597–603. 33. De Marinis F, Nelli F, Migliorino MR et al. Gemcitabine, paclitaxel,and cisplatin as induction chemotherapy for patients with biopsy-proven stage IIIA(N2) non-small cell lung carcinoma: a phase II multicenter study. Cancer. 2003;98: 1707–1715. 34. Rocco G. Results of cutting-edge surgery in stage IIIA-N2 nonsmall cell lung cancer. Curr Opin Oncol. 2009;21:105–109. 35. Guyatt G, Gutterman D, Baumann MH, AddreizzoHarris D, Hylek EM, Phillips B, Raskob G, Zelman Lewis S, Schunemann H. Grading strength of recommendations and quality of evidence in clinical guidelines. Chest. 2006;129:174–181.
12
Pneumonectomy After Induction Therapy for Stage IIIA Non-small-cell Lung Cancer Alessandro Brunelli and Majed Refai
Introduction Multimodality treatment has become the standard of care for locally advanced non small lung cancer (NSCLC). However, several observational studies in the past have shown that induction treatment may increase the risk of perioperative complications and mortality after pneumonectomy, questioning the real benefit of surgery when a resection greater than lobectomy is anticipated. Based on these findings, most current guidelines1,2 emphasize the risk of pneumonectomy after induction treatment and do not recommend this operation after chemotherapy or chemoradiotherapy, and indicate that the standard of care for stage IIIA NSCLC patients should be chemoradiotherapy outside of clinical trials. Therefore, the real benefit of a multimodality treatment including pneumonectomy should be carefully weighed against the increased risk of early mortality, severe complications, impaired quality of life and long term disability. However, in clinical practice, surgeons are often driven more by personal experience or attitudes than scientific evidence, particularly when evidence is weak and the topic is still controversial. The objective of this chapter is to present a systematic review of the current scientific evidence on pneumonectomy after induction treatment for stage IIIA in order to provide practical recommendations to be used in daily clinical practice. The basic assumption, in accordance with current guidelines,1,2 is that thoracic surgeons should always be involved and discuss these patients within the setting of a multidisciplinary team
including other colleagues specializing in the care of lung cancer patients (medical oncologists, radiotherapists, chest physicians). The decision to proceed with one or the other form of treatment should be carefully planned to minimize the occurrence of unplanned and detrimental outcomes.
Published Evidence Methods of Searching the Literature Published evidence on the topic of interest was found by searching the MEDLINE (2000–2009), Cancerlit (2000–2009) and the Cochrane Library. The review was limited to the years 2000–2009 and included only papers published in English language, randomized or non-randomized, including at least 50 pneumonectomies for retrospective observational studies and at least 20 pneumonectomies for randomized clinical trials. Papers addressing the issue of induction treatment and pulmonary surgery but in which a clear definition and description of relevant outcomes (early morbidity and mortality and long-term survival) in relationship to stage and type of operation was not provided were excluded from this systematic review. In case of multiple subsequent publications from the same center or organization including the same population only the most recent and comprehensive one was taken into consideration. In addition to MEDLINE, the proceedings of the largest international oncology meetings were also
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_12, © Springer-Verlag London Limited 2011
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searched for relevant abstracts not already published as full articles. Review papers were also searched for cross-references. The search was carried out in August 2009. Quality of evidence was assessed according to the methodology proposed by the American College of Chest Physicians.3 The search of the literature and grading of evidence was independently performed by the two authors of this review. Any differences were discussed and resolved.
Early and Long-term Outcomes Several observational studies have been published that investigated the effect of induction therapy (mainly neoadjuvant chemotherapy) on morbidity, mortality and long-term survival.4 Table 12.1 summarizes only those studies that have been selected according to the predefined criteria of this review analysis. In summary, most of these recent studies did not find an increased risk of morbidity or mortality after induction chemotherapy.5–9 The only observational case-matched analysis10 did not show any difference between patients treated with and without induction chemotherapy in terms of morbidity and mortality after pneumonectomy. The authors used several perioperative variables to construct a propensity score used to select two well-matched samples of 56 patients each. The incidence of 30 day and 90 day mortality rates were identical between the groups (7% and 12.5%, respectively). The incidence of bronchopleural fistula was also not different (4% vs. 5%, p = 0.7). A subgroup case-matched comparison between
patients undergoing induction chemoradiation versus those without any induction treatment did not show any differences in terms of early and late mortality, but the sample size consisted of only 21 patients per group. There are only five randomized studies addressing the issue of induction chemotherapy or induction chemoradiotherapy and pulmonary resection. However, none of these studies focussed specifically on pneumonectomies. Thus, information about this operation must be extrapolated and calculated from the subgroups analyses reported in the papers. Table 12.2 summarizes the five randomized trials,11–15 and includes also one prospective non-randomized study.16 Depierre and colleagues with the French Thoracic Cooperative Group11 reported a neoadjuvant chemotherapy trial including all cancer stages. From 1991 through 1997 they randomized 373 patients with stages IB, II, and IIIA together into two arms: primary surgery (PRS) vs. two cycles of preoperative chemotherapy (PCT) with mitomycin C, ifosfamide, and cisplatin bollowed by surgical resection followed by two additional cycles postoperatively. In both arms those patients found to have pathologic T3 or N2 disease also received postoperative radiotherapy. There were 98 pneumonectomies in the PRS arm (56%) and 87 (49%) in the PCT arm. The total number of treatment-related deaths after surgery was 16 in the PCT arm and nine in the PRS arm, and the difference was not significant (p = 0.16). This study failed to demonstrate any significant survival benefit for induction chemotherapy followed by
Table 12.1. Selected observational studies of induction therapy and pneumonectomy. Author
Year
Period
Patients
Mansour5
2007
1999–2005
Gudbjartsson6
2008
1996–2003
Alifano7
2008
2000–2006
Leo8
2006
1998–2005
Doddoli9
2005
1989–2003
60 CT/surgery 238 surgery only 35 CT/RT/surgery 95 surgery only 118 (74 CT/surgery for N2) 99 CT/surgery 103 surgery only 70 CT/surgery 30 CT/RT/surgery
IIIa patients Not specified 13 26 52 40 53 79 (not otherwise specified)
Early outcomes BPF: 1.7% vs 5.5% (early mortality not different) BPF: 3 vs 5 Mortality: 4 right pneum, 3 left pneum Mortality: 4.9% vs 3% BPF: 5.9% vs 5% Mortality 12% (30 day), 21% (90 day) BPF: 9% right, 2% left
CT chemotherapy; RT radiation therapy; BPF bronchopleural fistula; pneum pneumonectomy; path pathology.
Survival in IIIa
Quality of evidence
n/a
Moderate
1 year: 74% vs 72% 5 year: 46% vs 34% 5 year: 18.5% for N2, 30% for N0 to N1 n/a
Moderate
5 year: 19.8% (all stages). Path stages III,IV: 16.6% Path downstaged 34.1%
Moderate
Moderate Moderate
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12. Pneumonectomy After Induction Therapy for Stage IIIA Non-small-cell Lung Cancer Table 12.2. Selected randomized trials of induction therapy and pneumonectomy. Citation
Year
Period
Patients
Randomized clinical trials 2002 Depierre11
1991–1997
Van Meerbeeck12
2007
1994–2002
98 surgery only 87 CT/surgery 72 after CT or CT/RT
92 75 72
Not different (BPF 4 vs 1; deaths 4 vs 1) 5 deaths (7%)
Gilligan13
2007
1997–2005
Albain14
2009
1994–2001
19 15 All
Mortality not different between groups (stage not assessed) 14 postoperative deaths (88%)
Thomas15
2008
1995–2003
80 surgery only 65 CT/surgery 54 CT/RT/surgery vs 194 CT/RT only 50 CT/RT/surgery 54 CT/surgery/RT
41 50
18 112 (56 per group)
Prospective non randomized Garrido16 2007 1999–2003 Observational case-matched series Refai10 2010 2000–2007
Stage IIIa
Early outcomes
Survival
Quality of evidence
Not different (5 year 25%) Median 13.4 months; 5 year 12% Not different 5 year 44% Not different
Moderate
Mortality: 7 CT/RT/surgery vs 3 CT/surgery/RT
Not different
High
18
Mortality: 4 (22%)
Median 14.8 months
High
Not specified
Morbidity and mortality not different (BPF 2 vs. 3; deaths 4 vs. 4)
n/a
Moderate
Moderate Moderate High
CT chemotherapy; RT radiation therapy; BPF bronchopleural fistula.
surgery compared to surgery alone in locally advanced stage IIIA NSCLC. van Meerbeeck and colleagues12 on behalf of the European Organization for Research and Treat ment of Cancer (EORTC)-Lung Cancer Group reported a randomized trial comparing the effects of cisplatin-based induction chemotherapy in histologically proven stage IIIA patients subsequently treated with lung resection or definitive radiotherapy. Among the 72 pneumonectomies enrolled in the surgical arm, the perioperative mortality rate was 7%, but the overall survival rate was only 12%. The authors concluded that surgery after induction chemotherapy does not provide any survival benefit compared to radiotherapy, which was recommended as the treatment of choice in these locally advanced lung cancer patients. Gilligan and colleagues13 investigated whether patients with operable NSCLC of any stage may have better outcomes after induction treatment with platinum-based chemotherapy compared to surgery alone. The number of pneumonectomies in the surgery group was 80 (33%) versus 65 (28%) in the induction group plus surgery. Although the stage was not specifically reported for the pneumonectomy patients, the two groups had substantially similar perioperative mortality rates (three deaths (4%) in the surgery group versus three deaths (5%) in the induction group). Survival was not analyzed
separately in pneumonectomy patients, so no inferences can be drawn in this regard. Only two studies analyzed the effect of combined induction chemoradiation. Albain and colleagues14 reported results from a phase III study on patients with stage IIIA NSCLC with ipsilateral mediastinal nodal metastasis (N2). They compared patients undergoing induction concurrent chemoradiotherapy and radiation therapy (45 Gy) that were subsequejtly randomized to one of two groups: definitive radiotherapy (61 Gy) or lung resection. There were 54 pneumonectomies in the surgical group (29 right; 25 left) out of 155 total resections. Sixteen patients in the surgical arm died from causes not attributable to cancer and 14 of these patients died after pneumonectomy. The mortality rate after pneumonectomy was as high as 25%. These deaths were mainly attributed to acute respiratory distress syndrome. Overall survival was not better in those patients treated surgically, although progressionfree survival was longer. A case-matching subgroup analysis showed that the overall survival for pneumonectomy patients was not significantly better than patients treated with definitive radiotherapy. Median survival times and estimated 5-years survivals were 18.9 vs. 29.4 months, and 22% vs. 24%, respectively. Thomas and colleagues15 performed a randomized trial to assess the effect of preoperative
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chemoradiation on tumor resection, pathological response, and survival in patients with stage III NSCLC. The intervention group was to receive concurrent chemotherapy and radiotherapy followed by resection. The control group was to receive chemotherapy followed by resection, and then further radiotherapy. The number of pneumonectomies in this study was 104: 50 in the interventional group vs. 54 in the control group. Treatment related mortality in pneumonectomy patients was 7/50 (14%) in the interventional group versus 3/54 (5.5%) in the control group. The authors concluded that induction treatment with concurrent chemoradiation increased mediastinal downstaging but did not improve survival. Owing to the high mortality rate, they recommended that pneumonectomy should be avoided after chemoradiation.
Quality of Life and Residual Function To the best of our knowledge there is no paper specifically addressing the issue of quality of life or residual function in patients treated with induction therapy and pneumonectomy. Inferences need to be drawn from the existing literature on quality of life (QoL) and function after pneumonectomy. Pneumonectomy is consistently reported as one of the factors with the greatest impact on residual cardiopulmonary function and quality of life. Contrary to lesser resection, in which a gradual improvement in respiratory function has been described, this operation leads to an almost fixed loss of about 30–40% of the preoperative function.17–23 In general, exercise capacity has been shown to recover more than respiratory parameters postoperatively, presumably owing to other compensatory mechanisms (regarding cardiovascular system and peripheral oxygen extraction).17,18,22 In addition to the effect of pneumonectomy, induction treatment may cause important detrimental effects on the residual lung. Certain chemotherapeutic drugs which are frequently used for treating lung cancer, like taxanes and gemcitabine, can cause adverse reactions in the lungs with loss of function, particularly DLCO.24–27 Moreover, radiotherapy of the lung is known to cause radiation pneumonitis in 5–15% of patients and radiographic abnormalities in 60% of patients.28
Several authors have studied the long-term effects of pneumonectomy on the heart. Compared to lesser resections, pneumonectomy has been shown to cause an increase in pulmonary vascular resistance, pulmonary artery pressure, end-diastolic right ventricle volume and a consequent reduction of the ejection fraction, stroke volume and cardiac index.29–31 The attendant alterations in cardiorespiratory function are the basis of the sustained impairment in many dimensions of the residual quality of life reported by most authors after pneumonectomy,32–36 although some did not find extent of resection as a major determinant of residual QoL.37 Few studies have assessed the effect of induction treatment on the quality of life in lung resection candidates. Generally, the physical domains of these patients are worse than their counterparts at the time of surgery,32 but preoperative induction treatment seems to minimally influence quality of life postoperatively.13,37,38
Recommendations Induction chemotherapy is not associated with an increased surgical risk after pneumonectomy, but does not improve long-term survival compared to definitive radiotherapy or surgery alone (evidence quality moderate). We make a weak recommendation against pneumonectomy after induction chemotherapy except when performed in highly selected patients and in qualified thoracic surgery centers (grade of recommendation 2A). Induction chemoradiation is associated with high mortality rates after pneumonectomy and does not provide long-term survival benefits in these patients (evidence quality moderate). We make a strong recommendation against pneumonectomy after induction chemoradiation in these patients (grade of recommendation 1B).
A Personal View of the Data The role of multidisciplinary teams and of a meticulous preoperative functional evaluation repeated after the induction treatment according to recent guidelines2 is of paramount importance
12. Pneumonectomy After Induction Therapy for Stage IIIA Non-small-cell Lung Cancer
to assist in this difficult decision making process. With rare exceptions,16 most of the recent randomized and non-randomized studies have shown acceptable morbidity and mortality rates after induction chemotherapy and pneumonectomy.5–13 Improved patient selection, surgical technique and perioperative management, along with a reduced toxicity of the chemotherapeutic agents, have contributed to a lower incidence of postoperative adverse events compared to older series.4 Based on these findings, we think that, in wellselected patients and in qualified centers, pneumonectomy can be performed with reasonable safety after chemotherapy. Conversely, the combination of radiotherapy and chemotherapy before pneumonectomy has been reported to be associated with unacceptable perioperative mortality rates without improving long-perm survival compared to definitive radiotherapy.14,15 We think that only highly selected patients with very low surgical risk should be submitted to pneumonectomy after chemoradiation therapy. For the majority of patients and outside of clinical trials, such an operation does not appear warranted by current scientific evidence. Pneumonectomy is safe after induction chemotherapy for non-small cell lung cancer, but this treatment combination does not improve longterm survival (evidence quality moderate). We make a weak recommendation against pneumonectomy after induction chemotherapy (grade of recommendation 2A).
Pneumonectomy after induction chemoradiation is associated with high mortality rates and does not provide long-term survival benefit (evidence quality moderate). We make a strong recommendation against pneumonectomy after induction chemoradiation (grade of recommendation 1B).
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2. Brunelli A, Charloux A, Bolliger CT et al. ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy). Eur Respir J. 2009; 34:17–41. 3. Guyatt G, Gutterman D, Baumann MH et al. Grad ing strength of recommendations and quality of evidence in clinical guidelines. Report from an American College of Chest Physicians task force. Chest. 2006;129:174–181. 4. Stamatis G. Risk of neoadjuvant chemotherapy and radiation therapy. Thorac Surg Clin. 2008;18:71–80. 5. Mansour Z, Kochetkova EA, Ducrocq X et al. Induc tion chemotherapy does not increase the operative risk of pneumonectomy. Eur J Cardiothorac Surg. 2007;31:181–185. 6. Gudbjartsson T, Gyllstedt E, Pikwer A, Jonsson P. Early surgical results after pneumonectomy for non-small cell lung cancer are not affected by preoperative radiotherapy and chemotherapy. Ann Thorac Surg. 2008;86:376–382. 7. Alifano M, Boudaya MS, Salvi M et al. Pneumo nectomy after chemotherapy: morbidity, mortality and long-term outcome. Ann Thorac Surg. 2008;85:1866–1873. 8. Leo F, Solli P, Veronesi G et al. Does chemotherapy increase the risk of respiratory complications after pneumonectomy? J Thorac Cardiovasc Surg. 2006; 132:519–523. 9. Doddoli C, Barlesi F, Trousse D et al. One hundred consecutive pneumonectomies after induction therapy for non-small cell lung cancer: an uncertain balance between risks and benefits. J Thorac Cardiovasc Surg. 2005;130:416–425. 10. Refai M, Brunelli A, Rocco G et al. Does induction treatment increase the risk of morbidity and mortality after pneumonectomy? A multicenter casematched analysis. Eur J Cardiothorac Surg. 2010; 37:535–539. 11. Depierre A, Milleron B, Moro-Sibilot D et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small–cell lung cancer. J Clin Oncol. 2002;20:247–253. 12. van Meerbeeck JP, Kramer GW, Van Schil PE et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst. 2007;99:442–450. 13. Gilligan D, Nicolson M, Smith I et al. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRCLU22/NVALT2/EORTC 08012 multicentre randomized trial and update of systematic review. Lancet. 2007;369:1929–1937. 14. Albain KS, Swann RS, Rusch VW et al. Radiotherapy plus chemotharapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379–386.
124 15. Thomas M, Rube C, Hoffknecht P et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol. 2008;9: 636–648. 16. Garrido P, Gonzalez-Larriba JL, Insa A et al. Longterm survival associated with complete resection after induction chemotherapy in stage IIIA (N2) and IIIB (T4N0-N1) non-small-cell lung cancer patients: the Spanish Lung Cancer Group Trial 9901. J Clin Oncol. 2007;30:4736–4742. 17. Brunelli A, Xiume F, Refai M et al. Evaluation of expiratory volume, diffusion capacity, and exercise tolerance following major lung resection: a prospective follow-up analysis. Chest. 2007;131:141–147. 18. Bolliger CT, Jordaj P, Soler M et al. Pulmonary function and exercise capacity after lung resection. Eur Respir J. 1996;9:415–421. 19. Pelletier C, Lapointe L, LeBlanc P. Effects of lung resection on pulmonary function and exercise capacity. Thorax. 1990;45:497–502. 20. Larsen KR, Svendsen UG, Milman N et al. Cardio pulmonary function at rest and during exercise after resection for bronchial carcinoma. Ann Thorac Surg. 1997;64:960–964. 21. Nezu K, Kushibe K, Tojo T et al. Recovery and limitation of exercise capacity after lung resection for lung cancer. Chest. 1998;113:1511–1516. 22. Nugent AM, Steele IC, Carragher AM et al. Effect of thoracotomy and lung resection on exercise capacity in patients with lung cancer. Thorax. 1999;54:334–338. 23. Win T, Groves AM, Ritchie AJ et al. The effect of lung resection on pulmonary functikn and exercise capacity in lung cancer patients. Respir Care. 2007;52: 720–726. 24. Esteban E, Villanueva N, Muniz I et al. Pulmonary toxicity in patients treated with gemcitabine plus vinorelbine or docetaxel for advanced non-small cell lung cancer: outcome data on a randomized phase II study. Invest New Drugs. 2008;26:67–74. 25. Thomas AL, Cox G, Sharma RA et al. Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer: report of a phase I/II dose-escalating study. Eur J Cancer. 2000;36:2329–2334. 26. Leo F, Solli P, Spaggiari L et al. Respiratory function changes after chemotherapy: an additional risk for postoperative respiratory complications? Ann Thorac Surg. 2004;77:260–265.
A. Brunelli and M. Refai 27. Maas KW, van der Lee I, Bolt K et al. Lung function changes and pulmonary complications in patients with stage III non-small cell lung cancer treated with gemcitabine/cisplatin as part of combined modality treatment. Lung Cancer. 2003;41:345–351. 28. McDonald S, Rubin P, Phillips TL et al. Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems. Int J Radiat Oncol Biol Phys. 1995;31:1187–1203. 29. Smulders SA, Holverda S, Vonk-Noordegraaf A et al. Cardiac function and position more than 5 years after pneumonectomy. Ann Thorac Surg. 2007;83: 1986–1992. 30. Venuta F, Sciomer S, Andreetti C et al. Long-term Doppler echocardiographic evaluation of the right heart after major lung resections. Eur J Cardiothorac Surg. 2007;32:787–790. 31. Foroulis CN, Kotoulas CS, Kakouros S et al. Study of late effect of pneumonectomy on right heart pressures using Doppler echocardiography. Eur J Cardio thorac Surg. 2004;26:508–514. 32. Brunelli A, Socci L, Refai M et al. Quality of life before and after major lung resection for lung cancer: a prospective follow-up analysis. Ann Thorac Surg. 2007;84:410–416. 33. Sugimura H, Yang P. Long-term survivorship in lung cancer: a review. Chest. 2006;129:1088–1097. 34. Schulte T, Schniewind B, Dohrmann P et al. The extent of lung parenchyma resection significantly impacts long-term quality of life in patients with non-small cell lung cancer. Chest. 2009;135: 322–3229. 35. Balduyck B, Hendriks J, Lauwers P et al. Quality of life evolution after lung cancer surgery: a prospective study in 100 patients. Lung Cancer. 2007;56:423–431. 36. Ilonen IK, rasanen JV, Sihvo EI et al. Pneumonectomy: postoperative quality of life and lung function. Lung Cancer. 2007;58:397–402. 37. Handy JR Jr, Asaph JW, Skokan L et al. What happens to patients undergoing lung cancer surgery? Outcomes and quality of life before and after surgery. Chest. 2002;122:21–30. 38. Gralla RJ, Edelman MJ, Detterbeck FC et al. Assessing quality of life following neoadjuvant therapy for early stage non-small cell lung cancer (NSCLC): results from a prospective analysis using the Lung Cancer Symptom Scale (LCSS). Support Care Cancer. 2009;17:307–313.
13
Segmentectomy Versus Lobectomy for Stage I Lung Cancer in Patients with Good Pulmonary Function Brendon M. Stiles and Nasser K. Altorki
The initial surgical operation of choice for lung cancer was pneumonectomy.1 However, since the 1960’s lobectomy with lymph node dissection has been the standard resection technique used by most surgeons for patients with good pulmonary function.2,3 Anatomical segmentectomy may offer a lung-preserving alternative to lobectomy, much as lobectomy did to pneumonectomy. Anatomical segmentectomy was first described by Churchill and Belsey in 1939 for resection of bronchiectasis and tuberculosis.4 Segmentectomy for resection of lung cancer was subsequently performed by some surgeons; however, concerns were raised over the perceived higher risk of local recurrence.5–9 In order to better define the role of lesser resection, in 1995 the Lung Cancer Study Group (LCSG) reported a randomized trial of 247 low-risk patients with clinical T1N0 peripheral NSCLC assigned to either limited resection (anatomical segmentectomy or wedge resection) or lobectomy.10 The study showed that locoregional recurrence was significantly higher in patients treated by sublobar resections. Although patients treated by lobectomy had a higher 5-year survival compared to those treated by limited resection, the difference in survival did not achieve statistical significance (73% vs. 56%, p = 0.06). This trial arguably established lobectomy as the surgical standard of care for early stage disease. Despite the sentinel publication of the LCSG, several other groups continued to pursue lesser resections, particularly anatomic segmentectomy, for early lung cancer.11–13 This was particularly the case in Japan, where the Study Group of Extended
Segmentectomy for Small Lung Tumors organized a prospective multi-institutional trial, which produced several reports.14–16 A meta-analysis published in 2005 analyzed several of these series including the data from the LCSG.17 That analysis concluded that there was no survival difference between limited resection and lobectomy for stage I lung cancer. In this chapter we will review these and more recent studies to reassess the role of limited pulmonary resection, specifically anatomic segmentectomy, in patients thought to be able to tolerate a lobectomy. We will also discuss some of the factors one needs to consider in selecting patients for limited resection including tumor size, location, cell type, and radiographic characteristics.
Definitions and Approach to the Question “Limited” or “lesser” resections for lung cancer have typically been defined as anything less than a standard lobectomy. This description therefore encompasses a broad range of resection techniques, including wedge resections, non-anatomic segmentectomy, and anatomic segmentectomy with hilar dissection. For the purposes of this review, we define segmentectomy as an anatomical resection of the lung parenchyma that involves dissection, identification, and division of individual segmental arteries, veins, and bronchi. For the review, we did not have a minimal requirement for lymph node dissection, however it is our preference (and that of most authors of series presented
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here) to perform a standard lobar and mediastinal lymph node dissection. As do most of the series in the literature, we focused on patients with stage I non-small cell lung cancer, T1N0M0 (stage IA) or T2N0M0 (stage IB) in the 6th AJCC TNM staging system.18 With these criteria in mind, we performed a Medline web search of computer-archived bibiliographic data using the OVID interface (1950–November 2009), with keywords [limited resection OR sublobar resection OR limited pulmonary resection OR limited lung resection OR conservative resection OR conservative pulmonary resection] AND [lung cancer OR non small cell lung cancer OR non small cell lung carcinoma]. The search was limited to English language papers. Using these criteria, 266 manuscripts were identified. Manual selection of relevant studies was carried out. Although many series include patients with both good and poor pulmonary function, those series focusing only on patients with poor pulmonary function were excluded from consideration.
Evidence For and Against the Use of Limited Pulmonary Resection Randomized Control Trial The only randomized trial comparing limited resection (segmentectomy or wedge resection) with lobectomy for stage IA NSCLC was reported in 1995 by the LCSG.10 The trial reported on 247 patients (122 limited resections and 125 lobectomies) entered from 1982–1988. Absence of nodal metastases to the draining segmental, lobar, hilar and mediastinal lymph nodes was confirmed by sampling and frozen section examination prior to randomization. Locoregional recurrence (n = 21 versus 8, p = 0.008) was significantly higher in the limited resection group. Locoregional recurrence rates per person/year were 0.022 following lobectomy, 0.044 following segmental resection, and 0.086 after wedge resection. In the limited resection group more patients died with cancer (n = 30 versus 21, p = 0.09) and more died overall (n = 48 versus 38, p = 0.09). The study concluded that
limited resection for stage IA lung cancer carried a higher risk of recurrence and death and that lobectomy should remain the surgical standard. Several points warrant consideration, however. Many patients may have been clinically understaged. Remarkably, 495 of 771 patients registered for the study were not randomized, 189 because of benign disease and 129 because limited resection was not feasible due to tumor location or configuration. The trial was conducted before CT scans and PET scans became routine in the workup of lung cancer patients. Of patients undergoing limited resection (n = 122), wedge resection was performed in 33% (n = 40). As the purpose of this chapter is to compare segmentectomy versus lobectomy, the trial cannot be seen as definitive in that regard. Additionally, it should be noted that patients with tumor size up to 3 cm were included. Many subsequent studies have focused on patients with tumors 2 cm or less.
Meta-analysis In Japan, the focus of the Study Group of Extended Segmentectomy for Small Lung Tumors was on extended segmentectomy with complete lobar/ mediastinal lymph node dissection for patients with tumors less than 2 cm in diameter.14–16 In 2005, a meta-analysis was performed examining the pooled results of many of this group’s studies, as well as the LCSG randomized trial.17 The analysis was limited to studies comparing survival in clinical stage I NSCLC patients with a median follow-up of at least 2 years. Fourteen studies were identified. Limited resection (wedge or segmentectomy) was performed in 903 patients, while lobectomy was performed in 1887 patients. The reason for limited resection varied and included poor cardiopulmonary function in seven studies. Combined survival differences (survival rate for lobectomy minus that for limited resection) at 1, 3, and 5 years after resection were 0.7%, 1.9%, and 3.6% respectively, although none was statistically significant. The authors concluded that limited resection for stage I NSCLC led to survival comparable to lobectomy, but urged caution in interpreting their results due to interstudy heterogeneity. Such heterogeneity stemmed from differences in histology, patient sex, and reason for limited resection.
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13. Segmentectomy Versus Lobectomy for Stage I Lung Cancer in Patients with Good Pulmonary Function
Observational Studies Several studies, including some of those reviewed in the 2005 meta-analysis, deserve further consideration, particularly those in which limited resection was intentional and not for poor cardiopulmonary function (Table 13.1). For example, Kodama et al. reported a case-control series of 46 patients with cT1N0 NSCLC treated by intentional limited resection with curative intent.14 All patients had peripheral tumors less than 2 cm in size and all were treated by segmentectomy with regional lymph node dissection. The comparator or control group comprised 77 patients with stage I treated by lobectomy. The segmentectomy group had a 5-year survival of 93%, which was similar to survival in the control group. Locoregional recurrence was 2.2% in the segmentectomy group and 1.3% in the lobectomy group. Similarly, Okada et al. reviewed their prospective experience with 70 patients who had T1N0 NSCLC 2 cm or less treated by intentional limited resection.15 The authors performed what they termed an “extended segmentectomy,” which is essentially a segmental resection in which parenchymal division extends slightly beyond the anatomical segmental boundary. In this study segmentectomy was performed only after frozen section examination of the segmental, hilar and mediastinal nodes confirmed the absence of
metastatic disease. Patients with nodal disease were treated by lobar resection. Five-year survival of pathologic T1N0 patients was 87.1% in the extended segmentectomy group compared to 87.7% in the lobectomy group (p = 0.8). There were no local recurrences in the limited resection. The local recurrence rate for the lobectomy group was not reported in that study. Koike et al. reported their results of intentional limited resection for peripheral T1N0 NSCLC 2 cm or less.16 The limited resection group consisted of 60 segmentectomies and 14 wedge resections, which was compared to 159 patients treated by lobectomy. Intraoperative frozen section analysis of hilar and mediastinal lymph nodes was performed, and a standard lobectomy was done when lymph node metastases were detected. The 3-year and 5-year overall survival was 94.0% and 89.1% in the limited resection group compared to 97.0% and 90.1% in the lobectomy group. Tumor recurrence was noted in five patients after limited resection and in nine patients after lobectomy. Both the overall survival and the local recurrence rate were not significantly different between the two groups. In 2006, several of these authors updated and pooled their experience, reviewing patients enrolled in a nonrandomized Japanese prospective study.19 The results of the sublobar group (n = 305) were compared those of the lobar resection group (n = 262). Disease-free and overall
Table 13.1. Studies of intentional limited resection for stage I NSCLC. Study
Year
Kodama
1997
14
Okada15
2001
Number of patients 46 77
70 139
Yoshikawa
2002
55
Koike16
2003
74
40
159 Watanabe19
2005
34 57
Type of resection
Tumor size
Recurrence rate
Segmentectomy with frozen nodal analysis
Avg. 16.7 mm
93
Lobectomy with nodal dissection
Avg. 22.9 mm
Extended segmentectomy with frozen nodal analysis Lobectomy
< _ 2 cm T1N0 NSCLC
Local 2.2% Distant 4.3% Local 1.3% Distant 5.2% Local 0% Distant 1.4% N/A Local 1.8% Distant 5.5% Local 2.7% Distant 4.1% Local 1.3% Distant 4.4% Local 0% Distant 2.9% N/A
82
Extended segmentectomy with frozen nodal analysis Segmentectomy (60) and wedge (14) with frozen nodal analysis Lobectomy
Peripheral <2 cm T1N0 NSCLC
Extended segmentectomy (20) and wedge (14) with frozen nodal analysis Lobectomy
_ 2 cm T1N0 Peripheral < NSCLC
_ 2 cm T1N0 Peripheral < NSCLC
5-year survival (%)
88 87 88
89 90 93 84
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survivals were similar in both groups at 5 years (85.9% and 89.6% for the sublobar group and 83.4% and 89.1% for the lobar resection group, respectively). The local recurrence rate was 4.9% in the sublobar group and 6.9% in the lobectomy group. The authors concluded that extended segmentectomy is an alternative to lobectomy for T1N0 NSCLC measuring 2 cm or less. Since the publication of the prior meta-analysis, Watanabe et al. reported their results of intentional limited resection for T1N0 peripheral NSCLC 2 cm or less in size.20 Limited resection was done in 34 patients, wedge resection in 14, and extended segmentectomy in 20. Again, intraoperative examination of hilar and mediastinal lymph nodes showed no evidence of nodal metastases. Impressively, the 5-year survival after extended segmentectomy was 93% with no local recurrences. This compared favorably to the 84% 5-year survival after lobectomy. In 2007, Schuchert et al. also reported on their institutional series of patients undergoing segmentectomy.21 Although patients were presumably selected for segmentectomy based upon limited functional status or due to comorbidities, there was no significant difference in pulmonary function between this group (n = 182) and concurrent patients undergoing lobectomy (n = 246) at the same institution. Overall recurrence rates were similar between segmentectomy (17.6%) and lobectomy (16.7%). There was also no difference between recurrence-free or overall survival between the two groups. However, it should be noted that mean followup was only 18.1 months in the segmentectomy group compared to 28.5 months in the lobectomy group, a length of time that many would consider insufficient to assess recurrence and survival. In 2007 Sienal et al. published the results of an institutional study comparing segmentectomy (n = 49) to lobectomy (n = 150) for stage IA NSCLC.22 The majority of limited resections were likely performed for limited pulmonary function, although quantitative data were not given. In this study, with much longer follow-up duration (median 54 months), patients undergoing segmentectomy had higher local recurrence (16% vs. 5%, p = 0.005) and worse 5-year disease-specific survival (67% vs. 83%, p = 0.01).
Considerations in Limited Resection Tumor Size Tumor size is a critical factor in determining the feasibility and safety of limited resection. It is well established that tumor size is an important prognostic factor for survival in NSCLC.23–28 Several of these retrospective studies have shown that survival is better with smaller tumor size, particularly using a cutoff of £2 cm, findings that have helped lead to the new classification system, which divides T1 tumors into T1a and T2b at the 2 cm cutoff.29 Several of the studies in the meta-analysis used a cutoff of £2 cm to select patients for segmentectomy, as did the study of Watanabe et al.9,15,16,20 In the report of Schuchert et al., recurrence was only seen in 11% of stage IA patients, but in 27.4% of stage IB patients.21 Given the above evidence, a segmentectomy is more appropriate for T1a tumors (£2 cm in size).
Tumor Location Tumors considered for limited resection by a segmentectomy must be confined within the anatomical segmental boundaries without crossing intersegmental planes. Although segmentectomy may be performed for central tumors, the bulk of the evidence supporting segmentectomy with curative intent is accumulated from series with peripheral tumors located within the outer third of the lung. The traditional TNM classification does not consider tumor location as a prognostic factor. However, some studies suggest that central tumors are more likely to harbor lymph node metastases and have a poorer prognosis. For example, Ketchedjian et al. reported that central T1 tumors had a 50% incidence of lymph node involvement.30 Similarly, Lee et al reported that, for centrally located tumors, the incidence of occult N2 disease was 21.6% and was as high as 26.7% for tumors greater than 2 cm in size.31 In that same study, the incidence of occult N2 disease was 2.9% for peripherally located tumors. The high prevalence of nodal metastasis in central tumors suggests that these tumors may be best treated by a lobar rather than a sublobar resection. Also notable was the study of Sienel et al., which demonstrated a trend (p = 0.08) towards higher recurrence rates following segmentectomy in the
13. Segmentectomy Versus Lobectomy for Stage I Lung Cancer in Patients with Good Pulmonary Function
S1-3 segments (23%), compared to S4-10 segments (5%).22 No explanation was apparent for this phenomenon.
Intralobar Satellite Tumors One of the theoretical criticisms of a limited resection is the risk of intralobar satellite lesions that are unrecognized by preoperative radiographic studies or intraoperative palpation. The incidence of intralobar satellite lesions in small peripheral tumors is actually quite small in published series. Koike et al. examined 496 patients with clinical T1N0 peripheral NSCLC, and found that the incidence of intrapulmonary satellite lesions was only 1–2%.26 Even though the incidence of intralobar satellites may be low, great care must be taken at the time of a sublobar resection to carefully palpate the entire lobe. If suspicious lesions are found, a lobectomy rather than a limited resection may be more appropriate if the malignant nature of the satellite is histologically confirmed.
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spectrum of pathology, from pure noninvasive BAC to invasive adenocarcinomas with BAC features.33 The tumors are often characterized preoperatively by the appearance of a ground-glass opacity (GGO) on CT scan. With small BACs, many reports describe a complete absence of lymph node metastases and 5-year survival rates approaching 100%. If sublobar resection is contemplated, frozen section confirmation of the lack of an invasive component is prudent. Yoshida et al. reported a prospective trial of limited resection for peripheral tumors £2 cm with ground glass features (n = 50).34 The majority of patients (72%) underwent limited resection. Frozen section accuracy was 98%. No recurrence was seen at a median follow-up of 50 months. Koike et al. reported similar results in a prospective trial of limited resection for patients diagnosed with noninvasive BAC by intraoperative pathologic examination.35 With a median 51 month follow-up, 5-year disease-specific survival was 100% in 46 patients.
Preoperative Imaging Histological Classification The traditional TNM classification does not consider cell type as a prognostic factor for survival. Several studies have suggested that there is a difference in the incidence of lymph node metastases between squamous cell carcinoma and adenocarcinoma. Asamura et al. have shown that in squamous cell carcinomas £2 cm, lymph node involvement is rare.32 They examined 174 patients with peripheral resected NSCLC £2 cm for lymph node involvement. The authors found that lymph node involvement was much more rare in patients with squamous cell carcinoma (6.3%) compared to those with adenocarcinoma (21.1%). Lee et al. made similar observations in a study of occult mediastinal metastases in clinical stage I NSCLC.31 In that report, all 16 patients (8.2%) with occult N2 disease had adenocarcinoma as the primary tumor cell type. None of the 34 patients with squamous cell carcinomas harbored occult N2 metastases. Although this was not statistically significant (p = 0.082), the trend certainly suggests that adenocarcinoma cell type as compared to squamous cell carcinoma is a relative risk factor for occult N2 metastases. Bronchioloalveolar carcinoma (BAC) deserves special consideration. These tumors include a
Ideally, candidates for intentional limited resection could be identified based upon preoperative imaging characteristics. Yoshioka and Ichiguchi attempted to develop such a strategy based upon a retrospective review of imaging characteristics of 248 cT1N0M0 NSCLC tumors.36 They defined invasive tumors as those that had vascular or lymphatic invasion or lymph node involvement. They defined PET activity as grade 0 when no uptake was present, grade 1 if SUV was less than or equal to mediastinal background activity, and as grade 2 if SUV was higher than mediastinal background activity. Tumors that were GGOs were less likely to be invasive (2.3%) than tumors that had a solid component (32.9%). Based upon PET grades of 0, 1, or 2, invasion was present in 4.3%, 12.1%, and 32.6% of patients, respectively. They concluded that limited resection could be considered in patients with GGO type tumors and in those whose PET grade was 0-1. A note of caution regarding reliance upon imaging studies was sounded by Stiles et al.37 They reviewed 266 clinical stage IA patients, staged with CT and PET scans, who underwent surgical resection. The preoperative stage was correct in only 65% of patients. Twenty percent of patients were upstaged to pathologic stage II-IV. Characteristics
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that predicted upstaging were size >2 cm and PET positivity. Patients with PET positive tumors >2 cm in size were upstaged 55% of the time, those with tumors £2 cm and PET positive were upstaged 32% of the time, and those with tumors £2 cm and PET negative were upstaged only 17% of the time.
Surgical Approach Recent studies have compared thoracoscopic segmentectomy to thoracoscopic lobectomy or to open segmentectomy. In a retrospective study, Shapiro et al. compared 31 stage I NSCLC patients undergoing thoracoscopic segmentectomy to 113 undergoing thoracoscopic lobectomy.38 There were no differences in locoregional recurrence rates (3.5% vs. 3.6%), although mean follow-up was only 22 and 21 months, respectively. Schuchert et al. recently compared 104 patients undergoing thoracoscopic segmentectomy to 121 patients undergoing open segmentectomy.39 Those undergoing thoracoscopic segmentectomy had less complications and a shorter length of stay. Fewer lymph nodes were removed in the thoracoscopic group (6.4 vs. 9.1, p = 0.003). Despite this, there was no difference in locoregional recurrence between patients undergoing thoracoscopic (4.8%) and open (10.7%) segmentectomy. Death due to cancer was higher (p = 0.025) in the open group (16.5%) than in the thoracoscopic group (6.7%), although the mean follow-up was significantly longer in the open group (28 months vs. 16 months).
Current Clinical Trials Cancer and Leukemia Group B has activated (June 2007–April 2012) a phase III randomized trial (CALGB 140503) of lobectomy versus sublobar resection for £2 cm peripheral, node negative NSCLC. Eligibility criteria mandate a peripheral lung nodule £2 cm on preoperative CT scan, with the center of the tumor located in the outer third of the lung field. Patients are randomized intraoperatively into lobectomy versus sublobar resection (segmentectomy or wedge). Confirmation of N0 status by frozen section of mediastinal and major hilar nodal stations is required prior to randomization. The primary endpoint of the trial is disease free survival (DFS). Secondary endpoints include overall survival (OS), rate of loco-regional and systemic recurrence, and pulmonary function as measured by pulmonary expiratory flow rate 6 months after the surgery. The target accrual is 908 randomized patients over 5 years with 3 years of follow-up. The trial is supported by most American co-operative groups as well as NCI-Canada. As of early 2010, a multi-institutional trial was in the planning phase by the Japan Clinical Oncology Group (JCOG0802). The trial will randomize patients with £2 cm peripheral non-small cell lung cancer to lobectomy or segmentectomy. Target accrual is 1,100 cases over 3 years with 5 years of follow-up. Table 13.2 highlights the similarities and differences between the CALGB 140503 and the JCOG 0802 trials.
Table 13.2. Comparison of CALGB 140503 and JCOG0802 trials. Design Pre-registration eligibility criteria Intra-operative randomization criteria
CALGB 140503
JCOG0802
Randomized phase III
Randomized phase III
Peripheral £2 cm NSCLC N0 status confirmed by frozen exam: Right (level 4, 7, 10), Left (Level 5, 6, 7, 10)
Exclusion criteria Control arm Study arm Primary endpoint Secondary endpoints
Pure ground glass lesions Lobectomy Segmentectomy or wedge resection Disease free survival Overall survival, local and systemic recurrence rates, pulmonary function at 6 months
Target number/entry period/ follow-up Postoperative follow-up
1,297 cases, 908 eligible cases after randomization/ 5 years/3.25 years CT chest at 6 months, 1 year then yearly for 4 years
Peripheral £2cm NSCLC part-solid to solid on chest CT Free of non-curative factor (i.e. malignant pleural effusion and dissemination) Frozen exam of lymph nodes not required Carcinoid tumor Lobectomy Segmentectomy Overall survival Pulmonary function at 3 months and 1 year, disease free survival, local recurrence rate, adverse events, hospitalization, chest drainage amount, operative time, bleeding amount, number of auto-staplers 1,100 cases/3 years/5 years CT chest every 6 months
13. Segmentectomy Versus Lobectomy for Stage I Lung Cancer in Patients with Good Pulmonary Function
Conclusions and Recommendations Since the report of the Lung Cancer Study Group, lobectomy has been regarded by most thoracic surgeons as the gold standard for resection of early stage NSCLC in good-risk patients. Lobectomy and complete nodal dissection achieve the maximum survival benefit in patients with stage IA disease. Limited resection has been largely reserved for those patients with compromised cardiopulmonary status. However recent evidence, in particular a large meta-analysis, supports the use of intentional limited resection for small (£2 cm in size), peripheral stage I NSCLC. Such operations are safe, and carry a similar risk profile and survival outcomes compared to that of open lobectomy (evidence quality moderate). Careful intraoperative analysis of hilar and mediastinal lymph nodes must be performed to exclude occult lymph node metastases and ensure accurate staging to determine the appropriateness of limited resection and the need for adjuvant chemotherapy. Patients with pure GGOs on preoperative imaging or those with noninvasive BAC diagnosed by intraoperative pathologic examination may be particularly good candidates for limited resection. Conversely, patients with tumors >2 cm in size, those with central tumors, and those whose tumors are positive on preoperative PET scans are not good candidates for limited resection. We make a strong recommendation for anatomic segmentectomy in patients who are physiologic candidates for lobectomy for peripheral tumors £2 cm that are confined to an anatomic segment and in whom no hilar or mediastinal nodal involvement is detected on intraoperative staging (grade of recommendation 1B). Thoracoscopic and open segmentectomy have similar risk profiles and long-term clinical outcomes (evidence quality low). We make a weak recommendation for thoracoscopic segmentectomy in patients who are good candidates for limited resection (grade of recommendation, 2C). Future results from the randomized phase III limited resection trials CALGB 140503 and JCOG0802 for peripheral £2 cm NSCLC will hopefully clarify the role of sublobar resection as an alternative to lobectomy.
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Limited resection for peripheral stage I NSCLC is safe and has similar risk and survival outcomes to that of open lobectomy (evidence quality moderate). We make a strong recommendation for anatomic segmentectomy in patients with peripheral tumors <_2 cm that are confined to an anatomic segment and in whom no hilar or mediastinal nodal involvement is detected on intraoperative staging (grade of recommendation 1B).
Thoracoscopic and open segmentectomy have similar risk profiles and long-term clinical outcomes (evidence quality low). We make a weak recommendation for thoracoscopic segmentectomy in patients who are good candidates for limited resection (grade of recommendation 2C).
References 1. Oschner A, DeBakey M. Primary pulmonary malignancy: treatment by total pneumonectomy. Analysis of 79 collected cases and presentation of 7 personal cases. Surg Gynecol Obstet. 1939;68:435–441. 2. Churchill ED, Sweet RH, Soutter L, Scannell JG. The surgical management of carcinoma of the lung: a study of cases treated at the Massachusetts General Hospital from 1930–50. J Thorac Cardiovasc Surg. 1950;20:349–365. 3. Cahan WG. Radical lobectomy. J Thorac Cardiovasc Surg. 1960;39:555–572. 4. Churchill ED, Belsey R. Segmental pneumonectomy in bronchiectasis: the lingula segment of the left upper lobe. Ann Surg. 1939;109:481–499. 5. Churchill ED, Sweet RH, Scannell JG, Wilkins EW Jr. Further studies in the surgical management of carcinoma of the lung; a further study of the cases treated at the Massachusetts General Hospital from 1950 to 1957. J Thorac Surg. 1958;36:301–308. 6. Bonfils-Roberts EA, Clagett OT. Contemporary indications for pulmonary segmental resections. J Thorac Surg. 1972;63:433–438. 7. Jensik RJ, Faber LP, Milloy FJ, Monson Do. Segmental resection for lung cancer: a fifteen year experience. J Thorac Cardiovasc Surg. 1973;66:563–572. 8. Read RC, Yoder G, Schaeffer RC. Survival after conservative resection for T1N0M0 non-small cell lung cancer. Ann Thorac Surg. 1990;49:391–398. 9. Warren WH, Faber LP. Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five Year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg. 1994;107:1087–1094.
132 10. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non– small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg. 1995;60:615–622. 11. Landreneau RJ, Sugarbaker DJ, Mack MJ, Hazelrigg SR, Luketich JD, Fetterman L, Liptay MJ, Bartley S, Boley TM, Keenan RJ, Ferson PF, Weyant RJ, Naunheim KS. Wedge resection versus lobectomy for stage I (T1 N0 M0) non–small cell lung cancer. J Thorac Cardiovasc Surg. 1997;113:691–700. 12. Miller DL, Rowland CM, Deschamps C, Allen MS, Trastek VF, Pairolero PC. Surgical treatment of nonsmall cell lung cancer 1 cm or less in diameter. Ann Thorac Surg. 2002;73:1545–1551. 13. Keenan RJ, Landreneau RJ, Maley Jr RH, Singh D, Macherey R, Bartley S, Santucci T. Segmental resection spares pulmonary function in patients with stage I lung cancer. Ann Thorac Surg. 2004;78: 228–233. 14. Kodama K, Doi O, Higashiyama M, Yokouchi H. Intentional limited resection for selected patients with T1 N0 M0 non–small–cell lung cancer. A singleinstitution study. J Thorac Cardiovasc Surg. 1997;114:347–353. 15. Okada M, Yoshikawa K, Hatta T, Tsubota N. Is segmentectomy with lymph node assessment an alternative to lobectomy for non–small cell lung cancer of 2 cm or smaller? Ann Thorac Surg. 2001;71: 956–960. 16. Koike T, Yamato Y, Yoshiya K, Shimoyama T, Suzuki R. Intentional limited pulmonary resection for peripheral T1N0M0 small-sized lung cancer. J Thorac Cardiovasc Surg. 2003;125:924–928. 17. Nakamura H, Kawasaki N, Taguchi M, Kabasawa K. Survival following lobectomy vs limited resection for stage I lung cancer: a meta-analysis. Br J Cancer. 2005;92:1033–1037. 18. Sobin L, Wittekind Ch, eds. TNM Classification of Malignant Tumours, 6th ed. New York: Wiley-Liss; 2002:99–103. 19. Okada M, Koike T, Higashiyama M, Yamati Y, Kodama K, Tsubota N. Radical sublobar resection for smallsized non-small cell lung cancer: a multicenter study. J Thorac Cardiovasc Surg. 2006;132:769–775. 20. Watanabe T, Okada A, Imakiire T, Koike T, Hirono T. Intentional limited resection for small peripheral lung cancer based on intraoperative pathologic exploration. Jpn J Thorac Cardiovasc Surg. 2005;53: 29–35. 21. Schuchert MJ, Pettiford BL, Keeley S, D’Amato TA, Kilic A, Close J, Pennathur A, Santos R, Fernando HC, Landreneau JR, Luketich JD, Landreneau RJ. Anatomic segmentectomy in the treatment of stage I non-small cell lung cancer. Ann Thorac Surg. 2007;84:926–933. 22. Sienel W, Stremmel C, Kirschbaum A, Hinterberger L, Stoelben E, Hasse J, Passlick B. Frequency of local recurrence following segmentectomy of stage IA non-small cell lung cancer is influenced by segment localization and width of resection margins – impli-
B.M. Stiles and N.K. Altorki cations for patient selection for segmentectomy. Eur J Cardiothorac Surg. 2007;31:522–528. 23. Port JL, Kent MS, Korst RJ, Libby D, Pasmantier M, Altorki NK. Tumor size predicts survival within stage IA non-small cell lung cancer. Chest. 2003;124:1828–1833. 24. Lee PC, Korst RJ, Port JL, Kerem Y, Kansler A, Altorki NK. Long-term survival and recurrence in patients with resected non-small cell lung cancer 1 cm or less in size. J Thorac Cardiovasc Surg. 2006;132: 1382–1389. 25. Birim O, Kappetein P, Takkenberg, JJ, van Klaveren RJ, Bogers AJ. Survival after pathological stage IA nonsmall cell lung cancer: tumor size matters. Ann Thorac Surg. 2005;79:1137–1141. 26. Koike T, Terashima M, Takizawa T, Watanabe T, Kurita Y, Yokoyama A. Clinical analysis of smallsized peripheral lung cancer. J Thorac Cardiovasc Surg. 1998;115:1015–1020. 27. Okada M, Nishio W, Sakamoto T, Uchino K, Yuki T, Nakagawa A, Tsubota N. Effect of tumor size on prognosis in patients with non–small cell lung cancer. The role of segmentectomy as a type of lesser resection. J Thorac Cardiovasc Surg. 2005;129:87–93. 28. Nesbitt J.C, Putnam J.B Jr, Walsh GL, Roth JA, Mountain CF. Survival in early-stage non-small cell lung cancer. Ann Thorac Surg. 1995;60:466–472. 29. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L, International Association for the Study of Lung Cancer International Staging Committee, Participating Institutions. The IASLC lung cancer staging project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thor Onc. 2007;2:706–714. 30. Ketchedjian A, Daly BD, Fernando HC, Florin L, Hunter CJ, Morelli DM, Shemin RJ. Location as an important predictor of lymph node involvement for pulmonary adenocarcinoma. J Thorac Cardiovasc Surg. 2006;132:544–548. 31. Lee PC, Port JL, Korst RJ, Liss Y, Meherally DN, Altork NK. Risk factors for occult mediastinal metastases in clinical stage I non-small cell lung cancer. Ann Thorac Surg. 2007;84:177–181. 32. Asamura H, Nakayama H, Kondo H, Tsuchiya R, Shimosato Y, Naruke T. Lymph node involvement, recurrence, and prognosis in resected small, peripheral, non–small cell lung carcinomas: are these carcinomas candidates for video-assisted lobectomy? J Thorac Cardiovasc Surg. 1996;111:1125–1134. 33. Noguchi M, Morikawa A, Kawasaki M, Matsuno Y, Yamada T, Hirohashi S, Kondo H, Shimosato Y. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer. 1995;75:2844–2852. 34. Yoshida J, Nagai K, Yokose T, Nishimura M, Kakinuma R, Ohmatsu H, Nishiwaki Y. Limited resection trial for pulmonary ground-glass opacity nodules: fiftycase experience. J Thorac Cardiovasc Surg. 2005;129:991–996.
13. Segmentectomy Versus Lobectomy for Stage I Lung Cancer in Patients with Good Pulmonary Function 35. Koike T, Togashi K, Shirato T, Sato S, Hirahara H, Sugawara M, Oguma F, Usuda H, Emura I. Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg. 2009;88:1106–1111. 36. Yoshioka M, Ichiguchi O. Selection of sublobar resection for c-stage IA non-small cell lung cancer based on a combination of structural imaging by CT and functional imaging by FDG PET. Ann Thorac Cardiovasc Surg. 2009;15:82–88. 37. Stiles BM, Servais EL, Lee PC, Port JL, Paul S, Altorki NK. Point: clinical stage IA non-small cell lung cancer determined by computed tomography and positron emission tomography is frequently not pathologic IA non-small cell lung cancer: The problem of understaging. J Thorac Cardiovasc Surg. 2009;137:13–19.
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38. Shapiro M, Weiser TS, Wisnivesky JP, Chin C, Arustamyan M, Swanson SJ. Thoracoscopic segmentectomy compares favorably with thoracoscopic lobectomy for patients with small stage I lung cancer. J Thorac Cardiovasc Surg. 2009;137: 1388–1393. 39. Schuchert MJ, Pettiford BL, Pennathur A, Abbas G, Awais O, Close J, Killic, A Jack R, Landreneau JR, Landreneau JP, Luketich JD, Landreneau RJ. Anatomic segmentectomy for stage I non-small-cell lung cancer: comparison of video-assisted thoracic surgery versus open approach. J Thorac Cardiovasc Surg. 2009;138:1318–1325. 40. Yoshikawa K, Tsubota N, Kodama K, Ayabe H, Taki T, Mori T. Prospective study of extended segmentectomy for small lung tumors: the final report. Ann Thorac Surg. 2002;73:1055–1058.
14
Optimal Therapy for Patients with Marginal Lung Function and Peripheral Stage I Lung Cancer Gonzalo Varela and Marcelo F. Jiménez
Introduction The association between COPD and non-small cell lung cancer (NSCLC) has been proven in the medical literature.1 It has been also demonstrated that the lower the FEV1%, the higher the risk of developing NSCLC.2 Due to the association between both diseases, COPD patients are frequently referred for lung resection for NSCLC. In this chapter we review recently published evidence regarding the best therapeutic option for stage I NSCLC patients with marginal pulmonary function. Before focusing on therapeutics, we briefly discuss the criteria for accurately classifying a NSCLC patient in Stage cI and the concept of “marginal” pulmonary function. The first is important because surgery can be considered curative in tumors with neither distal nor regional extension and the second is needed to clarify who should be considered a high-risk patient due to poor pulmonary function. In order to obtain the best evidence from the literature, a search was performed in Medline (using OVID interface) during the period 2000– 2009 including the following terms: • For the section on VATS lobectomy: [video] OR [thoracic] OR [lobectomy] OR [VATS] OR [thoracoscopic] AND [non-small-cell lung carcinoma] OR [lung cancer] OR [early stage non-small cell lung carcinoma]. • For pulmonary segmentectomy and wedge resection: [limited pulmonary resection] OR [limited lung resection] OR [sublobar pulmonary resection] OR [wedge pulmonary resec-
tion] OR [lung parenchyma sparing resection] OR [pulmonary segmentectomy] OR [lung volume volume reduction] AND [non-small-cell lung carcinoma] OR [lung cancer] OR [early stage lung carcinoma]. • For stereotactic radiotherapy: [stereotactic radiotherapy] OR [high-dose radiotherapy] OR [hypofractionated radiotherapy] OR [nonsurgical therapy] AND [non-small-cell lung carcinoma] OR [lung cancer] OR [early stage non-small cell lung carcinoma]. • For radiofrequency ablation: [radiofrequency ablation] OR [percutaneous radiofrequency ablation] OR [non-surgical therapy] AND [non-small-cell lung carcinoma] OR [lung cancer] OR [early stage non-small cell lung carcinoma]. The searches were limited to articles in English and meta-analysis, randomized controlled trials, or practice guidelines. In the absence of any of the previous, clinical trials were also reviewed. Duplicate publications were excluded. Some systematically sound comparative retrospective studies have also been cited to justify the recommendation for future well-designed clinical trials.
Criteria for Classifying Clinical Stage I NSCLC Complete resection or eradication of the tumor is paramount in patients with NSCLC. In the absence of distant metastases, mediastinal lymph node
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involvement is the most important prognostic factor and influences further therapeutic strategies. To rule-out distant metastases, it is recommended that patients with lung cancer be assessed for curative treatment by a multidisciplinary team. All patients have to be interviewed asking for clinical symptoms related to distant metastases and undergo a thorough physical examination and standard laboratory tests as a screen for metastatic disease.3 Patients with abnormal clinical evaluations should undergo imaging for extrathoracic metastases. Site-specific symptoms warrant directed evaluation of that site with the most appropriate study. The use of routine of MRI or CT scan to exclude brain metastases in early stage cases is not generally recommended.4 According to the European Society of Thoracic Surgeons (ESTS) recommendations,5 in patients with lung cancer who are being considered for radical treatment, invasive staging can be omitted for small (<3 cm) peripheral tumors with negative mediastinal positron emission tomography (PET) images. However, invasive staging remains indicated in patients with central tumors, hilar N1 disease suspected by PET findings, and low FDG uptake of the primary tumor and lymph nodes ³16 mm on CT. In patients with pathological mediastinal FDG uptake, mediastinal nodal status should be histologically or cytologically documented. Transbronchial needle aspiration, ultrasound-guided bronchoscopy (EBUS-FNA) or esophagoscopy (EUS-FNA) and transthoracic needle aspiration (TTNA) provide cyto-histological diagnosis and are less invasive that surgical techniques. Nevertheless, due to their low negative predictive value, a more invasive surgical technique is indicated in case of negative results. Only after this complete workup the patient with peripheral NSCLC can be accurately classified in clinical stage I.
The Concept of Marginal Pulmonary Function An exhaustive review of the literature on this topic is outside the scope of this chapter since two clinical practice guidelines related to preoperative workup before lung resection have been recently
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published. The first one was prepared by the American College of Chest Physicians (ACCP)6 and the last, by a multidisciplinary group endorsed by the European Respiratory Society and the ESTS (ERS/ESTS).7 Several differences can be found between the guidelines. While in the ACCP document measuring DLCO is restricted to patients with FEV1 abnormal values or patients with unexplained dyspnea or diffuse parenchymal disease on radiological images, the ERS/ESTS guidelines recommend DLCO should be measured in all patients since low values are highly predictive of adverse postoperative outcomes. The indications for cardiopulmonary exercise tests (CPETs) are also different in the guidelines. In the American one, exercise tests are indicated in patients with ppoFEV1 or ppoDLCO under 40% of the predicted values for sex, age and height. In the ERS/ESTS document, CPETs are indicated in all patients with FEV1 or DLCO under 80% of their theoretical values. Despite these differences, both guidelines recommend that final decisions on high-risk patients should not be based only on actual FEV1 or on predicted postoperative FEV1 (ppoFEV1), except in the case of a ppoFEV1 under 30%. For the ACCP guidelines, these patients have to be considered high-risk, and surgery is usually not indicated. In such cases, the ERS/ESTS recommends estimation of ppo-peakVO2 and proceeding to surgery if the value is >30% or >10 mL/kg/min. In the American guidelines, the peak VO2 cut-off value for considering a high-risk procedure is 10–15 mL/kg/min. After reading both clinical guidelines, it can be concluded that measuring DLCO and peak VO2 are paramount for a thorough assessment of the risk of death or developing postoperative cardiorespiratory complications following lung resection. Unfortunately, a recent survey on preoperative assessment of pulmonary function has demonstrated a lack of agreement in fundamental areas and difficulties in putting current recommendations into practice.8 For the purposes of this review, we are considering as “marginal”, due to poor pulmonary function, the patient with ppoFEV1 around 30%, ppoDLCO around 40% of predicted values and/ or patients with peak VO2 around the limit of
14. Optimal Therapy for Patients with Marginal Lung Function and Peripheral Stage I Lung Cancer
10 ml/kg/min. Therapeutic alternatives in cases with marginal pulmonary function are the following:
VATS Lobectomy In a retrospective cohort study conducted using the SEER Medicare database, video-assisted lobectomy has been found at least as effective as conventional resection, in terms of long-term survival, when performed by high-volume surgeons or at high-volume teaching centers.9 Potential benefits of VATS lobectomy include oncologic outcomes equivalent to open lobectomy with lower morbidity and operative mortality in two recently published large series of cases.10,11 In both series, reported mortality was under 1%. Nevertheless, there is no evidence in the literature concerning the use of VATS surgery in patients with poor pulmonary function. In a meta-analysis by Cheng and co-workers,12 only three trials showed significant reduction in the rate of overall postoperative complications comparing VATS lobectomy to lobectomy via thoracotomy. These studies were underpowered due to an insufficient number of patients to show relevant differences for most clinical outcomes.
Preserving Lung Parenchyma: Segmentectomy and Wedge Resection Sublobar resection is sometimes recommended as an effective therapy in NSCLC patients with poor pulmonary function. Two questions have to be answered to enable recommendation of sublobar resection as the treatment of choice in these patients: is sublobar resection a reasonable option from an oncological point of view? And, does sublobar resection preserve pulmonary function better than lobectomy?
Effectiveness of Sublobar Resection in the Treatment of Stage CI NSCLC In the last five years, one meta-analysis13 and two systematic reviews of the literature on the topic14,15 have been published. Basically, all three studies
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conclude that survival after limited resection for stage I NSCLC is comparable to that after lobectomy, but they also state that, due to interstudy heterogeneity, this finding has to be confirmed by well designed randomized clinical trials. In fact, in the study by Nakamura et al.,13 the authors underline the higher rate of squamous tumors in the group of patients with sublobar resection. Chamogeorgakis et al.15 emphasize that, in the series of patients undergoing sublobar resection, a higher non-cancer related long-term mortality was found, which was attributed to higher perioperative risk related to comorbidity. In the paper by Rami-Porta and Tsuboi14 it is emphasized that wedge resection is followed by a higher rate of local relapse compared to anatomical segmentectomy. This finding does not affect long term survival in the elderly population. After publication of the above mentioned metaanalysis, some papers have appeared dealing with the effectiveness of sublobar resection in NSCLC.16–19 Only one of the investigations has been designed as a prospective phase II trial,19 but the authors focused only on bronchioloalveolar carcinoma; thus, conclusions cannot be extended to all types of NSCLC. In the article by Kodama et al.,16 the authors present a novel treatment algorithm for small peripheral lung lesions measuring 20 mm or less in diameter, employing semiquantitative assessments of GGO area on high resolution CT scan and intraoperative lavage cytologies of the resection margin of the lung. They found comparable survival after limited resection (including wide wedge resection in cases of pure GGO) and similar clinical outcomes with no local recurrences. Two papers17,18 are retrospective comparative analysis of case series treated by anatomical segmentectomy or lobectomy. In both cases segmentectomy offered comparable long-term and disease free survival. After reviewing the literature, it appears that limited pulmonary resection, preferably anatomical segmentectomy, can be offered as an alternative to lobectomy in patients with stage cI NSCLC (Table 14.1). Nevertheless, the type of evidence to support this statement is low and is based mainly on retrospective comparative case series and on meta-analysis in which the analyzed studies are affected by a high degree of inter-study heterogeneity.
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138 Table 14.1. Effectiveness of sublobar resection in the treatment of peripheral stage I NSCLC. First author (reference)
Type of study
Limitations
End-point
Nakamura13
Meta-analysis
Interstudy heterogeneity
1, 3, 5-year overall survival
Rami-Porta14
Meta-analysis
Interstudy heterogeneity
5-year survival, local relapse rate
Chamogeorgakis15
Systematic review of literature
Interstudy heterogeneity
Shapiro17
Comparative, retrospective Comparative, retrospective Controlled prospective
Limited to thoracoscopic approach Patients >75 year old
Long-term survival and short-term outcomes (hospital staying and mortality) Recurrence rate and mean survival
Kilic18 Kodama16
Koike19
No preoperative diagnosis of NSCLC. Benign cases excluded from survival analysis. Prospective, phase II trial Limited to non-invasive BAC
Does Segmentectomy Preserve Pulmonary Function Better Than Lobectomy? Several retrospective studies comparing functional changes in patients after lobecomy or segmentectomy20–23 concluded that segmentectomy preserves postoperative lung volumes better than lobectomy. In all these papers, the investigators did not differentiate between patients with normal preoperative function and those with emphysema. It is well known that lobectomy can be offered to patients with lung carcinoma located in a severely emphysematous lobe, despite very low preoperative and predicted postoperative values of FEV1.24 In these patients, lobectomy has an effect comparable to lung volume reduction surgery.25,26 In COPD patients without large emphysematous changes, the lung volume reduction effect has been retrospectively tested by several authors. The effect of lobectomy on FEV1 decrease has been evaluated in the early period27,28 or several months after surgery (Table 14.2).29–33 All the investigations conclude that the loss of pulmonary function after lobectomy is less in COPD patients. While in most papers the site of lobectomy has not been investigated as a variable influencing the correlation between expected and observed postoperative FEV1, some controversies can be found reviewing the papers by Kushibe et al.31 and Sekine et al.30
Disease-free and 5-year survival 5 and 10-year overall survival
5-year overall and disease-free survival
Conclusions Comparable survival after segmentectomy and lobectomy Segmentectomy and lobectomy are comparable. Wedge not recommended Comparable survival after segmentectomy and lobectomy Segmentectomy and lobectomy are comparable Segmentectomy and lobectomy are comparable Wide wedge resection, segmentectomy and lobectomy comparable in the settings of a prospective algorithm Wedge resection is an effective procedure
According to the first investigators, the loss of pulmonary function is reduced if an upper lobectomy is performed, while for the second, lower lobectomy is better for preserving pulmonary volumes. In two published reports, a comparison between segmentectomy and lobectomy was carried out.34,35 Interestingly, in the paper by Kashiwabara et al.,35 it was concluded that segmentectomy should be considered in patients with peripheral early NSCLC with normal predicted postoperative FEV1, while in patients with ppoFEV1 under 70%, segmentectomy offers no functional advantages over lobectomy. These seem to be promising preliminary results but, to date, there is not enough evidence in the literature to strongly recommend lobectomy in patients with marginal pulmonary function and peripheral NSCLC, except in the case when the pulmonary lobe containing the tumor is destroyed by emphysema.
Stereotactic Radiotherapy Radiotherapy is frequently reserved for patients with stage I NSCLC who are deemed unfit for surgery. Due to high local relapse rates and low overall long-term survival, conventional radiotherapy is not considered a good alternative to surgery. Stereotactic radiotherapy (SRT) is a form of highprecision radiotherapy delivery characterized by
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14. Optimal Therapy for Patients with Marginal Lung Function and Peripheral Stage I Lung Cancer Table 14.2. Influence of preoperative COPD/emphysema on postoperative FEV1 after lobectomy. First author (reference) Kashiwabara
Type of study 35
Santambrogio29 Sekine30
Retrospective comparative Retrospective comparative Retrospective comparative
Kushibe31
Retrospective comparative
Schattenberg32
Retrospective comparative Retrospective comparative
Baldi33
Brunelli27
Prospective comparative
Varela28
Prospective comparative Retrospective comparative
Edwards25
Yoshimoto23
Retrospective comparative
Patients
Cases compared
Outcomes
Conclusion
Segmentectomy offered functional advantages only in cases without emphysema 45 lobectomy 42 lobectomy Preoperative FEV1 FEV1 decrease 6 months after Less decrease of FEV1 in COPD in COPD cut-off 80% surgery patients 473 non COPD 48 COPD Preoperative FEV1 Ratio actual/ppoFEV1 1 month Less decrease of FEV1 in COPD cut-off 70% after surgery patients if lower lobectomy is performed 83 upper lobectomy 78 Preoperative FEV1 FEV1 decrease at 6 and 12 Less FEV1 decrease after upper lower lobectomy cut-off: 60% months after surgery lobectomy and in patients with preoperative FEV1<60% 79 consecutive cases COPD grades I-II FEV1 decrease 3 and 6 months FEV1 decrease was less than after surgery expected 49 non COPD 88 COPD Preoperative Ratio actual/ppoFEV1, 3–15 In patients with mild to severe FEV1cut-off: 65% months after surgery COPD, better preservation of postoperative FEV1 190 consecutive cases FEV1% continuous FEV1 loss % 10 days after Patients with preoperative FEV1 < variable lobectomy 70% had less decrease of their FEV1 185 consecutive cases FEV1% and FEV1/FVC Delta ppoFEV1 1st day after Less postoperative decrease in cases continuous variable lobectomy with lower COPD index cases 14 severe COPD 14 moderate Preoperative FEV1cut-off: Ratio actual/ppoFEV1, 3 Similar postoperative decrease in COPD 40% plus emphysema months after surgery spirometry in spite of destroyed lobe preoperative FEV1 values 24 lobectomy ppoFEV1 estimation by Difference actual and ppoFEV1, Surgical removal of lung areas with 65 segmentectomy image analysis or 6–17 months after surgery a CT number outside of the range resected pulmonary of -910 to -500 HU did not cause segments a loss of lung function 47 lobectomy 71 segmentctomy
Emphysema at HRCT scan Delta FEV1, 6 months after vs no emphysema surgery
the use of extremely high biological doses of radiation (equivalent to 100 Gy or more) usually delivered in three treatment fractions within a 2 week period. This is obtained by a reproducible immobilization system to avoid patient movement during treatment sessions, and measures to individually account for tumor motion during imaging, treatment planning and radiation delivery. With SRT, tissue surrounding the tumor is affected by a minimal radiation dose and, consequently, reported lung toxicity is usually a minor problem.36 Low pretreatment pulmonary volumes alone are not considered a contraindication to SRT.37 Most reports on the effectiveness of SRT, include patients who are unfit to undergo surgery, using variable criteria, and include only a minority of patients who refused surgery. This introduces a large patient selection bias compared to surgery, rendering overall survival less suitable for comparison.
Table 14.3. Treatment of cyto-histologically proven NSCLC with stereotactic radiotherapy. Prospective phase II studies including more than ten cases were evaluated. Author (reference) Zimmerman38 Koto39 Baumann41 Fakiris40 Ricardi42
Patients 68 31 57 70 62
3 year overall survival (%) 53 71.7 60 42.7 57.1
3 year cancer-specific survival (%) 73 83.5 88 81.7 72.5
In order to clarify the effectiveness of SRT in the treatment of early stage NSCLC, we reviewed papers38–42 reporting prospective phase II studies that include more than ten patients with histologically proven lung cancer (Table 14.3). These studies have the advantage of more homogeneous radiotherapy schemes and patient selection criteria. In all reviewed studies, 3-year cancer- specific survival (ranging 72–88%) is better than
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overall survival, showing a high mortality rate due to associated diseases. Cancer-specific survival reported in these series is superior to usually reported in non-stereotactic radiotherapy series. The study by Onishi et al.43 is a multi-institutional retrospective analysis. The authors included in their review nearly 100 patients who were deemed operable but refused surgery. In this subset, the 5-year overall survival rate observed after a biologically effective dose of 100 Gy was 70.8%, equivalent to the outcome after surgery. The effectiveness of SRT is in some ways difficult to evaluate. Tissue fibrosis and subclinical radiation pneumonitis are frequently observed at follow-up CT, and 18F-FDG PET is of limited value in distinguishing fibrosis from tumor recurrence as treated volumes can show 18F-FDG uptake up to 2 years after treatment.44
Radiofrequency Ablation (RFA) Several reports have been published on the usefulness of RFA in the treatment of patients with NSCLC.45–51 An accurate assessment of the influence of RFA on patient survival is not easy because of selection bias and small numbers of patients followed-up for short periods of time. In one of the published series of cases,45 overall one-year survival was 85% and was dependent on the tumor size (94% for tumors of 3 cm or less and 74% for tumors of more than 3cm in diameter). Mean survival in this report was 8.6 months. In another paper,46 mean survival of patients was significantly different between patients who had complete (19.7 months) and partial (8.7 months) tumor necrosis. No differences were found in mean survival between patients using a tumor size of 3cm as a cut-off. In patients with NSCLC included in a large multicenter study trial of 106 patients with cancer,50 the 2-year overall survival was 48%, with most of the patients dying from non-cancer related causes. Cancer-specific survival was 92% at 1 year and 73% at 2 years in this study. Similar results were published recently by Pennathur et al.51 Although RFA of early stage lung cancer is currently one of the hot topics in interventional radiology, scanty high-quality evidence regarding its outcomes (safety, local tumor control, and
G. Varela and M.F. Jiménez
survival) can be drawn from the literature because most clinical data have been derived from small retrospective studies. Based on our review, RFA treatment of lung tumors should not be considered standard therapy of small peripheral NSCLC, even in patient who are not candidates for lung resection due to medical comorbidity.
Recommendations Regarding Therapy in Patients with Marginal Function and Peripheral Early Stage NSCLC The following recommendations have been graded according to the criteria formulated by the ACCP ad-hoc task force.52 Although it has not been included among the recommendations, it is obvious that therapeutic decisions have to be made after instituting optimal bronchodilator therapy and the consequent re-evaluation of the patient.
Accuracy of Clinical Stage I Classification in Small Peripheral NSCLC Invasive mediastinal staging can be omitted if PET findings are negative in the mediastinum (moderate evidence). In cases with no mediastinal FDG uptake but hilar N1 disease suspected by PET findings and/or low FDG uptake of the primary tumor and lymph nodes ³16 mm on CT, cyto-histologal exam of mediastinal lymph nodes is indicated (moderate evidence). Extension to the mediastinum should also be confirmed by invasive techniques if PET is positive at the mediastinum (moderate evidence). Negative results at cytological examination of mediastinal lymph nodes should be confirmed by open biopsy techniques (moderate evidence). We make a strong recommendations (Grade 1B) for accurate mediastinal staging before choosing a definitive therapy in patients with small peripheral NSCLC and marginal pulmonary function.
Concept of Marginal Pulmonary Function Final decisions on operability of high-risk patients should not be based on actual or predicted FEV1
14. Optimal Therapy for Patients with Marginal Lung Function and Peripheral Stage I Lung Cancer
values alone (moderate evidence). The usefulness of measuring DLCO in all patients and peak VO2 in patients with limitations of FEV1 and/or DLCO has been proven in the literature (moderate evidence) and is strongly recommended (Grade 1B). High risk in patients are defined as having ppoFEV1<30%, ppoDLCO <40% and/or peakVO2 <10–15 mL/kg/min or peak VO2 <35% of predicted (moderate evidence), and surgery is strongly not recommended in these cases (Grade 1B).
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Stereotactic Radiotherapy Cancer-specific long-term survival in cases of peripheral early stage NSCLG and marginal pulmonary function treated by stereotactic radiotherapy are comparable to those obtained by surgical therapy (moderate evidence). Since no functional deterioration has been published as an adverse effect of the treatment (moderate evidence), stereotactic radiotherapy is weakly recommended (Grade 2A) if the risk of surgery is deemed too high.
Radiofrequency Ablation VATS Lobectomy Due to demonstrated lower postoperative morbidity (low evidence), VATS lobectomy is recommended in centers with previous experience in the procedure in patients with marginal pulmonary function who have to be treated by lobectomy (Grade 2B).
Sublobar Pulmonary Resection for Surgical Treatment of NSCLC Anatomical segmentectomy for patients with small peripheral NSCLC offers comparable long-term survival to lobectomy (low quality evidence) and better cancer-related survival than wedge resection (high quality evidence). Therefore, the authors recommend strongly against wedge resection as a therapeutic approach even in patients with marginal pulmonary function (Grade 1B). We make a weak recommendation for anatomical segmentectomy if the patient is considered absolutely unfit for lobectomy (Grade 2A). Due to the evidence of a volume reduction effect and postoperative improvement of pulmonary function (low evidence), patients with severe COPD and small peripheral NSCLC located in an emphysematous lobe should be treated by lobectomy (strong recommendation, Grade 1C). In patients with marginal pulmonary function and diffuse emphysema, segmentectomy offers no functional benefits compared to lobectomy (low evidence). A weak recommendation for lobectomy in these patients is made based on the literature (Grade 2C).
The benefits of RFA in the treatment of early stage NSCLC have not been proven to date and there is very low evidence regarding the influence of RFA on patient survival. We make a weak recommendation against RFA for management of stage cI NSCLC outside of a randomized clinical trial (Grade 2C).
Anatomical segmentectomy for patients with small peripheral NSCLC offers comparable long-term survival to lobectomy (low quality evidence), provides better cancer-related survival than wedge resection (high quality evidence), and is safe compared to standard surgical therapy. We make a weak recommendation for anatomical segmentectomy if the patient is considered absolutely unfit for lobectomy (recommendation grade 2A).
References 1. Wasswa-Kintu S, Gan WQ, Man SFP, Pare PD. Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis. Thorax. 2005;60:570–575. 2. Kuller LH, Ockene J, Meilahn E, Svedsen KH. Relation of forced expiratory volume in one second (FEV1) to lung cancer mortality in the multiple risk factor intervention trial (MRFIT). Am J Epidemiol. 1990;132:265–274. 3. Spiro SG, Gould MK, Colice GL. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes. Chest. 2007;132:149S–160S. 4. Silvestri GA, Gould MK, Margolis ML, Tanoue LT, McCrory D, Toloza E, Detterbeck F. Noninvasive staging of non-small cell lung cancer. Chest. 2007;132:178S–201S.
142 5. De Leyn P, Lardinois D, Van Schil PE, Rami-Porta R, Passlick B, Zielinski M, Waller DA, Lerut T, Weder W. ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer. Eur J Cardiothorac Surg. 2007;32:1–8. 6. Colice GL, Shafazand S, Griffin JP, Keenan R, Bolliger CT, American College of Chest Physicians. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines, 2nd ed. Chest. 2007;132(3 suppl):161S–177S. 7. Brunelli A, Charloux A, Bolliger CT, Rocco G, Sculier JP, Varela G, Licker M, Ferguson MK, Faivre-Finn C, Maria Huber R, Clini EM, Win T, De Ruysscher D, Goldman L, on behalf of the European Respiratory Society and European Society of Thoracic Surgeons joint task force on fitness for radical therapy. ERS/ ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemoradiotherapy). Eur Respir J. 2009;34:17–41. 8. Charloux A, Brunelli A, Bolliger CT, Rocco G, Sculier JP, Varela G, Licker M, Ferguson MK, Faivre-Finn C, Huber RM, Clini EM, Win T, De Ruysscher D, Goldman L. Lung function evaluation before surgery in lung cancer patients: how are recent advancers put into practice? A survey among members of the European Society of Thoracic Surgeons and of the Thoracic Oncology Section of the European Respiratory Society. Interact Cardiovasc Thorac Surg. 2009;d.o.i.10.1510/icvts.2009.211219 9. Farjah F, Wood DE, Mulligan MS et al. Safety and efficacy of video-assisted versus conventional lung resection for lung cancer. J Thorac Cardiovasc Surg. 2009;137:1415–1421. 10. McKenna RJ, Houck W, Fuller CB. Video-assisted thoracic surgery lobectomy: experience with 1100 cases. Ann Thorac Surg. 2006;81:421–426. 11. Onaitis MW, Petersen RP, Balderson SS, Toloza E, Burfeind WR, Harpole DH Jr, D’Amico TA. Thoracoscopic lobectomy is a safe and versatile procedure: experience with 500 consecutive patients. Ann Surg. 2006;244:420–425. 12. Cheng D, Downey RJ, Kernstine K, Stanbridge R, Shennib H, Wolf R, Ohtsuka T, Schmid R, Waller D, Fernando H, Yim A, Martin J. Video-assisted thoracic surgery in lung cancer resection: a meta-analysis and systematic review of controlled trials. Innov Technol Techniq Cardiothorac Vasc Surg. 2007;2: 261–292. 13. Nakamura H, Kawasaki N, Taguchi M, Kabasawa K. Survival following lobectomy vs limited resection for stage I lung cancer: a meta-analysis. Br J Cancer. 2005;92:1033–1037. 14. Rami-Porta R, Tsuboi M. Sublobar resection for lung cancer. Eur Respir J. 2009;33:426–435. 15. Chamogeorgakis T, Ieromonachos C, Georgiannakis E, Mallios D. Does lobectomy achieve better survival and recurrence rates than limited pulmonary resection for T1N0M0 non-small cell lung cancer patients? Interact CardioVasc Thorac Surg. 2009;8:364–372.
G. Varela and M.F. Jiménez 16. Kodama K, Higashiyama M, Takami K, Oda K, Okami J, Maeda J, Koyama M, Nakayama T. Treatment strategy for patients with small peripheral lung lesion(s): intermediate-term results of prospective study. Eur J Cardiothorac Surg. 2008;34:1068–1074. 17. Shapiro M, Weiser TS, Wisnivesky JP, Chin C, Arustamyan M, Swanson SJ. Thoracoscopic segmentectomy compares favorably with thoracoscopic lobectomy for patients with small stage I lung cancer. J Thorac Cardiovasc Surg. 2009;137:1388–1393. 18. Kilic A, Schuchert MJ, Pettiford BL, Pennathur A, Landreneau JR, Landreneau JP, Luketich JD, Landreneau RJ. Anatomic segmentectomy for stage I non-small cell lung cancer in the elderly. Ann Thorac Surg. 2009;87:1662–1666. 19. Koike T, Togashi K, Shirato T, Sato S, Hirahara H, Sugawara M, Oguma F, Usuda H, Emura I. Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg. 2009;88:1106–1111. 20. Harada H, Okada M, Sakamoto T, Matsuoka H, Tsubota N. Functional advantage after radical segmentectomy versus lobectomy for lung cancer. Ann Thorac Surg. 2005;80:2041–2045. 21. Keenan RJ, Landreneau RJ, Maley RH Jr, Singh D, Macherey R, Bartley S, Santucci T. Segmental resection spares pulmonary function in patients with stage I lung cancer. Ann Thorac Surg. 2004;78: 228–233. 22. Martin-Ucar AE, Nakas A, Pilling JE, West KJ, Waller DA. A case-matched study of anatomical segmentectomy versus lobectomy for stage I lung cancer in high-risk patients. Eur J Cardiothorac Surg. 2005;27:675–679. 23. Yoshimoto K, Nomori H, Mori T, Kobayashi H, Ohba Y, Shibata H, Tashiro K, Shiraishi S, Kobayashi T. Quantification of the impact of segmentectomy on pulmonary function by perfusion single-photonemission computed tomography and multidetector computed tomography. J Thorac Cardiovasc Surg. 2009;137:1200–1205. 24. Vaughan P, Oey I, Nakas A, Martin-Ucar A, Edwards J, Waller D. Is there a role for therapeutic lobectomy for emphysema? Eur J Cardiothorac Surg. 2007;31: 486–490. 25. Edwards JG, Duthie DJ, Waller DA. Lobar volume reduction surgery: a method of increasing the lung cancer resection rate in patients with emphysema. Thorax. 2001;56:791–795. 26. Choong CK, Meyers BF, Battafarano RJ, Guthrie TJ, Davids GE, Patterson GA. Lung cancer resection combined with lung volume reduction in patients with severe emphysema. J Thorac Cardiovasc Surg. 2004;127:1323–1331. 27. Brunelli A, Sabbatini A, Xiume’ F, Al Refai M, Borri A, Salati M, Marasco RD, Fianchini A. A model to predict the decline of the forced expiratory volume in one second and the carbon monoxide lung diffusion capacity early after major lung resection. Interact Cardiovasc Thorac Surg. 2005;4:61–65.
14. Optimal Therapy for Patients with Marginal Lung Function and Peripheral Stage I Lung Cancer 28. Varela G, Brunelli A, Rocco G, Jiménez MF, Salati M, Gatani T. Evidence of lower alteration of expiratory volume in patients with airflow limitation in the immediate period after lobectomy. Ann Thorac Surg. 2007;84:417–422. 29. Santambrogio L, Nosotti M, Baisi A, Ronzoni G, Bellaviti N, Rosso L. Pulmonary lobectomy for lung cancer: a prospective study to compare patients with forced expiratory volume in 1 s more or less than 80% of predicted. Eur J Cardiothorac Surg. 2001;20:684–687. 30. Sekine Y, Iwata T, Chiyo M, Yasufuku K, Motohashi S, Yoshida S, Suzuki M, Iizasa T, Saitoh Y, Fujisawa T. Minimal alteration of pulmonary function after lobectomy in lung cancer patients with chronic obstructive pulmonary disease. Ann Thorac Surg. 2003;76: 356–361. 31. Kushibe K, Takahama M, Tojo T, Kawaguchi T, Kimura M, Taniguchi S. Assessment of pulmonary function after lobectomy for lung cancer--upper lobectomy might have the same effect as lung volume reduction surgery. Eur J Cardiothorac Surg. 2006;29:886–890. 32. Schattenberg T,Muley T,Dienemann H,Pfannschmidt J. Impact on pulmonary function after lobectomy in patients with chronic obstructive pulmonary disease. Thorac Cardiovasc Surg. 2007;55:500–504. 33. Baldi S, Ruffini E, Harari S, Roviaro GC, Nosotti M, Bellaviti N, Venuta F, Diso D, Rea F, Schiraldi C, Durigato A, Pavanello M, Carretta A, Zannini P. Does lobectomy for lung cancer in patients with chronic obstructive pulmonary disease affect lung function? A multicenter national study. J Thorac Cardiovasc Surg. 2005;130:1616–1622. 34. Yoshimoto K, Nomori H, Mori T, Ohba Y, Shiraishi K, Tashiro K, Shiraishi S. Postoperative change in pulmonary function of the ipsilateral preserved lung after segmentectomy compared with that after lobectomy.Eur J Cardiothorac Surg.2009;doi:10.1016/j. ejcts.2009.07.002. 35. Kashiwabara K, Sasaki J, Mori T, Nomori H, Fujii K, Kohrogi H. Relationship between functional preservation after segmentectomy and volume-reduction effects after lobectomy in stage I non-small cell lung cancer patients with emphysema. J Thorac Oncol. 2009;4:1111–1116. 36. Baumann P, Nyman J, Hoyer M, Gagliardi G, Lax I, Wennberg B, Drugge N, Ekberg L, Friesland S, Johansson KA, Lund JS, Morhed E, Nilsson K, Levin N, Paludan M, Sederholm C, Traberg A, Wittgren L, Lewensohn R. Stereotactic body radiotherapy for medically inoperable patients with stage I non-small cell lung cancer - a first report of toxicity related to COPD/CVD in a non-randomized prospective phase II study. Radiother Oncol. 2008;88:359–367. 37. Henderson M, McGarry R, Yiannoutsos C, Fakiris A, Hoopes D, Williams M, Timmerman R. Baseline pulmonary function as a predictor for survival and decline in pulmonary function over time in patients undergoing stereotactic body radiotherapy for the treatment of stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2008;72:404–409.
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38. Zimmermann FB, Geinitz H, Schill S, Thamm R, Nieder C, Schratzenstaller U, Molls M. Stereotactic hypofractionated radiotherapy in stage I (T1-2 N0 M0) non-small-cell lung cancer (NSCLC). Acta Oncol. 2006;45:796–801. 39. Koto M, Takai Y, Ogawa Y, Matsushita H, Takeda K, Takahashi C, Britton KR, Jingu K, Takai K, Mitsuya M, Nemoto K, Yamada S. A phase II study on stereotactic body radiotherapy for stage I non-small cell lung cancer. Radiother Oncol. 2007;85:429–434. 40. Fakiris AJ, McGarry RC, Yiannoutsos CT, Papiez L, Williams M, Henderson MA, Timmerman R. Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys. 2009;75:677–682. 41. Baumann P, Nyman J, Hoyer M, Wennberg B, Gagliardi G, Lax I, Drugge N, Ekberg L, Friesland S, Johansson KA, Lund JA, Morhed E, Nilsson K, Levin N, Paludan M, Sederholm C, Traberg A, Wittgren L, Lewensohn R. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol. 2009;27:3290–3296. 42. Ricardi U, Filippi AR, Guarneri A, Giglioli FR, Ciammella P, Franco P, Mantovani C, Borasio P, Scagliotti GV, Ragona R. Stereotactic body radiation therapy for early stage non-small cell lung cancer: Results of a prospective trial. Lung Cancer. 2009;doi:10.1016/j.lungcan.2009.05.007. 43. Onishi H, Shirato H, Nagata Y, Hiraoka M, Fujino M, Gomi K, Niibe Y, Karasawa K, Hayakawa K, Takai Y, Kimura T, Takeda A, Ouchi A, Hareyama M, Kokubo M, Hara R, Itami J, Yamada K, Araki T. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: Updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol. 2007;2:S94–S100. 44. Hoopes DJ, Tann M, Fletcher JW, Forquer JA, Lin PF, Lo SS, Timmerman RD, McGarry RC. FDG-PET and stereotactic body radiotherapy (SBRT) for stage I nonsmall-cell lung cancer. Lung Cancer. 2007;56:229–234. 45. Akeboshi M, Yamakado K, Nakatsuka A, Hataji O, Taguchi O, Takao M, Takeda K. Percutaneous radiofrequency ablation of lung neoplasms: initial therapeutic response. J Vasc Interven Radiol. 2004;15: 463–470. 46. Lee JM, Jin GY, Goldberg SN, Lee YC, Chung GH, Han YM, Lee SY, Kim CS. Percutaneous radiofrequency ablation for inoperable non-small cell lung cancer and metastases: preliminary report. Radiology. 2004; 230:125–134. 47. Nguyen CL, Scott WJ, Goldberg M. Radiofrequency ablation of lung malignancies. Ann Thorac Surg. 2006;82:365–371. 48. Grieco CA, Simon CJ, Mayo-Smith WW, DiPetrillo TA, Ready NE, Dupuy DE. Percutaneous imageguided thermal ablation and radiation therapy: outcomes of combined treatment for 41 patients with inoperable stage I/II non-small-cell lung cancer. J Vasc Interv Radiol. 2006;17:1117–1124.
144 49. Hiraki T, Gobara H, Iishi T, Sano Y, Iguchi T, Fujiwara H, Tajiri N, Sakurai J, Date H, Mimura H, Kanazawa S. Percutaneous radiofrequency ablation for clinical stage I non-small cell lung cancer: results in 20 nonsurgical candidates. J Thorac Cardiovasc Surg. 2007 ;134:1306–1312. 50. Lencioni R, Crocetti L, Cioni R, Suh R, Glenn D, Regge D, Helmberger T, Gillams AR, Frilling A, Ambrogi M, Bartolozzi C, Mussi A. Response to radiofrequency ablation of pulmonary tumors: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol. 2008;9:621–628.
G. Varela and M.F. Jiménez 51. Pennathur A, Abbas G, Gooding WE, Schuchert MJ, Gilbert S, Christie NA, Landreneau RJ, Luketich JD. Image-guided radiofrequency ablation of lung neoplasm in 100 consecutive patients by a thoracic surgical service. Ann Thorac Surg. 2009;88: 1601–1608. 52. Guyatt G, Gutterman D, Baumann MH, AddrizzoHarris D, Hylek EM, Phillips B, Raskob G, Lewis SZ, Schünemann H. Grading strength of recommendations and quality of evidence in clinical guidelines. Report from an American College of Chest Physicians Task Force. Chest. 2006;129:174–181.
15
VATS Versus Thoracotomy for Major Lung Resection After Induction Therapy Mark F. Berry and Thomas A. D’Amico
Introduction Induction therapy has been considered a risk factor for morbidity and mortality after major lung resection via thoracotomy, but has been demonstrated to be feasible and effective in both prospective trials and retrospective studies. Induction therapy was initially felt to be a contraindication to performing major lung resection with video-assisted thoracoscopic surgery (VATS), but VATS resection after induction therapy has now also been shown to be feasible in small retrospective studies. Although the use of thoracotomy and VATS after induction therapy has never been prospectively directly compared in the literature, both approaches can be appro priate options depending on the specific circumstances. This chapter will review the significant published studies of major lung resection with both approaches after induction therapy. The studies reviewed were identified by a search of Pubmed (www.pubmed.org) with the search terms “(induction OR neoadjuvant) AND lung AND resection”. The Pubmed search covered the years 1992–2009 and was limited to the English language. The reviewed articles were selected based on the nature of the study and the number of patients involved. Only studies that provided detailed perioperative outcomes were included. Studies reporting outcomes after induction therapy and thoracotomy were further chosen for review such that all types of induction therapy (chemotherapy alone and chemotherapy with radiation therapy at both lower (<50 Gy) and higher (>50 Gy) doses) were included in the review.
All reports that involved 100 or more patients who underwent thoracotomy after induction therapy were reviewed. Studies that involved less than 100 patients were reviewed if the type of induction therapy reported was not covered in a larger report. All reports that involved ten or more patients who underwent major lung resection via VATS after induction therapy were reviewed.
Rationale and Use of Induction Therapy Before Lung Resection Surgeons are faced with considering pulmonary resection for patients who have received induction therapy in several circumstances. Induction therapy prior to surgical resection is typically planned for patients with locally advanced lung cancer (stages IIIA and IIIB, T3N1, T4 any N, and any N2 or N3), who generally can be separated into two groups. The first group includes patients with N2 disease considered resectable at the time of diagnosis. A significant proportion of these patients die of recurrent systemic disease despite adequate surgical resection, suggesting the presence of micrometastatic disease at the time of resection. The aim of induction therapy for these patients is to optimize distant disease control by administering chemotherapy at the time of the theoretically lowest micrometastatic burden, with the addi tional advantage of better patient tolerance and compliance for neoadjuvant therapy compared to adjuvant treatment.1 Prospective, randomized trials have demonstrated a benefit to induction
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chemotherapy for patients with clinical stage IIIA based on suspected N2 nodal involvement.2–4 The role of adding induction radiation therapy to chemotherapy is unclear, as induction chemotherapy and radiation therapy followed by surgical resection for patients with stage IIIA disease has been demonstrated to be feasible but has not been shown in randomized trials to improve survival.5,6 The second group of patients with locally advanced lung cancer who may be given induction therapy prior to attempting surgical resection are patients for whom an initial resection would not offer a survival advantage or for whom surgery is not technically feasible.1 Although the standard treatment for these patients is generally chemoradiotherapy alone, surgeons are sometimes asked to consider resection of residual disease after chemoradiation treatment due to the high rates of both locoregional and systemic failures.1 In addition, patients with locally advanced superior sulcus tumors (T3 or T4) and N0 or N1 disease are preferentially given induction chemotherapy and radiation therapy followed by surgery.7,8 Surgeons may also have to consider major pulmonary resection in other circumstances in which patients with lung cancer were given what was considered to be definitive chemotherapy with or without radiation therapy. These patients may have been initially deemed unsuitable for surgery for oncological or medical factors, such as initial clinical overstaging, patient refusal to consider surgery, poor lung function, or significant co-morbidities, only to have the patient or their oncologists reconsider that assessment after their initial course of therapy. Patients are also referred for major pulmonary resection after definitive chemotherapy or radiation therapy for complications of treatment, such as necrotic lung or lung abscess refractory to medical therapy. Finally, patients who previously have been treated with definitive chemotherapy and radiation therapy for a malignant process may develop a new malignancy for which surgery is deemed the optimal therapy.
an overall complication rate of 38%.9–17 Several early reports identified increased morbidity and mortality after the use of induction chemotherapy and radiation therapy.18,19 Advances in surgical and anesthetic techniques and peri-operative care may have reduced the impact of induction therapy, as subsequent reports have shown no significant difference in mortality or morbidity in patients receiving surgery alone versus pre-operative chemotherapy followed by surgery for non-small cell lung cancer.20–22 Despite these advances and recent studies, induction therapy likely does confer some increased surgical risk. A report from the Society of Thoracic Surgeons General Thoracic Surgery Database found that induction therapy was a risk for a prolonged length of hospital stay, which was considered a surrogate for morbidity, in a review of 4,979 lobectomies performed between 2002 and 2006.23 In addition, mortality was significantly higher in patients who underwent pneumonectomy compared to lobectomy after induction therapy in several prospective and retrospective studies.5,19,24,25 The risks of bleeding, bronchopleural fistula, and respiratory failure may be increased by induction therapy. Extensive hilar inflammation that occurs after induction therapy may increase the risk of life-threatening intra-operative bleeding, and proximal or intra-pericardial vessel control should be considered in these cases. Bronchial stump reinforcement with muscle or a pleural flap may be considered after induction therapy to reduce the chance of fistula formation.26 Although reports disagree on the role of induction chemotherapy and radiation on the development of acute lung injury and adult respiratory distress syndrome after lung resection, there is some consensus on a strategy to reduce the risks of patients after preoperative therapy: minimization of intravenous fluids and both the fraction of inspired oxygen and airway pressures as much as possible after anesthesia induction.27–33
Risks of Major Pulmonary Resection After Induction Therapy
Use of Thoracotomy After Induction Therapy
Multi-center series from the 1970s to the modern era report overall mortality rates of 0–11.6% for pneumonectomy and 1.0–4.4% for lobectomy, with
Early experience raised concerns over the feasibility of using induction chemotherapy with or without simultaneous thoracic radiation followed by
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15. VATS Versus Thoracotomy for Major Lung Resection After Induction Therapy
thoracotomy and major lung resection due to a high incidence of postoperative complications (Table 15.1). Fowler et al. reported a significant incidence of serious complications in 13 patients treated at the Fox Chase Cancer Center with 60 Gy radiation and concomitant 5-fluorouracil, cisplatin, and etoposide followed by thoracotomy and major lung resection.19 Six patients underwent lobectomy without mortality and one complication of adult respiratory distress syndrome (ARDS). Three of seven pneumonectomy patients died in the post-operative period, two due to ARDS and one due to bronchopleural fistula. Other studies from a similar time period also had significant morbidity and mortality when induction chemotherapy and radiation were given prior to major lung resection. Bonomi et al. reported that 6 of 16 patients who had received split-course thoracic radiation (total 40 Gy) and different combinations of carboplatin, paclitaxel, etoposide, and cisplatin followed by a thoracotomy (eight pneumonectomies, six lobectomies, one chest wall resection, and one exploration only with no resection) had serious postoperative complications, including one death form ARDS, two bronchopleural
fistulas, and one pneumonia.18 Deutsch et al. reported 3 perioperative deaths among 16 patients (19% mortality) with clinically staged IIIA non small cell lung cancer who received induction chemotherapy with carboplatin and etoposide followed by full course radiation therapy (60 Gy) and weekly carboplatin and then thoracotomy (six pneumonectomies); two of the deaths were due to respiratory failure after pneumonectomy.24 Another relatively early study found that chemotherapy alone without radiation therapy also significantly increased the morbidity of major lung resection. Roberts et al. reported significantly higher rates of major complications and reintubation in 34 patients who received induction chemotherapy compared to 67 patients who were not treated with induction therapy.34 Subsequent larger retrospective studies have expanded on the perioperative risks of induction therapy. Siegenthaler et al. retrospectively compared 76 patients that had received chemotherapy and then underwent lobectomy or greater resection for non small cell lung cancer with 259 patients who underwent surgery alone between 1996 and 1999 at MD Anderson Cancer Center.20
Table 15.1. Studies reporting on major lung resection via thoracotomy after induction therapy. Reference
na
Study design
Induction treatmentb
Summary of study findings
19
Fowler Bonomi18 Deutsch24 Roberts34
13 16 16 34
Retrospective Retrospective Retrospective Retrospective
Chemo/XRT (60 Gy) Chemo/XRT (40 Gy) Chemo/XRT (60 Gy) Chemo
Siegenthaler20
76
Retrospective
Chemo
Novoa35
42
Retrospective
Chemo
Martin25
470
Retrospective
Van Schil36 Stamatis37
149 350
Prospective Retrospective
Chemo (all)/XRT in 18% (50 Gy) Chemo Chemo/XRT (45 Gy)
Albain5
202
Prospective
Chemo/XRT (45 Gy)
Fujita38 Yokomise39 Cerfolio40 Sonett41 Bauman42
124 41 216 40 24
Retrospective Retrospective Retrospective Retrospective Retrospective
Chemo/XRT (40 Gy) Chemo/XRT (50 Gy) Chemo/XRT (60 Gy) Chemo/XRT (62 Gy) Chemo (all but 2)/ XRT (63.9 Gy)
43% pneumonectomy mortality 38% significant morbidity 19% overall mortality, 33% pneumonectomy mortality Significantly higher morbidity in induction therapy patients compared to surgery alone 1.3% mortality, 45% morbidity; similar outcomes for induction and non-induction patients Case-control study; induction patients did not have increased perioperative morbidity 2.4% lobectomy mortality; right pneumonectomy had significantly higher mortality than left (23.9% vs. 0%) 4.0% operative mortality 4.9% mortality and 44% morbidity; not using bronchial stump was risk for morbidity Treatment-related mortality of 1% for lobectomy and 26% for pneumonectomy 2.4% mortality; radiation >45 Gy was morbidity risk factor 0% mortality 2.3% mortality; intercostal muscle flap used in all patients 0% mortality 58% morbidity; vascularized flap used to cover stump in 19 patients
a
Number of patients in the study that had received induction therapy prior to major lung resection Radiation dose shown is a median value
b
Level of evidence Low Low Low Low Low Low Low Moderate Low Moderate Low Low Low Low Low
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Patients who received induction chemotherapy had a mortality of 1.3% and a perioperative morbidity of 44.7%, which statistically was similar to the patients who had surgery alone. The most common postoperative events for the induction patients were pneumonia (10.5%), transfusion (9.2%), reintubation (7.9%), and tracheostomy (5.3%). A case-control study also found no statistical difference in morbidity when 42 patients who had received induction chemotherapy were compared with 42 controls who had undergone surgery.35 The induction therapy group had 0% mortality and 26.2% overall morbidity. The largest published experience with thoracotomy after induction chemotherapy is a retrospective review of 470 patients (297 lobectomy, 97 pneumonectomy, 18 segmentectomy or wedge resection, 58 exploration only) treated at Memorial Sloan Kettering between 1993 and 1999, where 85 patients (18%) also received radiation (median dose 50 Gy, range 10–72 Gy).25 Overall mortality was 3.8% (2.4% for lobectomy and 11.3% for pneumonectomy) and morbidity was 38.1%. All deaths after pneumonectomy occurred after a right-sided procedure, for which the mortality was 23.9%. The most common complications were arrhythmia (12.3%), pneumonia (12.1%), prolonged air leak (9.6%), atelectasis requiring bronchoscopy (8.3%), need for transfusion (5.7%), respiratory failure (4%), and bronchopleural fistula (1.7%). Factors that predicted higher morbidity in multivariate analysis were right pneumonectomy, increased blood loss, and low percent predicted FEV1. The perioperative events observed in this retrospective study are similar to data collected in a multicenter prospective randomized controlled trial. Van Schil et al. reported a 4.0% mortality in the surgical arm of EORTC 08941, in which patients were given platinum-based chemotherapy and then randomized to surgical resection (149 patients) or radiation.36 The most common postoperative events were arrhythmia (9.5%), prolonged air leak (9%), empyema (8%), pneumonia (7.3%) and respiratory insufficiency (7.3%). The increased mortality associated with pneumonectomy as compared to lobectomy after induction therapy observed in the Memorial retrospective study was also similar to data from a multicenter prospective randomized controlled trial reported by Albain et al., in which patients with stage IIIA
M.F. Berry and T.A. D’Amico
non-small cell lung cancer were randomized to treatment with either concurrent chemotherapy (cisplatin and etoposide) and radiotherapy (45 Gy) followed by resection or concurrent chemotherapy and definitive radiotherapy (61 Gy) without surgery.5 In this study, one of 98 patients (1%) who underwent lobectomy after induction therapy had a treatment related death compared to 14 of 54 patients (26%) who underwent pneumonectomy after induction therapy. Several studies have reported results with larger numbers of patients who had been treated with both induction chemotherapy and radiation. Stamatis et al. reported a hospital mortality of 4.9% and an overall morbidity of 44% for 350 patients treated with cisplatin-based chemotherapy followed by concurrent chemoradiotherapy (one cycle cisplatin/etoposide with 45 Gy hyperfractionated accelerated radiotherapy) in a retrospective review of two phase II studies and one phase III study from 1991 to 2000.37 Resections were via thoracotomy and included lobectomy (45%), pneumonectomy (35%), sleeve lobectomy (11%), bilobectomy (4.3%), segmentectomy (0.6%), and exploration without lung resection (4%), with 32 patients also undergoing chest wall resection. The most common complications were prolon ged air leak more than 7 days (16%), arrhythmia (13%), and pneumonia (5.1%). Multivariate analysis showed that not using coverage on the bronchial stump was a significant morbidity risk factor. Fujita et al. found that radiation dose greater than 45 Gy was a tmorbidity risk factor in another retrospective review of 124 patients who received platinum-based chemotherapy and concurrent radiotherapy (median dose 40 Gy, with 23% of patients receiving more than 45 Gy) between 1990 and 2003.38 In this study, 90 patients had lobectomy and 25 patients had pneumonectomy with an overall 30 day mortality of 2.4%. The most common postoperative events were prolonged air leak (24.2%), arrhythmia (6.5%), and bronchopleural fistula (4%). Other relatively small retrospective studies have demonstrated similar surgical outcomes. Yokomise et al. reported on a single-surgeon series of 41 patients who were treated with platinum-based chemotherapy with concurrent radiation (50 Gy) followed by surgical resection (lobectomy or bilobectomy 28 patients, pneumonectomy 13 patients) with no mortalities.39
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15. VATS Versus Thoracotomy for Major Lung Resection After Induction Therapy
Several studies have been published involving patients who had received higher doses of radiation. Cerfolio et al. reported a mortality of 2.3% and overall morbidity of 37% (17% considered major) for 216 patients treated with induction chemotherapy and high dose radiation (median dose 60 Gy, range 60–72 Gy) followed by thoracotomy (lobectomy/bilobectomy 152, pneumonectomy 11, segmentectomy 14, wedge or no resection 35).40 All patients in this study had their bronchial stumps buttressed with intercostal muscle flaps. Sonett et al. reported 0% operative mortality for 40 patients (29 lobectomies and 11 pneumonectomies) with non small cell lung cancer that had received neoadjuvant therapy that included thoracic radiation (mean 62Gy, range 59.4–66.6 Gy) and concurrent platinum-based chemotherapy.41 Thirteen of the patients in this study had superior sulcus tumors and en-bloc chest wall resection in addition to their lung resection. All pneumonectomy patients had their bronchial stumps covered with an intercostal muscle flap except one patient, who developed a postoperative bronchopleural fistula. Six other patients had significant complications, including one postpneumonectomy pulmonary edema, one subarachnoid-pleural fistula after superior sulcus tumor resection, two prolonged atelectasis, and two post-operative pneumonias. Bauman et al. reported on 24 patients who were treated with definitive chemoradiation (median radiation dose 63.9 Gy with a range of 59.4–70.2 Gy, two of the patients received radiation alone) for locally advanced non small cell lung cancer, and then subsequently underwent salvage lung resection for local recurrence.42 The 24 patients had 25 lung resections (lobectomy 10, pneumonectomy 10, bilobectomy 4, wedge 1), and 19 patients had a vascularized flap used to cover
the bronchial stump (omentum 16, intercostal muscle 2, pericardial fat flap1). There was one peri-operative death and an overall morbidity of 58%, with the most common complications being supraventricular tachycardia (29%), pneumonia (17%), vocal cord palsy (17%), tracheostomy (8%), and major vessel injury (8%).
Use of VATS After Induction Therapy Several large series of the use of VATS to perform major lung resections for a variety of benign and malignant conditions have been published since the first description of this technique in 1993, though currently only approximately 10–20% of lobectomies done in the United States use VATS.43–46 Advantages of VATS pulmonary resections compared to procedures that involve a thoracotomy include a lower incidence of postoperative complications, shorter length of chest tube duration and hospital stay, decreased postoperative pain, preserved pulmonary function, and improved delivery of adjuvant chemotherapy.43–50 Until relatively recently, thoracoscopic lobectomy was not routinely applied to patients with non-small cell lung cancer who had undergone induction chemotherapy or radiation therapy due to concerns regarding the technical difficulty of hilar dissection in these patients. However, the safety and feasibility of thoracoscopic lobectomy after induction therapy has been demonstrated by small recent series (Table 15.2).51–53 The series with the largest number of patients that underwent thoracoscopic lobectomy after induction therapy was published by Duke Uni versity.51 This report reviewed and compared the outcomes of 12 patients who underwent VATS lobectomy after induction therapy with 85 patients
Table 15.2. Studies reporting on major lung resection via thoracoscopy after induction therapy. Reference
na
Study design
Induction treatment
Summary of study findings
Level of evidence
Petersen51
12
retrospective
Chemo (11 patients) + XRT (8 patients)
Low
Shaw53
10
retrospective
Chemo/XRT
Sahai52
10
retrospective
Chemo (all)/XRT (2 patients)
No peri-operative deaths for 12 VATS lobectomies (1 conversion to thoracotomy). 1 patient with postoperative bleeding and 1 patient with an unspecified major complication No peri-operative deaths for 10 VATS lobectomies. 2 patients with atrial arrhythmias and 1 patient with vocal cord paralysis Specific results of patients with induction therapy not reported.
a
number of patients in the study that had received induction therapy prior to major lung resection
Low
Low
M.F. Berry and T.A. D’Amico
150
who had a thoracotomy and lobectomy after induction therapy from 1996 to 2005. Patients were considered appropriate for a VATS approach if their tumors were less than 6 cm in diameter, gross multi-station disease was not present prior to therapy, and tumors did not involve the chest wall or airway. The 12 VATS lobectomy patients had median age of 60; 11 of the 12 had received platinum-based chemotherapy and 8 of the 12 also received radiation therapy. One patient required conversion to thoracotomy due to suspicion of tumor involvement of the chest wall. The thoracoscopy and thoracotomy patients had similar demographics, medical comorbidities, pulmonary function, as well as rate of preoperative radia tion use. Thoracoscopic lobectomy patients had median chest tube duration of 2 days and a median hospital stay of 4 days, both shorter than thoracotomy patients (4 and 5 days, respectively). Two significant complications were observed in the VATS group, one of which was postoperative bleeding; there were no peri-operative deaths. There were no significant statistical differences in 30-day mor tality, hemorrhage, pneumonia, respiratory failure, atrial fibrillation, or other major complications between the two approaches. Similar results have been observed by other groups. Shaw et al. reported on 10 patients who underwent thoracoscopic lobectomy after concurrent platinum-based chemotherapy and radiation in a series of 180 patients who had undergone thoracoscopic lobectomy at Mount Sinai Hospital between 2002 and 2006.53 The ten patients who had received induction therapy had a mean age of 68, median chest tube duration of 3 days, and median hospital stay of 3.5 days. None of the ten patients died, and complications include one patient with vocal cord paralysis and two patients with atrial arrhythmias. A study from Sahai et al. at the Roswell Park Cancer Institute that reported on the results of thoracoscopic pneumonectomy included a small subset of patients that had received induction therapy.52 Thoracoscopic pneumonectomy was attempted in 32 of 67 patients who underwent elective pneumonectomy between 2002 and 2008 and was successfully completed in 24, for a con version rate of 25%. Indications for conversion included tumor extension in five patients, adhesions in two patients, and bleeding in one patient.
Thoracoscopic and thoracotomy patients had similar length of stay, morbidity and mortality. Ten patients who underwent thoracoscopic pneumonectomy had received induction therapy (eight chemotherapy alone and two chemotherapy and radiation), though the effect of induction therapy on outcomes was not addressed.
Summary The majority of published studies examining thoracotomy and major lung resection after induction therapy are retrospective in nature, though many include large numbers of patients. The perioperative risks of major lung resection via thoracotomy are increased by induction chemotherapy with or without radiation, but can be minimized by careful patient selection, meticulous operative technique, and perioperative management (moderate quality evidence). We make a strong recommendation to perform major lung resection via thoracotomy in patients after induction therapy if they are appropriately restaged and have adequate physiologic reserve to tolerate surgery (recommendation grade 1B). Bronchial stump coverage with a vascularized flap reduces peri-operative morbidity, particularly when the dose of preoperative radiation is more than 45 Gy and when pneumonectomy has been performed (low quality evidence). We make a strong recommendation to use flap coverage of the bronchial stump in lobectomy patients who have received more than 45 Gy radiation and all pneumonectomy patients who have received induction therapy (recommendation grade 1C). Although induction therapy was initially felt to be a contraindication to performing major lung resection via VATS, VATS resection after induction therapy has now been shown to be feasible for selected patients in small retrospective studies. Although the use of thoracotomy and VATS after induction therapy has never been prospectively directly compared in the literature, both appro aches can be appropriate options depending on the specific circumstances. Lobectomy can be performed via VATS in selected patients after induction therapy with shorter hospital stays and at least equivalent complication rates compared to
15. VATS Versus Thoracotomy for Major Lung Resection After Induction Therapy
thoracotomy (low quality evidence). We make a weak recommendation to use VATS to perform lobectomy in selected patients after induction therapy (recommendation grade 2B). VATS can be used to safely perform pneumonectomy after induction therapy (low quality evidence). We make a weak recommendation to consider VATS as the approach to perform pneumonectomy in patients that have received induction therapy (recommendation grade 2C).
Personal View of the Data Our approach when considering major lung resection after induction therapy is based on the specific situation for each individual patient. For patients with stage IIIA non-small cell lung cancer based on N2 nodal involvement, we generally will consider induction therapy followed by resection via any approach only if the patient has limited involvement, such as in a single lymph node or no more than microscopic disease if more than one N2 node is involved. In general, we refer these patients for treatment with induction chemotherapy alone and then consider surgical resection if radiographic studies do not demonstrate disease progression and if disease resection can be accomplished with less than a pneumonectomy. We res tage the mediastinum of all potential resection patients with mediastinoscopy if endobronchial ultrasound was performed pre-induction treatment or with thoracoscopic lymph node resection if mediastinoscopy was used prior to therapy. Repeat mediastinoscopy is rarely used but is necessary if nodal station 4L is involved. Resection is then performed if frozen section analysis of the mediastinal lymph nodes does not reveal any evidence of malignancy. We preferentially use VATS as the approach for resection if the size and location of the patient’s malignancy is amenable to VATS lobectomy. If patients have also received induction radiation at a dose of more than 50 Gy, we will generally use a thoracotomy as the approach for resection and cover the bronchial stump with a muscle flap (intercostal or serratus). Patients are referred for consideration of radiation therapy after either resection or if restaging studies show that they are not resection candidates.
151
Lobectomy can be performed via VATS in patients after induction therapy with shorter hospital stays and at least equivalent complication rates compared to thoracotomy (low quality evidence). We make a weak recommendation to use VATS to perform lobectomy in patients after induc tion therapy (recommendation grade 2B). VATS can be used to safely perform pneumonectomy after induction therapy (low quality evidence). We make a weak recommendation to consider VATS as the approach to achieve pneumonectomy in patients that have received induction therapy (recommendation grade 2C).
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152 7. Rusch VW, Giroux DJ, Kraut MJ, Crowley J, Hazuka M, Winton T, Johnson DH, Shulman L, Shepherd F, Deschamps C, Livingston RB, Gandara D. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol. 2007;25:313–318. 8. Rusch VW, Giroux DJ, Kraut MJ, Crowley J, Hazuka M, Johnson D, Goldberg M, Detterbeck F, Shepherd F, Burkes R, Winton T, Deschamps C, Livingston R, Gandara D. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg. 2001;121:472–483. 9. Ginsberg RJ, Hill LD, Eagan RT, Thomas P, Mountain CF, Deslauriers J, Fry WA, Butz RO, Goldberg M, Waters PF. Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg. 1983;86:654–658. 10. Romano PS, Mark DH. Patient and hospital characteristics related to in-hospital mortality after lung cancer resection. Chest. 1992;101:1332–1337. 11. Wada H, Nakamura T, Nakamoto K, Maeda M, Watanabe Y. Thirty-day operative mortality for thoracotomy in lung cancer. J Thorac Cardiovasc Surg. 1998;115:70–73. 12. Rostad H, Strand TE, Naalsund A, Talleraas O, Norstein J. Lung cancer surgery: the first 60 days. A population-based study. Eur J Cardiothorac Surg. 2006;29:824–828. 13. Duque JL, Ramos G, Castrodeza J, Cerezal J, Castanedo M, Yuste MG, Heras F. Early complications in surgical treatment of lung cancer: a prospective, multicenter study. Grupo Cooperativo de Carcinoma Broncogenico de la Sociedad Espanola de Neumologia y Cirugia Toracica. Ann Thorac Surg. 1997;63:944–950. 14. Harpole DH Jr, DeCamp MM Jr, Daley J, Hur K, Oprian CA, Henderson WG, Khuri SF. Prognostic models of thirty-day mortality and morbidity after major pulmonary resection. J Thorac Cardiovasc Surg. 1999;117:969–979. 15. Allen MS, Darling GE, Pechet TT, Mitchell JD, Herndon JE 2nd, Landreneau RJ, Inculet RI, Jones DR, Meyers BF, Harpole DH, Putnam JB Jr, Rusch VW, ACOSOG Z0030 Study Group. Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg. 2006;81:1013–1019. 16. Licker M, de Perrot M, Hohn L, Tschopp JM, Robert J, Frey JG, Schweizer A, Spiliopoulos A. Perioperative mortality and major cardio-pulmonary complications after lung surgery for non-small cell carcinoma. Eur J Cardiothorac Surg. 1999;15:314–319. 17. Deslauriers J, Ginsberg RJ, Piantadosi S, Fournier B. Prospective assessment of 30-day operative morbidity for surgical resections in lung cancer. Chest. 1994;106:329S–330S.
M.F. Berry and T.A. D’Amico 18. Bonomi P, Faber LP, Warren W, Lincoln S, LaFollette S, Sharma M, Recine D. Postoperative bronchopulmonary complications in stage III lung cancer patients treated with preoperative paclitaxel-containing chemotherapy and concurrent radiation. Semin Oncol. 1997;24:S12–123–S112–S129. 19. Fowler WC, Langer CJ, Curran WJ Jr, Keller SM. Postoperative complications after combined neoadjuvant treatment of lung cancer. Ann Thorac Surg. 1993;55:986–989. 20. Siegenthaler MP, Pisters KM, Merriman KW, Roth JA, Swisher SG, Walsh GL, Vaporciyan AA, Smythe WR, Putnam JB Jr. Preoperative chemotherapy for lung cancer does not increase surgical morbidity. Ann Thorac Surg. 2001;71:1105–1111. 21. Perrot E, Guibert B, Mulsant P, Blandin S, Arnaud I, Roy P, Geriniere L, Souquet PJ. Preoperative chemotherapy does not increase complications after nonsmall cell lung cancer resection. Ann Thorac Surg. 2005;80:423–427. 22. Gilligan D, Nicolson M, Smith I, Groen H, Dalesio O, Goldstraw P, Hatton M, Hopwood P, Manegold C, Schramel F, Smit H, van Meerbeeck J, Nankivell M, Parmar M, Pugh C, Stephens R. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/ EORTC 08012 multicentre randomised trial and update of systematic review. Lancet. 2007;369: 1929–1937. 23. Wright CD, Gaissert HA, Grab JD, O’Brien SM, Peterson ED, Allen MS. Predictors of prolonged length of stay after lobectomy for lung cancer: a Society of Thoracic Surgeons General Thoracic Surgery Database risk-adjustment model. Ann Thorac Surg. 2008;85:1857–1865. 24. Deutsch M, Crawford J, Leopold K, Wolfe W, Foster W, Herndon J, Blackwell S, Yost R. Phase II study of neoadjuvant chemotherapy and radiation therapy with thoracotomy in the treatment of clinically staged IIIA non-small cell lung cancer. Cancer. 1994;74:1243–1252. 25. Martin J, Ginsberg RJ, Abolhoda A, Bains MS, Downey RJ, Korst RJ, Weigel TL, Kris MG, Venkatraman ES, Rusch VW. Morbidity and mortality after neoadjuvant therapy for lung cancer: the risks of right pneumonectomy. Ann Thorac Surg. 2001;72:1149–1154. 26. Sonobe M, Nakagawa M, Ichinose M, Ikegami N, Nagasawa M, Shindo T. Analysis of risk factors in bronchopleural fistula after pulmonary resection for primary lung cancer. Eur J Cardiothorac Surg. 2000; 18:519–523. 27. Busch E, Verazin G, Antkowiak JG, Driscoll D, Takita H. Pulmonary complications in patients undergoing thoracotomy for lung carcinoma. Chest. 1994;105: 760–766. 28. Kutlu CA, Williams EA, Evans TW, Pastorino U, Goldstraw P. Acute lung injury and acute respiratory distress syndrome after pulmonary resection. Ann Thorac Surg. 2000;69:376–380.
15. VATS Versus Thoracotomy for Major Lung Resection After Induction Therapy 29. Dulu A, Pastores SM, Park B, Riedel E, Rusch V, Halpern NA. Prevalence and mortality of acute lung injury and ARDS after lung resection. Chest. 2006; 130:73–78. 30. Ruffini E, Parola A, Papalia E, Filosso PL, Mancuso M, Oliaro A, Actis-Dato G, Maggi G. Frequency and mortality of acute lung injury and acute respiratory distress syndrome after pulmonary resection for bronchogenic carcinoma. Eur J Cardiothorac Surg. 2001;20:30–36. 31. Alam N, Park BJ, Wilton A, Seshan VE, Bains MS, Downey RJ, Flores RM, Rizk N, Rusch VW, Amar D. Incidence and risk factors for lung injury after lung cancer resection. Ann Thorac Surg. 2007;84:1085–1091. 32. Lee HS, Lee JM, Kim MS, Kim HY, Hwangbo B, Zo JI. Low-dose steroid therapy at an early phase of postoperative acute respiratory distress syndrome. Ann Thorac Surg. 2005;79:405–410. 33. Grichnik KP, D’Amico TA. Acute lung injury and acute respiratory distress syndrome after pulmonary resection. Semin Cardiothorac Vasc Anesth. 2004;8:317–334. 34. Roberts JR, Eustis C, Devore R, Carbone D, Choy H, Johnson D. Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer. Ann Thorac Surg. 2001;72:885–888. 35. Novoa N, Varela G, Jimenez MF. Morbidity after surgery for non-small cell lung carcinoma is not related to neoadjuvant chemotherapy. Eur J Cardiothorac Surg. 2001;20:700–704. 36. Van Schil P, Van Meerbeeck J, Kramer G, Splinter T, Legrand C, Giaccone G, Manegold C, van Zandwijk N. Morbidity and mortality in the surgery arm of EORTC 08941 trial. Eur Respir J. 2005;26:192–197. 37. Stamatis G, Djuric D, Eberhardt W, Pöttken C, Zaboura G, Fechner S, Fujimoto T. Postoperative morbidity and mortality after induction chemoradiotherapy for locally advanced lung cancer: an analysis of 350 operated patients. Eur J Cardiothorac Surg. 2002;22:292–297. 38. Fujita S, Katakami N, Takahashi Y, Hirokawa K, Ikeda A, Tabata C, Mio T, Mishima M. Postoperative complications after induction chemoradiotherapy in patients with non-small-cell lung cancer. Eur J Cardiothorac Surg. 2006;29:896–901. 39. Yokomise H, Gotoh M, Okamoto T, Yamamoto Y, Ishikawa S, Nakashima T, Masuya D, Liu D, Huang CL. Induction chemoradiotherapy (carboplatin-taxane and concurrent 50-Gy radiation) for bulky cN2, N3 non-small cell lung cancer. J Thorac Cardiovasc Surg. 2007;133:1179–1185. 40. Cerfolio RJ, Bryant AS, Jones VL, Cerfolio RM. Pulmonary resection after concurrent chemotherapy and high dose (60Gy) radiation for non-small cell lung cancer is safe and may provide increased survival. Eur J Cardiothorac Surg. 2009;35:718–723. 41. Sonett JR, Suntharalingam M, Edelman MJ, Patel AB, Gamliel Z, Doyle A, Hausner P, Krasna M. Pulmonary
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resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small- cell lung cancer. Ann Thorac Surg. 2004;78: 1200–1205. 42. Bauman JE, Mulligan MS, Martins RG, Kurland BF, Eaton KD, Wood DE. Salvage lung resection after definitive radiation (>59 Gy) for non-small cell lung cancer: surgical and oncologic outcomes. Ann Thorac Surg. 2008;86:1632–1638. 43. Boffa DJ, Allen MS, Grab JD, Gaissert HA, Harpole DH, Wright CD. Data from The Society of Thoracic Surgeons General Thoracic Surgery database: the surgical management of primary lung tumors. J Thorac Cardiovasc Surg. 2008;135:247–254. 44. Onaitis MW, Petersen RP, Balderson SS, Toloza E, Burfeind WR, Harpole DH Jr, D’Amico TA. Thoracoscopic lobectomy is a safe and versatile procedure: experience with 500 consecutive patients. Ann Surg. 2006;244:420–425. 45. McKenna RJ Jr, Houck W, Fuller CB. Video-assisted thoracic surgery lobectomy: experience with 1,100 cases. Ann Thorac Surg. 2006;81:421–425. 46. Roviaro G, Varoli F, Vergani C, Maciocco M, Nucca O, Pagano C. Video-assisted thoracoscopic major pulmonary resections: technical aspects, personal series of 259 patients, and review of the literature. Surg Endosc. 2004;18:1551–1558. 47. Villamizar NR, Darrabie MD, Burfeind WR, Petersen RP, Onaitis MW, Toloza E, Harpole DH, D’Amico TA. Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy. J Thorac Cardiovasc Surg. 2009;138:419–425. 48. Park BJ, Zhang H, Rusch VW, Amar D. Video-assisted thoracic surgery does not reduce the incidence of postoperative atrial fibrillation after pulmonary lobectomy. J Thorac Cardiovasc Surg. 2007;133: 775–779. 49. Cattaneo SM, Park BJ, Wilton AS, Seshan VE, Bains MS, Downey RJ, Flores RM, Rizk N, Rusch VW. Use of video-assisted thoracic surgery for lobectomy in the elderly results in fewer complications. Ann Thorac Surg. 2008;85:231–235. 50. Petersen RP, Pham D, Burfeind WR, Hanish SI, Toloza EM, Harpole DH Jr, D’Amico TA. Thoracoscopic lobectomy facilitates the delivery of chemotherapy after resection for lung cancer. Ann Thorac Surg. 2007;83:1245–1249. 51. Petersen RP, Pham D, Toloza EM, Burfeind WR, Harpole DH Jr, Hanish SI, D’Amico TA. Thoracoscopic lobectomy: a safe and effective strategy for patients receiving induction therapy for non-small cell lung cancer. Ann Thorac Surg. 2006;82:214–218. 52. Sahai RK, Nwogu CE, Yendamuri S, Tan W, Wilding GE, Demmy TL. Is thoracoscopic pneumonectomy safe? Ann Thorac Surg. 2009;88:1086–1092. 53. Shaw JP, Dembitzer FR, Wisnivesky JP, Litle VR, Weiser TS, Yun J, Chin C, Swanson SJ. Video-assisted thoracoscopic lobectomy: state of the art and future directions. Ann Thorac Surg. 2008:85:S705–S709.
16
Chest Tube Management After Lung Resection Melissa J. Ruiz and Mark K. Ferguson
Introduction Given the ongoing effort to reduce duration of hospitalization, chest tube management has become a critical area of study for thoracic surgeons. The limiting factor in discharge of thoracic surgery patients after major lung resection is typically the timing of chest tube removal. Some surgeons currently often discharge patients with chest tubes in place, but this practice is difficult to apply routinely in most settings because of lack of patient or family acceptance, a shortage of professional resources to help patients manage their tubes at home, and unavailability of drainage systems suitable for use in an outpatient setting. A strategy that reduces how long chest tubes need to stay in place could have a substantial effect on length of hospital stay and avoid the obstacles encountered when discharge with chest tubes in place is contemplated. Thoracic surgeons traditionally manage chest tubes based on experience and personal preference rather than following an evidence-based practice. This is largely due to the lack of substantive data on the subject. During the last decade several prospective randomized controlled trials evaluating a strategy for chest tube management after lung resection have been carried out. These trials have primarily focused on comparing the difference in air leak duration, the incidence of prolonged air leaks, chest tube duration, and length of stay between groups of patients with
chest tubes managed on suction versus water seal. This chapter evaluates the safety and efficacy of these proposed strategies. Advocates of placing chest tubes on suction after lung resection affirm that suction encourages the apposition of the parietal and visceral pleura. This, in turn, helps eliminate the space created by the resection as well as aids in the resolution of air leaks. Advocates of placing chest tubes on water seal, on the other hand, maintain that managing chest tubes on suction forces a greater volume of air through any pleural defect, thereby contributing to the persistence of the air leak. They cite the clinical observation that air leaks appear larger when chest tubes are on suction as evidence of this. In addition, they propose that placing chest tubes on water seal offers opportunity for earlier ambulation and reduces the need for nursing care. We performed a Pubmed search for prospective randomized controlled trials comparing these two strategies using the key terms [suction] AND [water seal] AND [chest tube] for the period 1980 through 2009. From the search results, we included in this chapter only prospective randomized controlled trials that examined these two chest tube management strategies after pulmonary resections in adults. The type of operation varied from bleb resection to lobectomy both via thoracotomy and video-assisted thoracoscopic surgery (VATS), excluding lung-volume reduction surgery (LVRS) and pneumonectomy (Table 16.1).
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_16, © Springer-Verlag London Limited 2011
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156 Table 16.1. Basics of trial designs. Author Cerfolio Marshall2 Ayed3 Brunelli4 Alphonso5 Brunelli6 1
Design
Year
Patients
Patients with air leak
PRCT PRCT PRCT PRCT PRCT PRCT
2001 2002 2003 2004 2004 2005
140 68 100 269 254 194
33 30 – 145 – 94
PRCT = prospective randomized controlled trial
Studies Demonstrating That Managing Chest Tube Off Suction Offers a Benefit In a prospective randomized controlled trial, Cerfolio and colleagues compared management of chest tubes on suction versus water seal after all types of lung resection excluding VATS procedures, LVRS, pneumonectomy or bronchoplastic resection (Tables 16.1 and 16.2).1 All chest tubes were placed on -20 cm H2O suction until the second post-operative day, at which point they were placed on suction or water seal based on pre-operative randomization. Almost a third of the patients randomized to water seal were placed back on suction due to radiographic findings, somewhat confounding the data. Of the 13 patients who remained on water seal, 12 patients resolved their air leaks by the third post-operative day. In contrast, 14 of the
15 patients on suction continued to have an air leak on the third post-operative day, at which point randomization was ended and data were analyzed. There was a significant difference in the number of air leaks that resolved during this 24-h period favoring water seal (Table 16.3). The authors concluded that water seal is the preferred strategy. Marshall and others compared suction versus water seal in a prospective randomized trial examining patients undergoing all types of lung resections excluding re-operative procedures and LVRS. All chest tubes were placed on an initial 5–30 min of suction (Tables 16.1 and 16.2).2 Patients were randomized to suction vs. water seal upon arrival to the recovery room. The patients randomized to suction had their chest tubes maintained on -20 cm H2O suction until resolution of their air leak, at which point their chest tubes were placed on water seal. More than a quarter of the patients with air leaks randomized to water seal were placed back on suction after radiographic discovery of a pneumothorax. Air leaks resolved on average 1 day sooner in the water seal group (Table 16.3). After correcting outcomes based on the length of staple lines, there was still a difference in air leak duration favoring the water seal group, and there also was a difference in chest tube duration favoring the water seal group. The authors found no difference in length of stay. Ayed et al. carried out a prospective randomized trial evaluating chest tube management after thoracoscopy for a primary spontaneous pneumothorax.3 The procedure included resection of visible blebs or
Table 16.2. Differences in study design. Author
Procedures included
Cerfolio1
Lung resection
Marshall2 Ayed3
Brunelli4 Alphonso5 Brunelli6
Excluded
VATS, LVRS, bronchoplastic resection or pneumonectomy Lung resection Re-operative; LVRS VATS apical pleurectomy with bullae/ Underlying lung disease; recurrent bleb resection or small apical PSP after surgery resection Lobectomy/bilobectomy via Chest wall resection; bronchoplastic thoracotomy procedures Lung resection LVRS Lobectomy/bilobectomy via Chest wall resection; bronchoplastic thoracotomy procedures
Initial time on suction
CX Ra
PTX on water seal
>24 h
Yes
5 of 18
28%
5–30 min 2h
Yes Yes
4 of 15 8 of 50
27% 0
~12 h
No
2
3%
None ~12 h
Yes No
2 of 123 1/1d
c
PTX to suctionb
2%/2%
Routine chest radiographs were obtained Percentage of patients in water seal group that were put on suction after recognition of pneumothorax on routine chest radiograph c The authors did not specify how the patients with pneumothoraces were managed d 1 patient in the water seal group and 1 in the alternate suction group LVRS lung volume reduction surgery, VATS video-assisted thoracoscopic surgery, PSP primary spontaneous pneumothorax, PTX pneumothorax, CXR chest radiograph a
b
157
16. Chest Tube Management After Lung Resection
bullae and an apical pleurectomy. All chest tubes were placed on suction for a period of 2 h. The patients were randomized on return to the hospital ward. Of the 100 patients included in this study, there were only 8 patients with air leaks, and air leak duration was not compared between the two groups. There was a difference in the number of prolonged air leaks (defined as air leaks lasting greater than 5 days) favoring the water seal group (Table 16.3). Eight patients in the water seal group developed small apical pneumothoraces that were not clinically significant and resolved without the use of suction. There was also a difference in the duration of chest tube duration and length of hospital stay, both favoring the water seal group.
Studies Demonstrating That Managing Chest Tubes Off Suction Offers No Benefit Brunelli et al. performed a prospective randomized controlled trial evaluating chest tube management after pulmonary lobectomy.4 Patients with an air leak were randomized to the suction group or the water seal group on the first post-operative day after having their chest tubes on -20 cm H2O suction for an initial overnight period. Chest radiographs were
obtained when clinically indicated. Two patients in the water seal group with large air leaks developed subcutaneous emphysema and experienced oxygen desaturation (3%, 2/72 patients). They were placed back on suction for a 24-h period and then placed back on water seal. The authors found no significant difference in air leak duration, chest tube duration, or incidence of prolonged air leak between the two groups, even after correcting for staple line length (Table 16.3). In addition they subdivided their patient population according to the type of lobectomy (upper vs. lower) and did not find a difference in the abovementioned outcome. In a prospective randomized controlled trial, Alphonso and others evaluated the difference between -20 cm H2O suction and no suction.5 The patients were randomized at the conclusion of the operation, including all lung resections except LVRS. Two patients were allocated to the suction group despite being randomized to the non-suction group based on clinical judgment. There were two patients in the no suction group and three patients in the suction group who developed pneumothoraces. The authors did not specify how these patients were managed, however they were included in the analyses on an intention to treat basis. The authors found no significant difference between the groups in air leak duration (Table 16.3) or in incidence of persistent air leaks (7.8% for suction versus 10.1% for no suction).
Table 16.3. Results of trials of chest tube management after lung resection. Difference in air leak duration
Difference in prolonged air leaks
Difference in CT duration
Difference in hospital stay
Preferred management
Evidence quality7
– –
– No (p = 0.06) Correcteda Yes (p =.02) Yes (p = 0.004)
– No (p = 0.18)
Water seal Water seal
Moderate Moderate
Ayed3
Yes (p = 0.001) Yes (p = 0.05) Correcteda Yes (p =.02) –
Yes (p = 0.004)
Water seal
Moderate
Brunelli4
No (p = 0.9)
No (p = 0.2)
No (p = 0.3)
Neitherb
Moderate
Alphonso5 Brunelli6
Correcteda No (p = 0.9) No (p = 0.62) No (p = 0.3)
– Yes (p = 0.002)
– Yes (p = 0.004)
Neither Alternate suctionb
High Moderate
Author Cerfolio1 Marshall2
Yes (p = 0.03) Defined as >5d No (p = 0.8) Defined as >7d
No Defined as >6d Yes (p = 0.02) Defined as >7d
Corrected for staple line length in each group Authors adopted policy of -10 cm H2O overnight and water seal during the day (alternate suction) – not evaluated CT chest tube, d day a
b
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An Alternate Strategy That Offers a Benefit Brunelli and co-workers evaluated the effectiveness of a strategy they described as alternate suction.6 The patients were managed on -10 cm H2O suction until the morning of the first postoperative day. Patients with air leaks were then randomized to either 24 h of water seal or the alternate suction group. The alternate suction group was managed on water seal during the day and -10 cm H2O of suction overnight. There was a difference in the incidence of prolonged air leaks, chest tube duration, and postoperative hospital stay favoring the alternate suction group (Table 16.3). There was no difference in air leak duration (Table 16.3). One patient in each group was placed back on -20 cm H20 of suction for severe subcutaneous emphysema and desaturation (1/47: 2% of either group).
Recommendations As demonstrated in Table 16.2, six prospective randomized controlled trials have been performed that addressed the issue of optimal chest tube management after lung resection. They had somewhat different study designs, making comparison of their results challenging. They were varied in the procedures they included and excluded as well as their definition of their water seal group. In addition, most patients were managed with an initial period of suction regardless of subsequent chest tube management. We conclude that managing lung resection patients off suction is safe (level of evidence high) and that it may lead to a quicker resolution of air leak and chest tube removal (level of evidence moderate). There is no evidence from these studies that suggests any benefit to length of hospital stay from managing chest tubes off suction. Based on these studies, we make a strong recommendation for managing chest tubes after major lung resection off suction (1B).7
Evidence That Managing Patients with Air Leaks Off Suction is Safe
Personal View of the Data
Both Cerfolio and Marshall obtained routine daily chest radiographs and demonstrated that patients with air leaks could have their chest tubes managed off suction safely, without the development of clinically important air spaces or tension pneumothoraces in the majority of patients so managed.12 Ayed demonstrated that managing a radiographically identified pneumothorax off suction was safe.3 However, it is notable that Ayed et al. studied a population with smaller resections than the other trials and had a smaller incidence of air leaks. The trials by Brunelli did not involve routine radiographs, and in this setting the incidence of clinically important events requiring a change of management was low (2%).4,6 The incidence of pneumothoraces in the water seal group of the study by Alphonso was 2%.5 From these studies, it appears that it is safe to manage chest tubes off suction, even in patients with air leaks. Whether obtaining routine chest radiographs is useful in managing patients after lung resection is not known.
The above trials offer a start to establishing a standard of care in the management of chest tubes. They give us a better understanding of the effects of suction versus water seal on air leak duration, incidence of prolonged air leak, chest tube duration, and hospital stay, but they do not clearly delineate the most effective strategy for chest tube management. Given the significant differences in their study designs, it is not possible to definitively conclude the most effective management without further trials, preferably multi-institutional with a standardized study design. Managing chest tubes off suction is safe, is at least as effective as suction, and offers other potential benefits such as earlier ambulation and decreased resource utilization. The 2005 trial by Brunelli et al. offers an interesting and promising compromise between the two traditional strategies, possibly combining the benefits of both.6 Given the results favoring the water seal group when patients spent an initial period on suction, it would be interesting to compare an alternate suction strategy to a water seal strategy that involved
16. Chest Tube Management After Lung Resection
a defined initial period on suction (e.g. 1–2 h postoperatively). This would aid in establishing whether the initial period spent on suction is the variable that offers an advantage as compared to alternating periods on and off suction. The alternate suction strategy could prove more beneficial, but not enough data exists at this time to merit identifying this approach as optimal for patient care.
Managing lung resection patients off suction is safe (quality of evidence high) and may lead to a quicker resolution of air leak and chest tube removal (quality of evidence moderate). We make a strong recommendation for managing chest tubes off suction after major lung resection (recommendation strength 1B).
References 1. Cerfolio RJ, Bass C, Katholi CR. Prospective randomized trial compares suction versus water seal for air leaks. Ann Thorac Surg. 2001;71:1613–1617.
159 2. Marshall MB, Deeb ME, Bleier JI, Kucharczuk JC, Friedberg JS, Kaiser LR, Shrager JB. Suction vs water seal after pulmonary resection: a randomized prospective study. Chest. 2002;121:831–835. 3. Ayed AK. Suction versus water seal after thorascopy for primary spontaneous pneumothorax: prospective randomized study. Ann Thorac Surg. 2003;75: 1593–1596. 4. Brunelli A, Monteverde M, Borri A, Salati M, Marasco RD, Al Refai M, Fianchini A. Comparison of water seal and suction after pulmonary lobectomy: a prospective randomized trial. Ann Thorac Surg. 2004;77:1932–1937. 5. Alphonso N, Tan C, Utley M, Cameron R, Dussek J, Lang-Lazdunski L, Treasure T. A prospective randomized controlled trial of suction versus nonsuction to the under-water seal drains following lung resection. Eur J Cardiothorac Surg. 2005;27: 391–394. 6. Brunelli A, Sabbatini A, Xiumè F, Refai, MA, Salati M, Marasco R. Alternate suction reduces prolonged air leak after pulmonary lobectomy: a randomized comparison versus water seal. Ann Thorac Surg. 2005;80:1052–1055. 7. Guyatt GH, Oxman AD, Kunz R, Jaeschke R, Helfand M, Liberati A, Vist GE, chunemann J. Incorporating considerations of resources use into grading recommendations. BMJ. 2008;336:1170–1173.
17
Management of the Pleural Space Early After Pneumonectomy K. S. Rammohan, Vasudev B. Pai, and Tom Treasure
Management of the hemithorax after pneumonectomy requires special considerations which are particular to this operation. Although they should be well known to all chest surgeons, they need to be explicitly set out for clarity: (1) the postpneumonectomy space, unlike other operative cavities, is held open by the rib cage; and (2) the movement of soft tissues and organs to fill the space (the heart and great vessels in the mediastinum) must in this instance be avoided. These two facts are self evident to chest surgeons. There is no air leak to contend with so tube drainage into a one way valve, usually water seal, which is a universal requirement after other lung resections, does not apply here. Some residual blood, and the seepage of lymph and pleural fluid, are desirable to fill the space and should not be evacuated. These ultimately form a coagulum which will stabilize the mediastinum.1 Acute or too complete emptying of the space should be avoided or this will shift the mediastinum and so distort the great veins or rotate the heart. These considerations are accommodated in three broadly different ways, with some variations within them. 1. No drainage tube. If this method is used it is necessary to make provision to adjust the volume of the space so that the mediastinum is in the desired position. During closure, the surgeon may ask the anesthesiologist to put some pressure on the remaining lung, or leave a tube temporarily to allow adjustment of the volume of the space and remove the tube before the patient wakes up. If there is a need to adjust the
position of the mediastinum in the post operative period, this is achieved by adding or removing air from the space, soon after surgery and at intervals thereafter, in one of two standard ways. (a) with a Maxwell Box (Fig. 17.1) to achieve a barely negative pressure in the space. (b) with a large syringe and a three way tap to adjust the position of the mediastinum as monitored by chest radiographs. 2. A chest tube is left in the space with its lowest hole at the level of the hilum. This tube is connected to an underwater seal and there are then a variety of ways of managing the drain. (a) The tube is left open. This will allow free drainage but coughing or straining may reduce the volume of the space. (b) The underwater seal is broken at intervals (say hourly) and the tube held in the air to allow the space pressure to match atmospheric pressure. (c) The tube is clamped and opened for a short period every hour to allow drainage of accumulated blood and/or entry of air to allow the space pressure to return to atmospheric pressure. 3. A tube is left as before and connected to a three chamber balanced drainage system (Fig. 17.2). This method is well described by Pezzella and colleagues.2 We looked for evidence of any advantage of one method over the others.
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frequented journals) were obtained in full from various sources including the University College London’s ejournals service, the Royal Society of Medicine and the British Library. The final selection of papers to include in the evidence table was made in discussion among all three authors.
Results
Figure 17.1 A Maxwell Box. The device has a piston and, by turning the tap at the top, it can be connected to the pleural space or the patient so that air can be added or removed. The pleural space can separately be connected to the manometer. It was devised for creating and topping up an artificial pneumothorax in the historical management of tuberculosis. Most if not all are now kept only as museum pieces. Provided by Peter Goldstraw, Professor of Thoracic Surgery, Imperial College, London From patient
} 1 cm
}
15 cm
Figure 17.2 A three chamber drainage system. This illustration is presented to ease comprehension. When it was devised in this form the three bottles and their connecting tubes, which had to be kept unlooped and unkinked, proved cumbersome. In contemporary practice commerically available self contained three chamber boxes are used, which make the system safer and simpler to use
Methods We searched the literature with no limits or filters in place to allow for maximal return. Search terms were (“pneumonectomy” [MeSH Terms] OR “pneumonectomy” [All Fields]) AND (“drainage” [MeSH Terms] OR “drainage” [All Fields]). All titles were read by two of the authors (KSR and VP) and were excluded if not relevant. If the decision required it, the abstract was read by at least two authors. Papers of interest (and some were in older and less
The combined search produced 791 results which were filtered as shown in Fig. 17.3. We found two surveys of practice. In the British Isles all of 72 surgeons performing pneumonectomy were surveyed about practice in 1999.3 This included management of the pneumonectomy space. No chest drain was left (Option 1 above) by 20%, the remainder followed Option 2 but with 11% leaving the drain open (2a) and the majority (69%) used some version of the clamped drain. No surgeon in that survey, in which there was copious detail of technique, reported use of a three bottle drainage system. A European survey of 120 departments in 2006 reported that 51% used a three chamber drainage system.4 There were five clinical reports in which a comparison was made between methods. (Table 17.1).5–9 None of the studies was randomized. All were retrospective comparisons, four comparing results when two different methods were used by team preference and one6 when a change in policy was made at a point in time. These non-randomized comparisons cannot exclude confounding. In Deslauriers’ series5 the patients who developed postpneumonectomy pulmonary edema (PPE) also had longer operating room times (184 vs. 143 min, p = 0.005), more extensive resections and higher pleural drainage when compared with the balanced drainage group. Furthermore, when a change in practice is adopted after a run of bad experience, there may well be other changes in management (ventilator pressures and intraoperative fluid management, for example) quite apart from the change determined by the surgeon. With those cautions in mind, it is striking that in both publications PPE was not seen in those patients in whom balanced drainage was employed (0/106 vs. 17/240).5,6
163
17. Management of the Pleural Space Early After Pneumonectomy Titles found by literature search N = 791
Excluded by title N = 770 Excluded by Abstract N=9
Abstracts read N = 21
Full papers retrieved and read N = 12
Papers used in the review N = 15
Papers excluded after reading N=5 Papers from other sources N=8
oedema.12 In 5/10 sheep with modest negative pressure to the postpneumonectomy space, contralateral PPE developed. Then in experiments mimicking options 1, 2 and 3 above, PPE developed in 3/9 with no drain, 3/9 with water seal, and 0/9 with balanced drainage. (This however does not prove it is due to hyperinflation. Distortion of the mediastinal vessels might have a similar effect for haemodynamic reasons.) Surgical emphysema is more likely to be seen if there is no drain or a clamped drain; the air in the space is driven by any coughing or straining into the tissues. It was not of any clinical significance in these studies.
Figure 17.3 A flow diagram of the literature sifting used in this review
There were three reports of animal studies. Two were in beagle puppies. The experiments were performed to address the problem of pulmonary oedema in the contralateral lung seen in neonates after surgery to repair diaphragmatic hernia.10,11 The studies showed that in these animals suction on the pneumonectomy space was likely to prove lethal if the mediastinal position was not corrected. In experiments on sheep Alvarez tested the hypothesis that hyperinflation of the contralateral lung might cause postpneumonectomy pulmonary
Recommendations All the methods described above are associated with successful clinical practice and, in the absence of direct comparison in rigorous trials, no recommendation can be made in favor of one over another. However, each method has its hazards and these should be well understood. If there is no tube, bleeding may go unnoticed for longer. If there is a tube drain to water seal it is at risk of being in advertently connected to suction with
Table 17.1 Results of studies of pleural space management after pneumonectomy Reference
Study period
Design
Deslauriers 19985
1988–1993
Retrospective comparison
Alvarez 20036
1993–2000
Retrospective comparison
Thomson 20067
1989–2004
Retrospective comparison
Pai 20078
2003–2004
Retrospective comparison
Rammohan 20099
2003–2009
Retrospective comparison
Allocation Team policy
Numbers
291 patients 80 no drain 132 water seal 77 balanced drainage Management policy 57 patients change mid 1996 from 28 water seal clamped drain to 29 balanced drainage balanced drainage. Team policy 46 patients 25 no drained 21 water seal Team policy 20 patients All drained in study 15 – clamped 5 – unclamped Team policy 86 patients 62 – drained and underwater seal broken hourly 24 – not drained
Outcome
Grade of evidence
PPE 2/80 11/132 0/77 PPE 4/28 0/29
Low
Length of stay 6.5 days 10.2 days Radiologically more surgical emphysema in clamped group (13/15 vs. 2/5)– no clinical correlation Radiologically more surgical emphysema in “no drain” group – no clinical correlation or difference in outcomes
Low
Low
Low
Low
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potentially disastrous effects due to mediastinal shift. An unclamped drain allows increasingly negative pressure to develop as the patient coughs or strains. We recommend that whichever protocol is adopted, it is used by all surgeons in the unit and all the staff are fully trained in that system and fully understand the pitfalls.
A Personal View of the Data Our instinct, when we have to choose amongst two or more methods with similar outcomes, is to prefer the simple over the complex. The no tube system has the apparent merits of simplicity. It also obviates the risk of inadvertent connection to suction. It theoretically reduces the risk of infection, although repeated needling of the space to correct mediastinal shift reduces this advantage. Other authorities have also expressed a preference for the no drain method.13–15 Balanced drainage has been seen as adding complexity to a very straightforward method that was satisfactory invoking an “ain’t broke, don’t fix it” response. The present authors have not had first hand experience with the balanced drainage system but have experience of all the nuances of 1(a) and (b) and of 2(a)–(c) and had considered their relative merits previously, albeit in imperfect studies.5,6 Having reviewed the evidence for this chapter, when any of us are next in a position to determine the protocol for the management of patients after pneumonectomy, we might prefer the balanced drainage system on the basis of the evidence we have reviewed. We would recommend that any group of surgeons, who need to review their protocol for management of pneumonectomy, should consider adopting the balanced drainage system.
A variety of methods for acute management of the post-pneumonectomy space are in clinical use and appear effective and safe (evidence quality low). No recommendation can be made for one system over another.
References 1. Andersen J, Egedorf J, Stougard J. The pleural space succeeding pneumonectomy. A roentgenological and clinical study of 167 cases of bronchogenic carcinoma Scand. J Thorac Cardiovasc Surg. 1968;2: 70–73. 2. Pezzella A, Conlan A, Carroll G. Early management of the postpneumonectomy space. Asian Cardiovasc Thorac Ann. 2000;8:398–402. 3. Khan IH, Vaughan R. A national survey of thoracic surgical practice in the UK. Int J Clin Pract. 1999;53:252–256. 4. Mattioli S, Berrisford RG, Lugaresi ML, Aramini B. Survey on chest drainage systems adopted in Europe. Interact Cardiovasc Thorac Surg. 2008;7:1155–1159. 5. Deslauriers J, Aucoin A, Gregoire J. Postpneumonec tomy pulmonary edema. Chest. Surg Clin N Am. 1998; 8:611–631. 6. Alvarez JM, Panda RK, Newman MA, Slinger P, Deslauriers J, Ferguson M. Postpneumonectomy pulmonary edema. J Cardiothorac Vasc Anesth. 2003;17:388–395. 7. Thomson JC,Ferreira Filho OF.Post-pneumonectomy thoracic drainage: to drain or not to drain? A retrospective study. J Bras Pneumol. 2006;32:290–293. 8. Pai V, Gangoli S, Tan C, Rankin S, Utley M, Cameron R et al. How best to manage the space after pneumonectomy? Theory and experience but no evidence. Heart Lung Circ. 2007;16:103–106. 9. Rammohan KS, Patel S, Butchart EG, Kulatilake EN, O’Keefe PA, Kornaszewska M. Pneumonectomies to drain or not to drain - that is the question. ESTS. 31–5–2009. Ref Type: Electronic Citation 10. Ramenofsky ML. The effects of intrapleural pressure on respiratory insufficiency. J Pediatr Surg. 1979; 14:750–756. 11. Raffensperger JG, Luck SR, Inwood RJ, Gora P, Hunt CE. The effect of overdistention of the lung on pulmonary function in beagle puppies. J Pediatr Surg. 1979;14:757–760. 12. Alvarez JM, Tan J, Kejriwal N, Ghanim K, Newman MA, Segal A et al. Idiopathic postpneumonectomy pulmonary edema: hyperinflation of the remaining lung is a potential etiologic factor, but the condition can be averted by balanced pleural drainage. J Thorac Cardiovasc Surg. 2007;133:1439–1447. 13. Goldstraw P. Postoperative management of the thoracic surgical patient. Baillieres Clinical Anaesthesi ology. Elsevier Ltd. 1987:207–231. 14. Deslauriers J, Gregoire J. Techniques of pneumonectomy: drainage after pneumonectomy. Chest Surg Clin N Am. 1999;9:437–447. 15. Wolfe WG, Lewis CW, Jr. Control of the pleural space after pneumonectomy. Chest Surg Clin N Am. 2002; 12:565–570.
18
Perioperative Prophylaxis Against Venous Thrombo-Embolism in Major Lung Resection Tom Treasure, Lee-Yee Chong, and Carlos E. Sharpin
Since the publication of the landmark meta-analysis from the Oxford group in 19881 it has been known that the use of subcutaneous heparin reduces the rate of deep vein thrombosis (DVT) and pulmonary embolism (PE) in surgical patients. It is generally accepted that DVT and PE have a common cause with an event ratio of about 10:1. For the purpose of an evidence base from which to make recommendations for prophylaxis, DVT and PE are considered together as venous thrombo-embolism (VTE). A strategy which results in a demonstrable reduction in the incidence of DVT can be expected to reduce PE and fatal PE commensurately. Thoracic surgeons will be aware that these premises have been disputed by their orthopaedic surgeon colleagues who perform lower limb joint replacements, particularly with respect to the knee joint. However, in thoracic surgery there has been no call to reject this common cause hypothesis. Since patients undergoing major lung resection usually have cancer and are older, they have two well recognised risk factors for VTE. Furthermore, it seems self evident that patients losing part or all of a lung are vulnerable to the consequences of PE.
Methods We consulted the existing guidelines concerning VTE prophylaxis which include those from UK’s National Institute for Health and Clinical Excellence
(NICE)3 and the American College of Chest Physicians (ACCP).4 We looked for specific guidance for thoracic surgery and identified publications specifically related to lung resection. From our work in Guideline Development for NICE we were aware of the paucity of evidence in thoracic surgery. We therefore considered evidence related to major surgery, and to cancer, which might be relevant to thoracic surgical practice. We augmented searches iteratively from citations of recent related publications and any other leads. We specifically looked for evidence to guide surgeons on two questions: 1. When should pharmacological prophylaxis be commenced? 2. For how long should it be continued?
Results There are specific recommendations for thoracic surgery from both NICE in 2010 and ACCP in 2008. NICE published its evidence tables, forest plots and references, categorised by means of prophylaxis and risk attributes of patients based on around 400 randomised controlled trials. The evidence table presented here illustrates specific points and is not relied on as the only source of evidence (Table 18.1).
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NICE (2010) Offer VTE prophylaxis to patients undergoing thoracic surgery who are assessed to be at increased risk of VTE. Start mechanical VTE prophylaxis at admission. Choose any one of: −− Anti-embolism stockings (thigh or knee length) −− Foot impulse devices −− Intermittent pneumatic compression devices (thigh or knee length) Continue mechanical VTE prophylaxis until the patient no longer has significantly reduced mobility. Add pharmacological VTE prophylaxis for patients who have a low risk of major bleeding, taking into account individual patient factors and according to clinical judgement. Choose one of: −− LMWH −− UFH (for patients with renal failure) Continue pharmacological VTE prophylaxis until the patient no longer has significantly reduced mobility (generally 5–7 days). Extend pharmacological VTE prophylaxis to 28 days postoperatively for patients who have had major cancer surgery in the abdomen or pelvis.
heparin was reported to reduce DVT without surgical concerns about excess bleeding.5 The design of this study was flawed in that the comparison was made with outcomes in the year prior to the introduction of heparin, rather than being a randomised study. However, it is in line with the effect seen in other better designed studies of use of unfractionated heparin in other forms of surgery and we have no reason to doubt the effect.
Timing of Use of Heparin In another early study, heparin was given 2.5 h before operation for the first patient of the day.6 The second patient was used as a control and heparin was delayed for 1–3 days. There were 13 PEs, mainly in cancer patients, 10 of them fatal, and 9 were confirmed at post mortem. The difference in postoperatively and preoperatively treated cancer patients was 7:1 (P < 0.01). Again, the design is flawed but the apparent effect is large and in the same direction and magnitude of other better designed studies. The concern about starting heparin prior to surgery is the risk of bleeding. It has been shown to not be a problem in major abdominal surgery7 and was not of clinical concern in thoracic surgery.5
ACCP guidance (2008)4 For patients undergoing major thoracic surgery, we recommend routine thromboprophylaxis with LMWH, LDUH (low dose unfractionated heparin – traditional heparin), or fondaparinux (each Grade 1C). For thoracic surgery patients with a high risk of bleeding, we recommend the optimal use of mechanical thromboprophylaxis with properly fitted GCS and/or IPC (Grade 1C).
Extended Use of Heparin With patients leaving hospital sooner after surgery and in the knowledge that the peak incidence of PE is 1–2 weeks after surgery, the question of extending prophylaxis has become important. In all of four studies addressing this question,8–11 two including thoracic patients and all including cancer operations, there were fewer DVTs in the group having extended prophylaxis, with the incidence reduced from about 10–4% on pooled data. Where the risk of bleeding was evaluated, there was no difference.8
Effectiveness of Heparin Prophylaxis in Thoracic Surgical Patients
Effectiveness of Intermittent Compression Devices in Thoracic Surgical Patients
In the 1970s VTE prophylaxis for surgery was being actively investigated and 125I was a favoured method in clinical research. Unfractionated
Again flawed by its design is a single study of the utility of IPC; the difference in the rate of PE was striking (2% versus 0%; p < 0.006).12
Population (N)
Abdominal surgery, mainly colorectal cancer N = 449 Abdominal or pelvic cancer surgery 1998–2000 N = 332
Major elective abdominal or thoracic surgery 1991–1993 N = 176
Major abdominal surgery N = 316
Extended prophylaxis 3–4 weeks
IPC vs. no IPC
Retrospective by non use (344) or use (362) of IPC introduced in 1998
Clinical PE
Clinically suspected DVT confirmed by ultrasound
Tinzaparin (LMWH) for 1 (control) DVT at 4 weeks by vs. 4 weeks venography Bleeding complications (LMWH)Dalteparin 7 days vs. Venography 28 days enoxaparin 28 days Enoxaparin (LMWH) 40 mg daily DVT, confirmed with for 6–10 days then continued venography for 21 days or stopped
Historical controls
RCT
Meta-analysis of two studies
RCT
Fatal PE (in bronchial cancer patients)
Clinical PE
Blood loss at operation
I positive
125
Outcome
Enoxaparin (LMWH) Pre (2 or 12 h) Excessive bleeding or immediately post operation
5000IU 12 hourly for 5 days Started 2.5 h pre-op, vs. started 24–72 h post-op vs. no prophylaxis
By operative order 1st case:1007 2nd case 932 Others: 481 minor operation or contraindication Play the winner (PTW) design
UFH 5000 u 12 hourly for 5 days vs. no prophylaxis
Intervention
Historical cohort year 1: (no prophylaxis) years 2 and 3: UFH
Design
a
Small sample size – imprecision
UFH unfractionated heparin,LMWH low molecular weight heparin, IPC intermittent pneumatic compression device, DVT deep vein thrombosis, PE pulmonary embolism
Mechanical prophylaxis – safety: no studies found
Lobectomy/bilobectomy For NSCLC Comparison 2007 Study 2008–2009 N = 316 Mechanical prophylaxis – effectiveness Nagahiro 200412 All general thoracic surgery 1995–2000 N = 406
Cardillo 200911
Bergqvist 20029
Rasmussen 200210
Duration of prophylaxis Lausen 19988
Bjerkeset 19977
Effectiveness of heparin prophylaxis Jackaman 19785 Lateral thoracotomy N = 183 (141 malignant) Timing of prophylaxis administration Le Brigand 1981 6 All thoracic surgery 1973–1977 N = 2420 (40% cancer)
Publication
Table 18.1 Results of studies on prophylaxis for VTE in thoracic surgery patients
No IPC: 7/344 IPC: 0/362 P < 0.006
1 week: 6/60 (10%) 4 weeks: 3/58 (5.2%) P = 0.49 1 week: 3/89 (3.4%) 4 weeks: 2/87 (2.3%) Control: 30/230 extended: 11/219 P = 0.02 At 25–30days: standard: 12% extended: 4.8% P = 0.02 At 3 months: standard: 13.8% extended: 5.5% P = 0.01 Extended: 2/184 control: 4/132 not stats sig
Pre-op: 27/153 Post- op: 24/163 not significant
With prophylaxis: 13 mainly in cancer patients without prophylaxis: Pre-op: 1 Post-op: 7 P < 0.01 with preoperative heparin
No prophylaxis: 32/63 (51%) UFH: 33/120 (28%) P < 0.05 “No evidence to suggest greater blood loss”
Results
Moderate
Very low
High
High
Lowa High
Lowa
Very low
Very low
Very low
Very low
Very low
GRADE quality
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Conclusions Patients undergoing lung resections for cancer have increased risk of VTE and increased susceptibility to its consequences. In a report from the Cleveland Clinic of 336 patients having a pneumonectomy, 25 patients (7.4%) had postoperative venous thromboembolism with a peak incidence 7 days after the operation.13 This was in spite of use of subcutaneous heparin up to the time of discharge, early ambulation, and “pneumatic stockings”. The hazards of VTE have not gone away. The event rates of both heparin-related serious bleeding and of clinically important VTE are low, and it is not possible to compute a nadir of risk for an individual patient based on a surgeon’s clinical experience; certainly not from memory. It has been well shown in the not dissimilar circumstances of warfarin anticoagulation to reduce stroke rates in isolated atrial fibrillation that a recent bad experience with bleeding makes clinicians reduce their prescription risk, contrary to evidence based best practice.14 Prophylaxis of VTE carries with it a risk of bleeding, but the evidence is that there is net benefit in using pharmacological prophylaxis in patients undergoing major surgery and in cancer patients and both arguments apply in thoracic surgical practice.
Recommendations All patients having major lung resection with a low risk of major bleeding should be offered double prophylaxis (pharmacological plus mechanical) as recommended by NICE. Patients with high risks of bleeding should have optimal use of mech anical thromboprophylaxis with properly fitted GCS and/or IPC as recommended by ACCP. Surgical teams should consider the evidence for starting heparin prophylaxis prior to surgery. Patients should be offered extended prophylaxis. If early evidence for the effectiveness of oral anticoagulants is sustained and this indication is approved, these should be considered as a logistically preferable means of administering thrombo prophylaxis.
Both mechanical and pharmacologic prophylaxis are effective in reducing the incidence of VTE in thoracic surgery patients (evidence grade moderate). Evidence from other the cancer related surgery populations show that these are safe (evidence grade low). In patients undergoing major lung resection a strong recommendation is made for the perioperative use of a combination of pharmacologic and mechanical VTE prophylaxis. continuing for a period of 4 weeks postoperatively. In patients who have an increased risk of bleeding mechanical VTE prophylaxis should be used (recommendation grade 1B).
References 1. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med. 1988;318:1162–1173. 2. Sharrock NE, Gonzalez D, V, Go G, Lyman S, Salvati EA. Potent anticoagulants are associated with a higher all-cause mortality rate after hip and knee arthroplasty. Clin Orthop Relat Res. 2008;466: 714–721. 3. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. National Institute for Health and Clinical Excellence (NICE). 2010. http://www.nice.org.uk/ g uidance/index.jsp?ac t ion=byID&o=12695, Accessed 5 April 2010. 4. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR et al. Prevention of venous thromboembolism: American College of Chest Phy sicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest. 2008;133(6 suppl):381S–453S. 5. Jackaman FR, Perry BJ, Siddons H. Deep vein thrombosis after thoracotomy. Thorax. 1978;33: 761–763. 6. Le Brigand H, Morille P, Garnier B, Bogaty-Yver J, Samama M, Spriet A. [Prevention of postoperative thrombo-embolic accidents following thoracic surgery by low-dose calcium heparinate: a comparative study (author’s transl)]. Sem Hop. 1981;57: 972–977. 7. Bjerkeset O, Larsen S, Reiertsen O. Evaluation of enoxaparin given before and after operation to pre-
18. Perioperative Prophylaxis Against Venous Thrombo-Embolism in Major Lung Resection vent venous thromboembolism during digestive surgery: play-the-winner designed study. World J Surg. 1997;21:584–588. 8. Lausen I, Jensen R, Jorgensen LN, Rasmussen MS, Lyng KM, Andersen M et al. Incidence and prevention of deep venous thrombosis occurring late after general surgery: randomised controlled study of prolonged thromboprophylaxis. Eur J Surg. 1998;164: 657–663. 9. Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le Moigne-Amrani A et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346:975–980. 10. Rasmussen MS. Preventing thromboembolic complications in cancer patients after surgery: a role for prolonged thromboprophylaxis. Cancer Treat Rev. 2002;28:141–144.
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11. Cardillo G, Carleo F, Carbone L, De Massimi A , Keinan F, Foncella D et al. How long should venous thrombophylaxis be given following pulmonary lobectomy for cancer? ICVTS 2009;9(Supplement 2):S83 12. Nagahiro I, Andou A, Aoe M, Sano Y, Date H, Shimizu N. Intermittent pneumatic compression is effective in preventing symptomatic pulmonary embolism after thoracic surgery. Surg Today. 2004;34:6–10. 13. Mason DP, Quader MA, Blackstone EH, Rajeswaran J, DeCamp MM, Murthy SC et al. Thromboembolism after pneumonectomy for malignancy: an independent marker of poor outcome. J Thorac Cardiovasc Surg. 2006;131:711–718. 14. Choudhry NK, Anderson GM, Laupacis A, RossDegnan D, Normand SL, Soumerai SB. Impact of adverse events on prescribing warfarin in patients with atrial fibrillation: matched pair analysis. BMJ. 2006;332(7534):141–145.
19
Perioperative Arrhythmia Prophylaxis for Major Lung Resection Daniela Molena, David Amar, and Bernard J. Park
Introduction Perioperative arrhythmia is one of the most common complications following general thoracic surgery. The most common types are atrial fibrillation, supraventricular tachycardia, atrial flutter and premature ventricular contractions. Sustained ventricular tachyarrhythmias are very rare after thoracic surgery and will not be discussed in this chapter. The reported incidence of postoperative supraventricular arrhythmias ranges between 4–33%, and onset typically peaks within the first 3 postoperative days.1 Although considered by some a minor, self-limited event, perioperative arrhythmia has been shown in recent studies to be associated with greater numbers of complications, longer hospital stays, and increased overall hospital costs.2–7 Furthermore, when arrhythmias persist or are recurrent, the risk of thromboembolic events, including stroke or transient neurological injury, increases. This warrants anticoagulation that can lead to bleeding complications and increased healthcare expenditures. As a result, there is growing interest in identifying high-risk patients to implement prophylactic strategies and improve clinical outcomes. While several prospective randomized studies have assessed the role of various pharmacologic agents in the prophylaxis of supraventricular arrhythmia after cardiac surgery, limited studies are available for non-cardiac thoracic surgery. This chapter addresses the potential benefits for the prevention of perioperative supraventricular arrhythmia, outlines the known risk factors associated with its development, and
reviews the prophylactic regimens available for prevention.
Search Strategy A literature search of English language publications from 1995 to 2009 was used to identify published data on perioperative arrhythmia prophylaxis after major lung surgery. Databases searched were PubMed, Embase, Scopus, Science Citation Index/ Social Sciences Citation Index and Cochrane Evidence Based Medicine. Terms used in the search were “tachycardia, supraventricular/prevention and control,” “heart supraventricular arrhythmia/prevention,” “atrial fibrillation/prevention and control,” “heart atrium fibrillation/prevention,”“arrhythmias, cardiac/prevention and control,” “heart arrhythmia/ prevention,” AND (“intraoperative complications” OR “perioperative complications” OR “postoperative complications”), “thoracic surgical procedures,” “thoracic surgery,” “thorax surgery,” “pneumonectomy,” and “lobectomy.” Where possible, references were limited to randomized controlled trials, review studies, comparative or cohort studies. The search yielded 40 articles. Sixteen articles were excluded because they were either specific to foregut surgery, cardiac surgery or addressed treatment of arrhythmias other than prophylaxis. Seven randomized controlled trials, two systematic reviews, one guideline, seven review articles and seven cohort studies were included in our analysis. The data was classified using the American College of Chest Physicians (ACCP) modified GRADE system.8
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_19, © Springer-Verlag London Limited 2011
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Clinical Relevance of Perioperative Supraventricular Arrhythmia The clinical significance of perioperative supra ventricular arrhythmia is controversial, and the association between arrhythmia and an increased rate of postoperative morbidity is not well known and most likely not explained by a cause and effect relationship. Nevertheless, the development of arrhythmia is a marker for increased postoperative risk of other complications, prolonged length of stay, need for readmission and increased mortality (Table 19.1). In our experience at Memorial Sloan-Kettering Cancer Center with 527 consecutive patients undergoing major pulmonary resections, the incidence of atrial fibrillation was 15%.4 Patients who developed postoperative atrial fibrillation had a higher rate of concomitant complications such as pneumonia and respiratory failure, prolonged length of stay, greater need for intensive care unit admission and higher mortality. In a prospective cohort study of 4181 patients who underwent major noncardiac thoracic procedures, the incidence of supraventricular arrhythmia was 7.6%.3 Fifty-one percent of these patients had at least one other complication, and their overall length of stay was approximately 2.5 days longer compared to the patients who did not develop arrhythmia. Similar results were reported by Vaporciyan and
colleagues in a retrospective review of 2588 pati ents undergoing thoracic surgery.5 The overall incidence of atrial fibrillation was 12.3%, and the development of arrhythmia was associated with a significant increase in hospital stay, mortality and hospital charges. When all other complications were excluded and patients with only atrial fibrillation were compared to patients without any complication, there was still a significant increase in hospital cost (approximately $6,400 per patient) for the patients who developed arrhythmia. Similarly, a propensity-matched study from the Cleveland Clinic showed that, even when atrial fibrillation was the only postoperative complication after lung cancer resection, length of hospital stay, in-hospital mortality and hospital costs were significantly higher.7 These findings support the notion that supraventricular arrhythmia is not a trivial complication, and its occurrence leads to increased use of hospital resources.
Risk Factors A strong effort has been dedicated to the identification of risk factors for perioperative atrial arrhythmias in order to direct prophylactic measures to the appropriate patients. As shown in several different studies, the most consistently recognized preoperative risk factor for the development of
Table 19.1 Incidence of atrial fibrillation (AF) and clinical outcome AF
No AF
Author (Year)
N
Incidence of AF (%)
Age
LOS
Morbidity (%)
Mortality (%)
Age
LOS
Brathwaite (1998)2 Polanczyk (1998)3 Cardinale (1999)9 Amar(2002)4
404
10
67
23
NR
23
64
13
NR
4
4,181
7.6
NR
15
51
NR
NR
8
13
NR
233
12
63
14
18
0
58
13
17
1.3
527
15
68
17
22
11
62
10
6
3
2,588
12
NR
16.6
NR
7.5
NR
8.2
NR
2
856
17
69
13.5
NR
NR
64
9.2
NR
NR
604
19
68
8
30
8
64
5
9
0
Vaporciyan (2004)5 Passman (2005)6 Roselli (2005)7
LOS length of stay (days); NR not reported
Morbidity (%) Mortality (%)
Study Type (Quality of evidence) Prospective cohort (low) Prospective cohort (low) Prospective cohort (low) Prospective cohort (low) Prospective cohort (low) Prospective cohort (low) Prospective cohort (low)
19. Perioperative Arrhythmia Prophylaxis for Major Lung Resection
atrial fibrillation following surgery is age over 60 years.2–7,9 In addition to older age, male gender, prior history of atrial fibrillation, and hypertension, preexisting cardiac conditions such as congestive heart failure and valvular disease as well as a history of asthma have also been implicated as independent predictors of atrial fibrillation after cardiothoracic surgery (Table 19.2).3–5 Using logistic regression analysis we found that male gender, advanced age and heart rate ³ 72 bpm on preoperative EKG were independent predictors of postoperative atrial fibrillation.6 A clinical risk score developed by assigning weighted point scores for the presence of each variable according to their regression coefficient (1 point for male gender and heart rate ³ 72 bpm, 3 and 4 points respectively for age 55 to 74 and ³ 75 years) was found to be predictive of atrial fibrillation risk in both the derivation and validation models. Patients with scores of 4, 5 and 6 had a risk of developing atrial fibrillation of 14%, 21% and 32% respectively.6 There is good evidence that the extent of pulmonary resection is a risk factor for arrhythmia. Anatomic pulmonary resections, such as lobectomy, bilobectomy and pneumonectomy, have been repeatedly associated with progressively increasing relative risk of postoperative arrhythmia compared with non-anatomic and sublobar resections.3,5,7,10 Harpole and coauthors, in a prospective analysis of 883 consecutive patients undergoing pulmonary resection for cancer, reported an incidence of atrial fibrillation of 1% after wedge or segmental resection versus 12% after lobectomy and 24% after pneumonectomy.10 The surgical approach may influence the rate of perioperative atrial fibrillation as well. Most of the previous studies examining postoperative atrial fibrillation have been in patients undergoing thoracotomy. With the growing interest in minimally invasive approaches to anatomic pulmonary Table 19.2 Risk factors for supraventricular arrhythmias Age > 60 years Male gender History of paroxysmal atrial fibrillation HR ≥ 72 bpm Major anatomic resection Intrapericardial procedure Elevated perioperative BNP level Postoperative increased WBC count
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resection, some authors have suggested that utilization of video-assisted thoracic surgery (VATS) may reduce the incidence of postoperative supraventricular arrhythmias. However, this remains controversial. Villamizar and coauthors reported a significantly lower incidence of atrial fibrillation among 697 patients after a VATS approach compared with 382 patients after thoracotomy (16% vs. 22% respectively, p = 0.01).11 Even when a propensity-matched approach was used, the difference persisted among the two groups (13% vs. 21%, p = 0.01). By contrast when we analyzed our own experience with VATS lobectomy, we found a similar incidence of atrial fibrillation in a group of 122 patients undergoing VATS lobectomy when compared to a group of 122 patients, age- and gender-matched, undergoing thoracotomy.12 Atrial fibrillation occurred in 12% of patients (15/122) undergoing video-assisted thoracic surgery and 16% of patients (20/122) undergoing thoracotomy (P = 0.36). Whitson and colleagues reported similar results in a systematic review of the existing literature of VATS versus thoracotomy for lobectomy in lung cancer patients.13 The mean rate of postoperative atrial fibrillation in 1,095 VATS patients was 5.2% (95% CI 2.0–8.4) versus 9.0% (95% CI 2.1–15.8) in 294 patients after thoracotomy (p = 0.33). Based on these results we prophylactically treat high risk patients regardless of the planned operative approach, although there are divergent results in published data. The use of serum markers as a potential prognostic tool has been suggested in recent studies. White blood cell count elevation has been used to further stratify patients at risk of developing arrhythmia. We recently showed that a twofold elevation in white blood cell count on the first postoperative day corresponded to a 3.3-fold increase in the likelihood of developing atrial fibrillation.14 Cardinale and others used the N-terminal pro-brain natriuretic peptide (NT- proBNP) as a predictor of postoperative atrial fibrillation.15 In a prospective study of 441 consecutive patients undergoing elective thoracic surgery for lung cancer, the incidence of atrial fibrillation was 68% in patients with a preoperative elevated NT-proBNP and 7% in those with normal values. The incidence of atrial fibrillation also was significantly higher in patients with normal preoperative NT-proBNP but with
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elevated values postoperatively. Both preoperative and postoperative NT-proBNP values were independent predictors of postoperative atrial fibrillation on multivariate analysis, with a relative risk of 35.8 (95% CI, 16.7–76.7), a positive predictive value of 64%, and a negative predictive value of 95%.
Prevention Strategies The results of the studies examining the efficacy of different pharmacologic strategies for the prevention of postoperative atrial fibrillation are summarized in Table 19.3. Two systematic reviews and one guideline paper also showed that calciumchannel blockers and b-blockers are effective in reducing postoperative supraventricular arrhythmia and their use should be individualized in order to minimize possible adverse events.23–25 In a randomized, double-blind, placebo controlled study of 330 patients prophylactically treated either with diltiazem or placebo after major lung resection, we demonstrated that diltiazem significantly reduced the overall incidence of postoperative arrhythmias (15% vs. 25%, p = 0.03) and nearly halved the incidence of clinically significant arrhythmias when compared to placebo (10% vs. 19%, p = 0.02).20 The treatment with diltiazem, started immediately after surgery and continued postoperatively for 2 weeks, was safe and very well tolerated by the patients. On the contrary, verapamil has been shown to be associated with significant adverse reactions to treatment. In a prospective, randomized study comparing verapamil to placebo in 199 patients undergoing lobectomy or pneumonectomy, 23% of patients experienced significant bradycardia and hypotension and had to be withdrawn from the study.16 Diltiazem was also shown to be superior to digoxin in reducing the overall incidence of supraventricular arrhythmia after standard or intrapericardial pneumonectomy. Digoxin therapy had no effect on the incidence of postoperative arrhythmias since patients prophylactically treated with digoxin had a similar incidence of arrhythmias as controls (31% vs. 28%).18 Moreover, digoxin was associated with more than four times higher risk of bradycardia compared with the placebo.23,24
D. Molena et al.
Even though ß-blockers have been reported to be effective in the prevention of atrial fibrillation after cardiac surgery,26 few studies evaluated their efficacy after thoracic surgery. A randomized, double-blind, placebo controlled trial of propranolol in patients undergoing major thoracic surgery showed only a trend toward effectiveness and a high incidence of hypotension (50%) and bradycardia (25%).18 In an early study amiodarone has been associated with a high incidence of side effects as well, mainly risk of developing adult respiratory distress syndrome.15 Nevertheless, more recent studies have shown that the short-term use of amiodarone to be safe after thoracic surgery.21,22 A recent prospective, randomized study evaluating amiodarone for prevention of atrial fibrillation after pulmonary resection in 130 patients showed a significantly lower incidence of atrial fibrillation in the amiodarone group than in the controls (13.8% vs. 32.3%), with a relative risk reduction of 57% and a low incidence of adverse events like respiratory complications.22 This study has been criticized for the lack of a doubleblind placebo controlled design that might have led to bias in the determination as to whether a patient had atrial fibrillation that required treatment. Also, there was a high rate of intraoperative atrial fibrillation which led to the exclusion of several patients and likely introduced selection biases. Partial sympathectomy with epidural analgesia has been reported as a prophylactic measure for supraventricular arrhythmias after thoracic surgery, but the results reported are mixed. Oka and colleagues randomized 50 patients undergoing surgical resection of primary lung cancer to receive either epidural bupivacaine or epidural morphine.27 Even though postoperative analgesia was not different in the two groups, the incidence of postoperative tachyarrhythmia was significantly less in the bupivacaine group (28% vs. 4.3%, p = 0.05). The number of patients in this study, however, was small and the two groups were not well matched for age with the patients in the morphine group being significantly older than those in the bupivacaine cohort (mean age 67 ± 8.6 years vs. 63.6 ± 7.9 years, respectively). A recent randomized trial of patient-controlled intravenous analgesia with opioids versus patient-controlled epidural analgesia with
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19. Perioperative Arrhythmia Prophylaxis for Major Lung Resection
ropivacaine actually showed the opposite results.28 In this small study (n = 48) the incidence of postoperative supraventricular tachycardia was significantly lower in the opioid group compared with the epidural group (14% versus 45%, p = 0.021). In addition, the frequency of supraventricular ectopic beats increased more in the epidural group. The role of prophylactic use of magnesium to reduce the incidence of atrial fibrillation after thoracic surgery is not clear unless hypomagnesemia is present. Terzi and co-authors showed a reduction in the incidence of atrial fibrillation from 27% to 11% (p = 0.008) in a group of patients randomized to magnesium when compared to controls.29 However this study was unblinded and control patients with hypomagnesemia received magnesium and digoxin after randomization. The preoperative use of statins also has been suggested to have a protective effect against postoperative development of atrial fibrillation and was associated with a threefold reduction in the incidence of this complication after major thoracic surgery in a recent observational study.30 Larger randomized studies are needed to evaluate the role of systemic inflammation in the development of atrial fibrillation in order to better target alternative prophylactic measures.
Conclusions and Recommendations Perioperative supraventricular arrhythmia is associated with higher postoperative morbidity, prolonged hospital stay and increased hospital cost (evidence quality moderate). Patients with two or more of the characteristics listed in Table 19.2 are considered at high risk of developing perioperative supraventricular arrhythmia (evidence quality moderate).We make a strong recommendation for selective use of prophylactic measures in high risk patients (recommendation grade 1B). Diltiazem significantly reduces the rate of postoperative atrial fibrillation after major lung resection with low side effects (evidence quality high). We make a strong recommendation for the use of diltiazem in high risk patients (recommendation grade 1A). The use of amiodarone might be efficacious in reducing postoperative atrial fibrillation but there are concerns regarding the development of postoperative respiratory complications associated with its use (evidence quality moderate). We make a weak recommendation against routine prophylactic use of amiodarone until larger studies better assess these concerns (recommendation grade 2B). Individual studies provide some evidence that other prophylactic measures like epidural analgesia, magnesium, or statins might reduce the incidence of postoperative arrhythmia and are safe
Table 19.3 Efficacy of prophylaxis for supraventricular arrhythmia Author (Year)
N
Van Mieghem (1996)16 Jakobsen (1997)17 Amar (1997)+
199
Bayliff (1999)19
99
Amar (2000)20
330
Lanza (2003)21
83
Tisdale (2009)22
130
30 70
Surgery type Lobectomy/ pneumonectomy Thoracotomy for lung resection Pneumonectomy Lobectomy/ pneumonec tomy/ esophagectomy Lobectomy/ pneumonectomy Pulmonary resection Lobectmy/bilobectomy / pneumonectomy
Study type (quality of evidence)
Incidence of AF/SVA Treatment
Control
PRCT (high)
Verapamil 8%
Placebo 14%
NS
Double-blind PRCT (moderate) PRCT (moderate)
Metoprolol 6.7%
Placebo 40%
< 0.05
Diltiazem 14% Digoxin 31% Propanolol 6%
Control 28%
0.09
Placebo 20%
0.071
Diltiazem 15%
Placebo 25%
0.03
Amiodarone 9.7%
Control 33%
0.025
Amiodarone 13.8%
Control 32.3%
0.02
Double-blind PRCT (high) Double-blind PRCT (high) Retrospective cohort study (low) PRCT (moderate)
AF atrial fibrillation; SVA supraventricular arrhythmia; PRCT prospective randomized controlled trial; NS not significant
P value
D. Molena et al.
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(evidence quality low). We make a weak recommendation for these other prophylactic interventions (recommendation grade 2C).
Perioperative supraventricular arrhythmia is associated with higher postoperative morbidity, prolonged hospital stay and increased hospital cost (evidence quality moderate). We make a strong recommendation for selective use of prophylactic measures in high risk patients (recommendation grade 1B).
Diltiazem significantly reduces the rate of postoperative atrial fibrillation after major lung resection with low side effects (evidence quality high). We make a strong recommendation for the use of diltiazem in high risk patients (recommendation grade 1A).
The use of amiodarone might be efficacious in reducing postoperative atrial fibrillation but there are concerns regarding the development of postoperative respiratory complications associated with its use (evidence quality moderate). We make a weak recommendation against routine prophylactic use of amiodarone until larger studies better assess these concerns (recommendation grade 2B).
A Personal View of the Data Postoperative supraventricular arrhythmia is a frequent complication in elderly patients undergoing thoracic surgery and it occurs in patients with higher morbidity, mortality, increased length of stay and hospital costs. Identification of highrisk patients would allow a more tailored and therefore more cost-effective use of prophylactic measures. At Memorial Sloan-Kettering Cancer Center we routinely start prophylactic measures in patients with two or more risk factors listed in Table 19.2. Diltiazem is the medication of choice
as an intravenous drip immediately postoperative and continued orally for one to two weeks after surgery. Whereas ß-blockers are rate dependent in achieving successful cardiac protection, diltiazem is not, as long as adequate plasma concentrations are achieved using recommended dosage. However, patients on preoperative ß-blockers should remain on them postoperatively in order to avoid rebound tachycardia. Diltiazem is added if heart rate remains above 80 bpm as long as the patient’s blood pressure can tolerate it. Statins are continued in the immediate postoperative period and hypomagnesemia and hypokalemia are monitored and corrected appropriately. More studies are needed to evaluate whether prophylactic treatment of perioperative supraventricular arrhythmia improves clinical outcomes, increases survival, shortens hospital stays and decreases overall hospital costs.
References 1. Amar D. Prevention and management of perioperative arrhythmias in the thoracic surgical population. Anesthesiol Clin. 2008;26:325–335. 2. Brathwaite D, Weissman C. The new onset of atrial arrhythmias following major non-cardiothoracic surgery is associated with increased mortality. Chest. 1998;114:462–468. 3. Polanczyk C, Goldman L, Marcantonio ER, Orav EJ, Lee TH. Supraventricular arrhythmia in patients having noncardiac surgery: clinical correlates and effect on length of stay. Ann Intern Med. 1998;129: 279–285. 4. Amar D, Zhang H, Leung DHY, Roistacher N, Kadish AH. Older age is the strongest predictor of postoperative atrial fibrillation. Anesthesiology. 2002;96:345–356. 5. Vaporciyan AA, Correa AM, Rice DC, Roth JA, Smythe WR, Swisher SG, Walsh GL, Putnam JB. Risk factors associated with atrial fibrillation after noncardiac thoracic surgery: analysis of 2588 patients. J Thorac Cardiovasc Surg. 2004;127:779–786. 6. Passman RS, Gingold DS, Amar D, Lloyd-Jones D, Bennett CL, Zhang H, Rusch VW. Prediction rule for atrial fibrillation after major noncardiac thoracic surgery. Ann Thorac Surg. 2005;79:1698–1703. 7. Roselli EE, Murthy SC, Rice TW, Houghtaling PL, Pierce CD, Karchmer DP, Blackstone EH. Atrial fibrillation complicating lung cancer resection. J Thorac Cardiovasc Surg. 2005;130:438–444. 8. Guyatt G, Gutterman D, Baumann MH, AddrizzoHarris D, Hylek EM, Phillips B, Raskob G, Lewis SZ, Schünemann H. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest. 2006;129:174–181.
19. Perioperative Arrhythmia Prophylaxis for Major Lung Resection 9. Cardinale D, Martinoni A, Cipolla CM, Civelli M, Lamantia G, Fiorentini C, Mezzetti M. Atrial fibrillation after operation for lung cancer: clinical and prognostic significance. Ann Thorac Surg. 1999;68: 1827–1831. 10. Harpole DH, Liptay MJ, DeCamp MM, Mentzer SJ, Swanson SJ, Sugarbaker DJ. Prospective analysis of pneumonectomy: risk factors for major morbi dity and cardiac dysrhythmias. Ann Thorac Surg. 1996;61:977–982. 11. Villamizar NR, Darrabie MD, Burfeind WR, Petersen RP, Onaitis MW, Toloza E, Harpole DH, D’Amico TA. Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy. J Thorac Cardiovasc Surg. 2009;138:419–425. 12. Park BJ, Zhang H, Rusch VW, Amar D. Video-assisted thoracic surgery does not reduce the incidence of postoperative atrial fibrillation after pulmonary lobectomy. J Thorac Cardiovasc Surg. 2007;133:775–779. 13. Whitson BA, Groth SS, Duval SJ, Swanson SJ, Maddaus MA. Surgery for early-stage non-small cell lung cancer: a systematic review of the videoassisted thoracoscopic surgery versus thoracotomy approaches to lobectomy. Ann Thorac Surg. 2008;86: 2008–2018. 14. Amar D, Goenka A, Zhang H, Park B, Thaler HT. Leukocytosis and increased risk of atrial fibrillation after general thoracic surgery. Ann Thorac Surg. 2006;82:1057–1061. 15. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, Salvatici M, Veronesi G, Veglia F, Fiorentini C, Spaggiari L, Cipolla CM. Increased perioperative N-terminal pro-B-type natriuretic peptide levels predict atrial fibrillation after thoracic surgery for lung cancer. Circulation. 2007;115:1339–1344. 16. Van Mieghem W, Tits G, Demuynck K, Lacquet L, Deneffe G, Tjandra-Maga T, Demedts M. Verapamil as prophylactic treatment for atrial fibrillation after lung operations. Ann Thorac Surg. 1996;61: 1083–1086. 17. Jakobsen CJ, Bille S, Ahlburg P, Rybro L, Hjortholm K, Andresen EB. Perioperative metoprolol reduces the frequency of atrial fibrillation after thoracotomy for lung resection. J Cardiothorac Vasc Anesth. 1997; 11:746–751. 18. Amar D, Roistacher N, Burt ME, Rusch VW, Bains MS, Leung DH, Downey RJ, Ginsberg RJ. Effects of diltiazem versus digoxin on dysrhythmias and cardiac function after pneumonectomy. Ann Thorac Surg. 1997;63:1374–1382. 19. Bayliff CD, Massel DR, Inculet RI, Malthaner RA, Quinton SD, Powell FS, Kennedy RS. Propranolol for the prevention of postoperative arrhythmias in general thoracic surgery. Ann Thorac Surg. 1999;67:182–186.
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20. Amar D, Roistacher N, Rusch VW, Leung DH, Ginsburg I, Zhang H, Bains MS, Downey RJ, Korst RJ, Ginsberg RJ. Effects of diltiazem prophylaxis on the incidence and clinical outcome of atrial arrhythmias after thoracic surgery. J Thorac Cardiovasc Surg. 2000;120:790–798. 21. Lanza LA, Visbal AI, DeValeria PA, Zinsmeister AR, Diehl NN, Trastek VF. Low-dose oral amiodarone prophylaxis reduces atrial fibrillation after pulmonary resection. Ann Thorac Surg. 2003;75:223–230. 22. Tisdale JE, Wroblewski HA, Wall DS, Rieger KM, Hammoud ZT, Young JV, Kesler KA. A randomized trial evaluating amiodarone for prevention of atrial fibrillation after pulmonary resection. Ann Thorac Surg. 2009;88:886–895. 23. Sedrakyan A, Treasure T, Browne J, Krumholz H, Sharpin C, van der Meulen J. Pharmacologic prophylaxis for postoperative atrial tachyarrhythmia in general thoracic surgery: evidence from randomized clinical trials. J Thorac Cardiovasc Surg. 2005;129:997–1005. 24. Shrivastava V, Nyawo B, Dunning J, Morritt G. Is there a role for prophylaxis against atrial fibrillation for patients undergoing lung surgery? Interact Cardiovasc Thorac Surg. 2004;3:656–662. 25. Dunning J, Treasure T, Versteegh M, Nashef SA, EACTS Audit and Guidelines Committee. Guidelines on the prevention and management of de novo atrial fibrillation after cardiac and thoracic surgery. Eur J Cardiothorac Surg. 2006;30:852–872. 26. Bradley D, Creswell LL, Hogue CW Jr, Epstein AE, Prystowsky EN, Daoud EG; American College of Chest Physicians. Pharmacologic prophylaxis: American College of Chest Physicians guidelines for the prevention and management of postoperative atrial fibrillation after cardiac surgery. Chest. 2005;128:39S–47S. 27. Oka T, Ozawa Y, Ohkubo Y. Thoracic epidural bupivacaine attenuates supraventricular tachyarrhythmias after pulmonary resection. Anesth Analg. 2001;93:253–259. 28. Jiang Z, Dai JQ, Shi C, Zeng WS, Jiang RC, Tu WF. Influence of patient-controlled i.v. analgesia with opioids on supraventricular arrhythmias after pulmonary resection. Br J Anaesth. 2009;103: 364–368. 29. Terzi A, Furlan G, Chiavacci P, Dal Corso B, Luzzani A, Dalla Volta S. Prevention of atrial tachyarrhythmias after non-cardiac thoracic surgery by infusion of magnesium sulfate. Thorac Cardiovasc Surg. 1996;44:300–303. 30. Amar D, Zhang H, Heerdt PM, Park B, Fleisher M, Thaler HT. Statin use is associated with a reduction in atrial fibrillation after noncardiac thoracic surgery independent of C-reactive protein. Chest. 2005;128:3421–3427.
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For Whom Is Lung Volume Reduction Surgery Effective? Keith S. Naunheim
Background Lung volume reduction (LVR) was first conceived by Brantigan1 in the early 1950s and reintroduced by Cooper2 in 1995 with excellent results in 20 patients. Multiple single institution studies were published in the ensuing two years all of which supported the supposition that LVR provided significant improvements in spirometry, exercise capacity and quality of life.3–8 However these papers described small numbers of patients with differing inclusion criteria that were treated with various surgical techniques with short and often incomplete follow-up. Although initially it was felt to be important that candidates exhibit heterogeneous distribution of emphysema with predominately upper lobe disease and no comorbidities, many investigators began broadening the narrow inclusion criteria and reported acceptable results with high risk patients.9,10 The procedure rapidly became widely disseminated and began being performed in the community hospital setting on an ever sicker and more fragile subset of patients with end stage emphysema. All these factors probably contributed to the damning report of poor clinical results of LVR performed in the Medicare population as reported to Congress by Shalala,11 who at that time was Secretary of Health and Human Services. In that report a high operative mortality rate and increased utilization of hospital services following LVR shed doubt on the clinical benefit and safety of LVR. These poor results led to a subsequent moratorium on reimbursement for LVR, and the Medicare administration insisted that reimbursement would
not be reconsidered until peer reviewed publications (preferably randomized controlled trials [RCT]) had definitively proven the efficacy of LVR and identified the appropriate patient population. The major questions to be answered in this chapter are identical to that posed by Medicare over 10 years ago: is lung volume reduction surgery effective and, if so, in what patient subset?
Search Strategy The literature review included the combined citations from an OVID Medline search using three strategies with a 1imitation to the modern LVR era (1995–2009). The first search strategy was Heading Pulmonary emphysema, subheading Surgery, Limit Human, English language. The second strategy was Heading Pulmonary disease, chronic obstructive, subheading Surgery, Limit Human, English language. The final search utilized just the specific term Lung reduction.
Literature Analysis The multiple single institution papers noted above were guilty of the noted shortcomings and must all be considered only mediocre quality. There have been some additional prospective studies documenting the results of larger single institution studies12,13 with longer (3–5 year) follow-up, as well as multi-institutional papers documenting results in hundreds of cases both short term and long.14,15
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However, all these articles suffer from inconsistent follow-up, a lack of medical controls, and a survivorship bias (since one cannot measure spirometry in dead or severely disabled people, results may appear artifactually improved). Thus, none rise above the level of moderate evidence quality. There have been five prospective RCTs reported on LVR surgery (Table 20.1). The earliest was that of Criner and colleagues16 in which 37 patients with diffuse end stage emphysema were randomized into either a medical arm (standard medical therapy plus pulmonary rehabilitation, n = 18) or bilateral lung volume reduction via median sternotomy (n = 19). Heterogeneity of disease with upper lobe predominance of disease was not a requirement for inclusion in this study. All patients underwent an initial course of pulmonary rehab which resulted in no significant improvement in spirometry or exercise capacity. Continued rehab in the medical group resulted in higher maximal oxygen consumption values which trended towards significance (p = 0.08). The surgical group had significant (p < 0.005) improvement in multiple spirometric and volumetric indices such as forced expiratory volume in 1 s (FEV1), functional vital capacity (FVC), and residual volume (RV). However, there were no significant improvements in oxygenation or exercise capacity measurements. In this study, crossover from the medical to the surgical arm was allowed after 6 months and this
occurred in 13 of the 18 medical cohort patients. Once the results of the crossover patients were added to those included initially in the surgical cohort, the investigators identified significant improvements in maximal oxygen consumption and exercise capacity as measured by the 6 min walk test (6MW). Although this study was elegantly and thoughtfully performed, it must be considered far from definitive not only due to the very small patient numbers but also to the fact that the intentional crossover strategy employed prevented any long-term follow-up with regard to function or survival. This study provides moderate quality evidence supporting LVR. Geddes and colleagues in 200017 authored a paper outlining results in 48 end stage emphysema patients randomly assigned to LVR surgery or continued medical therapy. The patients all had diffuse emphysema and there was no requirement for upper lobe predominance. All patients within the study first underwent optimization of their medical regimen (bronchodilator, steroids, oxygen, and antibiotics when indicated) followed by a 6 week course of pulmonary rehabilitation. After reassessment patients were randomized either to an open bilateral lung volume reduction procedure via median sternotomy or to continued medical therapy. Unfortunately, 5 of the initial 15 randomized patients expired early in the trial. Each of these patients were noted to have very
Table 20.1 Clinical results of LVR RCT Study Criner (excl) Criner (incl) Geddes Pompeo OBEST-CLVR NETT HR NETT NHR
Pts
FEV1
FVC
RV
DLCO
pCO2
6MW
Trdml
Dyspnea
QOL
Followup
Survival
EQ
37 37 48 60 83 140 1,078
+ + + + + NC +
+ + NC + NR NR +
+ + + + + NR +
+ + NC NR + NR +
+ + NC NC + NR +
NC + + + + NC +
NC + NR + NR NC +
NR NR NR + + NR +
NC + + NR + NC +
3 mos 3 mos 12 mos 6 mos 6 mos 12 mos 60 mos
NC NC NC NC NC +
Mod Mod Low Low Low High High
+ = clinically significant improvement documented - = clinically significant decrement NR = not reported NC = no change Pts number of randomized patients; FEV1 forced expiratory volume in 1 second; FVC forced vital capacity; RV residual volume; DLCO diffusing lung capacity for carbon monoxide; pCO2 partial pressure of carbon dioxide; 6MW six minute walk; Trdml treadmill exercise test; Dyspnea formalized dyspnea testing; QOL quality of life testing; Follow-up duration of follow-up; Survival survival comparison of LVR to controls; EQ level of evidence quality; excl results excluding crossover patients; incl results including crossover patients; CLVR Canadian Lung Volume Reduction study; OBEST Overholt Blue Cross Emphysema Surgical Trial; NETT National Emphysema Treatment Trial; HR high risk subset; NHR non high risk subset; Mod moderate
20. For Whom Is Lung Volume Reduction Surgery Effective?
poor exercise capacity (6 min walk < 150 m) as well as a predicted diffusing capacity for carbon monoxide of <30%. Following this discovery, the entry criteria were altered, but these early deaths caused the overall study mortality to be very high at 17% (five surgical, three medical, p = NS). This study also contained a crossover option, and 6 of the 21 medical patients alive at 6 months proceeded to LVR. The clinical results were mixed. Significant improvements were noted in quality of life assessment evaluated by Short Form 36 (SF36) up to 12 months, FEV1 at 3 months but not thereafter, and in RV throughout 12 months of follow-up. However there was no improvement in pO2, pCO2 or exercise capacity. The authors concluded that LVR offered significant short-term clinical benefit to appropriately selected patients but many critics of the study were less enthusiastic. They felt that the small sample size, variable inclusion criteria, high operative mortality, lack of exercise improvement, and failure to provide even midterm follow-up (due to crossover) mitigated any value demonstrated by the study, and this trial must be categorized as low quality for purposes of this review. An Italian RCT was reported by Pompeo and associates,18 who randomized 60 patients with diffuse end stage emphysema into surgical and medical cohorts. Patients randomized to the medical cohort underwent optimization of medical care and at least 6 weeks of pulmonary rehabilitation. The surgical group did not undergo rehabilitation but proceeded directly either to bilateral thoracoscopic (n = 17) or unilateral (in those with marked asymmetric disease, n = 13) LVR. Mortality was similar at 6 months (surgical 2/30, medical 1/30), but only the surgery grouped exhibited significant improvement in spirometry (FEV1, FVC), volumes (RV), pO2, dyspnea and exercise capacity. Crossover was allowed and occurred in 44% of the medical cohort, making comparisons problematic after the 6 month mark and any assessment of survival benefit impossible. Many criticized the study because it included both bullous and nonbullous emphysema, which in these patients was diffuse in nature rather than heterogeneous in distribution. Also, the motivation and effort of patients relegated to the medical arm was questioned, as these subjects may have delivered a suboptimal effort on follow-up testing in hopes of being offered
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surgical intervention at an earlier interval. Although this study presented encouraging findings, the small sample size, short follow-up, the allowance of crossover (with potential associated bias) and variations in both inclusion criteria and surgical technique detract from the overall quality of the evidence, and this study is graded as low quality. Another prospective RCT published was the combined results of two separate but very similar RCTs, one based in Canada (the Canadian Lung Volume Reduction trial, CLVR) and one in Massachusetts (Overholt Blue Cross Emphysema Surgery Trial, OBEST).19 Both studies enrolled patients with severe end stage emphysema but only the OBEST trial required heterogeneity as an inclusion criteria; CLVR enrolled patients with diffuse emphysema. Unfortunately, accrual was inadequate for both trials separately, but in hopes of salvaging some value from the expended time, money and effort, data from the two trials were combined and blended as best could be achieved. Inclusion criteria were quite similar for the two trials but because the OBEST trial specified a 2:1 allocation of LVR and medical therapy respectively, the distribution of patients between two cohorts was somewhat uneven. Ninety three patients were enrolled (CLVR 58, OBEST 35) and eventually randomized into the surgical (n = 54) and medical (n = 39) arms. Surgery consisted of bilateral stapled LVR performed via sternotomy in all but six patients who underwent a thoracoscopic procedure. Mortality at 6 months was no different between the medical and surgical patients. Unfortunately, no long-term results could be ascertained because both studies contained a crossover option for patients randomized to the medical cohort, which allowed for them to undergo LVR after 6 months if they were unsatisfied with medical therapy. However, at 6 months the surgical cohort demonstrated significant improvements in spirometry (FEV1), lung volumes (RV, total lung capacity [TLC]), diffusion parameters (pCO2, DLCO), dyspnea severity, quality of life with regard to physical functioning (SF-36) and exercise capacity (6MW). Overall, this paper, which represents a meta-analysis of the “post hoc” blending of two inadequately populated trials, suggested marked short term clinical improvement following LVR, results consistent with the prior RCTs.
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Overall evidence quality for this paper is low due to small numbers, inconsistent inclusion criteria, short duration of follow-up, and the post hoc nature of the analysis. The National Emphysema Treatment Trial (NETT) is the last and largest of the RCTs dealing with LVR. The intent of the study was not just to evaluate the effect of LVR but also to identify the optimal candidates. It involved 17 institutions which enrolled 1,218 patients with end stage emphysema, both diffuse and heterogeneous. The first NETT publication was prompted by the Data Safety and Monitoring Board, which noticed a specific high risk subset of patients that demonstrated poor results.20 Those patients with FEV1 <20% and who also had either homogeneous disease or a DLCO <20% were found, at the 6 month follow-up, to have a high mortality rate and to exhibit minimal if any improvement following surgery (evidence quality high). After this high risk group was identified, such patients were excluded from enrollment and the major positive findings resulting from the NETT trial were gleaned from the remaining 1,078 “non high risk” patients. Papers detailing the midterm21 and long-term22 results of the NETT demonstrated clinically significant improvements after LVR in spirometry (FEV1, FVC), lung volumes (RV), diffusing parameters (DLCO, pCO2), oxygenation (pO2, O2 utilization), quality of life (SF-36, Quality of Well Being survey), dyspnea (St. George’s Respiratory Quotient), exercise capacity (6 min walk, treadmill exercise test) and long-term survival. These papers are all of high quality and demonstrate definitively that LVR, when performed in appropriately selected patients, is likely to provide marked objective and subjective improvements in symptoms, exercise capacity and survival. As important as these results was the identification of prognostic factors predictive of success and failure. Two factors were identified as being profoundly predictive of improvement: the distribution of emphysema and the level of baseline exercise capacity. Patients with upper lobe predominance had better results than those without, and patients with low exercise capacity (using gender corrected thresholds) were more likely to benefit from LVR than those with high capacity. There was significant interplay between these two factors, and four distinct subgroups ultimately were
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identified: upper lobe predominance with low exercise capacity, upper lobe predominance with high exercise capacity, non-upper lobe predominance with low exercise capacity, and non upper lobe predominance with high exercise capacity. Patients with upper lobe predominance were very likely to benefit from LVR with respect to both exercise and symptoms, but those who also had low exercise capacity additionally showed a marked survival advantage as great as 15% at 5 years. Thus, this was the first RCT to identify who would and would not be a good candidate for LVR. Medicare has based its reimbursement policies wholly on the results of this trial and thus will pay only for bilateral LVR in patients with advanced upper lobe predominant emphysema who meet the NETT criteria; they will not pay for the procedure in those with lower lobe disease, alpha 1 antitrypsin (A1AT), homogeneous disease, extremely advanced disease (both FEV1 <20% and DLCO <20% predicted) and those with a contraindication to bilateral procedure (i.e. asymmetric unilateral disease or those with bilateral disease with history of a prior thoracotomy). However, one must be cautious of the potential tyranny of the RCT. One must not lose sight of the fact that the NETT, though a high quality study, was limited to an elderly population, and its results may not be universally applicable to all patients. For example, while one NETT publication documented a high mortality and lack of prolonged benefit from LVR performed in patients with A1AT,23 Weder and colleagues have documented good clinical results in selected patients with A1AT disease24 (moderate quality). The disparity in results may be due to the increased mean age in the NETT patients as compared to Weder’s patients (66 vs. 56 years), a difference that results from the funding algorithm of the NETT, which essentially limited enrollment to the elderly Medicare population. Similarly, the NETT was designed to evaluate solely bilateral LVR, as prior studies suggested that this strategy provides greater benefit than the unilateral approach. Thus, when Medicare decided to resume coverage for LVR because of the clinical benefit demonstrated in the NETT, the agency limited coverage to bilateral LVR procedures only because the value of unilateral LVR had not been proven in the setting of a large RCT. The CMS decision was carved in stone despite
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20. For Whom Is Lung Volume Reduction Surgery Effective?
many non-randomized single and multi-institution series which have documented excellent short and midterm results for unilateral LVR.3–6,14,15,25 As noted previously, these studies were far from definitive (evidence quality moderate) due to their size, differing inclusion criteria, lack of a control group and limited nature of follow-up; however such shortcomings do little to mitigate the fact that unilateral LVR in patients with end-stage emphysema results in marked clinical improvement in most patients for up to five years following LVR. Unilateral LVR is still not covered by Medicare. There are still other patient subsets which might actually benefit from LVR despite the lack of definitive confirmation in the form of an RCT. Ciccone13 (high quality) and McKenna26 (moderate quality) had both previously emphasized the importance of a heterogeneous distribution of emphysema and the NETT trial confirmed that the best results occurred in those patients with upper lobe predominance of emphysema. However, Weder27 rather convincingly argues that, throughout a five year follow-up interval, selected patients with homogeneous emphysema undergoing bilateral LVR demonstrate marked clinical improvement which is only slightly less than that enjoyed by patients with heterogeneous emphysema (evidence quality moderate). Similarly, Meyers and associates have shown that selected patients in the “high risk” subset identified in the NETT (those with both FEV1 and DLCO <20% predicted) could safely undergo bilateral LVR with reliably good results (evidence equality moderate).28 Because such patients were not found to benefit from LVR in the NETT, Medicare refuses to reimburse for LVR in this patient subset. Thus, while the NETT can be considered the most definitive trial to date, rigidly assuming that the provision of LVR should be strictly limited to a bilateral procedure performed on patients with bilateral symmetric upper lobe predominant emphysema would be doing the end stage emphysema population a disservice.
Summary and Recommendations Bilateral LVR provides clinically significant impr ovements in quality of life and exercise capa city for patients with heterogeneous upper lobe
predominant emphysema and is safe [evidence quality high]. Additionally, significant survival benefit is enjoyed by patients in the low exercise capacity subset [evidence quality high]. A strong recommendation is made for bilateral LVR in patients with upper lobe predominant emphysema [recommendation grade 1A]. Bilateral LVR provides clinically significant improvements in quality of life and exercise capacity for highly selected patients with homogeneous emphysema and is safe [evidence quality moderate]. A weak recommendation is made for bilateral LVR in patients with homogeneous emphysema [recommendation grade 2B]. Unilateral LVR provides clinically significant improvements in quality of life and exercise capacity for selected patients with upper lobe predominant emphysema and is safe [evidence quality moderate]. A weak recommendation is made for unilateral LVR in patients with upper lobe predominant emphysema [recommendation grade 2B].
A Personal View of the Data One of the major achievements of the NETT was the demonstration of the importance of appropriate patient selection. End stage emphysema patients comprise a very fragile patient population with a predisposition for life threatening complications of many types including those within the respiratory, cardiac and gastrointestinal realms. The best results are achieved in those patients who have upper lobe predominant disease with the absence of any significant comorbidity. Prior pleural inflammatory disease (i.e. empyema) or previous intrathoracic intervention (thoracotomy, pleurodesis) are contraindications to LVR. Although Medicare refuses to pay for unilateral procedures performed even when indicated (asymmetric or unilateral disease; history of prior thoracotomy), we still believe such patients can enjoy enough subjective (dyspnea, QOL) and objective (SaO2, exercise capacity) benefit to warrant unilateral LVR. Unfortunately, very few patients are being referred for LVR nationally. Experts are uncertain why this is but many believe that physicians essentially stopped referring patients for LVR following
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publication of the initial NETT paper documenting poor results in high risk patients.20 Despite the two subsequent papers21,22 documenting marked benefits in survival, exercise capacity and QOL, referrals remain infrequent and most LVR experts feel end-stage emphysema patients are being done a disservice. Pulmonologists appear to be waiting for the minimally invasive bronchoscopic version of LVR to be perfected prior to referring such patients for intervention. Although clinical results have been reported for the three current bronchoscopic methods (endobronchial valve placement, bronchial fenestration and instillation of biologic irritants and coagulants to achieve sclerosis and bronchial occlusion), none of these three methods approach the efficacy of surgical LVR and thus it appears that the end-stage emphysema population will continue to be neglected for the near future.
Bilateral LVR improves quality of life and exercise capacity in patients with heterogeneous upper lobe predominant emphysema, additionally improves survival in patients who also have low exercise capacity, and is safe [evidence quality high]. A strong recommendation is made for bilateral LVR in patients with upper lobe predominant emphysema [recommendation grade 1A].
Bilateral LVR improves quality of life and exercise capacity in selected patients with homogeneous emphysema and is safe [evidence quality moderate]. A weak recommendation is made for bilateral LVR in patients with homogeneous emphysema [recommendation grade 2B].
Unilateral LVR improves quality of life and exercise capacity in selected patients with upper lobe predominant emphysema and is safe [evidence quality moderate]. A weak recommendation is made for unilateral LVR in patients with upper lobe predominant emphysema [recommendation grade 2B].
References 1. Cooper JD, Trulock EP, Triantafillou AN, Patterson GA, Pohl MS, Deloney PA, Sundaresan RS, Roper CL. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg. 1995;109:106–119. 2. Brantigan OC, Mueller E. Surgical treatment of pulmonary emphysema. Am Surg. 1957;23:789–804. 3. Keenan RJ, Landreneau RJ, Sciurba FC, Ferson PF, Holbert JM, Brown ML, Fetterman LS, Bowers CM. Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg. 1996;111: 308–315. 4. McKenna RJ Jr, Brenner M, Fischel RJ, Gelb AF. Should lung volume reduction surgery be unilateral or bilateral? J Thorac Cardiovasc Surg. 1996;112:1331–1339. 5. Naunheim KS, Keller CA, Krucylak PE, Singh A, Ruppel G, Osterloh JF. Unilateral video-assisted thoracic surgical lung reduction. Ann Thorac Surg. 1996;61:1092–1098. 6. Fujita RA, Barnes GB. Morbidity and mortality after thoracoscopic pneumonoplasty. Ann Thorac Surg. 1996;62:251–257. 7. Argenziano M, Moazami N, Thomashow B, Jellen PA, Gorenstein LA, Rose EA, Weinberg AD, Steinglass KM, Ginsburg ME. Extended indications for volume reduction pneumoplasty in advanced emphysema. Ann Thorac Cardiovasc Surg. 1996;62:1588–1597. 8. Wilkens H, Demertzis S, Koenig J, Leitnaker CK, Schaefers HJ, Sybrecht GW. Lung volume reduction surgery versus conservative treatment in severe emphysema. Eur Respir J. 2000;16:1043–1049. 9. Eugene J, Dajee A, Kayaleh R, Gogia HS, Dos Santos C, Gazzaniga AB. Reduction pneumonoplasty for patients with a forced expiratory volume in 1 second of 500 milliliters or less. Ann Thorac Surg. 1997;63: 186–190. 10. Wisser W, Klepetko W, Senbaklavaci O, Wanke T, Gruber E, Tschernko E, Wolner E. Chronic hypercapnia should not exclude patients from lung volume reduction surgery. Eur J Cardio-Thorac Surg. 1998;14: 107–112. 11. Heath Care Financing Administration. Report to Congress. Lung Volume Reduction Surgery and MediCare Coverage Policy: Implications of Recently Published Evidence. Baltimore, MD: Heath Care Financing Administration; 1998. 12. Fujimoto T, Teschler H, Hillejan L, Zaboura G, Stamatis G. Long-term results of lung volume reduction surgery. J Cardiothorac Surg. 2002;21:483–488. 13. Ciccone AM, Meyers BF, Guthrie TJ et al. Long-term out- come of bilateral lung volume reduction in 250 consecutive patients with emphysema. J Thorac Cardiovasc Surg. 2003;125:513–525. 14. Lowdermilk GA, Keenan RJ, Landreneau RJ, Hazelrigg SR, Bavaria JE, Kaiser LR, Keller CA, Naunheim KS. Comparison of clinical results for unilateral and bilateral thoracoscopic lung volume reduction. Ann Thorac Surg. 2000;69:1670–1674.
20. For Whom Is Lung Volume Reduction Surgery Effective? 15. Naunheim KS, Kaiser LR, Bavaria JE, Hazelrigg SR, Magee MJ, Landreneau RJ, Keenan RJ, Osterloh JF, Boley TM, Keller CA. Long-term survival after thoracoscopic lung volume reduction: a multi-institutional review. Ann Thorac Surg. 1999;68:2026–2031. 16. Criner GJ, Cordova FC, Furukawa S, Kuzma AM, Travaline JM, Leyenson V, O’Brien GM. Prospective randomized trial comparing bilateral lung volume reduction surgery to pulmonary rehabilitation in severe chronic obstructive pulmonary disease. Am J Resp Crit Care Med. 1999;160:2018–2027. 17. Geddes D, Davies M, Koyama H, Hansell D, Pastorino U, Pepper J, Agent P, Cullinan P, MacNeill SJ, Goldstraw P. Effect of lung-volume-reduction surgery in pati ents with severe emphysema. N Engl J Med. 2000;343: 239–245. 18. Pompeo E, Marino M, Nofroni I, Matteucci G, Mineo TC. Reduction pneumoplasty versus respiratory rehabilitation in severe emphysema: a randomized study. Pulmonary Emphysema Research Group. Ann Thorac Surg. 2000;70:948–953. 19. Miller JD, Berger RL, Malthaner RA, Celli BR, Goldsmith CH, Ingenito EP, Higgins D, Bagley P, Cox G, Wright CD. Lung volume reduction surgery vs medical treatment: for patients with advanced emphysema. Chest. 2005;127:1166–1177. 20. National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med. 2001;345:1075–1083. 21. National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volumereduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348:2059–2073. 22. Naunheim KS, Wood DE, Mohsenifar Z, Sternberg AL, Criner GJ, DeCamp MM, Deschamps CC, Martinez FJ,
185 Sciurba FC, Tonascia J, Fishman AP, National Emphy sema Treatment Trial Research Group. Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial research group. Ann Thorac Surg. 2006;82: 431–443. 23. Stoller JK, Gildea TR, Ries AL, Meli YM, Karafa MT for the National Emphysema Treatment Trial Research Group. Lung volume reduction surgery in patients with emphysema and alpha-1 antitrypsin deficiency. Ann Thorac Surg. 2007;83:241–251. 24. Tutic M, Konrad E. Bloch, Lardinois D, Brack T, Russi EW, Weder W. Long-term results after lung volume reduction surgery in patients with alpha 1-antitrypsin deficiency. J Thorac Cardiovasc Surg. 2004;128: 408–413. 25. Meyers BF. Sultan PK. Guthrie TJ. Lefrak SS. Davis GE. Patterson GA. Cooper JD. Yusen RD. Outcomes after unilateral lung volume reduction. Ann Thorac Surg. 2008; 86:204–211. 26. McKenna RJ Jr, Brenner M, Fischel RJ, Singh N, Yoong B, Gelb AF, Osann KE. Patient selection criteria for lung volume reduction surgery. J Thorac Cardiovasc Surg. 1997;114:957–964. 27. Weder W, Tutic M, Lardinois D, Jungraithmayr W, Hillinger S, Russi EW, Bloch KE. Persistent benefit from lung volume reduction surgery in patients with homogeneous emphysema. Ann Thorac Surg. 2009;87:229–236. 28. Meyers BF, Yusen RD, Guthrie TJ, Patterson GA, Lefrak SS, Davis GE, Cooper JD. Results of lung volume reduction surgery in patients meeting a national emphysema treatment trial high-risk criterion. J Thorac Cardiovasc Surg. 2004; 127:829–835.
21
Support Therapy for Lung Failure James E. Lynch and Joseph B. Zwischenberger
The desire to find a way to support a failing lung has existed since the first physician watched his patient succumb to an acute lung injury; however, practical means to support the failing lung are relatively new. Most of the ideas, techniques, and equipment grew as an extension of cardiopulmonary bypass. From this core technology, many spin-off techniques have been developed. In this chapter we will discuss and evaluate the historical and current trends in lung support, from total gas exchange devices to devices meant only to augment gas exchange. Although some of these techniques have been around for 35 years, few have undergone rigorous scientific validation. With this in mind, we will highlight the landmark trials and present a balanced argument for their use in patients. It should be noted that the essence of evidence based medicine is data; in order for sufficient data to exist, a technology must be mature, standardized and disseminated. Many of the extracorporeal techniques in this chapter are cutting edge and, as such, do not have the necessary trials to generate the amount of data to allow evaluation in an evidence based manner. A grade of “weak” recommendation is not equivalent to harmful and should be viewed as a lack of data as opposed to a judgment on the efficacy of the technique. To identify potentially relevant citations, two reviewers (JEL, JBZ) independently searched Ovid MEDLINE, Ovid MEDLINE Daily Update, and OvidMEDLINE In-Process & Other Non-Indexed Citations from 1996 to January 2010 using the following Medical Subject Headings (MeSH) and text words: extracorporeal membrane oxygenation; paracorporeal artificial lung; artificial lung; arteriovenous
carbon dioxide removal; venovenous carbon dioxide removal; interventional lung assist; pumpless extracorporeal lung assist; and carbon dioxide removal. The search included both human and animal studies. The references of each article were manually reviewed for additional studies.
Extracorporeal Membrane Oxygenation ECMO It was a logical extension for early investigators that if the heart and lungs could be supported for a few hours in the operating room to facilitate cardiac surgery, that the same technique could be used on failing lungs in the intensive care unit. The first successful application of this technique, which would later be known as ECMO, was in a young trauma victim with acute respiratory distress syndrome (ARDS) who was successfully supported for 3 days.1 Although this first patient supported was an adult, ECMO would find its place early in the neonatal population. Bartlett et al. showed that a neonate with a persistent shunting of blood from right to left could be supported successfully with ECMO.2 Disease entities including meconium aspiration syndrome, pneumonia, sepsis, and congenital diaphragmatic hernia encompass the bulk of the patients supported. Early success and favorable clinical trials3–5 secured the role of ECMO in the treatment of neonatal respiratory failure. To date, over 23,000 neonates have been supported with ECMO for respiratory failure with an overall survival of 85%.6 The evidence is strong for the use
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of ECMO in the neonate with respiratory failure. It should exist as part of the algorithm at any center that cares for large numbers of high risk neonates. Even with this evidence, the number of neonates supported each year continues to decline, not because of a lack of efficacy, but in large part because of new support techniques such as nitric oxide, surfactant, and high frequency oscillatory ventilation (HFOV). Pediatric ECMO has been utilized for 30 years in severe respiratory failure and to date over 4,100 pediatric respiratory failure cases have been performed with an overall survival rate of 64%.6 Recently, ECMO for cardiac support in congenital heart patients and following staged repairs has seen rapid growth; in fact, more pediatric cardiac patients have been supported than pediatric respiratory patients. Over 8,100 combined cases of neonatal and pediatric cardiac support have been performed with a 60% survival rate.6 Indications for cardiac ECMO include failure to wean from cardiopulmonary bypass, cardiogenic shock, or cardiac arrest following cardiac surgery.7–10 ECMO has become synonymous with congenital repair. The evidence so far is not as convincing for the use of ECMO in the adult population. Although the first patient supported with ECMO was an adult, ECMO as a support technique for adult respiratory support did not enjoy early success. Trials in the 1970s and 1980s were not favorable for the use of ECMO as compared to conventional management. The earliest multicentered randomized trial of ECMO versus conventional management for respiratory failure was sponsored by the National Institutes of Health from 1975 to 1979.11 This trial was stopped early after just 90 of the planned 300 patients were enrolled. Survival in both the conventional and the ECMO groups was 10%. Problems with the study design included inclusion of patients with irreversible lung disease, inappropriately high ventilator settings in the ECMO group, excessive bleeding in the ECMO group, and a lack of experience in some centers with ECMO. However, the trial did demonstrate the ability of ECMO to support gas exchange for a number of days. In hindsight, this trial was done too early, involved poorly selected patients, and is not representative of how ECMO is performed today. Yet many still judge the technique by this trial from 30 years ago, and the results of this study
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still stifle enthusiasm for adult ECMO today. Recently, a randomized controlled trial of adult ECMO12 was published involving 180 patients randomized to either conventional management in a tertiary care center or to referral for ECMO at a single center. Although as a whole the ECMO group outcomes were favorable compared to the control group in terms of survival and the treatment appeared to be cost-effective, the intent to treat nature of the study weakened the conclu sions.13 Adult ECMO is often viewed as a “last resort” therapy with center-specific entry and exclusion criteria. Hemmila and coworkers14 reported their experience with 255 adult patients with ARDS supported with ECMO with 52% of the patients surviving to discharge. This retrospective study only included the most severely ill ARDS patients (PaO2/fiO2 £ 100, A-aDO2 ³ 600) who failed maximum medical management. This report and other observational studies15–17 have demonstrated the ability of specialized centers to produce betterthan-expected results for patients with ARDS when utilizing ECMO. The use of ECMO is likely to continue in specialized centers but unlikely to become a widespread treatment option for patients with ARDS until more rigorous evidence demonstrates efficacy in adults. Barriers to the widespread use of adult ECMO have been limited by the high cost of equipment required, the need for one-on-one nursing care as well as an ECMO specialist nurse or respiratory therapist trained to manage the ECMO equipment, and the lack of proof of efficacy from a large randomized trial. Without the evidence from a randomized, controlled trial impacting mortality, some hospitals are unwilling to incur the expense or manpower associated with an adult ECMO program. In addition, many of the existing ECMO centers were established for neonatal ECMO patients and consist of nurses and respiratory therapists who are not experienced with adults or are located in dedicated children’s hospitals that are unable to care for adult patients. ECMO continues to evolve as a support technique with improved equipment18–19 and better patient selection. It has also led to the use of offshoot extracorporeal techniques for the treatment of less severe respiratory failure, COPD, and as a bridge to lung transplant.
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21. Support Therapy for Lung Failure
Arterial-Venous Carbon Dioxide Removal (AVCO2R) Arterial-venous carbon dioxide removal is a gas exchange technique that allows for CO2 homeostasis while maintaining the gentle ventilation techniques shown to reduce mortality in ARDS patients.20–22 With small cannulas placed in the femoral artery and vein, a simple arterial-to-venous shunt is created. A low-resistance gas exchange device is interposed, and blood (<1.5 L/min) moves through the device because of the pressure difference between the arterial and venous system, allowing for removal of almost all metabolically produced CO2.23–24 AVCO2R provides some of the gas exchange benefits of ECMO, but does not require a pump, a dedicated specialist, or complex equipment. Early studies have shown that AVCO2R provides nearcomplete removal of metabolically produced CO2 in patients with acute respiratory failure.25 The European experience with AVCO2R, termed there as either pumpless extracorporeal lung assist (pECLA) or interventional lung assist (iLA), has outpaced the use of AVCO2R in the United States. Early reports of the first 70 patients were favorable26–27 although complication rates approaching 30% have been reported by other groups.28 AVCO2R has also been used for emergency transport of ARDS patients,29 as a bridge to transplant,30 and as a way to further reduce tidal volumes in ARDS patients.31 Few formal trials have been undertaken in Europe and no tracking registry exists, although an algorithm has recently been proposed as to when AVCO2R should be used.32 Hard data on the number of patients and their outcomes is scant, but a growing population of patients treated with AVCO2R are starting to make an impact in the literature through case series and case reports. Prospective, randomized outcomes studies will be necessary to establish the risk/benefit of this technique.
Venovenous Carbon Dioxide Removal (VVCO2R) The lessons of AVCO2R included the realization that, with the new generation gas exchangers, blood flows under 2 L/min were all that was
required to remove CO2. A drawback of AVCO2R was the need for a cannula in the femoral artery. This not only posed a risk if dislodged but also led to limb ischemia in some patients.28 This led to an adaptation of the AVCO2R technique termed venovenous carbon dioxide removal. In VVCO2R the arterial cannula is not used; instead, a conventional double lumen ECMO cannula that is percutaneously placed (usually in the internal jugular vein) is utilized in combination with a small centrifugal pump.33 In reality, VVCO2R is essentially limited venovenous (VV) ECMO. In contrast to VV ECMO, the flows utilized in VVCO2R are significantly less (<2.5 L/min blood flow), but because of improved cannula designs18 less recirculation occurs, allowing improved gas exchange at the lower flows. A low resistance gas exchanger replaces the previously high resistance membrane oxygenator, and the target level of anticoagulation is less (150–180 s Activated Clotting Time (ACT)). Overall, the system is much simpler, has lower circuit pressures, less blood flow, less recirculation, and a better safety profile than traditional ECMO. The simplicity of this system allows for its use in patients that are less severely ill than those placed on ECMO. This technique has been utilized in a patient with a COPD exacerbation,34 a post transplant patient with acute graft dysfunction (unpublished data), as a bridge to transplant in a COPD patient in which the patient was ambulatory and able to exercise,35 and as an adjunct to ventilation in ARDS patients. The promise of this technique includes avoidance of an arterial cannula with the associated limb ischemia, potential for ambulation, and no specialized team required, reducing overall costs. As technology continues to advance and cannula and gas exchanger design becomes more efficient, it is likely that most adult ECMO will be replaced by this limited version of gas exchange. To date, no randomized trials and few case reports exist about this technique.
Total Artificial Lung (TAL) Lung transplantation continues to provide the only treatment option for patients with chronic irreversible lung disease. No “bridge-to-transplant” device is currently widely available for end stage
190
lung disease. A total artificial lung would be the equivalent to dialysis for end stage renal disease or ventricular assist devices (VADs), which serve as a bridge to cardiac transplantation. This need is further illustrated by the high mortality and limited supply associated with the lung transplant waiting list.36 As technology advances, the first TALs will be utilized as a short-term bridge to recovery from a fatal but potentially recoverable injury, such as ARDS or smoke inhalation, lessening ventilatorinduced lung injury and converting a lethal lung injury into a recoverable one.37 Another scenario may be use of TAL as a short-term (weeks to months) bridge-to-transplant in the deteriorating patient on the transplant list but not expected to live until a donor lung becomes available. Next generation TAL technology could allow a phase of longer term bridge-to-transplant and patient rehabilitation, including restoring patients to ambulatory status, reversing end-organ dysfunction and allowing rebuilding of muscle mass, improving the patient performance status prior to transplant. Once long-term bridge to transplant becomes a reality, then the TAL will enter a final phase in its evolution as an alternative to transplant. VADs are currently entering this phase.38 The progressive development of a TAL for bridgeto-recovery, bridge-to-transplant, and eventually as effective palliation for end-stage lung disease is on the horizon. TALs are still in the early development phase. None are commercially available and many are still in bench and early animal testing. Ideal design and placement characteristics have yet to be decided. Most agree that the ideal design would include easy placement, preferably without the need for cardiopulmonary bypass, long term durability, easy change out, and minimal right heart strain. Several iterations of pumpless TALs have been tested,39–41 with most inducing an unacceptable amount of right heart strain. Integrated versions of the TALs and blood pumps seem to hold the most promise.42 Ideal placement and blood flow configurations still remain unsolved. Current options include inseries with the native lung (right atrium to pulmonary artery, or RA-PA), or in-parallel to the native lung (pulmonary artery to left atrium, or PA–LA). A pulmonary artery to pulmonary artery
J.E. Lynch and J.B. Zwischenberger
(PA–PA) configuration has been tried but abandoned due to excessive right heart strain and the relatively short human common PA. While all of the configurations create right heart strain, mathematical modeling by Boschetti and colleagues found the PA–PA configuration resulted in the most increase in right heart power.43 One approach to decrease right heart strain in a pumpless TAL is the PA–LA configuration, which creates a parallel circuit between the TAL and the native lung. A portion of blood is diverted to the TAL while the rest perfuse the native lung. The amount of blood flow to the TAL is dependent on the resistance in both circuits (native lung PVR and TAL resistance). The pressure gradient between the PA and the left atrium passively drives blood flow.44 Studies in healthy sheep have demonstrated an average of 30%-50% of cardiac output was diverted through the TAL; however, flow varied significantly from day 2 to day 6 after implant.45 This variable flow, resulting from fluctuating resistance, means that the PA–LA configuration provides an unpredictable level of support. Since large animal models of chronic pulmonary hypertension are not currently available, the performance of the PA–LA configuration in a patient population with pulmonary hypertension is unknown.46 A hybrid PA–LA configuration was also considered, splitting the blood return from the TAL to both the distal PA and the left atrium, but experiments demonstrated both variable blood flow and high right heart impedance.47 The RA–PA provides full support but requires a pump. Both integrated and component systems have been tested. The single unit design enhances the goal of ambulation and easy change out. The component systems separate the pump, allowing for easy trouble shooting and change out of each component separately.44 Our group has successfully mated a small axial flow pump to a commercially available gas exchange device in a RA–PA configuration for up to 2 weeks in normal sheep.42 Unlike our previous PA–PA configuration, the RA–PA does not require CPB for initiation. However, the risk of mechanical failure increases because the two devices can fail independently or as a unit. The configuration is currently in the early stages of animal testing. Other TAL systems are starting to appear in the literature. An integrated heart lung assist device
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21. Support Therapy for Lung Failure
from Japan combines a centrifugal blood pump with a hollow fiber oxygenator wrapped cylindrically around the pump. The resulting device is small and provides for efficient gas exchange.48 A group at the University of Maryland is developing a centrifugal pump/gas exchanger with moving filters that create a vortex pump.49 Early animal testing has been promising.
Summary and Recommendations In the 35 years since ECMO was first used clinically, strides in both the understanding of lung failure and in the technology and materials used for support have advanced (Table 21.1). We have advanced incrementally towards an era in which TALs might serve as a ‘replacement’ organ, bridgeto-transplant or even recovery for those crippled by respiratory disease. At present, the only extensively tested mechanical support for respiratory failure is ECMO. ECMO is relatively safe and provides improved outcomes for neonates with respiratory failure and congenital heart disease (evidence level moderate).
We make a strong recommendation that neonates with respiratory failure who have failed maximal medical management should be placed on ECMO (grade of recommendation 1B). ECMO improves outcomes in children with respiratory failure and is relatively safe (evidence quality low). We make a weak recommendation for ECMO for children with respiratory failure who have failed maximal medical management (grade of recommendation 2B). ECMO has been shown to improve outcomes in adults with respiratory failure who have failed maximal medical management, and appears to be safe and cost-effective. We make a weak recommendation that adults with respiratory failure should be placed on ECMO (grade of recommendation 2B). Although data are limited, it appears that adults with COPD exacerbation, severe ARDS, or who require bridge-to-transplant benefit from AVCO2R or VVCO2R and that such treatment is safe. We make a weak recommendation that adults with respiratory failure should be considered for AVCO2R or VVCO2R (grade of recommendation 2C). In the future, adults with irreversible or endstage lung diseases will be considered for TAL, but there is insufficient clinical experience to recommend this therapy at present.
Table 21.1 Characteristics of methods of mechanical support for lung failure CPB
ECMO
Setting
Cardiac surgery
Respiratory and/or cardiac failure
Respiratory failure/transport/ Respiratory failure/ COPD/ Respiratory failure/ irreversible bridge-to-transplant bridge-to- transplant lung disease/bridge-to-recovery
Location Type of support
Intrathoracic VA
Extrathoracic VA (cardiac) VV (respiratory)
Extrathoracic AV (CO2 primarily)
Extrathoracic VV (CO2 primarily)
Cannulation site
Neck
2 cannulas (percutaneous)
1 cannula (VVDL)
Not applicable in TAL
Blood flow % CO Ventilatory support
100% total None
Neck VA Neck VV 2 cannulas (surgical or percutaneous) 1 cannula (VVDL) 70–80% high Pressure Support +/- high PEEP
Groin
Number of cannulas
Direct/aorta SVC/ IVC 2 cannulas (surgical)
Extrathoracic PA-LA RA-LA PA-PA Transthoracic
10–15% low Low tidal volume
100% total Spontaneously breathing
Blood pump
Roller or centrifugal ACT >400 Hours
Roller or centrifugal
None
10–15% low Low tidal volume/ BiPAP/spontaneously breathing Roller or centrifugal
ACT 200–260 Days-weeks
ACT 180–200 Days-weeks
ACT 150–180 Days-weeks
Anti-coagulation Average length of support
AVCO2R/pECLA/iLA
VVCO2R
TAL
None if PA-LA or PA-PA Yes if RA-LA ACT 150–180 Days-weeks
pECLA pumpless extracorporeal lung assist; iLA interventional lung assist; VA venous-arterial; VV venous-venous; AV arterial-venous; PA pulmonary artery; RA right atrium; LA left atrium; VVDL veno-venous double lumen cannula; PEEP positive end expiratory pressure; BiPAP bilevel positive airways pressure; ACT activated clotting time
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ECMO is relatively safe and provides improved outcomes for neonates with respiratory failure and congenital heart disease (evidence level moderate). We make a strong recommendation that neonates with respiratory failure should be placed on ECMO (grade of recommendation 1B).
ECMO improves outcomes in children with respiratory failure and is relatively safe (evidence quality low). We make a weak recommendation for ECMO for children with respiratory failure (grade of recommendation 2B).
ECMO improves outcomes in adults with respiratory failure and appears to be safe and costeffective. We make a weak recommendation that adults with respiratory failure should be placed on ECMO (grade of recommendation 2B).
Adults with COPD exacerbation, severe ARDS, or who require bridge-to-transplant benefit from AVCO2R or VVCO2R, and such treatment is safe. We make a weak recommendation that adults with respiratory failure should be considered for AVCO2R or VVCO2R (grade of recommendation 2C).
References 1. Hill JD, O’Brien TG, Murray JJ, Dontigny L, Bramson ML, Osborn JJ, Gerbode F. Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med. 1972; 286: 629–634. 2. Bartlett RH, Gazzzaniga AB, Jefferies MR, Huxtable RF, Haiduc NJ, Fong SW. Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in infancy. Trans Am Soc Artif Intern Organs. 1976;22: 80–93. 3. Bartlett RH, Roloff DW, Cornell RG, Andrews AF, Dillon PW, Zwischenberger JB. Extracorporeal circulation in neonatal respiratory failure: a prospective randomized study. Pediatrics. 1985;76:479–487.
J.E. Lynch and J.B. Zwischenberger 4. O’Rourke PP, Crone RK, Vacanti JP, Ware JH, Lillehei CW, Parad RB, Epstein MF. Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: a prospective randomized study. Pediatrics. 1989;84:957–963. 5. UK Collaborative ECMO Trial Group. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet. 1996;348:75–82. 6. ECMO Registry of the Extracorporeal Life Support Organization (ELSO), Ann Arbor, MI; July 2009. 7. Klein MD, Shaheen KW, Whittlesey GC, Pinsky WW. Arciniegas E. Extracorporeal membrane oxygenation for the circulatory support of children after repair of congenital heart disease. J Thorac Cardiovasc Surg. 1990;100:498–505. 8. Anderson HL 3rd, Attori RJ, Custer JR, Chapman RA, Bartlett RH. Extracorporeal membrane oxygenation for pediatric cardiopulmonary failure. J Thorac Cardiovasc Surg. 1990;99:1011–1021. 9. Delius RE, Bove EL, Meliones JN, Custer JR, Moler FW, Crowley D, Amirikia A, Behrendt DM, Bartlett RH. Use of extracorporeal life support in patients with congenital heart disease. Crit Care Med. 1992;20:1216–1222. 10. Raithel RC, Pennington DG, Boegner E, Fiore A, Weber TR. Extracorporeal membrane oxygenation in children after cardiac surgery. Circulation. 1992;86: II305–II310. 11. Zapol WM, Snider MT, Hill JD, Fallat RJ, Bartlett RH, Edmunds LH, Morris AH, Peirce EC 2nd, Thomas AN, Proctor HJ, Drinker PA, Pratt PC, Bagniewski A, Miller RG Jr. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA. 1979;242:2193–2196. 12. Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, Hibbert CL, Truesdale A, Clemens F, Cooper N, Firmin RK, Elbourne D, CESAR Trial Collaboration. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374:1351–1363. 13. Zwischenberger JB, Lynch JE. Will CESAR answer the adult ECMO debate? Lancet. 2009;374:1307–1308. 14. Hemmila MR, Rowe SA, Boules TN, Miskulin J, McGillicuddy JW, Schuerer DJ, Haft JW, Swaniker F, Arbabi S, Hirschl RB, Bartlett RH. Extracorporeal life support for severe acute respiratory distress syndrome in adults. Ann Surg. 2004;240:595–605. 15. Kolla S, Awad SS, Rich PB, Schreiner RJ, Hirschl RB, Bartlett RH. Extracorporeal life support for 100 adult patients with severe respiratory failure. Ann Surg. 1997;226:544–564. 16. Lewandowski K, Rossaint R, Pappert D, Gerlach H, Slama KJ, Weidemann H, Frey DJ, Hoffmann O, Keske U, Falke KJ. High survival rate in 122 ARDS patients managed according to a clinical algorithm including extracorporeal membrane oxygenation. Intensive Care Med. 1997;23:819–835.
21. Support Therapy for Lung Failure 17. Peek GJ, Moore HM, Moore N, Sosnowski AW, Firmin RK. Extracorporeal membrane oxygenation for adult respiratory failure. Chest. 1997;112:759–764. 18. Wang D,Zhou X,Liu X,Sidor B,Lynch J,Zwischenberger JB. Wang-Zwische double lumen cannula - toward a percutaneous and ambulatory paracorporeal artificial lung. ASAIO J. 2008;54:606–611. 19. Peek G, Killer H, Reeves R, Sosnowski AW, Firmin RK. Early experience with a polymethyl pentene oxygenator for adult extracorporeal life support. ASAIO J. 2002;48:480–482. 20. Zwischenberger JB, Alpard SK, Conrad SA, Johnigan RH, Bidani A. Arteriovenous carbon dioxide removal: development and impact on ventilator management and survival during severe respiratory failure. Per fusion. 1999;14:299–310. 21. Barthelemy R, Galletti PM, Trudell LA, MacAndrew J, Richardson PD, Puel P, Enjalbert A. Total extracorporeal CO2 removal in a pumpless artery-to-vein shunt. Trans Am Soc Artif Intern Organs. 1982;28: 354–358. 22. Awad JA, Deslauriers J, Major D, Guojim L, Martin L. Prolonged pumpless arteriovenous perfusion for carbon dioxide extraction. Ann Thorac Surg. 1991;51: 534–540. 23. Brunston RL, Jr., Zwischenberger JB, Tao W, Cardenas VJ, Jr., Traber DL, Bidani A. Total arteriovenous CO2 removal: simplifying extracorporeal support for respiratory failure. Ann Thorac Surg. 1997;64:1599–1604. 24. Tao W, Deyo DJ, Brunston RL, Jr., Vertrees RA, Grochoske TL, Zwischenberger JB. Efficacy of a heparin removal device in comparison with protamine after hypothermic cardiopulmonary bypass. ASAIO J. 1997;43:M825–M30. 25. Conrad SA, Zwischenberger JB, Grier LR, Alpard SK, Bidani A. Total extracorporeal arteriovenous carbon dioxide removal in acute respiratory failure: a phase I clinical study. Intensive Care Med. 2001;27:1340–1351. 26. Zwischenberger JB, Conrad SA, Alpard SK, Grier LR, Bidani A. Percutaneous extracorporeal arteriovenous CO2 removal for severe respiratory failure. Ann Thorac Surg. 1999;68:181–187. 27. Liebold A, Philipp A, Kaiser M, Merk J, Schmid FX, Birnbaum DE. Pumpless extracorporeal lung assist using an arterio-venous shunt. Applications and limitations. Minerva Anestesiol. 2002;68:387–3891. 28. Bein T, Weber F, Philipp A, Prasser C, Pfeifer M, Schmid FX, Butz B, Birnbaum D, Taeger K. Schlitt HJ. A new pumpless extracorporeal interventional lung assist in critical hypoxemia/hypercapnia. Crit Care Med. 2006;34:1372–1377. 29. Haneya A, Philipp A, Foltan M, Mueller T, Camboni D, Rupprecht L, Puehler T, Hirt S, Hilker M, Kobuch R, Schmid C, Arit M. Extracorporeal circulatory systems in the interhospital transfer of critically ill patients: experience of a single institution. Ann Saudi Med. 2009;29:110–114. 30. Fischer S, Simon AR, Welte T, Hoeper MM, Meyer A, Tessmann R, Gohrbandt B, Gottlieb J, Haverich A,
193 Strueber M. Bridge to lung transplantation with the novel pumpless interventional lung assist device NovaLung. J Thorac Cardiovasc Surg. 2006;131: 719–723. 31. Muellenbach RM, Kredel M, Wunder C, Kustermann J, Wurmb T, Schwemmer U, Schuster F, Anetseder M, Roewer N, Brederlau J. Arteriovenous extracorporeal lung assist as integral part of a multimodeal treatment concept: a retrospective analysis of 22 patients with ARDS refractory to standard care. Eur J Anaest. 2008;25:897–904. 32. Zimmermann M, Bein T, Arlt M, Philipp A, Rupprecht L, Mueller T, Lubnow M, Graf BM, Schlitt HJ. Pumpless extracorporeal interventional lung assist in patients with acute respiratory distress syndrome: a prospective pilot study Crit Care. 2009;13:R10. 33. Cardenas VJ Jr, Miller L, Lynch JE, Anderson MJ, Zwischenberger JB. Percutaneous venovenous CO2 removal with regional anticoagulation in an ovine model. ASAIO J. 2006;52:467–470. 34. Cardenas VJ Jr, Lynch JE, Ates R, Miller L, Zwischenberger JB. Venovenous carbon dioxide removal in chronic obstructive pulmonary disease: experience in one patient. ASAIO J. 2009;55:420–422. 35. Garcia JP, Iacono A, Kon ZN, Griffith BP. Ambulatory extracorporeal membrane oxygenation: a new approach for bridge-to-transplantation. J Thorac Cardiovasc Surg. 2010 (epub ahead of print). 36. Christie JD, Edwards LB, Aurora P et al. Registry of the International Society for Heart and Lung Trans plantation: Twenty-fifth Official Adult Lung and Heart/Lung Transplantation report–2008. J Heart Lung Transplant. 2008;27:957–969. 37. Zwischenberger JR, Wang D, Lick SD, Deyo DJ, ALpard SK, Chambers SD. The paracorporeal artificial lung improves 5-day outcomes from lethal smoke/burninduced acute respiratory distress syndrome in sheep. Ann Thorac Surg. 2002;74:1011–1018. 38. Rose EA, Gelijns AC, Moskowitz AJ. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med. 2001;345:1435–1443. 39. Lynch WR, Montoya JP, Brant DO, Schreiner RJ, Iannettoni MD, Bartlett RH. Hemodynamic effect of a low resistance artificial lung in series with the native lungs of sheep. Ann Thorac Surg. 2000;69: 351–356. 40. Lick SD, Zwischenberger JB, Wang D, Deyo DJ, Alpard SK, Merz SI. Improved right heart function with a compliant in flow artifical lung in-series with the pulmonary circulation. Ann Thorac Surg. 2001;72: 899–904. 41. Lick SD, Zwischenberger JB, Alpard SK, Witt SA, Deyo DJ, Merz SI. Development of ambulatory artificial lung in an ovine survival model. ASAIO J. 2001;47(5):486–491. 42. Wang D, Lick SD, Zhou X, Liu X, Benkowski RJ, Zwischenberger JB. Ambulatory oxygenator right ventricular assist device for total right heart and
194 respiratory support. Ann Thorac Surg. 2007;84: 1669–1673. 43. Boschetti F, Perlman CE, Cook KE. Mockros LF. Hemodynamic effects of attachment modes and device design of a thoraci artificial lung. ASAIO J. 2000;46:42–48. 44. Lick SD, Zwischenberger JB. Artificial lung: bench toward bedside. ASAIO J. 2004;50:2–5. 45. Sato H, Griffith GW, Hall CM, Toomasian JM, Hirschl RB, Bartlett RH, Cook KE. Seven-day artificial lung testing in an in-parallel configuration. Ann Thorac Surg. 2007;84:988–991. 46. Haft JW, Montoya P, Alnajjar O, Posner SR, Bull JL, Iannettoni MD, Bartlett RH, Hirschl RB. An artificial lung reduces pulmonary impedance and improves
J.E. Lynch and J.B. Zwischenberger right ventricular efficiency in pulmonary hypertension. J Thorac Cardiovasc Surg. 2001;122:1094–1100. 47. Lynch WR, Montoya JP, Brand DO, Schreiner RJ, Iannettoni MD, Bartlett RH. Hemodynamic effect of a low-resistance artificial lung in series with the native lungs of sheep. Ann Thorac Surg. 2000;69:351–356. 48. Tsukiya T, Tatsumi E, Nishinaka T, Katagiri N, Takewa Y, Ohnishi H, Oshikawa M, Mizuno T, Taenaka Y, Takano H, Kitamura S. Design progress of the ultracompact integrated heart lung assist device – Part 1: effect of vaned diffusers on gas-transfer performances. Artif Organs. 2003;27:914–919. 49. Wu ZJ, Gartner M, Litwak KN, Griffith BP. Progress toward an ambulatory pump-lung. J Thorac Cardiovasc Surg. 2005;130:973–978.
Part 3
Esophagus
22
Optimal Management of Barrett Esophagus with High Grade Dysplasia Jennifer S. Chennat
Introduction The incidence of esophageal adenocarcinoma has risen by six-fold proportions from 1975 to 2001 within the United States.1 Barrett esophagus (BE) with biopsy-proven high-grade dysplasia (HGD) is the strongest risk factor for progression to carcinoma.2 Traditionally, this condition has been managed by esophagectomy, due to the concern of occult malignancy, estimated at approximately 40%.3,4 However, a more recent systematic literature analysis found that, although the frequency of occult cancer occurring within esophagectomy specimens in patients with HGD is about 39.9%, most of these patients had superficial cancers limited to the mucosa. In fact, the rate of invasive cancer, defined by at least submucosal invasion, was only 12.7%.5 Esophagectomy has also traditionally performed for BE with intramucosal carcinoma (IMC), despite a relatively low incidence of lymph node metastasis (less than 1%) associated with, T1a (non-invasive) disease.6,7 Additionally, the morbi dity and mortality of esophagectomy are still significant even in high volume centers, a factor that should be considered when selecting therapy for a disease that may be cured with less aggressive therapy.8,9 Although at first glance endoscopic surveillance is an appealing management option that could help identify early and potentially curable cancer, standard biopsy protocol techniques can miss early cancer, and thus surveillance has gone out of favor.10 With the advent of endoscopic modalities for treatment of BE/HGD, the paradigm of management has recently changed over the last several
years. The goals of endoscopic therapy of Barrett neoplasia are to preserve the esophagus while ablating or removing the entire BE segment. Focal Barrett resection is avoided due to the concern over the possibility of metachronous lesions developing. Data regarding long-term outcomes of complete Barrett ablation exist for photodynamic therapy (PDT) and endoscopic mucosal resection (EMR) techniques. Intermediate-term data have emerged for radiofrequency ablation (RFA) and cryotherapy. The objective of this chapter is to highlight evidence-based literature that describes the efficacy and safety of these contemporary endoscopic modalities within the context of traditional BE/HGD management. Argon coagulation and contact probe technology are not discussed in this chapter due to their lack of widespread use.
Data Search A Medline and PubMed search was conducted with search terms [Barrett esophagus] AND [high grade dysplasia] AND ([photodynamic therapy] OR [endoscopic mucosal resection] OR [radiofrequency ablation] OR [cryotherapy]). A total of 280 articles were identified using these search terms. Twentytwo articles were selected for review and inclusion. Articles were required to be written in English, and represent original work reflecting clinical trials (either randomized or non-randomized) or observational case series that documented outcomes and safety/efficacy. Case reports, review articles, editorials, and consensus guidelines were not included.
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_22, © Springer-Verlag London Limited 2011
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Results The data described below include a combination of randomized prospective trials, prospective observational, longitundinal case series, and retrospective chart reviews. It is sub-divided based on the four types of commonly practiced endoscopic therapies (PDT, EMR, RFA, and cryotherapy). Efficacy and safety data are presented in the following text and are summarized in Table 22.1. Subtle issues or concerns surrounding endoscopic therapy of BE neoplasia are highlighted.
PDT 5-aminolevulinic acid (ALA) PDT has been shown to have a 97% complete response rate for HGD treatment.11 Photofrin-PDT has demonstrated 5-year data that has shown a statistically significant rate of HGD elimination in the treated group versus a PPI control group.12 However, due to significant photosensitivity and stricture formation rate of about 30%, PDT has generally gone out of favor.13
EMR Focal EMR targeted at visible BE lesions with HGD or possible early cancer carries a high rate of synchronous or metachronous neoplasia
development, which ranged from 14% to 47%, and increased with longer observation times.14–20 With this issue in mind, complete Barrett era dication EMR (CBE-EMR) has been reported from a few select centers, with curative intent to remove all BE epithelium. Complete responses have ranged from 76% to 100%. The complications of EMR include stricture formation, with an incidence that approaches 50%, bleeding, and, rarely, perforation.21–25
RFA Due to the high rate of stenosis development after EMR and the technical skill required for successful performance, radiofrequency ablation (RFA) was introduced as a less invasive ablation alternative. In a randomized, multi-center, sham-controlled trial, an intention-to-treat analysis showed complete eradication of HGD occurred in 81% of those in the ablation group, as compared with 19% of those in the control group (P < 0.001). Patients in the ablation group had less disease progression (3.6% vs. 16.3%, P = 0.03) and developed fewer cancers (1.2% vs. 9.3%, P = 0.045). Chest pain, upper gastrointestinal bleeding, and a 6% esophageal stricture rate were encountered in the ablation group.26 This study has become the landmark publication to date showing that RFA has an
Table 22.1 Efficacy and safety summary of endoscopic barrett esophagus HGD therapies Author Pech11 Overholt12 Overholt13 Ell14 Nijhawa15 Buttar16 May17 Larghi19 Mino-Kenudson20 Seewald 21 Peters22 Lopes23 Larghi24 Chennat25 Shaheen26 Greenwald27 Dumot28
Treatment
Patients
PDT PDT PDT EMR EMR EMR/PDT EMR EMR EMR CBE-EMR CBE-EMR CBE-EMR CBE-EMR CBE-EMR RFA Cryotherapy Cryotherapy
35 138 103 35 25 17 28 40 18 12 37 41 24 49 38 45 26
CR (%) F/U (months) 97 77 94 97 100 100 100 100 75 100 81 76 88 97 81 94 28
60+ 60+ 58 12 15 13 34 23 23 9 11 32 28 23 12 10 24
Recurrence 30-Day Major Minor 5 yr survival Quality of (%) Mortality (%) Complications (%) Complications (%) (%) Evidence 3 13 5 14 17 13 24 45 47 0 0 24 13 3 1.5 NR 36
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 12 0 2 0 0 0 0 0 0 3 14 0 0 0 4 3
40 94 30 12 0 54 10 5 0 60 27 2 21 37 6 72 38
97 99 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Low Moderate Low Low Low Low Low Low Low Very Low Very Low Very Low Low Low Moderate Very Low Very Low
199
22. Optimal Management of Barrett Esophagus with High Grade Dysplasia
acceptable efficacy and safety profile, making it an attractive modality for use in HGD management.
Cryotherapy Cryotherapy is the most recent modality to arrive on the endoscopic BE therapy horizon. Reports of outcomes have small sample sizes, the therapy has not been evaluated in randomized trials, and there are limited data on long term outcomes.27,28
Issues Of key importance in the endoscopic management of Barrett HGD is that, of all endoscopic therapies, EMR is the only technique that provides tissue specimens for histopathologic assessment. The other options all ablate mucosa without tissue acquisition. It has previously been reported that EMR changes the staging of BE neoplasia compared to standard biopsy protocols, with almost 20% of patients upstaged compared to the stage initially found on referral biopsy specimens.25 Of this sub-group, 50% had either intramucosal carcinoma with lymphatic invasion or submucosal carcinoma. Had any other non-tissue acquiring modality been uniformly applied to this subgroup, there would have been failure to detect and adequately treat more advanced BE neoplasia. Another concern about endoscopic therapy is the presence and significance of sub-squamous BE epithelium. A recent article demonstrated that sub-squamous BE neoplasia was still technically possible to detect despite prior endotherapy.29 However, the long-term significance of subsquamous BE in the post-ablative esophagus remains to be defined. In an effort to better understand recurrence predictors, Ell and colleagues identified factors
that were most frequently associated with recurrence after endoscopic therapy. These included piecemeal resection, long-segment Barrett’s esophagus, no ablative therapy for remaining nondysplastic Barrett’s esophagus after complete response (CR) of dysplastic BE endotherapy, time until dysplasia CR achieved >10 months, and presence of multifocal neoplasia.30 To address these issues, several recent studies have reported initial favorable results of combined endoscopic mucosal resection of visible lesions and radiofrequency ablation of the remaining flat BE segment. There was no neoplasia recurrence in an overall approximate follow up time period.31,32
Recommendations When making recommendations regarding optimal management of HGD, one must also consider recent esophagectomy outcome data for BE early neoplasia. Table 22.2 summarizes these data within the context of morbidity, mortality, and recurrence rates.33–38 Based this more recent data overview, esophagectomy continues to be an acceptable treatment option in the absence of high-risk comorbidities, and should be offered as part of the consultative discussion with BE neoplasia patients. However, to date, no randomized controlled trials have been reported comparing endoscopic therapy and esophagectomy. The true delineation of optimal treatment choice (surgical vs. endoscopic) will only be determined after prospective randomized studies are conducted to assess comparative long-term outcomes, quality of life, and cost analysis. The review of current endoscopic data indicates that complete Barrett eradication for HGD provides good intermediate-term freedom from progression to cancer and is safe. It compares favorably
Table 22.2 Esophagectomy outcome data for barrett HGD treatment Author
No. of Patients
Fernando Tseng34 Reed35 Sujendran36 Rice37 Williams38 33
28 60 49 17 111 38
Mortality (%) 54 1.7 2 29 0 0
Morbidity (%) 4 29 NR 0 NR 37
F/up Period (months) 13 60+ 60+ 60+ 120 32
Overall Survival (%) 100 88 83 100 86 97
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to traditional surgical therapy for this problem (evidence quality moderate to low). A weak recommendation is made for endoscopic management of Barrett esophagus with HGD, including EMR for visible lesions and RFA for remaining areas of BE (recommendation grade 2B).
Personal View of the Data All BE patients referred for HGD/IMC management to my practice undergo joint consultation with an interventional endoscopist and surgeon. Patients are counseled on the risks and benefits of endoscopic versus surgical therapy. Two expert gastrointestinal pathologists review all referral pathology. The patients undergo index high definition white light endoscopic examination with narrow band imaging to further delineate any mucosal glandular architecture neoplastic changes. All patients undergo baseline endoscopic ultrasound to exclude local invasion and suspicious lymphadenopathy. All endoscopically visible lesions are treated with endoscopic mucosal resection. If the BE segment is 5 cm or less, the entire segment is removed by CBE-EMR. Due to concern about esophageal stricture formation, if the segment is longer than 5 cm, the flat BE areas are treated in a hybrid protocol with RFA or cryotherapy (after focal EMR of visible lesion is performed). This deviation from the above overall recommendation is due to the data on non-tissue acquiring modalities such as RFA and cyrotherapy being still relatively nascent, although promising. Due to our higher volume of EMR and comfort with treating its potential complications, when feasible, a tissue specimen is preferably obtained for accurate pathologic assessment. However, in most centers, case volume/expertise with EMR may be sub-optimal, so ablation of the remaining flat BE segment should be pursued. All patients should undergo intensive endoscopic follow up every 3–6 months, and enter into yearly surveillance once all BE is histologically eradicated. This type of rigorous endoscopic protocol is time/labor/resource intensive, and often cannot be embraced by physicians who must yield to the demands of a busy private practice. Such regimented treatment programs should be
implemented in multidisciplinary tertiary centers with versatile expertise in early BE neoplasia endoscopic detection, treatment, and complication management. Complete Barrett eradication for HGD provides good intermediate-term freedom from progression to cancer and is safe (evidence quality moderate to low). A weak recommendation is made for endoscopic management of Barrett esophagus with HGD, including EMR for visible lesions and RFA for remaining areas of BE (recommendation grade 2B).
References 1. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005;97:142–146. 2. Buttar NS,Wang KK, Sebo TJ, Riehle DM, Krishnadath KK, Lutzke LS, Anderson MA, Petterson TM, Burgart LJ. Extent of high-grade dysplasia in Barrett’s esophagus correlates with risk of adenocarcinoma. Gastro enterology. 2001;120:1630–1639. 3. Ferguson MK, Naunheim KS. Resection for Barrett’s mucosa with high-grade dysplasia: implications for prophylactic photodynamic therapy. J Thorac Cardiovasc Surg. 1997;114:824–829. 4. Pellegrini CA, Pohl D. High-grade dysplasia in Barrett’s esophagus: surveillance or operation? J Gastrointest Surg. 2000;4:131–134. 5. Konda VJ, Ross AS, Ferguson MK, Hart JA, Lin S, Naylor K, Noffsinger A, Posner MC, Dye C, Cislo B, Stearns L, Waxman I. Is the risk of concomitant invasive esophageal cancer in high-grade dysplasia in Barrett’s esophagus overestimated? Clin Gastroenterol Hepatol. 2008;6:159–164. 6. Buskens CJ, Westerterp M, Lagarde SM, Bergman JJ, ten Kate FJ, van Lanschot JJ. Prediction of appropriateness of local endoscopic treatment for high-grade dysplasia and early adenocarcinoma by EUS and histopathologic features. Gastrointest Endosc. 2004;60:703–710. 7. Stein HJ, Feith M, Bruecher BL, Naehrig J, Sarbia M, Siewert JR. Early esophageal cancer: pattern of lymphatic spread and prognostic factors for long-term survival after surgical resection. Ann Surg. 2005;24:566–573. 8. Birkmeyer JD, Siewers AE, Finlayson EV, Stukel TA, Lucas FL, Batista I, Welch HG, Wennberg DE. Hospital volume and surgical mortality in the United States. N Engl J Med. 2002;346:1128–1137. 9. Birkmeyer JD, Stukel TA, Siewers AE, Goodney PP, Wennberg DE, Lucas FL. Surgeon volume and operative mortality in the United States. N Engl J Med. 2003;349:2117–2127.
22. Optimal Management of Barrett Esophagus with High Grade Dysplasia 10. Falk GW, Rice TW, Goldblum JR, Richter JE. Jumbo biopsy forceps protocol still misses unsuspected cancer in Barrett’sesophagus with high-grade dysplasia. Gastrointest Endosc. 1999;49:170–176. 11. Pech O, Gossner L, May A, Rabenstein T, Vieth M, Stolte M, Berres M, Ell C. Long-term results of photodynamic therapy with 5-aminolevulinic acid for superficial Barrett’s cancer and high-grade intraepithelial neoplasia. Gastrointest Endosc. 2005;62:24–30. 12. Overholt BF, Wang KK, Burdick JS, Lightdale CJ, Kimmey M, Nava HR, Sivak MV Jr, Nishioka N, Barr H, Marcon N, Pedrosa M, Bronner MP, Grace M, Depot M. Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett’s highgrade dysplasia. Gastrointest Endosc. 2007;66: 460–468. 13. Bergein F. Overholt, Masoud Panjehpour, Daniel L. Halberg. Photodynamic therapy for Barrett’s esophagus with dysplasia and/or early stage carcinoma: long-term results. Gastrointest Endosc. 2003;58; 183–188. 14. Ell C, May A, Gossner L, Pech O, Günter E, Mayer G, Henrich R, Vieth M, Müller H, Seitz G, Stolte M. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett’s esophagus. Gastro enterology. 2000;118:670–677. 15. Nijhawan PK, Wang KK. Endoscopic mucosal resection for lesions with endoscopic features suggestive of malignancy and high-grade dysplasia within Barrett’s esophagus. Gastrointest Endosc. 2000;52: 328–332. 16. Buttar NS, Wang KK, Lutzke LS, Krishnadath KK, Anderson MA. Combined endoscopic mucosal resection and photodynamic therapy for esophageal neoplasia within Barrett’s esophagus. Gastrointest Endosc. 2001;54:682–688. 17. May A, Gossner L, Pech O, Fritz A, Günter E, Mayer G, Müller H, Seitz G, Vieth M, Stolte M, Ell C. Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett’s oesophagus: acute-phase and intermediate results of a new treatment approach. Eur J Gastroenterol Hepatol. 2002;14:1085–1091. 18. May A, Gossner L, Pech O, Müller H, Vieth M, Stolte M, Ell C. Intraepithelial high-grade neoplasia and early adenocarcinoma in short-segment Barrett’s esophagus (SSBE): curative treatment using local endoscopic treatment techniques. Endoscopy. 2002; 34:604–610. 19. Larghi A, Lightdale CJ, Memeo L, Bhagat G, Okpara N, Rotterdam H. EUS followed by EMR for staging of high-grade dysplasia and early cancer in Barrett’s esophagus. Gastrointest Endosc. 2005;62:16–23. 20. Mino-Kenudson M, Brugge WR, Puricelli WP, Nakatsuka LN, Nishioka NS, Zukerberg LR, Misdraji J, Lauwers GY. Management of superficial Barrett’s epithelium-related neoplasms by endoscopic muco sal resection: clinicopathologic analysis of 27 cases. Am J Surg Pathol. 2005;29:680–686.
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21. Seewald S, Akaraviputh T, Seitz U, Brand B, Groth S, Mendoza G, He X, Thonke F, Stolte M, Schroeder S, Soehendra N. Circumferential EMR and complete removal of Barrett’s epithelium: a new approach to management of Barrett’s esophagus containing highgrade intraepithelial neoplasia and intramucosal carcinoma. Gastrointest Endosc. 2003;57:854–859. 22. Peters FP, Kara MA, Rosmolen WD, ten Kate FJ, Krishnadath KK, van Lanschot JJ, Fockens P, Bergman JJ. Stepwise radical endoscopic resection is effective for complete removal of Barrett’s esophagus with early neoplasia: a prospective study. Am J Gastroenterol. 2006;101:1449–1457. 23. Lopes CV, Hela M, Pesenti C, Bories E, Caillol F, Monges G, Giovannini M. Circumferential endoscopic resection of Barrett’s esophagus with highgrade dysplasia or early adenocarcinoma. Surg Endosc. 2007;21:820–824. 24. Larghi A, Lightdale CJ, Ross AS, Fedi P, Hart J, Rotterdam H, Noffsinger A, Memeo L, Bhagat G, Waxman I. Long-term follow-up of complete Barrett’s eradication endoscopic mucosal resection (CBE-EMR) for the treatment of high grade dysplasia and intra mucosal carcinoma. Endoscopy. 2007;39:1086–1091. 25. Chennat J, Konda VJ, Ross AS, de Tejada AH, Noffsinger A, Hart J, Lin S, Ferguson MK, Posner MC, Waxman I. Complete Barrett’s eradication endoscopic mucosal resection: an effective treatment modality for high-grade dysplasia and intramucosal carcinoma - an American single-center experience. Am J Gastroenterol. 2009;104:2684–2692. 26. Shaheen NJ, Sharma P, Overholt BF, Wolfsen HC, Sampliner RE, Wang KK, Galanko JA, Bronner MP, Goldblum JR, Bennett AE, Jobe BA, Eisen GM, Fennerty MB, Hunter JG, Fleischer DE, Sharma VK, Hawes RH, Hoffman BJ, Rothstein RI, Gordon SR, Mashimo H,Chang KJ,MuthusamyVR,Edmundowicz SA, Spechler SJ, Siddiqui AA, Souza RF, Infantolino A, Falk GW, Kimmey MB, Madanick RD, Chak A, Lightdale CJ. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med. 2009;360:2277–2288. 27. Greenwald BD, Dumot JA, Horwhat JD, Lightdale CJ, Abrams JA. Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus. Dis Esophagus. June 9, 2009, e-published ahead of print. 28. Dumot JA, Vargo JJ 2nd, Falk GW, Frey L, Lopez R, Rice TW. An open-label, prospective trial of cryospray ablation for Barrett’s esophagus high-grade dysplasia and early esophageal cancer in high-risk patients. Gastrointest Endosc. 2009;70:635–644. 29. Bronner MP, Overholt BF, Taylor SL, Haggitt RC, Wang KK, Burdick JS, Lightdale CJ, Kimmey M, Nava HR, Sivak MV, Nishioka N, Barr H, Canto MI, Marcon N, Pedrosa M, Grace M, Depot M. Squamous overgrowth is not a safety concern for photodynamic therapy for Barrett’s esophagus with high-grade dysplasia. Gastroenterology. 2009;136:56–64.
202 30. Pech O, Behrens A, May A, Nachbar L, Gossner L, Rabenstein T, Manner H, Guenter E, Huijsmans J, Vieth M, Stolte M, Ell C. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s oesophagus. Gut. 2008;57:1200–1206. 31. Pouw RE, Gondrie JJ, Sondermeijer CM, ten Kate FJ, van Gulik TM, Krishnadath KK, Fockens P, Weusten BL, Bergman JJ. Eradication of Barrett esophagus with early neoplasia by radiofrequency ablation, with or without endoscopic resection. J Gastrointest Surg. 2008;12:1627–1636. 32. Pouw RE, Wirths K, Eisendrath P, Sondermeijer CM, Kate FJ, Fockens P, Deviere J, Neuhaus H, Bergman JJ. Efficacy of radiofrequency ablation combined with endoscopic resection for Barrett’s esophagus with early neoplasia. Clin Gastroenterol Hepatol. August 11, 2009, e-published ahead of print. 33. Fernando HC, Luketich JD, Buenaventura PO, Perry Y, Christie NA. Outcomes of minimally invasive
J. S. Chennat esophagectomy (MIE) for high-grade dysplasia of the esophagus. Eur J Cardiothorac Surg. 2002;22:1–6. 34. Tseng EE, Wu TT, Yeo CJ, Heitmiller RF. Barrett’s esophagus with high grade dysplasia: surgical results and long-term outcome—an update. J Gastrointest Surg. 2003;7:164–170. 35. Reed MF, Tolis G Jr, Edil BH et al. Surgical treatment of esophageal high-grade dysplasia. Ann Thorac Surg. 2005;79:1110–1115. 36. Sujendran V, Sica G, Warren B, Maynard N. Oeso phagectomy remains the gold standard for treatment of high-grade dysplasia in Barrett’s oesophagus. Eur J Cardiothorac Surg. 2005;28:763–766. 37. Rice TW. Pro: esophagectomy is the treatment of choice for high-grade dysplasia in Barrett’s esophagus. Am J Gastroenterol. 2006;101:2177–2179. 38. Williams VA, Watson TJ, Herbella FA, Gellersen O, Raymond D, Jones C, Peters JH. Esophagectomy for high grade dysplasia is safe, curative, and results in good alimentary outcome. J Gastrointest Surg. 2007;11:1589–1597.
23
Induction Therapy for Resectable Esophageal Cancer Richard G. Berrisford and Marcello Migliore
Introduction A number of factors need to be considered when attempting to analyze the potential utility of induction therapy in patients with clinically resec table esophageal cancer. Many factors reflect prob lems with older staging and therapeutic concepts. In addition, prior publications frequently fail to adequately isolate patients by stage and cell type in reporting outcomes of induction therapy. These features lead to difficulties in identifying appro priate therapeutic options based on outdated reports, and will be discussed in detail below.
Surgery Without Induction Therapy: Outcome and Radicality Surgery has contributed to the treatment of pati ents with esophageal cancer for nearly 100 years.1 During this time, huge progress has been made in refining preoperative staging, patient selection, operative technique and postoperative care. The overall survival for patients undergoing resection worldwide, however, is poor: it is widely quoted as 15–20% at 5 years,2 reflecting the propensity of esophageal cancer to spread to nodes and more distant sites at an early clinical T (cT) stage.3 This figure is misleading. Derived from pub lished studies, it overestimates survival at a worldwide level and underestimates the potential global benefit of multimodality therapy. However, drawn from selected publications, it is biased, and fails to recognise the much better outcomes of more radical approaches which report 40% survival at 5 years.4,5 Radical, en bloc resection
may improve survival in patients with nodal dis ease, although there is a paucity of randomised trials reporting on results of radical surgery. Induction therapy should not be seen as an alter native to radical surgery but as complementary. Whether or not induction treatment offers addi tional survival advantage to radical en bloc resec tion cannot be assessed on current evidence. We can only assess induction therapy in the light of the (largely non-radical) resections which make up the literature.
Stage Correct identification of preoperative stage, and therefore allocation of induction therapy to appro priate patients, is challenging. Patients with early stage disease, namely UICC Stage II,6 may have poorer survival after induction therapy. In early cT stage, appropriately specified and technically accomplished EUS can accurately determine stage in up to 80% of esophageal tumors, although accu racy is lower for tumors at the gastroesophageal junction.7 In moderately advanced cT stage, EUS is less able to accurately identify T2 disease com pared with T1 and T3 disease, a key distinction.8 With regard to nodal disease, EUS may accurately identify cN1 in up to 80% of nodes with four ultra sound features of malignancy.9 However only 25% of malignant nodes have all four features, so EUS guided fine needle aspiration is an important adjunct for accurate lymph node assessment.9 Accurate assessment of cN0 status will prevent patients who would be upstaged via EUS from inappropriately being excluded from induction
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therapy. Regarding cM status, most randomised clinical trials assessing induction therapy were carried out before the introduction of spiral CT and PET. Study populations will have inevitably included patients with M1 disease which may have obscured the magnitude of potential benefit.
Histology and Tumor Location There are fundamental differences between squa mous carcinoma of the esophagus and adenocar cinoma of the lower third of the esophagus and gastroesophageal junction. Etiology, epidemiol ogy, tumor biology, pattern of recurrence, progno sis and susceptibility to induction therapy are different.10 Yet many studies have combined both cell types in their populations with apparently similar outcomes. More recent trials have focused on one cell type, in particular adenocarcinoma, incorporating gastric cancer, with appropriate subanalysis for region. Some authors have argued strongly for a rigor ous preoperative allocation to Type I, II or III junctional tumor category,11 difficult though this is. This postdates most trials on induction therapy and leads us to question whether knowledge of tumor type would better inform the decision on induction therapy in individual patients. However, recent studies question the importance of this categorization, finding little difference in nodal spread from different locations.12
Principles Behind Induction Therapy There are several theoretical advantages to adding chemotherapy to surgery. In patients whose tumors respond, there is a reduction in local tumor activity, downsizing the primary with a higher chance of R0 resection, and dysphagia is relieved allowing better preoperative nutrition. Systemic micrometastases are potentially eradicated.13 Chemotherapeutic agents may act at molecular, cellular and tissue levels as radiosensitizers14 and may also destroy radioresistant tumor clones. While many studies have focussed on fluorouracil or bleomycin and cisplatin,15 the dosage and dos ing schedules have varied considerably, making the evidence difficult to compare. Multimodality
induction therapy with chemotherapy and radio therapy can be sequential or concurrent, discussed below.
Response to Therapy The aim of induction therapy is to achieve a path ological complete response in as many patients as possible, as this does appear to confer a significant survival advantage.16 Objective evidence of response judged by barium esophagogram like wise predicts a significant survival advantage.17 Patients who do not respond to induction therapy may be subjected to a potentially harmful delay in proceeding to resection, during which time the tumor can spread. Determining poor response to induction therapy at an early stage may allow more timely surgery.
Evidence Methods An initial search was undertaken in Google Scholar, the Cochrane Database of Systematic Reviews (CDSR), MEDLINE and EMBASE and for meta-analyses and systematic reviews. Eligible tri als were identified from these publications, then a more detailed search was conducted for trials published between 2004 and 2009 in MEDLINE and EMBASE using a simplified version (Appendix 1) of the search described for the 2009 Cochrane review protocol.18 This search provided 122 results. The Cochrane Central Register of Controlled Trials (CENTRAL) was searched for this time period and a manual search was made to identify recently reported trials in abstracts from the American Digestive Diseases Week (DDW) pub lished in Gastroenterology, the United European Gastroenterology Week (UEGW) published in Gut and the Annual meetings of the American Society of Clinical Oncology (ASCO) published in the Journal of Clinical Oncology. Recommendations given are graded according to the ACCP GRADE system.19
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Induction Chemotherapy Meta Analyses There are two meta analyses published in the last 5 years close together, both of which consider the same eight randomized controlled trials16,20–25,31 listed in Table 23.1. A further Cochrane systematic review published in 2007 was withdrawn owing to exclusion critera26 and a new protocol has been prepared pending publication of a new systematic review.18 Melthaner and colleagues, whose 2006 Cochrane review27 updated two previous versions,28,29 found some evidence to suggest that preoperative che motherapy improved survival, but this was incon clusive (HR 0.88, 95% CI 0.75–1.04). This review found that induction chemotherapy made no dif ference in rates of resection, completeness of resection, tumor recurrence or non-fatal compli cation rates. Gebski and colleagues published a meta analy sis of both induction chemotherapy and induction chemoradiotherapy in 2007.10 They reported a hazard ratio of 0.90 (95% CI 0.81–1.00, p = 0.05) for induction chemotherapy, indicating a 2 year absolute survival benefit of 7%. They found a difference in survival between patients with squamous and adenocarcinoma. The hazard ratio for induction chemotherapy in patients with SCC was not significant (0.88; 95% CI 0.75–1.03; p = 0.12), but in patients with adenocarcinoma the
hazard ratio was significant (0.78; 95% CI 0.64– 0.95; p = 0.014). An earlier meta analysis published by Urschel did not demonstrate a survival advantage for induction chemotherapy but showed a lower resection rate with a higher proportion of R0 resections.30
Randomised Trials Of the eight clinical trials on which the two recent meta analyses were based, four showed some improvement in survival with induction chemo therapy16,22,25,31 and four did not.20,21,23,24 The largest trial (n = 802), the UK Medical Rese arch Council (MRC) OEO2,31 showed a significant survival advantage to induction chemotherapy (HR 0.79, 95% CI 0.67–0.93), despite there being no difference in rate of resection or pattern of recurrence between the groups. The long term results are now available in abstract form32; 5 year survival was 23% in the induction chemotherapy arm compared with 17% in the surgery only arm. The hazard ratio for survival was 0.84 (95% CI 0.72–0.98; p = 0.003). Disease free survival was also better in the induction therapy arm (HR 0.82; 95% CI 0.71–0.95; p = 0.008). There was no differ ence in benefit between squamous (n = 247) and adenocarcinoma (n = 533) (HR 0.81 and 0.86, respectively). The second largest trial (n = 467), the USA Intergroup Trial 113,20 quoted in these meta
Table 23.1. Randomised controlled trials of induction chemotherapy in resectable esophageal carcinoma. Study
Patients
Histology (%)
Hazard Ratio (95% CI)
Notes Survival advantage in responders No difference in survival No difference in survival No difference in survival No difference. Responders had improved survival. Highly significant long term survival in objective responders17 Only complete responders had significantly higher survival Similar effect for both histologies. Significant long term survival benefit32 Significant survival benefit Significant survival benefit
Roth Nygaard21 Maipang23 Schlag24 Law25 Kelsen20 Ancona16 MRC31
39 106 46 46 147 467 96 802
SCC (95) SCC (100) SCC (100) SCC (100) SCC (100) SCC (44) Adeno (51) SCC(100) SCC (31) Adeno (66)
0.71 (0.36–1.43) 1.22 (0.82–1.81) 1.61 (0.79–3.27) 0.97 (0.60–1.57) 0.73 (0.53–1.00) 1.07 (0.87–1.32) 0.85 (0.50–1.44) 0.79 (0.67–0.93)
Cunningham33 Boige34
503 224
Adeno (100) Adeno (100)
0.75 (0.60–0.93) 0.69 (–50–0.95)
22
CI confidence limits; SCC squamous cell cancer; Adeno adenocarcinoma
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analyses, showed no difference in survival between the groups (HR 1.07; 95% CI 0.87–1.32). Neither did it show a difference in pattern of recurrence nor any difference in outcome between squamous (n = 204) and adenocarcinoma (n = 236). The long term overall outcomes reported in 2007 showed no difference in survival with induction chemo therapy in the groups overall.17 However, patients with objective tumor regression after chemother apy seen on barium esophagogram had highly sig nificantly improved survival compared to those without objective regression or undergoing sur gery only (regression vs no regression HR 2.83; (95% CI 1.84–4.35; p < 0.0001). There were other significant differences between the Intergroup Trial 113 and the MRC OEO2 trials: the USA trial used three cycles of a higher dose of cisplatin compared with two preoperative cycles in OEO2. Patients in the USA Intergroup Trial also underwent postoperative chemotherapy. Seventy one percent completed preoperative chemother apy with a median time to surgery of 93 days com pared with 90% of patients in the OEO2 before surgery at median 63 days. However, operative mortality in the surgery only arm of OEO2 was high at 10%. More patients in the USA trial received postoperative radiotherapy. So there are signifi cant differences in the protocols of these trials which could explain their different findings.10 There are two important trials which have been published since the 2006/2007 meta analyses, one in abstract form. Both showed significant survival advantage with induction chemotherapy. The Medical Research Council Adjuvant Gas tric Infusional Chemotherapy (MAGIC) trial33 (n = 503) randomized patients with adenocarci noma of the stomach (n = 372), esophagogastric junction (n = 58) or lower esophagus (n = 73) to three preoperative and three postoperative cycles of epirubicin, cisplatin and fluorouracil compared to surgery alone. The perioperative chemotherapy group had a higher likelihood of overall survival (HR 0.75; 95% CI 0.60–0.93; p = 0.009, 5 year survival 36% vs. 23%) and of progression free survival (HR 0.66; 95% CI 0.53–0.81; p < 0.001). Postoperative complication rates and operative mortality were similar in both arms, and resected tumors were significantly smaller and less advanced in the chemotherapy arm. The French 9703 Trial reported its final results at ASCO in 2007, available as an abstract.34 Patients
with body, cardia and lower esophageal adenocar cinoma (n = 224) were randomized to 2–3 cycles of preoperative cisplatin and fluoruracil and sur gery against surgery alone. The R0 resection rate was significantly higher in the induction chemo therapy arm. Disease free survival was higher (HR 0.65; 95% CI 0.48–0.89; p = 0.003) and overall survival was better (HR 0.60; 95% CI 0.50–0.95; p = 0.02) in patients receiving induction therapy. A third trial, the EORTC 40954, comparing induction chemotherapy with surgery alone closed prematurely due to low recruitment. Its abstract reported a significantly increased rate of R0 resections.
Induction Chemoradiotherapy Meta Analyses There are three meta analyses reporting on induc tion chemoradiotherapy in the last five years.10,35,36 The systematic review and meta analysis pub lished by Fiorica and colleagues in 2004 reviewed the literature to 2002. They identified six ran domised controlled trials and showed a significant reduction in three year mortality with induction chemoradiotherapy (OR 0.53; 95% CI 0.31–0.93; p = 0.03) with significant downstaging of tumor in the induction arm. However, they also reported a higher postoperative mortality in the induction arm (11.9% for induction arm compared to 6.2% for surgery only; OR 2.10; 95% CI 1.18–3.73). Their decision to include data from the Irish Trial by Walsh37 without appropriate data confirmation from source has been criticized,38 as its inclusion was critical to the significance of the meta analysis findings. The meta analysis by Greer and colleagues, pub lished in 2005,35 did not consider randomized con trolled trials published after 2003. They reported a small, non-significant survival advantage to induc tion chemoradiotherapy. This analysis does not comment on operative mortality. The third meta analysis by Gebski and col leagues in 2007 reported a literature search up to 2006. Ten randomised comparisons of induction chemoradiotherapy versus surgery alone are included, comprising of eight publications, one thesis and one abstract (n = 1,724 patients). The hazard ratio for all-cause mortality with induction chemoradiotherapy versus surgery alone was 0.81 (05% CI 0.70–0.93; p = 0.002). This corresponded
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to a 13% absolute difference in survival at 2 years and was similar for squamous and adenocarci noma. Unlike the previous meta analysis, this find ing was significant even if data from the Walsh trial was excluded. Gebski and colleagues do not report on the effect of induction chemoradiotherapy on postop erative mortality, perhaps reflecting three studies included which showed no difference in operative mortality.39–41 Other authors also report similar mortality risks.42,43 However, increased operative mortality after induction chemoradiotherapy is highlighted by others,44,45 and there is a significant drop-out rate for surgery after induction treat ment.41 Furthermore, two randomised controlled trials showing equivalent survival for chemora diotherapy alone compared with chemoradiother apy plus surgery report operative mortality of 12.8%46 and three month mortality of 9.3%47 in the induction-surgery arms. These results may explain the underuse of esophagectomy in the treatment of resectable esophageal cancer reported from the SEER database.48
Randomised Trials Randomised controlled trials assessing induction chemoradiotherapy are summarised in Table 23.2. Three randomized controlled trials have assessed sequential chemotherapy and radiotherapy; they did not show a significant overall survival advan tage.21,49,50 The EORTC trial49 showed improved dis ease free survival for squamous cancer, but overall survival was no different; postoperative mortality was 12.3% in the induction arm compared with 3.6% in the control arm. Sequential protocols do not take advantage of the radiosensitization poten tial of chemotherapeutic agents. Five randomised controlled trials have asses sed concurrent chemoradiotherapy.37,39–41,51 Two of these closed early; a single institution trial from Korea was stopped early due to an unexpectedly high dropout rate for esophagectomy in the induc tion arm.41 The CALGB 9781 Trial39 was closed due to poor recruitment, reporting on only 50 patients. Of the three completed trials37,40,51 only one, the Irish trial reported by Walsh and colleagues,37 found a significant survival advantage with con current induction chemoradiotherapy. This small trial (n = 113) reported median survival in the induction arm of 16 months compared to just 11
Table 23.2. Randomised controlled trials of induction chemoradiotherapy in resectable esophageal carcinoma. Study
Patients Histology (%)
Nygaard21 Le Prise50 Bossett49 Urba51
78 82 293 100
Walsh37 Burmeister40,a
113 256
Lee41,b Tepper39,c
101 56
SCC (100) SCC (100) SCC (100) SCC (25) Adeno (75) Adeno (100) SCC (37) Adeno (62) SCC (100) SCC (25) Adeno (75)
Schedule
Hazard Ratio (95% CI)
Sequential Sequential Sequential Concurrent
0.76 (0.45–1.28) 0.85 (0.50–1.46) 0.96 (0.73–1.27) 0.74 (0.48–1.12)
Concurrent Concurrent
0.58 (0.38–0.88) 0.94 (0.70–1.26)
Concurrent Concurrent
0.88 (0.48–1.62) 0.40 (0.18-0.87)
Completed but underpowered Stopped early due to unexpectedly high dropout rate for esophagectomy c Closed prematurely due to poor recruitment SCC squamous cell cancer; Adeno adenocarcinoma a
b
months in the surgery only arm (p = 0.01). The 3 year survival in the induction arm was 32% com pared to just 6% in the surgery only arm. While there were significantly fewer involved lymph nodes in the induction arm and a 25% pathologi cal complete response rate, the very poor outcomes of the surgery only arm have significantly com promised the value of this study.
Induction Chemotherapy vs. Induction Chemoradiotherapy There is one recently published randomized con trolled trial comparing induction chemotherapy with induction chemoradiotherapy.52 This trial was closed early due to low recruitment, but showed an improved survival at three years with chemoradiotherapy (H.R. 0.67; 95% CI 0.41–1.07). However, operative mortality in the chemoradio therapy group was 10.2% vs. 3.8% (p = 0.26).
Induction Radiotherapy The Cochrane review of preoperative radiother apy,53 updated in 2009, reports five randomized controlled trials comparing radiotherapy followed by surgery with surgery alone.21,54–57 No clear evi dence was found to support induction radiother apy (OR 0.89%; 95% CI 0.78–1.01; p = 0.062); absolute survival benefit was reported as 3% at 2 years and 4% at 5 years.
208
Recommendations Induction therapy for resectable adenocarci noma of the esophagus improves long-term sur vival and is safe (evidence quality high). We make a strong recommendation for induction chemotherapy with epirubicin, cisplatin and flu oropyrimidines for patients with resectable adenocarcinoma of the lower esophagus or esophagogastric junction (grade of recommen dation 1B). Induction therapy for resectable squamous cell carcinoma of the esophagus pro vides a long-term survival advantage in patients who experience a complete pathologic response and is safe (evidence quality moderate). We make a strong recommendation for induction chemo therapy with cisplatin and fluoropyrimidines for patients with resectable squamous carcinoma of the esophagus, and that esophagectomy be offered to patients with objective tumor response (recommendation grade 1B). Neither concurrent nor sequential induction chemoradiotherapy reliably improves long-term survival in resectable esophageal cancer, and such therapy is associated with an increase in operative mortality (evidence quality high). We make a strong recommendation against routine use of induction chemoradiotherapy for resectable can cer of the esophagus or gastroesophageal junction (recommendation grade 1A). Induction radiotherapy does not improve longterm survival in patients with resectable esophageal cancer but appears safe (evidence quality high). We make a strong recommendation against radiother apy alone as induction therapy in resectable esoph ageal cancer (grade of recommendation 1A).
A Personal View of the Data The recommendations above are made on the basis of published evidence. That evidence is dependent on the quality of staging, induction therapy and surgery at the time that the studies were undertaken. Multislice CT, EUS and PET scanning were not available to many of the patients undergoing treatment, most resections were not radical, and therefore the true stage of patients in comparative groups was unknown.
R.G. Berrisford and M. Migliore
The significant outcome of the MAGIC trial33 underpins our recommendation for induction che motherapy in patients with adenocarcinoma of the lower third of the esophagus and gastroesophageal junction. This is supported by the meta analysis from Gebski and colleagues10 and by the French 9703 trial outcome.34 The seemingly negative findings of the Intergroup Trial 113,20 already discussed, should be re-evaluated in the light of its late findings, report ing very significant survival benefit in objective responders.17 While pathological complete response is relatively uncommon after induction chemother apy, complete or partial response does significantly benefit some patients. In our opinion, physicians currently do not focus sufficiently on evaluating objective response. Future trials need to focus on identifying non-responders early and moving them on quickly to radical surgery or radiotherapy. We have recommended induction chemother apy in patients with squamous carcinoma based on the modest but significant survival benefit in the large OEO2 trial.31 Neither the 2006 Cochrane meta analysis nor the 2007 Gebski meta-analysis show a survival advantage for squamous carci noma, but in there was a sustained survival benefit in the long term outcomes of OEO2 in patients with squamous carcinoma,32 the largest rando mised trial to date. In our opinion, there is not robust evidence to recommend induction concurrent chemoradiother apy outside a randomized trial. While pathological complete response is achieved in many more patients compared to induction chemotherapy, it is at a cost, in a significant number of trials, of drop-out for resection or increased operative mortality. There is insufficient focus in the current literature on the effect of induction chemoradiotherapy on operative mortality. We emphasize that, contrary to our rec ommendations, some national guidelines do recom mend induction concurrent chemoradiotherapy. There is a need for randomised controlled trials employing current chemtherapeutic agents, radio therapy planning and delivery as induction ther apy. They should stipulate rigorous quality criteria for accurate staging with EUS, EUS-FNA and PET CT, together with reassessment after induction therapy by PET, followed by quality controlled rad ical surgery. It would be valuable to incorporate into such trials more traditional objective tests of response such as the barium esophagogram.
23. Induction Therapy for Resectable Esophageal Cancer
Induction therapy for resectable adenocarci noma of the esophagus improves long-term survival and is safe (evidence quality high). We make a strong recommendation for induction chemotherapy for patients with resectable ade nocarcinoma of the esophagus (recommenda tion grade 1B).
Induction therapy for resectable squamous cell carcinoma of the esophagus provides a longterm survival advantage in patients who experi ence a complete pathologic response and is safe (evidence quality moderate). We make a strong recommendation for induction chemotherapy for patients with resectable squamous carci noma of the esophagus, and that esophagec tomy be offered to patients with objective tumor response (recommendation grade 1B).
Neither concurrent nor sequential induction chemoradiotherapy reliably improves long-term survival in resectable esophageal cancer but is associated with an increase in operative mortal ity (evidence quality high). We make a strong recommendation against routine use of induc tion chemoradiotherapy for resectable cancer of the esophagus (recommendation grade 1A). Acknowledgements The authors thank Dr. Elizabeth Toy, Consultant Oncologist, for her comments on the manu script. The authors would like to thank DJS Newman at Exeter Health Library for his help with performing the literature search.
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209 4. Peyre CG, Hagen JA, DeMeester SR, Altorki NK, Ancona E, Griffin SM, Holscher A, Lerut T, Law S, Rice TW, Ruol A, van Lanschot JJB, Wong J, DeMeester TR. The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection. Ann Surg. 2008;248:549–556. 5. Omloo JM, Lagarde SM, Hulscher JBF, Reitsma JB, Fockens P, van Dekken H, ten Kate FJW, Obertop H, Tilanus HW, van Lanschot JJ. Extended transtho racic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clini cal trial. Ann Surg. 2007;246:992–1001. 6. Sobin LH, Wittekind C. TNM Classification of Malignant Tumours (UICC). New York: Wiley-Liss; 2002. 7. May A, Gunter E, Roth F, Gossner L, Stolte M, Vieth M, Ell C. Accuracy of staging in early oesophageal cancer using high resolution endoscopy and high resolution endosonography: a comparative, pro spective, and blinded trial. Gut. 2004;53:634–640. 8. Rice TW, Blackstone EH, Adelstein DJ, Zuccaro G Jr, Vargo JJ, Goldblum JR, Murthy SC, DeCamp MM, Rybicki LA. Role of clinically determined depth of tumor invasion in the treatment of esophageal carcinoma. J Thorac Cardiovasc Surg. 2003;125: 1091–1102. 9. Bhutani MS, Hawes RH, Hoffman BJ. A comparison of the accuracy of echo features during endoscopic ultrasound (EUS) and EUS-guided fine-needle aspi ration for diagnosis of malignant lymph node inva sion. Gastrointest Endosc. 1997;45:474–479. 10. Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J. Survival benefits from neoadju vant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol. 2007;8:226–234. 11. Siewert RJ, Feith M, Werner M, Stein HJ. Adeno carcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg. 2000;232:353–361. 12. Leers JM, DeMeester SR, Chan N, Ayazi S, Oezcelik A, Abate E, Banki F, Lipham JC, Hagen JA, DeMeester TR. Clinical characteristics, biologic behavior, and survival after esophagectomy are similar for adenocarcinoma of the gastroesophageal junction and the distal esophagus. J Thorac Cardiovasc Surg. 2009;138:594–602. 13. Goldie JH, Coldman AJ. The genetic origin of drug resistance in neoplasms: implications for systemic therapy. Cancer Res. 1984;44:3643–3653. 14. Hennequin C, Favaudon V. Biological basis for chemo-radiotherapy interactions. Eur J Cancer. 2002;38:223–230. 15. Kleinberg L, Gibson MK, Forastiere AA. Chemo radiotherapy for localized esophageal cancer: regimen selection and molecular mechanisms of radiosensiti zation. Nat Clin Pract Oncol. 2007;4:282–294.
210 16. Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, Zaninotto G, Bonavina L, Peracchia A. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a random ized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001;91:2165–2174. 17. Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by sur gery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007;25:3719–3725. 18. Slanger TE, Schwarzbach M, Hofheinz R, Kienle P, Jensen K, Ronellenfitsch U. Perioperative chemo therapy versus primary surgery for locoregion ally advanced resectable adenocarcinoma of the stomach, gastroesophageal junction and lower esophagus. Cochrane Database Syst Rev. 2009; CD008107. 19. Guyatt G, Gutterman D, Baumann MH, ddrizzo-Har ris D, Hylek EM, Phillips B, Raskob G, Lewis SZ, Schunemann H. Grading strength of recommenda tions and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest. 2006;129:174–181. 20. Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998; 339:1979–1984. 21. Nygaard K, Hagen S, Hansen HS, Hatlevoll R, Hultborn R, Jakobsen A, Mantyla M, Modig H, Munck-Wikland E, Rosengren B,. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a ran domized, multicenter study of pre-operative radio therapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg. 1992;16: 1104–1109. 22. Roth JA, Pass HI, Flanagan MM, Graeber GM, Rosenberg JC, Steinberg S. Randomized clinical trial of preoperative and postoperative adjuvant chemo therapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg. 1988;96:242–248. 23. Maipang T, Vasinanukorn P, Petpichetchian C, Cham roonkul S, Geater A, Chansawwaang S, Kuapanich R, Panjapiyakul C, Watanaarepornchai S, Punperk S. Induction chemotherapy in the treatment of patients with carcinoma of the esophagus. J Surg Oncol. 1994;56:191–197. 24. Schlag PM. Randomized trial of preoperative che motherapy for squamous cell cancer of the eso phagus. The Chirurgische Arbeitsgemeinschaft Fuer Onkologie der Deutschen Gesellschaft Fuer Chirurgie Study Group. Arch Surg. 1992;127: 1446–1450.
R.G. Berrisford and M. Migliore 25. Law S, Fok M, Chow S, Chu KM, Wong J. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a pro spective randomized trial. J Thorac Cardiovasc Surg. 1997;114:210–217. 26. Wu AW, Xu GW, Wang HY, Ji JF, Tang JL. Neoadjuvant chemotherapy versus none for resectable gastric cancer. Cochrane Database Syst Rev. 2007;CD005047. 27. Malthaner RA, Collin S, Fenlon D. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev. 2006;3: CD001556. 28. Malthaner R, Fenlon D. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev. 2001;CD001556. 29. Malthaner R, Fenlon D. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev. 2003;CD001556. 30. Urschel JD, Vasan H, Blewett CJ. A meta-analysis of randomized controlled trials that compared neoad juvant chemotherapy and surgery to surgery alone for resectable esophageal cancer. Am J Surg. 2002;183:274–279. 31. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002;359: 1727–1734. 32. Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemother apy in esophageal cancer. J Clin Oncol. 2009;27: 5062–5067. 33. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van d, V, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, MAGIC TP. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20. 34. Boige V, Pignon J, Saint-Aubert B, Lasser, Conroy T, Bouche O, Segol P, Bedenne L, Rougier P, Ychou M. Final results of a randomized trial comparing pre operative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial. ASCO Meeting Abst. June 20, 2007;25(18_suppl): 4510. 35. Greer SE, Goodney PP, Sutton JE, Birkmeyer JD. Neoadjuvant chemoradiotherapy for esophageal carcinoma: a meta-analysis. Surgery. 2005;137: 172–177. 36. Fiorica F, Di BD, Schepis F, Licata A, Shahied L, Venturi A, Falchi AM, Craxi A, Camma C. Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis. Gut. 2004;53: 925–930. 37. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal ther apy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335:462–467.
23. Induction Therapy for Resectable Esophageal Cancer 38. DeMeester SR. Reoperative chemoradiotherapy for oesophageal cancer: a systematic review and metaanalysis. Gut. 2005;54:440–441. 39. Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008;26:1086–1092. 40. Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, Ackland S, Gotley DC, Joseph D, Millar J, North J, Walpole ET, Denham JW. Surgery alone versus chemoradiotherapy followed by sur gery for resectable cancer of the oesophagus: a ran domised controlled phase III trial. Lancet Oncol. 2005;6:659–668. 41. Lee JL, Park SI, Kim SB, Jung HY, Lee GH, Kim JH, Song HY, Cho KJ, Kim WK, Lee JS, Kim SH, Min YI. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiother apy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol. 2004;15:947–954. 42. Rice DC, Correa AM, Vaporciyan AA, Sodhi N, Smythe WR, Swisher SG, Walsh GL, Putnam JB, Jr., Komaki R, Ajani JA, Roth JA. Preoperative chemoradiotherapy prior to esophagectomy in elderly patients is not associated with increased morbidity. Ann Thorac Surg. 2005;79:391–397. 43. Doty JR, Salazar JD, Forastiere AA, Heath EI, Kleinberg L, Heitmiller RF. Postesophagectomy morbidity, mortality, and length of hospital stay after preoperative chemoradiation therapy. Ann Thorac Surg. 2002;74:227–231. 44. D’Journo XB, Michelet P, Papazian L, ReynaudGaubert M, Doddoli C, Giudicelli R, Fuentes PA, Thomas PA. Airway colonisation and postoperative pulmonary complications after neoadjuvant therapy for oesophageal cancer. Eur J Cardiothorac Surg. 2008;33:444–450. 45. Hagry O, Coosemans W, De LP, Nafteux P, Van RD, Van CE, Hausterman K, Lerut T. Effects of preopera tive chemoradiotherapy on postsurgical morbidity and mortality in cT3-4 +/- cM1lymph cancer of the oesophagus and gastro-oesophageal junction. Eur J Cardiothorac Surg. 2003;24:179–186. 46. Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seeber S, Klump B, Budach W, Teichmann R, Schmitt M, Schmitt G, Franke C, Wilke H. Chemoradiation with and without surgery in patients with locally advanced squamous cell carci noma of the esophagus. J Clin Oncol. 2005;23: 2310–2317. 47. Bedenne L, Michel P, Bouche O, Milan C, Mariette C, Conroy T, Pezet D, Roullet B, Seitz JF, Herr JP, Paillot B, Arveux P, Bonnetain F, Binquet C. Chemoradiation
211 followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007;25:1160–1168. 48. Paulson EC, Ra J, Armstrong K, Wirtalla C, Spitz F, Kelz RR. Underuse of esophagectomy as treatment for resectable esophageal cancer. Arch Surg. 2008; 143:1198–1203. 49. Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, Lozach P, Ollier JC, Pavy JJ, Mercier M, Sahmoud T. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell can cer of the esophagus. N Engl J Med. 1997;337:161–167. 50. Le PE, Etienne PL, Meunier B, Maddern G, Ben HM, Gedouin D, Boutin D, Campion JP, Launois B. A ran domized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer. 1994; 73:1779–1784. 51. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001;19:305–313. 52. Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, EngenhartCabillic R, Bitzer M, Konigsrainer A, Budach W, Wilke H. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009; 27:851–856. 53. Arnott SJ, Duncan W, Gignoux M, Hansen HS, Launois B, Nygaard K, Parmar MK, Rousell A, Spilopoulos G, Stewart G, Tierney JF, Wang M, Rhugang Z. Preoperative radiotherapy for esopha geal carcinoma. Cochrane Database Syst Rev. 2005; CD001799. 54. Wang M, Gu XZ, Yin WB, Huang GJ, Wang LJ, Zhang DW. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treat ment of esophageal carcinoma: report on 206 patients. Int J Radiat Oncol Biol Phys. 1989;16: 325–327. 55. Launois B, Delarue D, Campion JP, Kerbaol M. Preoperative radiotherapy for carcinoma of the esophagus. Surg Gynecol Obstet. 1981;153:690–692. 56. Gignoux M, Roussel A, Paillot B, Gillet M, Schlag P, Dalesio O, Buyse M, Duez N. The value of preoperative radiotherapy in esophageal cancer: results of a study by the EORTC. Recent Results Cancer Res. 1988; 110:1–13. 57. Arnott SJ, Duncan W, Kerr GR, Walbaum PR, Cameron E, Jack WJ, Mackillop WJ. Low dose preop erative radiotherapy for carcinoma of the oesopha gus: results of a randomized clinical trial. Radiother Oncol. 1992;24:108–113.
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Appendix 1 Search protocol used 1. EMBASE 2. EMBASE 3. EMBASE 4. EMBASE 5. EMBASE 6. EMBASE 7. EMBASE
exp DRUG THERAPY/ exp MULTIMODALITY CANCER THERAPY/ COMBINED MODALITY THERAPY/ NEOADJUVANT THERAPY/ exp ADJUVANT THERAPY/ PHOTOCHEMOTHERAPY/ ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS/ 9. EMBASE “ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOL*1”.af 10. EMBASE exp ANTINEOPLASTIC AGENTS/ 11. EMBASE 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 9 OR 10 12. EMBASE exp ADENOCARCINOMA/ 13. EMBASE ESOPHAGEAL SQUAMOUS CELL CARCINOMA/ 14. EMBASE 12 OR 13 15. EMBASE exp ESOPHAGUS/ 16. EMBASE ESOPHAGOGASTRIC JUNCTION/ 17. EMBASE LOWER ESOPHAGUS SPHINCTER/ 18. EMBASE STOMACH/ 19. EMBASE 15 OR 16 OR 17 OR 18 20. EMBASE 14 AND 19 21. EMBASE exp STOMACH NEOPLASMS/ 22. EMBASE STOMACH ADENOCARCINOMA/ OR STOMACH CARCINOGENESIS/ OR STOMACH CARCINOID/ OR STOMACH CARCINOMA/ OR STOMACH LYMPHOMA/ OR STOMACH TUMOR/ 23. EMBASE Exp STOMACH CANCER/ 24. EMBASE STOMACH CANCER/ 25. EMBASE exp ESOPHAGEAL NEOPLASMS/ 26. EMBASE ESOPHAGUS TUMOR/ 27. EMBASE ESOPHAGUS CANCER/ 28. EMBASE exp ESOPHAGUS CANCER/ 29. EMBASE 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 30. EMBASE 20 OR 29 31. EMBASE ESOPHAGUS RESECTION/ 32. EMBASE ESOPHAGECTOMY/ 33. EMBASE exp ESOPHAGUS SURGERY/ 34. EMBASE GASTRECTOMY/ 35. EMBASE exp STOMACH SURGERY/ 36. EMBASE SURGERY/ 37. EMBASE 31 OR 32 OR 33 OR 34 OR 35 OR 36 38. EMBASE 30 AND 37 39. EMBASE 11 AND 38 40. EMBASE exp RANDOMIZED CONTROLLED TRIAL/ 41. EMBASE exp CONTROLLED CLINICAL TRIAL/ 42. EMBASE 40 OR 41 43. EMBASE 39 and 42 [Limit to: Publication Year 2004-Current and Human] 44. MEDLINE exp DRUG THERAPY/
918,871 results 9,645 results 9,645 results 13,126 results 38,821 results 1,712 results 93,883 results
45. MEDLINE 46. MEDLINE 47. MEDLINE 48. MEDLINE 49. MEDLINE 50. MEDLINE 51. MEDLINE
0 results 771,649 results 1,409,300 results 16,656 results 1,206 results 17,855 results 26,157 results 4,737 results 4,737 results 42,001 results 63,129 results 850 results 43,569 results 19,715 results
40,425 results 24,810 results 25,004 results 1,609 results 11,669 results 23,451 results 64,190 results 64,394 results 5,907 results 5,907 results 11,747 results 8,823 results 28,701 results 35,250 results 73,161 results 11,946 results 3,251 results 176,320 results 188,954 results 188,954 results 93 results 885,767 results
52. MEDLINE 53. MEDLINE 54. MEDLINE 55. MEDLINE 56. MEDLINE 57. MEDLINE 58. MEDLINE 59. MEDLINE 60. MEDLINE 61. MEDLINE 62. MEDLINE 63. MEDLINE 64. MEDLINE
65. MEDLINE 66. MEDLINE 67. MEDLINE 68. MEDLINE 69. MEDLINE 70. MEDLINE 71. MEDLINE 72. MEDLINE 73. MEDLINE 74. MEDLINE 75. MEDLINE 76. MEDLINE 77. MEDLINE 78. MEDLINE 79. MEDLINE 80. MEDLINE 81. MEDLINE 82. MEDLINE 83. MEDLINE 84. MEDLINE 85. MEDLINE
exp MULTIMODALITY CANCER THERAPY/ COMBINED MODALITY THERAPY/ NEOADJUVANT THERAPY/ exp ADJUVANT THERAPY/ PHOTOCHEMOTHERAPY/ ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS/ “ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOL*1”.af exp ANTINEOPLASTIC AGENTS/ 44 OR 45 OR 46 OR 47 OR 48 OR 49 OR 50 OR 51 OR 52 exp ADENOCARCINOMA/ ESOPHAGEAL SQUAMOUS CELL CARCINOMA/ 54 OR 55 exp ESOPHAGUS/ ESOPHAGOGASTRIC JUNCTION/ LOWER ESOPHAGUS SPHINCTER/ STOMACH/ 57 OR 58 OR 59 OR 60 56 AND 61 exp STOMACH NEOPLASMS/ STOMACH ADENOCARCINOMA/ OR STOMACH CARCINOGENESIS/ OR STOMACH CARCINOID/ OR STOMACH CARCINOMA/ OR STOMACH LYMPHOMA/ OR STOMACH TUMOR/ Exp STOMACH CANCER/ STOMACH CANCER/ exp ESOPHAGEAL NEOPLASMS/ ESOPHAGUS TUMOR/ ESOPHAGUS CANCER/ exp ESOPHAGUS CANCER/ 63 OR 64 OR 65 OR 66 OR 67 OR 68 OR 69 OR 70 62 OR 71 ESOPHAGUS RESECTION/ ESOPHAGECTOMY/ exp ESOPHAGUS SURGERY/ GASTRECTOMY/ exp STOMACH SURGERY/ SURGERY/ 73 OR 74 OR 75 OR 76 OR 77 OR 78 72 AND 79 53 AND 80 exp RANDOMIZED CONTROLLED TRIAL/ exp CONTROLLED CLINICAL TRIAL/ 82 OR 83 81 and 84 [Limit to: Publication Year 2004-Current and Human]
0 results 118,757 results 5,853 results 0 results 9,616 results 82,647 results 82,647 results 679,133 results 1,479,430 results 231,237 results 0 results 231,237 results 36,473 results 5,524 results 0 results 45,929 results 78,746 results 2,878 results 62,548 results 0 results
62,548 results 62,548 results 31,456 results 0 results 31,456 results 31,456 results 89,137 results 89,433 results 0 results 4,275 results 0 results 22,402 results 0 results 30,336 results 56,447 results 12,121 results 2,181 results 291,215 results 82,977 results 369,202 results 41 results
24
Optimal Surgical Approach to Esophagectomy for Cancer Brechtje A. Grotenhuis, Bas P.L.Wijnhoven, and Jan J.B. van Lanschot
Introduction Surgery is the primary curative therapy for patients with esophageal cancer. It is now widely recognized that a surgical procedure such as esophagectomy has lower mortality and morbidity rates when performed in high-volume centers.1,2 Nevertheless, esophagectomy is still associated with a substantial operative risk.3,4 For continuous improvement of esophagectomy outcome, an optimal treatment strategy should not only be based on proper patient selection by means of accurate staging and preoperative risk assessment. Optimization of the surgical approach for patients with esophageal cancer has also been the focus of many studies over the last years. Two major surgical approaches in case of esophagectomy for cancer have emerged during the past decades: a radical esophagectomy with extended lymphadenectomy (transthoracic esophagectomy – TTE) and a more limited surgical procedure with only regional lymphadenectomy (transhiatal esophagectomy – THE). TTE aims to improve locoregional control and longterm survival by performing a wide excision of the tumor in combination with an en bloc lymph node dissection in both the mediastinum and upper abdomen. An additional advantage of an extended resection is the improved pathological lymph node staging leading to a potential shift from falsely node-negative patients to correctly node-positive patients, so-called stage migration. On the contrary, THE aims to minimize surgical trauma and thus to improve short-term outcome by means of decreased early morbidity and mortality. Further
more, newly developed operative strategies focus on minimally invasive esophagectomy (MIE) for esophageal cancer surgery in the hope of decreasing patient’s morbidity after esophagectomy. Driven by the early success of the development of minimally invasive techniques for the treatment of other (mostly benign) upper GI conditions, thoracoscopic esophagectomy was first reported in 1992 by Cuschieri.5,6 The goal of minimally invasive techniques is to decrease the trauma applied to the tissues by replacing the surgeon’s hand by small instruments. The absence of tissue distraction of the abdominal and chest walls also lessens the overall inflammatory response to surgery. It is hypothesized that the decrease in stress response can lead to a decrease in blood loss, postoperative pain sensation and overall morbidity, thus allowing faster postoperative recovery. The purpose of this chapter is to assess the present literature and offer suggestions for an optimal surgical treatment of esophageal carcinoma. We will compare the two open procedures (TTE versus THE) with regard to staging of the tumor, shortterm outcome and long-term survival. In the second part of the chapter, we will discuss the presently available literature with regard to the feasibility and potential advantages of MIE.
Methods A review of the English-language literature (1990– 2009) concerning surgical techniques for esophageal cancer was performed. All human studies
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comparing TTE with THE for carcinoma of the esophagus or the gastroesophageal junction as well as studies describing the outcome after MIE were identified, using the medical subject headings ‘esophageal cancer’ and ‘surgery’. All titles and abstracts were scanned, and appropriate citations were reviewed. Adenocarcinoma and squa mous cell carcinoma have not been analyzed separately. The literature search was confined to studies displaying the short-term and long-term (in terms of overall 5-year survival) outcome after TTE and THE, as well as studies reporting on the outcome after MIE. With regard to the open procedures, studies comparing TTE with THE were divided into three groups: meta-analyses, randomized clinical trials (RCTs) and prospective nonrandomized comparative studies. For the relatively new technique of MIE, nonrandomized reports were studied comparing the minimally invasive technique with the open procedure with regard to short-term outcome, whereas the results of only a few studies have become available with regard to long-term outcome following MIE.
Open Esophagetomy: Transthoracic Versus Transhiatal Effect on Staging TTE with extended lymphadenectomy can offer better insight in the lymphatic dissemination of tumor cells. Dissecting more lymph nodes increa ses the chance of finding a tumor positive node, which may influence pathological staging of the tumor (stage-migration). On the contrary, due to a limited regional lymphadenectomy with the inferior pulmonary veins as a cranial boundary, patients operated upon through the transhiatal route may be staged falsely as node-negative when positive nodes in the upper and middle part of the chest have not been dissected. The diagnostic yield of an extended lymphadenectomy has been studied7: 37% of patients who underwent TTE showed tumor-positive nodes in extended fields. In 20% of patients positive nodes were found in the abdomen (mainly at the celiac trunk) and in 20% in the mediastinum, where subcarinal nodes were mostly affected. Extended resection led to tumor
upstaging in 23% of patients, however, mainly due to positive nodes at the celiac trunk (20%) which can also be resected during THE.7 More recently, proponents of an extended resection with en bloc lymphadenectomy showed that the number of removed lymph nodes is an independent predictor of survival after esophagectomt for cancer8 and that the number of involved lymph nodes can be used to predict the likelihood of systemic disease.9
Clinical Effects on Short- and Long-term Outcome Meta-analysis One meta-analysis of the English-language literature between 1990 and 1999 comparing TTE with THE for carcinoma of the esophagus and/or the gastroesophageal junction has been published.10 In this study, RCTs, comparative studies and case-series describing 50 patients or more were included. The differences between TTE and THE with regard to perioperative morbidity, early mortality and long-term survival, limiting transthoracic resection to the standard en bloc and two-field approaches, were systematically reviewed. Perioperative blood loss was significantly higher after TTE. TTE resection was also associated with a higher risk of pulmonary infection, chyle leakage and wound infection. In contrast, vocal cord paralysis and anastomotic leakage were more frequent after THE. Patients operated via the transthoracic route stayed slightly longer in the ICU, and also longer in the hospital. The in-hospital mortality was significantly higher after TTE (9.2% vs. 5.7%), although this difference was not confirmed in the three (small) RCTs which were available at that time. There were no differences in long-term survival between TTE and THE resections. However, if only the comparative studies were taken into account, there was a significant 5-year survival benefit for patients operated through TTE. From this meta-analysis it was concluded that there was a paucity of RCTs and high-quality prospective comparative studies.
RCTs Only few studies have been conducted that randomly compared both open surgical techniques for esophageal cancer.3,11–13 Goldminc et al. have
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24. Optimal Surgical Approach to Esophagectomy for Cancer
performed a randomized trial of 67 patients undergoing esophagectomy for cancer through the transhiatal or transthoracic route.11 A few of the included patients (N = 29) underwent preoperative chemo- or radiotherapy, in a randomized setting.14 No differences between the groups were found in postoperative complications and survival. Long-term survival data have now become available, but no significant differences have been detected between both groups.15 Jacobi et al. have randomized 32 patients between TTE and THE for esophageal cancer.13 TTE was found to be associated with an increased intraoperative pulmonary strain, which was completely compensated during the postoperative course resulting in a comparable recovery within 30 days. Since the aim of this study was to evaluate the effects of both techniques on perioperative cardiopulmonary function, no survival data were reported. Chu et al. have performed a randomized trial comparing TTE and THE in 39 patients with a tumor in the distal third of the esophagus.12 Again, no statistical differences in short-term outcome were identified. Long-term survival data have now become available: after a minimal potential follow-up of 5 years no significant difference between the two groups has been detected.15 Hulscher et al. have performed a large randomized two-center trial (‘Dutch trial’).3 Patients with adenocarcinoma of the mid/distal esophagus or adenocarcinoma of the gastric cardia substantially involving the distal esophagus were randomly assigned to TTE with two-field lymphadenectomy or limited THE. A total of 114 patients were assigned to undergo TTE, and 106 patients to undergo THE. Perioperative morbidity was higher after TTE, especially pulmonary complications were seen more often (TTE 57% versus THE 27%), but there was no difference with regard to in-hospital mortality (p = 0.45). Although the difference in survival was not statistically significant, there was a trend towards a survival benefit with the extended approach at 5 years: disease-free survival was 39% in the TTE group, compared to 27% in the THE group. Recently, complete 5-year survival data have become available.16 After TTE and THE 5-year survival rates were 36% and 34%, respectively (p = 0.71). In a subgroup analysis based on the location of the primary tumor,17 no overall survival benefit for either surgical approach was seen in 115 patients with a type II junctional
tumor (TTE 27% versus THE 31%, p = 0.81). However, in 90 patients with a type I esophageal tumor an absolute survival benefit of 14% was seen with the transthoracic approach (51% vs. 37%, p = 0.33). Furthermore, there was evidence to suggest that the treatment effect differed depending on the number of positive lymph nodes in the resection specimen.16 In patients without positive lymph nodes or patients with more than eight positive lymph nodes, locoregional disease-free survival after TTE was comparable to that after THE. Patients with one to eight positive lymph nodes in the resection specimen (N = 104) showed a 5-year locoregional disease-free survival advantage if operated through TTE (64% versus THE 23%, p = 0.02). In conclusion, there was no significant overall survival benefit for either approach. However, compared to THE, TTE with extended lymphadenectomy for type I esophageal adenocarcinoma showed an ongoing trend towards better 5-year survival. For type II junctional adenocarcinoma an extended approach does not result in a survival benefit, which confirms the previously published results of a RCT by Sasako et al. in which no improvement in survival has been shown after a left thoracoabdominal approach when compared to THE in this subgroup of tumors.18
Nonrandomized Comparative Studies After publication of the meta-analysis comprising all available literature between 1990 and 1999,10 another three nonrandomized comparative studies comparing TTE with THE for esophageal cancer have been conducted from prospective databases. Two studies reported on short-term outcome after esophagectomy, showing similar overall morbidity rates after TTE and THE.19,20 With regard to overall 5-year survival, the three studies showed contradictive results: a survival benefit in favor of TTE (51% versus THE 22%, p = 0.04),21 an improved survival after THE (31% versus 23% TTE, p = 0.02)20 and no difference in survival between both techniques (TTE 34% versus THE 53%, p = 0.23)19 were reported. However, the study in which a survival benefit after THE was observed, comprised a multicenter study from a nationwide database and after adjusting for differences in patient and institutional factors, the survival advantage was no longer statistically significant.20
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Summary
Furthermore, TTE used to be associated with a significantly higher mortality rate, but this difference was not detected in the more recent Dutch study. Overall, results are in line with large comparative studies (TTE versus THE) in which esophagectomies for benign disease were also included, that showed a similar short-term outcome for TTE and THE.22,23
The results of a meta-analysis, the most recent large RCT (‘Dutch trial’) and three recent comparative studies with regard to the short-term outcome after esophagectomy for cancer have been summarized in Table 24.1. In both the meta- analysis and the RCT significantly higher pulmonary morbidity rates were observed after TTE.
Table 24.1. The results of the meta-analysis and most recently published RCT and comparative studies with regard to the short-term outcome after esophagectomy for cancer (pulmonary and cardiac complications, mortality and length of hospital stay). Number of patients
Pulmonary complications Meta-analysis - earlier randomized - earlier comparative - comparative + noncomparative Hulscher – RCT Morgan Chang
% patients with complications
Statistics
TTE
THE
TTE
THE
RR
95% CI
p-value
51 765 2,070 114 119 643
48 698 2,397 106 32 225
37.3% 22.9% 18.7% 57% – –
43.8% 26.1% 12.7% 27% – –
0.85 – 1.47 – – –
0.53–1.38 – 1.29–1.68 – – –
– – – <0.001 – –
35 563 1,638 114 119 643
36 458 1,084 106 32 225
17.1% 10.3% 6.6% 26% – –
22.2% 9.0% 19.5% 16% – –
0.77 – 0.34 – – –
0.30–1.90 – 0.27–0.41 – – –
– – – ns – –
70 1,375 3,942 114 119 643
68 1,164 3,301 106 32 225
1.4% 9.8% 9.2% 4% 4% 13.1%
8.8% 7.2% 5.7% 2% 6% 6.7%
0.12 – 1.60 – – –
0.04–1.12 – 1.42–1.89 – – –
– – – ns ns 0.009
54 679 1,198 114 119 643
52 654 1,397 106 32 225
21.2 20.6 21.0 19 17 21
19.5 19.3 17.8 15 17 21
– – – – – –
– – – – – –
ns – <0.001 <0.001 ns ns
Cardiac complications Meta-analysis - earlier randomized - earlier comparative - comparative + noncomparative Hulscher – RCT Morgan Chang Mortality Meta-analysis - earlier randomized - earlier comparative - comparative + noncomparative Hulscher – RCT Morgan Chang Hospital stay Meta-analysis - earlier randomized - earlier comparative - comparative + noncomparative Hulscher – RCT Morgan Chang
Author
Year
Hulscher et al. Hulscher et al.3 Morgan et al.19 Chang et al.20
10
2001 2002 2007 2008
Evidence Meta-analysis RCT Prospective comparative Prospective comparative
N
Neoadjuvant therapy
50 studies 220 patients 151 patients 868 patients
Mixed No Yes, all patients Mixed
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24. Optimal Surgical Approach to Esophagectomy for Cancer
Due to the heterogeneity of the studies, especially with regard to tumor type and application of neoadjuvant therapy, a formal meta-analysis of the long-term survival data cannot be performed. The results of the described studies with regard to the long-term outcome after esophagectomy for cancer in terms of 5-year overall survival are summarized in Table 24.2. Although the smallest nonrandomized comparative study (in which only patients with advanced locoregional disease were included) showed a survival benefit in favor of TTE, the metaanalysis as well as all RCTs did not reveal any differences in overall survival between TTE and THE for the overall patient groups. However, TTE and THE had a similar in-hospital mortality, and for type I tumors there was a clinically relevant higher survival rate for TTE (although not statistically significant, most likely due to a type II error) as shown in the largest RCT.
Minimally Invasive Esophagectomy Operative Techniques and Learning Curve Since the late nineties several publications have become available that discuss the feasibility of minimally invasive approaches for esophagectomy. Many different techniques are described, without a consensus with regard to the most optimal approach. Development and refining of novel techniques in MIE is mainly driven by centers and surgeons pioneering this technically challenging cancer operation. The approaches described for MIE are summarized in Table 24.3. As with most new surgical techniques MIE is fraught with potential pitfalls in nearly every step of the procedure. Many series on open esophagectomy discuss the fact that morbidity
Table 24.2. The results of the meta-analysis and most recently published RCT and comparative studies with regard to the long-term outcome after esophagectomy for cancer (5-year overall survival). Number of patients
Overall 5-year survival Meta-analysis - earlier randomizeda - earlier comparative - comparative + noncomparative Hulscher – RCT Morgan Chang Rizzettob a
Percentage of surviving patients
Statistics
TTE
THE
TTE
THE
RR
95% CI
– 807 2,677 114 199 643 40
– 499 2,264 106 32 225 18
– 35.2% 23.0% 36% 34% 22.7% 51%
– 24.9% 21.7% 34% 53% 30.5% 22%
– 1.41 1.06 – – 0.95 –
– 1.68–1.89 0.96–1.18 – – 0.75–1.20 –
p-value
– – – ns ns – 0.04
Note: At the time of publication of the meta-analysis, long-term survival data were not available for the three earlier published RCTs. Only patients with advanced locoregional disease were included.
b
Author
Year
Hulscher et al. Hulscher et al.3 Morgan et al.19 Chang et al.20 Rizetto et al.21
10
2001 2002 2007 2008 2008
Evidence Meta-analysis RCT Prospective comparative Prospective comparative Prospective comparative
N 50 studies 220 patients 151 patients 868 patients 58 patients
Neoadjuvant therapy Mixed No Yes, all patients Mixed Yes, all patients
Table 24.3. Operative techniques that have been described for MIE in the literature. Operative Techniques Transthoracic esophagectomy
Transhiatal esophagectomy Robot-assisted esophagectomy
Totally minimally invasive procedure (thoracoscopic and laparoscopic esophagectomy with cervical or intra-thoracic anastomosis) Hybrid procedures (thoracosopic esophageal moblization with a small laparotomy and cervical anastomosis or laparoscopic gastric mobilization with thoracotomy and intrathoracic anastomosis) Totally laparoscopic esophagectomy Hand-assisted laparoscopic esophagectomy (with a small laparotomy for specimen removal and oversewing the gastric tube) DaVinci robot
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and mortality rates decrease with experience.24 Although little is known regarding the learning curve for MIE, it has been suggested that it may persist for more than 50 procedures.25,26 In a group of 81 patients who underwent a thoracoscopic esophagectomy, it appeared that operation time, blood loss and pulmonary complication rate were less and that the number of retrieved lymph nodes was higher in the second half of the series.27 Similar findings have been reported by Song et al. in a smaller cohort of patients.28 However, it remains difficult to determine when a surgeon is proficient in MIE.
Patient Selection Both tumor-related and patient-related factors should be evaluated before commencing MIE. Early (submucosal) cancer is considered by many surgeons as an excellent starting point. Once technical advances have been made, more advanced disease can also be resected by minimally invasive techniques. Early studies on MIE showed an overrepresentation of early disease in the MIE group,29 whereas in more recent studies stage distribution more or less equals that in open surgery. However, bulky disease can be difficult to completely and safely resect via a minimally invasive approach. It has been questioned if the radicality of the resection and the extent of the lymphadenectomy in particular can be as complete as with open surgery. Furthermore, the physical condition of the patient must be at least equal to that of patients planned for open surgery: the cardiopulmonary status must be excellent or good to withstand the fluid shifts and the systemic inflammatory reaction. The time needed for one-lung ventilation in MIE (with the patient in left lateral position) also may be longer than for open surgery. When
thoracoscopic esophagectomy in prone position is chosen, no formal single lung ventilation is required since gravity and establishment of a pneumothorax with gas insufflation usually suffices for an excellent exposure. No history of previous thoracic or abdominal surgery seems most important when performing MIE in order to obtain access and to dissect in a safe way. Finally, neoadjuvant therapy might increase the risk of surgical morbidity in MIE.
Clinical Effects on Short- and Long-term Outcome Recent review articles pooled the data on studies comparing open with minimally invasive esophagectomy in terms of short-term outcome, resulting in a total number of more than a thousand patients that underwent MIE in these reviews.26,30–32 The short-term outcome of different techniques for MIE is summarized in Table 24.4. In general, there were no differences when comparing the transthoracic MIE with open TTE or the transhiatal MIE with open THE. The mortality rate of MIE was around 2.5% based on the weighted means of the included studies and is more or less similar to open series from expert centers.26,31 One should realize that the definitions of mortality (30day mortality versus in-hospital mortality) vary among studies. The overall complication rate reported for MIE was 40–50%.26,31,32 Some studies report lower overall morbidity rates for MIE as compared to open surgical controls but, in general, no statistical significance was reached.30,32 The mean pulmonary complication rate was 13–22%,26,31 but again there is a wide variability in definitions. Most studies report that blood loss seems to be less in MIE.30,32 Hospital stay tended to be reduced in most studies on MIE as compared to open surgery, and the same was true with regard to time spent in
Table 24.4. Short-term outcome of different techniques for MIE, as adapted from two systematic reviews.26,31 No. studies Gemill et al.31 Different MIE techniques Decker et al.26 Transhiatal MIE Transthoracic MIE a
Presented as median value.
No. patients
Conversion (%)
Mortality (%)
Overall morbidity (%)
Pulmonary complications (%)
Hospital staya (days)
23
1,398
4.9
2.3
46.2
13.2
11.0
17 29
433 1,499
7.0 5.6
4.6 2.4
46.1 47.7
22.0 21.7
10.0 12
219
24. Optimal Surgical Approach to Esophagectomy for Cancer Table 24.5. Long-term 5-year survival following MIE.
Martin Yamamoto Smithers Zingg a
No. patients
Tumor stage
34
I–IV
112 332 56
I–II I–IV I–III
Approach Thoracoscopically assisted (N = 15), thoracoscopy + hand-assisted laparoscopy (N = 21) Thoracoscopically assisted Thoracoscopically assisted (N = 309), total MIE (N = 23) Thoracoscopically assisted (N = ?), thoracoscopy + hand-assisted laparoscopy (N = ?)
5-year survival (%)
Locoregional recurrence
22a
Not reported
52 41 39a
Not reported Not reported Not reported
Estimated from Kaplan-Maier survival curve in original paper.
Author
Year
Neoadjuvant therapy
Martin et al.34 Yamamoto et al.35 Smithers et al.36 Zingg et al.33
2005 2005 2007 2009
Mixed Mixed Mixed Mixed
ICU.30,32 These data however can be easily biased due to different hospital policies towards ICU admittance and timing of extubation. Overall, selection bias is inevitably introduced in the studies comparing open esophagectomy with MIE. Some studies prospectively collected their data on MIE, and compared these results to retrospectively gathered data from open series or matched controls. Other reports are retrospective in nature or do not provide insight in the type of data collection. In a recent study in which MIE was compared with open esophagectomy an attempt was made to match the controls (open esophagectomy) with the cases (MIE) with regard to tumor stage and patient characteristics.33 The results showed that the open procedure and MIE have comparable morbidity and mortality rates.33 With regard to the long-term outcome after MIE, it appears that approximately 50% of papers published on MIE until 2007 do not report on oncological outcome data or any follow-up.26 Details on the level and type of lymph node dissection also is lacking in many reports. Although the number of removed lymph nodes is stated in most papers, the exact location of these nodes remains unclear. Furthermore, an open en bloc TTE entails removal of the primary tumor together with the azygos vein, thoracic duct, ipsi- with- or without contralateral pleura and various lymph nodal stations. However, most series on MIE do
not report on removing these structures and therefore the oncological safety of MIE in advanced tumors can be questioned. Complete microscopic tumor resection (pR0) was achieved in approximately 90% and is comparable with the open technique.26,31 Median lymph node yield was 14–18 lymph nodes,26,31 which in general did not differ with open surgery.30 Finally, there are only scant data on long-term outcome after MIE. Results with regard to 5-year survival following MIE are summarized in Table 24.5. However, adequate data on disease recurrence are lacking.
Summary Although MIE is feasible, there is no evidence from the literature to suggest that MIE is superior to open esophagectomy, in particular because valid direct comparisons with open surgery are lacking. Many studies are biased by surgeons’ experience and case selection (tumor stage). Nevertheless, rough comparisons with reports on open surgery suggest that a reduction in blood loss and respiratory complications plus a more rapid postoperative recovery are areas in which minimally invasive surgery might prove superior in terms of short-term outcome. More importantly, prospective controlled studies will be required to more accurately define the survival and recurrence pattern following MIE as compared to open techniques. A successful randomized trial requires a group of surgeons with sufficient experience of the procedure to reach agreement on the appropriate questions, and to reach consensus on the definition of the procedure to be tested against open surgery.
220
Conclusions and Recommendations TTE and THE have similar in-hospital mortality rates, and for type I tumors TTE has clinically relevant higher survival rates (although not statistically significant, most likely due to a type II error) as shown in the largest RCT (evidence quality high). We strongly recommend TTE in patients with a tumor of the esophagus (who are fit for major surgery) and THE in patients with a tumor at the gastroesophageal junction or cardia, unless positive lymph nodes have been identified at or proximal to the carina (recommendation grade 1B). MIE is feasible and safe, but long-term outcomes are as yet not known; there is insufficient evidence from the literature to adequately evaluate MIE compared to open esophagectomy (evidence quality low). We make a weak recommendation for open esophagectomy rather than MIE for cancers of the esophagus and gastroesophageal junction (recommendation grade 2C).
TTE and THE have similar in-hospital mortality rates and for type I tumors TTE has clinically relevant higher survival rates (evidence quality moderate). We strongly recommend TTE in patients with a tumor of the esophagus, and THE in patients with a tumor of the gastroesophageal junction or cardia (recommendation grade 1B)
MIE is feasible and safe, but long-term outcomes are as yet not known (evidence quality low). We make a weak recommendation for open esophagectomy rather than MIE for cancers of the esophagus or gastroesophageal junction (recommendation grade 2C).
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221 25. Bizekis C, Kent MS, Luketich JD, Buenaventura PO, Landreneau RJ, Schuchert MJ, Alvelo-Rivera M. Initial experience with minimally invasive Ivor Lewis esophagectomy. Ann Thorac Surg. 2006;82: 402–406. 26. Decker G, Coosemans W, De Leyn P, Decaluwe H, Nafteux P, Van Raemdonck D, Lerut T. Minimally invasive esophagectomy for cancer. Eur J Cardio thorac Surg. 2009;35:13–20. 27. Osugi H, Takemura M, Higashino M, Takada N, Lee S, Ueno M, Tanaka Y, Fukuhara K, Hashimoto Y, Fujiwara Y, Kinoshita H. Learning curve of videoassisted thoracoscopic esophagectomy and extensive lymphadenectomy for squamous cell cancer of the thoracic esophagus and results. Surg Endosc. 2003;17:515–519. 28. Song SY, Na KJ, Oh SG, Ahn BH. Learning curves of minimally invasive esophageal cancer surgery. Eur J Cardiothorac Surg. 2009;35:689–693. 29. Luketich JD, Alvelo-Rivera M, Buenaventura PO, Christie NA, McCaughan JS, Litle VR, Schauer PR, Close JM, Fernando HC. Minimally invasive esophagectomy: outcomes in 222 patients. Ann Surg. 2003;238:486–494. 30. Biere SS, Cuesta MA, van der Peet DL. Minimally invasive versus open esophagectomy for cancer: a systematic review and meta-analysis. Minerva Chir. 2009;64:121–133. 31. Gemmill EH, McCulloch P. Systematic review of minimally invasive resection for gastro-oesophageal cancer. Br J Surg. 2007;94:1461–1467. 32. Verhage RJ, Hazebroek EJ, Boone J, Van Hillegers berg R. Minimally invasive surgery compared to open procedures in esophagectomy for cancer: a systematic review of the literature. Minerva Chir. 2009;64:135–146. 33. Zingg U, McQuinn A, DiValentino D, Esterman AJ, Bessell JR, Thompson SK, Jamieson GG, Watson DI. Minimally invasive versus open esophagectomy for patients with esophageal cancer. Ann Thorac Surg. 2009;87:911–919. 34. Martin DJ, Bessell JR, Chew A, Watson DI. Thor acoscopic and laparoscopic esophagectomy: initial experience and outcomes. Surg Endosc. 2005;19: 1597–1601. 35. Yamamoto S, Kawahara K, Maekawa T, Shiraishi T, Shirakusa T. Minimally invasive esophagectomy for stage I and II esophageal cancer. Ann Thorac Surg. 2005;80:2070–2075. 36. Smithers BM, Gotley DC, Martin I, Thomas JM. Comparison of the outcomes between open and minimally invasive esophagectomy. Ann Surg. 2007;245:232–240.
25
Extent of Lymph Node Dissection in Esophageal Cancer Thomas W. Rice and Eugene H. Blackstone
Introduction Lymphadenectomy is a standard component of esophagectomy, but how extensive it should be for accurate cancer staging and to maximize survival is controversial. In developing recommendations for extent of lymphadenectomy during esophagectomy, we will first review new knowledge about the anatomy of the esophageal lymphatics, both within the esophageal wall and the “region,” and its implications for regional lymph node metastases, which in turn affect survival. We will then review the literature to develop recommendations for extent of lymphadenectomy during esophagectomy. Finally, we will examine controversies surrounding the mechanisms by which lymphadenectomy influences survival following esophagectomy.
Esophageal Lymphatics Mural Lymphatics A recent immunohistochemical study of the esophageal mural lymphatics using lymphatic endothelial marker D2-40 has provided new insight into this lymphatic anatomy (Fig. 25.1).1 There is a dense longitudinal plexus of lymphatic vessels in the lamina propria. Rare perforating lymphatics drain into a sparse circumferential lymphatic network in the outer margin of the submucosa. Perforating lymphatics from the submucosal plexus, usually running with an artery and
vein, penetrate the inner circular layer of the muscularis propria. Here, they drain into a circumferential intramuscular plexus. Afferent lymphatics, again accompanied by an artery and vein, drain the intramuscular plexus into the lymphatic channels in the adventitia. No direct connections from the lamina propria network to the thoracic duct have been identified. The number and circumferential extent of mural lymphatics vary by as much as a factor of 3 among patients. This lymphatic anatomy of the esophageal wall is different from and more complex than previously thought, consisting of longitudinal networks at the boundaries of the mucosa, submucosa, and inner circular muscle layer. Lymphatic variability among patients is the norm. There are important clinical implications of a dominant lamina propria lymphatic network in promoting regional lymph node metastases. This new understanding of esophageal lymphatic anatomy shifts the focus from the submucosa to the lamina propria as the leading source of regional lymph node metastases in superficial esophageal cancers. It brings to light the inadequacy of a one-dimensional descriptor – depth of tumor invasion – in the classification of the primary tumor (T) and its relation to lymphatic metastases. It explains why tumor length, a reflection of longitudinal invasion of mural lymphatics, may be a better predictor of lymph node metastases2,3 and survival than simple depth of invasion.2–5 It begs for the addition of circumferential involvement in the classification of T and investigation of its association with lymphatic metastases.6 Theoretically, tumor volume (depth, length,
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_25, © Springer-Verlag London Limited 2011
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Figure 25.1. The esophageal wall and its lymphatics.
and circumference) may be the best primary tumor characteristic predicting regional lymph node metastases and survival. This anatomic arrangement explains in part the importance of lymphovascular invasion (LVI) as a predictor of regional lymph node metastases and survival, an additional descriptor for staging and a factor directing therapy.3,7–9 It also explains why histologic grade, a simple measure of tumor biology and invasiveness, is critical in staging, treatment, and survival of early-stage cancers.8–11
Regional Lymphatics and Lymph Nodes Unlike other tubular gastrointestinal organs or the lung, where lymphatic drainage is centripetal to the root of the mesentery or hilum, respectively, esophageal lymphatic drainage is longitudinal (Fig. 25.1); that is, lymphatic metastases develop orthogonal to tumor invasion.12 Implications of the longitudinal nature of lymphatic drainage are that anatomic location of the primary cancer and location of the nodes to which lymphatics drain from that cancer may not coincide. For this reason, the definition of a regional lymph node now includes any periesophageal lymph node extending from cervical to celiac nodes.9
Although regional lymph nodes may be found scattered in the region of the extramural lymphatic network, they are generally concentrated. The majority of cervical lymph nodes are located about the recurrent laryngeal nerves and the carotid sheath. The major thoracic hub is located in the region of the tracheobronchial bifurcation and pulmonary hilum. These nodes drain both the esophagus and the lung, and the direction of lymph flow may be either cephalad or caudad. Below this, most lymph flow proceeds caudad. The major abdominal hub of regional lymph nodes is located at the esophagogastric junction, cardia, and lesser omentum. In contrast to the thoracic hub, it is more diffuse. There are marked differences in the adventitial lymphatic system according to the side of the esophagus on which the lymphatic is found.13 Lymphatic drainage from the right side of the esophagus is longitudinal and multistationed; longitudinal lymphatics are less well developed on the left side of the esophagus and frequently drain into the thoracic duct.13 Existence of direct routes from mural and extramural lymphatics to the thoracic duct, without relay through regional lymph nodes, has been documented14–16; however, the exact patterns and occurrence of these pathways are highly variable.
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It is a revolutionary concept that the esophagus comprises a single region drained by a lymphatic system that is not uniformly distributed, but it is a reality. The clinical implications of this redefinition are important for extent of lymphadenectomy.
Prognostic Importance of Metastatic Lymph Node Burden Recent analysis demonstrates that number of regional lymph nodes containing metastases (positive nodes) is the most important prognostic factor in resectable esophageal cancers.9–11,17 In classifying N, the data support convenient coarse groupings of number of positive nodes (0, 1–2, 3–6, 7 or more) and have been designated N1 (1–2), N2 (3–6), and N3 (7 or more).9,11,17 Nevertheless, there are no sharp cut-points; rather, each additional positive node increases risk. Lymph node burden is predictive of distant metastases; survival of patients with 9 or more positive nodes is equivalent to that of patients with distant metastatic disease.17,18
Methodology of Literature Search Ten searches were performed (Table 25.1) that identified literature from the last 10 years; these were limited to publications in English and Table 25.1. Terms used to identify relevant literature for review. 1. Cochrane review, systematic review, meta analysis, Medline, MESH heading for esophageal cancer and lymphadenectomy 2. Esophageal neoplasms and lymph node excision 3. Esophageal neoplasms, extent of lymph node excision 4. Esophageal cancer, role of lymphadenectomy 5. Esophageal neoplasms, esophageal cancer, esophagectomy, neoplasm staging, lymph node/s, lymph node excision, lymphatic metastases, and lymphadenectomy 6. Esophageal cancer, regional node metastases, regional lymph node metastases, and distant metastases 7. Esophageal cancer, regional lymphatic metastases, and immunohistochemistry 8. Esophagus or esophageal cancer/neoplasm, lymph node excision, lymph node surgery, lymphadenectomy, 3-field lymphadenectomy 9. Surgery for esophageal cancer, transhiatal, transthoracic 10. Esophageal neoplasms or esophagectomy, lymph node surgery or excision or sentinel lymph node biopsy, prognosis, risk management, survival, mortality, and treatment outcomes
information concerning humans. Additionally, from the bibliography of key papers and the authors’ libraries, important older and in-press manuscripts were added.
Extent of Lymphadenectomy Number of Lymph Nodes Resected Only one study has examined the number of resected lymph nodes necessary to adequately predict positive lymph node classification (pN+).19 Although the sensitivity of classifying pN+ continued to improve up to 100 nodes examined, maximum increase of sensitivity occurred from 0 to 6 nodes, and over 90% sensitivity was reached at 12 nodes. Many recent studies have attempted to identify a specific number of lymph nodes that should be resected and examined to maximize survival (Table 25.2). These analyses examine goodness of fit or P values to test for a statistically significant effect of number of resected lymph nodes on survival. It is evident that no single number exists, but a range from >10 to >40 nodes was identified, depending on data source and method of analysis.20–27 Evidence from these studies, however, indicates that the number is greater than the typical U.S. experience of 13 ± 9 nodes resected, as recently reported by the American College of Surgeons study group.28 Rizk and colleagues29 used the modern machine learning technique random forests analysis in analyzing data from the Worldwide Esophageal Cancer Collaboration (WECC)10 to identify the optimal lymphadenectomy to maximize 5-year survival. This technique allows complex interactions among variables to be identified and can account for nonlinear relationships, such as between T and N classifications. The recommendations based on this unique analysis are to resect a minimum of 10 lymph nodes for T1 cancers, 20 for T2, and 30 for T3. Beyond a finite number of regional nodes, complications may limit the benefit of more extensive lymphadenectomy. Lymphadenectomy of more than 60 nodes was identified in a multivariable analysis of a single-center experience as an independent predictor of airway injury as measured
T.W. Rice and E.H. Blackstone
226 Table 25.2. Number of lymph nodes resected to maximize survival. Author
Source
Twine Altorki21
SI SI
Rizk22 Greenstein23 Groth24 Schwarz25 Chen26 Peyre27
SI SEER SEER SEER NODB International database
20
No. of Patients
Analysis
No. of Lymph Nodes
237 264
MVA MVA
336 977 4,882 5,620 3,144 2,303
RPA MVA RPA MVA MVA MVA
>10 >40 (stages I-II) >16 (stages III-IV) ³18 ³18 >30 >30 12 23
Grade Low Low Low Moderate Moderate Moderate Moderate Moderate
MVA multivariable analysis; NODB National Oncology Database; RPA recursive partitioning analysis; SEER Surveillance, Epidemiology and End Results program; SI single institution.
by postoperative tracheobronchial erosions, ulcers, and fistulae.30
Anatomic Extent of Lymph Node Dissection The possibility of cervical lymph node metastases from esophageal cancers has prompted use of 3-field lymphadenectomy, which has variable definitions but includes a “2-field” lymphadenectomy (which also has a variable definition) and cervical dissection of lymph nodes in the region of recurrent laryngeal nerves, carotid artery and internal jugular vein, and supraclavicular nodes. The seminal paper of Akiyama and colleagues31 cited an occurrence of cervical nodal metastases of 46%, 29%, and 27% for primary squamous cell carcinomas of the upper, middle, and lower thoracic esophagus, respectively. This analysis of a single-institution experience of 717 patients with R0 resections from a series of 913 esophagectomies for esophageal cancer has been the main evidence supporting 3-field lymphadenectomy. The reported 5-year survival difference of 55% for 3-field lymphadenectomy versus 38% for 2-field lymphadenectomy (P=.0013) is attributed to lymphadenectomy extent. However, there is a temporal bias, because 393 underwent 2-field lymphadenectomy from 1973 to 1984 and 324 underwent 3-field lymphadenectomy from 1984 to 1993. This is also an unmatched comparison of highly selected patients whose characteristics are unstated and may differ between groups. The authors admit that the apparent effect on survival might be explained by stage migration in patients undergoing more extensive lymphadenectomy.
This experience has prompted many single- institution studies that report “better than expec ted” results using 3-field lymphadenectomy. Kato and colleagues32 randomized surgeons who performed either 3-field or 2-field lymphadenectomy to treat 150 esophageal cancer patients. Compared with the 2-field group, 3-field patients were younger (P < 0.05) and had better 3-year survival (48% versus 34%; P < 0.01), respectively. The magnitude of improved lymph node staging was readily apparent. In the 3-field group, 43 patients were cN+, 49 were pN+, 69 ± 6.9 nodes were resected, and 3.7 ± 6.8 nodes were positive; in 2-field patients, these data were 46, 48, 36.4 ± 17.6, and 3.2 ± 4.3, respectively. Characteristics of the surgeons were not stated, but in-hospital mortality was five times greater for patients undergoing 2-field lymphadenectomy (P < 0.05). In a nationwide survey conducted by the Japanese Society for Esophageal Diseases, 1,791 patients underwent 3-field lymphadenectomy and 2,799 2-field lymphadenectomy. Survival analysis demonstrated a difference at 5 years of 34% versus 27%, respectively, but this difference was not seen in early- or advanced-stage patients.33 These studies are two excellent examples from the 3-field lymphadenectomy literature. The purported therapeutic benefit of 3-field lymphadenectomy is just as possibly the result of patient selection, surgeon experience, and improved staging. No randomized studies have been performed to provide high-grade evidence for or against the necessity of 3-field lymphadenectomy. For upper thoracic and cervical esophageal cancers, a cervical dissection is required to sample lymph nodes directly in the region of the cancer.
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For accurate staging, there is no argument that 3-field lymphadenectomy is superior to lesser lymphadenectomy. However, if the patient has been accurately staged with a lesser lymphadenectomy, there is no need to perform 3-field lymphadenectomy for staging. Patients with more than 5 lymph node metastases; simultaneous cervical, mediastinal, and abdominal metastases; or cervical lymph node metastases from lower thoracic esophageal cancers did not experience a survival benefit from 3-field lymphadenectomy.34 The importance of number of lymph nodes resected versus location of lymph node metastases has recently been examined in patients undergoing 3-field lymphadenectomy.35 Depth of tumor invasion was the sole predictor of survival; however, in a reanalysis restricted to lymph node factors only, number of lymph node metastases and abdominal lymph node metastases, but not cervical lymph node metastases, were predictors of survival. Three-field lymphadenectomy may come with a price. In a review of 36 studies of 3-field lymphadenectomy, 30-day mortality ranged from 0% to 3.7% and in-hospital mortality from 0% to 10.3% (average 4%).36 Complications occurred on average in 45% of patients (range 38–47%). The most frequent complication was sepsis (27%), half of which were secondary to anastomotic leak. In the nationwide Japanese survey, 3-field lymphadenectomy was more likely than 2-field lymphadenectomy to be complicated by recurrent laryngeal nerve palsy, 20% versus 14% (P < 0.01), respectively.33 Three-field lymphadenectomy was identified in a multivariable analysis of a single-center experience as an independent predictor of airway injury as measured by postoperative tracheobronchial erosions, ulcers, and fistulae.30
Transhiatal esophagectomy is at the other extreme of lymphadenectomy. A formal lymphadenectomy is not performed, and lymph node sampling is limited to a restricted area accessible only by abdominal and cervical incisions. However, three randomized trials could not demonstrate a survival difference when compared with transthoracic resections (Table 25.3). In subset analysis, patients undergoing transthoracic esophagectomy with 1–8 nodes positive had better survival than those receiving a transhiatal esophagectomy.39,40 Again, this effect ascribed to therapy may also be explained by improved staging of pN1 and pN2 patients.
Improving Lymph Node Yield It is imperative that lymph nodes be resected at esophagectomy. Nevertheless, there may be discrepancies among lymph nodes excised, lymph nodes retrieved from the specimen, and lymph nodes examined. Removal of named packets of nodal material resulted in 16 ± 9 nodes per case, as opposed to 10 ± 8 nodes (P < 0.001) when an entire specimen was submitted for pathologists to dissect.28 A dedicated and experienced technician must process the specimen. In a recent study of gastric resections for adenocarcinoma, the pathology technician was an important healthcare-related factor influencing lymph node recovery.41 Finally, the role of the pathologist in carefully reviewing all nodes is critical.42 Lymphadenectomy and lymph node assessment requires a dedicated team. Simple light microscopic review of regional lymph nodes of pN0 patients may not be sufficient to detect all lymph node metastases. Immuno histochemical assessment of regional lymph nodes in 20 pN0 patients revealed micrometastases in 5 patients (20%) and in 2.8% of lymph nodes
Table 25.3. Randomized studies of transhiatal (THE) versus transthoracic (TTE) esophagectomy. Author
Source
Goldminc37 Chu38
SI SI
Hulsher39
2 institutions
No. of Patients 67 39 220
Omloo40 ICU intensive care unit; OR operating room; SI single institution.
Differences for THE Shorter OR time Shorter OR time Increased OR hypotension Fewer complications, shorter ICU and hospital stays Fewer lymph nodes resected
Predictors of survival
Grade
Lymph node metastases None
Low Low
TTE provides survival benefit for patients with 1–8 positive nodes
Moderate
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228
examined.43 Not surprisingly, micrometastases were associated with locoregional recurrence, distant metastases, and reduced survival. The role of lymph node assessment beyond simple light microscopy remains to be defined.
Mechanism of Survival Improvement The superior survival seen with extensive lymphadenectomy is in large part explained by improved staging. Purification of stage grouping is experienced predominately in the separation of pN0 from pN+ (Fig. 25.2). However, this effect is also seen in pN+ patients, prompting reclassification of pN into pN1, pN2, and pN3. The survival benefit of extended lymphadenectomy experienced only in pN+ patients, ascribed to therapy, could also be explained by stage migration in pN+ patients.44 If there is a therapeutic benefit of 3-field lymphadenectomy, it is confined to patients with a small lymph node burden.
Recommendations
Personal View
An understanding of the lymphatic anatomy of the esophagus is critical for any surgeon treat ing esophageal cancer. Lymphadenectomy is a component of esophagectomy. The role of
100
Survival (%)
80 60 0 40 20 0
≥6 0
2
lymphadenectomy is primarily as a staging procedure to allow prognostication and post-surgical treatment. The stage-migration effect of lymphadenectomy is seen for both node-negative and node-positive patients. The therapeutic effect of lymphadenectomy, if any, is limited to patients with a small lymph node burden. The chance of curing a patient with a significant metastatic lymph node burden (N3) by surgery is remote. Addition of a third field (cervical) is indicated for upper thoracic and cervical esophageal cancers; however, its routine use is not supported by the data and is associated with increased, specific morbidity. Based on the best data and analyses available, we recommend that for accurate determination of N+, at least 12 lymph nodes should be resected (evidence level low). To maximize 5-year survival, we recommend that 30 lymph nodes should be resected if T classification is unknown and 10 lymph nodes resected for T1 cancers, 20 for T2, and 30 for T3 (evidence level moderate). The surgical approach is dictated by patient factors, clinical stage, and surgeon expertise.
5
4
6
8
1 2 3 4 10
Years
Figure 25.2. Survival according to number of positive regional lymph nodes from the Worldwide Esophageal Cancer Collaboration database (With permission).
Lymphadenectomy is directed by cancer and patient factors. Histopathologic cell type, histologic grade, LVI, and primary tumor location, length, and percent circumferential involvement are determined from esophagoscopy, biopsy, and, where appropriate, endoscopic mucosal resection (EMR). cTNM is determined by the combination of endoscopic esophageal ultrasonography (EUS), EUS directed fine-needle aspiration (EUS FNA) of regional lymph nodes, and fused computed tomography and positron emission tomography (CT PET). Cardiopulmonary status is the main determinant of a patient’s ability to tolerate an extensive lymphadenectomy. It may be difficult to differentiate high-grade dysplasia (HGD) from T1a cancers by pathologic review of biopsy or EMR specimens. Because HGD is incapable of metastasizing to regional lymph nodes and T1a cancers infrequently metastasize to regional lymph nodes (and if so, usually to a single node), we attempt a sampling of at least 10 regional lymph
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nodes during esophagectomy. We favor a transhiatal approach for most cHGD and cT1a cancers. For T1b and T2 cancers, the same cancer and patient factors are considered in determining extent of lymphadenectomy. Because of potential clinical staging inaccuracies, these cancers are treated similarly.45 At thoracotomy, we perform a more formal lymphadenectomy, resecting at least 20 regional lymph nodes. If a cT1bN0M0 cancer has a poor prognosis (poorly differentiated, long, more than 25% circumferential involvement, or LVI present), a more extensive lymphadenectomy of more than 30 regional lymph nodes is performed. If understaging of a cT2N0M0 cancer is suspected, similarly, a more extensive lymphadenectomy of more than 30 nodes is done. For cT3, cN1, and cN2 cancers, esophagectomy alone is unlikely to be curative. At esophagectomy, after induction therapy, we perform an extensive lymphadenectomy of more than 30 regional lymph nodes. cN3 cancers are treated nonsurgically. When any cancer characteristics are in doubt, a lymphadenectomy of more than 30 regional lymph nodes is performed.
The role of lymphadenectomy is primarily as a staging procedure; any therapeutic effect is limited to patients with a small lymph node burden (evidence level low). Addition of a third field (cervical) is indicated for upper thoracic and cervical esophageal cancers (evidence level low) but is associated with increased morbidity. We recommend that for nodal staging at least 12 lymph nodes should be resected (evidence level low). To maximize 5-year survival, we recommend that 30 lymph nodes should be resected if T classification is unknown, 10 lymph nodes for T1 cancers, 20 for T2, and 30 for T3 (evidence level moderate).
Acknowledgments Funded in part by the Daniel and Karen Lee Endowed Chair in Thoracic Surgery (Dr. Rice) and the Kenneth Gee and Paula Shaw, Ph.D., Chair in Heart Research (Dr. Blackstone).
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230 13. Saito H, Sato T, Miyazaki M. Extramural lymphatic drainage from the thoracic esophagus based on minute cadaveric dissections: fundamentals for the sentinel node navigation surgery for the thoracic esophageal cancers. Surg Radiol Anat. 2007;29: 531–542. 14. Riquet M, Le Pimpec Barthes F, Souilamas R, Hidden G. Thoracic duct tributaries from intrathoracic organs. Ann Thorac Surg. 2002;73:892–898. 15. Kuge K, Murakami G, Mizobuchi S, Hata Y, Aikou T, Sasaguri S. Submucosal territory of the direct lymphatic drainage system to the thoracic duct in the human esophagus. J Thorac Cardiovasc Surg. 2003; 125:1343–1349. 16. Murakami G, Sato I, Shimada KC, Kato Y, Imazeki T. Direct lymphatic drainage from the esophagus into the thoracic duct. Surg Radiol Anat. 1994;16: 399–407. 17. Ishwaran H, Blackstone EH, Apperson-Hansen C, Rice TW. A novel approach to cancer staging: application to esophageal cancer. Biostatistics. 2009;10: 603–620. 18. Peyre CG, Hagen JA, DeMeester ST, Van Lanschot JJ, Hölscher A, Law S, Ruol A, Ancona E, Griffin SM, Altorki NK, Rice TW, Wong J, Lerut T, DeMeester TR. Predicting systemic disease in patients with esophageal cancer after esophagectomy: a multinational study on the significance of the number of involved lymph nodes. Ann Surg. 2008;248:979–985. 19. Dutkowski P, Hommel G, Böttger T, Schlick T, Junginger T. How many lymph nodes are needed for an accurate pN classification in esophageal cancer? Evidence for a new threshold value. Hepatogastro enterology. 2002;49:176–180. 20. Twine CP, Lewis WG, Morgan MA, Chan D, Clark GW, Havard T, Crosby TD, Roberts SA, Williams GT. The assessment of prognosis of surgically resected oeso phageal cancer is dependent upon the number of lymph nodes examined pathologically. Histopatho logy. 2008;55:46–52. 21. Altorki NK, Zhou XK, Stiles B, Port JL, Paul S, Lee PC, Mazumdar M. Total number of resected lymph nodes predicts survival in esophageal cancer. Ann Surg. 2008;248:221–226. 22. Rizk N, Venkatraman E, Park B, Flores R, Bains MS, Rusch V. The prognostic importance of the number of involved lymph nodes in esophageal cancer: implications for revisions of the American Joint Committee on Cancer staging system. J Thorac Cardiovasc Surg. 2006;132:1374–1381. 23. Greenstein AJ, Litle VR, Swanson SJ, Divino CM, Packer S, Wisnivesky JP. Effect of the number of lymph nodes sampled on postoperative survival of lymph node-negative esophageal cancer. Cancer. 2008;112:1239–1246. 24. Groth SS, Virnig BA, Whitson BA, DeFor TE, Li Z, Tuttle TM, Maddaus MA. Determination of the minimum number of lymph nodes to examine to maximize survival in patients with esophageal
T.W. Rice and E.H. Blackstone c arcinoma: data from the Surveillance Epidemiology and End Results database. J Thorac Cardiovasc Surg. 2010;139:612–620. 25. Schwarz RE, Smith DD. Clinical impact of lymphadenectomy extent in resectable esophageal cancer. J Gastrointest Surg. 2007;11:1384–1393. 26. Chen YJ, Schultheiss TE, Wong JY, Kernstine KH. Impact of the number of resected and involved lymph nodes on esophageal cancer survival. J Surg Oncol. 2009;100:127–132. 27. Peyre CG, Hagen JA, DeMeester SR, Altorki NK, Ancona E, Griffin SM, Hölscher A, Lerut T, Law S, Rice TW, Ruol A, van Lanschot JJ, Wong J, DeMeester TR. The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection. Ann Surg. 2008;248:549–556. 28. Veeramachaneni NK, Zoole JB, Decker PA, Putnam JB Jr, Meyers BF. Lymph node analysis in esophageal resection: American College of Surgeons Oncology Group Z0060 trial. Ann Thorac Surg. 2008;86: 418–421. 29. Rizk NP, Ishwaran H, Rice TW, Chen LQ, Schipper PH, Kesler KA, Law S, Lerut T, Reed CE, Salo JA, Scott WJ, Hofstetter WL, Watson TJ, Allen MS, Rusch VW, Blackstone EH. Optimum lymphadenectomy for esophageal cancer. Ann Surg. 2009;250:1–5. 30. Maruyama K, Motoyama S, Sato Y. Tracheobronchial lesions following esophagectomy: erosions, ulcers, and fistulae, and the predictive value of lymph noderelated factors. World J Surg. 2009;33:778–784. 31. Akiyama H, Tsurumaru M, Udagawa H, Kajiyama Y. Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg. 1994;220:364–372. 32. Kato H,Watanabe H, Tachimori Y, Iizuka T. Evaluation of neck node dissection for thoracic esophageal carcinoma. Ann Thorac Surg. 1991;51:931–935. 33. Isono K, Sato H, Nakayama K. Results of a nationwide study on the three-field lymph node dissection of esophageal cancer. Oncology. 1991;48:411–420. 34. Nishimaki T, Suzuki T, Suzuki S, Kuwabara S, Hatakeyama K. Outcomes of extended radical esophagectomy for thoracic esophageal cancer. J Am Coll Surg. 1998;186:306–312. 35. Shimada H, Okazumi S, Matsubara H, Nabeya Y, Shiratori T, Shimizu T, Shuto K, Hayashi H, Ochiai T. Impact of the number and extent of positive lymph nodes in 200 patients with thoracic esophageal squamous cell carcinoma after three-field lymph node dissection. World J Surg. 2006;30:1441–1449. 36. Tachibana M, Kinugasa S, Yoshimura H, Dhar DK, Nagasue N. Extended esophagectomy with 3-field lymph node dissection for esophageal cancer. Arch Surg. 2003;138:1383–1389. 37. Goldminc M, Maddern G, Le Prise E, Meunier B, Campion JP, Launois B. Oesophagectomy by a transhiatal approach or thoracotomy: a prospective randomized trial. Br J Surg. 1993;80:367–370.
25. Extent of Lymph Node Dissection in Esophageal Cancer 38. Chu KM, Law SY, Fok M, Wong J. A prospective randomized comparison of transhiatal and transthoracic resection for lower-third esophageal carcinoma. Am J Surg. 1997;174:320–324. 39. Hulscher JB, van Sandick JW, de Boer AG, Wijnhoven BP, Tijssen JG, Fockens P, Stalmeier PF, ten Kate FJ, van Dekken H, Obertop H, Tilanus HW, van Lanschot JJ. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med. 2002;347:1662–1669. 40. Omloo JM, Lagarde SM, Hulscher JB, Reitsma JB, Fockens P, van Dekken H, Ten Kate FJ, Obertop H, Tilanus HW, van Lanschot JJ. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clinical trial. Ann Surg. 2007;246:992–1000. 41. Schoenleber SJ, Schnelldorfer T, Wood CM, Qin R, Sarr MG, Donohue JH. Factors influencing lymph
231 node recovery from the operative specimen after gastrectomy for gastric adenocarcinoma. J Gastro intest Surg. 2009;13:1233–1237. 42. Metze K. The association between overall survival and the total number of dissected lymph nodes: an artifact caused by the surgical pathologist. Ann Surg. 2009;249:693–694. 43. Buskens CJ, Ten Kate FJW, Obertop H, Izbicki JR, van Lanschot JJB. Analysis of micrometastatic disease in histologically negative lymph nodes of patients with adenocarcinoma of the distal esophagus or gastric cardia. Dis Esophagus. 2007;21:488–495. 44. Altorki N, Kent M, Ferrara C, Port J. Three-field lymph node dissection for squamous cell and adenocarcinoma of the esophagus. Ann Surg. 2002;236:177–183. 45. Rice TW, Mason DP, Murthy SC, Zuccaro G Jr, Adelstein DJ, Rybicki LA, Blackstone EH. T2N0M0 esophageal cancer. J Thorac Cardiovasc Surg. 2007;133:317–324.
26
Salvage Esophagectomy for Persistent Disease After Definitive Chemoradiotherapy Wayne Hofstetter
Introduction The optimal management of locally advanced cancer of the esophagus remains controversial. Given recent advances in the results of combined concurrent chemoradiation, medical and radiation oncologists are dubious about the additional benefit of surgical resection in patients that respond to non-surgical therapy. However, despite a perceived complete local-regional response, many patients will manifest persistent or recurrent disease that is potentially resectable. This chapter aims to discuss the feasibility and pitfalls of opting for salvage esophagectomy.
Methods Multiple search strategies in PUBMED using keywords esophageal cancer, salvage, selective surgery, definitive chemoradiation,chemoradiotherapy and non-operative were performed. There were no limits placed on language. These searches were supported by the ‘related article’ feature in PUBMED and cross-referenced through the reference section of recent manuscripts. Search time limits were not required due to the temporal nature of this topic. The quality of evidence in the studies was classified using the GRADE system previously cited and described in this book. The topic of cervical esophageal cancer was omitted from the search and the following discussion.
Evidence for Definitive Chemoradiation Therapy The biologic heterogeneity of patients with esophageal cancer is diverse. A lack of accurate staging technologies results in an inability to recognize patients with systemic disease versus those curable by local-regional treatment modalities. His torically, this has resulted in discouraging surgical outcomes. Furthermore, esophagectomy continues to be regarded as an operation that is associated with significant potential for morbidity, mortality, and changes in quality of life. Therefore, patients who were either incapable or unwilling to undergo resection have been treated medically. Limited success with innovative medical therapy led to the inevitable conclusion that patients with better performance status and potentially curable disease may perform well with medical therapy as an alternative to resection.1 In fact, there are a number of phase II and III trials illustrating the potential of non-surgical therapy to produce short and long term survival (Table 26.1).1–10 One of the landmark studies of medicalonly therapy in potentially curable patients describes the long-term follow up of patients treated with chemotherapy and radiation versus radiation alone. This intergroup study initiated by the Radiation Therapy Oncology Group (RTOG 85-01/INT 0123) reported that median and 5-year survival of 14.1 months and 27% was observed without surgical therapy.2 A follow up to this study
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234 Table 26.1. Randomized controlled trials of definitive non-surgical therapy for esophageal cancer. Reference
Study interval
Histology
N
Schema
Results
Level of evidence
26% vs. 0% 5 year OS 56% vs. 52% persistence of disease
259
CRT vs. RT CRT with Higher dose RT vs. Standard CRT vs. CRT + S
High High
17.7 vs. 19.3 MS
172
CCRT vs. CCRT + S
24% vs. 31% 3 year OS (p = 0.02) surgery improves DFS
High (but did not reach accrual goals) High
Cooper et al. (RTOG 85-01) Minsky et al. (RTOG 94-05)4
1986–1990 1995–1999
SCCA/ACA SCCA/ACA
129 236
Bedenne et al.5
1993–2000
SCCA/ACA
Stahl et al.6
1994–2002
SCCA
3
was a publication of mature data from both randomized and non-randomized patients, the majority of whom had squamous cell carcinoma.3 The authors reported 5-year survival of 14% and 26% in the non-randomized and randomized patient cohorts, respectively. The ability to achieve prolonged survival with medical therapy was encouraging; however, there were a significant number of patients that failed local-regionally in that trial, reported to be more than 56%. The next RTOG trial (94-05) was designed to address this with higher amounts of radiation.4 The results were disappointing; this trial illustrated that higher radiation levels failed to improve survival or localregional control, and therefore the 50.4 Gy dose of radiation described in the INT-0123 trial became the standard neoadjuvant and definitive dose for radiation for thoracic esophageal carcinoma treated with concurrent chemotherapy. Given the weight of these trials and further evidence in surgical series illustrating pathologic complete response in patients treated with multimodality therapy, there were groups that were of the opinion that surgery was merely documenting the response to therapy rather than complementing the outcome.11 The ensuing controversy led to a potential treatment paradigm flip. Rather than seeking derived benefit from adjuvant or neoadjuvant therapies over and above surgical resection, the question arose: what is the additional benefit of esophagectomy in patients who respond to alternative local-regional treatment modalities?
Chemoradiation with or Without Surgery In current literature there are two randomized controlled trials comparing the addition of surgery to definitive chemoradiation therapy.5,6 Both trials
primarily involve squamous cell carcinoma of the esophagus. The Bedenne et al. study randomized only patients who responded to chemoradiation either to a surgery or observation arm. Two hundred fifty patients were evaluated (129 surgical, 130 definitive chemoradiation therapy; 11% adenocarcinoma). Median survival was 17.7 months versus 19.3 months, and overall survival evaluated at 2 years was found to be 34% versus 40%, respectively (p = NS). Although there were some benefits found in the surgical arm, such as improved localregional control and increased freedom from palliative procedures (such as stents), the off-set was significantly higher treatment related toxicity in the surgical arm. Mortality analyzed at 90-days was 9.3% versus 0.8%.5 The fact that local control did not lead to an increase in overall survival in this study may exemplify the difficulty with esophagectomy after concurrent chemoradiation in a multi-institutional study and the systemic nature of advanced esophageal cancer. The Stahl et al study involved induction chemotherapy prior to chemoradiation in both arms, presumably in an effort to decrease distant failure.6 All patients in this trial had squamous cell carcinoma. This study randomized 172 patients (86 to chemoradiation plus surgery versus 86 to definitive chemoradiation). Similar to the Bedenne study, freedom from local-regional recurrence was better with surgery, and in the Stahl trial diseasefree survival was reported to be significantly improved with surgery compared to observation (64% versus 41% at 2-years; p = 0.003). However, in contrast, the Stahl trial, which randomized all patients rather than responders only, illustrated a small survival advantage in the surgery arm (31% versus 24% at 3-years; p = 0.02). Again, there was a significant increase in treatment-related mortality reported in the surgical arm (12.8% versus 3.5%; p = 0.03). Overall, this study illustrated that
26. Salvage Esophagectomy for Persistent Disease After Definitive Chemoradiotherapy
patients who underwent surgery were less likely to die of cancer but were at increased risk for treatment-related toxicity. Another finding of interest on sub-group analysis was that non-responders who achieved a complete (R0) resection reached 32% three-year survival. This was in contrast to responders, who achieved greater than 50% threeyear survival regardless of the treatment arm. The take-away from these two studies is that in patients who respond to medical therapy, the offset of increased toxicity seen in multi-institutional trials involving combined modality therapy including surgery detracts from a potential disease-free survival advantage obtained by the addition of surgery.
Salvage Esophagectomy Definitive chemoradiation therapy as a treatment algorithm has created a unique subgroup of patients who either manifest residual viable tumor or re-present with recurrence in a local-regional distribution in the absence of metastatic disease. These patients face limited treatment alternatives but may consider the option of salvage esophagectomy. Patients who have had a prolonged period of recuperation following chemoradiation causing a delay in resection secondary to decline in performance status will often be reconsidered for esophagectomy some months later. Those patients resected greater than three months after completion of chemoradiation are often also considered salvage resection patients as well. There are many prospective, non-randomized and retrospective publications describing the feasibility of salvage esophagectomy (Table 26.2). Whereas most focus on squamous cell carcinoma,
Table 26.2. Retrospective reviews of salvage resection. Reference Swisher et al. Nakamura et al.16 Tomimaru et al.15 Chao et al.20 Oki et al.19 Borghesi et al.17 Nishimura et al.12 Tachimori et al.13 14
Study interval
N
Histology
Level of evidence
1987–2000 1992–2002 1985–2004 1997–2004 1994–2005 1999–2005 2000–2006 2000–2006
13 27 24 27 14 10 46 59
SCCA/ACA SCCA SCCA SCCA SCCA SCCA/ACA SCCA SCCA
Low Low Low Low Low Low Low Low
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there is very limited published experience on salvage resection for adenocarcinoma.12–23 Most of the published data are small retrospective series ranging from 10 to 46 patients. An adept and comprehensive review by Gardner-Thorpe summarizes nine published series totaling 105 patients.24 As described in that review, the indication for salvage in over 50% of the resected cases was for persistent disease, while local-regional recurrence in the absence of metastatic disease was the indication in 43%. The absolute percentage of patients who will present for salvage resection after definitive medical therapy is not known, and depends on many factors such as initial stage, indications for resection, patient demographics, referral patterns, etc. However, there is one report by Nishimura et al indicating that 16% of the thoracic esophageal cancer patients who underwent definitive CXRT at their institution were referred for salvage resection.12
Patient Selection Patients who presented with known systemic disease prior to any therapy or who are re- presenting for local-regional therapy and have evidence of systemic disease are typically not candidates for salvage resection. A re-staging work up should be performed prior to considering salvage resection, and this should include methods to rule out systemic disease such as integrated PET/CT. Endoscopy is used to assess the extent of esophageal and gastric involvement for resection and reconstruction planning. Endoscopic ultrasound is not reliable for assessing esophageal wall invasion after radiation treatment but can be very helpful when combined with transesophageal or transbronchial fine needle aspiration. These modalities can offer histologic confirmation of disease when there is question of non-regional lymph node or adrenal gland involvement, for example, that would preclude salvage resection. Bronchoscopy is necessary in patients with proximal tumors above or adjacent to the carina when there is suspicion for direct invasion into the airway. Endobronchial ultrasound (EBUS) can be helpful in this situation as well. A physiologic work up consisting of serum laboratory analyses, cardiac and pulmonary evaluations should be considered prior to resection.
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Surgical Resection We perform salvage resection exactly as a standard esophagectomy with some caveats. Reported series have consisted of cases performed as transhiatal, McKeown and Ivor Lewis approaches.12–23 There is no literature supporting a limited lymphadenectomy for salvage resection, and therefore we continue to advocate a complete resection. However, one review does describe significantly fewer three-field lymphadenectomies performed for salvage compared to planned esophagectomy (41% vs. 91%).13 Two-field lymphadenectomy has been described, and there is no direct evidence that this contributes to significant morbidity.14 Caveats that should occur to the surgeon are the need to consider alternative methods of reconstruction and the possibility for resection of primary tumor with a subsequent staged reconstruction effort at a later date either due to poor patient performance or for lack of a safe conduit.15 One of the more striking morbidities that have been reported in multiple series describing salvage esophagectomy is the rate of conduit necrosis, quoted as high as 25%.16 Most surgeons would agree that the stomach is the most robust and straight-forward esophageal replacement; however, for patients with lower esophageal tumors, review of the radiation treatment plan will often reveal inclusion of the entire stomach within the treatment field, usually to a high dose. The latent period between the completion of radiation and the surgical resection may affect the extent of radiation damage and potentially jeopardize the viability of the stomach when transposed into the chest. In these situations we make a practice of carefully examining the stomach intra-operatively for signs of damage or suitability as a reconstruction conduit. Questions regarding potential viability of the stomach will prompt one of several responses: harvest of omentum to transpose into the chest to wrap the gastric and anastomotic suture/staple lines; consideration for use of a different conduit such as a pedicled or super-charged jejunal or colon interposition; or esophageal resection with delayed reconstruction. All of these options are discussed with the patient and appropriate surgical support from ancillary services is secured prior to surgery.
Another potential drawback to salvage resection is the potential for incomplete resection. Available data reports indicate that 25–70% of resections performed in a salvage situation are R1 or R2.14–17
Toxicity Another barrier to adopting salvage resection as the primary treatment modality for thoracic esophageal cancer is the described toxicity associated with salvage resection (Table 26.3). In-hospital deaths rates range from 7% to 33%,12– 23 which is significantly higher than optimal. Hos pital stays were longer in general (14–47 days), and this may be due to an increased incidence of conduit necrosis, pulmonary toxicities and/or anastomotic leak. As previously mentioned, conduit necrosis, when described, was seen in up to 25% and anastomotic leak in 15–39% of patients undergoing salvage resection. In fact, many of the perioperative deaths described in these series were related to anastomotic leak or conduit necrosis despite aggressive medical and surgical efforts to rescue these patients. Other reported discrepancies from standard, planned resection include increased operating time, potential for more blood loss and prolonged intensive care unit stays of 4–121 days.
Outcome Patients who have undergone salvage resec tion represent a highly selected group of patients with potentially favorable biology. Less fortunate Table 26.3. Toxicity of salvage resection. Reference
N
Swisher et al.14 Nakamura et al.16 Tomimaru et al.15 Chao et al.20 Oki et al.19 Borghesi et al.17 Nishimura et al.12 Tachimori et al.13 Meunier et al.22
13 27 24 27 14 10 46 59 6
R1 (%) Leak (%) 20 33 33a 37a 50 70a 0 15 NS
38a 22 21 15a 29 20 22 31a 33
Length of stay (days) 29.4a 40 NS 22.4 NS 21 47 38 47
Mortality (%) 15 8 13 29a 7 10 15 8a 33
denotes a significant difference from reported comparison group when applicable; NS = not specified.
a
26. Salvage Esophagectomy for Persistent Disease After Definitive Chemoradiotherapy
patients with poor performance status, progressive systemic disease, or unresectable local-regional recurrence are, by definition, eliminated from this group, thus improving the appearance of the overall outcome for this selected group. With this in mind, the reported 5 year overall survival is up to 60% in patients who were fortunate enough to undergo an R0 resection.14 However, as a group that includes R0-1 resections, long term survival is intermediate, ranging from 0 to 35% at 5 years.12–23 There is limited data for patients with adenocarcinoma undergoing salvage resection. We presented a review exclusively describing salvage resection for adenocarcinoma: 45 patients who presented for resection after definitive chemoradiation for adenocarcinoma of the esophagus achieved a 47% overall 5-year survival. Despite an observed increase in peri-operative morbidity and mortality, the survival was not statistically different from a comparison group of 300 patients who underwent planned resection.25
Conclusions and Recommendations To date, the optimal approach for the treatment of patients with locally advanced esophageal cancer, either squamous cell or adenocarcinoma, has not been clearly decided. Illustrating this point, a survey of United States physicians patterns of practice published in 2005 indicated that, for patients receiving radiotherapy for esophageal cancer between the years of 1996–1999, 56% of them received chemoradiation alone.26 Among this group, 88% of them were of a known stage between stage I–III. Responses to this survey underscore the heterogeneity of our treatment practices and the individualization of esophageal cancer care for patients in the US. It also emphasizes that definitive chemoradiation is an attractive offer to patients considering esophagectomy who are already weakened by therapy. At this time, patients receive definitive chemoradiation due to a variety of reasons. Because the currently accepted dose of neoadjuvant radiation is equivalent to a definitive dose at 50.4 Gy, patients may begin therapy with a multimodality treatment plan that included surgery at the outset. However, due to patient intolerance to therapy, or a perceived complete response,
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or refusal to proceed to resection, neoadjuvant therapy can be transformed to definitive with a decision rather than additional therapy. The results of trials comparing chemoradiation with or without surgery have illustrated that cure is possible without surgical resection. However, appropriately choosing the patient who requires further local-regional control as opposed to one who would not benefit from resection compels the question of selective surgical resection. There have been two recent prospective, nonrandomized trials that sought to evaluate a selective surgical approach as an adjunct to definitive medical therapy.27,28 Both show high clinical response rates to therapy and suggest that a selective surgical approach using chemoradiotherapy represents a survival advantage over surgery alone. Although these reports included exclusively squamous cell patients, a recent phase II study including patients with adenocarcinoma was completed by the RTOG (protocol 0246) showing the feasibility of this approach.29 None of these studies was designed to show superiority over a tri-modality chemoradiotherapy plus surgery approach, and therefore conclusions cannot be reached on this question. In conclusion, salvage resection is a reasonable option to treat selected patients with local regional recurrence after failed definitive therapy, as it provides reasonable long-term survival. Although this option comes at higher risk than surgery alone or surgery as part of planned trimodality therapy, it is reasonably safe (evidence quality low). Challenges remain to reduce peri-operative morbidity and mortality. Focus on controlling the leak rate at the esophageal anastomosis would likely result in a significant improvement in the outcomes of this surgery. We strongly recommend that patients with persistent or recurrent local-regional esophageal cancer after definitive medical therapy should be considered for salvage resection (grade of recommendation 1C).
A Personal Approach to the Problem Our approach to this subset of patients is individualized. Potential salvage candidates are workedup to exclude evidence of metastatic disease, and
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for physiologic capability. Integrated PET/CT and EGD/EUS with FNA of “game-changing” nonregional adenopathy is performed. Pulmonary function and cardiac stress are routine evaluations. We offer salvage resection to any patient that appears to have the physiologic reserve for resection and has disease limited to a local-regional distribution. At times, patients that have undergone extensive medical treatment appear too debilitated to consider surgery. We have employed therapeutic stalling in these cases. Patients are allowed to recover while undergoing physical and pulmonary rehabilitation programs. Re-evaluation will frequently reveal a much healthier patient that could be a candidate for resection. In our experience this recovery period can last weeks to several months. This must be tempered with the knowledge that long latent periods between therapy and surgery can lead to tumor growth and potential R1 resection or inoperability. Chosing the correct time to operate is a decision based experience. We also strongly recommend that any patient who has chosen to undergo observation rather than resection after chemoradiation undergo routine surveillance with upper endoscopies and PET imaging. The endoscopies must be paired with biopsies, as evidence of recurrence can be detected at a micro rather than macro-scopic level. PET is helpful when there is an increasing SUV at the primary, especially when it is within the wall of the esophagus where EGD would not detect the recurrence. As mentioned in the above text, specific note is made of the radiation fields as it relates to the potential replacement conduit. Those patients that have had higher doses of radiation to the entire stomach (in excess of 60–70 Gy) are considered for alternative conduits or staged reconstruction. We do not rule a patient out for surgery based on their history of radiation dose or age per se. Armed with little more than anecdotal data, we prefer to perform an anastomosis with at least one non-radiated organ (ie either at an area of non/minimally radiated esophagus or an area of non-radiated or minimally radiated conduit). Despite the above mentioned approach, there is still room to improve surgical techniques and these may translate to better overall outcomes in this challenging group of patients.
Salvage resection for selected patients with local regional recurrence after failed definitive therapy for esophageal cancer provides reasonable long-term survival and is reasonably safe (evidence quality low). We strongly recommend that patients with persistent or recurrent localregional esophageal cancer after definitive medical therapy should be considered for salvage resection (grade of recommendation 1C).
References 1. Leichman L, Herskovic A, Leichman CG, Lattin PB, Steiger Z, Tapazoglou E, Rosenberg JC, Arbulu A, Asfaw I, Kinzie J. Nonoperative therapy for squamouscell cancer of the esophagus. J Clin Oncol. 1987;5: 365–370. 2. al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, Cooper J, Byhardt R, Davis L, Emami B. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol. 1997;15:277–284. 3. Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, Asbell SO, Graham MV, Leichman LL. Chemoradiotherapy of locally advan ced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radia tion Therapy Oncology Group. JAMA. 1995;281: 1623–1627. 4. Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal SA, Kelsen DP. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002; 20:1167–1174. 5. Bedenne L, Michel P, Bouché O, Milan C, Mariette C, Conroy T, Pezet D, Roullet B, Seitz JF, Herr JP, Paillot B, Arveux P, Bonnetain F, Binquet C. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007;25:1160–1168. 6. Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seeber S, Klump B, Budach W, Teichmann R, Schmitt M, Schmitt G, Franke C, Wilke H. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005;23:2310–2317. 7. Ajani JA, Winter K, Komaki R, Kelsen DP, Minsky BD, Liao Z, Bradley J, Fromm M, Hornback D, Willett CG. Phase II randomized trial of two nonoperative regimens of induction chemotherapy followed by
26. Salvage Esophagectomy for Persistent Disease After Definitive Chemoradiotherapy chemoradiation in patients with localized carcinoma of the esophagus: RTOG 0113. J Clin Oncol. 2008;26:4551–4556. 8. Algan O, Coia LR, Keller SM, Engstrom PF, Weiner LM, Schultheiss TE, Hanks GE. Management of adenocarcinoma of the esophagus with chemoradiation alone or chemoradiation followed by esophagectomy: results of sequential nonrandomized phase II studies. Int J Radiat Oncol Biol Phys. 1995;32: 753–761. 9. Adams R, Morgan M, Mukherjee S, Brewster A, Maughan T, Morrey D, Havard T, Lewis W, Clark G, Roberts S, Vachtsevanos L, Leong J, Hardwick R, Carey D, Crosby T. A prospective comparison of multidisciplinary treatment of oesophageal cancer with curative intent in a UK cancer network. Eur J Surg Oncol. 2007;33:307–313. 10. Morgan MA, Lewis WG, Casbard A, Roberts SA, Adams R, Clark GW, Havard TJ, Crosby TD. Stagefor-stage comparison of definitive chemoradiotherapy, surgery alone and neoadjuvant chemotherapy for oesophageal carcinoma. Br J Surg. 2009;96: 1300–1307. 11. Hennequin C, Quero L, Baruch-Hennequin V, Maylin C. [Do locally advanced esophageal cancer still need surgery?] [Article in French] Cancer Radiother. 2008;12:831–836. 12. Nishimura M, Daiko H, Yoshida J, Nagai K. Salvage esophagectomy following definitive chemoradiotherapy. Gen Thorac Cardiovasc Surg. 2007;55:461–465. 13. Tachimori Y, Kanamori N, Uemura N, Hokamura N, Igaki H, Kato H. Salvage esophagectomy after highdose chemoradiotherapy for esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 2009;137: 49–54. 14. Swisher SG, Wynn P, Putnam JB, Mosheim MB, Correa AM, Komaki RR, Ajani JA, Smythe WR, Vaporciyan AA, Roth JA, Walsh GL. Salvage esophagectomy for recurrent tumors after definitive chemotherapy and radiotherapy. J Thorac Cardiovasc Surg. 2002;123:175–183. 15. Tomimaru Y, Yano M, Takachi K, Miyashiro I, Ishihara R, Nishiyama K, Sasaki Y, Ishikawa O, Doki Y, Imaoka S. Factors affecting the prognosis of patients with esophageal cancer undergoing salvage surgery after definitive chemoradiotherapy. J Surg Oncol. 2006; 93:422–428. 16. Nakamura T, Hayashi K, Ota M, Eguchi R, Ide H, Takasaki K, Mitsuhashi N. Salvage esophagectomy after definitive chemotherapy and radiotherapy for advanced esophageal cancer. Am J Surg. 2004;188: 261–266. 17. Borghesi S, Hawkins MA, Tait D. Oesophagectomy after definitive chemoradiation in patients with locally advanced oesophageal cancer. Clin Oncol (R Coll Radiol). 2008;20:221–226. 18. Ishikura S, Nihei K, Ohtsu A, Boku N, Hironaka S, Mera K, Muto M, Ogino T, Yoshida S. Long-term toxicity after definitive chemoradiotherapy for
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squamous cell carcinoma of the thoracic esophagus. J Clin Oncol. 2003;21:2697–2702. 19. Oki E, Morita M, Kakeji K, Ikebe M, Sadandaga N, Egasira A et al. Salvage esophagectomy after definitive chemoradiotherapy for esophageal cancer. Dis Esophagus. 2007;20:301–304. 20. Chao YK, Chan SC, Chang HK, Liu YH, Wu YC, Hsieh MJ, Tseng CK, Liu HP. Salvage surgery after failed chemoradiotherapy in squamous cell carcinoma of the esophagus. Eur J Surg Oncol. 2009;35:289–294. 21. Hironaka S, Ohtsu A, Boku N, Muto M, Nagashima F, Saito H, Yoshida S, Nishimura M, Haruno M, Ishikura S, Ogino T, Yamamoto S, Ochiai A. Nonrandomized comparison between definitive chemoradiotherapy and radical surgery in patients with T(2–3)N(any) M(0) squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys. 2003;57:425–433. 22. Meunier B, Raoul J, Le Prisé E, Lakéhal M, Launois B. Salvage esophagectomy after unsuccessful curative chemoradiotherapy for squamous cell cancer of the esophagus. Dig Surg. 1998;15:224–226. 23. Murakami M, Kuroda Y, Okamoto Y, Kono K, Yoden E, Kusumi F, Hajiro K, Matsusue S, Takeda H. Neo adjuvant concurrent chemoradiotherapy followed by definitive high-dose radiotherapy or surgery for operable thoracic esophageal carcinoma. Int J Radiat Oncol Biol Phys. 1998;40:1049–1059. 24. Gardner-Thorpe J, Hardwick RH, Dwerryhouse SJ. Salvage oesophagectomy after local failure of definitive chemoradiotherapy. Br J Surg. 2007;94:1059–1066. 25. Hofstetter W, Maru D, Correa A, Lee J, Shah N, Ajani J, Erasmus J, Komaki R, Mehran R, Rice D,Vaporciyan A, Walsh G, Bhutani M, Roth J, Swisher S. Salvage resection for esophageal adenocarcinoma after failed definitive chemoradiation. In press. 26. Suntharalingam M, Moughan J, Coia LR, Krasna MJ, Kachnic L, Haller DG, Willet CG, John MJ, Minsky BD, Owen JB. Outcome results of the 1996–1999 patterns of care survey of the national practice for patients receiving radiation therapy for carcinoma of the esophagus. J Clin Oncol. 2005;23:2325–2331. 27. Ariga H, Nemoto K, Miyazaki S, Yoshioka T, Ogawa Y, Sakayauchi T, Jingu K, Miyata G, Onodera K, Ichikawa H, Kamei T, Kato S, Ishioka C, Satomi S, Yamada S. Prospective comparison of surgery alone and chemoradiotherapy with selective surgery in resectable squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys. 2009;75:348–356. 28. Wilson KS, Lim JT. Primary chemo-radiotherapy and selective oesophagectomy for oesophageal cancer: goal of cure with organ preservation. Radiother Oncol. 2000;54:129–134. 29. Swisher S, Winter K, Komaki R, Ajani J, Wu T-T, Hofstetter W, Konski A, Willett C. ASTRO-RTOG 0246-040307. A phase II study of a Paclitaxel based chemoradiation regimen with selective surgi cal salvage for resectable locoregionally advanced esophageal cancer: initial reporting of RTOG 0246. In press
240 30. Urschel JD, Ashiku S, Thurer R, Sellke W. Salvage of planned esophagectomy after chemoradiation therapy for locally advanced esophageal cancer – a review. Dis Esophagus. 2003;16:60–65. 31. Urschel JD, Sellke FW. Complications of salvage esophagectomy. Med Sci Monit. 2003;9:RA173–180.
W. Hofstetter 32. Siersema P, Hillegersberg R. Treatment of locally advanced esophageal cancer with surgery and chemoradiation. Curr Opin Gastroenterol. 2008;24:535–540. 33. Matsubara H. Salvage surgery for esophageal carcinoma after definitive chemoradiation therapy. Ann Thorac Cardiovasc Surg. 2007;13:293–295.
27
Barrett Mucosa in the Cervical Remnant After Esophagectomy for Cancer Xavier Benoit D’Journo and André Duranceau
Introduction Gastric interposition is usually considered the operation of choice following esophageal resection. The gastric conduit is either fashioned as a tube or uses the complete stomach for esophageal reconstruction for both malignant and benign conditions. Substantial physical and physiological alterations are made to the organ: the blood supply is altered and bilateral vagotomy modifies the motor function and the emptying capacity. The reservoir capacity is modified, the normal antireflux barrier is removed and the reconstruction is positioned in the posterior or anterior mediastinum. For these reasons, normal gastrointestinal function is rare after esophagectomy.1 A number of reports show that esophagectomy and esophageal reconstruction with a gastric transplant is associated with a significant deterioration of quality of life that persists during the follow-up period.2–5 Symptoms of dumping, delayed gastric emptying, aspiration, reflux of ingested food or of a gastro-duodenal refluxate are frequently mentioned as altering the perception of comfort following reconstruction.6,7 Anatomically, every defense mechanism against reflux is removed with the esophageal resection. When the stomach is used for reconstruction either as a complete gastric transplant or fashioned as a tube, it is positioned in a negative pressure environment. The intrathoracic stomach is then in free communication with the proximal and the distal digestive tract while exposed to the mechanical effects of the positive intra-abdominal pressure and negative intrathoracic pressure. When the
proximal esophageal remnant is anastomosed to the gastric body, the squamous mucosa is placed in direct contact with the oxyntic mucosa and the acid secreting parietal cells. Moreover, the pyloroplasty used to facilitate gastric emptying also favors the duodenogastric reflux of bile and pancreatic secretions. The reconstruction then becomes a model of free duodeno-gastro-esophageal reflux with its related long-term damage to the mucosa. Among them, development of Barrett’s esophagus is a critical long-term complications of sub total esophagectomy with its potential dysplastic changes. The goal of this review is to clarify the prevalence of Barrett’s esophagus in the esophageal remnant after subtotal esophagectomy, to determine the best strategies to obtain the diagnosis, and to identify some factors affecting the development of such lesions.
Methods A Medline search was conducted. Additional references and search pathways were sourced from the references of reviewed articles. The search includes all articles from Medline between January 1996 to August 2009 using the PUBMED interface. Keywords included: esophagectomy OR esophageal remnant OR retrosternal stomach OR pyloroplasty OR gastric drainage OR pyloromyotomy OR columnar lined metaplasia OR Barrett’s esophagus. A total of 100 papers were identified. We reviewed the current evidence in the literature
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review and classified it according to the GRADE system.8 When data on Barrett’s esophagus in the esophageal remnant were missing, we extended the search to reflux esophagitis. Of these 100 papers, there were 7 observational studies that investigated the incidence of columnar lined metaplasia in the esophageal remnant Table (27.1). We selected four main factors that are likely to affect the development of mucosal damage and in turn the appearance of Barrett’s Esophagus in the esophageal remnant: pyloric drainage, the level of the anastomosis, the route of reconstruction, and medical therapy following the operation. One meta-analysis was found that summarized nine randomized controlled trials investigating the role of the pyloroplasty after esophagectomy. This study, together with the best three RCTs, were selected (Table 27.2).
Prevalence of Barrett’s Esophagus in the Esophageal Remnant Because there is no correlation between symptoms and mucosal damage in the esophageal remnant,9–12 endoscopy and endoscopic biopsies are the only reliable methods to document mucosal integrity in the esophageal remnant. Several endoscopic classifications are available for clinicians for the description of damage. However, biopsies are the only reliable method to document the columnar mucosa and the intestinal metaplasia cells that define Barrett’s esophagus.
Endoscopic Prevalence The reported prevalence of mucosal damage visualized in the esophageal remnant after reconstruction
Table 27.1. Incidence of columnar lined metaplasia in the esophageal remnant. Study
Follow-up Median (range) months
Patients
Gastric metaplasia
Cardiac metaplasia
Intestinal metaplasia
Columnar metaplasia
14 (1–44) 60 (36–120) 36 (3–118) 26 (2–67) 16 (1–39) 120 35 (1–295)
83 32 40 48 66 101 84
4 3 0 0 6 – 13
0 9 10 0 0 – 12
2 (2%) 3 (9%) 9 (22.5%) 13 (27%) 9 (14%) 23 (23%) 17 (20%)
6 (7%) 15 (46%) 19 (47.5%) 24 (50%) 15 (23%) 36 (36%) 42 (50%)
Gutshow7 Oberg12 Dresner22 O’Riordan14 Franchimont13 Da Rocha24 D’Journo19
Progression – 7 of 19 – – 2 of 36 12 of 42
Evidence quality Low Low Low Low Low Very low Low
Table 27.2. Esophagectomy with or without pyloroplasty: evidence based reports. Author
Patient group
Urshel et al. (2002)
25
Fok et al. (1991)26
Mannell et al. (1990)29
Kobayashi et al. (1996)27
Outcome
Meta-analysis of RCTs on the Mortality drainage vs. no drainage effect of pyloric drainage on Anastomotic leaks patients outcome 9 RCTs 553 Pulmonary morbidity patients Pyloric drainage complications Fatal pulmonary aspiration Gastric outlet obstruction PRCT, 200 patients undergoing Mortality drainage vs. no drainage Lewis Tanner esophagectomy Anastomotic leaks Pyloroplasty n = 100, Control Pulmonary morbidity n = 100 Fatal pulmonary aspiration Gastric outlet obstruction PRCT, 40 patients undergoing Mortality drainage vs. no drainage retrosternal gastric Fatal pulmonary aspiration reconstruction Pyloroplasty Gastric outlet obstruction n = 20, Control n = 20 PRCT, 67 patients undergoing Food ejection time of foods (min) retrosternal gastric Rapid turnover protein reconstruction Pyloroplasty Prognostic nutritional count n = 34, Control n = 33
Results
Grade system
0.92 (95% CI 0.34–2.44) p = 0.77 0.90 (95% CI 0.47–1.76) p = 0.77 0.69 (95% CI 0.42–1.14) p = 0.15 2.55 (95% CI 0.34–19) p = 0.36 0.25 (95% CI 0.04–1.6) p = 0.14 0.18 (95% CI 0.03–0.97) p= 0.046 Pyloroplasty: 4 vs. Control: 3 Pyloroplasty: 5 vs. Control: 5 Pyloroplasty: 23 vs. Control: 16 Pyloroplasty: 0 vs. Control: 2 Pyloroplasty: 0 vs. Control: 13 Pyloroplasty: 1 vs. Control: 3 Pyloroplasty: 0 vs. Control: 3 Pyloroplasty: 1 vs. Control: 9
High
Pyloroplasty:19 vs. Control:33 No differences No differences
Very low
High
Low
27. Barrett Mucosa in the Cervical Remnant After Esophagectomy for Cancer
with a gastric transplant varies from 1% to 72%.8,12– 14 If endoscopic examination is used routinely after the operation, the prevalence and incidence of mucosal damage can be better defined. Maier reported esophagitis in 12 of 18 patients (66%) in the esophageal remnant after retrosternal gastric transplant.15 Using the Los Angeles classification,16 Shibuya observed severe esophagitis (grade C or D) in 75% of their patients.10 In another series of 48 patients, Yamamato found reflux esophagitis in 28 of their 48 patients (58.3%). Visual damage could be classified within all categories of mucosal breaks but the majority (67%) had Los Angeles grade C or D damage. Barrett’s metaplasia was seen and documented in 9 of the 28 patients (31%) with evidence of reflux damage and in 3 of the 20 (15%) patients with no evidence of mucosal alterations.11 Using the Savary-Miller classification,17 Franchimont assessed 47 patients endoscopically at a median of 489 days after surgery. All had endoscopic evidence of mucosal damage, the majority with severe lesions. Barrett’s metaplasia was seen in 13.5% of their patients.13 Using the MUSE classification proposed by Armstrong,18 our group observed mucosal damage in 60% of 84 patients after the operation.19 Barrett’s metaplasia was seen in 25% of these patients.
Histologic Evidence of Mucosal Damage The severity of mucosal damage in the esophageal remnant may progress from reflux esophagitis to columnar lined metaplasia. Table 27.1 summarizes the main observational studies on the prevalence of Barrett’s esophagus in the esophageal remnant. The incidence of reflux esophagitis is significantly higher when documented by biopsies. Wang, using electron microscopy, reported mucosal damage consistent with reflux in 90% of their patients.20 Our group has observed that, even when no visual mucosal damage is present, histological evidence of a reflux insult can be documented in 75% of patients.19 This strongly suggests an absence of correlation between endoscopic findings and histological evidence of mucosal damage from reflux exposure. The severity of mucosal lesions in the esophageal remnant can be classified in the same way as in idiopathic reflux disease: inflammation, mucosal-breaks (erosion
243
and ulceration) and columnar lined metaplasia. Inflammation in the squamous epithelium refers to a white cells and mononuclear infiltrates. Basal cell hyperplasia can also be seen as a reaction to abnormal reflux exposure. Replacement of the squamous epithelium by a columnar lined mucosa containing gastric, cardiac or specialized intestinal goblet cells represents advanced damage from reflux exposure. A diagnosis of Barrett’s esophagus in the esophageal remnant implies the presence of intestinal metaplastic cells in the histologic evaluation.21 Dresner observed in a longitudinal study over 36 months the sequential development of columnar metaplasia in 47% of their 40 patients after esophagectomy. Basal cell hyperplasia and mononuclear cell inflammatory infiltrates were observed in 28 patients in their cohort. Basal cell hyperplasia was correlated with the degree of inflammation. Grade I-III esophagitis was identified in 14 patients and esophageal columnar epithelium in 19 patients. Biopsies taken from the columnar regeneration revealed cardiac-type epithelium in ten patients and intestinal metaplasia in nine. No gastric metaplasia was found. Seven of the 10 serially followed patients with cardiac metaplasia showed progression from cardiac-type epithelium to intestinal metaplasia.22 In contrast, Gutshow found metaplastic changes containing gastric type cells in 4 patients and specialized intestinal metaplasia in 2 of their 83 patients with a follow up of 26–166 months. None of their patients showed a cardiac type metaplasia.8 Franchimont reported on the histology of the esophageal remnant in 66 patients who had a gastric pull-up after esophagectomy: 19 patients (28%) had normal squamous mucosa, 32 (28%) had inflammation in the squamous epithelium, 6 (9%) had islets of gastric-type mucosa, and 9 (13%) had intestinal metaplasia.13 O’Riordan et al. reported that development of a columnar lined mucosa in the esophageal remnant is time-related, suggesting chronic acid and bile exposure.14 The previous presence of intestinal metaplasia and adenocarcinoma in the resected esophagus did not seem to influence the reappearance of the metaplasia for these authors. In their series of 48 patients, 24 (50%) developed columnar metaplasia and in 13 (54%) specialized intestinal metaplasia was documented. The duration of reflux was most significant, with increasing
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prevalence over time. Intestinal metaplasia app eared in 13 patients at a median of 61 months after esophagectomy, compared with 20 months for the 35 patients who were intestinal metaplasia- negative. The prevalence of columnar metaplasia did not relate to the magnitude of acid or bile reflux, to preoperative neoadjuvant therapies, or to the original tumor histology. This is in contrast to the observation of Oberg et al. who reported that columnar metaplasia in the cervical esophagus after esophagectomy is more common in patients having Barrett’s esophagus preoperatively.12 The same concern exists for the progression from dysplasia to carcinoma formation in the metaplastic epithelium. Most reported series show a relatively short follow up after esophagectomy. A longer endoscopic and histologic assessment period might reveal a higher prevalence of such changes.
Development of Barrett’s Esophagus Our group19 reported that the prevalence of columnar metaplasia in the esophageal remnant increases with time. It becomes evident in 28% of patients in less than 12 months, increases to 49% between 1 and 3 years and is seen in 76% of the regularly assessed cohort beyond 3 years. The appearance of specialized intestinal metaplasia follows the same trend, being seen in 13% of patients during the first year, in 34% of them between 1 and 3 years and in 40% of them 3 years or more after the anastomosis. O’Riordan also reported that these lesions appeared in correlation with time suggesting a chronic exposure to a mixed refluxate of acid and bile.14 Columnar lined metaplasia was evident in 36% of their patients in less than 1 year, in 47% between 1 and 3 years, and in more than 60% after 3 years. Oberg suggested that the development of metaplasia appeared early and that it affected 30–65% of patients at any time during their evolution.12
Neoplastic Transformation Little information exists describing the process of transformation from intestinal metaplasia to established neoplasia in an esophageal remnant. Lord reported a case of an adenocarcinoma in one patient 42 years after gastric transplant.22 Recently, Gusthow reported a case of a documented transformation 28 months after subtotal esophagectomy.23
Da Rocha et al. report a 10-year follow-up of 101 post-esophagectomy patients for chagasic achalasia. Among them, there were five patients with neoplastic transformation (three squamous cell carcinoma and two adenocarcinomas).24 Based on the existing data, the risk of neoplastic transformation in the area of Barrett’s metaplasia is low (10%). These few cases reported in the literature, with the documented progression in the prevalence of intestinal metaplasia over time in the esophageal remnant, probably justify endoscopic surveillance every 1–2 years. A better supported recommendation for the esophageal remnant assessment may emerge from improved knowledge on the appearance of the various types of mucosal damage with their natural evolution with or without treatment.
Factors Affecting Function and Damage in the Esophageal Remnant Pyloric Drainage Procedure The significance and value of adding a pyloroplasty or a pyloromyotomy at the end of the interposed stomach is still debated.25–30 On one hand, it may facilitate gastric emptying, thus favoring a reduced exposure to reflux. On the other hand, it may also promote duodenal reflux and, in turn, facilitate the formation of a damaging refluxate containing pancreato-biliary secretions mixed with gastric acid secretions. This mixture then has open access to the esophageal remnant. Although many observations are reported on the effects of pyloric drainage to facilitate gastric conduit emptying, few observations have actually examined its effects on reflux in the esophageal remnant. There is also good evidence that appropriate gastric emptying of the transplant still occurs despite an intact pylorus. Table 27.2 summarizes the results of the main prospective and randomized observations on pyloroplasty when a gastric transplant is completed.25–30
Level of Anastomosis Hu et al. reported that reflux in the esophageal remnant was less severe with an anastomosis created in the apex of the right chest in a retro-aortic position. They compared their patients to a group with a sub
27. Barrett Mucosa in the Cervical Remnant After Esophagectomy for Cancer
aortic anastomosis and to another with reconstruction anterior to the aortic arch.31 Bemelman suggested that with a lower anastomosis, more of the stomach is affected by positive intra-abdominal pressure favoring greater reflux.32 McKeown suggested performing the anastomosis in the neck to decrease acid exposure in the esophageal remnant.33 Comparing 74 patients, Shibuya demonstrated that reflux esophagitis was present in 56.4% of patients with a neck anastomosis and in 88.6% of patients with an intrathoracic anastomosis.10 De Leyn also found a significantly higher incidence of reflux esophagitis in patients with an intrathoracic anastomosis when compared to patients with a cervical anastomosis (89% versus 56%).34 These results are similar to our observation: in the 84 patients assessed, we found that endoscopic mucosal damage was present in 46% of patients with a left neck reconstruction, whereas damage was documented in 81% of patients with a right apical intrathoracic anastomosis. Histopathologic damage was observed in 63% of the patients when the anastomosis was in the neck and in 89% if the anastomosis was in the right chest.19 Walther et al. randomized 83 patients to a neck or chest anastomosis. They found no difference in their long-term outcome on the diameter of the anastomosis and on stricture formation.35 In terms of quality of life, in a prospective longitudinal study, the surgical technique and the position of the esophagogastrostomy were not found to alter the perception of symptoms or to affect the quality of life.2 Despite arguments suggesting that left cervical reconstruction favors less mucosal damage compared to an intrathoracic reconstruction, there is no evidence at present that a reconstruction creating a common cavity between esophagus and stomach offers a better protection at any level. The level of the anastomosis does affect the rate of development of reflux esophagitis in the esophageal remnant. A left cervical anastomosis favors less reflux symptoms and less visual damage. However, given enough time, mucosal damage will appear, suggesting that the level of the anastomosis simply delays reflux damage in the esophageal remnant.
Route of Reconstruction Despite the disruption of normal antireflux mechanisms, the route of reconstruction may affect the esophageal exposure to gastric and duodenal
245
content. Katsoulis used 24-h ambulatory bilirubin monitoring in patients following a transhiatal subtotal esophagectomy and a gastric tube interposition placed either in the posterior mediastinum or in the substernal position.36 These two groups of patients were compared to 8 healthy volunteers. The gastric interposition, when positioned in the posterior mediastinum, was found to be exposed to a higher duodenal refluxate, while a substernal interposition resulted in reflux exposure considered even lower than what is seen in healthy individuals. In contrast, Maier found reflux esophagitis at endoscopy in 12 of 18 patients following a retrosternal reconstruction.15 In a randomized control trial, Van lanschot et al. observed that the functional results of the gastric transplant when using a retrosternal route were similar to those obtained with the prevertebral reconstruction.37 However in a small prospective randomized trial, Gawad found poorer radionucleide gastric emptying with the gastric transplant in a retrosternal position when compared to a prevertebral location. This slower gastric emptying had no significant impact on the patients’ quality of life.38
Medical Therapy Following the Operation Proton pomp inhibitors and prokinetics may help to protect the integrity of the esophageal remnant but their specific role is still unclear. In a recent report, acid suppression with PPI (proton pump inhibitor) has been used by Okuyama and colleagues. They monitored gastric 24 h pH in 44 patients after a gastric transplant for esophageal reconstruction. Initially, their treatment group included patients who were symptomatic while showing acid production in their stomachs. Subsequently, their prevention group included all patients with acid secretion, independently of them being symptomatic or not. When treating the patients in their treatment group with the PPI medication, 81% reported relief of their symptoms. Gastric acidity was significantly more prevalent in symptomatic patients, but there was no correlation between symptoms and acid exposure in the esophageal remnant. These authors suggest prophylactic administration of PPI medication following reconstruction of the esophagus with a gastric transplant.39 In contrast, Franchimont observed, in a retrospective analysis of 87 patients,
X. B. D’Journo and A. Duranceau
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that PPI medication following esophagectomy and gastric interposition did not prevent the occurrence of Barrett’s esophagus in 13% of his population.13 Prokinetics, mostly the motilin agonist Erythromycin, have been shown to improve the gastric transplant emptying following esophagectomy,40,41 but their prophylactic role in protecting the esophageal remnant from reflux has not been documented.
Summary and Recommendations After subtotal esophagectomy, the prevalence of Barrett’s esophagus in the esophageal remnant is estimated between 40% and 60% after 3 years. Endoscopic biopsies are the only available method to rule out mucosal damage or Barrett’s esophagus in the esophageal remnant. The risk of neoplastic transformation may justify the routine use of endoscopic surveillance. We suggest endoscopic examination every 1 or 2 years to rule out progressive mucosal damage from reflux. Pyloroplasty avoids gastric outlet obstruction and prevents pulmonary complications. Its effects on reflux prevention and on development of Barrett’s esophagus are still unknown. The level of anastomosis in the neck as opposed to the chest delays the development of mucosal damage and Barrett’s esophagus in the esophageal remnant. Based on the existing information, there is no strong evidence documenting that the route of reconstruction and the position of the transplant influence the appearance of reflux esophagitis or Barrett’s esophagus in the esophageal remnant. There is at present no prospective and randomized observation providing evidence that PPI medication influences or prevents reflux esophagitis in the esophageal remnant. Several factors influence the development of Barrett’s esophagus in the esophageal remnant following gastric interposition. Mucosal damage resulting from a mixed refluxate is an unavoidable consequence of esophageal resection followed by an esophagogastrostomy whether positioned in the neck or in the chest. One third of the postesophagectomy patients may develop a Barrett’s esophagus, and the same risks of neoplastic transformation seem to exist in these patients over time
when columnar lined mucosa has developed in the esophageal remnant. Regular endoscopic follow up is suggested in order to be able to offer proper medical treatment if reflux damage is documented. Gastric interposition creates an in vivo model of GERD and is certainly not an ideal esophageal substitute. Just as for its idiopathic form, reflux esophagitis and new columnar lined metaplasia after subtotal esophagectomy should be seen as a major complication of this type of reconstruction. Surgical treatment can be considered if mucosal damage resists treatment, mainly when accompanied by pulmonary aspiration problems. Both these treatments are open for investigation by well planned studies. Barrett’s esophagus appears to develop over time after gastric pull-up for reconstruction after esophagectomy; surveillance endoscopy for this problem is safe and effective in making an accurate diagnosis (evidence quality low). We make a weak recommendation for routine surveillance endoscopy to identify potentially worrisome mucosal changes in the esophageal remnant after esophagectomy (recommendation grade 2B). Barrett’s esophagus appears to develop over time after gastric pull-up for reconstruction after esophagectomy; surveillance endoscopy for this problem is safe and effective in making an accurate diagnosis (evidence quality low). We make a weak recommendation for routine surveillance endoscopy to identify potentially worrisome mucosal changes in the esophageal remnant after esophagectomy (recommendation grade 2B).
References 1. McLarty AJ, Deschamps C, Trastek VF, Allen MS, Pairolero PC, Harmsen WS. Esophageal resection for cancer of the esophagus: long-term function and quality of life. Ann Thorac Surg. 1997;63:1568–1572. 2. Egberts JH, Schniewind B, Bestmann B et al. Impact of the site of anastomosis after oncologic esophagectomy on quality of life - a prospective, longitudinal outcome study. Ann Surg Oncol. 2008;15:566–575. 3. Blazeby JM, Metcalfe C, Nicklin J, Barham CP, Donovan J, Alderson D. Association between quality of life scores and short-term outcome after surgery
27. Barrett Mucosa in the Cervical Remnant After Esophagectomy for Cancer for cancer of the oesophagus or gastric cardia. Br J Surg. 2005;92:1502–1507. 4. Barbour AP, Lagergren P, Hughes R, Alderson D, Barham CP, Blazeby JM. Health-related quality of life among patients with adenocarcinoma of the gastrooesophageal junction treated by gastrectomy or oesophagectomy. Br J Surg. 2007;95:80–84. 5. Lagergren P, Avery KN, Hughes R et al. Health-related quality of life among patients cured by surgery for esophageal cancer. Cancer. 2007;110:686–693. 6. Lerut TE, van Lanschot JJ. Chronic symptoms after subtotal or partial oesophagectomy: diagnosis and treatment. Best Pract Res Clin Gastroenterol. 2004; 18:901–915. 7. Gutschow C, Collard JM, Romagnoli R, Salizzoni M, Holscher A. Denervated stomach as an esophageal substitute recovers intraluminal acidity with time. Ann Surg. 2001;233:509–514. 8. Guyatt G, Gutterman D, Baumann MH, AddrizzoHarris D, Hylek EM, Phillips B, Raskob G, Lewis SZ, Schünemann H. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest. 2006;129:174–181. 9. Yuasa N, Sasaki E, Ikeyama T, Miyake H, Nimura Y. Acid and duodenogastroesophageal reflux after esophagectomy with gastric tube reconstruction. Am J Gastroenterol. 2005;100:1021–1027. 10. Shibuya S, Fukudo S, Shineha R et al. High incidence of reflux esophagitis observed by routine endoscopic examination after gastric pull-up esophagectomy. World J Surg. 2003;27:580–583. 11. Yamamoto S, Makuuchi H, Shimada H et al. Clinical analysis of reflux esophagitis following esophagectomy with gastric tube reconstruction.J Gastroenterol. 2007;42:342–345. 12. Oberg S, Johansson J,Wenner J,Walther B. Metaplastic columnar mucosa in the cervical esophagus after esophagectomy. Ann Surg. 2002;235:338–345. 13. Franchimont D, Covas A, Brasseur C, Laethem JL, El-Nakadi I, Deviere J. Newly developed Barrett’s esophagus after subtotal esophagectomy. Endoscopy. 2003;35:850–853. 14. O’Riordan JM, Tucker ON, Byrne PJ et al. Factors influencing the development of Barrett’s epithelium in the esophageal remnant postesophagectomy. Am J Gastroenterol. 2004;99:205–211. 15. Maier A, Tomaselli F, Sankin O et al. Acid-related diseases following retrosternal stomach interposition. Hepatogastroenterology. 2001;48:899–902. 16. Lundell LR, Dent J, Bennett JR et al. Endoscopic assessment of esophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172–180. 17. Savary M, Miller G. The Esophagus: Handbook and Atlas of Endoscopy. Solothurn (Switzerland): Verlag Gassmann; 1978; 119–159. 18. Armstrong D, Monnier P, Nicolet M, Blum AL, Savary M. Endoscopic assessment of oesophagitis. Gullet. 1991;1:63–67.
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19. D’Journo XB, Martin J, Rakovich G, Brigand C, Gaboury L, Ferraro P, Duranceau A. Mucosal damage in the esophageal remnant after esophagectomy and gastric transposition. Ann Surg. 2009; 249:262–268. 20. Wang Q, Liu J, Zhao X, Lei J, Cong Q, Li W, Li B, Wang F, Cao F, Zhang X, Zhang H, Zhang H. [Can esophagogastric anastomosis prevent gastroe sophageal reflux]. Zhonghua Wai Ke Za Zhi. 1999; 37: 71–73, 3. 21. Spechler SJ, Zeroogian JM, Antonioli DA, Wang HH, Goyal RK. Prevalence of metaplasia at the gastro-oesophageal junction. Lancet. 1994; 344:1533–1536. 22. Dresner SM, Griffin SM, Wayman J, Bennett MK, Hayes N. Human model of duodenogastro- oesophageal reflux in the development of Barrett’s metaplasia. Br J Surg. 2003;90:1120–1128. 23. Lord RV, Wickramasinghe K, Johansson JJ, Demeester SR, Brabender J, Demeester TR. Cardiac mucosa in the esophageal remnant after esophagectomy is an acquired epithelium with Barrett’s-like features. Surgery. 2004;136:633–640. 24. Gutschow CA, Vallböhmer D, Stolte M, Oh D, Danenberg K, Danenberg P, Schneider PM, Hölscher AH. Adenocarcinoma developing in de novo Barrett’s mucosa in the remnant esophagus after esophagectomy: clinical and molecular assessment. Dis Esophagus. 2008;21:6–8 25. da Rocha JR, Ribeiro U Jr, Sallum RA, Szachnowicz S, Cecconello I. Barrett’s esophagus (BE) and carcinoma in the esophageal stump (ES) after esophagectomy with gastric pull-up in achalasia patients: a study based on 10 years follow-up. Ann Surg Oncol. 2008;15:2903–2909. 26. Urschel JD, Blewett CJ, Young JE, Miller JD, Bennett WF. Pyloric drainage (pyloroplasty) or no drainage in gastric reconstruction after esophagectomy: a meta-analysis of randomized controlled trials. Dig Surg. 2002;19:160–164. 27. Fok M, Cheng SW, Wong J. Pyloroplasty versus no drainage in gastric replacement of the esophagus. Am J Surg. 1991;162:447–452. 28. Kobayashi A, Ide H, Eguchi R, Nakamura T, Hayashi K, Hanyu F. The efficacy of pyloroplasty affecting to oral-intake quality of life using reconstruction with gastric tube post esophagectomy. J Jpn Ass Thor Surg. 1996;44:770–778. 29. Yildirim S, Köksal H, Celayir F, Erdem L, Oner M, Baykan A. Colonic interposition vs. gastric pull-up after total esophagectomy. J Gastrointest Surg. 2004;8:675–678. 30. Mannell A, McKnight A, Esser JD. Role of pyloroplasty in the retrosternal stomach: results of a prospective, randomized, controlled trial. Br J Surg. 1990;77:57–59. 31. Chattopadhyay TK, Shad SK, Kumar A. Intragastric bile acid and symptoms in patients with an intrathoracic stomach after oesophagectomy. Br J Surg. 1993;80:371–373.
248 32. Hu J, Li R, Sun L, Ni Y. Influence of esophageal carcinoma operations on gastroesophageal reflux. Ann Thorac Surg. 2004;78:298–302. 33. Bemelman W, Verburg J, Brummelkamp W, Klopper PJ. A physical model of the intrathoracic stomach. Am J Physiol. 1988;254: 168–175. 34. McKeown KC. Total oesophagectomy – three-staged resection. In: Jamieson GG, ed. Surgery of the Oesophagus. Churchill Livingstone: Edinburgh. 1988;677–685. 35. De Leyn P, Coosemans W, Lerut T. Early and late functional results in patients with intrathoracic gastric replacement after oesophagectomy for carcinoma. Eur J Cardiothorac Surg. 1992;6:79–84. 36. Walther B, Johansson J, Johnsson F, Von Holstein CS, Zilling T. Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis. Ann Surg. 2003;238: 803–812. 37. Katsoulis IE, Robotis I, Kouraklis G, Yannopoulos P. Duodenogastric reflux after esophagectomy and
X. B. D’Journo and A. Duranceau gastric pull-up: the effect of the route of reconstruction. World J Surg. 2005;29:174–181. 38. van Lanschot JJ, van Blankenstein M, Oei HY, Tilanus HW. Randomized comparison of prevertebral and retrosternal gastric tube reconstruction after resection of oesophageal carcinoma. Br J Surg. 1999; 86: 102–108. 39. Gawad KA, Hosch SB, Bumann D et al. How important is the route of reconstruction after esophagectomy: a prospective randomized study. Am J Gastroenterol. 1999;94:1490–1496. 40. Okuyama M, Motoyama S, Maruyama K, Sasaki K, Sato Y, Ogawa J. Proton pump inhibitors relieve and prevent symptoms related to gastric acidity after esophagectomy. World J Surg. 2008;32: 246–254. 41. Hölscher AH, Voit H, Buttermann G, Siewert JR. Function of the intrathoracic stomach as esophageal replacement. World J Surg. 1988;12:835–844. 42. Siewert JR, Hölscher AH. Function of the intrathoracic stomach. Dis Esophagus. 1988;660–663.
28
Partial or Total Fundoplication for GERD in the Presence of Impaired Esophageal Motility David I. Watson
Laparoscopic antireflux surgery is well established for the surgical treatment of gastroesophageal reflux, and excellent longer term outcomes have now been reported following both total (Nissen) and partial fundoplication. Even though the most commonly performed operation remains a Nissen fundoplication, some surgeons advocate the routine use of a partial fundoplication, either anterior or posterior, and excellent long term outcomes have also been reported following these procedures.1–3 In most centers standard pre-operative work up for antireflux surgery includes esophageal manometry, and in the majority of patients undergoing surgery a normal motility pattern in the body of the esophagus will be demonstrated. In these patients either a Nissen or partial fundoplication can be performed, according to each individual surgeon’s preferences. However, some individuals undergoing antireflux surgery will have disordered or impaired esophageal body peristalsis at preoperative assessment, and the management of these individuals is more controversial. Some surgeons advocate a Nissen fundoplication as the treatment of choice for these patients, whereas others modify the surgical approach to a partial fundoplication, and some even withhold surgery altogether from individuals with significant esophageal dysmotility. Hence, when deciding whether to undertake antireflux surgery, as well as what type of surgery to perform for patients with impaired esophageal motility, it is important to consider the outcomes for antireflux surgery in patients with impaired peristalsis, and the evi-
dence for “tailoring” surgery according to preoperative esophageal manometry outcomes.
Impaired Esophageal Motility and Post-fundoplication Dysphagia It is widely believed that patients with impaired esophageal motility have an increased risk of postoperative dysphagia following fundoplication. In particular, this is of greatest concern following Nissen fundoplication.4,5 It is well accepted that a Nissen fundoplication produces an overcompetent valve at the gastro-esophageal junction, and this might contribute to post-operative side effects, such as troublesome dysphagia, inability to belch, gas bloat, etc., in some patients.6 Early postoperative dysphagia occurs in virtually all patients following fundoplication, but this resolves in most patients over time.7 Unfortunately, in a small number of patients, troublesome dysphagia can persist, and this can require either long term dietary modification or reintervention, and it is proposed that this might be more likely in patients with impaired esophageal body motility. Esophageal manometry demonstrates various changes following Nissen fundoplication.8 These include increased resting lower esophageal sphincter pressure, incomplete swallowing-induced lower esophageal sphincter relaxation, and a “ramp” pressure associated with swallowing. Ramp pressure is due to increased distal esophageal intraluminal pressure, which occurs immediately below the
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esophageal peristaltic pressure wave.6 This is thought to be due to increased resistance at the lower esophageal sphincter, with impaired sphincter opening during swallowing. Increased ramp pressure has been shown to be associated with post-fundoplication dysphagia, and ramp pressures are higher following Nissen fundoplication compared to partial fundoplication.6 Hence, if esophageal peristalsis is weak or absent, it might be insufficient to overcome any increased resistance at the lower esophageal sphincter. For this reason, constructing a partial fundoplication, which generates less resistance to transit across the lower esophageal sphincter, might reduce the risk of post-fundoplication dysphagia. This provides a theoretical framework for the concept of modifying the surgical approach in patients with impaired motility.
The Tailored Approach In the 1990’s, some surgeons advocated “tailoring” the type of antireflux procedure, according to pre-operative manometric parameters.4,5,9–11 The concept proposed was to construct a Nissen fundoplication in patients with normal esophageal motility, and a partial fundoplication in patients with impaired motility. Series of patients with poor pre-operative motility who underwent a partial fundoplication have been described, and good outcomes have been reported.4,12 Such outcomes have been put forward as evidence to support the “tailoring” concept. Unfortunately, however, this is not high level evidence, and only comparisons of outcomes following Nissen vs. partial fundoplication in patients with impaired motility will confirm or refute this concept. An alternative to the tailored approach is to routinely construct a partial fundoplication in all patients undergoing antireflux surgery, irrespective of whether patients have normal or impaired peristalsis at preoperative evaluation. This is a “one size fits all” approach, and if followed, tailoring becomes unnecessary. However, for this concept to be valid, long term outcomes following partial fundoplication procedures must be at least equivalent to those following Nissen fundoplication. A further view is that patients with impaired peristalsis have too great a risk of post-fundoplication dysphagia, and they should therefore not
undergo surgery for reflux. This view, however, is relatively easy to refute, as many surgical series describe excellent results in this patient group following fundoplications of all types.
Defining Impaired Peristalsis When considering surgical treatment for reflux in patients with impaired peristalsis, it is important to understand and define the problem of “impaired peristalsis”. Unfortunately, there is no well accepted definition, and different definitions are applied across different studies. This makes any review of published literature difficult, and comparisons between studies have limited validity. Unfortunately, many of the definitions appear to be opportunistic, with the criteria for dividing patients into subgroups with poor vs. normal peristalsis in many studies appearing to be selected so that similar sized groups can be defined for statistical comparison. This means that most studies evaluating this problem included many patients with relatively mild motility disturbances and fewer patients with more severe impairment. This limits the generalisability of these studies to the problem of severe impairment. Impaired peristalsis is defined according to two manometric parameters: the amplitude of peristalsis in the distal esophagus, and the proportion of swallows that generate a peristaltic wave which propagates the full length of the esophagus. The threshold for normal peristaltic amplitude ranges between 20 and 40 mm Hg in various studies, and the threshold for normal peristaltic propagation ranges from 60% to 80% of evaluated swallows.4–6,8 Hence, patients who are defined as having impaired peristalsis in some studies are considered to have normal peristalsis in others. At the more severe end of the spectrum of impaired peristalsis are the patients with an aperistaltic esophagus – i.e. no normal peristalsis. Everyone agrees that these patients have impaired motility. Similarly, patients with the connective tissue disease, scleroderma, are often troubled by reflux, and their disease can also be associated with an aperistaltic esophagus. These patients with an aperistaltic esophagus should, perhaps, be considered separately to other patients who still have some esophageal peristalsis, albeit impaired to a variable extent.
28. Partial or Total Fundoplication for GERD in the Presence of Impaired Esophageal Motility
A Partial Fundoplication for Patients with Impaired Peristalsis? Many studies have demonstrated good outcomes in patients selected according to esophageal manometry outcomes to undergo a Nissen fundoplication if normal motility is present, or a partial (usually posterior) fundoplication if peristalsis is deficient.4,5,9,10,12 In these studies, the outcomes in the subgroup of patients undergoing a partial fundoplication are generally good. However, this is not surprising, as results from the routine application of a partial fundoplication are also good.13 Hence, these studies do not provide any high level evidence to support the idea that patients with impaired peristalsis will have a poor outcome following a Nissen fundoplication. Of note, many uncontrolled studies, as well as randomised trials of partial vs. Nissen fundoplication,1,2,14 have described excellent success following partial fundoplication procedures. Success rates of approximately 90% have been reported at late (10 or more years) follow-up after both anterior and posterior partial fundoplication,1,3 and these results are supported by late outcomes from randomised trials which demonstrate a low risk of late post-operative dysphagia following a partial fundoplication.1,3 Hence, the idea that a partial fundoplication is an option for the treatment of all patients, with or without impaired esophageal peristalsis, is supported by these studies. Consequently, there is evidence to support the routine use of a partial fundoplication in all patients, irrespective of the status of their esophageal peristalsis, and if such an approach were to be followed, tailoring becomes unnecessary.
Nissen Fundoplication in Patients with Impaired Peristalsis Outcomes following Nissen fundoplication in patients with impaired peristalsis have been reported by many surgeons. All of these studies claim equivalent outcomes in patients with vs. without impairment,11,15,16 with similar rates of post-operative dysphagia, and a similar overall success rate in patients with impaired vs. normal peristalsis. However, in many of the studies, the
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cohort of patients with impaired peristalsis included predominantly patients with mild motility disturbances. Only a few studies stratified their patients so that outcomes following Nissen fundoplication in patients with more severe motility disorders could be determined. Beckingham et al.18 compared the outcomes for 33 patients with esophageal dysmotility to 48 patients with normal motility. In this study a stringent definition of dysmotility was applied, with less than 50% propagation of peristalsis required for inclusion. Outcomes were similar in patients with vs. without impaired peristalsis. In their series they also included 16 patients who were defined as having a severe motility disorder (mean peristaltic amplitude <20 mm Hg with 50% or less propagation of swallows), and 5 of these patients had an aperistaltic esophagus. The outcome in these patients was still good, and dysphagia was no more common in patients with severe impairment of motility. Baigrie et al.19 described a cohort of 31 patients with impaired motility who underwent a Nissen fundoplication. This series included three patients with an aperistaltic esophagus. Patients with both mild and more severe motility disturbances all had a good outcome, and the incidence of post-fundoplication dysphagia was acceptable. Bessell et al.20 described 846 patients who underwent a Nissen or posterior partial fundoplication. Fifteen patients had an aperistaltic esophagus. Six underwent a Nissen and 9 a posterior partial fundoplication. The clinical outcomes, including dysphagia, were similar for both procedures, leading these authors to conclude that tailoring the type of fundoplication according to preoperative esophageal motility was not necessary.
Randomized Controlled Trials Four randomized controlled trials of Nissen vs. posterior partial fundoplication have attempted to address the question of tailoring the type of fundoplication to preoperative manometric outcomes (Table 28.1). The first of these was reported by Rydberg et al.21,22 In their study patients were defined as having impaired peristalsis if the amplitude of the distal esophageal peristaltic pressure wave was less than 30 mm Hg. Using this definition,
D.I. Watson
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Table 28.1. Randomised trials of Nissen vs. posterior partial fundoplication which addressed tailoring the fundoplication type according to esophageal motility. Author Rydberg21,22 Zornig24,25,26
Chrysos23 Booth27
Total No. patients Patients with impaired (Nissen vs. Posterior) peristalsis (Nissen vs. Posterior)
Definition of impaired peristalsis
Patients with absent peristalsis
Outcome (Nissen vs. Posterior)
106 (53 vs. 53) 200 (100 vs. 100)
67
Amplitude of peristalsis £30 mm Hg
7 (4 vs. 3)
No difference
100 (50 vs. 50)
Propagation £60% swallows or amplitude of peristalsis <40 mm Hg
Not specified
33 (14 vs. 19) 127 (64 vs. 63)
33 (14 vs. 19) 52 (26 vs. 26)
Amplitude of peristalsis £30 mm Hg
Not specified
Less dysphagia after partial, but not influenced by tailoring No difference
Propagation £70% swallows or amplitude of peristalsis £30 mm Hg
Not specified
67 of 106 patients had impaired peristalsis, and a subgroup of 7 patients had an aperistaltic esophagus. The clinical outcomes of dysphagia and reflux control in this subset were similar following both Nissen and posterior partial fundoplication. Chrysos et al.23 applied the same definition of impaired peristalsis in a randomized trial of 33 patients, and they too identified no outcome differences for the two fundoplication types. Zornig et al.24–26 reported a larger study which applied a similar design. Two hundred patients were randomized to undergo a Nissen vs. posterior partial fundoplication, and 100 were determined to have impaired peristalsis. Impaired peristalsis was defined as propagation of 60% or less swallows at manometric assessment, or a distal esophageal peristaltic amplitude of less than 40 mm Hg. Although their trial showed less dysphagia following posterior partial fundoplication, the magnitude of the reduction in dysphagia was similar for patients defined as having normal vs. impaired peristalsis, and they too concluded that tailoring was unnecessary. The fourth randomized trial, by Booth et al.,27 was published recently. One hundred twenty seven patients were randomized to either a Nissen or a posterior partial fundoplication, and 52 patients were deemed to have impaired peristalsis, defined as the propagation of 70% or less swallows, or more than 30% of swallows with a peristaltic amplitude of less than 30 mm Hg in the distal esophagus. As with the other randomized trials, no differences were seen for the patients with normal vs. impaired peristalsis. The conclusions drawn from all of these trials was that tailoring,
Less dysphagia after partial, but not influenced by tailoring
i.e. selectively performing a posterior partial fundoplication for patients with impaired peristalsis and a Nissen fundoplication for patients with normal peristalsis, was not justified. It is likely, however, that none of these trials adequately addressed the issue of tailoring. This is because the manometric definition of impaired peristalsis in each trial led to the inclusion of many patients with only mild impairment of peristalsis, and it is likely that these patients can readily undergo either a partial or a Nissen fundoplication with the expectation of a good outcome. It is conceivable that a definition of impaired peristalsis which led to the inclusion of only patients with more severe impairment might have yielded a better cohort of patients. However, this would also have reduced the number of patients available for analysis, and each of the published studies would then have been statistically underpowered. By applying a loose definition, each trial failed to assess the question of tailoring in patients with more severe peristaltic disturbances. Furthermore, these trials do not inform decision making in patients with an aperistaltic esophagus.
Outcomes in Patients with an Aperistaltic Esophagus Fundoplication in patients with an aperistaltic esophagus is more controversial, and some clinicians avoid antireflux surgery altogether in these individuals. This is because some believe that the risk of troublesome dysphagia following surgery
28. Partial or Total Fundoplication for GERD in the Presence of Impaired Esophageal Motility
is too high.4,28 Unfortunately, however, in some of these patients medication is ineffective, and for them surgery is the only effective treatment option. An even more difficult subgroup of patients with an aperistaltic esophagus includes the individuals with scleroderma. Gastro-esophageal reflux is very common in patients with scleroderma, and surgery is often withheld, despite ineffective medical therapy. Case series of patients undergoing Nissen fundoplication which have included patients with an aperistaltic esophagus all suggest a good outcome in this subgroup, although the number of patients studied has been very small. Beckingham et al.18 reported a good outcome following a Nissen fundoplication in 5 patients with an aperistaltic esophagus. In an early report from our group we also performed a Nissen fundoplication in 3 patients with an aperistaltic esophagus, and the clinical outcome was good.19 Bessell et al.20 performed a Nissen fundoplication in six and a posterior partial fundoplication nine patients with an aperistaltic esophagus, and they also demonstrated good clinical outcomes following both fundoplication types. Only one study has directly addressed the use of antireflux surgery in patients with an aperistaltic esophagus. This study reported the outcome following fundoplication in 26 patients with an aperistaltic esophagus, including 6 with systemic scleroderma.29 The patients with an aperistaltic esophagus represented 1.8% of overall laparoscopic antireflux surgery workload. Twenty two patients underwent an anterior partial fundoplication and 4 had a Nissen procedure. The success rate was approximately 90% at 1 and 5 years follow-up. Twenty three of the 26 patients were able to eat a normal diet after surgery, and surgical reintervention for dysphagia was undertaken in only one patient. In this study, however, the issue of “tailoring” in patients with an aperistaltic esophagus was not addressed, and the conventional “wisdom” which recommends the use of a partial fundoplication for patients with an aperistaltic esophagus was followed. However, 4 patients did undergo a Nissen fundoplication, and their outcome was similar to those who underwent a partial fundoplication. These outcomes do support the view that antireflux surgery can achieve a good outcome in patients with an aperistaltic
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esophagus, and surgery should not be withheld from this sub-group.
Recommendations The quality of evidence addressing the question of whether a Nissen or partial fundoplication should be performed in patients with impaired esophageal motility is low, and it is further hampered by the application of different definitions of impaired peristalsis in different studies. Uncontrolled studies have demonstrated good outcomes following partial and Nissen fundoplication, but do not provide information which proves the relative superiority of either approach. Whilst the randomized trials of posterior partial vs. Nissen fundoplication all report equivalent outcomes for both fundoplication types, the trials generally included patients with relatively mild motility disorders, and most failed to define the proportion of patients with more severe disorders. Nissen and partial fundoplications achieve an equally good outcome in patients with moderately impaired motility and are safe (evidence quality low), permitting a weak recommendation for either procedure for management of GERD in this population (Grade 2B). For patients with severe impairment of peristalsis, including an aperistaltic esophagus, a weak recommendation is made for partial fundoplication (grade 2C).
A Personal Approach to Patients with Impaired Motility In the absence of good quality evidence, I and many other surgeons continue to apply a modified tailored approach to the management of some patients with impaired peristalsis. For patients with mild to moderate motility disturbances, tailoring to either a partial or a Nissen fundoplication is probably unnecessary, and the choice of procedure is decided according to surgeon and patient preferences. For patients with severe impairment of motility, including those with an aperistaltic esophagus, I routinely perform a partial fundoplication, my preference being an anterior 180° partial wrap.
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Nissen and partial fundoplications achieve an equally good outcome in patients with moderately impaired motility and are safe (evidence quality low), permitting a weak recommendation for either procedure for management of GERD in this population (Grade 2B). For patients with severe impairment of peristalsis, including an aperistaltic esophagus, a weak recommendation is made for partial fundoplication (grade 2C).
References 1. Cai W, Watson DI, Lally CJ, Devitt PG, Game PA, Jamieson GG. Ten-year clinical outcome of a prospective randomized clinical trial of laparoscopic Nissen versus anterior 180 degrees partial fundoplication. Br J Surg. 2008;95:1501–1505. 2. Baigrie RJ, Cullis SN, Ndhluni AJ, Cariem A. Random ized double-blind trial of laparoscopic Nissen fundoplication versus anterior partial fundoplication. Br J Surg. 2005;92:819–823. 3. Hagedorn C, Lönroth H, Rydberg L, Ruth M, Lundell L. Long-term efficacy of total (Nissen-Rossetti) and posterior partial (Toupet) fundoplication: results of a randomized clinical trial. J Gastrointest Surg. 2002;6: 540–545. 4. Kauer WK, Peters JH, DeMeester TR, Heimbucher J, Ireland AP, Bremner CG. A tailored approach to antireflux surgery. J Thorac Cardiovasc Surg. 1995;110: 141–146. 5. Hunter JG, Trus TL, Barum GD, Waring JP. A physiologic approach to laparoscopic fundoplication for gastroesophageal reflux disease. Ann Surg. 1996;223: 673–687. 6. Anderson JA, Myers JC, Watson DI, Gabb M, Mathew G, Jamieson GG. Concurrent fluoroscopy and manometry reveal differences in laparoscopic Nissen and anterior fundoplication. Dig Dis Sci. 1998;43:847–853. 7. Lafullarde T, Watson DI, Jamieson GG, Myers JC, Game PA, Devitt PG. Laparoscopic Nissen fundoplication: five-year results and beyond. Arch Surg. 2001;136: 180–184. 8. Mathew G, Watson DI, Myers JC, Holloway RH, Jamieson GG. Oesophageal motility before and after laparoscopic Nissen fundoplication. Br J Surg. 1997;84: 1465–1469. 9. Fuchs KH, Heimbucher J, Freys SM, Theide A. Manage ment of gastro-esophageal reflux disease 1995; Tailored concept of anti-reflux operations. Dis Esoph. 1994;7: 250–254. 10. Swanstrom LL. Partial fundoplications for gastroesophageal reflux disease: indications and current status. J Clin Gastroenterol. 1999;29:127–132.
D.I. Watson 11. Bremner RM, DeMeester TR, Crookes PF, Costantini M, Hoeft SF, Peters JH, Hagen J. The effect of symptoms and nonspecific motility abnormalities on outcomes of surgical therapy for gastroesophageal reflux disease. J Thorac Cardiovasc Surg. 1994;107: 1244–1249. 12. Patti MG, De Bellis M, De Pinto M, Bhoyrul S, Tong J, Arcerito M, Mulvihill SJ, Way LW. Partial fundoplication for gastroesophageal reflux. Surg Endosc. 1997;11: 445–448. 13. Rice S, Watson DI, Lally CJ, Devitt PG, Game PA, Jamieson GG. Laparoscopic anterior 180 degrees partial fundoplication: five-year results and beyond. Arch Surg. 2006;141:271–275. 14. Catarci M, Gentileschi P, Papi C, Carrara A, Marrese R, Gaspari AL, Grassi GB. Evidence-based appraisal of antireflux fundoplication. Ann Surg. 2004;239: 325–337. 15. Mughal MM, Bancewicz J, Marples M. Oesophageal manometry and pH recording does not predict the bad results of Nissen fundoplication. Br J Surg. 1990;77: 43–45. 16. Booth M, Stratford J, Dehn TC. Preoperative esophageal body motility does not influence the outcome of laparoscopic Nissen fundoplication for gastroesophageal reflux disease. Dis Esoph. 2002;15:57–60. 17. Goss B, Shacham Y, Szold A. Complete fundoplication has similar long-term results in patients with and without esophageal body dysmotility. Surg Endosc. 2003;17:567–570. 18. Beckingham IJ, Cariem AK, Bornman PC, Callanan MD, Louw JA. Oesophageal dysmotility is not associated with poor outcome after laparoscopic Nissen fundoplication. Br J Surg. 1998;85:1290–1293. 19. Baigrie RJ, Watson DI, Myers JC, Jamieson GG. Outcome of laparoscopic Nissen fundoplication in patients with disordered preoperative peristalsis. Gut. 1997;40:381–385. 20. Bessell JR, Finch R, Gotley DC, Smithers BM, Nathanson L, Menzies B. Chronic dysphagia follow ing laparoscopic fundoplication. Br J Surg. 2000;87: 1341–1345. 21. Rydberg L, Ruth M, Abrahamsson H, Lundell L. Tailoring antireflux surgery: A randomized clinical trial. World J Surg. 1999;23:612–618. 22. Rydberg L, Ruth M, Lundell L. Does oesophageal motor function improve with time after successful antireflux surgery? Results of a prospective, randomised clinical study. Gut. 1997;41:82–86. 23. Chrysos E, Tsiaoussis J, Zoras OJ, Athanasakis E, Mantides A, Katsamouris A, Xynos E. Laparoscopic surgery for gastroesophageal reflux disease patients with impaired esophageal peristalsis: total or partial fundoplication? J Am Coll Surg. 2003;197:8–15. 24. Fibbe C, Layer P, Keller J, Strate U, Emmermann A, Zornig C. Esophageal motility in reflux disease before and after fundoplication: a prospective, randomized, clinical, and manometric study. Gastroenterology. 2001;121:5–14.
28. Partial or Total Fundoplication for GERD in the Presence of Impaired Esophageal Motility 25. Zornig C, Strate U, Fibbe C, Emmermann A, Layer P. Nissen vs Toupet laparoscopic fundoplication. Surg Endosc. 2002;16:758–766. 26. Strate U, Emmermann A, Fibbe C, Layer P, Zornig C. Laparoscopic fundoplication: Nissen versus Toupet two-year outcome of a prospective randomized study of 200 patients regarding preoperative esophageal motility. Surg Endosc. 2008;22:21–30. 27. Booth MI, Stratford J, Jones L, Dehn TC. Randomized clinical trial of laparoscopic total (Nissen) versus
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posterior partial (Toupet) fundoplication for gastrooesophageal reflux disease based on preoperative oesophageal manometry. Br J Surg. 2008;95:57–63. 28. Little AG. Gastro-oesophageal reflux and oesophageal motility diseases. Who should perform antireflux surgery? Ann Chir Gynaecol. 1995;84:103–105. 29. Watson DI, Jamieson GG, Bessell JR, Devitt PG. Laparoscopic fundoplication in patients with an aperistaltic esophagus and gastroesophageal reflux. Dis Esoph. 2006;19:94–98.
29
Surgical Management of Non-acid Reflux Unresponsive to Medical Therapy Alexander J. Greenstein, James P. Dolan, and John G. Hunter
Introduction Gastroesophageal reflux disease (GERD), the most common upper gastrointestinal disorder in the United States, is typically treated medically. Referral for surgery has traditionally been reserved for those with complications of reflux, inability to tolerate medication or refractory symptoms despite medication. With the evolution of laparoscopic antireflux surgery (LARS) as a durable, safe and successful option, confidence in the procedure has increased and its popularity has risen to the point that it is considered a reasonable alternative to chronic medical therapy when performed by experienced surgeons.1,2 In order to maintain viability of this surgical option, good outcomes must be maintained, one aspect of which is appropriate patient selection. Selection is conventionally based on preoperative investigations that establish evidence of acid reflux in the absence of other pathology. Minimum requirements include upper gastrointestinal endoscopy and esophageal manometry. In those institutions where selective 24 h pH monitoring is employed, it is typically used for those patients with absence of esophagitis (non-erosive esophageal disease) or lack of typical symptoms. A treatment dilemma arises for the subset of patients for whom 24 h pH results are negative or for whom results that do not correlate with symptoms. Caution is typically advised when considering LARS for these patients and/or any who do not respond well to acid-suppressive medication. Clearly, patients with persistent non-acid reflux would not benefit from the mainstay of reflux
treatment – an increase in the proton pump inhibitor (PPI) dose, which will switch the pH of the refluxate from acid to non-acid without changing the total number of reflux episodes.3,4 Therefore, when persistently symptomatic, these patients are left with few good options beyond lifestyle modification and weight loss. Pharmacologic options include administration of the GABA agonist baclo fen which has been shown to decrease transient lower esophageal sphincter relaxations5–8 and relieve symptoms of postprandial reflux.9 Further data, however, will be needed before routine use of this medication can be recommended, and its use is often complicated by side effects such as nausea, somnolence and lightheadedness. After exhaustion of conservative therapies, patients are often left with the possibility of surgery. As LARS for nonacid reflux unresponsive to medical therapy remains a controversial topic without level 1 evidence supporting its use, it is important for the practicing surgeon to have a better understanding of the current literature. After briefly reviewing the topic of LARS for nonerosive esophagitis, this chapter will continue with a discussion of the limited evidence for performing surgery for non-acid reflux.
Definitions and Evaluation Prior to a discussion of the literature, it is imperative to commence with a precise definition of the patient population at hand as well as a description of the new techniques available to evaluate these patients. Historically, endoscopic findings and pH monitoring have been used to separate GERD into (1)
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_29, © Springer-Verlag London Limited 2011
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erosive reflux disease: endoscopically documented esophageal erosions in the distal esophagus; (2) non-erosive reflux disease (NERD): endoscopically normal esophagus and abnormal distal esophageal acid exposure; and (3) hypersensitive esophagus: endoscopically normal esophagus, normal distal esophageal acid exposure, and positive symptom association with acid and/or non-acid reflux. Some authors have broadened the definition of NERD to include patients with an endoscopically normal esophagus but abnormal distal esophageal acid exposure, a hypersensitive esophagus, or even functional heartburn. Persistent symptoms in patients with GERD who have been medically optimized can be due to several causes, and differentiation of patients with symptoms related to non-acid reflux (pH > 4) from those without abnormal reflux can be challenging. While esophageal pH monitoring can only identify patients with symptoms due to the acidity of gastric contents reaching the esophagus, there are several possible reasons for reflux symptoms. Assuming that they are of esophageal origin, symptoms may reflect non-acid exposure, the sensitivity of the esophagus to acid, the volume of the refluxate or the distensibility of the esophagus. To better address this degree of complexity, recent advances have been made in the ability to quantify gastric reflux and symptom association, the most important being multichannel intraluminal impedence (MII) testing. MII is a novel technique based on the measurement of electrical conductivity across a pair of closely spaced intraluminal electrodes. By placing these electrodes in a catheter that spans the length of the esophagus, impedence (resistance to electron flow) changes that occur in response to the movement of material within the esophagus (antegrade or retrograde) can be recorded. Moreover, as each bolus material (i.e. air, saliva, refluxed food) produces a specific impedence change, precise details can be obtained. When combined with pH monitoring, MII can detect gastroesophageal reflux at all pH levels, acid and non-acid, off or on antacid medication. A consensus statement has identified MII-pH as the most sensitive method for identifying all types of reflux episodes, and it is especially useful for those patients with normal endoscopic findings and persistent symptoms despite maximal medical therapy.10
A.J. Greenstein et al.
Typically, the administration of MII-pH testing is similar to that of conventional pH monitoring. The patient fasts for 4–6 h, after which time the MII-pH catheter is placed transnasally with catheter positioning based on the manometric detection of the lower esophageal sphincter (LES). Over the next 24 h, the patient enters all events (meals, medications, symptoms and body position) and maintains a diary of activities while an attached recording device collects all impedence and pH data. Although the use of this technique is increasing, it is not currently available in all practices and specialized referral may be needed. Nevertheless, MII-pH testing serves as the foundation for recent studies on non-acid reflux and a basic understanding of this modality is thus important for the practicing foregut surgeon.
Background Studies and NERD Prior to discussing the data, it is important to identify whether or not the study in question utilized MII-pH testing. We will focus on the most current studies that employed MII-pH testing instead of the older literature which tended to group together patients with atypical GERD or with NERD or those with normal preoperative 24 h pH testing. Specifically, articles published after 2000 were identified using a keyword search that included the terms “antireflux”, “non-acid”, “atypical”, “fundop lication” and “impedence”. Unfortunately, it is impossible to know how many of the patients in older studies had non-acid reflux, as this phenomenon could not specifically be measured. In addition, there are several studies that focus on the utility of MII-pH but do not address surgical intervention or do not specifically identify a non-acid reflux group. Therefore, the focus of this chapter will be on the small number of surgical manuscripts with a clearly defined non-acid reflux group. Before moving on to the MII-pH based literature, however, it is worthwhile to review the literature on NERD as well as one important article that served as a bridge to the era of MII-pH testing. In general, the majority of recent articles on NERD have been in favor of LARS, making the issue less controversial than that of non-acid reflux. It is, however, important to mention the
29. Surgical Management of Non-acid Reflux Unresponsive to Medical Therapy
topic in order to put doubts to rest and distinguish it from the non-acid reflux question at the center of our discussion. In 2002, a comparison was made between a series of 59 patients with NERD and 148 patients with erosive esophagitis (EE), all of whom then underwent LARS. The only significant difference between the two groups preoperatively was a higher mean DeMeester score (DMS) for the EE patients. While postoperative symptomatic improvement with typical symptoms and “well being scores” were significantly different from the pre-op period for both NERD and EE patients, both groups benefited equally from LARS.11 In 2003, two additional studies followed with a comparison of LARS for NERD and EE patients. The first study compared a matched sample of 89 EGD-normal patients with the same number of EE patients (Barretts or peptic stricture) who underwent LARS. In all cases, preoperative 24-h pH monitoring showed pathological values, and again the EE patients had a significantly (p < 0.05) higher mean preoperative DMS compared to the EGDnormal patients. Postoperatively, patient satisfaction with surgery was comparable in both groups: 95% rated long-term outcome as excellent or good and would undergo surgical treatment again if necessary. Finally, quality of life score was significantly improved (p < 0.01) for both groups within the first 3 postoperative months.12 In the second study, 84 patients without esophagitis were compared with 330 patients with esophagitis. Preoperative DMS were again higher in the esophagitis group, but at an average of 20 months postoperative, reflux symptom scores were similar between the two groups, and there was a significant reduction in both typical and atypical symptoms for both groups.13 Further evidence in favor of LARS for NERD has been supplied by two additional recent studies.14,15
Studies of Non-acid Reflux In 2004, a study examining the outcomes of LARS in patients with normal preoperative 24-h pH test results was published.16 In this study, a prospective database was used to identify patients who underwent Nissen fundoplication between 1997 and 2002 for typical symptoms of GERD but had
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normal pH studies. Fifteen patients with normal preoperative DMS (median 11.4) were compared with 208 consecutive patients with abnormal preoperative DMS (median 49.6). After 8.8 months (median), 6 of 15 patients with pre-op normal DMS scores continued to have typical GERD symptoms more than once per week after surgery while only 8% of the patients with abnormal DMS preoperatively experienced typical GERD symptoms over a similar time period (P < 0.01). The strongest predictor for poor outcome was normal preoperative pH (odds ratio = 9, P = 0.01). The authors concluded that surgery is not a good initial strategy in patients with reflux symptoms but normal pH test results. Presumably, this article advises against surgical therapy for non-acid reflux, but without MII-pH testing, one can only speculate on whether or not the group with a normal DMS was truly refluxing. The authors admit as much, adding that MII-pH testing should be employed in the future as a preoperative tool for these patients. One early study using MII-pH testing showed that LARS might be applied to patients with chronic cough and well documented non-acid reflux.17 This retrospective uncontrolled study specifically looked at patients with persistent cough despite twice daily PPI. From a group of 50 patients, 13 were identified with a positive association between the cough and impedance detected nonacid reflux. Six of these 13 patients underwent LARS, and 17 months postoperatively (median), five patients stated that they were asymptomatic. Despite the lack of details, objective evidence and a control group for this study, the study suggests that operative intervention may play a role for patients with clearly defined symptomatic non-acid reflux. Another study from 2006 that focused on the surgical implications for MII-pH had similar conclusions. In this publication, the authors evaluated the response to LARS in 19 patients undergoing Nissen fundoplication following MII-pH testing while on twice daily PPI dosing 18. Before surgery, 18 of 19 patients had a positive symptom index (at least half of symptoms associated with reflux), 14 of whom had non-acid reflux, and one had a negative symptom index. After a mean follow-up of 14 months, 16 of the patients with positive symptom indices were asymptomatic and no longer were taking any antireflux medication. While
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the authors reveal that patients with a positive symptom association by MII-pH monitoring can benefit from LARS, they do not specifically differentiate acid from non-acid reflux patients.Although the data suggest that patients with non-acid reflux should show symptomatic improvement following surgery, this is again an uncontrolled study without objective endpoint data. In 2008, the findings of an additional study with a subjective endpoint but a larger patient population were released.19 In total, 153 patients enrolled in a prospective database underwent MII-pH for GERD – these patients were either not responsive to or not compliant with PPI therapy. LARS was performed on 62 of these patients who had one or more of the following findings: an abnormal percent of time with pH < 4 in distal esophagus, a total number of refluxes detected at MII > 73, or a Symptom Index of at least 50%. In total, 17 patients had a normal pH study but an abnormal MII-pH study, presumably reflecting a population of nonacid reflux patients. At 6 and 12 months follow-up, 98% of all 62 patients were “satisfied” with the procedure and there was a significant reduction in the DMS reported for the 62 patients analyzed as a group. Although this study again does not isolate the non-acid patients, it implies that they would benefit, at least subjectively, from LARS. In a final study, also from 2008, objective MII endpoint data on LARS for non-acid reflux patients was published.20 Building on a prior study that revealed that LARS can prevent occurrences of transient lower esophageal sphincter relaxation,21 the authors performed MII-pH testing on 15 consecutive patients before (median 15 days) and after (median 7 months) surgery. The number of acid and non-acid reflux episodes was calculated with the patient in both upright and recumbent positions and the DMS were calculated. The authors were then able to use MII-pH to distinguish four different types of waveforms they labeled “non-acid reflux”, “swallow-induced reflux”, “intraesophageal reflux”, and “no retrograde movement”. A positive
.symptom index was defined as one for which 50% or more of the events were preceded by reflux. Post LARS, the overall number of reflux episodes was statistically reduced in both the upright and recumbent positions (p < 0.05) and this reduction was obtained due to the postoperative control of both the acid (p < 0.05) and non-acid (p < 0.05) reflux episodes. While 12 of the 15 patients showed a positive symptom index preoperatively, none had a positive symptom index in the post-op period. Again, although this article lacks a control group, the authors here add objective evidence from pre and post operative MII-pH studies displaying that LARS can protect the esophagus from both acid and non-acid reflux.
Summary Table 29.1 provides a summary of the most recent literature regarding LARS for non-acid reflux. The data described are observational in nature without control groups and all but one are based on subjective endpoints and are therefore provide only low quality evidence. Nevertheless, in GERD, success is often defined by symptom improvement or resolution. The literature reveals that patients who have been tested via MII-pH studies and shown to have non-acid reflux can be helped by surgical intervention. Assuming that there is no contraindication to surgery and that a skilled laparoscopic surgeon with fundoplication experience is available, we provide a weak recommendation (Grade 2C) in favor of LARS for patients identified by MII-pH studies as having non-acid reflux.22
Personal View of the Data Surgical intervention is clearly proven to be both safe and effective for acid-based reflux in both the
Table 29.1. Recent reports on utility of antireflux surgery for non-acid reflux in patients selected by MII-pH monitoring. Author
Year
Type of study
No. patients
Pre-op measurement
Post-op measurement
Post-op improvement
Tutuian17 Mainie18 del Genio19 del Genio20
2006 2006 2008 2008
Observational Observational Observational Observational
5 14 17 15
Objective Objective Objective Objective
Subjective Subjective Subjective Objective
Yes Yes Yes Yes
29. Surgical Management of Non-acid Reflux Unresponsive to Medical Therapy
short and long term. Physiologically, the Nissen procedure has been shown to increase the distal esophageal sphincter pressure to an amplitude three times the preoperative levels and restore the esophagogastric junction competence.23 Therefore, there is no reason to believe that an antireflux procedure would be effective for acid reflux events but not for non-acid reflux events. Historically, patients with persistent reflux symptoms despite PPI therapy, especially those with negative pH studies, have been viewed with caution by the practicing foregut surgeon. These symptoms may be due to a variety of causes, and it is critical to clarify the etiology of the symptoms prior to proceeding with surgery. Non-acid reflux, also known as “volume reflux”, is a term that was created to describe the phenomenon that symptomatic reflux episodes can exist even in the setting of normal acid exposure and it has been associated with typical24 and atypical symptoms25 of gastroesophageal reflux disease. With the advent of MII-pH monitoring, it has become feasible to identify symptomatic patients with non-acid reflux and differentiate them from patients with no reflux, thus improving the selection process for surgery. It is our belief that patients with symptomatic non-acid reflux definitively confirmed by MII-pH monitoring can benefit from LARS. Standardized guidelines with regards to specific MII-pH indications for surgery, however, still need to be established, and larger prospective and/or randomized trials should be performed to strengthen the evidence.
Antireflux surgery provides symptomatic benefits for patients with non-acid reflux as identified by MII-pH studies and is safe (low quality evidence). We make a weak recommendation for intervention antireflux surgery in these patients (recommendation grade 2C).
References 1. Hunter JG, Trus TL, Branum GD, Waring JP, Wood WC. A physiologic approach to laparoscopic fundoplication for gastroesophageal reflux disease. Ann Surg. 1996;223:673–687. 2. Carlson MA, Frantzides CT. Complications and results of primary minimally invasive antireflux procedures:
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a review of 10,735 reported cases. J Am Coll Surg. 2001;193:428–439. 3. Vela MF, Camacho-Lobato L, Srinivasan R, Tutuian R, Katz PO, Castell DO. Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology. 2001;120:1599–1606. 4. Tamhankar AP, Peters JH, Portale G, Hsieh CC, Hagen JA, Bremner CG, DeMeester TR. Omeprazole does not reduce gastroesophageal reflux: new insights using multichannel intraluminal impedance technology. J Gastrointest Surg. 2004;8:890–898. 5. Koek GH, Sifrim D, Lerut T, Janssens J, Tack J. Effect of the GABA(B) agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors. Gut. 2003;52: 1397–1402. 6. Vela MF, Tutuian R, Katz PO, Castell DO. Baclofen decreases acid and non-acid post-prandial gastrooesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther. 2003;17:243–251. 7. Johnsson F, Holloway RH, Ireland AC, Jamieson GG, Dent J. Effect of fundoplication on transient lower oesophageal sphincter relaxation and gas reflux. Br J Surg. 1997;84:686–689. 8. Rydberg L, Ruth M, Lundell L. Mechanism of action of antireflux procedures. Br J Surg. 1999;86:405–410. 9. Ciccaglione AF, Marzio L. Effect of acute and chronic administration of the GABA B agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease. Gut. 2003;52:464–470. 10. Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastrooesophageal reflux monitoring: Review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut. 2004;53:1024–1031. 11. Bammer T, Freeman M, Shahriari A, Hinder RA, DeVault KR, Achem SR. Outcome of laparoscopic antireflux surgery in patients with nonerosive reflux disease. J Gastrointest Surg. 2002;6:730–737. 12. Kamolz T, Granderath FA, Schweiger UM, Pointner R. Laparoscopic nissen fundoplication in patients with nonerosive reflux disease. long-term quality-oflife assessment and surgical outcome. Surg Endosc. 2005;19:494–500. 13. Desai KM, Frisella MM, Soper NJ. Clinical outcomes after laparoscopic antireflux surgery in patients with and without preoperative endoscopic esophagitis. J Gastrointest Surg. 2003;7:44–52. 14. Omura N, Kashiwagi H, Yano F, Tsuboi K, Ishibashi Y, Kawasaki N, Suzuki Y, Yanaga K. Therapeutic effects of laparoscopic fundoplication for nonerosive gastroesophageal reflux disease. Surg Today. 2006;36: 954–960. 15. Lord RV, DeMeester SR, Peters JH, Hagen JA, Elyssnia D, Sheth CT, DeMeester TR. Hiatal hernia, lower esophageal sphincter incompetence, and effectiveness of nissen fundoplication in the spectrum of gastroesophageal reflux disease. J Gastrointest Surg. 2009; 13:602–610.
262 16. Khajanchee YS, Hong D, Hansen PD, Swanstrom LL. Outcomes of antireflux surgery in patients with normal preoperative 24-hour pH test results. Am J Surg. 2004;187:599–603. 17. Tutuian R, Mainie I, Agrawal A, Adams D, Castell DO. Nonacid reflux in patients with chronic cough on acid-suppressive therapy. Chest. 2006;130:386–391. 18. Mainie I, Tutuian R, Agrawal A, Adams D, Castell DO. Combined multichannel intraluminal impedancepH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic nissen fundoplication. Br J Surg. 2006;93:1483–1487. 19. del Genio G, Tolone S, del Genio F, Aggarwal R, d’Alessandro A, Allaria A, Rossetti G, Brusciano L, del Genio A. Prospective assessment of patient selection for antireflux surgery by combined multichannel intraluminal impedance pH monitoring. J Gastrointest Surg. 2008;12:1491–1496. 20. del Genio G, Tolone S, del Genio F, Rossetti G, Brusciano L, Pizza F, Fei L, del Genio A. Total fundoplication controls acid and nonacid reflux: evaluation by pre- and postoperative 24-h pH-multichannel intraluminal impedance. Surg Endosc. 2008;22:2518–2523.
A.J. Greenstein et al. 21. Bahmeriz F, Dutta S, Allen CJ, Pottruff CG, Anvari M. Does laparoscopic antireflux surgery prevent the occurrence of transient lower esophageal sphincter relaxation? Surg Endosc. 2003;17:1050–1054. 22. Guyatt G, Gutterman D, Baumann MH, AddrizzoHarris D, Hylek EM, Phillips B, Raskob G, Lewis SZ, Schunemann H. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of chest Physicians task force. Chest. 2006;129:174–181. 23. del Genio G, Rossetti G, Brusciano L, Limongelli P, Pizza F, Tolone S, Fei L, Maffettone V, Napolitano V, del Genio A. Laparoscopic nissen-rossetti fundoplication with routine use of intraoperative endoscopy and manometry: technical aspects of a standardized technique. World J Surg. 2007;31:1099–1106. 24. Bredenoord AJ, Weusten BL, Curvers WL, Timmer R, Smout AJ. Determinants of perception of heartburn and regurgitation. Gut. 2006;55:313–318. 25. Sifrim D, Dupont L, Blondeau K, Zhang X, Tack J, Janssens J. Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring. Gut. 2005;54:449–454.
30
Prophylactic Antireflux Surgery in Lung Transplantation Michael S. Griffin and Andrew G. N. Robertson
Introduction Longterm survival of lung allograft recipients is lower than for other solid organ transplants, due to chronic allograft dysfunction manifested as Bronchiolitis Obliterans Syndrome(BOS).1,2 Chro nic micro-aspiration, secondary to gastro-esoph ageal reflux, may contribute to BOS and up to 75% of patients have Gastro-esophageal reflux disease (GERD) following lung transplanta tion.3–10 This chapter looks at the evidence base supporting prophylactic antireflux surgery in lung transplant recipients.
Methodology A literature search was performed using OVID Medline, Pubmed and EMBASE. Search terms inclu ded “lung transplantation”,“gastro-esophageal reflux disease” and “fundoplication”. Reference lists from important articles were examined to retrieve further papers. Only English articles were included.
Findings Anti-reflux Surgery The first documented case of GERD as a reversible cause of decreasing lung function, was reported in 2000 by Palmer et al. After anti-reflux surgery the patient had improved FEV1 and resolution of
bronchial inflammation 11. The Duke University Transplant Group have since published several seminal papers (Table 30.1),6,12–15 each an update of a continuing program, suggesting that anti-reflux surgery may lead to increased survival and improved lung function post-transplantation by preventing lung damage through reflux.10
Timing of Surgery: A Role for Fundoplication Before Lung Transplant? Introduction of fundoplication has not been sys tematic, but has been considered in patients with end stage lung disease (Table 30.1).10,16,17 Performing anti-reflux surgery in this high risk population is controversial. There is a risk of morbidity and mortality and some patients derive little benefit. Potential benefits include an immediate protec tion from microaspiration.16 In one series (n = 19) there was no statistical significant decrease in pulmonary function post-operatively (mean fol low up 15 months). Four of 19 patients were subse quently transplanted but another four patients died before lung transplant due to respiratory fail ure.16 One patient with pulmonary fibrosis had a significant improvement in FEV1 from 77% of pre dicted to 103% and was removed from the trans plant list.16 The second series (n = 15) demonstrates that in selected patients antireflux surgery can be safe in the prelung transplant population. No information on lung function is described. This series did not demonstrate an improvement in lung function in the 15 pretransplant nor 17 posttransplant patients undergoing fundoplication.17
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264 Table 30.1. Studies of prophylactic antireflux surgery for lung transplant patients. Author Date
Unit
No of patients undergoing fundoplication
Outcome
PFTs
Survival
Quality of evidence
Lau 200212 Davis 20036 O’Halloran 200413 Cantu 200414 Balsara 200815 Linden 200616 Gasper 200717 Burton 200918
D D D D D H UCSF M
18 43 28 76 184 19 32 21
Feasability Survival Safety Survival BOS Pre-transplant lung function Safety pre & post transplant QoL
Improved Improved Improved Improved Improved Slowed decline in some patients n/a Slowed decline
n/a Improved n/a Improved None None n/a n/a
Very low Low Low Low Low Very low Very low Very low
D Duke University, H Harvard University, UCSF University of California, San Francisco, QoL Quality of Life
Early Versus Late Fundoplication in Lung Transplantation Initial studies suggested that decreased FEV1 posttransplant was reversible if fundoplication was performed early. Therefore Cantu (2004) evalu ated the effect of early versus late fundoplication. Fundoplication was performed in 76 patients if pH studies showed a total acid time of >10% or there was an unexplained decrease in FEV1.14 Freedom from BOS was significantly better at 1 year (100% vs. 90–92%; p = 0.01) and 3 years (100% vs. 47–62%; p = 0.03) in patients undergo ing early fundoplication. This was reflected in sur vival, with a significant difference after one year in patients who underwent early fundoplication (100%), when compared to the rest of the patients (90–98%) (p = 0.02). This was more pronounced at 3 years (100% vs. 69–86%; p = 0.03).14 A survival advantage was engendered by early fundoplica tion, even when compared to patients with a “nor mal” pH study. This may be partly due to a “normal” pH study including those with mild reflux with a mean acid exposure of 7.9%, suggest ing that any degree of reflux may be deleterious to this patient group. There were several limitations to this study.10 Firstly it was retrospective, with a non-random analysis and secondly, the group who underwent early fundoplication surgery was small (n = 14) and had limited followed up.14 The most recent data (abstract publication) demonstrated that 15.9% of those undergoing early fundoplica tion (n = 67) developed BOS compared to 47.7% in those undergoing late fundoplication (n = 117) (p < 0.0001) at 1 year post transplant. This is the most up-to-date data available on this study and this shows no difference in one year survival.15 A recent
study of late fundoplication (mean 768 days posttransplant) suggests late intervention may stabi lise lung function and slow decline but does not improve FEV1 (Table 30.1).18
Indications for Surgery There is no consensus within the lung transplant community regarding investigation of reflux and indications for intervention.19 Patients have been assessed pre-operatively, in the early post trans plant period and later.6,14,18–20 Indications for surgery have been varied and include symptomatic reflux, deteriorating lung function, evidence of reflux on pH, pH-impedance, endoscopy, barium swallow, or biochemical, pathological, bronchoscopic or radio logical evidence of aspiration.6,18–20 Biomarkers (pepsin and bile salts) have been used to document aspiration21–24 and have been suggested as an indi cation for surgery. No current evidence supports this. Most units currently state an advocacy for some form of anti-reflux surgery in either patients with demonstrable reflux or more pragmatically, in symptomatic patients with reflux.19
Pre-operative Assessment and Perioperative Care for Fundoplication Surgery Patients need to undergo a thorough pre-operative assessment. Adequate lung function FEV1 (>50% predicted) is needed and immunosuppression must be taken rigorously. If routine pre-operative tests are abnormal, surgery should be postponed until the patient is stable.9 Postoperative mechani cal ventilation should be used with caution. Fluid balance should be regulated and diuretics given
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30. Prophylactic Antireflux Surgery in Lung Transplantation
liberally. Central venous pressure and arterial line monitoring are not routinely required.9,13 Routine anaesthetics and standard antibiotics should be prescribed, e.g. a second generation cephalosporin. A multidisciplinary approach is necessary. Infec tions should actively be sought out and treated.9
Choice of Procedure Open approaches to anti-reflux surgery have excel lent long term success rates (25 year success rate of 70–80%) in controlling reflux.25 The laparoscopic approach, first performed in 1991, is now the pro cedure of choice and has been shown to be as suc cessful in the control of reflux as open procedures in the medium to long-term.26 Laparoscopic sur gery requires an increased operative time, but has the advantage of a shorter hospital stay, lower operative morbidity and faster time to recovery.26 These benefits are important in lung transplant recipients. Studies in the non-transplant popula tion are conflicting, whether a Nissen fundoplica tion is more effective than a partial wrap.28–32 Published studies in the lung transplant popula tion favour laparoscopic Nissen Fundoplication, unless dysmotility is present.9,10,14 A recent trans plant study has favoured laparoscopic Toupet fun doplication. This has been shown to be effective at controlling symptoms of reflux and has reduced the rate of further deterioration in lung function.18 In non transplant patients, recent randomised con trol trials suggest that a wrap need not be tailored for dysmotility.29,33 In the presence of severe oesophageal dysfunction a partial fundoplication should be considered.9,12,14,27 In one published series post-transplant, the surgeon had to convert at least three procedures to open fundoplication due to severe abdominal adhesions.6,9 Extra surgical pro cedures have been simultaneously performed: for repair of hiatal hernia (5–10%)9,18; for gastric drain age in patients with gastroparesis (9%), predomi nantly pyloroplasties, but a gastrojejunostomy has been reported.9 Up to 15% of patients have needed a gastric or jejunal feeding tube.9,18 Other reported simultaneous procedures performed with posttransplant fundoplication include a distal gas trectomy for a perforated peptic ulcer9 and a cholecystectomy.18 In summary, in the lung trans plant population, the evidence for improved lung function and survival is based pre-dominantly on
Nissen fundoplication.10,14 Partial fundoplication (Toupet) has been shown to control reflux and to stabilise or slow decline of lung function.18
Safety of Surgery One study showed laparoscopic Nissen fundoplica tion to be safe in lung transplant recipients with no significant complications occurring.13 Compared to the non-transplant population there is no significant differences in operative time or blood loss.13 The transplant population had an increased length of stay (2.89 days vs. 0.71 days) due to transplant comorbidity.13 Complications include pneumonia, urinary tract infections, nausea, ileus and dysphagia.9 Specific problems in the postoperative period include temporary dysphagia (7%), nausea (7%),9 discomfort from gas bloat and increased flatulence.1
Quality of Life In a study of laparoscopic Toupet fundoplication in transplant recipients, three quarters of patients had an improvement in quality of life and reflux scores. 88% rated the results of their surgery as excellent or good. Reported side effects included mild dysphagia (60%), belching and increased flatulence. Mean BMI decreased over the first 6 months post fundoplication.18
Recommendations From our critique of the current literature, we make the following recommendations. All patients should be assessed for reflux pre-transplant or in the early post-transplant period. The evidence to support pre-transplant fundoplication is limited and surgery should be performed in the posttransplant period. Fundoplication should be per formed early within 90 days post-transplant to have maximum benefit. The laparoscopic approach should be favoured. Current evidence favours a Nissen fundoplication to prevent decline in lung function. Fundoplication should be performed on those with: a pH < 4 > 10%, symptomatic reflux, reflux and decreasing PFTs or reflux and aspira tion. Patients should undergo careful pre-opera tive selection, should be clinically stable and
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should have a FEV1 > 50% predicted. A multidisci plinary approach should be used in pre-operative and peri-operative periods.
Personal View of the Findings There is a growing body of evidence to support the role of prophylactic antireflux surgery in the lung transplant population. Early fundoplication (<90 days) in selected patients is safe and results suggest that it may retard the development of BOS, and extend survival.10,14 However current data from different units and even from the same unit is conflicting. There is also a wide variation in practice between transplant centres. More solid guidelines need to be created.10 We believe this to be a priority since current evidence suggests a benefit with early surgery and little benefit for surgery in more advanced disease. The next step should be standardisation of surgical practice. This may then allow appropriate multi-centred randomised controlled trials.19 Lung transplant patients benefit from posttransplant fundoplication as a result of decrea sed BOS, and improved long-term survival (evidence quality low). We make a strong rec ommendation for total fundoplication within 90 days after transplant in patients with abnor mal pH testing, symptomatic reflux, reflux with decreasing PFTs, or reflux and aspiration (rec ommendation grade 1C).
Acknowledgments European Society for Organ Transplant ation and British Lung Foundation (AGNR).
References 1. Robertson AGN, Griffin SM, Murphy D et al. Targeting allograft injury and inflammation in the manage ment of post-lung transplant Bronchiolitis Obliterans Syndrome. Am J Transplant. 2009;9:1272–1278. 2. Belperio JA, Weigt SS, Fishbein MC, Lynch JP, 3rd. Chronic lung allograft rejection: mechanisms and therapy. Proc Am Thorac Soc. 2009;6:108–121. 3. D’Ovidio F, Keshavjee S. Gastroesophageal reflux and lung transplantation. Dis Esopha. 2006;19:315–320.
M.S. Griffin and A.G.N. Robertson 4. Hadjiliadis D, Duane Davis R, Steele MP et al. Gastroesophageal reflux disease in lung transplant recipients. Clin Transplant. 2003;17:363–368. 5. Young LR, Hadjiliadis D, Davis RD, Palmer SM. Lung transplantation exacerbates gastroesophageal reflux disease. Chest. 2003;124:1689–1693. 6. Davis RD, Jr., Lau CL, Eubanks S et al. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg. 2003;125: 533–542. 7. D’Ovidio F, Mura M, Ridsdale R et al. The effect of reflux and bile acid aspiration on the lung allograft and its surfactant and innate immunity molecules SP-A and SP-D. Am J Transplant. 2006;6:1930–1938. 8. Robertson AGN, Ward C, Pearson J et al. Longitudinal changes in gastro-oesophageal reflux from three months to six months post lung transplantation. Thorax. 2009;64:1005–1007. 9. Hartwig MG, Appel JZ, Davis RD. Antireflux surgery in the setting of lung transplantation: strategies for treating gastroesophageal reflux disease in a highrisk population. Thorac Surg Clin. 2005;15:417–427. 10. Robertson AGN, Ward C, Pearson JP, Corris PA, Dark JH, Griffin SM. Lung transplantation, gastro-esopha geal reflux and fundoplication. Ann Thorac Surg. 2010;89:653–660. 11. Palmer SM, Miralles AP, Howell DN, Brazer SR, Tapson VF, Davis RD. Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplanta tion. Chest. 2000;118:1214–1217. 12. Lau CL, Palmer SM, Howell DN et al. Laparoscopic antireflux surgery in the lung transplant population. Surg Endosc. 2002;16:1674–1678. 13. O’Halloran EK, Reynolds JD, Lau CL et al. Laparo scopic Nissen fundoplication for treating reflux in lung transplant recipients. J Gastrointest Surg. 2004;8: 132–137. 14. Cantu E, 3rd, Appel JZ, 3rd, Hartwig MG et al. Early fundoplication prevents chronic allograft dysfunc tion in patients with gastroesophageal reflux dis ease. Ann Thorac Surg. 2004;78:1142–1151. 15. Balsara KR, Cantu E, Bush EL et al. Early fundoplica tion reduces the incidence of chronic allograft dys function in patients with gastroesophageal reflux disease. J Heart Lung Transplant. 2008;27:S125. 16. Linden PA, Gilbert RJ, Yeap BY et al. Laparoscopic fundoplication in patients with end-stage lung dis ease awaiting transplantation. J Thorac Cardivasc Surg. 2006;131:438–446. 17. Gasper WJ, Sweet MP, Hoopes C et al. Antireflux sur gery for patients with end-stage lung disease before and after lung transplantation. Surg Endosc. 2008;22: 495–500. 18. Burton PR, Button B, Brown W et al. Medium-term out-come of fundoplication after lung transplanta tion. Dis Esophag. 2009; e-published ahead of print. 19. Robertson AG, Shenfine J, Ward C et al. A call for standardization of antireflux surgery in the lung
30. Prophylactic Antireflux Surgery in Lung Transplantation transplantation population. Transplantation. 2009; 87:1112–1114. 20. Halsey KD, Wald A, Meyer KC, Torrealba JR, Gaumnitz EA. Non-acidic supraesophageal reflux associated with diffuse alveolar damage and allograft dysfunction after lung transplantation: a case report. J Heart Lung Transplant. 2008;27:564–567. 21. Stovold R, Forrest IA, Corris PA et al. Pepsin, a bio marker of gastric aspiration in lung allografts: a putative association with rejection. Am J Respir Crit Care Med. 2007;175:1298–1303. 22. Ward C, Forrest IA, Brownlee IA et al. Pepsin like activity in bronchoalveolar lavage fluid is suggestive of gastric aspiration in lung allografts. Thorax. 2005;60:872–874. 23. D’Ovidio F, Mura M, Tsang M et al. Bile acid aspira tion and the development of bronchiolitis obliterans after lung trans-plantation. J Thorac Cardiovasc Surg. 2005;129:1144–1152. 24. Blondeau K, Mertens V, Vanaudenaerde BA et al. Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J. 2008;31:707–713. 25. Luostarinen M, Isolauri J, Laitinen J et al. Fate of Nissen fundoplication after 20 years. A clinical, endoscopical, and functional analysis. Gut. 1993;34:1015–1020. 26. Kelly JJ, Watson DI, Chin KF, Devitt PG, Game PA, Jamieson GG. Laparoscopic Nissen fundoplication: clinical outcomes at 10 years. J Am Coll Surg. 2007;205: 570–575.
267 27. Darling G, Deschamps C. Technical controversies in fundoplication surgery. Thorac Surg Clin. 2005;15: 437–444. 28. Stewart GD, Watson AJ, Lamb PJ et al. Comparison of three different procedures for antireflux surgery. Br J Surg. 2004;91:724–729. 29. Strate U, Emmermann A, Fibbe C, Layer P, Zornig C. Laparoscopic fundoplication: Nissen versus Toupet two-year outcome of a prospective ran domized study of 200 patients regarding preopera tive esophageal motility. Surg Endosc. 2008;22: 21–30. 30. Cai W, Watson DI, Lally CJ, Devitt PG, Game PA, Jamieson GG. Ten-year clinical outcome of a pro spective randomized clinical trial of laparoscopic Nissen versus anterior 180(degrees) partial fundopli cation. Br J Surg. 2008;95:1501–1505. 31. Baigrie RJ, Cullis SN, Ndhluni AJ, Cariem A. Random ized double-blind trial of laparoscopic Nissen fun doplication versus anterior partial fundoplication. Br J Surg. 2005;92:819–823. 32. Fein M, Bueter M, Thalheimer A et al. Ten-year out come of laparoscopic antireflux surgery. J Gastro intest Surg. 2008;12:1893–1899. 33. Booth MI, Stratford J, Jones L, Dehn TC. Randomized clinical trial of laparoscopic total (Nissen) versus posterior partial (Toupet) fundoplication for gas tro-oesophageal reflux disease based on preopera tive oesophageal manometry. Br J Surg. 2008;95: 57–63.
31
Optimal Initial Therapy for Achalasia Lars Lundell
More than 300 years ago Thomas Willis described a 38 year old man who presented with an inability to swallow.1 After a variety of considerations he came to a conclusion that the patient’s problem was caused by lower esophageal narrowing leading to massively dilated esophagus. After the diagnosis, Sir Willis designed a novel device to alleviate the underlying defects and thereby constructed the first dilator. This device consisted basically of a piece of whale bone with a sponge adapted to its distal end. With the subsequent development of mechanical dilators those rapidly established themselves as standard therapy in achalasia. Rigid dilators where widely applied through the early and mid nineteenth century with a reported symptomatic improvement in more than half of the patients. Later on, based on the limitation and difficulties with repeated dilations, it was natural that surgical methods developed. Heller reported his early surgical experience in 1913 when he successfully had treated achalasia cases by undertaking a cardiomyotomy.2 The idea behind this surgical approach was to destroy the “spastic” sphincter. This original technique comprised of an anterior and posterior partial myotomy extending 8 cm or more along the distal esophagus onto the proximal stomach. As expected, the myotomy not only relieved the cardiospasm but induced profound and uncontrolled reflux. Later investigators suggested that the original Heller cardiomyotomy was perhaps too extensive in its nature, whereafter an isolated anterior cardiomyotomy was first described in 1918. This operation has thereafter incorrectly been referred to as a Heller myotomy
but subsequently has been the gold standard for surgical treatment of achalasia.3 Initially, the surgical approach was established through a laparotomy, but soon discussions went into the direction of trying the extra abdominal approach addressing the problem through a left thoracotomy. One of the strongest arguments in favor of the transthoracic approach to cardiomyotomy has been that the EG-junction remains untouched and that the gastric portion of the LES is not entirely divided, whereby the operation does not necessarily lead to reflux requiring an antireflux procedure. During recent years, thoracocopic and laparoscopic approaches to cardiomyotomy have been developed (see below).
Epidemiology and Pathophysiologic Considerations The characteristics of the disease result from damage to the innervation of the anatomic area of the esophageal body and LES. The esophageal myenteric plexus seems to be the primary neurologic target, with the end result of this process the formation of inflammatory changes as represented by a selected loss of postganglionic inhibitory neurones containing NO and VIP.4,5 Since postganglionic cholinergic neurones are spared, cholinergic stimulation continues unopposed, resulting in impaired LES relaxation. Although not proven, current evidence suggests that some insult to the esophagus, perhaps in the form of a viral infection,
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results in major neuronal plexus inflammation. This inflammation may then lead to an autoimmune response in vulnerable individuals who may be genetically predisposed as well. Subsequently, chronic inflammation leads to destruction of the inhibitory myenteric ganglionic cells resulting in the clinical syndrome of achalasia. Achalasia is a rare disease, and estimation of its true incidence or even prevalence is further complicated by the fact that it may even be asymptomatic. Most studies addressing the epidemiology have been retrospective, and it is understandable that the incidence figures vary from 0.03 to 1.5 cases per 100,000 inhabitants per year. There seem to be no race and gender predilections; two incidence or presentation peaks are present; one in the 20–40 age ranges and the second one in the seventh decade.6–9 Little is known concerning the natural history of the disease and it is assumed that long term poor esophageal emptying and food retention leads to progressive esophageal dilatation. Csendes and co-workers10 studied 14 patients who refused treatment after the diagnosis of the disease. The patient came for clinical consultation 5 years after the initial diagnosis and all patients had severe dysphagia and poor quality of life, with a mean weight loss of 12 kg. At radiography the maximal diameter of the esophageal body had increased from 29.2 mm at presentation to 59.5 mm, which corresponds to a rate of dilatation of 6.9 mm/year over the 5 year period. With an increasing degree of esophageal dilatation, regurgitation, especially nocturnal regurgitation, becomes a predominant symptom with the potential of pulmonary complication due to chronic aspiration. It seems as if early and adequate therapies can minimize these problems related to progression and the occurrence of complications. Consequently, failure to improve esophageal emptying by relieving the obstruction at the LES may lead to further deterioration and the development of end stage disease in the form of mega-esophagus.11
Evaluating Response to Treatment As no therapy for achalasia addresses and/or reverses the underlying esophageal pathology, therapeutic efficacy can only be assessed by symptomatic and/or functional improvements. Several
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investigators have noted that evaluating response to treatment by symptom relief alone may be inaccurate. Some patients report good or excellent relief of symptoms despite having grossly abnormal esophageal studies. Compared to the pretherapy situation, these patients often experience a significant improvement but a detailed history may disclose that the patients indeed have some residual symptoms. An explanation for this phenomenon may be that patients with chronic symptoms subjectively interpret even minimal improvement in esophageal emptying as dramatic.12 Moreover, patients may have unrealistic expectations of the therapy and report little symptomatic improvement despite having normal esophageal emptying on barium esophagogram. There is also evidence to suggest that a diminished visceral sensitivity occurs with aging, and alterations in esophageal sensation may well be an important factor for the subjective perception of symptoms in achalasia as well. Studies on visceral sensation in achalasia patients compared with normal individuals have demonstrated deficiencies and may explain poor perception of esophageal distension and retention in achalasia. In fact, it has been suggested that symptoms in achalasia patients are related more to the patients’ tolerance and adaptation rather than to the degree of LES relaxation. Patients with a longer duration of symptoms may have adapted to their dysphagia better than those with shorter duration, thus accounting for less symptomatic relief after treatment in patients with longer duration of achalasia.12–14 The conventional symptom assessment with focus on swallowing difficulties forms the basic for all research and clinical evaluations. This is to some degree a subjective measurement, and comparison across studies are thus difficult because the definitions of success may vary from symptoms based on very strict criteria to more liberal end points such as the lack of need for repeat treatment.11,13,14 Several disease-specific symptom assessment systems exist but the measurement properties of these are often poorly defined and insufficiently validated. The question is always whether even achalasia-specific health related quality of life instruments may, to a better extent, cover the multi-dimensional aspects of achalasia and its consequences for each individual patient than by using a simpler and more conventional assessment tool?
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Based on the understanding and comprehension of the pathogenesis of idiopathic achalasia, it is understandable that there is little capacity, for regeneration or recovery of abnormal or absent peristalsis as a response to any type of therapy. Consequently, even today so many years after Sir Thomas Willis’ milestone observation, the contemporary therapeutic aims are to alleviate symptoms by opening the LES. This can theoretically be accomplished by pharmacological means, mechanical dilatation, or by surgical myotomy.
Pharmacotherapy Pharmacologic improvement in lower esophageal sphincter relaxation can be accomplished by use of calcium channel blockers, long acting nitrates, beta 2 agonists, anticholinergics, and phosphodiesterase blockers. Outcome data on drug treatment usually vary widely. Quite promising data have emerged from newer studies including the use of sublingual nifedipine and of a beta 3 receptor agonist, the latter yielding a prolonged and dose-dependent LES inhibition. Overall, most pharmacological studies have observed a drug related effect on LES nadir or basal pressure in the range of 50% of that reached by pneumatic dilatation or surgical myotomy. It is therefore recommended that drug therapy should not be used as a primary treatment of idiopathic achalasia. Another pharmacological approach is represented by Botulinum toxin (Botox) which blocks the presynaptic release of acetylcholine. This injection is followed by a reversible paralysis of the sphincter muscle. Botox injection was first used for symptomatic relief of achalasia patients more than a decade ago. A series of controlled as well as uncontrolled studies have since been published demonstrating a temporary symptomatic success rate in the range of 70–90%. The effectiveness of Botox is, however, restricted by its reversible nature as a neurotoxin. This leads to recurrence in the vast majority of patients and it is not used clinically as frequently as it used to be. As a nonoperative therapy, Botox intuitively holds appeal for the elderly and physiologically compromised patient, including poor candidates for even pneumatic dilatation. In this context it should, however, be emphasized that Botox injection may sometimes
complicate the subsequent surgical myotomy, necessitating a careful and selected use of the agent.15–17
Mechanical Dilation The technique of forceful dilation of the gastroesophageal junction is still considered by many as the first line therapy after the diagnosis has been established. The objective of this therapy is to produce a controlled overstretching of the LES, thereby rendering it incompetent by breaking the muscle fibers, leading to control of symptoms. Modern dilation devices allow a safe and controlled inflation of a rigid balloon to pressures of 10–12 psi for a period varying from 60 s to 3 min. It has not been clarified if the diameter of the balloon has to bee more than 30 mm to be truly successful, as a post-procedure LES pressure of <10 mm Hg is required for a successful therapeutic outcome. The short term success rate varies from 60% to 80%, and even up to a 90% success rate has been reported after repeated dilations. The proportion of patients who need repeated dilatation ranges from 15% to 65%. Although the early efficacy of pneumatic dilatation is indisputable, the long-term results are less encouraging and are considered by some to be virtually unclear. Very few well designed controlled and prospective longterm follow up studies have been published until quite recently. At best, 50% of patients have been reported to have adequate control of symptoms after either 5 or 12 years of follow up. In some of these studies about 35% of patients who report severe dysphagia refuse repeat dilation because of their dislike for the procedure itself.11,17–23 Although generally considered to represent conservative treatment, dilation is not entirely painless. The procedure can be performed on an outpatient basis with observation of the patients for a defined period of time to identify symptoms of tear or perforation. Based on published data, it can be surmised that a more generous use of general anesthesia for this procedure would enhance the long-term compliance with this therapeutic regimen. When esophageal perforation occurs in conjunction with pneumatic dilation, it is usually identified above the cardia on the left posterolateral side of the distal oesophagus. The incidence
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of this complication varies widely in the literature, from 0% to 20%, and is probably related to both the operator (endoscopist) and the procedure. A long duration of the disease and an increased number of dilations increase the risk. When signs of such a complication occur (chest pain predominantly) this should be taken seriously and a prompt evaluation should be instituted. If conservative treatment measures are not followed by an adequate response, immediate operation is mandatory. The perforation can be closed effectively, a myotomy completed, and the damage covered by a partial fundoplication.19–21 Studies in the literature suggest that a higher post dilation LES pressure predicts symptom recurrence after pneumatic dilation.11,22 In addition, the need for re-treatment after dilation appears to decrease with the use of higher balloon diameters. However, the latter finding is mainly based on incomplete data on post-treatment manometry, and it remains unclear whether the longer remission rate after use of a higher diameter balloon is attributable to a lower post-dilation LES pressure or some other factors. No doubt the majority of patients with recurrence symptoms, especially those with recurrence after several years, may well undergo repeat dilation. Additional unfavorable prognostic factors that have been associated with the outcome of dilation are male gender and end stage achalasia.
Aspects on Surgical Treatment It is now generally accepted that a cardiomyotomy is the surgical procedure of choice in uncomplicated achalasia. To offer the patients adequate symptom control, the myotomy should not only divide the intraabdominal portion of the sphincter but needs to be extended onto the stomach as well in order to divide the oblique gastric fiber portion of the sphincter. Four groups of patients have traditionally been considered good candidates for surgical myotomy: • Those of younger age (<40 years) • Those who do not respond adequately to conservative treatment • Patients who are considered high risk for failure after conservative dilation such as those with
previous gastroesophageal junction surgery, esophageal diverticula, or a distorted lower esophageal anatomy secondary to a sigmoidshaped or grossly dilated distal esophagus • Patients who explicitly prefer surgery rather than a dilation-based strategy For adequate relief of symptoms in achalasia patients, both layers of the esophageal muscular wall have to be divided at the time of surgery for a distance of 5–7 cm through the lower esophageal sphincter, extending the myotomy at least 2 cm onto the stomach wall. A variety of different methods have been practiced in order to tailor the extent of the myotomy to the level that controls food obstruction but does not lead to uncontrolled reflux. Preoperative manometry is frequently used for this purpose, but no firm conclusions can be drawn from the literature on the true value of this technology. The efficacy of surgical myotomy is undisputed, although the success rate may decline over time. The magnitude and the character of the long term failures need to be better determined within the framework of controlled clinical trials. As a result of successful surgical therapy for achalasia, a different disease may be induced (i.e. gastroesophageal reflux disease). Accordingly, a debate has emerged as to whether a prophylactic antireflux procedure is indicated as an adjunct to myotomy. Moreover, controversies exist as to the ideal type of fundoplication that should be performed. In fact, even a total Nissen fundoplication has been used in this setting, although this is theoretically a questionable approach from a functional as well as manometric point of view (Fig. 31.1).24,25 The pros and cons of partial anterior versus a partial posterior fundoplication have been debated and need further clinical trials to be fully elucidated. The most popular type of antireflux repair currently is the Dor anterior partial fundoplication.
What Is the Best Initial Therapy? Regarding the choice of initial therapy in newly diagnosed achalasia, few high quality data are available to guide the clinician. However, two randomized trials have so far been completed that support the rationale for use of myotomy and antireflux
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31. Optimal Initial Therapy for Achalasia LES (mm Hg)
GERD symptoms (%)
Dysphagia (%)
Myotomy Heller + Nissen Follow up Initial treatment Total cost
Dilation Heller + Dor 0 0
5
10 15 Percent
20
25
2000
4000 Euro
6000
8000
Figure 31.2. Comparison of median direct medical costs during the first year after initiation of allocated treatment for achalasia. (Data from26)
Figure 31.1. Comparison between Dor and Nissen fundoplication after Heller myotomy. (Data from24)
repair. The outcome is clear in favor of the surgical strategy. Health related quality of life (QoL) assessments within these trials have shown a normalization of QoL after the surgical procedure but a corresponding normalization was also the effect of repetitive dilatation, with dysphagia as well as overall scores being profoundly improved. Some years ago Csendes and co-workers18 randomized a corresponding group of patients, of whom some suffered from Chagas disease, to either an open operation or endoscopic pneumatic dilation. In this landmark study a less rigid and updated dilation protocol was followed, but despite this significant difference, the outcomes were in favor of the operation-based strategy because of a progressive accumulation of failures over time among those submitted to dilation. Only one randomized clinical trial has until now been published comparing dilation with laparoscopic cardiomyotomy and partial fundoplication.19 It can be argued that the methodology of that study was somewhat disputable, with the use of a predefined composite definition of treatment failure, which might be too rigid and not clinically fully relevant. However, on overt perforation in association with the dilation represent an undisputable failure at the time when it requires surgical correction. Health economic assessment is always an issue in comparing endoscopy-based strategies to conventional surgical approaches. As part of a randomized controlled clinical trial it was shown that 18,19
the initial treatment cost and total cost were significantly higher for those undergoing laparoscopic myotomy compared to those who had pneumatic dilation (Fig. 31.2).26 The differences in initial treatment cost were due to a higher cost for the therapeutic procedure and for the in hospital stay. A general problem in health economic evaluations is the uncertainty inherent in cost estimates. One problem is that the cost estimates can’t accurately be separated from charges. The corresponding sensitivity analyses, however, revealed that even larger changes in cost estimates did not alter the significance of the recorded differences. Moreover, it is always questionable which time span is most relevant in a strict comparison between treatment strategies for defined chronic disease entities. It is well known that individual decision makers sometimes take a rather limited time horizon into account. From a societal point of view it may be more significant to cover a longer time period.
Issues Regarding Surgical Treatment At the end of the twentieth century there was a clear shift from open surgery through the chest or abdomen towards minimally invasive procedures through the chest or the abdomen. Based on the fact that surgical treatment has become the treatment of choice for patients with the disease,27 some issues still exist that need to be discussed in
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order to tailor and develop the surgical treatment of achalasia as effectively as possible: • Should it be done through the chest or via laparotomy? • Which is the optimal distal extent of myotomy? • Is there a need for an antireflux procedure added to the myotomy? • If a fundoplication is added, which is the optimal design of the repair? • What is the true long-term outcome of surgical therapy? The critical issue of how long the myotomy should be addresses the dilemma of reducing outflow resistance and at the same time preventing sphincter disruption to the degree that it leads to uncontrollable gastroesophageal reflux disease. A recent systematic review and a meta-analysis evaluated the development of postoperative gastroesophageal reflux, and both found that adding an antireflux procedure after laparoscopic myotomy dramatically decreased the incidence of gastroesophageal reflux symptoms from roughly 30% down to below 10%, without altering the resolution of dysphagia (Figs. 31.3 and 31.4).28,29 Therefore, it can be concluded that addition of an antireflux procedure is crucial for a satisfactory outcome in the treatment of achalasia, and the addition of a fundoplication does not add symptoms that can be explained by an exaggerated outflow obstruction, provided that a total fundoplication is not constructed. A straightforward comparison has not yet been completed between an anterior and posterior partial fundoplication in this clinical setting. Proponents of the latter procedure argue that it
20
Percent
15
Abnormal 24hr pH Study Normal 24hr pH Study
10 5 0
Heller
Heller + Dor
Figure 31.3. Prevalence of post-myotomy esophageal acid exposure in achalasia. (Data from28)
No fundoplicaton Fundoplication
GERD
Symptom Improvement 0
20
40 60 Percent
80
100
Figure 31.4. GERD and symptom improvement after laparoscopic myotomy. (Data from29)
prevents the re-approximation of the myotomy and may be better than an anterior fundoplication in preventing postoperative reflux. On the other hand, defenders of the anterior repair argue that it is easy to perform, also prevents re-approximation of the myotomy, protects the myotomy in case of microperforation, and leaves the posterior anatomy of the EG-junction intact. Future results of prospective randomized studies will, hopefully, settle this controversy. Laparoscopic myotomy has proven over time to be the approach that consistently produces the most durable symptom relief. In most cases, posterior esophageal dissection is not needed, but if a Toupet fundoplication is preferred this dissection is a vital part of the operation. There are some theoretical advantages of leaving the posterior attachments intact, which also provides an anchor to help keep the gastroesophageal junction in the proper anatomic location. Incomplete extension of the myotomy onto the stomach may be an important mechanism behind failure, including the inability of the myotomy to relieve dysphagia30 (Table 31.1). The gastric extension is also the part of the procedure where most perforations occur. Therefore, during all these procedures a so called “leak test” with insufflation of air into the esophagus and stomach under water is advisable.31 When comparing transabdominal myotomy with transthoracic procedures almost a thousand patients have been collected and carefully evaluated in each group.29 Symptom control was found to be fairly similar, whereas the addition of an antireflux procedure during an open transabdominal
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Table 31.1. Comparison of outcomes after standard or extended myotomy with partial anterior (Dor) or posterior (Toupet) fundoplication for achalasia. Symptoms Dysphagia severitya Dysphagia frequencyb Heartburn frequencyb Regurgitation frequencyb Chest pain frequencyb
Standard myotomy/Dor
Extended myotomy/Toupet
P value
5.3 (2.2) 2.1 (1.2) 1.7 (1.6) 0.8 (1.3) 0.6 (1.1)
3.2 (2.4) 1.2 (1.0) 1.3 (1.4) 0.3 (0.8) 0.3 (0.7)
0.001 0.001 0.36 0.19 0.71
Rated on a 0 (normal) to 10 (worst ever experienced) visual analog scale Rated on a 5-point scale in which 0 = never and 4 = several times daily numbers in repesent mean and (standard deviation) (Data from30)
a
b
100
Laparoscopic
Normal Acid Exp
Thoracoscopic
80 Percent
GERD
Symptom Improvement
Abnormal Acid Exp
60 40 20
0
20
40 60 Percent
80
0
100
Figure 31.5. Symptom improvement and post-treatment gastroesophageal reflux (GERD) after laparoscopic or thoracoscopic myotomy for achalasia. (Data from29)
7-10 Years
10-20 Years
>20 Years
Figure 31.6. Esophageal acid exposure after myotomy and fundoplication for achalasia. (Data from32) 35 30 25 Percent
myotomy had a significant impact on the rate of symptom improvement (with a more successful outcome in those having a combined procedure; Fig. 31.5). Both transabdominal and transthoracic approaches evolved into the minimal invasive counterparts. Improved results seem to follow the laparoscopic approach associated with reports of high prevalence of postoperative gastroesophageal reflux with the thoracoscopic procedure and predominant limitations such as technical difficulties in performing the myotomy in the plane perpendicular to the esophagus. This has led to the less frequent use of thoracoscopic approach over time. Another critical issue that needs to be addressed in future clinical trials concerns the need for more and better information on the true long-term results after myotomy and partial fundoplication. The available rather scarce data suggest that clinical deterioration is seen after initial good clinical results if very long follow-up is performed.32 Moreover, late failures might well be due to a progression of abnormal acid reflux (Figs. 31.6 and 31.7). Endoscopic esophagitis increases as does the presence of short and long segment Barretts
20 15 10 5 0
7-10years
10-20years
>20years
Figure. 31.7. Development of esophagitis after myotomy and fundoplication for achalasia. (Data from32)
esophagus. Csendes and co-workers32 also found that there is no change of LES pressure over time after surgery, and if acid reflux is measured by 24 h pH-monitoring, it shows an increase of abnormal reflux the longer the follow up is completed. Finally, an additional dimension has recently been introduced to the selection of patients for therapy. Kahrilas’ group33 suggested that subgroups of achalasia could be defined, which are discernible by high-resolution manometry investigations
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and thereby exhibit differential clinical character istics: • Type I patients are characterized by minimal contractility (pressurization) in the esophageal body, i.e. the classic type. • Type II patients have no peristalsis but exhibit intermittent compartmentalized esophageal pressures. • Type III patients have spastic contractions in the distal esophagus. The major finding of this group was that achalasia patients subgrouped by high-resolution manometry responded differently to therapy. Type II patients had a good response to any type of therapy. The finding of a Type III pattern was a strong negative predictor of response to any therapy. An additional finding was that, although esophageal myotomy was a more effective therapy in most of these patients than pneumatic dilatation, it was mainly attributable to a predominantly favorable response in type I patients.
dure of choice in patients with achalasia (recommendation grade 1B).
Compared to endoscopic therapy, surgical therapy provides better clinical outcomes and freedom from re-intervention in the management of achalasia (evidence quality high). A strong recommendation is made for surgical myotomy as initial therapy for achalasia (recommendation grade 1B).
Improved surgical results are evident with laparoscopic rather than transthoracic approaches (evidence quality high), extension of the myotomy onto the stomach (evidence quality high), and with the addition of a partial fundoplication (evidence quality high). A strong recommendation is made for laparoscopic myotomy and partial fundoplication as the surgical procedure of choice in patients with achalasia (recommendation grade 1B).
Summary and Recommendations The available data indicate that endoscopic and surgical therapies for achalasia are safe and effective, although the results deteriorate over time (evidence quality moderate). Compared to endoscopic therapy, surgical therapy provides better clinical outcomes and freedom from re-intervention (evidence quality high). A strong recommendation is made for surgical myotomy as initial therapy for achalasia (recommendation grade 1B). A laparoscopic approach produces better outcomes than transthoracic approaches (evidence quality high). Extension of the myotomy onto the stomach, rather than limiting the myotomy to the distal extent of the LES, results in greater relief of dysphagia (evidence quality moderate). The addition of a partial fundoplication substantially reduces the incidence of gastroesophageal reflux after myotomy for achalasia, and this does not adversely influence relief of dysphagia postoperatively (evidence quality high). A strong recommendation is made for laparoscopic myotomy and partial fundoplication as the surgical proce-
References 1. Willis T. Pharmaceutice Rationalis Sive Diatriba Do Medicamentorum Operationibus in Humano Corpore. London: Hagae Comitis; 1674. 2. Heller E. Extramuköse Kardioplastik beim chronischen Kardiospasmus mit Dilatation des Oesophagus. Mitt Grenzgeb Med Chir. 1914;27:141–149. 3. Zaaijer JH. Cardiospasm in the aged. Ann Surg. 1923; 77:615–617. 4. Kraichely RE, Farrugia G. Achalasia: physiology and etiopathogenesis. Dis Esophagus. 2006;19:213–223. 5. Park W, Vaezi MF. Etiology and pathogenesis of achalasia: the current understanding. Am J Gastroenterol. 2005;100:1404–1414. 6. Sonneberg A, Massey BT, McCarthy DJ, et al. Epi demiology of hospitalization for achalasia in the United States. Dig Dis Sci. 1993;38:233–244. 7. Mayberry JF, Atkinson M. Variations in the prevalence of achalasia in Great Britain and Ireland: an epidemiological study based on hospital admissions. Q J Med. 1987;62:67–74. 8. Howard PJ, Maher L, Pryde A, et al. Five years prospective study of the incidence, clinical features, and diagnosis of achalasia in Edinburgh. GUT 1992;33: 1011–1015.
31. Optimal Initial Therapy for Achalasia 9. Mayberry JF, Atkinson M. Epidemiology and demographics of achalasia. Gastrointest Endosc Clin N Am. 2001;11:235–248. 10. Csendes A, Larrain A, Ayala M. Motility studies in 50 patients with achalasia of the esophagus. Am J Gastr oenterol. 1974;62:333–336. 11. Hulselmans M, Vanuytsel T, Degreef T, Sifrin D, Coosemans W, Lerut T, Tack J. Long-term outcome of pneumatic dilation in the treatment of achalasia. Clin Gastroenterol Hepatol. 2010;8:30–35. 12. Castell DO. Esophageal disorders in the elderly. Gastroenterol Clin North Am. 1990;19:235–254. 13. Nguyen NQ, Holloway RH. Recent developments in esophageal motor disorders. Curr Opin Gastroenterol. 2005;21:478–484. 14. Dogan I, Mittal RK. Esophageal motor disorders: recent advances. Curr Opin Gastroenterol. 2006;22: 417–422. 15. Boeckxstaens GE, Jonge WD, van den Wijngaard RM, Benninga MA. Achalasia: from new insights in pathophysiology to treatment. J Pediatr Gastroenterol Nutr. 2005;41(Suppl 1):S36–S37. 16. Roberts KE, Duffy AJ, Bell RL. Controversies in the treatment of gastroesophageal reflux and achalasia. World J Gastroenterol. 2006;12:3155–3161. 17. Wang L, Li YM, Li L. Meta-analysis of randomized and controlled treatment trials for achalasia. Dig Dis Sci. 2009;54:2303–2311. 18. Csendes A, Velasco N, Braghetto I, et al. A prospective randomised study comparing forceful dilatation and esophagomyotomy in patients with achalasia of the esophagus. Gastroenterology. 1981;80:789–795. 19. Kostic S, Kjellin A, Ruth M, Lönroth H, Johnsson E, Andersson M, Lundell L. Pneumatic dilatation or laparoscopic cardiomyotomy in the management of newly diagnosed idiopathic achalasia. Results of a randomized controlled trial. World J Surg. 2007;31: 470–478. 20. Mikaeli J, Bishehsari F, Montazeri G, Yaghoobi M, Malekzadeh R. Pneumatic balloon dilatation in achalasia: a prospective comparison of safety and efficacy with different balloon diameters. Aliment Pharamacol Ther. 2004;20:431–436. 21. Khan AA, Shah SWH, Alam A, Butt AK, Shafqat F. Sixteen years follow up of achalasia: a prospective study of graded dilatation using Rigiflex balloon. Dis Esophagus. 2005;18:41–45.
277 22. Gideon RH, Castell DO, Yarze J. Prospective randomized comparison of pneumatic dilatation technique in patients with idiopathic achalasia. Dig Dis Sci. 1999;9:1853–1857. 23. West RL, Hirsch DP, Bartelsman JFWM, deBordst J, et al. Long term results of pneumatic dilation in achalasia followed for more than 5 years. Am J Gastroenterol. 2002;97:1346–1351. 24. Rebecchi F, Giaccone C, Farinella E, Campaci R, Morino M. Randomized controlled trial of laparoscopic Heller myotomy plus Dor fundoplication versus Nissen fundoplication for achalasia long-term results. Ann Surg. 2008;248:1023–1030. 25. Zaninotto G, Costantini M, Rizzett C, Zanatta Z, Guirroli E, Portale G, Nicoletti L, Battaglia G, Ruol A, Ancona E. Four hundred laparoscopic myotomies for esophageal achalasia, a single center experience. Ann Surg. 2008;248:986–993. 26. Kostic S, Johnsson E, Kjellin A, Ruth M, Lönroth H, Andersson M, Lundell L. Health economic evaluation of therapeutic strategies in patients with idiopathic achalasia: results of a randomized trial comparing pneumatic dilatation with laparoscopic cardiomyotomy. Surg Endosc. 2007;21:1184–1189. 27. Spiess AE, Kahrilas PJ. Treating achalasia: from whalebone to laparoscope. JAMA. 1998;280:638–642. 28. Richards WO, Torquati A, Holzman MD, Khaitan L, Byrne D, Lutfi R, Sharp KW. Heller myotomy versus Heller myotomy with Dor fundoplication for achalasia. A prospective randomized double blind clinical trial. Ann Surg. 2004;240:405–415. 29. Campus GH, Vittinghof E, Rabl C, Takata M, Gaden stätter M, Lin F, Ciovica R. Endoscopic and surgical treatment of achalasia. Ann Surg. 2009;249:45–57. 30. Oelschlager BK, Chang L, Pellegrini CA. Improved outcome after extended gastric myotomy for achalasia. Arch Surg. 2003;138:490–497. 31. Kostics S, Lönroth H, Lundell L. Leakage testing at the time of surgical oesophageal myotomy. Dig Surg. 2004;21:223–226. 32. Csendes A, Braghetto I, Burdiles P, Korn O, Csendes P, Henriquez A. Very late results of esophagomyotomy for patients with achalasia. Ann Surg. 2006;243:196–203. 33. Pandolfino JE, Kwiatek MA, Nealis T, Bulsiewicz W, Post J, Kahrilas PJ. Achalasia: a new clinically relevant classification by high-resolution manometry. Gastroenterology. 2008;135:1526–1533.
32
Stenting for Esophageal Perforation and Anastomotic Leak Jessica M. Leers and Arnulf H. Hölscher
Introduction Discontinuity of the esophagus is a critical and potential life-threatening condition with a high rate of morbidity and mortality.1,2 Most often esophageal discontinuities are caused by iatrogenic perforations, traumatic perforations, spontaneous esophageal perforations or anastomotic leaks after esophagectomy. As invasive endoscopic techniques became more popular, the overall incidence of esophageal perforations has risen and the leading cause of perforation has shifted from spontaneous or traumatic to iatrogenic which nowadays account for more than 60% of all perforations.3 Another common etiology is esophagectomy. The overall rate for mediastinal leak following esophagectomy with stapled intrathoracic anastomosis in recently published studies ranges from 3.5% to 8.0%.1,2,5 Despite advances in surgical and endoscopic techniques as well as intensive care treatment over the past several decades, overall mortality of intrathoracic anastomotic leaks still ranges from 20% to 50%.2,6,7 Traditionally, surgery has been the standard approach to treatment of intrathoracic anastomotic leak. Here, a repeat thoracotomy with debridement and further therapy depending on local condition in the thorax was performed. Whether a primary repair or an esophageal diversion is the adequate surgical therapy was a subject of debate in recent decades.8–10 Open surgery, however, is associated with severe morbidity as well as mortality and hospitalization. An alternative to open
surgery is non-operative management with no oral intake, percutaneous pleural and perianastomotic drainage, nasogastric decompression and intravenous broad spectrum antibiotics until the restitution of continuity is confirmed. Yet, this leads to prolonged hospital stay in many cases and often requires long-term parenteral nutrition. This conservative management is only appropriate in small leaks in patients with no or minor symptoms.2,3,11,12 Recently, with the advances in endoscopic techniques, stent implantation has become a treatment alternative. Initially, stents were only used as palliative treatment in patients with malignant disease. More recently, applications have expanded and now also include patients with benign disease and a broad spectrum of types of esophageal disruption. A variety of stents are commercially available, including metal and plastic stents both with and without coverage. The most appropriate indications for stenting esophageal leaks and the optimal material for stents are still controversial.13,14 The purpose of this chapter is to review the present literature on endoscopic stent placement for intrathoracic leaks of the esophagus due to anastomotic leaks or perforations. This review is based on results of a literature search in Pubmed and includes publications from January 1998 to October 2009. A total of 18 observational studies for stent placement in esophageal leaks were found and analyzed. The published data is mostly derived from small series with heterogeneous patient selection criteria, a wide variety of stent types, and numerous management concepts.
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Symptoms and Diagnosis of Esophageal Leak and Esophageal Perforation Esophageal disruption is associated with a mortality rate of 15–50%. This rate is highly dependent on the location of injury and time from initial presentation to diagnosis and treatment. These factors influence the diverse symptoms and strongly determine outcome of patients.2,4,15 Symptoms of esophageal disruption are diverse and are influenced by mechanism and location of injury as well as time from injury to treatment. There are no specific symptoms associated with esophageal disruption. Yet, pain, leukocytosis, fever and cough may be the most common signs. The clinical course can be uneventful or rapidly lead to sepsis. Thus, successful endoscopic management of esophageal leak and perforation depends on early, preferably instant, diagnosis and prompt treatment.16,17 The time from esophageal disruption to diagnosis is of paramount importance to morbidity and mortality rates. Johnsson and colleagues described a mortality rate of nearly 50% in patients when time of perforation to diagnosis and stent treatment was longer than 24 h compared to 0% if stent treatment was performed within 24 h.18 These findings are supported by data of Fischer and colleagues, who reported a series of 15 patients divided into two groups with respect to elapsed time interval between diagnosis and treatment. The early group consisted of seven patients with a maximum delay of 45 min. The median delay of treatment in the later group was 123 h. The average hospital stay was 5 and 44 days, respectively, demonstrating the substantial effect of time from event to treatment.19 In a series of 19 patients with spontaneous perforation, the mean time from onset of symptoms associated with an episode of emesis to stent placement was 22 h (range 6–78 h). A total of 17 patients were healed with stent placement. Two patients with leak at the gastroesophageal junction experienced continued leak and needed surgical intervention.17 Anastomotic leaks are responsible for approximately 30–40% of postoperative deaths after esophagectomy.1,2,5 Postoperative anastomotic leaks in patients treated with esophagectomy occur typically within the first 7 days after surgery,
J.M. Leers and A.H. Hölscher
but clinical signs are diverse and, once clinically apparent, endoscopic findings usually demonstrate an already visible lesion indicating a longer process. Sarela and colleagues point out the importance of prompt exploration and reanastomosis in cases of early postoperative leak in order to achieve a low morbidity and mortality.20 Huenerbein and colleagues present the only study which compares surgical and endoscopic stent treatment for esophageal leaks. They conclude that mortality was not observed after stent insertion, whereas 20% died of septic complications and multi-organ failure after surgery.13 The accurate diagnosis of an esophageal leak can be difficult. There are three diagnostic modalities available to confirm an esophageal leak: contrast swallow, CT scan and flexible endoscopy. A prospective, randomized trial demonstrated that, compared to contrast swallow alone, an additional CT scan improves sensitivity of detecting an anastomotic leak. In dubious cases Hogan et al. recommended endoscopy to provide a definite diagnosis.21 Endoscopy after esophagectomy theoretically bears the risk of a disruption of the esophagogastric anastomosis. Yet, in the hands of experienced endoscopists, it is safe and can add clinical information that radiologic studies cannot. Endoscopy is especially important to diagnose any gastric conduit necrosis and precisely locate areas of leak.2 A further advantage of endoscopy is the opportunity of immediate treatment. Computed tomography of the neck, chest and abdomen can be helpful to characterize the extent of the extravazation and to identify infected fluid collections that need drainage or demand an open procedure.
Types of Esophageal Stents There are no studies that directly compare different types of stent in the treatment of esophageal leak or perforation. However, because of the longstanding indication in this field, more data exists in the palliative treatment of unresectable esophageal cancers with esophageal stents.22 For malignant esophageal obstruction, two prospective, randomized trials, comparing silicone and metal
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stents exist.23,24 Both trials reported similar rates of technical success of more than 95% with similar rates of necessary reintervention. Symptom control for the main complaint of dysphagia was more than 90% in both groups. In these studies, complications with plastic stents were more common than with metal stents (43–47% vs. 0–16%) which lead to a prolonged hospital stay (6–12 vs. 4–5 days). Mortality associated with stent insertion was only seen in the silicone stent group. Self-expandable plastic stents (SEPS) were developed for the treatment of leaks and strictures in patients with benign disease. They are easier to remove, causing less damage to the esophageal wall. Clearly, migration into the stomach is more frequent due to a lower radial force. Self-expandable metallic stents (SEMS) exhibit good radial force which results in a low rate of migration. However, removal of the stent harbors a substantial risk of damage to the mucosa or transmural damage of the esophagus. In order to avoid this major complication, the time frame between stenting and removal has to be limited to 6 weeks maximum. Nevertheless, the most appropriate type of stent for treatment of esophageal leaks remains unknown and the discussion is controversial.25
mortality and morbidity rates are low in this subgroup of patients.21,26,27 In patients with esophageal leak after esophagectomy, interventional stent treatment exhibits more complications. A particularly common complication is stent migration as, in contrast to tumor stenosis, the size of the lumen is not reduced.26,27
Underlying Disease Endoscopic stent placement for esophageal disruption can be applied in a variety of underlying diseases. These include anastomotic leaks after esophagectomy for esophageal cancer, traumatic esophageal perforation, spontaneous esophageal perforations (i.e. Boerhaave syndrome), iatrogenic perforation due to diagnostic endoscopy or therapeutic interventions such as dilatation and tumor perforation of esophageal cancer. The extent of the influence of the type of underlying disease on success rate of stent application remains unclear. There are only few studies available that separate the cause of esophageal leak. A group of patients that particularly benefits from stent therapy is patients after iatrogenic perforation because esophageal disruption is usually detected immediately after the trauma and the size of the leak is mostly small. Consequently,
Treatment and Complications All published studies report safe stent placement without immediate morbidity. Technical success rates range from 95% to 100% (Table 32.1).13,14,17–19,26–38 Clearly, the introduction of self-expandable stents has revolutionized stent placement making the procedure easy and comfortable to perform. In addition, all studies were performed in centers with great experience of esophageal surgery. Treatment related complications, including bleeding, stent kinking, and immediate stent dislocation, are rare events and were reported in very few cases (Table 32.2).28,29 Further complications during the clinical course were deep vein thrombosis, respiratory failure and prolonged ileus.14,17 Immediate occlusion of the esophageal perforation was achieved in 73–100% of patients. In a subgroup of patients, it was necessary to place a second stent to achieve complete sealing. Only a small percentage (up to 10%) of patients could not be treated with stent implantation successfully and needed open surgical intervention.14,26
Supportive Therapy Treatment of esophageal leak and perforation is an interdisciplinary challenge and includes intensive care, surgery and endoscopy. Additional endoscopic and surgical procedures that can be used as supportive therapy in patients with esophageal leaks are percutaneous endoscopic gastrostomy, endoscopic esophageal dilation, percutaneous thoracic drainage, and mechanical ventilation. Parenteral administration of a broad spectrum antibiotic is imperative. Patients should not be started on an oral diet before a CT or an esophageal swallowing study verifies the occlusion of the
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282 Table 32.1. Outcomes of stent placement for esophageal anastomotic leak or perforation. Author Roy-Choudry Doniec28 Siersema25 White38 Gelbmann30 Huenerbein13 Langer32 Schubert34 Johnsson18 Fischer19 Freeman29 Freeman27 Tuebergen14 Kauer31 Freeman17 Leers26 Dai36 Salminen37
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Year
Patients
Leak/Perforation
2001 2003 2003 2003 2004 2004 2005 2005 2005 2006 2007 2007 2008 2008 2009 2009 2009 2009
14 21 11 9 9 9 24 12 22 15 21 17 32 10 19 31 22 10
14/0 18/3 3/8 0/9 5/4 9/0 24/0 12/0 2/20 0/15 5/16 17/0 24/10 10/0 0/19 16/15 22/0 2/8
Stent type
Technical success (%)
Sealing rate (%)
Healing rate (%)
100 100 100 100 100 100 92 100 95 100 100 100 100 100 100 100 100 100
84 90 91 100 78 89 89 100 95 100 95 94 78 90 89 94 95 80
93 81 82 – 66 100 89 92 77 100 95 94 81 70 89 87 95 80
Mixed SEMS (Ultraflex) Flamingo/Ultraflex SEMS (Wallstent/Ultraflex) SEPS (Polyflex) SEPS (Polyflex) SEPS (Polyflex) SEPS (Polyflex) SEMS (Ultraflex) SEMS (Ultraflex) SEPS (Polyflex) SEPS (Polyflex) SEMS (Ultraflex) SEMS (Choostent) SEPS (Polyflex) SEMS (Ultraflex) SEPS (Polyflex) SEMS (Ultraflex/Hanaro)
SEMS self expanding metal stent; SEPS self expanding plastic stent
Table 32.2. Complications associated with stent placement for esophageal anastomotic leak or perforation. Author
Year
Roy-Choudry Doniec28 Siersema25 White38 Gelbmann30 Huenerbein13 Langer32 Schubert34 Johnsson18 Fischer19 Freeman29 Freeman27 Tuebergen14 Kauer31 Freeman17 Leers26 Dai36 Salminen37
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2001 2003 2003 2003 2004 2004 2005 2005 2005 2006 2007 2007 2008 2008 2009 2009 2009 2009
Stent type
Stent migration (%)
Mixed SEMS (Ultraflex) Flamingo/Ultraflex SEMS (Wallstent/Ultraflex) SEPS (Polyflex) SEPS (Polyflex) SEPS (Polyflex) SEPS (Polyflex) SEMS (Ultraflex) SEMS (Ultraflex) SEPS (Polyflex) SEPS (Polyflex) SEMS (Ultraflex) SEMS (Choostent) SEPS (Polyflex) SEMS (Ultraflex) SEPS (Polyflex) SEMS (Ultraflex/Hanaro)
– 5 9 0 30 22 37 17 14 – 24 18 6 40 24 3 23 10
Complication rate (%) 7 76 – – 33 22 46 17 13 40 24 – 24 0 24 – 9 –
Stent extraction (%) 7 57 64 – 67 100 50 100 77 80 95 100 70 50 100 84 100 100
Overall mortality (%) 7 29 0 0 33 0 25 0 23 7 5 0 15 20 0 6 5 50
SEMS self expanding metal stent; SEPS self expanding plastic stent
esophageal leak. Some authors advocate the placement of percutaneous gastrostomies17,27 to maintain enteral nutrition, whereas other authors reported the start of enteral nutrition starting at the first postinterventional day.14,26,34,35 Huenerbein and colleagues compared 11 patients who were treated surgically with 9 patients with endoscopic stent treatment. Stent patients had earlier oral intake (11 vs. 23 days), shorter duration of ventilation (9 vs. 17 days) including
shorter intensive course (35 vs. 57 days) leading to a shorter hospital stay (35 vs. 57 days).13
Stent Removal Definite results of endoscopic treatment of esophageal discontinuity become apparent only after stent removal. In contrast to plastic stents, most
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metallic stents become deeply embedded in the esophagus wall, making endoscopic retrieval difficult. Major complications after stent retrieval are rare. Siersema and colleagues reported an esophagorespiratory fistula 2 weeks after stent removal in a patient in whom the stent had been in place for 14 weeks.35 More recently, most publications advocate stent removal within 4–6 weeks after stent placement. Doniec et al. at all reported three patients with stenosis after removal of the stent which was successfully treated with elastic bougie distension and corticosteroid injection.28 No other complications of stent removal have been reported.13,14,17–19,26–38
Impact on Clinical Practice
Summary of the Published Data
Authors’ Approach to Esophageal Perforation and Anastomotic Leak
Standardization or randomization of therapy is impossible to achieve in esophageal leaks and perforations as events are rare and extent of leaks, interval from event to diagnosis, and treatment and patient health status are inhomogenous. Consequently, all studies without exception are case series or observational studies with a low quality of evidence. Therefore, several caveats have to be addressed. Various types of esophageal stents are used (self expandable metallic vs. plastic). The underlying diseases in the published series are quite diverse. The study cohorts suffered from leaks as well as perforations and from both malignant and benign diseases. Furthermore, there are no commonly used criteria for the indication of conservative, endoscopic and surgical treatment. Thus, confounding factors such as time from event to diagnosis and treatment diminish the comparability of previous results. As alluded to earlier, the published data is mostly based on case series or observational studies including only few patients. However, all authors concluded that placement of esophageal stents is feasible, safe and effective in the treatment of patients with esophageal leak and perforation. We make a strong recommendation for endoscopic stent placement for esophageal leak and perforation (recommendation grade 1C). Limiting factors might be delay in treatment, extent of defect, connection to the pleural cavity and septic condition of the patient.
Due to the fact that esophageal disruption is a relatively rare clinical picture many questions regarding the endoscopic stent placement of esophageal disruption remain. Only case series and observational studies with small number of patients are available and represent low quality evidence. However, a few important observations do emerge. Technical success rate reaches 95–100% and the procedure itself is a low risk procedure. The overall mortality with 0–40% is comparable or even lower to the mortality reported in the literature for open surgical therapy.
Our main diagnostic tools in cases of suspected esophageal perforation or anastomotic leak are endoscopy and contrast enhanced spiral CT scan. This gives us data on site and extent of the lesion and whether it is contained or not. Furthermore, details on the vascularisation of the tissue, especially the conduit in the region of the anastomosis, are of great importance. We choose stenting especially in cases of contained leaks of a size that can be safely covered with a prosthesis and only in cases in which mediastinal abscesses are absent. There is a tremendous difference between iatrogenic perforations and spontaneous esophageal rupture. Patients with Boerhaave’s syndrome mostly provoke the esophageal rupture by intense vomiting, and often food is propelled in the mediastinum or even into the pleural cavity. These patients are not good candidates for stenting, as much infectious material would remain in the mediastinum or the pleural sac. Patients with iatrogenic perforation are usually fasting before the procedure and therefore stenting the esophageal defect is an elegant minimally invasive procedure with good chances of healing. Stent dislocation can be a problem which needs to be detected and corrected. One has to remember that some lesions do have the capability to heal by conservative treatment, mainly gastric tube and antibiotics. Therefore, the cost intensive technique of stenting has to be clearly indicated. In our institution, stenting is the procedure of choice for anastomotic leaks, for example following
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esophagogastrostomy, especially in the typical cases around the seventh postoperative day. These anastomotic leaks are mostly contained and stent position is sufficiently stable as the prosthesis can be safely anchored in the anastomotic ring. In our view, contraindications to stenting are ischemia of the conduit, large leaks that cannot be safely covered by stenting, and leaks with direct and large connection to the pleural space or abdominal cavity. Leaks that occur very early in the postoperative phase are not suitable for stenting because these lesions are not safely contained by the surrounding tissues. Further, it is not possible technically to safely anchor a stent in a leak of the conduit itself. In our experience, the best results can be achieved with self expandable covered metal stents, as they exhibit good stability and density. In our department, endoscopic stenting is performed by the operating surgeons and is available 24 h a day. It is our procedure of choice for esophageal perforations and anastomotic leaks and has lead to a substantial reduction in reoperations and in long lasting conservative treatments. Placement of esophageal stents is feasible, safe and effective in the treatment of patients with esophageal leak and perforation (evidence quality low). We make a strong recommendation for endoscopic stent placement for esophageal leak and perforation (recommendation grade 1C).
References 1. Karl RC, Schreiber R, Boulware D, Baker S, Coppola D. Factors effecting morbidity, mortality, and survival in patients undergoing Ivor Lewis esophagogastrectomy. Ann Surg. 2000;231:635–643. 2. Griffin SM, Lamb PJ, Dresner SM, Richardson DL, Hayes N. Mediastinal leak following radical oesopha gectomy. Br J Surg. 2001;88:1346–1351. 3. Brinster CJ, Singhal S, Lee L, Marshall MB, Kaiser LR, Kucharczuk JC. Evolving options in the management of esophageal perforation. Ann Thorac Surg. 2004;77: 1475–1483. 4. Crestanello JA, Deschamps C, Cassivi SD, Nichols FC, Allen MS, Schleck C, Pairolero PC. Selective management of intrathoracic anastomotic leak after esophagectomy. J Thorac Cardiovasc Surg. 2005;129: 254–260.
J.M. Leers and A.H. Hölscher 5. Hölscher AH, Schneider PM, Gutschow C, Schröder W. Laparoscopic ischemic conditioning of the stomach for esophageal replacement. Ann Surg. 2007;245: 241–246. 6. Urschel JD. Esophagogastrostomy anastomotic leaks complicating esophagectomy: a review. Am J Surg. 1995;169:634–640. 7. Rizk NP, Bach PB, Schrag D, et al. The impact of complications on outcomes after resection for esophageal cancer and gastroeseophageal junction carcinoma. J Am Coll Surg. 2004;198:42–50. 8. Mitchell JD. Anastomotic leak after esophagectomy. Thorac Surg Clin. 2006;16:1–9. 9. Hölscher AH, Vallböhmer D, Brabender J. The prevention and management of perioperative complications. Best Pract Res Clin Gastroenterol. 2006;20: 907–923. 10. Matory YL, Burt M. Esophagogastrectomy: reoperation for complications. J Surg Oncol. 1993;54:29–33. 11. Page RD, Shackcloth MJ, Russell GN, Pennefather SH. Surgical treatment of anastomotic leaks after oesophagectomy. Eur J Cardiothorac Surg. 2005;27: 337–343. 12. Eroglu A, Turkyilmaz A, Aydin Y, Yekeler E, Karaoglanoglu N. Current management of esophageal perforation: 20 years experience. Dis Esophagus. 2009;22:374–380. 13. Hünerbein M, Stroszczynski C, Moesta KT, Schlag PM. Treatment of thoracic anastomotic leaks after esophagectomy with self-expanding plastic stents. Ann Surg. 2004;240:801–807. 14. Tuebergen D, Rijcken E, Mennigen R, Hopkins AM, Senninger N, Bruewer M. Treatment of thoracic esophageal anastomotic leaks and esophageal perforations with endoluminal stents: efficacy and current limitations. J Gastrointest Surg. 2008;12:1168–1176. 15. Vallböhmer D, Hölscher AH, Hölscher M, Bludau M, Gutschow C, Stippel D, Bollscheiler E, Schröder W. Options in the management of esophageal perforation: analysis over a 12-year period. Dis Esophagus. 2009, Oct 26 (e-pub). 16. Fischer A, Thomusch O, Benz S, von Dobschuetz E, Baier P, Hopt UT. Nonoperative treatment of 15 benign esophageal perforations with self-expandable covered metal stents. Ann Thorac Surg. 2006;81: 467–472. 17. Freeman RK, Van Woerkom JM, Vyverberg A, Ascioti AJ. Esophageal stent placement for the treatment of spontaneous esophageal perforations. Ann Thorac Surg. 2009;88:194–198. 18. Johnsson E, Lundell L, Liedman B. Sealing of esophageal perforation or ruptures with expandable metallic stents: a prospective controlled study on treatment efficacy and limitations. Dis Esophagus. 2005;18: 262–266. 19. Fischer A, Thomusch O, Benz S, von Dobschuetz E, Baier P, Hopt UT. Nonoperative treatment of 15 benign esophageal perforations with self-expandable covered metal stents. Ann Thorac Surg. 2006;81: 467–472.
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20. Sarela AI, Tolan DJ, Harris K, Dexter SP, Sue-Ling HM. Anastomotic leakage after esophagectomy for cancer: a mortality-free experience. J Am Coll Surg. 2008;206:516–523. 21. Hogan BA, Winter DC, Broe D, Broe P, Lee MJ. Prospective trial comparing contrast swallow, computed tomography and endoscopy to identify anastomotic leak following oesophagogastric surgery. Surg Endosc. 2008;22:767–771. 22. Ramirez FC, Dennert B, Zierer ST, Sanowski RA. Esophageal self-expandable metallic stents–indications, practice, techniques, and complications: results of a national survey. Gastrointest Endosc. 1997;45:360–364. 23. Conio M, Repici A, Battaglia G, De Pretis G, Ghezzo L, Bittinger M, Messmann H, Demarquay JF, Blanchi S, Togni M, Conigliaro R, Filiberti R. A randomized prospective comparison of self-expandable plastic stents and partially covered self-expandable metal stents in the palliation of malignant esophageal dysphagia. Am J Gastroenterol. 2007;102:2667–277. 24. Verschuur EM, Repici A, Kuipers EJ, Steyerberg EW, Siersema PD. New design esophageal stents for the palliation of dysphagia from esophageal or gastric cardia cancer: a randomized trial. Am J Gastroenterol. 2008;103:304–312. 25. Siersema PD. Treatment of esophageal perforations and anastomotic leaks: the endoscopist is stepping into the arena. Gastrointest Endosc. 2005;61:897–900. 26. Leers JM, Vivaldi C, Schäfer H, Bludau M, Brabender J, Lurje G, Herbold T, Hölscher AH, Metzger R. Endoscopic therapy for esophageal perforation or anastomotic leak with a self-expandable metallic stent. Surg Endosc. 2009;23:2258–2262. 27. Freeman RK, Ascioti AJ, Wozniak TC. Postoperative esophageal leak management with the Polyflex esophageal stent. J Thorac Cardiovasc Surg. 2007;133: 333–338. 28. Doniec JM, Schniewind B, Kahlke V, Kremer B, Grimm H. Therapy of anastomotic leaks by means of covered self-expanding metallic stents after esophagogastrectomy. Endoscopy. 2003;35:652–658. 29. Freeman RK, Van Woerkom JM, Ascioti AJ. Esophageal stent placement for the treatment of
i atrogenic intrathoracic esophageal perforation. Ann Thorac Surg. 2007;83:2003–2007. 30. Gelbmann CM, Ratiu NL, Rath HC, Rogler G, Lock G, Schölmerich J, Kullmann F. Use of self-expandable plastic stents for the treatment of esophageal perforations and symptomatic anastomotic leaks. Endos copy. 2004;36:695–699. 31. Kauer WK, Stein HJ, Dittler HJ, Siewert JR. Stent implantation as a treatment option in patients with thoracic anastomotic leaks after esophagectomy. Surg Endosc. 2008;22:50–53. 32. Langer FB, Wenzl E, Prager G, Salat A, Miholic J, Mang T, Zacherl J. Management of postoperative esophageal leaks with the Polyflex self-expanding covered plastic stent. Ann Thorac Surg. 2005;79: 398–403. 33. Roy-Choudhury SH, Nicholson AA, Wedgwood KR, Mannion RA, Sedman PC, Royston CM, Breen DJ. Symptomatic malignant gastroesophageal anastomotic leak: management with covered metallic esophageal stents. AJR Am J Roentgenol. 2001;176: 161–165. 34. Schubert D, Scheidbach H, Kuhn R, Wex C, Weiss G, Eder F, Lippert H, Pross M. Endoscopic treatment of thoracic esophageal anastomotic leaks by using silicone-covered, self-expanding polyester stents. Gastrointest Endosc. 2005;61:891–896. 35. Siersema PD, Homs MY, Haringsma J, Tilanus HW, Kuipers EJ. Use of large-diameter metallic stents to seal traumatic nonmalignant perforations of the esophagus. Gastrointest Endosc. 2003 Sept;58: 356–361. 36. Dai YY, Gretschel S, Dudeck O, Rau B, Schlag PM, Hünerbein M. Treatment of oesophageal anastomotic leaks by temporary stenting with self-expanding plastic stents. Br J Surg. 2009;96:887–891. 37. Salminen P, Gullichsen R, Laine S. Use of selfexpandable metal stents for the treatment of esophageal perforations and anastomotic leaks. Surg Endosc. 2009;23:1526–1530. 38. White RE, Mungatana C, Topazian M. Expandable stents for iatrogenic perforation of esophageal malignancies. J Gastrointest Surg. 2003;7:715–719.
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Lengthening Gastroplasty for Managing GERD and Giant Paraesophageal Hernia Lee L. Swanstrom and Trudie A. Goers
Hiatal hernias result from a multifactorial combination of the failure of diaphragmatic integrity, degeneration of the phrenoesophageal suspensory ligament, and the normal pressure differential between the thorax and abdomen; some combination of these factors results in the cephalad migration of the gastroesophageal junction (GEJ) and the anatomic shortening of the esophagus. These changes are often combined with some degree of gastroesophageal reflux (GER). GER can lead to chronic esophageal irritation and damage, with resulting thickening of the mucosal layers, sometimes development of intestinal type columnar epithelium, and progressive fibrosis and damage of the muscularis mucosa. In especially severe and chronic cases there can even be transmural changes in the mediastinum with hypervascularity and thickening of the normally pliable areolar tissues. These factors can lead to loss of the usual elasticity of the esophagus as well as causing it to be more fixed within the mediastinum. When this process is combined with hiatal herniation (or perhaps even partially causing such migration?) it can lead to not only anatomic shortening of the esophagus but also non-reversible shortening of the esophagus, which can make it impossible to replace the GEJ into the abdominal during anti-reflux surgery or paraesophageal hernia (PEH) repair. Different surgical strategies have been proposed and used for dealing with the intrinsically shortened esophagus. These include wide mediastinal mobilization of the esophagus (to presumably eliminate the factor of mediastinal changes and fixation), letting the antireflux repair reside within the mediastinum, or performing an esophageal
lengthening procedure to relocate the GEJ into the abdomen. There are also a number of different lengthening procedures that have been described. Lengthening procedures are relatively rarely performed, and therefore there is a relative dearth of comparative evidence regarding its exact role in anti-reflux surgery (ARS). Literature regarding esophageal shortness and lengthening procedures was obtained by web based queries of English and European literature using the Pubmed, and Ovid medical search engines. Terms including “short esophagus”, “gastroplasty”, “Collis”, “para-esophageal hernia” and “esophageal lengthening” were used. There were no time limitations to the search however only English language publications were used. Quality of data was classified according to the American College of Chest Physician’s Task force guidelines for grading strength of recommendation and quality of evidence in clinical guidelines.1 A total of 49 peer reviewed publications were found that specifically dealt with this topic.
History and Variations of Lengthening Gastroplasty J. Leigh Collis first described the lengthening procedure associated with his name in 1957.2 It was originally conceived as a solution to “irreducible hiatal hernias, Esophagitis and strictures” and initially did not include any sort of antireflux procedure. It was quite controversial at the time, and this transthoracic hand-sewn procedure had high
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complication rates and poor success at stopping the process of GER. Almost 2 decades later, Orringer, Urschel and Pearson revived the procedure with the addition of a Belsey IV (Pearson, Urshel) or a Nissen (Orringer) fundoplication.3–5 For the most part, literature on the Collis in the 1950s, 1960s and 1970s consisted of technical reports on variations of the original procedure or complications of the procedure. The one exception was Pearson’s 1976 publication that presented prospectively gathered and retrospectively reviewed data on 277 patients performed over 10 years. Follow-up timing was variable but 26 patients had more than 5 years follow-up with at least subjective follow-up and good results in 96%.3 These early publications established the value of a lengthening procedure for short esophagus and the need for a concomitant antireflux procedure. During the 1980s a variety of modifications were introduced to the original Collis – Belsey/ Nissen procedure. These included the use of surgical staplers to create the gastroplasty,6 the “uncut Collis”7 and a technique of transabdominal Collis gastroplasty.8 No high grade studies have been performed to compare the merits or outcomes of these techniques and use of one over the other remains the surgeon’s choice. Finally, following the laparoscopic “revolution” of the early 1990s – which mostly replaced open reflux and hiatal hernia surgery with laparoscopic approaches – laparoscopic Collis gastroplasty was introduced in 1996.9 There are currently three different laparoscopic techniques described for gastroplasty: transthoracic/laparoscopic,9 circular plus linear stapler (Steichen technique)10 and the wedge gastroplasty.11 There are no comparative studies to date to determine superiority of one approach over the other.
Incidence of the Intrinsically Short Esophagus Lack of identification of a shortened esophagus in patients undergoing an anti-reflux surgery can lead to failure of the procedure and can subject these patients to extensive discomfort, repeated testing and reoperation.12 The presence of a short esophagus is important to identify in the
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preoperative assessment of patients in order to aid operative planning or establish the need for referral for complicated cases.13–15 Most surgeons agree that the condition of shortened esophagus exists. However, the prevalence of the condition still remains controversial: it has been estimated in multiple studies to be between 0% and 27.5%.9,10,16–18 This disparity is both due to the difference in opinion as to what defines a shortened esophagus and what diagnostic studies should be employed to identify it. Several studies have shown that reliable factors that correlate with an intraoperative finding of short esophagus include presence of an esophageal stricture, a type III paraesophageal hernia, the finding of Barrett’s esophagus on endoscopy, and identification of the location of gastroeophageal junction 5 or more cm above diaphragmatic hiatus.10,13,19–21 Algorithms that are used to preoperatively identify shortened esophagus have a lower than desired sensitivity and even worse specificity: of patients who are preoperatively diagnosed with short esophagus after thorough testing with manometry, endoscopy and esophagram, approximately 20% will be found to have an esophagus amendable to mobilization and intraabdominal relocation, foregoing the need for gastroplasty.22,23 There may be a factor of timing in this which partly explains the radical differences in incidence. Early studies tend to have a higher incidence but also were conducted in the era preceding effective acid suppressive medication. Since esophagitis and strictures are a known risk for intrinsic shortening – it follows that these patients may have had more extensive esophageal damage or active disease. Data that exist regarding shortened esophagus in patients with GERD are mainly observational (quality of evidence low). That being said, many reports have been made by different groups with many years of experience and well recorded cases in their institutional databases. However, with the possibility of prospective studies in the future, the outcomes could vary and recommendations may change. The published studies of many experienced groups advise that thorough preoperative testing be performed and assessed carefully. Then, should the likelihood of shortened esophagus be high, appropriate surgical planning or referral to a center than often performs complicated esophageal surgery should be made.
33. Lengthening Gastroplasty for Managing GERD and Giant Paraesophageal Hernia
Superiority of Various Techniques There are no direct prospective comparisons between different techniques of gastroplasty techniques (cut, uncut, stapled, sewn, transthoracic, transabdominal, open, laparoscopic). All reports of these options are from longitudinal prospective or retrospective single institution studies or reports (low quality evidence). There are direct and indirect comparative reports comparing the Collis gastroplasty to alternative techniques of esophageal lengthening which include: circular myotomy,24 extended mediastinal mobilization,25 Hill esophagogastropexy,26 truncal vagotomy,27 esophagectomy and others. The Allen paper on circular myotomy24 included 14 patients with a follow-up of 5 years and a 60% success rate – it had no comparisons with other techniques and is essentially a pilot study. A prospective study by O’Rourke et al. looked at extended mediastinal dissection as a successful management strategy for short esophagus in 205 patients and showed equal outcomes compared to ARS alone in normal length esophagi.25 This study, however, excluded those who needed a Collis procedure (3.5%). Jobe et al.26 reported a retrospective study with objective follow-up in a group of PEH patients, 6 patients with short esophagus who underwent a Hill procedure and 28 patients with a normal length esophagus who underwent a Hill, evaluated with contrast swallow studies at 3 years. There was a high recurrence rate but no difference between the two groups was identified. Finally, a recent retrospective report from Oelschlager et al.,27 supported the performance of a truncal vagotomy to lengthen the esophagus but concentrated on the absence of side effects from the procedure rather than its superiority over other techniques.
Outcomes of Gastroplasty There are no randomized long-term and only one multi-institutional prospective studies looking at the outcomes of Collis procedures. Aside from technical descriptions, the majority of reported studies are single institution case series – mostly retrospectively assessed. They report on the feasibility and relative safety of the various procedures
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described and uniformly encourage adoption of the technique even though no comparative data are offered.28–31 The only prospective study was from eight international centers enrolling 180 patients and looking at the length of esophageal dissection required for 2.5 cm of intra-abdominal esophageal length. Twenty six patients (14%) required a Collis procedure to meet that requirement intraoperatively. There was no long term follow-up reported, however.32 There was also a retrospective case matched cohort study comparing Collis–Nissen patients (14) to patients undergoing regular Nissen procedures from a single institution. Outcomes were QOL and symptoms and were the same for both groups (87% satisfaction in each group).33 There are two papers published looking at long term objective testing of post-operative Collis patients. One from our group looked at patient satisfaction, GERD symptoms, endoscopic esophagitis and pH and manometry prospectively gathered and with a mean follow-up of 14 months.18 There was a 14% long term dysphagia rate (all resolved with endoscopic dilation). Fourteen percent of patients complained of residual heartburn, though one had no abnormal acid exposure on pH monitoring. There was esophagitis noted in 36% of patients and pH testing was abnormal in 50%. This was postulated to be due to ectopic gastric mucosa above the antireflux valve resulting from the lengthening procedure. Martin also found 30% of esophageal pH studies to be abnormal in their series even though the patients were asymptomatic.34 These reports offer evidence confirming that fundoplication combined with a Collis procedure is effective at stopping regurgitation and other symptoms of GERD and has high patient satisfaction scores, but is nonphysiologic due to hypomotility of the neoesophagus and has a high incidence of ectopic acid secretion that can cause asymptomatic esophagitis. For that reason, both authors cautioned against using the Collis routinely and encouraged its use only if all other maneuvers failed.
Conclusions and Recommendations Collis gastroplasty remains an important clinical tool for the esophageal surgeon. It is a flexible
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approach to the intrinsically shortened esophagus that, while not totally physiologic, is probably better than the alternatives for this challenging problem, which include intrathoracic fundoplication (high rates of chest pain and dysphagia), truncal vagotomy (risk of dumping), repair under tension (high failure rate), or an esophagectomy (2–5% mortality). Identifying who needs a Collis procedure is best determined by intraoperative findings – though there are predictors for patients at high risk. Therefore, a decision to do a lengthening procedure remains dependent on the operating surgeon, and hinges on their biases, subjective assessment of esophageal length and recurrence risk, and comfort with performing the procedure. Because of the risk of postoperative sequelae (mostly esophagitis from postoperative ectopic gastric mucosa and dilatation of an amotile distal esophagus) it is recommended that these patients be on some sort of surveillance program. The esophagogastric junction is unable to be reduced below the diaphragm only in a small percentage of patients undergoing fundoplication surgery, as extensive mediastinal mobilization of the esophagus achieves adequate intraabdominal length in a large number of patients (evidence quality moderate). Giant hiatal hernias, GEJ > 5 cm above the diaphragm on barium swallow, strictures, and Barrett esophagus are all significant predictors of a short esophagus (low quality evidence). The Collis gastroplasty with a partial or complete fundoplication is a safe and effective treatment for intrinsically short esophagus (Table 33.1) (low quality evidence). There is no proof of superiority of one technique of Collis gastroplasty over any other (very low quality evidence). The Collis gastroplasty is a non physiologic procedure with decreased motility and risk of ectopic acid production and esophagitis (low quality evidence). We make a strong recommendation that a Collis
gastroplasty should only be used as part of an antireflux operation or for repair of a paraesophageal hiatal hernia after all efforts at esophageal mobilization have been exhausted (recommendation grade 1C).
The Authors’ Personal Approach to the Problem Our own approach to the short esophagus is one of being prepared to perform a Collis procedure – but only doing it if absolutely necessary. Our default approach to reflux or giant hiatal hernias is laparoscopic, and 98% of repairs are performed that way. We currently expect that 2% of routine antireflux surgeries, 5% of PEH repairs, and 15% of reoperative surgeries will need a lengthening procedure. We apply preoperative risk stratification using the criteria outlined by Gastel14 and ourselves17 and will counsel the patient, schedule for a “possible Collis,” and position the patient appropriately if they have the GEJ > 5 cm above the hiatus, Barrett esophagus, strictures or herniation after a fundoplication. We prefer a transthoracic approach via thoracoscopy9 although we have adopted the left chest approach with articulating staplers as described by Filipi et al.13 Our preference is based on the cost savings and efficiency of a single staple firing as opposed to multiple firings and our comfort with operating in the chest. We no longer use double lumen endo tracheal ventilation which notoriously slows the anesthesia process and instead use low pressure capnothorax to collapse the left lung. Postoperative follow-up for these patients always includes motility, endoscopy and pH studies at 6 months. As mentioned above, while more than 90% of these patients express satisfaction with the results, over 50% have some esophagitis
Table 33.1. Incidence and outcomes of Collis gastroplasty from selected experiences (pooled results). Procedure Transthoracic Collis/Belsey Transthoracic Collis/Nissen “Uncut” Collis Laparoscopic transthoracic Collis Laparoscopic “wedge fundectomy”
References 3, 5 4, 33, 34 32 13, 36 11
Incidence (% of ARS) Acute complications (%) NR 14–27 NR 3.5 4.5
18–25 40 (dysphagia) 18 2 0
Good or excellent results (%)
Abnormal postoperative esophageal pH monitoring (%)
70–82 87 85–100 88 84
37 33 NR 50 80
33. Lengthening Gastroplasty for Managing GERD and Giant Paraesophageal Hernia
and motility irregularities that deserve continued follow-up.35
The Collis gastroplasty with a partial or complete fundoplication is a safe and effective treatment for intrinsically short esophagus, but is a non physiologic procedure with decreased motility and risk of ectopic acid production and esophagitis (low quality evidence). We make a strong recommendation that a Collis gastroplasty should only be used after all efforts at esophageal mobilization have been exhausted (recommendation grade 1C).
References 1. Guyatt G, Gutterman D, Baumann MH, AddrizzoHarris D, Hylek EM, Phillipps B, Raskob G, ZelmanLewis S, Schunemann H. Grading strength of recommendations and quality of evidence in clinical guidelines. Chest. 2006;129;174–181. 2. Collis JL. An operation for hiatus hernia with short esophagus. J Thorac Surg. 1957;34:768–773. 3. Pearson FG, Henderson RD. Long-term follow-up of peptic strictures managed by dilatation, modified Collis gastroplasty, and Belsey hiatus hernia repair. Surgery. 1976;80:396–404. 4. Orringer MB, Orringer JS. The combined CollisNissen operation: early assessment of reflux control. Ann Thorac Surg. 1982;33:534–539. 5. Urschel HC Jr, Razzuk MA. “Collis-Belsey” fundoplication for uncomplicated hiatal hernia and gastroesophageal reflux. Ann Thorac Surg. 1979;27:564–566. 6. Bingham JAW. Evolution and early results of creating an anti-reflux valve in the stomach. Proc Roy Soc Med. 1974;67:4–8. 7. Demos NJ, Smith N, Williams N. A gastroplasty for short esophagus and reflux esophagitis: experimental and clinical studies. Ann Surg. 1975;181:178–181. 8. Steichen FM. Abdominal approach to the Collis gastroplasty and Nissen fundoplication. Surg Gynecol Obstet. 1986;162:272–274. 9. Swanstrom LL, Marcus DR, Galloway GQ. Laparo scopic Collis gastroplasty is the treatment of choice for the shortened esophagus. Am J Surg. 1996;171: 477–481. 10. Johnson AB, Oddsdottir M, Hunter JG. Laparoscopic Collis gastroplasty and Nissen fundoplication: a new technique for the management of esophageal foreshortening. Surg Endosc. 1998;12:1055–1060. 11. Terry ML, Vernon A, Hunter JG. Stapled-wedge Collis gastroplasty for the shortened esophagus. Am J Surg. 2004;188:195–199.
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12. Morino M, Giaccone C, Pellegrino L, Rebecchi F. Laparoscopic management of giant hiatal hernia: factors influencing long-term outcome. Surg Endosc. 2006;20:1011–1016. 13. Awad ZT, Filipi CJ. The short esophagus: pathogenesis, diagnosis, and current surgical options. Arch Surg. 2000;136:113–114. 14. Gastal OL, Hagen JA, Peters JH, Campos GMR, Hashemi M, Theisen J, Bremner CG, DeMeester TR. Short esophagus: analysis of predictors and clinical implications. Arch Surg. 1999;134:633–638. 15. Lin E, Swafford B, Chadalavada R, Ramshaw BJ and Smith CD. Disparity between symptomatic and physiologic outcomes following esophageal lengthening procedures for antireflux surgery. J Gastrointest Surg. 2004;8:31–39. 16. Awad ZT, Mittal SK, Roth TA, Anderson PI, Wilfley WA, Filipi CJ. Esophageal shortening during the era of laparoscopic surgery. World J Surg. 2001;25:558–561. 17. Urbach DR, Khajanchee YS, Glasgow RE, Hansen PD, Swanstrom LL. Preoperative determinants of an esophageal lengthening procedure in laparoscopic antireflux surgery. Surg Endosc. 2001;15:1408–1412. 18. Jobe BA, Horvath KD, Swanstrom LL. Postoperative function following laparoscopic collis gastroplasty for shortened esophagus. Arch Surg. 1998;133:867–874. 19. Pearson FG. Peptic esophagitis, stricture, and short esophagus. Esophageal surgery. New York: Churchill Livingstone; 1995. 20. Mattioli S, D’Ovidio F, Di Simone MP, Bassi F, Brusori S, Pilotti V Felice V, Gerruzzi L, Guernelli N. Clinical and surgical relevance of the progressive phases of intrathoracic migration of the gastroesophageal junction in gastroesophageal reflux disease. J Thorac Cardiovasc Surg. 1998;116:267–275. 21. Luketich JD, Raja S, Fernando HC, Campbell W, Christie NA, Buenaventura PO, Weigel TL, Keenan RJ, Schauer PR. Laparoscopic repair of giant paraesophageal hernia: 100 consecutive cases. Ann Surg. 2000;232: 608–618. 22. Ritter, MP, Peters, JH, DeMeester, TR, Gadenstatter, M, Oberg, S, Fein, M, Hagan, JA, Crookes, PF, Bremner, CG. Treatment of advanced gastroesophageal reflux disease with Collis gastroplasty and Belsey partial fundoplication. Arch Surg. 1998;133:523–525. 23. Luketich JD, Grondin SC, Pearson FG. Minimally invasive approaches to acquired shortening of the esophagus: laparoscopic Collis-Nissen gastroplasty. Semin Thorac Cardiovasc Surg. 2000;12:173–178. 24. Allen SM, Matthews HR. Circular myotomy and Belsey repair for acquired shortening of the oesophagus. Eur J Cardiothorac Surg. 1993;7:645–647. 25. O’Rourke RW, Khajanchee YS, Urbach DR, Lee NN, Lockhart B, Hansen PD, Swanstrom LL. Extended transmediastinal dissection: an alternative to gastroplasty for short esophagus. Arch Surg. 2003;138: 735–740. 26. Jobe BA, Aye RW, Deveney CW, Domreis JS, Hill LD. Laparoscopic management of giant type III hiatal
292 hernia and short esophagus. Objective follow-up at three years. J Gastrointest Surg. 2002;6:181–188. 27. Oelschlager BK, Yamamoto K, Woltman T, Pellegrini C. Vagotomy during hiatal hernia repair: a benign esophageal lengthening procedure. J Gastrointest Surg. 2008; 12:1155–1162. 28. Garg N, Yano F, Filipi CJ, Mittal SK. Long-term symptomatic outcomes after Collis gastroplasty with fundoplication. Dis Esophagus. 2009;22:532–538. 29. Chen LQ, Ferraro P, Martin J, Duranceau AC. Antireflux surgery for Barrett’s esophagus: comparative results of the Nissen and Collis-Nissen operations. Dis Esophagus. 2005;18:320–328. 30. Richardson JD, Laron GM, Polk HC. Intrathoracic fundoplication for shortened esophagus. Am J Surg. 1982;143:29–35. 31. Demos NJ. The stapled, uncut gastroplasty for hiatal hernia: 24 years’ follow-up. Dis Esophagus. 1999;12: 14–21.
L.L. Swanstrom and T.A. Goers 32. Mattioli S, Lugaresi ML, Costantini M, Del Genio A, Di Martino N, Fei L, Fumagalli U, Maffettone V, Monaco L, Morino M, Rebecchi F, Rosati R, Rossi M, Santi S, Trapani V, Zaninotto G. The short esophagus: intraoperative assessment of esophageal length. J Thorac Cardiovasc Surg. 2008;136:834–841. 33. Youssef YK, Shekar N, Lutfi R, Richards WO, Torquati A. Long-term evaluation of patient satisfaction and reflux symptoms after laparoscopic fundoplication with Collis gastroplasty. Surg Endosc. 2006;20: 1702–1705. 34. Martin CJ, Cox MR, Cade RJ. Collis-Nissen gastroplasty fundoplication for complicated gastro-esophageal reflux disease. Aust N Z J Surg. 1991;15:512–518. 35. Horvath KD, Swanstrom LL, Jobe B. The short esophagus: pathophysiology, incidence, presentation and treatment in the era of laparoscopic anti-reflux surgery. Ann Surg. 2000;232:630–640.
34
Optimal Therapy for Cricopharyngeal Diverticula Giovanni Zaninotto and Christian Rizzetto
Introduction and Historical Notes Cricopharyngeal diverticula (also known as Zenker’s diverticula) are protrusions of pharyngeal mucosa through an area of relative weakness in the posterior wall of the pharynx, in the socalled Killian’s triangle between the obliquelypositioned inferior constrictor muscle and the transversely-oriented cricopharyngeal muscle.1 A higher hypopharyngeal pressure during swallowing and a lower resistance of the posterior wall of the hypopharynx are fundamental factors in the pathogenesis of cricopharyngeal diverticula. Cricopharyngeal spasm, cricopharyngeal incoordination, impaired upper esophageal sphincter opening, and structural changes in the cricopharyngeal muscle have all been implicated in the etiology of Zenker’s diverticula.2,3 Both the cricopharyngeal anomaly and the presence of a sac may contribute to the symptoms. The poorly-compliant cricopharyngeus may cause a sensation of dysphagia (intrinsic dysphagia), and so may the progressively enlarging volume of the sac (as it fills with food residue) due to direct compression of the underlying esophagus (extrinsic dysphagia). Food regurgitation, noisy swallowing, halitosis and the presence of a lump in the neck are all signs relating primarily to the presence of the sac and depend on its size. Pouch carcinoma has been reported only rarely (in less than 0.4% of cases),4 but should nonetheless be considered when undertaking surgery. Treatment is indicated for Zenker’s diverticula, regardless of their size, to relieve disabling symptoms of oropharyngeal dysphagia and pharyngo-oral
regurgitation, and to prevent the life-threatening complications of aspiration pneumonia and lung abscess, which can occur in the elderly. The poor nutritional status associated with the swallowing disorder and the tendency of the pouch to expand progressively are further arguments in favor of early treatment. Pill-entrapment in the pouch is another concern in patients with severe comorbidities requiring life-saving drug therapy. The strategy for dealing with pharyngeal pouches has evolved over the past century, reflecting changes in our understanding of the underlying pathophysiology and technological advances. Two different approaches have been proposed: open surgery or transoral endoscopic surgery. Surgical procedures initially focused on the pouch (a two-step operation was adopted at first, creating a cutaneous fistula before dividing the diverticulum). With improved suturing techniques, the pouch could be separated from the esophagus and sutured directly. In the 1960s, the introduction of water-perfused manometry enabled the identification of the upper esophageal sphincter (UES) and an active role was hypothesized for the cricopharyngeal muscle (which forms at least a part of the UES) in the pathogenesis of the pharyngeal pouch. The physiology and role of the UES were further clarified more recently,5,6 and UES myotomy to ease the functional obstruction has since become an essential step in the surgical treatment for pharyngeal diverticula, together with pouch excision or plication. Transoral endoscopy treats the disorder by dividing the septum between the diverticulum and the esophageal lumen to facilitate the passage of
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the bolus. As early as 1917 Mosher reported dividing the bar between the diverticulum and the esophagus with the aid of a rigid endoscope and a cautery, but the technique was abandoned not long afterwards because of the unacceptable rate of complications, especially mediastinitis.7 In 1960 Dohlman and Mattson described an endoscopic approach that involved using a modified rigid esophagoscope to expose the cricopharyngeal bar and an electrocautery to divide it; they successfully treated over 100 patients.8 Overbeek further refined the endoscopic approach using an operating microscope with a 400 mm lens and a carbon dioxide laser.9 The availability of the modern laparoscopic stapler, which enables the septum to be transected with a minimal risk of leakage (as proposed by Collard in 1993) has facilitated the diffusion of this approach.10 Given the rarity of Zenker’s diverticula, there has been no randomized controlled trial comparing the open procedure with endoscopic stapling, and there is a shortage of sound evidence for most of the procedures used to treat the condition. It seems that the choice between open and endoscopic methods varies by geographical region and the surgeon’s specialization: endoscopic stapling is the procedure of choice in Europe but is less common in the United States11; head and neck surgeons are more likely to favor endoscopic treatments, while general and thoracic surgeons prefer open surgery. The aim of this review was thus to ascertain the level of evidence on the procedures most often used to treat Zenker’s diverticula, considering a number of (mainly retrospective) studies and our findings in a series of patients.
Study Selection Criteria We considered studies that evaluated the surgical and/or endoscopic outcome in patients with Zenker’s diverticula. Articles were sought in the Medline and Pubmed databases using the search terms: Zenker’s diverticulum, cricopharyngeal diverticulum, endoscopic diverticulostomy, diverticulectomy, cricopharyngeal myotomy and endoscopic treatment. Given the rarity of the condition, the search spanned a 20-year period. The two authors (GZ and CR) independently reviewed and extracted the data of interest in abstract form, and
any discrepancies were settled by mutual agreement. The articles extracted had to be in English and in the full-text version. For this systematic review, the studies were evaluated and selected on the basis of the completeness of the data and inclusion criteria and the quality of the method. The initial search identified 519 potential articles from which we excluded the case reports (114). We extracted the article in English version (390) and 134 relevant articles were selected and reviewed. Data was extracted from 37 studies which met the inclusion criteria.8–44
Open Surgery A left incision anteromedial to the sternocleidomastoid muscle is the most preferred approach. The diverticulum is carefully dissected from its attachments to the surrounding tissues. The cricopharyngeal muscle fibers are divided posteriorly at the midline from the neck of the sac down to the esophagus over a length of 4–5 cm. After completing the myotomy, either diverticulectomy or diverticulopexy is performed. Diverticulectomy is performed using a stapler; alternatively, the diverticulum may be suspended upside down and sutured to the prevertebral fascia (diverticulopexy) or, in the case of small diverticula, it can be invaginated below the pharyngeal muscle layer or left untouched. Open surgery effectively eliminates the symptoms in 90–95% of patients. Mortality and morbidity are in the range of 0–2.3% and 2.5–46%, respectively. Additional treatment or reoperation are required for 5% of patients (Table 34.1). Controversial issues relating to open surgery include: (1) the need for UES myotomy; (2) the extent of the myotomy (downwards and upwards); and (3) diverticulectomy versus diverticulopexy.
The Need for UES Myotomy Although the vast majority of surgeons perform a myotomy, there is no clinical evidence to support the need for it. In a landmark study on open surgery (despite the years that have elapsed, it still represents the largest reported series of open diverticulectomies), Payne12 included 888 patients treated with and without myotomy between 1944
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34. Optimal Therapy for Cricopharyngeal Diverticula Table 34.1. Open procedures for Zenker’s diverticula. Author
Year
Type of operation
Patients
Complications (%)
Mortality rate (%)
Success rate (%)
Recurrence rate (%)
Follow-up (months)
Payne Konowitz19 Schmit22 Laccourreye20 Fraczek21 Gutschow14 Colombo16 Bonavina32 Rizzetto15
1983 1989 1992 1994 1998 2001 2003 2007 2008
M+D M+D−P M M+D−P M+D−P M+D−P D +/− M M+D M+D−P
888 32 48 43 37 47 79 116 77
6.1 18 – 30 46 13 15.2 2.5 13
1.2 0 2.1 2.3 0 0 0 0.8 0
93 100 70 100 95 90 81 94 95
3.6 0 30 0 0 8 12 – 5
60–168 5–60 64 6–24 1–228 – – 48 41
12
D diverticulectomy; M myotomy; P diverticulopexy
and 1978, with a median follow-up of 14 years. Symptoms improved in 93% of these patients; the post-operative mortality rate was 1.2% and the recurrence rate was 3.6%. More recently (1992), adding cricopharyngeal myotomy to the diverticulectomy made no difference to the results.13 It was Gutschow who suggested that the morbidity rate can be reduced by adding UES myotomy to the diverticulectomy, mainly thanks to a lower incidence of leakage from the esophageal suture. Five of his six patients who developed salivary fistula after diverticulectomy had not had a myotomy, suggesting that the incidence of pharyngo-esophageal leakage increased among patients without any UES myotomy.14 When the reasons why diverticulectomy and UES myotomy were unsuccessful were analyzed by physiological features, Rizzetto and Zaninotto demonstrated that surgery significantly reduced the UES resting and intrabolus pressures in all patients, but those who subsequently developed recurrent dysphagia (4/77; 5.2%) had a higher postoperative UES intrabolus pressure than in asymptomatic patients, suggesting that an incomplete UES myotomy might be responsible for the persistence/recurrence of symptoms.15 ColomboBenkmann and colleagues recommended a selective use of UES myotomy only in patients whose cricopharyngeal muscle appeared to have thickened, as assessed by intraoperative palpation. Thirty-two patients had diverticulectomy alone and UES myotomy was added in 47. The two groups had equally good results after more than 5 years of follow-up based on a symptom questionnaire. Postoperative symptoms persisted in rather more patients in the group that had myotomy (23%) than in the non-myotomized group (13%).
Unfortunately, no manometry was performed and only a subjective selection criterion was used.16
Extent of UES Myotomy The cricopharyngeal muscle is anatomically rather slender (1 cm wide), while the UES – as measured by manometry – extends approximately 2.5–3 cm, suggesting that the cricopharyngeal muscle is just one of the sphincter’s component parts. Lerut et al. recommended extending the myotomy further downwards (by up to 5 cm) on the assumption that histological anomalies might be detected beyond the confines of the cricopharynx proper and into the striated muscle of the upper esophagus.17 In another study, intraoperative manometry demonstrated a reduction in sphincter pressure after a myotomy 2 cm long, but a further significant reduction was achieved when the myotomy was extended to 4 cm. In the same study, Duranceau suggested extending the myotomy another 2 cm upwards to include the fibers of the inferior constrictor of the pharyngeal muscle.18
Diverticulectomy Versus Diverticulopexy Proponents of pouch suspension claim that the morbidity of the procedure is reduced by avoiding sutures, especially in the case of small pouches and difficult or hazardous diverticulectomies. Konowitz and Biller19 compared 20 patients undergoing myotomy and diverticulectomy with 12 undergoing myotomy and suspension. The latter group had a lower morbidity rate (0% vs. 20%) and a shorter hospital stay, with a faster resumption of oral intake. There were no recurrences in either group. Similar results were reported in
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another two studies, which recorded fewer leaks and shorter hospital stays for diverticulopexy patients than in diverticulectomy patients.20,21 Schmidt reported on 48 patients with small diverticula undergoing myotomy alone under local anesthesia. The mortality rate was 2.1%, the hospital stay lasted 2.7 days, and 70% of the patients had good or excellent results.22 There is still conflicting evidence in favor of one or other technique, however. Modern stapling devices (with three rows of suture) have substantially reduced the risk of anastomotic leakage, in medium-to-large diverticula at least, but pouch suspension or invagination may be useful for small diverticula (<2 cm).
Endoscopic Techniques General anesthesia is used and patients are placed supine with their neck extended. A Weerda diverticuloscope is inserted transorally with the long tip placed inside the esophagus and the shorter tip in the sac. The instrument is spread gently to expose the septum separating the lumen of the posterior sac from that of the anterior esophagus. A telescope connected to a camera and screen provides excellent exposure. An endoscopic linear cutting stapler is used to divide the exposed septum of tissue. A V-shaped opening is created between the sac and the esophagus so as to form a common cavity. Depending on the size of the pouch, further stapling may be required: a small residual spur often results, but it is safer to divide too little than to risk perforation and mediastinitis. Laser cautery or the
harmonic scalpel have recently been proposed for dividing the common wall. In an effort to avoid the need for general anesthesia, a number of authors have reported using a soft diverticuloscope and flexible endoscopy, dividing the septum with the aid of a needle knife papillotome or argon plasma coagulator.23 After endoscopic diverticulostomy, dynamic fluoroscopy with barium swallow shows that the pouch empties rapidly into the esophagus without any pooling of the contrast agent. Although some degree of radiographic abnormality is common after endoscopic treatment, there is no apparent correlation between the degree of deformity or residual pouch and any symptomatic recurrences. A partial or complete regression of the symptom is reportedly achieved in 78–96% of patients soon after the operation (radiologic evaluation is not readily applicable to endoscopic treatments, since the posterior wall of the diverticulum is not transected and some pouch remains). Late recurrences may develop in 10–20% of cases. Mortality is low (0–0.5%) and major complications (leakage from the diverticulostomy, aspiration pneumonia, perforation, transient vocal fold paralysis) occur in 1–5% of the patients treated. Endoscopic techniques have the unquestionable advantages over open surgery of shorter operating times, a quicker return to oral intake, shorter hospital stays and a speedier recovery (Table 34.2). The most frequent reasons for converting from endoscopic to open surgery are difficulty in extending the neck or opening the mouth sufficiently to accommodate the diverticuloscope, excessively small pouches or mucosal tearing.24 Unfortunately, information on cases in which it proved impossible to treat
Table 34.2. Endoscopic procedures for Zenker’s diverticula. Author
Year
Type of operation
Patients
Complications (%)
Mortality rate (%)
Success rate (%)
Nyrop27 Hoffmann26 Chang25 Costamagna36 Vogelsang35 Rabenstein34 Bonavina32 Rizzetto15 Fama29 Kos28
2000 2003 2003 2007 2007 2007 2007 2008 2009 2009
CO2 laser CO2 laser Stapler Needle knife Needle knife APC Stapler Stapler Harmonic scalpel CO2 laser
61 119 159 11 31 41 181 51 25 189
10 – 2 0 7 3 5.5 5.8 20 2.6
0 0 0 0 0 0 0 0 0 0
87 90.3 88 91 84 95 87 78.5 96 80
APC argon plasma coagulation
Recurrence rate (%) Follow-up (months) 10 5 12 9 – – 10 15 4 20
37 12–36 32 6.5 26 16 60 40 10 –
34. Optimal Therapy for Cricopharyngeal Diverticula
Zenker’s diverticula transorally is rarely reported. Controversial issues relating to the endoscopic methods include: (1) techniques for dividing the septum; (2) diverticulostomy for very large or small (>2 cm) diverticula; (3) rigid versus flexible endoscope.
Techniques for Dividing the Septum The use of endoscopic stapling was refined and made popular in the United States by Richard Scher,25 with his publication on 159 patients treated with an endoscopic stapler-assisted diverticulostomy from 1995 to 2002. Scher’s group found that 98% of their patients reported complete or partial symptom improvement, an average hospital stay of less than 1 day, a 2% major complication rate, and a 12% recurrence rate after a 32-month follow-up. The rare major complications included aspiration pneumonia, perforation, and transient vocal fold paralysis. The results of treating Zenker’s diverticula using the endoscopic CO2 laser to divide the tissue bridge are also favorable. In one study on 119 patients, there were no cases of postoperative mediastinitis and 90% of patients were asymptomatic 1–3 years later.26 Nyrop reported on 61 patients treated endoscopically with the CO2 laser: 8% had postoperative emphysema in the neck and 3% developed signs of mediastinitis (none required reoperation); 92% of the patients were satisfied with the outcome and 70% were asymptomatic after a median follow-up of 37 months.27 Kos from the Netherlands used different CO2 laser endoscopic devices, assessing the efficacy of endoscopic Zenker’s diverticulotomy with the CO2 laser and the Acuspot, as compared with the historical results of using a CO2 laser without the Acuspot or electrocautery diverticulotomy. A total of 229 endoscopic Zenker’s diverticulotomies were performed in 189 patients: as of 1995, micro-endoscopic diverticulotomy with the CO2 laser and Acuspot was performed in 61 cases (group A); from 1984 to 1995, micro-endoscopic diverticulotomy was performed with the CO2 laser in 113 cases (group B); and before 1984, endoscopic diverticulotomy was performed with electrocautery in 55 cases (group C). After the procedure, there was no dysphagia in 84.6%, 78.4% and 72% of the patients in the three groups, respectively.
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Repeat surgery was required in 13% of patients in group A, 19.6% of patients in group B, and 24.3% patients in group C.28 The harmonic scalpel was recently added to the surgeon’s armamentarium for the treatment of Zenker’s diverticulum. Two groups in the United States separately published their preliminary findings in patients treated using this technique.29,30 The first study evaluated 25 patients treated successfully and safely with the harmonic scalpel: five (20%) experienced minor complications (one patient with a history of cardiac disease had a non-ST-elevation myocardial infarction, one had aspiration pneumonia, two had chest pain and one had subcutaneous emphysema). None of the patients had hemorrhage, infection or mediastinitis. Only one patient had recurrent dysphagia after a follow-up of 10 months.29 The second study considered 48 consecutive patients in whom a total of 52 endoscopic procedures were attempted and 50 were completed, using the stapler in 28, the Harmonic Ace in 20, and both in two.30 Two procedures were aborted due to anatomical limitations. Forty-four patients (88%) reported complete resolution of their symptoms. Six complications (12%) were reported; five (17.9%) relating to the stapler and one (5%) to the Harmonic Ace (the difference between these two groups was not significant). The mean size of the diverticula was smaller in the harmonic scalpel group than in the stapler group. Patients with a diverticulum larger than 2 cm were more likely to have postoperative complications than those with smaller diverticula. A longer follow-up is needed, however, to assess the long-term success of this new technique and the incidence of recurrences.
Diverticulostomy in Very Large (>6 cm) or Small (<2 cm)Diverticula Multiple stapler firing may be needed to dissect the bar of a large diverticulum. Roth and co-workers31 compared the outcome in patients undergoing endoscopic stapling with single versus multiple rows of staples: the postoperative leakage rate was higher among the latter than for patients stapled with a single row (36% vs. 0%, p < 0.05). Patients with multiple rows of stapling also had a longer hospital stay and took longer to return to clear
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fluids and a solid diet (p < 0.05). On the other hand, there was no difference in recurrence rate or patient satisfaction between the two groups. It may be difficult to accommodate the anvil of the stapler inside a small pouch (<2 cm) and the blade that cuts between the rows of staples leaves a few millimeters uncut distally for safety reasons, so the distal UES fibers may remain undivided when small diverticula are treated this way. Bonavina and coworkers reviewed 181 cases treated transorally: long-term follow-up data showed that most patients with a large diverticulum (>3 cm) were asymptomatic after the procedures (93.6%), while those treated for small diverticula (<3 cm) had a recurrence rate of 50%.32 Rizzetto and co-workers confirmed the efficacy of transoral diverticulostomy using pharyngoesophageal manometry: the UES resting pressures were substantially reduced and the intrabolus pressure was eliminated. Eleven patients (21.5%) complained of persistent postoperative dysphagia: 9 of these 11 symptomatic patients had a diverticulum less than 3 cm long, which meant a 36% likelihood of recurrence in the subgroup of patients with transorally-treated small diverticula. These patients were also significantly younger and had lower overall symptom scores. Manometric studies in the nine patients with severe dysphagia after their operation revealed an incomplete UES relaxation and a persistently high pharyngeal intrabolus pressure in four cases (44.5%), three of which were retreated with open approach, revealing uncut muscle fibers just beyond the end of the stapler line.15
Rigid Versus Flexible Endoscope Donovan33 reported his experience with the endoscopic management of Zenker’s diverticulum in 72 consecutive patients ranging in age from 44 to 93 years: the procedure with the flexible endoscope was feasible in 61 patients (85%), and it resulted in complete symptom resolution in 47 of them. The most common risk factors for recurrence were the size of the diverticulum (more than 3 cm) and the amount of redundant mucosa. There was one major complication (esophageal tear), and three minor complications (mucosal abrasions) occurred. Flexible endoscopic treatment may be particularly advantageous for high-risk
G. Zaninotto and C. Rizzetto
elderly patients who might benefit from a rapid procedure with no general anesthesia and without the need to hyperextend the neck. Despite most authors recommending that the procedure be restricted to high-risk elderly patients, some centers offer the flexible endoscopic approach to all symptomatic patients referred for treatment. The three methods mainly used to cut the septum for the flexible endoscopic approach are: needle knife incision, argon plasma coagulator (APC) and monopolar coagulation using the forceps. Complications after flexible endoscopic treatment for Zenker’s diverticula relate to the sedation, aspiration, perforation, and bleeding. Throat pain is not uncommon and should be anticipated. Perforation can range from subcutaneous or mediastinal emphysema to cervical abscess and mediastinitis. Uncomplicated cervical or mediastinal emphysema occurs in 0–23% of patients and regresses within 2–5 days.34–36 Bleeding occurs in 0–10% of patients after endoscopic diverticulostomy.Intra-procedural bleeding can be treated by electrocoagulation using the needle knife tip or hot biopsy forceps, the APC probe, injection of diluted epinephrine and/or the application of endoclips.35 The results suggest that the outcomes of the different endoscopic approaches are similar, though APC treatment appears to be associated with more endoscopic sessions. The success rate after flexible endoscopic therapy (defined as a decrease in the frequency and severity of symptoms) is around 90%.
Open Versus Endoscopic Approaches Given the rarity of the disease, there are unfortunately no randomized, controlled trials comparing open procedures versus endoscopic stapling for Zenker’s diverticula, but several literature reviews conducted from 1990 to 2002 have specifically compared open with endoscopic procedures.37–43 Endoscopic stapling takes less time and carries lower complication and mortality rates, and requires shorter hospital stays and less time to return to oral intake than open procedures. Both endoscopic stapling and open surgery afford good symptom relief. A long-term follow-up for endoscopic stapling is still lacking, however, whereas open procedures are known to have durable results.
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34. Optimal Therapy for Cricopharyngeal Diverticula
As mentioned previously, two recent publications15,32 retrospectively evaluating the experience of a high-volume institution showed that Zenker’s diverticula can be treated effectively by either endoscopic diverticulostomy or open surgery. The endoscopic procedure is better suited to mediumsized diverticula (3–5 cm), whereas it carries a greater risk of failure when applied to small diverticula (in terms of persistent severe dysphagia due to incomplete dissection of the UES fibers). Analyzing the treatment failures showed that they are caused by persistently noncompliant UES fibers opposing the bolus outflow, as revealed indirectly by an unchanged pharyngeal intrabolus pressure. The strongest indication for endoscopic diverticulostomy is, therefore, a medium-sized diverticulum in which the stapler cartridge can be accommodated and the stapler can achieve an adequate cricopharyngeal myotomy, whereas diverticula shorter than 3 cm should be seen as a formal contraindication to the transoral approach.
Treatment of Recurrent Zenker’s Diverticula Repeat diverticulectomy and myotomy for a recurrent Zenker’s diverticulum following a failed open procedure is generally successful, albeit with a higher morbidity rate. Endoscopic stapling of a recurrent pouch after endoscopic or open surgery is technically feasible and relatively easy. Koay44 reported that it was no more difficult than a primary procedure. There was no increase in the related morbidity, in contrast with the significant increase associated with second open procedures. Flexible endoscopic treatment using the electrocautery or CO2 laser may be particularly advantageous in this subset of patients.
Summary Surgery for pharyngeal pouch has evolved as our understanding of the underlying pathophysiology has improved. UES dysfunction plays a central role in the pathogenesis of pharyngeal pouches and reducing its high pressure zone is now considered
a necessary step of both endoscopic and open surgical treatments. Open myotomy alone is probably the most effective and safest procedure for very small pouches, particularly those less than 2 cm in size, since excision may entail unnecessary morbidity. Diverticulopexy appears to be safer than diverticulectomy, and no less effective when combined with open myotomy, for medium-sized pouches. Excision and myotomy are warranted for massive pouches, particularly in young patients or when a potential pouch carcinoma is a concern. Endoscopic stapling is an effective procedure that carries a minimal morbidity and is likely to be used more and more. Although follow-up data are still limited, recurrence rates may be slightly higher with this method, but this drawback is offset by the lower morbidity rate and the ease with which the procedure can be repeated successfully.
Recommendations Open and endoscopic approaches for Zenker’s diverticulum are safe and produce similar good quality early results in experienced hands (evidence quality low). Although the intermediate follow-up of patients treated endoscopically with stapling, and the longer-term follow-up of patients treated with the Dohlman procedure suggest similar outcomes, a longer follow-up is available only for the open approach, and we strongly recommend open myotomy – which remains the standard method of care – for treating young patients fit for surgery with Zenker’s diverticula (recommendation grade 2B). Endoscopic approaches may eventually prove to be preferable for old patients with medium-sized pouches, as complications are minimal and symptom relief rate is high. Either an open procedure or flexible endoscopic laser treatment is safe and effective for patients who have a limited capacity for neck extension, and the choice depends on the surgeon’s preference and skill (evidence quality low). There is insufficient comparative data to make a recommendation for one approach over the other in this group of patients. Endoscopic therapy is insufficiently effective for patients with small diverticula (equal or less than 2 cm; evidence quality low) and we recommend open myotomy for patients with small
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Zenker’s diverticula (recommendation grade 2B). Endoscopic stapling is safe and effective for patients with a recurrent pouch after an open procedure, and avoids the higher complication rates evident with redo open myotomy (evidence quality low). We make a weak recommendation for endoscopic therapy of recurrent Zenker’s diverticula after failed open myotomy (recommendation grade 2C).
Personal Approach Endoscopic diverticulostomy is very safe and effective, but the size of the stapler’s anvil makes it better suited to medium-sized diverticula (3–5 cm), whereas in patients with small pouches (<3 cm) it carries a greater risk of failure in terms of persistent severe dysphagia, probably due to incomplete section of the UES. Open surgery assures a complete and effective myotomy of the UES and it is effective for all sizes of diverticula, particularly in patients with small diverticula, for whom it should be considered the treatment of choice. It is important to bear in mind, however, that some of its potential complications, e.g. leakage or laryngeal nerve palsy, may have disastrous effects in an elderly patients with comorbidities.
Open and endoscopic approaches for Zenker’s diverticulum are safe and produce similar good quality early results in experienced hands (evidence quality low). Longer follow-up is available for the open approach, and we make a weak recommendation for open myotomy for treating fit patients with Zenker’s diverticula, (recommendation grade 2B).
Endoscopic therapy is insufficiently effective for patients with small diverticula (equal or less than 2 cm; evidence quality low). We make a weak recommendation for open myotomy for patients with small Zenker’s diverticula (recommendation grade 2B).
References 1. Killian G. The mouth of the esophagus. Laryngoscope. 1907;17:421–428. 2. Knuff TE, Benjamin SB, Castell DO. Pharyngo esophageal (Zenker’s) diverticulum: a reappraisal. Gastroenterology. 1982;82:734–736. 3. Zaninotto G, Costantini M, Boccù C, Anselmino M, Parenti A, Guidolin D, Ancona E. Functional and morphological study of the cricopharyngeal muscle in patients with Zenker’s diverticulum. Br J Surg. 1996;83:1263–1267. 4. Bradley PJ, Kochaar A, Quraishi MS. Pharyngeal pouch carcinoma: real or imaginary risks? Ann Otol Rhinol Laryngol. 1999;108:1027–1032. 5. Cook IJ, Gabb M, Panagopoulos V, Jamieson GG, Dodds WJ, Dent J, Shearman DJ Pharyngeal (Zenker’s) diverticulum is a disorder of upper esophageal sphincter opening. Gastroenterology. 1992;103: 1229–1235. 6. Chiao GZ, Kahrilas PJ. Zenker’s diverticulum: new pieces to the pathogenesis puzzle. Am J Gastroenterol. 1993;88:1796–1797. 7. Jamieson GG, Duranceau AC, Payne WS. Pharyngooesophageal diverticulum. In: Jamieson GG, ed. Surgery of the Oesophagus. Edinburgh, UK: Churchill Livingstone; 1988:435–443. 8. Dohlman G, Mattson O. The endoscopic operation for hypopharyngeal diverticula. Arch Otolaryngol. 1960;71:744–752. 9. van Overbeek JJ. Meditation on the pathogenesis of hypopharyngeal (Zenker’s) diverticulum and a report of endoscopic treatment in 545 patients. Ann Otol Rhinol Laryngol. 1994;103:178–185. 10. Collard JM, Otte IB, Kestens PJ. Endoscopic stapling technique of esophagodiverticulostomy for Zenker’s diverticulum. Ann Thorac Surg. 1993;56:573–576. 11. Siddiq MA, Sood S. Current management in pharyngeal pouch surgery by UK otorhinolaryngologists. Ann R Coll Surg Engl. 2004;86:247–252. 12. Payne WS, King RM. Pharyngoesophageal (Zenker’s) diverticulum. Surg Clin North Am. 1983;63:815–824. 13. Payne WS. The treatment of pharyngoesophageal diverticulum: the simple and complex. Hepatogastro enterology. 1992;39:109–114. 14. Gutschow CA, Hamoir M, Rombaux P, Otte J-B, Goncette L, Collard JM. Management of pharyngoesophageal (Zenker’s) diverticulum: which technique? Ann Thorac Surg. 2002;74:1677–1683. 15. Rizzetto C, Zaninotto G, Costantini M, Bottin R, Finotti E, Zanatta L, Guirroli E, Ceolin M, Nicoletti L, Ruol A, Ancona E. Zenker’s diverticula: feasibility of a tailored approach based on diverticulum size. J Gastrointest Surg. 2008;12:2057–2065. 16. Colombo-Benkmann M, Unruh V, Krieglstein C, Senninger N. Cricopharyngeal myotomy in the treatment of Zenker’s diverticulum. J Am Coll Surg. 2003;196:370–378.
34. Optimal Therapy for Cricopharyngeal Diverticula 17. Lerut T, van Raemdonck D, Guelinckx P, Dom R, Geboes K. Zenker’s diverticulum: is a myotomy of the cricopharyngeus useful? How long should it be? Hepatogastroenterology. 1992;39:127–131. 18. Pera M, Yamada A, Hiebert CA, Duranceau A. Sleeve recording of upper esophageal sphincter resting pressures during cricopharyngeal myotomy. Ann Surg. 1997;225:229–234. 19. Konowitz PM, Biller HF. Diverticulopexy and cricopharyngeal myotomy: treatment for the high-risk patient with a pharyngoesophageal (Zenker’s) diverticulum. Otolaryngol Head Neck Surg. 1989;100: 146–153. 20. Laccourreye O, Ménard M, Cauchois R, Huart J, Jouffre V, Brasnu D, Laccourreye H. Esophageal diverticulum: diverticulopexy versus diverticulectomy. Laryngoscope. 1994;104:889–892. 21. Fraczek M, Karwowski A, Krawczyk M, Paczkowski PM, Pawlak B, Pszenny C. Results of surgical treatment of cervical esophageal diverticula. Dis Esophagus. 1998;11:55–57. 22. Schmit PJ, Zuckerbraun L. Treatment of Zenker’s diverticula by cricopharyngeus myotomy under local anesthesia. Am Surg. 1992;58:710–716. 23. Hashiba K, de Paula AL, da Silva JG, Cappellanes CA, Moribe D, Castillo CF, Brasil HA. Endoscopic treatment of Zenker’s diverticulum. Gastrointest Endosc. 1999;49:93–97. 24. Sen P, Bhattacharyya AK. Endoscopic stapling of pharyngeal pouch. J Laryngol Otol. 2004;118:601–606. 25. Chang CY, Payyapilli RJ, Scher RL. Endoscopic staple diverticulostomy for Zenker’s diverticulum: review of literature and experience in 159 consecutive cases. Laryngoscope. 2003;113:957–965. 26. Hoffmann M, Scheunemann D, Rudert HH, Maune S. Zenker’s diverticulotomy with the carbon dioxide laser: perioperative management and long-term results. Ann Otol Rhinol Laryngol. 2003;112:202–205. 27. Nyrop M, Svendstrup F, Jørgensen KE. Endoscopic CO2 laser therapy of Zenker’s diverticulum - experience from 61 patients. Acta Otolaryngol Suppl. 2000; 543:232–234. 28. Kos MP, David EF, Mahieu HF. Endoscopic carbon dioxide laser Zenker’s diverticulotomy revisited. Ann Otol Rhinol Laryngol. 2009;118:512–518. 29. Fama AF, Moore EJ, Kasperbauer JL. Harmonic scalpel in the treatment of Zenker’s diverticulum. Laryngoscope. 2009;119:1265–1269. 30. Sharp DB, Newman JR, Magnuson JS. Endoscopic management of Zenker’s diverticulum: stapler assisted versus Harmonic Ace. Laryngoscope. 2009;119: 1906–1912. 31. Roth JA, Sigston E, Vallance N. Endoscopic stapling of pharyngeal pouch: a 10-year review of single versus multiple staple rows. Otolaryngol Head Neck Surg. 2009;140:245–249.
301 32. Bonavina L, Bona D, Abraham M, Saino G, Abate E. Long-term results of endosurgical and open surgical approach for Zenker diverticulum. World J Gastro enterol. 2007;13:2586–2589. 33. Visosky AM, Parke RB, Donovan DT. Endoscopic management of Zenker’s diverticulum: factors predictive of success or failure. Ann Otol Rhinol Laryngol. 2008;117:531–537. 34. Rabenstein T, May A, Michel J, Manner H, Pech O, Gossner L, Ell C. Argon plasma coagulation for flexible endoscopic Zenker’s diverticulotomy. Endoscopy. 2007;39:141–145. 35. Vogelsang A, Preiss C, Neuhaus H, Schumacher B. Endotherapy of Zenker’s diverticulum using the needle-knife technique: long-term follow-up. Endoscopy. 2007;39:131–136. 36. Costamagna G, Iacopini F, Tringali A, Marchese M, Spada C, Familiari P, Mutignani M, Bella A. Flexible endoscopic Zenker’s diverticulotomy: cap-assisted technique vs. diverticuloscope-assisted technique. Endoscopy. 2007;39:146–152. 37. van Eeden S, Lloyd RV, Tranter RM. Comparison of the endoscopic stapling technique with more established procedures for pharyngeal pouches: results and patient satisfaction survey. J Laryngol Otol. 1999; 113:237–240. 38. Smith SR, Genden EM, Urken ML. Endoscopic stapling technique for the treatment of Zenker’s diverticulum vs. standard open-neck technique. Arch Otolaryngol Head Neck Surg. 2002;128: 141–144. 39. Mirza S, Dutt SN, Minhas SS, Irving RM. A retrospective review of pharyngeal pouch surgery in 56 patients. Ann R Coll Surg Engl. 2002;84:247–251. 40. Zaninotto G, Narne S, Costantini M, Molena D, Cutrone C, Portale G, Costantino M, Rizzetto C, Basili U, Ancona E. Tailored approach to Zenker’s diverticula. Surg Endosc. 2003;17:129–133. 41. Safdar A, Curran A, Timon CV. Endoscopic stapling vs conventional methods of surgery for pharyngeal pouches: results, benefits and modifications. Ir Med J. 2004;97:75–76. 42. Zbären P, Schär P, Tschopp L, Becker M, Häusler R. Surgical treatment of Zenker’s diverticulum: transcutaneous diverticulectomy versus microendoscopic myotomy of the cricopharyngeal muscle with CO2 laser. Otolaryngol Head Neck Surg. 1999;121:482–487. 43. Chang CW, Burkey BB, Netterville JL, Courey MS, Garrett CG, Bayles SW. Carbon dioxide laser endoscopic diverticulotomy versus open diverticulectomy for Zenker’s diverticulum. Laryngoscope. 2004;114: 519–527. 44. Koay CB, Commins D, Bates GJ. The role of endoscopic stapling diverticulotomy in recurrent pharyngeal pouch. J Laryngol Otol. 1998;112:954–955.
35
Management of Distal Esophageal Pulsion Diverticula Andrew C. Chang
Esophageal diverticular disease is an uncommon entity for which appropriate treatment remains somewhat controversial. The acquired diverticulum is typically classified by its location (upper, middle, epiphrenic) and pathogenesis (traction, pulsion). Traction diverticula have been ascribed to inflammation and adhesions from periesophageal lymph nodes arising from, for example, pulmonary tuberculosis or histoplasmosis. Pulsion diverticula arise from a number of factors, most notably esophageal dysmotility, functional or mechanical distal esophageal obstruction, and focal weakness of the esophageal wall. While mid-esophageal diverticula can arise from traction forces exerted by inflammatory changes in adjacent tracheobronchial lymphatics, location alone does not rule out pulsion forces as the main etiology in developing an esophageal diverticulum.1–3 In a recent evaluation of patients diagnosed with mid- or distal esophageal diverticular disease by barium esophagogram, over 90% (10/11) of subjects with an isolated mid-esophageal diverticulum were found to have a motility disturbance, although most were found to have a non-specific disorder. Radiographic evidence of adjacent inflammation was identified in only 27% (3/11) of these patients. In contrast, a nonspecific motility disorder was identified in only 1/11 patients with a distal esophageal diverticulum.3
Summary of Evidence The literature on management of mid-to-distal esophageal pulsion diverticula is descriptive and consists of a number of case series. English language
publications were identified by Medline search, and peer-reviewed reports from 1990 to 2009 were evaluated for this article. The occurrence of distal esophageal (epiphrenic) pulsion diverticula is quite uncommon, such that controlled clinical trials evaluating various aspects of operative approach have not been undertaken. Most reports describe a heterogeneous population treated by a variety of surgical approaches and strategies for symptom palliation. Case reports without detailed description of preoperative findings or operative outcomes were excluded. For all of the studies described in this review, the overall consensus supports surgical intervention for patients, and results following non-operative management are limited.4 The quality of the evidence overall is low.
Indications for Operation It has been accepted generally that operation for epiphrenic diverticular disease should be undertaken only in patients with moderately or severely incapacitating symptoms such as dysphagia and regurgitation, and life-threatening complications, particularly aspiration.5 While there is near-unanimous agreement in the literature that patients with symptomatic disease should undergo operation, some also have advocated operation for patients with a large diverticulum, whether or not symptoms are present, on the basis that such patients are at risk for significant morbidity from occult or frank aspiration of retained contents in larger diverticula.6 While Belsey and others have found that the size of the diverticular pouch correlated poorly with symptoms,7–9 a recent study has suggested
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_35, © Springer-Verlag London Limited 2011
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such a correlation.10 In a retrospective review of a single institution’s radiographic files, 32 subjects were identified as having an epiphrenic diverticulum, of which 27 resided within 10 cm of the esophagogastric junction. These investigators found a significant positive correlation between patient symptoms and pouch size, with 100% (10/10) of patients with a diverticulum over 5 cm in diameter reporting symptoms, compared with 41% (7/17) of patients who had diverticula less than 5 cm. In addition, symptomatic patients were more likely to have preferential filling of the pouch rather than the distal esophagus during esophagogram, suggesting that this radiographic finding could be used to help identify clinically significant diverticula.10 In this retrospective study, however, no esophageal motility studies were available other than what was available as part of the radiographic evaluation. Moreover, the indications for obtaining an esophagogram were not provided in this study, leaving the question unaddressed of whether a large (>5 cm) diverticulum diagnosed incidentally should be treated operatively without further evidence of symptomatic or anatomic progression. A series of reports published by investigators at the Mayo Clinic1,8 comprises the largest cumulative experience with surgical management of esophageal pulsion diverticulum that also describes outcomes of subjects treated non-operatively. In these two reports, encompassing over 25 years of institutional experience, 116 patients diagnosed with an epiphrenic diverticulum were treated without operation, including 3 who were felt to be inoperable due to co-morbidities. Of the remaining 113 patients, 84 were felt to have minimal or no symptoms attributable to the diverticulum, with 36 of these 84 patients lost to followup. None of the remaining 48 of these 84 patients was noted to have progression of symptoms or pulmonary aspiration. In contrast, in 29 patients for whom operation had been recommended but refused, either symptom progression or pulmonary aspiration were reported in 15, 3 required repeat esophageal dilatation and 2 underwent operation for symptom progression. Mortality occurred in 5/116 patients, but all of the deaths occurred in the cohort of 29 patients who had refused operation, including two deaths related to aspiration and one due to esophageal carcinoma. Since 1992, investigators have reported outcomes for an additional 72 patients with mid-to-distal
esophageal pulsion diverticula treated without operation (Table 35.1), including 39 patients who were noted to have minimal to no symptoms, 14 who declined operation and 4 with significant co-morbidities and who were felt to be at risk prohibitive for operation. An additional patient died of aspiration pneumonia11 before the recommended operation could be performed. Reasons for non-operative management were not specified in 15 patients.12,13 In this group of 72 patients, deaths related to aspiration were reported in 2 patients and symptom progression occurred in 8 patients, none of whom had been categorized as being asymptomatic or having minimal symptoms. While these collated data suggest that patients with minimal or no symptoms related to distal esophageal pulsion diverticula can be managed without operation, such patients should be followed for the onset of symptoms particularly related to esophageal dysmotility and regurgitation.14 “Minimal” symptoms include dysphagia that can be managed by esophageal dilatation or reflux-related symptoms responsive to pharmacologic management or behavioral modification.
Need for Diverticulectomy An esophageal leak following operation for a pulsion diverticulum can be a devastating and potentially lethal complication. Of the 457 subjects reported in the studies reviewed, hospital mortality occurred in 17 (3.7%), with 9 deaths (53%) directly attributed to complications arising from an esophageal leak. Among the 42 patients reported as having an esophageal leak related to diverticulectomy or diverticulopexy, hospital mortality was 21%. Although some have advised that diverticulectomy be undertaken primarily only for patients with a history of undigested food retention, aspiration, chronic cough, evidence of mucosal inflammation14,15 or larger pouch size,16,17 of the 457 subjects reviewed, only 52 (11%) were treated without diverticulum resection (Table 35.2). Criteria for diverticulopexy, imbrication, or other non-resectional approaches have included pouch characteristics such as a wide neck and absence of any dependent portion.11,18 In addition, in some patients undergoing operation for a small but symptomatic diverticulum, exposure of the pouch and subsequent esophagomyotomy can
Non-operative Surgical evaluation Non-operative Non-operative Non-operative Surgical evaluation Non-operative Non-operative Non-operative Non-operative Non-operative
Approach
b
a
Metastatic prostate carcinoma Esophageal carcinoma c “Unrelated” cause-of-death
Fekete17 Hudspeth12 Altorki6 Castrucci15 Jordan14 Nehra11 Klaus13 Zaninotto5 Total
Debas1 Benacci8
Author
37 8 71 3 9 3 24 6 3 6 19 189
Sample size NA 60 83 NA NA NA 64 72 NA 26 46
Mean or median followup interval (mo)
Table 35.1. Outcomes following non-operative management.
13 0 71 3 NA 0 16 3 0 NA 17 123
Asymptomatic or “minimal”
1 1 NA 2 7
41
3
Prohibitive risk
3 1
1 36
Not followed or lost
43
3 7 2 2
24 5
Refused
0 0 2 0 0 1 1b 2c 11
3 2a
Deaths
0 0 1 0 0 1 0 0 4
2 0
Aspiration deaths
19
4 7 0/35 0 6 1 0/13 1
Symptom progression
6
1
1 0/13
0
4
Aspiration
2 3 10
3
Required dilation(s)
2 4
2
Operation scheduled
35. Management of Distal Esophageal Pulsion D iverticula 305
Open Open Open Open Open Open Open Open Open Open Open Open Open Open Openg Open Lap Lap Lap Lap Lap Lap Lap Lap Lap VATS VATS VATS Lap/VATS Lap/Thoracotomy
Allen30
N
24 17 18 19 27 16 17 33 9 27 19 18 35 44 7 23 11 3 10 6 13 7 15 13 10 5 1 7 2 1 457
77
3 1 2
1
3 4
16 8 5 5
7 1 5 5
62
4
2
1
1
1 10
1 4 4
w/ myotomy
21 4 1 5 12 3
Alone
7
4
3
10
2 (2 C-N)
3 (T)
1
2 2
w/ fundoplication
Diverticulectomy w/ myotomy, intact LES
b
a
Fundoplication type: A, Hill; B, Belsey; C-N, Collis-Nissen; D, Dor; N, Nissen; R-Y, Roux-en-Y; T, Toupet 210 subjects diagnosed over the study period c Nissen fundoplication d In two subjects resection not necessary after myotomy e Vagotomy, fundoplication, one patient each f Although evaluation of 21 patients reported, only 7 had undergone operation at the reporting institution g Includes two subjects converted to thoracotomy from laparoscopic myotomy and fundoplication
Total
Debas1b D’Ugo16 Fekete17 Streitz20 Altorki6 Benacci8 Hudspeth12 Castrucci15 Jordan14 Nehra11 Varghese23 Reznik21 Zaninotto5 D’Journo18 Rosati29 Neoral28 Klaus13 Fraiji32 Del Genio24 Tedesco33 Zaninotto5 Melman22 Fernando19 van der Peet31 Klaus13 Fernando19
Technique
Author
Table 35.2. Reviewed literature, operative details and outcomes.
233
5 (4 T, 1 N)
7 (7B) 4 13 33 (29 B, 4 N) 32 (B) 3 (1 B, 2 D) 13 (B) 11 (7 D, 4 T) 3 (3 D) 5 (4 T, 1 N) 6 (5 D, 1 T) 13 (13 N) 7 (7 D)f 12 (D) 12 (2 D, 10 T) 8 (8 T)
14 (B) 6 (4B, 1N, 1A)
6 12 (2B, 3 C-B, 7A) 3 (B) 10 (5D, 2T, 3B)
w/ myotomy/ fundoplicationa
4
2
2
1
1
Myotomy
37
10 (9 B, 1 R-Y)
4 1 (C-N)
6 (6D)
3d
9 (6 D, 3 B) 4
16
9
2 1
3
1
Esophagectomy
No resection Myotomy/ fundoplicationa
11
3c
3c
4c 2e
2c
Other
17 (4)
0 1 (5) 0 0 1 (5)
1 (4) 1 (6) 1 (6) 1 (5) 3 (11) 0 1 (6) 3 (9) 0 2 (7) 0 1 (6) 1 (3) 0 0 0 0 0 0 0 1 (8) 0
Mortality (%)
Leak (%)
42 (11)
1/13 (8) 4/20 (20) 1/5 (20) 1/6 (17) 4/20 (20)
5/24 (21) 1/16 (6) 1/17 (6) 1/8 (13) 2/23 (9) 1/16 (6) 1/14 (7) 6/29 (21) 1/9 (11) 2/17 (12) 1/15 (7) 1/13 (8) 2/34 (6) 1/35 (3) 4/22 (18) 0/13 1/11 (9) 1/3 (33) 1/6 (17) 0/6 3/13 (23) 0/7
306 A.C. Chang
307
35. Management of Distal Esophageal Pulsion D iverticula
result in “resorption” of the pouch, obviating the need for diverticulectomy.
Role for Esophagomyotomy The role for esophagomyotomy for treatment of an associated esophageal motility disorder remains the greatest point of controversy in the surgical management of a distal pulsion esophageal diverticulum. Several authors have attempted to spare the lower esophageal sphincter by limiting esophagomyotomy to abnormal areas of esophageal dysmotility, or by excluding myotomy completely if normal LES function is demonstrated.14,19,20 The rationale for limited esophagomyotomy arises from the premise that myotomy of a hypotonic or normally-functioning LES adds the additional risk of additional operative dissection and reflux-related complications, or potential distal obstruction incurred even by a partial fundoplication.5 Streitz et al.20 in particular recommended against esophagomyotomy crossing the LES if normal relaxation and amplitude of the LES were
documented by manometry, preferring instead to perform either LES-sparing esophagomyotomy or no myotomy at all. In their study, among six patients who had diverticulectomy without LES esophagomyotomy, one patient experienced a leak which was attributed to operative technique, whereas ten patients treated with diverticulectomy and LES-dividing esophagomyotomy had no leak. No recurrent diverticula were reported over a median follow-up period of 7 years. More recently, Fernando and colleagues19 reported a recurrent diverticulum arising in two of six patients treated by diverticulectomy alone or resection with LES-sparing esophagomyotomy. The purpose of esophagomyotomy is to relieve distal obstruction in order to limit postoperative leak, recurrent diverticulum or recurrent symptoms. Although preoperative esophageal manometry was attempted in most of the patients described in the reports reviewed for this article, fewer than 15% were reported as having normal esophageal function (Table 35.3). Notably, stationary esophageal manometry studies may not detect
Table 35.3. Preoperative findings. Author Debas1a D’Ugo16 Fekete17 Streitz20 Altorki6 Benacci8b Hudspeth12 Castrucci15 Rosati29 van der Peet31 Nehra11 Klaus13 Fraiji32 Del Genio24 Fernando19 Tedesco33 Varghese23 Reznik21 Zaninotto5 D’Journo18 Melman22 Total
Sample size
Hiatal hernia
DES
Achalasia
18 19 27 16 17 33 9 27 11 5 18 11 6 13 20 21 35 44 22 23 13 408
12 2 9
4 3 1 3 2 3
6 4 4 4 7 8
16
6
5
9
5
4 6 8 2
2 9 9 2 54
18 2 3 4 95
3 16 23 9 5 95
4 2
Manometric disorder NOS
Hypertensive LES/“nutcracker”
Normal manometry
2 8 9 1 2 7 6 7 1 2 2 5
3 3
3 1
1 1 1
3 3
2 7 5 12 8 2 5 93
Incomplete
Other
17 5 0 25 20 0
3
6 1 5
13 3 4 7 2 3
1
3 2
4 5 5 3 2 6 46
2 2 3
2 4
8 2 2 48
Normal (%)
1
15 70 40 0 38 0 0 11 11 15 0 36 9 15
6
DES diffuse esophageal spasm; LES lower esophageal sphincter; NOS not otherwise specificied a 210 subjects diagnosed over the study period b 112 subjects diagnosed over the study period, including 47 asymptomatic and 24 with minimal symptoms; Of 41 patients recommended operation, 8 either refused or were not surgical candidates
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intermittent esophageal dysmotility. When continuous ambulatory esophageal manometry was included as part of the diagnostic evaluation, all patients in one study were found to have esophageal dysmotility.11 Should an anatomic obstruction be identified, such as that arising from a previous fundoplication, leiomyoma or prosthetic device,21 then diverticulectomy without myotomy might be considered as long as the cause of distal mechanical obstruction is corrected. Other than in such uncommon clinical settings, routinely extending the myotomy onto the stomach prevents complications related to occult LES dysfunction not detectable by esophageal motility testing.11,22,23
Indications for Antireflux Procedure Once an esophagomyotomy is carried across the esophagogastric junction, most groups recommend also performing a partial fundoplication, either an anterior (Dor) or posterior (Toupet) procedure if a transabdominal/laparoscopic approach is used or a modified Belsey fundoplication if a transthoracic repair is undertaken.6,21,23 Of the reviewed studies, only 35/283 patients whose operative treatment included an antireflux operation and for whom sufficient operation details were provided had undergone Nissen fundoplication (Table 35.2). Notably, in one report of 13 patients undergoing laparoscopic diverticulectomy, esophagomyotomy and Nissen fundoplication,24 esophageal leak was reported in three subjects (23%). While a number of factors may contribute to esophageal leak following resection of a pulsion diverticulum, such an outcome highlights the potential risk conferred by complete fundoplication even with concomitant esophagomyotomy following a diverticulectomy. While there are no reports that directly compare the efficacy of a concomitant antireflux operation as part of the surgical treatment of esophageal pulsion diverticula, some insight regarding the issue of postoperative gastroesophageal reflux can be gleaned from recent surgical trials conducted in patients with achalasia. Several investigators have demonstrated the benefits of either a partial25 or complete26 fundoplication in the amelioration of postoperative reflux following esophagomyotomy. In a prospective, randomized
double-blind trial of 43 subjects with achalasia,25 the addition of an anterior partial fundoplication during esophagomyotomy significantly reduced gastroesophageal reflux from 48% (10/21) to 9% (2/23), assessed 6 months following operation. Similarly, in a prospective trial of 20 patients with achalasia randomized to esophagomyotomy with or without Nissen fundoplication, esophageal acid exposure and use of antireflux medication was reduced significantly after esophagomyotomy for achalasia with the inclusion of a Nissen fundoplication.26 In the treatment of achalasia, however, esophagomyotomy and complete fundoplication rather than a partial antireflux procedure appears to increase intermediate-term (at least 60 months) postoperative dysphagia as demonstrated in a prospective, randomized trial evaluating these two techniques.27
Operative Approach As minimal access approaches have been utilized more frequently in the treatment of a variety of esophageal diseases, there have been more reports regarding laparoscopic or thoracoscopic management of esophageal pulsion diverticula. The rates of complications, particularly esophageal leak and death, appear to be similar between open and minimal access approaches when the entire reviewed experience is analyzed (Table 35.2). In retrospective analysis of more recently reported series (Table 35.4), esophageal leak occurred in 12/89 (13%) patients following minimal access operations, compared with 4/120 (3%) patients following open transthoracic operations (p < 0.01). This significant difference likely reflects a number of variables, including patient selection and surgeon “learning curve.”24 Moreover, in some studies, a minimal access approach may have been selected due to patient comorbidity, making an open transthoracic operation less feasible.28 While minimal access approaches appear to be feasible for the treatment of distal esophageal pulsion diverticula, surgeon and institutional experience likely are important factors.19 Although laparoscopic strategies appear to be acceptable for the treatment of small-to-medium sized diverticula, larger diverticula or those that are more proximal should be addressed by transthoracic approaches,5 preferably from the left chest. Several
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35. Management of Distal Esophageal Pulsion D iverticula Table 35.4. Esophageal leak rates, recent literature. Author Minimal Access Rosati29 van der Peet31 Neoral28 Klaus13 Fraiji32 Del Genio24 Fernando19 Tedesco33 Melman22 Total Thoracotomy Nehra11 Varghese23 Reznik21 D’Journo18 Total
Sample size
Period studied
Esophageal leak
11 5 3 11 6 13 20 7 13 89
1994–2001 1993–1999
1 1 1 1 0 3 4 0 1 12
18 35 44 23 120
1987–1996 1976–2005 1987–2005 1977–2008
1996–2000 1999–2001 1994–2002 1997–2002 1994–2002 1999–2006
1 2 1 0 4
Leak (± SD) (%)
Operative mortality (%)
9 20 33 9 0 23 20 0 8 13 ± 11 11 6 6 2 0 3 ± 3*
0 0 0 0 0 1 (8) 1 (5) 0 0 2 1 (6%) 1 (3%) 0 0 2
*p < 0.01, chi-squared test
authors acknowledge that laparoscopic dissection of the upper aspect of a diverticulum neck can be more difficult,24 possibly contributing to suture line leakage.29
Summary and Recommendations Operative repair of an esophageal pulsion diverticulum reduces dysphagia, regurgitation and aspiration for patients with a symptomatic epiphrenic diverticulum (quality of evidence low). Given the reported rates of complications, particularly esophageal leak, regardless of surgical approach, a weak recommendation is made for restricting operative intervention for mid-to-distal esophageal diverticula to patients with symptoms attributable to the diverticulum, particularly aspiration or dysphagia, regardless of pouch size [recommendation grade 2C]. It can be difficult to discern whether patient symptoms arise from the diverticulum or from an underlying esophageal motility disorder. Esophagomyotomy carried across the gastric cardia helps reduce the possibility of distal obstruction and appears to be safe. A weak recommendation is made for carrying the myotomy across the gastric cardia, especially if a diverticulum is resected, in order both to address any documented or occult esophageal dysmotility and to
reduce the risk of developing a suture/staple line leak (recommendation grade 2C). The role of an antireflux operation following diverticulectomy and esophagomyotomy remains controversial. Recognizing that fundoplication may not always prevent clinically significant gastroesophageal reflux and that fundoplication potentially can also increase distal esophageal lumen pressure, in balance there appears to be an advantage in performing a fundoplication if the myotomy is carried across the gastric cardia, and performing a partial fundoplication in this setting appears to be safe (evidence quality low). A weak recommendation is made for performing a partial fundoplication in patients in whom the myotomy is extended across the gastric cardia (recommendation grade 2C).
A Personal View of the Data The surgical management of distal esophageal pulsion diverticular disease remains challenging and requires thorough patient assessment and preoperative evaluation. Clinical experience and judgment as well as careful reassessment of patient outcomes following operation remain important, as there remains no single definitive evidencebased treatment strategy. In contrast to operations for gastroesophageal reflux or achalasia, during
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which the risk for esophageal leak or other major perioperative complication is low, there remains considerable risk for suture leak following esophageal diverticulectomy, with associated morbidity or even death. As reported recently, this observer’s institutional experience with the treatment of distal esophageal pulsion diverticula reflects a strong preference for left posterolateral thoracotomy, although the majority of patients presented with pouches directed towards the right chest, in order to obtain complete exposure of the diverticular pouch. With this approach, diverticulectomy, long esophagomyotomy and a Belsey-type posterior fundoplication can be accomplished with minimal operative mortality or complication and with good-to-excellent functional outcomes.23
Operative repair of an esophageal pulsion diverticulum reduces dysphagia, regurgitation and aspiration for patients with a symptomatic epiphrenic diverticulum (quality of evidence low). A weak recommendation is made for restricting operative intervention for mid-todistal esophageal diverticula to patients with symptoms attributable to the diverticulum (recommendation grade 2C).
Esophagomyotomy carried across the gastric cardia helps reduce the possibility of distal obstruction and appears to be safe. A weak recommendation is made for carrying the myotomy across the gastric cardia, especially if a diverticulum is resected (recommendation grade 2C).
There appears to be an advantage in performing a fundoplication if the myotomy is carried across the gastric cardia, and performing a partial fundoplication in this setting is safe (evidence quality low). A weak recommendation is made for performing a partial fundoplication in patients in whom the myotomy is extended across the gastric cardia (recommendation grade 2C).
References 1. Debas HT, Payne WS, Cameron AJ, Carlson HC. Physiopathology of lower esophageal diverticulum and its implications for treatment. Surg Gynecol Obstet. 1980;151:593–600. 2. Evander A, Little AG, Ferguson MK, Skinner DB. Diverticula of the mid- and lower esophagus: pathogenesis and surgical management. World J Surg. 1986;10:820–828. 3. do Nascimento FA, Lemme EM, Costa MM. Esophageal diverticula: pathogenesis, clinical aspects, and natural history. Dysphagia. 2006;21:198–205. 4. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines. Chest. 2006;129:174–181. 5. Zaninotto G, Portale G, Costantini M, et al. Longterm outcome of operated and unoperated epiphrenic diverticula. J Gastrointest Surg. 2008;12:1485–1490. 6. Altorki NK, Sunagawa M, Skinner DB. Thoracic esophageal diverticula. Why is operation necessary? J Thorac Cardiovasc Surg. 1993;105:260–264. 7. Belsey R. Functional disease of the esophagus. J Thorac Cardiovasc Surg. 1966;52:164–188. 8. Benacci JC, Deschamps C, Trastek VF, Allen MS, Daly RC, Pairolero PC. Epiphrenic diverticulum: results of surgical treatment. Ann Thorac Surg. 1993;55:1109–1113. 9. Orringer MB. Epiphrenic diverticula: fact and fable. Ann Thorac Surg. 1993;55:1067–1068. 10. Fasano NC, Levine MS, Rubesin SE, Redfern RO, Laufer I. Epiphrenic diverticulum: clinical and radiographic findings in 27 patients. Dysphagia. 2003;18:9–15. 11. Nehra D, Lord RV, DeMeester TR, et al. Physiologic basis for the treatment of epiphrenic diverticulum. Ann Surg. 2002;235:346–354. 12. Hudspeth DA, Thorne MT, Conroy R, Pennell TC. Management of epiphrenic esophageal diverticula. A fifteen-year experience. Am Surg. 1993;59:40–42. 13. Klaus A, Hinder RA, Swain J, Achem SR. Management of epiphrenic diverticula. J Gastrointest Surg. 2003; 7:906–911. 14. Jordan PH Jr, Kinner BM. New look at epiphrenic diverticula. World J Surg. 1999;23:147–152. 15. Castrucci G, Porziella V, Granone PL, Picciocchi A. Tailored surgery for esophageal body diverticula. Eur J Cardiothorac Surg. 1998;14:380–387. 16. D’Ugo D, Cardillo G, Granone P, Coppola R, Margaritora S, Picciocchi A. Esophageal diverticula. Physiopathological basis for surgical management. Eur J Cardiothorac Surg. 1992;6:330–334. 17. Fekete F, Vonns C. Surgical management of esophageal thoracic diverticula. Hepatogastroenterology. 1992;39:97–99. 18. D’Journo XB, Ferraro P, Martin J, Chen LQ, Duranceau A. Lower oesophageal sphincter dysfunction is part of the functional abnormality in epiphrenic diverticulum. Br J Surg. 2009;96:892–900.
35. Management of Distal Esophageal Pulsion D iverticula 19. Fernando HC, Luketich JD, Samphire J, et al. Minimally invasive operation for esophageal diverticula. Ann Thorac Surg. 2005;80:2076–2080. 20. Streitz JM Jr, Glick ME, Ellis FH Jr. Selective use of myotomy for treatment of epiphrenic diverticula. Manometric and clinical analysis. Arch Surg. 1992; 127:585–587. 21. Reznik SI, Rice TW, Murthy SC, Mason DP, AppersonHansen C, Blackstone EH. Assessment of a patho physiology-directed treatment for symptomatic epiphrenic diverticulum. Dis Esophagus. 2007;20: 320–327. 22. Melman L, Quinlan J, Robertson B, et al. Esophageal manometric characteristics and outcomes for laparoscopic esophageal diverticulectomy, myotomy, and partial fundoplication for epiphrenic diverticula. Surg Endosc. 2009;23:1337–1341. 23. Varghese TK Jr, Marshall B, Chang AC, Pickens A, Lau CL, Orringer MB. Surgical treatment of epiphrenic diverticula: a 30-year experience. Ann Thorac Surg. 2007;84: 1801–1809. 24. del Genio A, Rossetti G, Maffetton V, et al. Lapa roscopic approach in the treatment of epiphrenic diverticula: long-term results. Surg Endosc. 2004;18: 741–745. 25. Richards WO, Torquati A, Holzman MD, et al. Heller myotomy versus Heller myotomy with Dor fundoplication for achalasia: a prospective randomized double-blind clinical trial. Ann Surg. 2004;240: 405–415.
311 26. Falkenback D, Johansson J, Oberg S, et al. Heller’s esophagomyotomy with or without a 360 degrees floppy Nissen fundoplication for achalasia. Longterm results from a prospective randomized study. Dis Esophagus. 2003;16:284–290. 27. Rebecchi F, Giaccone C, Farinella E, Campaci R, Morino M. Randomized controlled trial of laparoscopic Heller myotomy plus Dor fundoplication versus Nissen fundoplication for achalasia: long-term results. Ann Surg. 2008;248:1023–1030. 28. Neoral C, Aujesky R, Bohanes T, Klein J, Kral V. Laparoscopic transhiatal resection of epiphrenic diverticulum. Dis Esophagus. 2002;15:323–325. 29. Rosati R, Fumagalli U, Bona S, et al. Laparoscopic treatment of epiphrenic diverticula. J Laparoendosc Adv Surg Tech A. 2001;11:371–375. 30. Allen TH, Clagett OT. Changing concepts in the surgical treatment of pulsion diverticula of the lower esophagus. J Thorac Cardiovasc Surg. 1965;50:455–462. 31. van der Peet DL, Klinkenberg-Knol EC, Berends FJ, Cuesta MA. Epiphrenic diverticula: minimal invasive approach and repair in five patients. Dis Esophagus. 2001;14:60–62. 32. Fraiji E, Jr., Bloomston M, Carey L, et al. Laparoscopic management of symptomatic achalasia associated with epiphrenic diverticulum. Surg Endosc. 2003;17: 1600–1603. 33. Tedesco P, Fisichella PM, Way LW, Patti MG. Cause and treatment of epiphrenic diverticula. Am J Surg. 2005;190:891–894.
Part 4
Diaphragm
36
Giant Paraesophageal Hernia: Optimal Surgical Approach Kelly M. Galey and Thomas J. Watson
Introduction Surgery for sliding hiatal hernia and gastroesophageal reflux disease (GERD) is widely accepted and practiced. With the advent, refinement, and popularization of minimally invasive techniques, laparoscopic antireflux surgery has become the mainstay of operative therapy in most institutions where appropriate expertise exists. The outcomes following laparoscopic fundoplication, including symptom relief, quality of life indices, side effects, complications, objective control of GERD, and reintervention rates, have been well-elucidated and have generally been judged favorably when compared to medical therapy or open surgical alternatives. With our aging population, the prevalence of patients presenting with a giant paraesophageal hernia (PEH) and intrathoracic stomach appears to be increasing, though the data confirming this trend are sparse. The potentially serious or lifethreatening complications of such large hernias are well-described, including obstruction, ischemia, bleeding or ulceration, and underscore the importance of surgical correction in appropriate cases. On the other hand, such large hernias may pose a significant challenge to the surgeon given the complexities of the anatomy, the associated deficits in tissue integrity, foregut functional and structural derangements, and the comorbidities of this often elderly and frail cohort of patients. As a result, the decision for or against surgical intervention, as well as the technical details of the
various operative procedures and approaches, are the subject of much ongoing controversy and discussion. This chapter focuses on the treatment of giant PEH and the relevant issues of controversy. First, should all giant PEH be repaired at the time of initial identification? Second, is a transthoracic or transabdominal approach superior? Third, if a transabdominal approach is chosen, is laparotomy or laparoscopy preferred? Should all patients undergo an esophageal lengthening procedure in an effort to prevent recurrent hiatal herniation? Lastly, should mesh, either synthetic or a bioprosthetic, be placed at the hiatus for reinforcement? For the purposes of this discussion, a giant PEH is defined specifically as any hiatal hernia where at least 30% of the stomach is intrathoracic, including type II, type III, and type IV hernias. Type I hiatal hernias are defined as those where the esophagogastric junction (EGJ) has migrated above the diaphragmatic hiatus. Symptoms of such hernias are predominated by reflux and the indications for surgery follow the principles of reflux management. Pure type II hernias occur when the fundus of the stomach herniates alongside the esophagus while the EGJ remains intraabdominal and represent less than 10% of all hiatal hernias.1,2 Type III hernias have the EGJ migrated above the hiatus as well as a paraesophageal gastric component, while type IV hernias are those in which other intraabdominal organs have herniated into the chest alongside the esophagus and stomach.
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Controversies Should All Giant PEH Be Repaired at the Time of Diagnosis? Although the argument has lasted more than 50 years, whether all giant PEH should be repaired is still a major source of controversy. Experience shows that operative mortality in the acute setting is high (Table 36.1),3–9 especially in comparison to elective repair, providing a rationale to consider surgical intervention prior to the onset of complications. In their landmark study of 1,030 patients, Skinner and Belsey concluded that all patients diagnosed with Type II hernias should undergo operative repair, in that 6 of 21 (29%) minimally symptomatic patients treated conservatively by them eventually died of complications from the hernia.1 Of note, patients with type III hernias were included in the Type I group because of the presence of reflux, and outcomes following operative repair of these hernias were not further subclassified. Another classic study by Hill demonstrated a 30% risk of urgent or emergent surgical intervention in patients with a PEH followed without surgery. The mortality after emergent presentation was 20%.10 These two studies laid the foundation for the management paradigm of giant PEH for years, espousing the principle that all such hernias should be repaired at the time of diagnosis regardless of symptoms. Later, Treacy and Jamieson (1987)5 provided data supporting the concept that most type II, III, and IV hiatal hernias are symptomatic, in that over 85% of patients evaluated by them had symptoms attributable to the hernia. Secondly, they analyzed their experience in terms of mode of presentation. Of the patients presenting electively (n = 53), 45% (24) were initially managed conservatively and 54% (13) of these patients eventually went on to have surgery due to symptom recurrence. Importantly, none of these patients required urgent surgery. In their cohort of patients presenting acutely, however, the mortality was 36%, with one patient not reaching the operating room. Operative mortality for patients operated on urgently was 11% compared to 0% in the group undergoing elective repair.
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Luketich, et al. recently reported their experience at the University of Pittsburgh with 662 patients undergoing laparoscopic repair of giant PEH.11 Those undergoing elective operation had a postoperative mortality of 0.5%, while the mortality was 7.5% for those undergoing an urgent procedure. Stylopoulos and colleagues utilized a Markov Monte Carlo decision analytic model to project outcomes in a hypothetical cohort of patients presenting with asymptomatic or minimally symptomatic PEH and treated by either elective laparoscopic repair or watchful waiting.12 The input variables for the patients undergoing elective operation were estimated from a pooled analysis of 20 published studies, while those for watchful waiting and emergency surgery were derived from the 1997 HCUP-NIS database and the surgical literature published from 1964–2000. From these analyses, the estimated operative mortality following emergency surgery was 5.4%, while it was 1.4% following elective repair. The risk of an asymptomatic patient requiring emergency surgery was 1.1% annually, with an 18% lifetime risk for patients over 65. Also for patients over age 65, elective repair was associated with an average reduction of 0.13 quality-adjusted lifeyears. Watchful waiting was considered the optimal treatment strategy in 83% of patients and elective repair in the other 17%. Thus, watchful waiting was considered a reasonable alternative in patients with asymptomatic or minimally symptomatic PEH. Several observations are important in interpreting these and similar data. First, the results may not be translatable to patients with symptoms, who constitute the majority of those presenting with an intrathoracic stomach. Secondly, 18% represents a considerable lifetime risk of developing acute obstructive symptoms. Despite their advanced age, 85% of the study cohort was alive 5 years later and nearly 70% at 10 years. This attests to the longevity of even elderly patients and affirms the length of time patients will be susceptible to complications of a watchful waiting approach. Finally, the risks of emergent repair are considerable. Few population-based analyses have assessed the morbidity and mortality of either elective or emergent PEH repair. Poulose and colleagues
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36. Giant Paraesophageal Hernia: Optimal Surgical Approach Table 36.1. Open surgery for giant PEH.
Patients Ellis
3
51
20 Transabdominal Anatomic repair 22 Transabdominal repair with gastrostomy 6 Transabdominal repair with gastropexy 2 Transabdominal Nissen 1 Transthoracic anatomic repair Pearson4 430 Belsey Mark IV with Collis 54 with giant PEH Treacy5
Recurrence Ugent or Follow up assessment: Patients Perioperative Perioperative Study design/Quality emergent (%) (months) with assessment (%) Recurrence (%) complications (%) mortality (%) of evidence NR
Symptomatic: 84
9
25
2
Retrospective Case series
Low
NR
Range
Symptomatic: 90
0
19
0
NR
NR
Low Retrospective Case series
27
0
Low Retrospective Case series
Retrospective Case series
1–20 years
Allen6
54 (2/3 Transabdominal, 1/3 Transthoracic) 43 Fundoplication 11 Anatomic repair only 124
Altorki7
80 Transthoracic Collis-Nissen 19 Belsey Mark IV 13 Transthoracic Nissen 4 Transabdominal Nissen 2 Transabdominal Collis-Nissen 3 Esophagogastrectomy 3 Anatomic repair only 47
Geha8
28 Belsey Mark IV with Collis 18 Transthoracic Collis-Nissen 1 Transabdominal Collis-Nissen 100
Low9
75 Transabdominal anatomic repair with gastropexy 7 Transabdominal anatomic repair 18 Transthoracic anatomic repair 35 additionally had fundoplication 72 NR 69 Transabdominal Hill 3 Transabdominal Nissen
Mean 54
14
4
Symptomatic: NR Median 24 Median 60 Median 42
Symptomatic: 97
19 55 1
Low
30
Median 45
Symptomatic: 91
7
42
2
Retrospective Case series
Low
20
NR
NR
0
6
2
Retrospective Case series
Low
30
Radiographic or Endoscopic: 88
5
24
0
Prospective Case series Low
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assessed outcomes following surgery in 1,005 octogenarians with PEH using the 2005 Nationwide Inpatient Sample.13 Patients undergoing elective PEH repair had a 2.5% mortality and an average length of stay of 7 days, compared to a 15.7% mortality and an average length of stay of 14.3 days following emergent surgery. The authors concluded that elective repair of PEH regardless of symptoms may be warranted and may minimize mortality. Sihvo reported a population-based analysis from Finland.14 Of 563 patients undergoing either elective or emergent PEH repair over a 15 year period, mortality was 2.7%. The absolute number of patients undergoing emergent and elective repair was not reported although there were 12 deaths after emergent and 3 after elective repair. The authors estimated that 13% of deaths could have been prevented by routine elective surgery. More recently, a study from the University of Rochester utilizing the New York Statewide Planning and Research (SPARCS) database and analyzing New York state hospital admissions for giant PEH found that 53% of admissions for PEH were emergent.15 Patients who were admitted emergently for giant PEH were significantly older (68 vs. 62 years of age), had higher mortality (2.7% vs. 1.2%, p < 0.0001), longer length of stay (LOS) (7.3 vs. 5.0 days, p < 0.0001) and higher cost ($28,484 vs. $24,069, p < 0.001) compared to those admitted electively. Of note, only 34% of patients admitted emergently underwent surgical repair during their initial admission with an operative mortality of 5%. For patients admitted electively for surgery, the in-hospital mortality was 1%, significantly lower than patients undergoing emergent repair. Greater LOS and higher costs were also associated with emergent repairs. To summarize, while the risks of emergent surgery may have decreased over the past 50 years, elective surgery is clearly safer than urgent/emergent intervention for PEH. Most patients presenting with PEH experience symptoms, even though their elucidation may require some diligence and insight on the part of the treating physician, and should be considered for surgical correction. The decision to repair a PEH, however, should be tailored: an individual who is truly asymptomatic or minimally symptomatic, elderly or with multiple co-morbidities may reasonably be observed while
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a relatively healthy, young and significantly symptomatic person might best undergo elective surgical correction. Based on the available data, there is room for judgment as to whether operative intervention or expectant management is appropriate for a given individual presenting with a giant PEH.
Is a Transthoracic or Transabdominal Approach Superior? The optimal route for repair of PEH has been debated, with both transthoracic and transabdominal approaches possessing inherent advantages and disadvantages. In the majority of cases, however, it is likely that either route will yield good results and the surgeon should perform the operation he/she knows best. Arguments for a transthoracic repair are better ability to mobilize the esophagus proximally to the level of the aortic arch, improved identification and protection of the main vagal trunks while providing access to allow division of hilar branches, optimal visualization of the hernia sac to facilitate reduction, and the ability to palpate the esophagus to assess tension and possible shortening. Visualization is aided, particularly in obese individuals, compared to an open laparotomy. A thoracotomy, however, requires single lung ventilation and is associated with the potential for significant incisional pain and a higher chance of postoperative respiratory complications, both of which may be major concerns in this frequently elderly, frail and kyphotic cohort of patients. On the other hand, the open transabdominal approach generally provides adequate visualization and is generally less morbid. A gastropexy or pyloric drainage procedure can be more readily added, if needed, and additional abdominal pathology may be addressed as well. All of the available data regarding operative approach consist of retrospective, non-randomized case series; to date, no randomized trials have been performed. Skinner and Belsey’s results on 632 patients undergoing a transthoracic Belsey Mark IV procedure demonstrated 85% of patients to have a good to excellent symptomatic outcome with a hernia recurrence rate of 7%.1 Geha et al.8 found no symptomatic recurrences in 82 patients undergoing transabdominal repair of a paraesophageal hernia. Of 18 patients approached
36. Giant Paraesophageal Hernia: Optimal Surgical Approach
transthoracically, 2 patients required reoperation for gastric volvulus. Mortality for the entire cohort was 2%. A landmark study by Maziak et al.16 reported on 94 patients undergoing repair of giant PEH, 97% via a transthoracic approach. All underwent a fundoplication as part of the procedure and 80% underwent a gastroplasty. Two postoperative deaths (2%) occurred and two patients were lost to follow-up. Among the remaining 90 patients, the median follow-up was 72 months, with 93% reporting a good or excellent symptomatic result. Only two patients required reoperation. A more recent review by Patel et al.17 reported on 240 patients undergoing a transthoracic PEH repair. Early complications requiring reoperation occurred in 12 patients (5%) and the initial operative mortality was 1.7%. Satisfactory symptomatic results occurred in 86%, and routine postoperative barium esophagograms showed an intact repair in 71%. Only 4 patients (2%) required reoperation for symptomatic hernia recurrence.
319
open repair. Recurrence as demonstrated by esophagography was significantly greater, however, in the laparoscopic group (42% vs. 15%). The laparoscopic experience described by Wiechmann et al.31 contrasts with this report, in that the recurrence rate for hiatal herniation was only 6.8% as demonstrated by barium esophagography. Mortality was 1.9%. The largest experience to date with laparoscopic repair of giant PEH comes from the University of Pittsburgh.11 The laparoscopic procedure was successfully completed in 98.5% of 662 cases attempted with a postoperative mortality of 1.7%. Follow-up barium esophagograms were available in 67% (445/662) at least 3 months after surgery. Recurrent hiatal herniation was identified in 15.7% (70/445) at a median follow-up of 22 months. Most recurrences, however, were noted to be small and asymptomatic. Reoperation was required in only 3.2% of patients (21/662) at a median follow-up of 25 months.
Is Open Laparotomy or Laparoscopy Superior?
Is an Esophageal Lengthening Procedure Always Necessary?
Results of laparoscopic PEH repair have been extensively published, underscoring the vast utilization of this approach (Table 36.2).11,18–31 Early studies demonstrated much higher recurrence rates following laparoscopic repair than with an open approach, either transthoracic or transabdominal. The follow-up from series of patients undergoing open repair, however, frequently has not been as detailed in that recurrence often has been assessed in terms of symptoms without objective studies, such as flexible upper endoscopy or barium contrast esophagogram, to exclude asymptomatic recurrent hiatal herniation or other anatomic failure. A study by Hashemi et al.21 compared the three operative approaches and evaluated their results using symptom questionnaires (94% completed) and video esophagography (75% completed). With 27 patients in the open group and 27 in the laparoscopic group, no significant difference in risk factors for recurrence, morbidity or mortality was seen. There was, however, a significant decrease in length of stay in the laparoscopic group (3 vs. 9 days), and also a decrease in time to oral diet (1 vs. 3 days) compared to the group undergoing an
Esophageal body shortening is thought to be secondary to transmural fibrosis resulting from repetitive esophageal injury, such as from chronic GERD. A shortened esophagus can compromise the success of a fundoplication in that a recurrent hiatal hernia may result if the esophagus is placed under excessive tension. Attempts to predict the presence of acquired shortening of the esophageal body are generally based on the results of preoperative investigations. Risk factors for shortening include a large (>5 cm) or irreducible hiatal hernia in the upright position as assessed by barium esophagography or flexible upper endoscopy, a history of esophageal stricture, recurrent hiatal herniation after failed fundoplication, or long segment Barrett’s esophagus. A shortened esophagus can also be suspected on stationary esophageal manometry as evidenced by a lower than normal distance between the upper and lower esophageal sphincters. An important principle regarding esophageal shortening, however, is that the ultimate determination of its presence is made intraoperatively and is based on the inability to deliver an adequate length of esophagus into the abdomen to allow fundoplication without undue esophageal tension.
K.M. Galey and T.J. Watson
320 Table 36.2. Laparoscopic surgery for giant PEH. Patients in series
Follow up (months)
Symptomatic: NR
Recurrence (%)
Trus18
76
Swanstrom19
60 Laparoscopic Nissen 15 Laparoscopic, other 1 Converted to open 52
Mean 18
Symptomatic: 94
8
Hashemi20
48 Laparoscopic Nissen 4 Laparoscopic Toupet 54
Mean:
Radiographic 75
29
Dahlberg21
11 Transabdominal Nissen 2 Transabdominal partial fundoplication 14 Transthoracic Nissen 27 Laparoscopic Nissen 2 Converted to open 37
Terry22
35 Laparoscopic Nissen 2 Converted to open 118
Wiechmann23
105 Laparoscopic Nissen 10 Laparoscopic Toupet 3 Laparoscopic Dor 60
Leeder24
41 Laparoscopic Nissen 18 Laparoscopic Toupet 1 Laparoscopic Dor 6 Converted to open 53 All with gastropexy
Andujar25
9 Laparoscopic fundoplication with mesh 5 Laparoscopic crural repair with mesh 24 Laparoscopic fundoplication primary 13 Laparoscopic crural repair 2 Laparoscopic gastropexy 4 Converted to open 166 128 Laparoscopic Nissen 23 Laparoscopic Toupet 14 Laparoscopic gastropexy 1 Laparoscopic Dor 2 Converted to open
NR
Recurrence assessment: Patients with assessment (%)
7
Perioperative Study design quality complications (%) of evidence 17
Retrospective case Series Low
Open 34
Open: 15
12
Retrospective case Series Low Retrospective Comparative series
Open: 15 Low
Laparoscopic 17
Laparoscopic 42
Laparoscopic: 11
Median 15
Radiographic: 67
13
31
Mean 26
Symptomatic: 79
4
10
Radiographic: 73
(Includes patients without PEH) 7
Mean 19
Retrospective case Series Low Retrospective case Series Low
NR
Retrospective case Series Low
Mean 23
Symptomatic: 98
9
13
Retrospective Comparative series
Low
Mean 15
Radiographic: 72
25
8
Retrospective case Series Low
321
36. Giant Paraesophageal Hernia: Optimal Surgical Approach Table 36.2. (continued) Patients in series
Follow up (months)
Recurrence assessment: Patients with assessment (%)
Recurrence (%)
Mean 18
Radiographic: 100
35
Perioperative Study design quality complications (%) of evidence
Morino26
65
Grotenhuis27
14 Laparoscopic Nissen 37 Laparoscopic Nissen with mesh 14 Laparoscopic Collis-Nissen 210
Boushey28
84 Laparoscopic Nissen 110 Laparoscopic anterior partial fundoplication 1 Laparoscopic Toupet 19 Converted to open 58
Mean 6
Symptomatic: 100
17
26
Hazebroek29
56 Laparoscopic Nissen 2 Laparoscopic gastropexy 1 Converted to open 35
Mean 43
Symptomatic: 86
NR
9
Low Prospective case Series
Morris-Stiff30
35 Laparoscopic posterior partial fundoplication 1 Converted to open 23
Mean 6
Symptomatic: 100
0
0
Low Prospective case Series
Luketich11
11 Laparoscopic Toupet 12 Laparoscopic crural repair only 662
<1%
77 35
Retrospective case Series Low
0 Mean 43
Symptomatic: 95
NR
15
Retrospective case Series Low
Retrospective case Series
Low Median 25
Radiographic: 92
408 Laparoscopic Collis-Nissen 239 Laparoscopic Nissen 10 Converted to open 88 With mesh
The presence of shortening, therefore, is subject to interobserver variability regarding what constitutes “undue tension” and may be dependent upon operative approach. The esophagus should be mobilized as far proximally into the mediastinum as technically possible before the determination of shortening is made. A transthoracic approach may afford better mobilization than can be achieved transabdominally, either by laparoscopy or in an open fashion. Not only can the mid to upper thoracic esophagus be dissected by the transthoracic route, but also vagal branches to the pulmonary hilum can be divided. In addition, a thoracotomy allows the surgeon to palpate the esophagus
16
19
Retrospective case Series
Low
directly to assess tension. Laparoscopy may lead to an underestimation of esophageal shortening in that the diaphragm is elevated by the presence of a pneumoperitoneum, delivering more esophagus into the abdomen than may be present in the undistended state. Given the multiple factors that can influence the assessment of esophageal shortening, as well as the subjective nature of the determination, it is not surprising that different series report quite discrepant rates of its presence and the benefit of a lengthening procedure (Table 36.3).7,18,27,32–37 Even individual surgeons have modified their practice patterns over time relative to the usage of Collis
K.M. Galey and T.J. Watson
322 Table 36.3. Esophageal lengthening procedure in repair of giant PEH. Follow up average (months) range
Recurrence assessment: Patients with assessment (%)
Median 45
Symptomatic 91
Tsuboi35
47 28 Collis-Belsey 18 Transthoracic Collis-Nissen 1 Transabdominal Collis-Nissen 185 96 BelseyMark IV (no Collis) 89 Nissen-Collis 203 112 Laparoscopic Collis-Nissen 69 Laparoscopic Nissen 1 Laparoscopic Collis partial wrap 18 Laparoscopic other, no Collis 3 Conversions to open 68 56 Laparoscopic Collis-Nissen 12 Open Collis-Nissen 240 231 Transthoracic Collis-Nissen 8 Transthoracic Nissen 1 Belsey Mark IV (no Collis) 65 14 Laparoscopic Nissen 37 Laparoscopic Nissen with mesh 14 Laparoscopic Collis-Nissen 11 Laparoscopic Collis-Nissen
<3
Radiographic NR
Whitson36
61 Laparoscopic Collis-Nissen
Mean 18
Radiographic 69
Houghton37
232 113 Collis-Nissen 3 Collis-Toupet 115 Nissen 1 Toupet
Patients in series Altorki
7
Alexiou32
Pierre33
Lin34
Patel17
Morino26
Recurrence (%) 7
Study design quality of evidence Retrospective case Series Low
Median 132 Median 120 Median 18
Symptomatic 94 97 Symptomatic 75
Retrospective case Series 12 1 3
Low Retrospective case Series Low
Mean 30
Radiographic 37
16
Retrospective case Series
Mean 29
Radiographic 64
12
Low Retrospective case Series Low
Mean 18
Radiographic 100
35 77 35 0 9 Type III PEH pts, 33% 5
Retrospective case Series Low Retrospective case Series
Low Retrospective case Series Low Retrospective case Series
Median 14
Symptomatic 77
3
Median 17
74
6
Low
gastroplasty, as evidenced by the University of Pittsburgh experience where gastroplasty was added in 86% of early cases as compared to only 53% of later cases.11
Should the Hiatus Be Reinforced with Mesh? Given the relatively high rate of recurrent hiatal herniation reported after repair of PEH, particularly when performed via a laparoscopic approach, efforts have been made to modify the technical components of the procedure to improve long-term
outcomes. One such modification is the use of mesh, either synthetic or biologic, to reinforce the crural repair. Multiple single institution studies have reported rates of recurrent hiatal herniation with or without mesh and have demonstrated mixed results relative to the utility of mesh for this purpose (Table 36.4).27,38–46 A prospective randomized trial compared two techniques of laparoscopic repair of PEH, with or without the use of a biologic prosthesis to reinforce the crural closure.43 In this study, 9% of patients undergoing mesh reinforcement and 24% of patients without mesh had developed a
323
36. Giant Paraesophageal Hernia: Optimal Surgical Approach Table 36.4. Use of prosthetic material in the repair of giant PEH.
Study
Patients
Mesh material technique
Follow up (months)
Frantzides38
72
PTFE Keyhole
Champion39
36 Laparoscopic Nissen 36 Laparoscopic Nissen with mesh 52
Polypropylene
Mean 25
Radiographic 52
Granderath40
42 Laparoscopic Nissen with Onlay mesh 9 Tilley fundoplication with mesh 1 Collis gastroplasty with mesh 100 Polypropylene
Mean 12
Radiographic 100
Gryska41
50 Laparoscopic Nissen 50 Laparoscopic Nissen with mesh 135 Laparoscopic Nissen with mesh
Granderath42
40
Morino26
20 Laparoscopic Nissen 20 Laparoscopic Nissen with mesh 65
Oelschlager43
14 Laparoscopic Nissen 37 Laparoscopic Nissen with mesh 14 Laparoscopic Collis-Nissen 108
Ringley44
57 Laparoscopic Nissen 51 Laparoscopic Nissen with mesh 44
Fumagalli45
Hazebroek46
22 Laparoscopic Nissen 22 Laparoscopic Nissen with mesh 6 Laparoscopic Nissen with mesh 19 Laparoscopic Nissen with mesh
Mean 40
Recurrence assessment: Patients with assessment (%) Recurrence (%) Radiographic 100
Quality of evidence
Prospective Randomized
High
Prospective case Series
Low
Prospective Randomized
High
Prospective case Series
Low
Prospective Randomized
High
Retrospective case series
Low
Prospective Randomized
High
Prospective case Series
Low
22 0
Onlay
4
26 8
PTFE
Mean 64
Symptomatic 96
V Onlay Polypropylene
Mean 12
Radiographic 100
Onlay
PTFE, Polyprene, and mix
Study design
6
0 0 Mean 18
Radiographic 100
35 77 35 0
Biologic (Surgisis)
Mean 6
Radiographic 90
U Onlay
24 9
Biologic (AlloDerm) V Onlay
Mean 10
Biologic (Surgisis)
Mean 12
Radiographic 100
50
Prospective case Series
Low
U Onlay PTFE
Mean 31
Radiographic 72
29
Prospective case Series
Low
Crural Reinforcement
Radiographic 84 100 68
9 0
324
recurrent hiatal hernia as assessed by barium upper gastrointestinal examination at a follow-up of 6 months. The results support the notion that the failure rate of laparoscopic repair of such large hernias is high, even in experienced hands, though may be lessened by the use of biologic mesh reinforcement at the hiatus.
Conclusions The treatment of giant PEH remains a challenge for the surgeon, given the characteristics of the patient population presenting with this condition and both the anatomic and physiologic considerations inherent to operative repair. The decision regarding whether, and when, to operate may be difficult and may require considerable judgment on the part of the treating physician. Surgical repair has a good chance of providing symptomatic relief and is relatively safe (evidence quality low). We make a weak recommendation that operation should be considered at the time of diagnosis if the patient is experiencing significant symptoms relative to the hernia or associated GERD and if physiologically fit (recommendation grade 2C). A strategy of watchful waiting, however, seems appropriate for the minimally symptomatic individual, particularly if elderly or otherwise a poor surgical candidate based on comorbidities or performance status. The esophageal surgeon should be well-versed in a variety of operative approaches and techniques in that a “one size fits all” paradigm is not appropriate for management of all of the various presentations of this disease. The optimal approach and technical details of the procedure must consider patient, anatomic and physiologic factors and should be individualized. The experience of the surgeon obviously is important in determining which procedure ultimately is rendered. That being said, laparoscopy clearly is the most common approach chosen in most centers with the available expertise, given the inherent advantages of a minimally invasive procedure. While good results have been reported with transthoracic repair of PEH, a thoracotomy preferably is avoided given the often elderly or frail nature of this patient cohort as well as the
K.M. Galey and T.J. Watson
potential for prolonged post-thoracotomy pain. A transthoracic approach may be suitable in select cases, however, such as the morbidly obese individual, the reoperative setting, or when concomitant thoracic pathology needs to be addressed. While the available data suggests a possible higher recurrence rate with laparoscopy, the data are limited by the lack of prospective controlled trials, the non-contemporaneous nature of the comparative studies, as well as the thoroughness with which recurrences have been objectively assessed particularly after open repair. All approaches to surgical repair provide similar intermediate-term results and are safe (evidence quality low). We make a weak recommendation for a laparoscopic approach to repair of PEH in patients without specific complicating factors that would favor use of a thoracotomy approach (recommendation grade 2C). The need for an esophageal lengthening procedure is quite dependent upon surgeon judgment as well as the operative approach. Some experienced surgeons, the authors included, have diminished their rate of utilization of Collis gastroplasty over time as refinements in operative technique have been achieved. The addition of a gastroplasty is not without risk, given the need for creation of a staple line in the neo-esophagus and the fact that acid secreting mucosa is left at the level of, or above, a fundoplication. A Collis gastroplasty also requires some technical expertise; a poorly constructed neo-esophagus can lead to a poor functional outcome. Use of an esophageal lengthening procedure at the time of PEH repair is technically challenging and engenders an increased risk of complications, but is effective when true esophageal shortening is identified (evidence quality low). For these reasons, we make a weak recommendation against the routine use of a lengthening procedure in patients undergoing repair of a PEH (recommendation grade 2B). Given the potential for recurrent hiatal herniation after repair of PEH, reinforcing the hiatus with mesh, particularly if the crural fibers appear at all attenuated, reduces the likelihood of radiographic hernia recurrence and is safe (evidence quality moderate). We recommend the use of a biosynthetic mesh to reinforce the crural repair at the time of PEH repair (recommendation grade 1B).
325
36. Giant Paraesophageal Hernia: Optimal Surgical Approach
A Personal View of the Data Given the challenges in decision making and operative repair frequently encountered in patients presenting with a giant PEH, the importance of referral to an appropriate center cannot be overstated. The ultimate goal is to achieve a safe, effective and durable result with a low rate of complications, mortality and side effects. The authors’ bias is to avoid placement of synthetic mesh in the region of the hiatus, given numerous case reports of mesh erosion into the esophagus or stomach. Essential elements of PEH repair include sac reduction, hiatal closure, and fixation of the stomach in the abdomen, preferably via fundoplication. When circumstances make the performance of a fundic wrap risky (e.g. attenuated crural fibers, poor quality esophageal tissue, medically unstable patient during surgery), an alternative to gastric fixation is gastropexy with or without gastrostomy. The available data suggest that favorable outcomes can be achieved in the vast majority of patients when carefully selected and a well-qualified surgeon with suitable experience performs the operation. Elective surgical repair of PEH provides symptomatic relief and is relatively safe (evidence quality low). We make a weak recommendation for PEH repair at the time of diagnosis for symptomatic patients who are physiologically fit (recommendation grade 2C). All approaches to surgical repair provide similar intermediate-term results and are safe (evidence quality low). We make a weak recommendation for a laparoscopic approach for repair of PEH (recommendation grade 2C). Routine use of an esophageal lengthening procedure at the time of PEH repair is technically challenging and engenders an increased risk of complications (evidence quality low). We make a weak recommendation against the routine use of a lengthening procedure in patients undergoing repair of a PEH (recommendation grade 2B).
Reinforcing the hiatus with mesh reduces the likelihood of radiographic PEH recurrence and is safe (evidence quality moderate). We recommend the use of a biosynthetic mesh to reinforce the crural repair at the time of PEH repair (recommendation grade 1B).
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37
Diaphragm Pacing for Acute Respiratory Failure Raymond P. Onders
Introduction Mechanical ventilation is required in greater than 33% of patients in intensive care units (ICU) across the United States, and has increased at 4% per year over the past decade.1,2 Over 20% of ICU patients are on a ventilator greater than 7 days, with 40–60% of their ventilator time spent weaning after their initial acute event resolves. Over 100,000 tracheostomies are done in the United States yearly because of prolonged mechanical ventilation. Furthermore, mechanical ventilation results in a higher cost of treatment estimated at $16 billion annually with mechanically ventilated patients consuming a majority of ICU dollars.3–5 With an aging society, the incidence of patients requiring prolonged mechanical ventilation is increasing.6 There is an estimated 500 new high spinal cord injury (SCI) patients yearly in the United States who develop acute respiratory failure with subsequent need for long-term mechanical ventilation. The complexity of mechanical ventilation along with its negative attributes has been well documented. These include increased loss of sense of smell, difficulty with transfers, equipment malfunction, decreased mobility, embarrassment from noise, tubes and tracheostomy, increased respiratory infections, decreased survival rates and increased cost approaching $200,000 a year per patient.7,8 Complications of acute mechanical ventilation include barotrauma, ICU delirium, sleep disordered breathing, posterior lobe atelectasis and impaired hemodynamics, all of which are improved by maintaining a more natural negative
chest pressure.9–11 Ventilator associated pneumonia (VAP) is the leading source of infection in this patient population.12 Studies have documented a 1–3% risk per day of acquiring a VAP during the course of mechanical ventilation, with the greatest risk occurring in the first week. These untoward sequelae result in increased mechanical ventilator days, hospital days, and hospital costs, and have a documented mortality rate ranging from 20% to 50%.13,14 Ventilator induced diaphragm dysfunction (VIDD) occurs very rapidly and has been documented in numerous animal models.15–20 Dysfunc tion may be characterized as a de-conditioning of the diaphragm muscle fibers associated with disuse. Changes in the diaphragm’s contractile properties, either from myofibril shortening or from alterations in the electrochemical transport mechanisms, are also seen. There is a conversion of muscle fiber type from slow twitch oxidative to fast twitch glycolytic that occurs with periods of diaphragm disuse. All of these findings account for the weaning difficulty encountered following prolonged periods of mechanical ventilatory support. With recent human studies confirming that adverse diaphragm changes occur in as little as 12 h of mechanical ventilation, it is evident that measures to shorten the duration of mechanical ventilation would be advantageous.21,22 The concept of diaphragm stimulation can be traced back to the eighteenth century; however, Glenn was the first to use electrical stimulation of the phrenic nerve to achieve diaphragm movement to replace mechanical ventilation.23–25 In this phrenic nerve stimulation system and in subsequent
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European systems, an electrode is placed either cuffed around or next to the phrenic nerve to treat ventilator dependency from SCI or congenital central hypoventilation syndrome (CCHS). Although the phrenic nerve stimulation system has proven to be successful it is still rarely used. Direct phrenic nerve stimulation with a cuff electrode system is not an option for a temporary system to help diaphragm function for acute respiratory failure in ICU patients because of the possibility of phrenic nerve injury. Complete phrenic nerve transection or severe nerve injury would lead to permanent diaphragm paralysis with long term implications for patients. Because of this risk, direct intramuscular diaphragm pacing and transvenous phrenic nerve pacing have been developed that obviate any risk of phrenic nerve injury and could be used temporarily in acute respiratory failure. Laparoscopic implantation of a diaphragm pacing system (DP) has shown significant benefits in over 300 implanted patients worldwide in various research protocols designed to overcome the detrimental effects of positive pressure mechanical ventilation and facilitate weaning. The DP system is a percutaneous electrode system with an external impulse pulse generator that overcomes patients’ loss of control of the diaphragm so that diaphragm negative pressure ventilation occurs with stimulation. Laparoscopically, the diaphragm is mapped to identify the motor point, which is the area of the diaphragm that when stimulated causes the greatest contraction of the diaphragm. Electrodes are placed directly in the diaphragm. DP then conditions the diaphragm to overcome atrophy and allows weaning of patients from ventilators. The remainder of this chapter will focus on the available evidence of either direct intramuscular diaphragm pacing or transvenous phrenic nerve pacing for acute respiratory failure. These two methods will most likely have a role in future applications in the ICU highlighting direct diaphragm pacing because of the much greater clinical human data that is available. There have been numerous animal models as mentioned earlier concerning diaphragm pacing but this chapter will deal only with available human data. A literature search through the US National Library of Medicine Pubmed.gov was performed initially with the following key words: diaphragm pacing, phrenic nerve pacing, mechanical ventilation and
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diaphragm dysfunction. The references for the review articles or chapters where likewise searched for appropriate papers. Only English language abstracts or papers that deal with the human experience of intramuscular diaphragm pacing or temporary techniques for phrenic nerve pacing then compromised the review. Since this is a relatively new and small field there was no limitation based on year of research.
Diaphragm Pacing for Spinal Cord Injured Patients Patients with high cervical spinal cord injury immediately develop acute respiratory failure because of lack of control of intact phrenic lower motor neurons, phrenic nerves and diaphragms. DP bypasses the lack of control with direct stimulation of the diaphragm, producing a stimulated negative pressure tidal volume to allow for ventilation. The first implant was in 2000 and a series of several early case reports described the results.26–31 Although these could be classified as observational low quality studies, the DP system does have an on/off characteristic that allows assessment of its effect on a patient. When the device is turned off there is no ventilation, providing the equivalent of paired control information. In evaluating this technology it is important to note that it is difficult to do a randomized trial in this patient group because of the rare nature of the disease, with only 300–500 new patients a year in the United States. A prospective multi-center trial FDA approved trial, a total of 50 (37 male) patients were implanted with a DP system with failure only in the second patient due to a false positive phrenic nerve study.8,32,33 There was no peri-operative mortality. There were no operative time differences between study sites. The average age was 36 years (18–74) and time from injury to implantation 5.6 years (range 0.3–27). Ninety-eight percent of the patients had DP stimulated tidal volumes 15% above the basal metabolic needs for 4 or more continuous hours with 50% of patients utilizing DP for continuous 24 h ventilation. During the over 75 cumulative years of follow-up there have been three unrelated deaths (one sepsis, two cardiac). Age and time from injury directly affects conditioning time
37. Diaphragm Pacing for Acute Respiratory Failure
to achieve ventilation with DP. Younger patients and those with more recent injuries wean from the ventilator faster. In long term analysis of patient satisfaction (24 patients), over 60% reported less secretions, over 95% reported greater freedom and independence, 100% would recommend DP to others, and no patients have stopped utilization. This multi-center trial has shown that DP implantation is safe and easily reproducible; and can provide natural diaphragm ventilation. Most importantly is the patients’ perception of improved quality of life that DP provided. The quality of the evidence in this study is considered moderate, especially in an orphan disease with the small number of new patients annually. This quality of life improvement has been separately analyzed and reported by a group lead by Similowski.34 Basic pleasures such as olfaction and taste with and without pacing were analyzed and were significantly improved with pacing. This group also reported an improved ability to go outside of the home, participation in leisure activities and improved relationships with others. As experience has expanded there have been three additional publications that outline the success of DP in specific groups of patients. One report identified that in ten patients injured as children DP can successfully be implanted at adult ages with caution that severe scoliosis can delay the weaning process.7 Six centers have recently reported their combined results analyzing 20 patients with preexisting cardiac pacemakers demonstrating there were no cardiac or device to device interactions. In this report, over 70% of patients were able to utilize DP full time, 24 h day-1, with no mechanical ventilation.35 Finally, six children, with the smallest weighing only 15 kg, were successfully implanted demonstrates that DP is able to provide ventilation in the pediatric population.36
Diaphragm Pacing For Temporary Use in Acute Respiratory Failure The concept of temporary use of diaphragm pacing for acute respiratory failure has been outlined in the literature and even discussed during future applications of natural orifice transluminal endoscopic surgery.37,38 The laparoscopic DP system has
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reached a critical mass of knowledge and may be an appropriate first step for patients with acute respiratory failure. The human experience has slowly been growing but the quality of the evidence in all cases can only be considered low or very low with no randomized trials available to support its use. DP can convert mechanical ventilator induced Type IIb muscle fibers to transition to more functional Type I muscle fibers as shown in the SCI trials. In a case report of an SCI patient who had a phrenic nerve cuff electrode system for ventilation with only one side functional, it was concluded that functional electrical stimulation (FES) of only 30 min a day can suppress pathologic diaphragmatic attenuation and preserve diaphragm thickness and function.39 DP implanted during a high risk surgical procedure with an expected need for mechanical ventilation post-operatively could maintain the Type I fibers of the diaphragm and shorten the time for weaning once the acute episode is over. Several trauma centers that have been implanting for SCI injured patients early after their injury have used DP to allow rapid weaning from the ventilator and then subsequent wean from DP when the patient recovers from their spinal cord injury.36 These are isolated case reports with low quality of evidence because of non-randomization (could the patient have been weaned just as fast without DP?) but show the possibility of using DP as a temporary tool to help manage patients in the ICU. Positive pressure mechanical ventilation “pushes” air, in causing an increase in airway pressures, whereas natural breathing “pulls” air in when the diaphragm contracts. Barotrauma, which occurs in greater than 10% of mechanically ventilated patients, is associated with peak pressures of greater than 40 cm H2O and is associated with pneumothorax, interstitial emphysema, and pneumomediastinum. Various alveolar dysfunctions and injuries (including surfactant depletion) are associated with high pressures. According to Boyle’s Law (V = k/P), ventilator pressures will be decreased when negative pressure is added to the system to sustain the same volumes. Ten patients who were implanted with DP were evaluated to assess the effects when DP was used simultaneously with mechanical ventilation.32 DP utilization led to 19% increase in respiratory system compliance, a 21% decrease in peak airway pressure and a 24%
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increase in tidal volume. The problem with this report was that DP was synchronized to mechanical ventilation only for a brief period of time, and long term effects was not addressed. Mechanical ventilation detrimentally impacts the cardiovascular system from increased intrathoracic pressures leading to decreased filling pressure in the right ventricle and impeding systemic venous return. As a consequence, low cardiac output develops in accordance with Starling’s law. Significant improvements in hemodynamic function were observed in human clinical experiments using a transvenous technique to stimulate the phrenic nerve.40 Fourteen humans were studied with this technique in the postoperative period after cardiac operations and had temporary phrenic pacing for 2–6 h. Comparing values on standard ventilation and then ventilating with transvenous stimulation of the phrenic nerve, diaphragm pacing reduced pulmonary arterial pressure, right atrial pressure, left atrial pressure, total pulmonary vascular resistance and augmented cardiac output. The transvenous technique had significant practical limitations because of the difficulty in pacing both phrenic nerves with a single catheter, risk of cardiac dysrhythmias and predisposing patients to the risk of vascular thrombosis. Another recent report highlights the beneficial effects of diaphragm pacing on cardiac performance.41 In this series 35 patients who were undergoing open heart surgery had temporary left diaphragm electrodes placed. Diaphragm stimulation, if synchronized to the onset of ventricular contraction, improved left ventricle systolic function reproducibly for at least 1 h without causing symptoms. A limitation of this study is that they limited the stimulation to 1 h, but it does show that the direct diaphragm pacing electrodes can be placed during other chest operations similar to the way temporary cardiac pacing electrodes are presently placed. Mechanical ventilation preferentially ventilates the anterior lobes of the lung, which predisposes the patient to atelectasis and subsequent pneumonia in the posterior lobes. PEEP is presently used with mechanical ventilation to prevent alveolar collapse and decrease functional residual capacity (FRC). However, PEEP is limited by barotrauma and its effect on cardiac preload and cardiac output. Diaphragm pacing in synchronization with a ventilator could improve posterior lobe ventilation
and subsequently decrease atelectasis and ventilator associated pneumonia. This was studied in group of 12 patients who were undergoing general anesthesia by stimulating the right phrenic nerve in the neck through surface stimulation.42 The patients then underwent computed tomography (CT) scans and right lung atelectasis was compared to lung on the non-stimulated side. Phrenic nerve stimulation reduced the dependent atelectasis as visualized by CT scans. One can easily surmise that reducing atelectasis will reduce the risk of VAP. A recent study has shown that pacing, as opposed to mechanical ventilation, decreases annual hospitalizations for pulmonary infections from two per year to less than one per year when comparing SCI patients on standard mechanical ventilation to those utilizing a pacing system.43 Other recent publication on DP, although not comparing mechanical ventilation to DP, do report a decrease in the expected rate of pulmonary infections.35,36 A large prospective multi-center study addressing the ability of DP to delay the need for mechanical ventilation in 106 patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) has recently been completed with early results published.44 The results showed a significant improvement in survival, especially in those patients needing a simultaneous gastrostomy tube. Historically, gastrostomy tube placement alone in ALS patients has a 30 day mortality rate of 25%, while in the study simultaneous DP and gastrostomy tube placement the 30 day mortality was 0%. The most likely reason for this is the decrease in atelectasis and subsequent pneumonia, which supports future DP use in the ICU.
Summary of Evidence and Current Recommendations There has been an expanding knowledge and utilization of DP over the last several years. A growing number of peer reviewed prospective studies with that have recently been published or are in the process of being published will increase the quality of evidence and increase the strength of recommendations.A large prospective multi-center study of DP designed to determine whether DP can delay the need for mechanical ventilation in
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ALS patients involves a large battery of pulmonary tests and long term analysis of use of DP, and will help in designing and supporting trials for DP in acute respiratory failure. At present, DP should be offered to spinal cord injured patients who require mechanical ventilation if a rapid wean from the ventilator is not predicted. The subjective patient benefits for long term use of diaphragm pacing appear overwhelming in favor of DP: no patients who were using DP would choose to go back to mechanical ventilation. Diaphragm pacing provides improved quality of life including improved taste and smell, decreased pulmonary infections and decreased cost of care for spinal cord injured patients with acute respiratory failure, and appears to be safe (moderate quality evidence). We make a strong recommendation for diaphragm pacing for spinal cord injury patients who are ventilator dependent (recommendation grade 1B). In patients with acute respiratory failure from causes other than spinal cord injury, there is not enough evidence to recommend routine use of DP at this time although the concept is well founded in early experience. Well designed trials with peer-reviewed publication need to be done before a high level recommendation can be made. Temporary diaphragm pacing improves respiratory compliance, decreases atelectasis, decreases peak airway pressures, improves cardiac hemodynamics, maintains slow twitch Type 1 muscle fibers, decreases muscle atrophy, and appears to be safe when used in patients who are on mechanical ventilators from acute respiratory failure (very low quality of evidence). We make a weak recommendation for temporary diaphragm pacing system in non-spinal cord injured patients who have acute respiratory failure (recommendation grade 2C).
Diaphragm pacing improves quality of life and decreases complications for spinal cord injury patients with acute respiratory failure, and appears to be safe (moderate quality evidence). We make a strong recommendation for diaphragm pacing for spinal cord injury patients who are ventilator dependent (recommendation grade 1B).
Temporary diaphragm pacing improves diaphragm physiology and cardiopulmonary function and appears to be safe in patients on mechanical ventilation for acute respiratory failure (very low quality of evidence). We make a weak recommendation for temporary diaphragm pacing in non-spinal cord injury patients who have acute respiratory failure (recommendation grade 2C).
References 1. Dasta JF, McLaughlin TP, Mody SH, et al. Daily cost of an intensive care unit day: the contribution of mechanical ventilation. Crit Care Med. 2005;33: 1266–1271. 2. Hopkins RO, Spuhler VJ, Thomsen GE. Transforming ICU culture to facilitate early mobility. Crit Care Clin. 2007;23:81. 3. Zilberberg M, Wit M, Pirone J, Shore AF. Growth in adult prolonged acute mechanical ventilation: implications for healthcare delivery. Crit Care Med. 2008:36;1451–1455. 4. Cox CE, Carson SS, Govert JA, et al. An economic evaluation of prolonged mechanical ventilation. Crit Care Med. 2007;35:1918–1927. 5. Cox CE, Carson SS, Lindquist JH, et al. Differences in one-year health outcomes and resource utilization by definition of prolonged mechanical ventilation: a prospective cohort study. Crit Care Med. 2007;11:R9. 6. Carson SS, Cox CE, Holmes GM, et al. The changing epidemiology of mechanical ventilation: a population-based study. J Intensive Care Med. 2006;21: 173–182. 7. Onders RP, Elmo MJ, Ignagni AR. Diaphragm pacing stimulation system for tetraplegia in individuals injured during childhood or adolescence. J Spinal Cord Med. 2007;30:25–29. 8. Onders RP, Elmo M, Khansarinia S, Bowman B, Yee J, Road J, et al. Complete Worldwide experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients. Surg Endosc. 2009;23: 1433–1440. 9. Anzueto A, Frutos-Vivar F, Esteban A, et al. Incidence, risk factors and outcome of barotrauma in mechanically ventilated patients. Intensive Care Med. 2004;30: 612–619. 10. BittoT,MannionJD,StephensonLW,et al Pneumothorax during positive-pressure mechanical ventilation. J Thorac Cardiovasc Surg. 1985;89:585–591. 11. Walder B, Haase U, Rundshagen I. Sleep disturbances in critically ill patients. Anaesthesist. 2007;56:7–17. 12. Chastre J. Ventilator-associated pneumonia. Semin Respir Crit Care Med. 2006;27:1–3.
334 13. Cocanour CS, Ostrosky-Zeichner L, Peninger M, et al. Cost of a ventilator-associated pneumonia in a shock trauma intensive care unit. Surg Infect. 2005;6:65–72. 14. Warren DK, Shukla SJ, Olsen MA, et al. Outcome and attributable cost of ventilator-associated pneumonia among intensive care unit patients in a suburban medical center. Crit Care Med. 2003;31:1312–1317. 15. Vassilakopoulos T, Petrof BJ. Ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med. 2004;169:336–341. 16. Anzueto A, Peters JI, Tobin MJ, de los Santos M, Seidenfield, J, Moore G, Cox WJ, Coalsons J. Effects of prolonged controlled mechanical ventilation on diaphragmatic function in healthy adult baboons. Crit Care Med. 1997;25:1187–1190. 17. Gayan-Ramirez G, Decramer M. Effects of mechanical ventilation on diaphragm function and biology. Eur Respir J. 2002;20:1579–1586. 18. Capdevila X, Lopez S, Bernard N, et al. Effects of controlled mechanical ventilation on respiratory muscle contractile properties in rabbits. Intensive Care Med. 2003;29:103–110. 19. Radell PJ, Remahl S, Nichols DG, et al. Effects of prolonged mechanical ventilation and inactivity on piglet diaphragm function. Intensive Care Med. 2002;28: 358–364. 20. Vijayan K, Thompson JL, Norenberg KM, Fitts RH, Riley DA. Fiber type susceptibility to eccentric contraction-induced damage of hind-limb unloaded rat AL muscles. J Appl Physiol. 2001;90:770–776. 21. Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;35:1327–1335. 22. Powers S, Kavazis A, Levine S. Prolonged mechanical ventilation alters diaphragmatic structure and function. Crit Care Med. 2009;37:347–353. 23. Glenn WW. Diaphragm pacing: present status. Pacing-Clin-Electrophysiol. 1978;1:357–370. 24. Glenn WW, Hogan JF, Loke JSO, Ciesielski TE, Phelps ML, Rowedder R. Ventilatory support by pacing of the conditioned diaphragm. N Engl J Med. 1984;310: 1150–1155. 25. Glenn WW, Phelps ML, Elefteriades JA, Dentz B, Hogan JF. Twenty years of experience in phrenic nerve stimulation to pace the diaphragm. Pacing Clin Electrophysiol. 1986;9:780–784. 26. Dimarco AF,Onders RP,Kowalski KE,Miller ME,Ferek S, Mortimer JT. Phrenic nerve pacing in a tetraplegic patient via intramuscular diaphragm electrodes. Am J Respir Crit Care Med. 2002;166:1604–1606. 27. Onders RP, Aiyar H, Mortimer JT. Characterization of the human diaphragm muscle with respect to the phrenic nerve motor points for diaphragmatic pacing. Am Surgeon. 2004;70:241–247. 28. Onders RP, Ignagni AI, Aiyer H, Mortimer JT. Mapping the phrenic nerve motor point: the key to a successful laparoscopic diaphragm pacing system in the first human series. Surgery. 2004;136;819–826.
R.P. Onders 29. Onders R, DiMarco A, Ignagni A, Mortimer J. The learning curve for investigational surgery: lessons learned from laparoscopic diaphragm pacing for chronic ventilator dependence. Surg Endosc. 2005;9:633–637. 30. DiMarco AF, Onders RP, Ignangi AI, Kowalski KE, Stephan S, Mortimer JT. Phrenic nerve pacing via intramuscular diaphragm electrodes in tetraplegic subjects. Chest. 2005;127;671–677. 31. Dimarco AF, Onders RP, Ignagni A, Kowolski KE. Inspiratory muscle pacing in spinal cord injury: case report and clinical commentary. J Spinal Cord Med. 2006;29:95–108. 32. Onders RP. Phrenic nerve and diaphragm motor pacing. In: GA Patterson, FG Pearson, JD Cooper, J Deslauriers, TW Rice, JD Luketich, AEMR Lerut, eds. Pearson’s Thoracic and Esophageal Surgery, 3rd ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2008: 1145–1457. 33. Onders RP. Diaphragm and gastric pacing. In Soper NJ, Swanstrom LL, Eubanks WS, eds. Mastery of Endoscopic and Laparoscopic Surgery, 3rd ed. Philadelphia PA: Lippincot Williams & Wilkins; 2009: 597–606. 34. Adler D, Gonzalez-Bermejo J, Duguet A, Demoule A, Le Pimpec-Barthes F, Hurbault A, et al. Diaphragm pacing restores olfaction in tetraplegia. Eur Respir J. 2009;34:365–370. 35. Onders RP, Khansarinia S, Weiser T, Chin C, Hungness E, Soper N, DeHoyos A, Cole T, Ducko C. Multi-center analysis of cardiac interactions with diaphragm pacing for ventilation: positive implications for ventilation in intensive care unit. Submitted to Surgery. 36. Onders RP, Ponsky TA, Elmo MJ, Lidsky K, Barksdale E. First reported experience with intramuscular diaphragm pacing in replacing positive pressure mechanical ventilators in children. Submitted to J Pediatr Surg. 37. Pavlovic D, Wendt M. Diaphragm pacing during prolonged mechanical ventilation of the lungs could prevent respiratory muscle fatigue. Medical Hypotheses. 2003;60:398–403. 38. Onders R, McGee M, Marks J, Chak A, Schilz R, Rosen M, Ignagni A, Faulx A, Elmo MJ, Schmoisch S, Ponsky J. Diaphragm pacing with natural orifice transluminal endoscopic surgery (NOTES): potential for difficult to wean intensive care unit (ICU) patients. Surg Endosc. 2007;21;475–479. 39. Ayas NT, McCool FD, Gore R, Lieberman SL, Brown R. Prevention of human diaphragm atrophy with short periods of electrical stimulation. Am J Respir Crit Care Med. 1999;159:2018–2020. 40. Onders Ishii, K, Kurosawa, K, Koyanagi H, Nakano K, Sakakibara N, Sato I, Noshior M, Ohsawa M. Effects of bilateral transvenous diaphragm pacing on hemodynamic function in patients after cardiac operations. Experimental and clinical study. J Thorac Cardiovasc Surg. 1990;100:108–114.
37. Diaphragm Pacing for Acute Respiratory Failure 41. Roos M, Kobza R, Jamshide P, Bauer P, Resink T, Schlaepfer R, Stulz P, Zuber M, Erne P. Improved cardiac performance through pacing-induced diaphragmatic stimulation: a novel electrophysiologic approach in hear failure management? Europace. 2009;11:191–199. 42. Hedenstierna G, Tokics L, Lunquiest H, Andersson T, Standberg A, Bismar B. Phrenic nerve stimulation during halothane anesthesia: effects on atelectasis. Anesthesiology. 1994;80:751–760.
335 43. Hirschfield S, Exner G, Luukkaala T, Baer GA. Mechanic ventilation or phrenic nerve stimulation for treatment of spinal cord-induced respiratory insufficiency. Spinal Cord. 2008:46:738–742. 44. Onders RP, Calin AM, Elmo MJ, Sivashankaran S, Katirji B, Schilz R. Amyotrophic lateral sclerosis: the Midwestern surgical experience with diaphragm pacing stimulation system shows that general anesthesia can be safely performed. Am J Surg. 2009;197: 386–390.
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Synthetic Reinforcement of Diaphragm Closure for Large Hiatal Hernia Repair Brant K. Oelschlager and Eelco B. Wassenaar
Introduction Repair of large hiatal hernias has traditionally been a difficult procedure and is associated with significant morbidity and mortality. Repair via thoracotomy or laparotomy leads to morbidity and mortality rates of 20% and 2% respectively.1,2 With more modern perioperative care and minimally invasive techniques, morbidity and mortality have improved. Perhaps for this reason and also the increased life expectancy of patients, attention has focused more on longer term outcomes, including recurrence. Large hiatal hernia repairs are very difficult due to the large defects and attenuated muscle, and defy the surgical principles of closing muscle without tension. Not surprisingly, the recurrence rate is high. While it has been debated that there may be some differences in recurrence rates based on the approach used, the recurrence rate generally seems to be between 8% and 27%.3–5 As with most other types of hernias, mesh has been used to reduce tension on repairs of large hiatal hernias by many authors.6,7 However, there remain concerns regarding using mesh at the hiatus, which is a dynamic structure, including mesh erosion, ulceration, stricture and dysphagia.6,8–10 As a result, when biomaterials were developed for abdominal wall hernia repair, it stimulated interest in their use for hiatal hernia repair. Because these meshes serve only as a temporary matrix permitting the patient’s own tissue to replace the biomaterial, the problems that were seen with synthetic meshes would hopefully be avoided while providing a decrease in recurrence rates.
The goal of this chapter is to provide recommendations on the following issues: (1) is there a benefit in using mesh in the repair of large hiatal hernias; and (2) if mesh is used should it be prosthetic/nonabsorbable mesh or biologic/absorbable mesh?
Literature Search To assess the evidence for use of mesh at the hiatus during large hiatal hernia repair, a PubMed search was performed for studies comparing repairs with and without mesh. The following [MeSH] terms were used for the search: “surgical mesh” and “hiatal hernia”. This search produced 100 results. The abstracts were reviewed to determine eligible studies. Only abstracts after 1995 were considered that had full-text versions available and were published in peer-reviewed journals in the English language.The abstracts of the references in the most recent subject review11 were also assessed to find suitable studies. Through the related articles link in PubMed other abstracts were assessed. All manuscripts describing randomized trials (n = 6) and retrospective studies which compared series with and without mesh (n = 12) were analyzed. When multiple studies were described from the same institution the manuscript describing the longest follow-up was used.12,13 Studies describing antireflux operations without a focus on large hiatal hernia repair were excluded.6,14,15 Studies with less than 40 patients (empirically chosen) were excluded.16–18 The study of Leeder et al. was excluded because their technique of hernia
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_38, © Springer-Verlag London Limited 2011
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reduction and sac excision was changed during the study.19 A total of three randomized trials20–22 and six retrospective studies23–28 were found to be suitable for the analysis. To assess the evidence when using mesh, either non-absorbable or absorbable mesh, the following [MeSH] terms were used in the search: “hernia, hiatal” and “surgical mesh”. There were 101 results. No series comparing prosthetic with biologic mesh were found. Only case reports were found as well as one collection of case reports29 reporting on mesh-related complications such as erosion or stricture. Four animal studies on the use of prosthetic or biologic mesh were found in the literature.30–33 The outcome variables that will be evaluated are recurrence, both radiographic and symptomatic, and complication rates, focusing on dysphagia and mesh-related complications.
Randomized Clinical Trials Frantzides et al. published the first randomized trial comparing simple cruroplasty and mesh repair using polytetrafluoroethylene (PTFE) mesh in 2002 (Table 38.1).22 They included patients with a hiatal defect of at least 8 cm, as determined by upper GI study (UGI) and esophagogastroduodenoscopy (EGD), and randomized them to either cruroplasty with interrupted nonabsorbable sutures (n = 36) or cruroplasty with onlay repair using PTFE cut in a keyhole fashion (n = 36). All patients underwent a fairly standard surgical approach, which included reduction of
the hernia sac and mobilization of 4–5 cm of esophagus into the abdomen, and all patients received a 3 cm long 360° Nissen fundoplication created over a bougie. Patients were then followed at intervals of 1 week, 2 weeks, 1 month, 3 months and then yearly. At 3 months an EGD and UGI were performed in all patients; a repeated UGI was done thereafter every 6 months. All patients were followed for at least 1 year and some were followed up to 6 years (median 30 months). They found eight recurrences (22%) in the simple cruroplasty group, all of which were symptomatic (though details on symptoms were not included) and occurred in the first 6 months post-operatively. No recurrences were found in the mesh group, which was a statistically significant difference (p < 0.006). During follow-up neither erosions nor strictures of the esophagus were seen, nor was post-operative dysphagia mentioned. Granderath et al. published a randomized trial comparing simple sutured crural closure (n = 50) versus posterior 1 × 3 cm polypropylene onlay mesh prosthesis (n = 50) in 100 patients who underwent Nissen fundoplication for gastroesophageal reflux disease.21 While not exclusively a study of large hiatal hernias, approximately 40% of their patients had a hiatal hernia > 5 cm determined by EGD and UGI, and the study is therefore is germane to our analysis. During follow-up, manometry, pH-testing and an UGI was performed at 1 year and symptoms were evaluated at 1 week, 6 weeks, 3 months and 1 year post-operatively. An upper endoscopy was performed at 6 weeks or when symptoms were present. Patients in both groups had good control of GERD, with one patient in each group having recurrent heartburn
Table 38.1. Study results on mesh versus no mesh. Author Frantzides et al. Oelschlager et al.20 Granderath et al.21 Ringley et al.23 Muller-Stich et al.24 Jacobs et al.25 Zaninotto et al.26 Soricelli et al.27 Total 22
N without mesh
N with mesh
36 57 50 22 39 93 19 37 353
36 51 50 22 17 127 35 138 476
Follow-up (months)
Mesh material
30 6 12 7 52 38 71 89
PTFE Surgisis® Polypropylene Alloderm® Multiple prosthetic Surgisis® Goretex®/polypropylene Polypropylene
Recurrences without mesh (%)
Recurrences with mesh (%)
8 (22) 12 (24) 13 (26) 2 (9) 7 (19) 12 (20) 8 (23) 7 (19) 69 (20)
0 4 (9) 4 (8) 0 0 3 (3.3) 3 (4.2) 3 (2.2) 17 (3.6)
Study type RCT RCT RCT Retrospective Retrospective Retrospective Retrospective Retrospective
Outcomes of studies on mesh versus no mesh in large hiatal hernia repairs. RCT: randomized controlled trial; Retrospective: retrospective case-comparison study
38. Synthetic Reinforcement of Diaphragm Closure for Large Hiatal Hernia Repair
symptoms and 46 in each group having a normal pH test at 1-year. The recurrence rate (intrathoracic wrap migration) as evaluated by UGI was 8% in the mesh group versus 26% in the non-mesh group (p < 0.001). The dysphagia rate was significantly higher in the mesh group at 1 week (16% vs. 4%), 6 weeks (12% vs. 4%) and at 3 months (12% vs. 4%), but was the same at 1 year postoperatively (4% vs. 4%). There was no mention of mesh erosion or strictures. We also performed a randomized trial comparing mesh and simple cruroplasty, ours being a multi-centered trial for paraesophageal hernias.20 This multicenter study included patients with a paraesophageal hernia with a fixed gastric component and greater than 5 cm hiatal opening on UGI. The patients were randomized to cruroplasty using interrupted suture alone (n = 57) or to cruroplasty with the addition of a biologic mesh (4-ply Surgisis®, 7 × 10 cm, Cook Surgical, Bloomington, IN) cut in a U configuration (n = 51). Before cruroplasty was performed the hernia sac was reduced and excised. A Nissen fundoplication was created between 2.5 and 3 cm in length over a bougie. During follow-up an upper GI series was performed 6 months post-operatively showing a significant difference in recurrence with 12 patients (24%) in the primary repair group versus 4 patients (9%) in the mesh repair group having a recurrent hiatal hernia ³ 2 cm. There was no difference in dysphagia, other GI symptoms, or quality of life (QoL, using SF-36) between groups post-operatively. Patients with a recurrent hernia had significantly worse symptoms and quality of life than patients without a recurrent hernia. There were no mesh erosions or strictures during follow-up.
Retrospective Cohort Studies Ringley et al. performed a sequential cohort study of laparoscopic paraesophageal hernia repairs comparing primary repair (22 consecutive, historical patients) to 22 patients with biologic mesh (4 × 8 cm piece of human acellular dermal matrix: Alloderm®; LifeCell Co, Branchburg, NJ) (Table 38.1).23 The mean hiatal hernia was 5.7 cm as measured on UGI, and all patients received a Nissen
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fundoplication. Follow-up consisted of UGI or EGD at 6 months. All patients in the primary suture group underwent evaluation after a mean of 9.5 month and 15 (68%) patients in the mesh group underwent evaluation at mean follow-up of 6.7 months. There were two recurrences (9%) in the suture group versus none in the mesh group. One patient in each group reported dysphagia during follow-up that responded well to esophageal dilation. During their short follow-up they did not find any erosions or strictures. Müller-Stich et al. reported on a cohort of 56 patients, for whom Prolene* or VYPRO I (Ethicon, Spreitenbach, Switzerland) was placed in a butterfly configuration behind the esophagus on top of the cruroplasty in 16 patients with particularly large hernias early in the series and regularly in the last 11 patients.24 In the other 40 patients a primary cruroplasty was performed without mesh reinforcement. A fundoplication was performed in all patients. Follow-up was done using a standardized questionnaire (95% of patients) and UGI (93%) after a mean of 52 months. A hernia recurrence was found in seven patients (four symptomatic) with primary closure (19%) and in none when mesh was used (p = 0.085). The authors report similar symptomatic outcomes between the two groups, although dysphagia was not one of the queried symptoms. There were no meshrelated complications. Jacobs et al. published their results on 220 patients who had a fundoplication in conjunction with posterior cruroplasty, with the primary indication being GERD and not large hiatal hernia.25 From 1997 to 2000 they operated 93 patients with primary closure of the crura, and thereafter until 2005 they added Surgisis® mesh in 127 patients with posterior cruroplasty. All patients received a Nissen fundoplication unless they had pre-operative poor peristalsis or dysphagia. Follow-up was done at 1 week, 1 month and on an as needed basis thereafter. For this study patients were contacted for symptomatic follow-up and asked to submit to an EGD or UGI. Mean follow-up was 3.2 years for 72% of mesh patients and 3.8 years for 63% of primary closure patients. Twenty percent of patients in the mesh group reported symptoms at followup versus 44% in the no mesh group. Recurrence was confirmed in 3 patients in the mesh group and in 12 patients in the no mesh group. Transient
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dysphagia was reported in 79% of patients in the mesh group. It generally resolved within 4 weeks, although chronic dysphagia requiring treatment was reported by four patients (4.3%). It is unclear how many, if any, patients in the mesh group had chronic dysphagia. There were no mesh erosions or infections. Zaninotto et al. report their results of treatment for large type III hiatal hernia repairs in 54 patients.26 Hernias were assessed on barium swallow study and defined as more than one-third of the stomach in the chest. In 35 patients a composite Gore-tex® mesh (WL Gore, Flagstaff, AZ) was hand sewn to a polypropylene 7.5 cm square mesh. It was precut in a keyhole fashion with a 3 cm hole and fixed around the esophagus with tacks to the right and left pillars of the crus. The other 19 patients had primary closure of the crus only without mesh reinforcement. In all patients either a Nissen or a Toupet fundoplication was performed. Median symptomatic follow-up was 71 months. Of the 54 patients, 12 were symptomatic after surgery (22.2%). One patient with mesh had severe dysphagia 2 days after surgery that prompted a reoperation with removal of mesh. After a median of 64 months in the primary closure group and 33 months in the mesh group, a barium swallow and or endoscopy was obtained in 98% of patients. They found recurrence of the hernia in 8 of 19 patients without mesh and 3 of 35 patients with mesh (p = 0.01). Of note is that all three recurrences in the mesh group occurred in the first 8 months post-operatively. All 11 recurrences also were symptomatic. They report one case of mesh erosion into the esophagus requiring esophagectomy after reoperation for recurrence at which time they added Prolene mesh. Soricelli et al. published the most recent article with a series of operations for gastro-esophageal reflux disease.27 From 1992 to 2007 their technique evolved from primary closure to hiatoplasty with polypropylene mesh. They report the results of 175 patients with a hiatal hernia ³ 3 cm as measured on UGI. Of these, 37 patients had primary closure and 138 had either bridging mesh or hiatoplasty with mesh. All patients received a Nissen fundoplication. They report a follow-up on 87% of patients with a mean of 105 months (longer for non-mesh patients). Follow-up after more than 1 year involved UGI or EGD when symptoms were present. The recurrence rate for non-mesh patients
B.K. Oelschlager and E.B. Wassenaar
(7, 19%) was higher than when mesh was used (3, 2.2%). They report 14 patients (4.7%) with postoperative dysphagia but do not mention if these patients had mesh repair or not. One patient had a mesh-related complication that required mesh removal. Kamolz et al. reported 200 patients (100 with polypropylene mesh and 100 without mesh) who underwent laparoscopic Nissen fundoplication for GERD.28 Although the patients did not have hiatal hernias per se, they compared the two groups specifically on dysphagia, so we believe the findings are relevant for this chapter. After a follow-up of at least 1 year they found that during the first 3 months after the operation there were more patients with mesh complaining of dysphagia than patients without mesh. One year post-operatively this difference had disappeared, and 95% of patients in both arms had no complaints of dysphagia at all. Quality of life (as measured by the gastrointestinal quality of life index) improved after the operation in both arms and to the same extent.
Case Series and Animal Studies on Mesh-Related Complications Stadlhuber et al. report 28 cases from six different institutions of mesh complications after prosthetic reinforcement of hiatal closure.29 Most complications occurred after implantation of prosthetic mesh (21 patients; polypropylene, PTFE, DualMesh®), six were after use of biologic mesh (Alloderm®, Surgisis®) and one was after use of first prosthetic mesh and later biologic mesh. They did not report the time between the operation and the complication. Twenty-three patients were reoperated with mesh removal and ten of these had (partial) esophagectomy/gastrectomy or a cervical esophagostomy. All resections were in patients with prosthetic mesh and the esophagostomy was in the patient with both a prosthetic mesh (Goretex®) and a biologic mesh (Surgisis®). They conclude that complications related to synthetic mesh placement at the hiatus are more common than reported. Desai et al. show their results of Surgisis® mesh used in six dogs with paraesophageal hernia repair.30 There were no erosions or stricture formation, and native ingrowth was noted 1 year after
38. Synthetic Reinforcement of Diaphragm Closure for Large Hiatal Hernia Repair
placement of the biomaterial. Jansen et al. used a polypropylene mesh and a composite mesh and placed it circularly around the esophagus in 20 rabbits.31 After 3 months the rabbits were sacrificed at which time the meshes had shrunk 50%. A large number of rabbits had mesh migration into the esophageal wall, more so with polypropylene mesh use than with composite mesh use. Smith et al. presented their results of DualMesh use in 13 pigs at the hiatus.32 The pigs were sacrificed 3 or 28 weeks after placement. All grafts were completely encapsulated and no erosions were seen. MüllerStich et al. used a circular polypropylene mesh at the hiatus in pigs.33 After 6 weeks there was no tendency toward stenosis, migration or erosion.
Summary and Recommendations The goal of this chapter is to provide a recommendation on whether to use mesh during large hiatal hernia repair. There are three randomized trials that have addressed this issue, although each has its weaknesses. The primary weakness is the relatively short follow-up in each study. The study of Frantzides et al. had very complete follow-up for at least 1 year, but thereafter it was not very clear how the patients were evaluated.22 All recurrences (only in the non-mesh group) were seen the first 6 months and none thereafter. Considering the nature of the disease, we would expect more recurrences to follow during longer follow-up. Also, there was no regimented method of following symptoms and potential side-effects such as dysphagia. The study of Granderath et al. had complete follow-up at 1 year but not longer, and was not specifically focused on large hiatal hernias.21 They did, however, study symptoms and control of reflux by pH monitoring, and found a higher short-term incidence of dysphagia in the patients with mesh. Our study provided detailed analysis of symptoms, QoL, as well as anatomic recurrence in a multicenter study. In addition, it is the only randomized trial to study the utility of biologic mesh. However, it was limited by its very short follow-up, so it cannot answer the question of durability of these repairs.20 When radiographic recurrence rate was analyzed as a primary outcome measure there was clear evidence in all three randomized trials, as
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well as in the cohort studies, that the use of mesh led to lower recurrence rates than primary closure without mesh. The question of whether this lower radiographic recurrence rate also led to lower symptomatic recurrence rate is more difficult to answer. We did not find a difference in symptomatic outcome between our two groups, even though all the patients in the study with recurrent hiatal hernias had slightly worse clinical symptoms and QOL outcomes.20 Frantzides et al. mentioned that all radiographic recurrences also were symptomatic (though the details of these symptoms were not clear).22 Granderath et al. reported no difference in symptomatic control of reflux symptoms at 1-year follow-up.21 Müller-Stich et al. compared both groups on radiographic as well as symptomatic outcomes, and did find a difference both in radiographic as well as symptomatic recurrence rate.24 This difference did not reach statistical significance, and the difference was smaller in the symptomatic recurrence rate. Follow-up in the mesh group was also significantly shorter in this study than in the non-mesh group. It is also difficult to come to strong conclusions on the basis of these studies, as the randomized trials used three different types of mesh, three different sizes of mesh, and three different methods of placement (key-hole vs. onlay vs. U-shape). Whether the use of synthetic mesh leads to more post-operative dysphagia than simple cruroplasty is not clear. Only Kamolz et al. and Granderath et al. (both from the same research group) reported specifically on this subject and they both showed an increase in dysphagia the first months after surgery, which disappears at 12 months post-operatively.21,28 However, they used only a very small strip of mesh posteriorly away from the esophagus. Only two studies mentioned a mesh complication, although one did lead to an esophagectomy.26,27 Most studies had relatively short follow-up, so they were not well suited to study mesh complications. It seems that mesh complications are so rare that the only reports are case reports or a single report in retrospective series. Stadlhuber et al. published the only series of mesh complications at the hiatus, collected from multiple institutions throughout the United States with substantial experience and referral centers for hiatal hernia related complications.29 Our trial using biologic mesh did not reveal clear mesh-related
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complications, though the follow-up admittedly is limited. The exception is the Stadlhuber study that had 28 potentially mesh-related problems. This study was not very convincing, in our analysis, in showing that these complications were actually related to the use of biologic mesh.29 Considering the results of Stadlhuber’s study, the animal studies and the limited information in the randomized trials and retrospective cohort studies on mesh complications, it is not possible to provide a strong and clear recommendation on what type of mesh to use. There are disadvantages of using prosthetic mesh around the hiatus, considering the severe complications that have been reported and that were seen in animal studies, but the incidence of these complications is not known. The use of biologic mesh appears to be safer based on only short-term data, since these materials are usually absorbed within 6 months and therefore should not lead to late complications. There is high quality evidence that use of mesh during large hiatal hernia repair prevents shortterm radiographic recurrence. Synthetic mesh may do a better job at preventing these recurrences than biologic mesh, but probably at some cost, as there is moderate quality evidence that use of synthetic mesh leads to an increase in dysphagia rate, the severity and persistence of which likely depend on the type of mesh and its configuration when placed. The use of synthetic mesh can lead to severe, life-threatening complications, but there is no information about the rate of erosion or stricture after its use. The use of mesh in diaphragm closure leads to lower short-term radiographic recurrence rates for patients undergoing repair of a large hiatal hernia and appears to be safe (evidence quality high). Long-term results regarding recurrence and safety are unknown. We make a weak recommendation for use of mesh when repairing large hiatal hernias (recommendation grade 2A). It is likely that synthetic mesh is superior to biologic mesh with regards to preventing recurrences. However, the frequency of mesh-related complications, such as dysphagia, stricture, and erosions, is not known, it too seems more frequent with synthetic mesh (evidence quality low). The data are not sufficient to permit a recommendation regarding the ideal type of mesh to use in repair of large hiatal hernia. The decision comes down to
weighing the benefit of preventing recurrences and the trade-off of potential complications. Unfortunately, at this time, the decision must be made in the face of unclear comparative data on the relative risks/benefits of each mesh type.
Personal View Large hiatal hernia repair is a very difficult operation which, in our opinion, should be performed by surgeons with substantial experience in performing complex hiatal hernia repairs. We prefer the laparoscopic approach due to its low morbidity and mortality rates34 and advantages of easy access and excellent visualization of the hiatus and mediastinum.35 The repair should incorporate at least the following steps: 1. Return of the herniated contents into the abdominal cavity in a tension-free manner with adequate esophageal length 2. Circumferential excision of the hernia sac 3. Re-approximation of the diaphragmatic hiatus, and 4. Anchoring the stomach in the subdiaphragmatic position35 Due to the compelling evidence of lower recurrence rates, we believe mesh is a necessary component of large hiatal hernia repair. We share the concerns that the use of synthetic mesh could lead to complications such as erosion or stricture of the esophagus. Biologic mesh theoretically has the advantage of being a bioscaffold leading to a strong repair by the patient’s own tissue,36 and because the mesh is replaced by native tissue it is likely that there is less chance of mesh erosion or stricture. Therefore, we currently employ the use of biologic mesh in our large hiatal hernia repairs. The use of mesh in diaphragm closure leads to lower short-term radiographic recurrence rates for patients undergoing repair of a large hiatal hernia and appears to be safe (evidence quality high). Long-term results regarding recurrence and safety are unknown. We make a weak recommendation for use of mesh when repairing large hiatal hernias (recommendation grade 2A).
38. Synthetic Reinforcement of Diaphragm Closure for Large Hiatal Hernia Repair
References 1. Ellis FHJ, Crozier RE, Shea JA. Paraesophageal hiatus hernia. Arch Surg. 1986;121:416–420. 2. Pearson FG, Cooper JD, Ilves R, Todd TR, Jamieson WR. Massive hiatal hernia with incarceration: a report of 53 cases. Ann Thorac Surg. 1983;35:45–51. 3. Patel HJ, Tan BB, Yee J, Orringer MB, Iannettoni MD. A 25-year experience with open primary transthoracic repair of paraesophageal hiatal hernia. J Thorac Cardiovasc Surg. 2004;127:843–849. 4. Low DE, Unger T. Open repair of paraesophageal hernia: reassessment of subjective and objective outcomes. Ann Thorac Surg. 2005;80:287–294. 5. Mehta S, Boddy A, Rhodes M. Review of outcome after laparoscopic paraesophageal hiatal hernia repair. Surg Laparosc Endosc Percutan Tech. 2006; 16:301–306. 6. Granderath FA, Schweiger UM, Kamolz T, Pasiut M, Haas CF, Pointner R. Laparoscopic antireflux surgery with routine mesh-hiatoplasty in the treatment of gastroesophageal reflux disease. J Gastrointest Surg. 2002;6:347–353. 7. Carlson MA, Frantzides CT. Laparoscopic repair of paraesophageal hiatal hernia. Surg Endosc. 2004; 18:1821. 8. Paul MG, DeRosa RP, Petrucci PE, Palmer ML, Danovitch SH. Laparoscopic tension-free repair of large paraesophageal hernias. Surg Endosc. 1997;11: 303–307. 9. Trus TL, Bax T, Richardson WS, Branum GD, Mauren SJ, Swanstrom LL, Hunter JG. Complications of laparoscopic paraesophageal hernia repair.J Gastrointest Surg. 1997;1:221–228. 10. Kelty CJ, Falk GL. Mesh repairs in hiatal surgery. The case against mesh repairs in hiatal surgery. Ann R Coll Surg Engl. 2007;89:479–481. 11. Davis SSJ. Current controversies in paraesophageal hernia repair. Surg Clin North Am. 2008;88:959–978. 12. Carlson MA, Richards CG, Frantzides CT. Laparoscopic prosthetic reinforcement of hiatal herniorrhaphy. Dig Surg. 1999;16:407–410. 13. Frantzides CT, Richards CG, Carlson MA. Laparo scopic repair of large hiatal hernia with polytetrafluoroethylene. Surg Endosc. 1999;13:906–908. 14. Basso N, De Leo A, Genco A, Rosato P, Rea S, Spaziani E, Primavera A. 360 degrees laparoscopic fundoplication with tension-free hiatoplasty in the treatment of symptomatic gastroesophageal reflux disease. Surg Endosc. 2000;14:164–169. 15. Turkcapar A, Kepenekci I, Mahmoud H, Tuzuner A. Laparoscopic fundoplication with prosthetic hiatal closure. World J Surg. 2007;31:2169–2176. 16. Keidar A, Szold A. Laparoscopic repair of paraesophageal hernia with selective use of mesh. Surg Laparosc Endosc Percutan Tech. 2003;13:149–154. 17. Athanasakis H, Tzortzinis A, Tsiaoussis J, Vassilakis JS, Xynos E. Laparoscopic repair of paraesophageal hernia. Endoscopy. 2001;33:590–594.
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18. Hui TT, Thoman DS, Spyrou M, Phillips EH. Mesh crural repair of large paraesophageal hiatal hernias. Am Surg. 2001;67:1170–1174. 19. Leeder PC, Smith G, Dehn TC. Laparoscopic management of large paraesophageal hiatal hernia. Surg Endosc. 2003;17:1372–1375. 20. Oelschlager BK, Pellegrini CA, Hunter J, Soper N, Brunt M, Sheppard B, Jobe B, Polissar N, Mitsumori L, Nelson J, Swanstrom L. Biologic prosthesis reduces recurrence after laparoscopic paraesophageal hernia repair: a multicenter, prospective, randomized trial. Ann Surg. 2006;244:481–490. 21. Granderath FA, Schweiger UM, Kamolz T, Asche KU, Pointner R. Laparoscopic Nissen fundoplication with prosthetic hiatal closure reduces postoperative intrathoracic wrap herniation: preliminary results of a prospective randomized functional and clinical study. Arch Surg. 2005;140:40–48. 22. Frantzides CT, Madan AK, Carlson MA, Stavropoulos GP. A prospective, randomized trial of laparoscopic polytetrafluoroethylene (PTFE) patch repair vs simple cruroplasty for large hiatal hernia. Arch Surg. 2002;137:649–652. 23. Ringley CD, Bochkarev V, Ahmed SI, Vitamvas ML, Oleynikov D. Laparoscopic hiatal hernia repair with human acellular dermal matrix patch: our initial experience. Am J Surg. 2006;192:767–772. 24. Muller-Stich BP, Holzinger F, Kapp T, Klaiber C. Laparoscopic hiatal hernia repair: long-term outcome with the focus on the influence of mesh reinforcement. Surg Endosc. 2006;20:380–384. 25. Jacobs M, Gomez E, Plasencia G, Lopez-Penalver C, Lujan H, Velarde D, Jessee T. Use of surgisis mesh in laparoscopic repair of hiatal hernias. Surg Laparosc Endosc Percutan Tech. 2007;17:365–368. 26. Zaninotto G, Portale G, Costantini M, Fiamingo P, Rampado S, Guirroli E, Nicoletti L, Ancona E. Objective follow-up after laparoscopic repair of large type III hiatal hernia. Assessment of safety and durability. World J Surg. 2007;31:2177–2183. 27. Soricelli E, Basso N, Genco A, Cipriano M. Longterm results of hiatal hernia mesh repair and antireflux laparoscopic surgery. Surg Endosc. 2009; Apr 3 [Epub ahead of print]. 28. Kamolz T, Granderath FA, Bammer T, Pasiut M, Pointner R. Dysphagia and quality of life after laparoscopic Nissen fundoplication in patients with and without prosthetic reinforcement of the hiatal crura. Surg Endosc. 2002;16:572–577. 29. Stadlhuber RJ, Sherif AE, Mittal SK, Fitzgibbons RJJ, Michael Brunt L, Hunter JG, Demeester TR, Swanstrom LL, Daniel Smith C, Filipi CJ. Mesh complications after prosthetic reinforcement of hiatal closure: a 28-case series. Surg Endosc. 2009;23:1219–1226. 30. Desai KM, Diaz S, Dorward IG, Winslow ER, La Regina MC, Halpin V, Soper NJ. Histologic results 1 year after bioprosthetic repair of paraesophageal hernia in a canine model. Surg Endosc. 2006;20: 1693–1697.
344 31. Jansen M, Otto J, Jansen PL, Anurov M, Titkova S, Willis S, Rosch R, Ottinger A, Schumpelick V. Mesh migration into the esophageal wall after mesh hiatoplasty: comparison of two alloplastic materials. Surg Endosc. 2007;21:2298–2303. 32. Smith GS, Hazebroek EJ, Eckstein R, Berry H, Smith WM, Isaacson JR, Falk GL, Martin CJ. Evaluation of DualMesh for repair of large hiatus hernia in a porcine model. Surg Endosc. 2008;22:1625–1631. 33. Muller-Stich BP, Mehrabi A, Kenngott HG, Fonouni H, Reiter MA, Kuttymoratov G, Nickel F, Linke GR, Wolf I,Koninger J,Gutt CN. Is a circular polypropylene
B.K. Oelschlager and E.B. Wassenaar mesh appropriate for application at the esophageal hiatus? Results from an experimental study in a porcine model. Surg Endosc. 2009;23:1372–1378. 34. Draaisma WA, Gooszen HG, Tournoij E, Broeders IA. Controversies in paraesophageal hernia repair: a review of literature. Surg Endosc. 2005;19:1300–1308. 35. Wolf PS, Oelschlager BK. Laparoscopic paraesophageal hernia repair. Adv Surg. 2007;41:199–210. 36. Badylak S, Kokini K, Tullius B, Simmons-Byrd A, Morff R. Morphologic study of small intestinal submucosa as a body wall repair device. J Surg Res. 2002;103:190–202.
Part 5 Airway
39
Stents for Benign Airway Obstruction Jon O. Wee and Scott J. Swanson
Traechobronchial stents are used to treat a variety of disorders that lead to airway obstruction. These include neoplasms, strictures that occur following intubation or surgery, trauma, extrinsic compres sion, tracheal malacia, infection, or even some inflammatory disorders such as polychondritis. Most stents are placed for palliation from malig nancy such as lung cancer1 with good restoration of airway patency. Use of tracheal stents in the nonmalignant setting, however, has not been as successful in providing long term benefit. Most reports note excellent short term results in improv ing respiratory physiology.2 However, several stud ies also note high complication and reoperative rates that reach 45% or higher.3–6 Reported com plications include obstructing granulation tissue, stent migration, metal fatigue and fracture, mucous plugging, halitosis, and recurrent infec tions. An ideal stent would be able to establish a patent airway, have limited migration, produce minimal granulation tissue formation, be easily deployable, and be economically affordable. Sev eral stents have been produced to try to address all of these needs but none encompasses all of these characteristics. In addition, there are no randomized, double blind studies that truly evaluate the efficacy of var ious stents. Most articles are retrospective analyses or case reports. Most are small in number with less than 50 patients evaluated over a period of years. Stent technology is also evolving such that once enough experience is developed in one type of stent, a newer version is released that promises better outcomes and less complications, but with out substantive data supporting these promises.
In this article we will address the evidence for use of two classes of stents, the traditional silicone stents and the self expanding metal stents, in man aging benign airway problems. Literature is taken from the fields of thoracic surgery, radiology, pul monary, and otolaryngology. The vast majority of evidence is of low quality as it is all retrospective observational data.
Literature Search A Pubmed search was performed using keywords [benign] AND [tracheal stent]. Articles were lim ited to the English language. Single case reports were excluded. Most of the articles reviewed were within the past 10 years.
Silicone Stents Silicone stent have a long history with a variety of tracheal conditions. The first silicone stent was a Montgomery T-tube introduced in 1965.7 Prior to this, early airway stents were made of acrylic and were quite stiff. The silicone stent was much more pliable and easier to handle. The Montgomery T-tubes were often used during tracheal recon struction to prevent anastomotic stenosis. Cooper et al. published a series of 47 patients treated with Montgomery T-tubes, 36 of whom had benign lesions.8 Montgomery tubes were associated with minimal tissue reaction, preservation of normal
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respiration, and minimal migration because of the horizontal limb securing it to the neck. The only disadvantage was mucous plugging, which could be cleared with access from the horizon tal limb. The silicone stent most often used today is the Dumon stent.9 Dumon developed a silicone stent without the horizontal limb, hence avoiding a tra cheostomy. In more recent versions of this stent raised studs were created on the exterior surface to help prevent migration. Insertion requires gen eral anesthesia and a rigid bronchoscopy. Since 1990, more than 10,000 of these stents have been placed.10,11 The loss of the horizontal limb, how ever, is associated with an increased rate of migra tion as well as mucous impaction compared to the T-tubes. Shin et al. reviewed complication rates of vari ous plastic and metallic stents.12 One hundred sixty-three patients who received silicone stents for benign tracheal lesions obtained relief. However, there was a 16% rate of sputum reten tion, 10% experienced stent migration, and 4% developed granulation tissue formation. Fifty-four of 163 patients had their stents removed after 18–32 months. Dumon published a 7 year experience with Dumon stents at four European centers in 1996.13 One thousand five hundred seventy-five stents were placed for 1,058 patients. Of these, 360 patients had 598 stents placed for benign indica tions. Stent migration occurred in 9.5%, granula tion tissue in 8%, and mucous plugging in 4%. The mean duration of the stent for a benign indication was 14 months. Martinez-Ballarin published results in 63 patients with silicone stents.14 After 18 months, 27 patients had their stents removed, 17 of whom did not need replacement. Brichet et al. utilized Dumon stents in 17 patients.15 Only three were cured without need for further treatment and nine had a permanent placement for palliation. Puma et al. reported 45 patients with silicone stent placement.16 In nine patients, the stent was used as a bridge to definitive surgery. Ten patients had their stents removed without any recurrence of symptoms. In 2009 Carretta and others published their experience with Montgomery T-tubes in 75 pati ents over a span of 24 years.17 Of these, 27 patients
had some sort of T-tube complication such as stent dislocation (4%), granulation formation (19%), subglottic edema (4%), and sputum retention (9%), and 27% of the patients required some treat ment for their complications. Seven patients had their Dumon stents replaced with Montgomery T-tubes due to migration of the stents. After 5 years, 82% of the patients continued to have their T-tubes in place, with many patients followed for more than 10 years. Liu reported a 9 year experience in 2002 with Montgomery T-tubes in 53 patients. Only 72% of patients were considered successful in this review.18 After removal of the tube, 11% of patients devel oped partial obstruction from subglottic granula tion formation. Another study reviewed 37 patients who had T-tubes placed over a 3 year period. Six patients developed obstructive granulation tissue while the 31 others had good long term success.19 Results of silicone stents for management of airway problems are summarized in Table 39.1.
Plastic Stents In contrast to the solid silicone stents, the Polyflex stent (Boston Scientific) provides a self expand ing stent that is fully covered in silicone. Experi mental observation with the Polyflex stent in animal models with benign tracheal stenosis, however, noted an 83% migration rate with 50% mortality from acute airway obstruction.20 Severe granulation tissue formation was observed at each end of the stent. In another study in sheep, two of four stents were expelled with coughing within 6 months.21
Table 39.1. Results of silicone stents. Study Shin Dumon13 MartinezBallarin14 Carretta17a 12
Liu18a Gildea22
Patients
Comment
Evidence quality
163 360 63
10% migration, 4% granulation 9.5% migration, 8% granulation 17 of 27 patients did not need replacement of their stent 82% of patients still had stent after 5 years 72% of patients considered successful Polyflex stent not recommended
Low Low Low
75 53 12
Montgomery T-tubes
a
Low Low Low
39. Stents for Benign Airway Obstruction
Gildea et al. reported their experience with 16 Polyflex stent used in 12 patients with benign bronchotracheal obstruction. Ninety percent of these patients obtained immediate relief, but the complication rate was 75%. Stent migration was most common, with some patients expectorating the stent less than 24 h after placement. Mucous impaction was seen in 25% of patients. The authors have since abandoned the use of the Polyflex stents in this setting.22
Uncovered or Partially Covered Self Expanding Metal Stents Self expanding metal stents (SEMS) include the Palmaz stent, Wallstent, and the Ultraflex stent, among others.23 The Palmaz is made of balloon expandable stainless steel mesh. The Wallstent is a self expandable stent made from a cobalt alloy, and the Ultraflex is made from Nitinol, which is a nickel–titanium alloy that exhibits some shape memory. The Ultraflex stents come in uncovered and partially covered varieties. These metal stents are inviting because the delivery system is much easier than a classic silicone stent. They do not require rigid bronchoscopy and can be delivered through a regular ET tube. Delivery can be directly observed bronchoscopically or with fluoroscopy. They can also adapt better to irregular lumens. Pulmonary function evaluation before and after stent placement in benign tracheal obstruction demonstrated a significant improvement in FEV1 and FVC 30 days post placement in non-transplant patients.2 These improvements were less evident at 13 months follow-up, though patients still indi cated symptomatic improvement. However, concerns over these stents arise from increasing obstructive complications with granu lation tissue, stent fracture, halitosis and infection, as well as difficulty with extraction if necessary. Rempey et al. reviewed their experience with these wire stents.10 Metallic bare metal wire stents in place for more than 4–6 weeks become epithelial ized and are difficult if not impossible to remove. Twenty-five to 50% of stents required removal by 16 months. Partially covered stents seem to be more amenable to removal, but these still required piecemeal extractions.5
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Gaissert et al. published a retrospective analysis of 15 patients with benign airway obstruction treated with self expanding metal stents3 (six Wallstents and nine Ultraflex stents, of which three were partially covered). The median duration of follow-up was 8 months. All developed tracheal obstruction and dyspnea. Significant granulation tissue was present both above and below the stents. More importantly, the majority of these patients were found to be amenable to surgical resection when their pre-stent studies were evaluated. They recommended against the use of SEMS in benign tracheobronchial lesions. Madden et al. reviewed 31 patients treated with Ultraflex stents, 25 covered and 6 uncovered.4 Twenty-one were placed in the trachea. Com plications were noted in 48% of patients, with granulation tissue formation being most common (11 of 15 patients with complications). Granulation tissue formed at either end and throughout the uncovered portions of the stents. Interestingly, 13 patients died in a median time of 1 month follow ing insertion. None of the deaths was directly attributable to the stents. Median follow-up of the survivors was 22 months. The vast majority of patients with respiratory insufficiency were weaned from the ventilator following stent placement. Saad and colleagues also placed expandable metallic stents in 11 lung transplant patients and 21 other patients with benign tracheal lesions.24 They also observed a high incidence of stent related com plication (53.7%), attributed to infection (15.9%), granulation tissue (14.6%), and stent migration (4.7%). Mean follow-up was 330 days. Fourteen of 16 patients were able to be weaned off of mechani cal ventilation following stent placement. Eller et al. performed a retrospective review of 16 patients with a total of 26 stents deployed for benign airway disease.25 Sixteen stents were the partially covered Ultraflex type, while the others were all uncovered bare metal stents. Mean follow-up was 20 months. Eighty-seven percent of patients had a complication requiring an intervention to maintain a patent airway; 81% of patients developed granu lation tissue causing restenosis, 31% of patients required a tracheostomy, and 56% of stents were removed or expelled. They also did not recommend tracheal stents for benign tracheal stenosis. Thornton et al. reviewed 40 patients treated with expandable bare metallic stents.26 A total of
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93 procedures were performed ranging from 1 to 18 procedures per patient with follow-up of up to 6 years. At 1 year following placement, primary patency decreased to 60%; 46% of stents retained patency at 6.8 years. Assisted patency, that is fol lowing reintervention, was 90% at 6.8 years. Five year survival for this group was 38% at 5 years, although the deaths were not directly attributable to the stent.
Fully Covered Self Expanding Metallic Stents This newer class of stents utilizes a more complete covering of the metal to avoid some of the prob lems elucidated earlier. Partially covered stents such as the Ultraflex have as their proximal and distal ends approximately 1.5 cm of bare wire scaf fold to allow for granulation. The Aero stent from Merit Endotek is a completely covered stent with a nitinol scaffold. Dooms et al. published a retro spective analysis of 17 patients treated with fully covered self expanding metal stents (Silmet from Novatech, Aero from Alveolus, and Niti-S from Taewoong Medical Co.27). Twenty fully covered stents were placed. The majority of complications were seen within the first 12 weeks after place ment. Only 25% of stents placed remained in place after 12 weeks. The most common complication was stent migration, which occurred in 60% of cases. The authors have since abandoned the uses of fully covered self expanding metallic stents for benign tracheal disease. Results of metallic stents for management of airway problems are summarized in Table 39.2. Table 39.2. Results of self expanding metal stents. Study
Patients
Gaissert Madden4 Saad24 Eller25
15 31 32 16
Thornton26
40
Dooms27a
17
3
Comment All developed obstruction 48% of patients had complications 53.7% of patients had complications 87% had complications, 81% granulation 60% 1 year and 46% 7 year stent patency Authors abandoned use
Fully covered metallic stent
a
Evidence quality Low Low Low Low Low Low
Recommendations Silicone stents provide adequate long term pal liation of benign tracheal obstruction and are safe to use (low quality evidence). We make a weak recommendation for use of silicone stents in the management of benign tracheal obstruc tion when resection is not feasible (recommen dation grade 2B). Self expanding metallic stents can also provide symptomatic relief for benign tracheal obstruction but are associated with a higher level of complications (low quality evi dence). We make a weak recommendation against the routine use of self expanding metal stents for benign tracheal obstruction (recommendation grade 2B).
Personal Views Benign tracheal obstructions are difficult lesions to address. Surgical resection is the first option if possible.28,29 However, some patients have co-morbidities that preclude surgical resection. Hence, the decision to place stent as well as the type of prosthesis can be challenging. There is no ideal stent that is easily placed, provides pat ency of the airway with no granulation forma tion or migration, is easily removal, and is cost effective. The wide variety and evolving techno logy in both delivery of the stent as well its composition make a uniform recommendation impossible. Hence, each case must be individual ized to the patient. For inoperable benign tra cheal lesions, the Dumon or Montgomery T-Tubes are our first choice if rigid bronchos copy is feasible. We try to avoid SEMS in these situations given their high rate of complications. However, if a self expanding metallic stent is required, we prefer a partially covered Ultraflex stent. We have not personally evaluated the fully covered self expanding metallic stents, but are unlikely to do so until further experience is garnered in the malignant population. This is in contrast to our patient population with malig nant airway obstruction, in which a SEMS is pre ferred due to the ease of deployment and stability of the stent.
39. Stents for Benign Airway Obstruction
Silicone stents provide adequate long term pal liation of benign tracheal obstruction and are safe to use (low quality evidence). We make a weak recommendation for use of silicone stents in the management of benign tracheal obstruc tion when resection is not feasible (recommen dation grade 2B). Self expanding metallic stents can also provide symptomatic relief for benign tracheal obs truction but are associated with a higher level of complications (low quality evidence). We make a weak recommendation against the routine use of self expanding metal stents for benign tra cheal obstruction (recommendation grade 2B).
References 1. Stohr S, Bolliger CT. Stents in the management of malignant airway obstruction. Monaldi Arch Chest Dis. 1999;54:264–268. 2. Gotway MB, Golden JA, LaBerge JM, Webb WR, Reddy GP, Wilson MW, Kerlan RK Jr, Gordon RL. Benign tracheobronchial stenoses: changes in shortterm and long-term pulmonary function testing after expandable metallic stent placement. J Comput Assist Tomogr. 2002;26:564–572. 3. Gaissert HA, Grillo HC, Wright CD, Donahue DM, Wain JC, Mathisen DJ. Complications of benign tracheobronchial strictures by self-expanding metal stents. J Thorac Cardiovasc Surg. 2003:126:744–747. 4. Madden BP, Loke TK, Sheth AC. Do expandable metallic airway stents have a role in the manage ment of patients with benign tracheobronchial disease? Ann Thorac Surg. 2006;82:274–278. 5. Noppen M, Stratakos G, D’Haese J, Meyzman M, Vinken W. Removal of covered self-expandable metal lic airway stents in benign disorders: indications, technique, and outcomes. Chest. 2005;127:482–487. 6. Sesterhenn AM, Wagner HJ, Alfke H, Werner JA, Lippert BM. Treatment of benign tracheal stenosis utilizing self-expanding nitinol stents. Cardiovasc Intervent Radiol. 2004;27:355–360. 7. Montgomery M. T-tube tracheal stent. Arch Otolaryngol. 1965;82:320–321. 8. Cooper JD, Pearson FG, Patterson GA, Todd TR, Ginsberg RJ, Goldberg M, Waters P. Use of silicone stents in the management of airway problems. Ann Thorac Surg. 1989;47:371–378. 9. Dumon JF. A dedicated tracheobronchial stent. Chest. 1990;97:328–332. 10. Rampey AM, Silvestri GA, Gillespie MB. Combined endoscopic and open approach to the removal of
351 expandable metallic tracheal stents. Arch Otolaryngol Head Neck Surg. 2007;133:37–41. 11. Schmidt B, Olze H, Borges AC, John M, Liebers U, Kaschke O, Hakke K, Witt C. Endotracheal balloon dilatation and stent implantation in benign stenoses. Ann Thorac Surg. 2001;71:1630–1634. 12. Shin JH, Song HY, Shim TS. Management of tracheo bronchial strictures. Cardiovasc Intervent Radiol. 2004;27:314–324. 13. Dumon JF, Cavaliere S, Diaz-Jimenez JP, Vergnon JM, Venuta F, Dumon MC, Kovitz K, Seven-year experi ence with the Dumon prosthesis. J Bronchosc Inter vent Pulmonol. 1996;3:6–10. 14. Martinez-Ballarin JI, Diaz-Jimenez JP, Castro MJ, Moya JA. Silicone stents in the management of benign tracheobronchial stenoses. Tolerance and early results in 63 patients. Chest. 1996;109:626–629. 15. Brichet A, Verkindre C, Dupont J, Carlier ML, Darras J, Wurtz A, Ramon P, Marquette CH. Multidisciplinary approach to management of postintubation tracheal stenoses. Eur Respir J. 1999;13:888–893. 16. Puma F, Ragusa M, Avenia N, Urbani M, Droghetti A, Daddi N, Daddi G. The role of silicone stents in the treatment of cicatricial tracheal stenoses. J Thorac Cardiovasc Surg. 2000;120:1064–1069. 17. Carretta A, Casiraghi M, Melloni G, Bandiera A, Ciriaco P, Ferla L, Puglisi A, Zannini P. Montgomery T-tube placement in the treatment of benign tra cheal lesions. Eur J Cardiothorac Surg. 2009;36: 352–356. 18. Liu HC, Lee KS, Huang CJ, Cheng CR, Hsu WH, Huang MH. Silicone T-tube for complex laryngotra cheal problems. Eur J Cardiothorac Surg. 2002;21: 326–330. 19. Liu YH, Wu YC, Hsieh MJ, Ko PJ, Liu HP, Lin PJ. Montgomery T-tube insertion using a rigid bron choscope under direct observation. ANZ J Surg. 2006;76:853–854. 20. Bolliger CT, Wyser C, Wu X, Hauser R, Studer W, Dalquen P, Perruchoud AP. Evaluation of a new selfexpandable silicone stent in an experimental tra cheal stenosis. Chest. 1999;115:496–501. 21. Puma F, Farabi R, Urbani M, Santoprete S, Daddi N, Di Meo A, Gialletti R, Tocchi A, Daddi G. Long-term safety and tolerance of silicone and self-expandable airway stents: an experimental study. Ann Thorac Surg. 2000;69:1030–1034. 22. Gildea TR, Murthy SC, Sahoo D, Mason DP, Mehta AC. Performance of a self-expanding silicone stent in palliation of benign airway conditions. Chest. 2006;130:1419–1423. 23. Chin CS, Litle V, Yun J, Weiser T, Swanson SJ. Airway stents. Ann Thorac Surg. 2008;85:S792–S796. 24. Saad CP, Murthy S, Krizmanich G, Mehta AC. Selfexpandable metallic airway stents and flexible bron choscopy: long-term outcomes analysis. Chest. 2003;124:1993–1999. 25. Eller RL, Livingston WJ, Morgan CE, Peters GE, Sillers MJ, Magnuson JS, Rosenthal EL. Expandable
352 tracheal stenting for benign disease: worth the com plications? Ann Otol Rhinol Laryngol. 2006;115: 247–252. 26. Thornton RH, Gordon RL, Kerlan RK, LaBerge JM, Wilson MW, Wolanske KA, Gotway MB, Hastings GS, Golden JA. Outcomes of tracheobronchial stent place ment for benign disease. Radiology. 2006;240:273–282. 27. Dooms C, De Keukeleire T, Janssens A, Carron K. Performance of fully covered self-expanding metallic
J.O. Wee and S.J. Swanson stents in benign airway strictures. Respiration. 2009;77:420–426. 28. Grillo HC, Donahue DM, Mathisen DJ, Wain JC, Wright CD. Postintubation tracheal stenosis. Treatment and results. J Thorac Cardiovasc Surg. 1995;109:486–493. 29. Grillo HC, Mathisen DJ, Wain JC. Laryngotracheal resection and reconstruction for subglottic stenosis. Ann Thorac Surg. 1992;53:54–63.
40
Tracheal Reconstruction with Autologous and Engineered Tissues Etienne Grunenwald, Emmanuel Moss, and Moishe Liberman
Introduction Tracheal reconstruction remains one of the greater challenges in thoracic surgery. Primary anastomosis is the gold standard in patients requiring resection of anything except extreme lengths of trachea. End-to-end tracheal anastomosis can be safely accomplished following resection of up to one half of the adult trachea. As a result, this approach is available in the vast majority of cases of benign stenosis and in many cases of tumor invasion. The lack of an ideal substitute to replace the trachea’s mechanical and physiological functions is primarily responsible for the shortcomings of tracheal reconstructive surgery in rare patients requiring lengthier resections.Historically, the only therapeutic options in cases of long stenoses or tumors were resection with T-tube placement, terminal tracheostomy, stenting, or other palliative treatments. The options for non end-to-end tracheal reconstruction vary as a function of the resultant defect. A partial, or non-circumferential, defect must be patched with a material ensuring a hermetic seal, while a circumferential defect will require reconstruction with a rigid tubular structure to restore airway continuity. Belsey and Grillo outlined the key biological principles required of an ideal tracheal substitute.1,2 In addition to possessing lateral rigidity and longitudinal flexibility, it must be biocompatible, non immunogenic, resistant to bacterial colonization, completely airtight, and allow for respiratory epithelium resurfacing as well easy implantation with reproducible results.
Many substitutes have been tested, both experimentally and clinically, with variable results. These replacements include autologous tissues, allotransplantation, synthetic materials, and tissue engineered materials. However, owing to the absence of a proven tracheal substitute, the literature in tracheal reconstructive surgery consists of feasibility studies rather than comparative trials. Proposed recommendations are thus limited by the relative weakness of available evidence. This chapter will discuss the existing options for tracheal reconstruction, addressing both partial and circumferential resection. A literature review was performed using a Medline search for reports in humans published between 1950 and 2009 using the keywords [trachea] AND [reconstruction] OR [replacement]. All relevant articles were reviewed, ranging from larger case studies to unique case reports.
Summary of Published Data Circumferential Defect As mentioned above, primary anastomosis should always be the goal of tracheal reconstruction. In 1973, Grillo and colleagues reported their series of 100 consecutive cases of tracheal resection with primary anastomosis over a 10 year period.3 Resu lts overall were excellent, with 73 of 84 tracheal stenosis patients having a good or excellent result and 4 with a satisfactory result. Of the 11 patients
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with primary tracheal tumors, 9 were disease free at follow-up ranging from 6 months to 10 years. Grillo’s group later published their entire series of 503 patients with post-intubation tracheal stenosis who underwent resection and reconstruction with primary anastomosis.4 Results were again quite good, with 93.7% of patients having a good or satisfactory outcome following resection of lengths from 1.0 to 7.5 cm. In 2008, Marulli and colleagues reported on 34 patients with benign tracheal stenosis, 97% of whom had a good or excellent result at mean follow-up of 6.5 years.5 Similar results have been reported following resection of malignant disease.6–8 These results have been reproduced in the pediatric population as well, although anastomotic complications are reportedly increased with tracheal resection of greater than 30%.9 In children with longer stenoses, good results have been obtained with the technique of slide tracheoplasty. A recent review of a single institution’s experience demonstrated exc ellent short term results, reporting 0% mortality, which they attribute to aggressive perioperative surveillance and treatment.10 Reported long-term results have also been good.11 The particular anatomical qualities of the trachea are such that there are limits to the length of trachea that can be resected while allowing for primary anastomosis. These limits can be extended by various well-described release maneuvers.12 Anatomical experiments have shown that resection of as much as 6 cm, or 50%, of the tracheal length can be safely reconstructed with an end-toend tracheal anastomosis.13 In light of the relatively large patient numbers in each case series and the paucity of evidence regarding other treatment modalities of tracheal reconstruction, we consider there to be a moderate quality of evidence concerning primary anastomosis. Several attempts have been made to find a suitable circumferential tracheal replacement to add ress cases where primary anastomosis has been deemed impossible; however, the ideal solution has yet to be established. An extensive list of synthetic conduits has been used to this end. In a large review, Toomes cited 46 experimental or clinical studies utilizing 17 different materials between 1948 and 1980, all of which reported poor results,14 Since that time, however, there are several published series deserving mention. In 1990, Neville
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and colleagues reported the largest series of tracheal reconstruction using a solid prosthesis.15 They replaced the trachea of 35 patients with a molded silicone prosthesis fashioned with thick rims of Dacron mesh at the sewing ends. No postoperative deaths were observed. Ten patients (29%) developed anastomotic granulation requiring recurrent bronchoscopic treatment or tracheostomy.16 They also report two instances of prosthesis migration and one dehiscence that required replacement with a T-tube. Overall, very few patients survived without symptoms. Toomes and colleagues reported even less favorable results with the Neville prosthesis.14 Of the nine patients in their series, two died perioperatively, while three others later succumbed to prosthesis related complications, which included innominate artery erosion and mediastinitis. Granulation tissue and sputum retention were also described in four patients. Reports of Teflon prostheses describe good longitudinal elasticity and strong lateral rigidity, but the postoperative course was often complicated by distal fracture, poor adhesion to viable tissue and sputum retention.16–18 Experi mental studies have suggested that porous prostheses, such as Marlex mesh, would permit tissue ingrowth and eventual epithelialization of the lumen.19 In 1984 Pearson and colleagues published their series of 39 patients who underwent tracheal resection for primary neoplasm.19,20 A porous prosthesis of heavy-duty Marlex mesh was used in six patients requiring extensive resection. Three of these patients later died of innominate artery erosion and one patient developed anastomotic granulation requiring reoperation. Conversely, there were only two postoperative deaths in the 33 patients who underwent primary reconstruction. The authors conclude that this limited experience with prosthetic reconstruction was clearly unsatisfactory (very low quality of evidence). Various autologous tissues have been used to reconstruct circumferential tracheal defects. Tra cheal reconstruction with an autologous tube was first attempted by Fonkalsrud in 1963 and then again in 1971 when he unsuccessfully attempted esophageal interposition in the setting of tracheal agenesis and tracheal stricture.21,22 Almost 40 years later, Martinod’s and Jaillard’s groups reported promising results when replacing the trachea with autologous and allogenic aorta in sheep and pig
40. Tracheal Reconstruction with Autologous and Engineered Tissues
models23–25 They found formation of an epithelial surface in the aortic grafts as well as cartilage formation. Encouraged by these findings, similar interventions were attempted in humans. Azorin and colleagues described the case of an aortic autograft, using the infrarenal abdominal aorta for tubular tracheal reconstruction. An intraluminal silicone stent was inserted to prevent collapse with respiration.26 The postoperative period was complicated by an acute respiratory distress episode secondary to granulation tissue at the proximal anastomosis, which was successfully treated by placement of a second stent. Unfortunately the patient died 6 months postoperatively of complications from pneumonia; however, bronchoscopic examination of the neotrachea revealed wellhealed anastomoses and no signs of graft necrosis. Brian described another case of technically successful aortic autograft, however, the patient died 5 weeks postoperatively from a massive pulmonary embolus.27 More recently, three cases of tracheal reconstruction with aortic allograft were described. The use of non-autologous aorta thus avoided the need for concomitant invasive aortic surgery. Wurtz and colleagues implanted fresh aortic homografts in two patients with extensive tracheal tumors.28 Bronchoscopic biopsy at 1 year revealed the development of a respiratory epithelium and no evidence of rejection, despite lack of immunosuppressive therapy. The intraluminal stent was left in place for 2 years as a preventative measure. Davidson reported a case of tracheal reconstruction using a banked aortic homograft. Implantation was performed following anastomotic failure of a recently repaired tracheo-esophageal fistula.29 The patient died on postoperative day 10 of mediastinitis with dehiscence of the distal anastomosis (very low quality of evidence). Transplantation of the human trachea remains an unsolved technical problem in thoracic surgery. The lack of a well-defined blood supply makes direct revascularization difficult and favors graft necrosis. Indirect revascularization by muscle or fascial or omental wrapping has been well-studied experimentally.30–36 Additionally, in the absence of strong immunosuppressive therapy, tracheal imm unogenicity leads to rejection and subsequent stenosis.37–40 Although researchers have successfully addressed these issues in animal models, only three cases of human circumferential tracheal
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allotransplantation have been reported. In 1979, Rose and colleagues described a case of a tracheal allograft that was implanted heterotopically to allow revascularization by the sternocleidomastoid muscle. Transfer into the orthotopic position was performed 3 weeks later.41 Despite the lack of immunosuppressive therapy, the authors reported a satisfactory initial result, with no evidence of rejection, ischemia, or infection. Unfortunately, no information on the long-term result exists. In 1993, Levashov and colleagues performed a single-stage orthotopic tracheal transplantation in a 24-yearold female patient with idiopathic fibrosing mediastinitis.42 The patient received immunosuppressive therapy and indirect revascularization was accomplished with omental wrapping. Early rejection (at 10 days) was successfully treated with adjustment of immunosuppression, resulting in a good functional outcome at 2 months and epithelialization of the anastomosis. However, progressive stenosis, beginning at 4 months was ultimately necessitated permanent stenting of the trachea. It remains unclear whether this outcome was the result of late shrinking of the graft due to ischemia or of underlying disease progression. Klepetko and colleagues recently reported a case of concomitant lung and tracheal transplantation.43 The donor trachea was initially wrapped in omentum and implanted into the recipient’s abdominal wall as a stoma for graft surveillance. Orthotopic relocation never occurred because primary tracheal reanastomosis was achieved, however, macroscopic and histologic examination of the allograft revealed a mechanically stable trachea with viable cartilage and respiratory epithelium. Finally, although the details of laryngotracheal reconstruction are beyond the scope of this chapter, the successful orthotopic total laryngeal transplantation reported in 2001 signifies an important advance in the field. At 40 months the patients had normal speech, ability to swallow, and an “immeasurably improved quality of life”48 (very low quality of evidence). Some progress has been made recently in tube reconstruction using myocutaneous flaps. There have been two reports of a two-stage procedure with creation of a reinforced cervical myocutaneous flap, termed a “sandwich artificial trachea”.44,45 The length of tracheal resection was 6 and 5.5 cm. The procedure entailed implantation of a preshaped memory alloy mesh into a supraclavicular
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subcutaneous pouch. This was followed 3 months later by tubularization and implantation of a sternocleidomastoid-platysma myocutaneous flap. This approach yielded good results in each case at 5 and 30 months, respectively. Two techniques of tube reconstruction based on a radial forearm flap have been reported in individual patients.46,47 Both single-stage procedures consist of radial forearm flap harvesting and tubularization, with the skin on the endoluminal surface. In one report, the skin served as the new airway luminal lining and graft rigidity was achieved by external suspension with a biodegradable mesh. The patient’s course was uneventful at 1-year follow-up. In the second report, graft rigidity was achieved with incorporation of an endoluminal silicone-polyester stent (Polyflex, Boston Scientific) into the anastomosis. Postoperatively, this patient required cauterization of granulation tissue growing into the trachea, underwent repeated dilatation procedures for subglottic stenosis just proximal to the stent, and was treated for recurrent airway infections. The patient died 16 months postoperatively, likely from complications of metastatic disease (very low quality of evidence). Recent work in animal models with tissue- engineered prostheses has yielded promising results, with realization of the fundamental elements for a tissue-engineered trachea.49–54 Although it will take several more years before the advent of a viable tissue-engineered tracheal substitute to be used dependably in humans, early human case reports are very promising. Macchiarini and colleagues were the first to report successful airway patching using this technology.55 They reported good results up to 12 weeks postoperatively showing complete inclusion of the patch. Omori and colleagues described placement of a tissue- engineered patch on a Marlex mesh for tracheoplasty following partial resection for thyroid cancer.56 Last year Macchiarini reported successful implantation of a tissue engineered graft fashioned from an allogenic donor trachea.57 Successful replacement of the patient’s left main bronchus was accomplished (very low quality of evidence).
Non-Circumferential Defect Various methods for reconstruction of partial tracheal defects have been described with variable success. Autologous tissues used have included
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pedicled muscle flaps, chondromuscular flaps, myocutaneous flaps, and pericardium. Reinforced myocutaneous free flaps have also been reported. Non-autologous tissues have included non-viable tracheal allograft and pericardial covered mesh materials. The majority of reports have very limited patient numbers and short follow-up. The most frequently reported and variably employed method of reconstruction for partial tracheal defects is a pedicled muscle flap. Published results have generally been good, with the largest series consisting of 41 patients who underwent tracheocarinal reconstruction with extrathoracic muscle flaps.58 The authors used, in order of preference, latissimus dorsi, serratus anterior, or pectoralis major muscles. Defects comprising less than 30% of the tracheal circumference were closed using an unsupported muscle flap. Flaps were reinforced with an embedded rib segment for defects between 30% and 50% of tracheal circumference, while larger defects were considered a contraindication to the procedure. Defects ranged from 2 × 1 to 8 × 4 cm. Early results were good, with a 7.3% perioperative mortality in a relatively sick population. Muscle flap necrosis was noted on bronchoscopic follow-up in four patients and was promptly treated with debridement and creation of a new muscle flap. Several variations of local rotational chondromuscular flaps have been used. Guerrissi and Nouraei reported on eight patients who underwent a two-stage procedure with cartilage implantation of onto sternohyoid muscle followed later by creation of a rotational flap to close a modest sized tracheal defect.59,60 Good results were noted clinically and bronchoscopically at up to 12 months follow-up. Equally positive results have been reported with larger chondromuscular flaps in cases of more extensive tracheal defects, including pectoral and deltopectoral muscles.61,62 A report on 11 sternocleidomastoid periosteal flaps described good results at up to 40 months follow-up with all but one patient being successfully weaned from tracheostomy.63 Myocutaneous flaps for non- circumferential tracheal resection have been reported primarily in the context of complex neck and tracheal reconstruction. Yu reported good results in 18 patients following reconstruction with an anterolateral thigh flap, 4 of which required closure of a relatively small (3 × 1.5 cm) tracheal defect.64 Other authors have reported good results
40. Tracheal Reconstruction with Autologous and Engineered Tissues
at up to 6 months with the use of latissimus dorsi and pectoralis muscles for defects up to 8.5 cm in length65,66 (very low quality of evidence). Pericardial patches have been used with success for tracheal defects in both the pediatric and adult population. Fanous and colleagues described their series of 26 pediatric patients, 21 of whom enjoyed asymptomatic long-term survival.67 Other authors have reported equally good outcomes.68,69 Evidence in the adult population is limited to individual case reports with short follow-up70–72 (low quality of evidence). Several methods of partial reconstruction with non-autologous tissue have been reported. Sharpe published his series of 82 consecutive patients who underwent surgery for tracheal resection and reconstruction, 22 of whom received a composite prosthesis of Marlex mesh covered by pericardium, mostly in the context of secondary tracheo-carinal malignancy.73 In the 20 patients with non-circumferential reconstruction, two post-operative deaths occurred, although there was no evidence of graft failure. One of the two patients who underwent prosthetic tubular reconstruction died in the postoperative period, also without evidence of graft failure (very low quality of evidence). Crypopreserved or chemically treated tracheal allografts have been used to reconstruct long stenotic defects without requiring immunosuppression.74,75 This procedure, initially developed by Herberhold and colleagues, entails almost complete circumferential resection of the diseased tracheal segment, leaving only the posterior tracheal wall. The homograft is anastomosed and a temporary stent remains in place for approximately 12 weeks, until complete reepithelialization has occu rred. Herberhold reported favorable results in a large series of 112 patients, including 20 children.76,77 There were no cases of rejection; operative mortality was 5%, and 30 patients requiring prolonged stenting for an average of 8.4 months. Histological studies revealed ingrowth of a columnar epithelium with rudimentary cilia. In the few children who have undergone tracheal homograft transplantation, it appears that the trachea elongates but the diameter remains fixed. This shortcoming can be overcome with the use of adult-sized grafts, thus avoiding the need for replacement as the child grows. Jacobs and colleagues reviewed the entire North American and worldwide pediatric
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experience with this technique (including Herberhold’s series), in which 95% of cases followed one or more previous failed repairs.78,79 At a mean follow-up of 5 years (from 5 months to 14 years), 26 of 31 children were alive (84%) and only two deaths were reported secondary to treatment failure. Twenty-two patients were asymptomatic and without airway problems, with only a minority requiring recurrent bronchoscopic intervention for overgrowth of granulation tissue. Genden described a modification of Herberhold’s technique consisting of a two-staged allograft tracheoplasty.80 In his series of nine patients, the allograft was initially placed into a subcutaneous pocket along the native trachea. Fourteen days later, the composite graft was removed and used to close the tracheal defect, with the epidermis rota ted intraluminally to serve as a neo-epithelium. All of the patients were followed with bronchoscopy and CT scan, demonstrating successful epithelial coverage and a satisfactory airway lumen.
Summary and Recommendations The summary of published results in the previous section exposes both the variety of surgical options and the overall lack of evidence in the field of tracheal reconstruction (Table 40.1). No studies comparing reconstructive techniques have been performed; therefore, comparisons of techniques with similar levels of evidence are not possible. Primary anastomosis following circumferential tracheal resection offers reproducible and durable results, with low morbidity and mortality. Patients are relatively symptom free in the majority of cases (evidence quality moderate). We make a strong recommendation for primary anastomosis regardless of underlying pathology (recommendation grade 1B). Evidence is limited for all other methods of tracheal reconstruction, with only small case series and case reports existing in the literature. In cases of circumferential tracheal resection, reinforced myocutaneous flaps appear feasible with acceptable morbidity and good short and midterm results (evidence quality very low). We make a weak recommendation for use of reinforced myocutaneous flaps when primary anastomosis is not an option
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358 Table 40.1. Outcomes of different techniques of tracheal reconstruction. Method of reconstruction Circumferential reconstruction
Series
Patients
Primary anastomosis
Grillo (4) Marulli (5)
537
Prosthetic interposition
Toomes (14) Neville (15) Pearson (19)
50
Tracheal Allograft (Fresh) Rose (41) Levashov (42) 3 Klepetko (43) Aortic homograft
Wurtz (28) Davidson (29) 3
Aortic autograft
Azorin (26) Brian (27)
2
Myocutaneous flap
Zhao (44) Cai (45) Maciejewski (46) Beldholm (47) Macchiarini (55) Omori (56) Ris (58) Guerrissi (59)
4
Tissue engineering
Non-circumferential Muscular flaps reconstruction ( + /– reinforcement) Tracheal homograft Herberhold (78) Jacobs (preserved) (79) Pericardial patch
Fanous (67) Dunham (68) Bando (69)
Marlex/pericardial patch Sharpe (73)
2 49
Outcome Reproducible long term results
Method of choice. Resection of up to 6 cm or 50% of trachea High rate of morbidity and Death from fatal hemorrhage, mortality mediastinitis, dehiscence, hypergranulation Technical success, limited Requires immunosuppression follow-up, requires intraluminal stent Technical success, requires No immunosuppression intraluminal stent Early death not related to Invasive graft failure, requires intraluminal stent Good mid-term results One or two-stage procedures
Technical success, limited Tubular or patch follow-up reconstruction Good technical and Chondromuscular for wider functional results defects
92 adults Good long term results 31 children 56 Good long term results in the pediatric population 22 Good results in limited number of patients
(recommendation grade 2C). Aortic autograft, aortic allograft, and fresh tracheal allograft show interesting early results in a very limited number of reported cases (evidence quality very low). Tissue engineering of the trachea has shown great promise experimentally and in two reports of clinical application for bronchial reconstruction (evidence quality very low). Encouraged by favorable experimental evidence, we make a weak recommendation for use of these methods under the auspices of a clinical study (recommendation grade 2C). Silicone and Marlex prostheses have been associated with significant accumulation of granulation tissue and major mortal complications, including innominate artery fistula and dehiscence (evidence quality low). We make a strong recommendation against the use of prostheses for circumferential tracheal reconstruction (recommendation grade 1C). In cases of partial tracheal resection, there are several reconstructive techniques that have been
Comment
Level of evidence Low
Low
Very low
Very low Very low
Very low
Very low Low
No immunosuppression
Low
Well studied for congenital stenosis. Adult literature limited to case reports Marlex on extraluminal surface
Low
Low
favorably reported in the literature. Success has been demonstrated when using muscular flaps with or without cartilaginous reinforcement (evidence quality low). We make a strong recommendation for reconstruction with muscular flaps for lengthy tracheal defects and chondromuscular flaps for wider defects (recommendation grade 1C). Pericardial patch reconstruction has had good reported results in the treatment of congenital stenosis; however, there are very few reports of use in other contexts (evidence quality low). We strongly recommend use of pericardial patches in treatment of lengthy congenital stenosis (recommendation grade 1C). Individual series suggest that pericardial patching externally supported with Marlex is feasible and produces good results (evidence quality low). We make a weak recommendation for use of pericardial patches reinforced with Marlex in cases of secondary malignancy involving the trachea (recommendation grade 2C).
40. Tracheal Reconstruction with Autologous and Engineered Tissues
Our View of the Evidence Primary anastomosis is our method of choice for tracheal reconstruction due to reproducible results with low associated morbidity. Tracheal substitutes should be used only in exceptional cases where end-to-end anastomosis is not possible. Other options discussed above are used on a caseby-case basis and typically as a bail-out option. Aortic allograft transplantation is of particular interest because of exciting experimental results demonstrating neocartilage growth; however, the feasibility of this has not yet been proven clinically. Engineered tissues would appear to be an ideal substitute because they are created using autologous tissue, although the clinical application of this process is only in its infancy. At the current time it is costly, not easily available, and entails a significant preparation delay. In our practice the indications for partial tracheal resection are very rare and limited to certain cases of recurrent disease following failure of primary resection and re-anastomosis or tracheal invasion by secondary malignancy. In these instances, the defect can be patched using several methods mentioned above depending on each surgeon’s previous experience and personal preference. In reconstructive surgery of the trachea, there is no substitute for meticulous preoperative evaluation and planning. Extensive tracheal release maneuvers (including bilateral pericardial hilar release) will often facilitate primary anastomosis, which would be otherwise impossible. Although primary anastomosis will be attainable in the vast majority of cases, an airway surgeon must be prepared for any eventuality. Primary anastomosis following circumferential tracheal resection offers good results and is safe (evidence quality moderate). We make a strong recommendation for primary anastomosis after tracheal resection regardless of underlying pathology (recommendation grade 1B). Use of reinforced myocutaneous flaps has acceptable morbidity and good midterm results (evidence quality very low). We make a weak recommendation for use of reinforced myocutaneous flaps when primary anastomosis is not an option (recommendation grade 2C).
359
In cases of partial tracheal resection, success and safety have been demonstrated for muscular flaps with or without cartilaginous reinforcement (evidence quality low). We make a strong recommendation for reconstruction with muscular flaps for lengthy tracheal defects and chondromuscular flaps for wider defects (recommendation grade 1C).
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360 15. Neville WE, Bolanowski JP, Kotia GG. Clinical experience with the silicone tracheal prosthesis. J Thorac Cardiovasc Surg. 1990;99:604–613. 16. Graziano JL, Spinazzola A, Neville WE. Prosthetic replacement of the tracheal carina. Ann Thorac Surg. 1967;4:1–11. 17. Ekestrom S, Carlens E. Teflon prosthesis in tracheal defects in man. Acta Chir Scand. 1959;Suppl 245: 71–75. 18. Kramish D, Morfit HM. The use of a Teflon prosthesis to bridge complete sleeve defects in the human trachea. Am J Surg. 1963;106:704–708. 19. Pearson FG, Henderson RD, Gross AE, Ginsberg RJ, Stone RM. The reconstruction of circumferential tracheal defects with a porous prosthesis. An experimental and clinical study using heavy Marlex mesh. J Thorac Cardiovasc Surg. 1968;55:605–616. 20. Pearson FG, Todd TR, Cooper JD. Experience with primary neoplasms of the trachea and carina. J Thorac Cardiovasc Surg. 1984;88:511–518. 21. Fonkalsrud E, Martelle R, Maloney J. Surgical treatment of tracheal agenesis. J Thorac Cardiovasc Surg. 1963;45:520–525. 22. Fonkalsrud E, Sumida S. Tracheal replacement with autologous esophagus for tracheal stricture. Arch Surg. 1971;102:139–142. 23. Martinod E, Seguin A, Holder-Espinasse M, et al. Tracheal regeneration following tracheal replacement with an allogenic aorta. Ann Thorac Surg. 2005;79:942–949. 24. Martinod E, Seguin A, Pfeuty K, et al. Long-term evaluation of the replacement of the trachea with an autologous aortic graft. Ann Thorac Surg. 2003; 75:1572–1578. 25. Jaillard S, Holder-Espinasse M, Hubert T, et al. Tracheal replacement by allogenic aorta in the pig. Chest. 2006;130:1397–1404. 26. Azorin JF, Bertin F, Martinod E, Laskar M. Tracheal replacement with an aortic autograft. Eur J Cardio thorac Surg. 2006;29:261–263. 27. Brian E, Gounant V, Fulgencio J-P, Milleron B, Bazelly B. Tracheal replacement using the abdominal aorta. Comments on a case report. Rev Pneumol Clin. 2007;63:224–229. 28. Wurtz A, Porte H, Conti M, et al. Tracheal replacement with aortic allografts. N Engl J Med. 2006;355: 1938–1940. 29. Davidson MB, Mustafa K, Girdwood RW. Tracheal replacement with an aortic homograft. Ann Thorac Surg. 2009;88:1006–1008. 30. Li J, Xu P, Chen H. Successful tracheal autotransplantation with two-stage approach using the greater omentum. Ann Thorac Surg. 1997;64:199–202. 31. Li J, Xu P, Chen H, Yang Z, Zhang Q. Improvement of tracheal autograft survival with transplantation into the greater omentum. Ann Thorac Surg. 1995;60: 1592–1596. 32. Lopez-Rivero L, Quevedo S, Freixinet J, et al. Experimental tracheal revascularization with omentum. Eur J Cardiothorac Surg. 1993;7:540–542.
E. Grunenwald et al. 33. Mayer E, Cardoso PF, Puskas JD, Patterson GA, Oelert H. Revascularization of heterotopic isotransplants of the rat trachea using an omentum flap. Pneumologie. 1992;46:190–195. 34. Morgan E, Lima O, Goldberg M, Ferdman A, Luk SK, Cooper JD. Successful revascularization of totally ischemic bronchial autografts with omental pedicle flaps in dogs. J Thorac Cardiovasc Surg. 1982;84:204–210. 35. Delaere PR, Liu Z, Feenstra L. Tracheal autograft revascularization and transplantation. Arch Otola ryngol Head Neck Surg. 1994;120:1130–1136. 36. Delaere PR, Liu ZY, Hermans R, Sciot R, Feenstra L. Experimental tracheal allograft revascularization and transplantation. J Thorac Cardiovasc Surg. 1995; 110:728–737. 37. Bujia J, Wilmes E, Hammer C, Kastenbauer E. Tracheal transplantation: demonstration of HLA class II subregion gene products on human trachea. Acta Otolaryngol. 1990;110:149–154. 38. Pacheco CR, Rivero O, Porter JK. Experimental reconstructive surgery of the trachea. J Thorac Surg. 1954;27:554–564. 39. Beigel A, Steffens-Knutzen R, Muller B, Schumacher U, Stein H. Tracheal transplantation. III. Demon stration of transplantation antigens on the tracheal mucosa of inbred rat strains. Arch Otorhinolaryngol. 1984;241:1–8. 40. Neville WE, Bolanowski PJ, Soltanzadeh H. Homograft replacement of the trachea using immunosuppression. J Thorac Cardiovasc Surg. 1976;72: 596–601. 41. Rose KG, Sesterhenn K, Wustrow F. Tracheal allot ransplantation in man. Lancet. 1979;1(8113):433. 42. Levashov Y, Yablonsky PK, Cherny SM, Orlov SV, Shafirovsky BB, Kuznetzov IM. One-stage allotransplantation of thoracic segment of the trachea in a patient with idiopathic fibrosing mediastinitis and marked tracheal stenosis. Eur J Cardiothorac Surg. 1993;7:383–386. 43. Klepetko W, Marta GM, Wisser W, et al. Heterotopic tracheal transplantation with omentum wrapping in the abdominal position preserves functional and structural integrity of a human tracheal allograft. J Thorac Cardiovasc Surg. 2004;127:862–867. 44. Zhao F, Zhang Y, Liu S, Yu J. Artificial trachea reconstruction with two-stage approach using memoryalloy mesh. Chin Med J. 2003;116:1949–1951. 45. Cai C, Jiang RC, Li ZB, et al. Two-stage tracheal reconstruction of primary tracheal non-Hodgkin lymphoma with nitinol mesh stent and cervical myocutaneous flap. Ann Thorac Surg. 2008;85: e17–e19. 46. Maciejewski A, Szymczyk C, Półtorak S, Grajek M. Tracheal reconstruction with the use of radial forearm free flap combined with biodegradative mesh suspension. Ann Thorac Surg. 2009;87:608–610. 47. Beldholm BR, Wilson MK, Gallagher RM, Caminer D, King MJ, Glanville A. Reconstruction of the trachea with a tubed radial forearm free flap. J Thorac Cardiovasc Surg. 2003;126:545–550.
40. Tracheal Reconstruction with Autologous and Engineered Tissues 48. Strome M, Stein J, Esclamado R, et al. Laryngeal transplantation and 40-month follow-up. N Engl J Med. 2001;344:1676–1679. 49. Walles T, Giere B, Hofmann M, et al. Experimental generation of a tissue-engineered functional and vascularized trachea. J Thorac Cardiovasc Surg. 2004; 128:900–906. 50. Mertsching H, Walles T, Hofmann M, Schanz J, Knapp WH. Engineering of a vascularized scaffold for artificial tissue and organ generation. Bioma terials. 2005;26:6610–6617. 51. Grimmer JF, Gunnlaugsson CB, Alsberg E, et al. Tracheal reconstruction using tissue-engineered cartilage. Arch Otolaryngol Head Neck Surg. 2004;130: 1191–1196. 52. Kim J, Suh SW, Shin JY, Kim JH, Choi YS, Kim H. Replacement of a tracheal defect with a tissue- engineered prosthesis: early results from animal experiments. J Thorac Cardiovasc Surg. 2004;128: 124–129. 53. Kojima K, Ignotz RA, Kushibiki T, Tinsley KW, Tabata Y, Vacanti CA. Tissue-engineered trachea from sheep marrow stromal cells with transforming growth factor beta2 released from biodegradable microspheres in a nude rat recipient. J Thorac Cardiovasc Surg. 2004;128:147–153. 54. Kamil SH, Eavey RD, Vacanti MP, Vacanti CA, Hartnick CJ. Tissue-engineered cartilage as a graft source for laryngotracheal reconstruction: a pig model. Arch Otolaryngol Head Neck Surg. 2004;130: 1048–1051. 55. Macchiarini P, Walles T, Biancosino C, Mertsching H. First human transplantation of a bioengineered airway tissue. J Thorac Cardiovasc Surg. 2004;128:638–641. 56. Omori K, Nakamura T, Kanemaru S, et al. Regenerative medicine of the trachea: the first human case. Ann Otol Rhinol Laryngol. 2005;114:429–433. 57. Macchiarini P, Jungebluth P, Go T, et al. Clinical transplantation of a tissue-engineered airway. Lancet. 2008;372(9655):2023–2030. 58. Ris H-B, Krueger T, Cheng C, Pasche P, Monnier P, Magnusson L. Tracheo-carinal reconstructions using extrathoracic muscle flaps. Eur J Cardiothorac Surg. 2008;33:276–283. 59. Guerrissi JO, Guerrissi JA, Miranda MG. Functional reconstruction of the trachea: prelaminated chondromuscular flap. J Craniofacial Surg. 2009;20:868–871. 60. Nouraei SAR, Nouraei SM, Sandison A, Howard DJ, Sandhu GS. The prefabricated sternohyoid myocartilagenous flap: a reconstructive option for treating recalcitrant adult laryngotracheal stenosis. Laryngo scope. 2008;118:687–691. 61. Nakahira M, Nakatani H, Takeuchi S, Higashiyama K, Fukushima K. Safe reconstruction of a large cervico-mediastinal tracheal defect with a pectoralis major myocutaneous flap and free costal cartilage grafts. Auris Nasus Larynx. 2006;33:203–206. 62. Shinohara H, Yuzuriha S, Matsuo K, Kushima H, Kondoh S. Tracheal reconstruction with a prefa bricated deltopectoral flap combined with costal
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c artilage graft and palatal mucosal graft. Ann Plast Surg. 2004;53:278–281. 63. Friedman M, Toriumi DM, Owens R, Grybauskas VT. Experience with the sternocleidomastoid myoperiosteal flap for reconstruction of subglottic and tracheal defects: modification of technique and report of long-term results. Laryngoscope. 1988;98:1003–1011. 64. Yu P. One-stage reconstruction of complex pharyngoesophageal, tracheal, and anterior neck defects. Plast Reconstr Surg. 2005;116:949–956. 65. Wu LY, Halim AS, Sain AHM. Laminated pedicled latissimus dorsi myocutaneous flap for single-stage reconstruction of a composite anterior neck and tracheal defect. J Otolaryngol. 2005;34:69–72. 66. He J, Xu X, Chen M, et al. Novel method to repair tracheal defect by pectoralis major myocutaneous flap. Ann Thorac Surg. 2009;88:288–291. 67. Fanous N, Husain S, Ruzmetov M, Rodefeld M, Turrentine M, Brown J. Anterior pericardial tracheoplasty for long-segment tracheal stenosis: long-term outcomes. J Thorac Cardiovasc Surg. 2009 Nov 10 (Epub ahead of print). 68. Dunham ME, Holinger LD, Backer CL, Mavroudis C. Management of severe congenital tracheal stenosis. Ann Otol Rhinol Laryngol. 1994;103:351–356. 69. Bando K, Turrentine MW, Sun K, et al. Anterior pericardial tracheoplasty for congenital tracheal stenosis: intermediate to long-term outcomes. Ann Thorac Surg. 1996;62:981–989. 70. Fica M, Rodríguez P, Prats R, Mañana M. Tracheal hamartoma: pericardial flap replacement of membranous tracheal wall. Eur J Cardiothorac Surg. 2002;21:355–357. 71. Gorenstein LA, Abel JG, Patterson GA. Pericardial repair of a tracheal laceration during transhiatal esophagectomy. Ann Thorac Surg. 1992;54:784–786. 72. Okike N, Payne WS, Cortese DA, Dines DE. Pericardial reconstruction of the membranous trachea after resection of adenoid cystic carcinoma (cylindroma). Mayo Clin Proc. 1978;53:808–810. 73. Sharpe DA, Moghissi K. Tracheal resection and reconstruction: a review of 82 patients. Eur J Cardiothorac Surg. 1996;10:1040–1046. 74. Moriyama H, Sasajima T, Hirata S, Yamazaki K, Yatsuyanagi E, Kubo Y. Revascularization of canine cryopreserved tracheal allografts. Ann Thorac Surg. 2000;69:1701–1706. 75. Bujia J, Wilmes E, Hammer C, Kastenbauer E. A comparison of class II antigenicity of human tracheal allografts stored in cialit and in merthiolate. Laryngoscope. 1990;100:1337–1340. 76. Herberhold C. Tracheal reconstruction with a preser ved homograft. Laryngorhinootologie. 2001;80:57–60. 77. Herberhold C, Stein M, Bierhoff E, Kost S. Tracheal reconstruction with preserved tracheal homograft– new aspects. Laryngorhinootologie. 1999;78:54–56. 78. Jacobs JP, Elliott MJ, Haw MP, Bailey CM, Herberhold C. Pediatric tracheal homograft reconstruction: a novel approach to complex tracheal stenoses in children. J Thorac Cardiovasc Surg. 1996;112:1549–1560.
362 79. Jacobs JP, Quintessenza JA, Andrews T, and colleagues. Tracheal allograft reconstruction: the total North American and worldwide pediatric experiences. Ann Thorac Surg. 1999;68:1043–1052.
E. Grunenwald et al. 80. Genden EM, Govindaraj S. Allograft tracheoplasty technique for management of refractory tracheal stenosis. Ann Otol Rhinol Laryngol. 2006;115: 302–305.
41
Optimal Management of Malacic Airway Syndromes Cameron D. Wright
Tracheobronchomalacia (TBM), although uncommon, is increasingly recognized as a medical condition that may require treatment among patients with pulmonary disorders.1,2 The diagnosis of TBM is now often made on a CT scan done for reasons other than the confirmation of a suspected diagnosis of TBM. These “incidental” diagnoses of TBM need to be viewed with caution, as radiographic abnormalities do not always correlate with physiologic effects. TBM most often co-exists with chronic obstructive pulmonary disease (COPD), and it remains difficult to judge to what extent each diagnosis contributes to the symptoms of each patient. Typical symptoms that patients seek treatment for include dyspnea, cough, inability to clear secretions, and recurrent pulmonary infections. TBM can be treated by airway stent insertion (self-expanding metallic or silicone) or by membranous wall tracheobronchoplasty. A Pubmed search was done to locate relevant articles using three key words: tracheomalacia OR tracheomalacia treatment OR tracheomalacia stent for the period December 2003 to September 2009. Only English language articles were reviewed. There were no randomized controlled trials reported. Case reports, small case series and articles about treatment of focal tracheomalacia were discarded. The remaining articles were reviewed with respect to the cited literature for any additional relevant articles. Evidence was graded and treatment recommendations were generated based upon recommendations of the American College of Chest Physicians.3
Self-Expanding Metallic Stents for TBM Self-expanding metallic stents (Wallstent – Boston Scientific, Galway, Ireland; Ultraflex – Boston Scien tific, Watertown, MA) have been placed for a variety of benign indications, including TBM. There are numerous reports of cases and small series that indicate there are many severe complications that occur in these patients with the passage of time.4–7 These include obstructing granulation tissue, mucus plugging, recurrent infections, stent migration, metal fatigue, stent fracture, halitosis, and difficulty with removal when indicated. Death has been reported as well. The Food and Drug Admini stration (FDA) issued a warning on 7/29/2005 regarding use of these stents for benign indications, restricting their use for only inoperable patients.8 Madden and colleagues reported on 31 patients, of whom 7 had tracheomalacia treated with an Ultraflex expandable metallic stent (Table 41.1).4 Complications were frequent and occurred in all patients with TBM. Four of the seven patients with TBM died during follow-up, none reportedly from
Table 41.1. Results of self-expanding stent placement for tracheobron chomalacia. Study
Year Patients Improved (%) Complications (%) Evidence quality
Saad 2003 Madden4 2006
5 7
5
Chan6
2008
23
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_41, © Springer-Verlag London Limited 2011
75 Not stated 83
57 100 (57% mortality) 80
Low Low Low
363
C.D. Wright
364
a stent complication. Unfortunately, there was no evaluation of the success of stent placement. Saad and colleagues reported on metallic stent insertion in 82 patients, of whom 5 had TBM.5 Both Wall stents and Ultraflex stents were used. Improvement was noted in 75% of patients. Comp lications were noted in 57% of patients, including granulation tissue in 33%, infection in 19%, migration in 5%, and hemoptysis in 14%. Chan and colleagues reported on 35 patients, of whom 23 had TBM.6 Both Wallstents and Ultraflex stents were used. Improvement was noted in 83% of patients. Complications occurred in 80% of patients. Major complications included obstructive granulomas in 24%, stent fracture in 20%, and stent migration in 12%.
Silicone Stents for TBM Ernst and colleagues reported a prospective study of 58 patients who had silicone stent insertion for severe TBM (Table 41.2).9 Many patients (57%) had COPD, and most patients had diffuse TBM (80%). Self-reported symptoms improved in 45 patients. Quality of life scores improved in 19 of 27 patients, dyspnea scores improved in 22 of 24 patients, and functional status improved in 18 of 26 patients. Complications were most frequent during the first 3 months. There were 21 cases of mucus plugging, 14 of infection, stent migration in ten, severe cough in three, subglottic edema in three, and stent fracture in one. Murgu and colleagues reported on 15 patients with TBM who had silicone stent insertion as definitive treatment.10 All patients were judged to be poor operative candidates.All patients improved at least one functional class. Three patients had stent related complications within 48 h of stent insertion. Twenty-six stent related complications
Table 41.2. Results of silicone stent placement for tracheobronchomalacia. Study
Year
Patients
Ernst9
2007
58
Murgu10 2007
15
Improved Symptomatic improvement in 78% Functional class improved in 100%
Complications Evidence (%) quality 76
Low
83
Low
were observed in 10 of the 12 patients. Most patients required bronchoscopic reintervention and in many this was necessary on an emergent basis. Three patients died during follow-up and no deaths appeared to be related to the stent.
Membranous Wall Tracheobronchoplasty Some patients with TBM who are relatively fit are candidates for membranous wall tracheobronchoplasty. The posterior membranous wall of the trachea is reefed and sutured to a strip of polypropelene mesh to stabilize the membranous wall and reconfigure the trachea back to a more normal shape. Only two series have been recently been reported (Table 41.3).11,12 Wright and colleagues reported a retrospective series of 14 patients.11 Presenting symptoms included dyspnea (79%), severe cough (36%), recurrent infections (36%), and difficulty clearing secretions (36%). There were two (14%) early complications (ileus and pneumonia). There were no postoperative deaths. The mean length of stay was 8.8 days. All patients were subjectively impro ved in the early postoperative period. The forced expiratory volume during the first second (FEV1; percent of predicted) improved from 51% to 73% and peak expiratory flow rate improved from 49% to 70%. Ten patients were available for long-term follow-up: six were judged to have an excellent result, two had a good outcome and two experienced a poor result. Majid and colleagues reported a prospective series of 35 patients who underwent tracheobronchoplasty.12 Presenting symptoms were dyspnea (94%), severe cough (74%), and recurrent pulmonary infections (51%). Twenty of the 35 Table 41.3. Results of membranous wall tracheobronchoplasty for tracheo bronchomalacia. Study
Year
Patients Improvement
Wright11 2005
14
2008
35
Majid12
Early – 100% Late – 80% Quality of life improved in 81%
Morbidity 14% complications 0% mortality 43% complications
6% mortality
Evidence quality Low Low
365
41. Optimal Management of Malacic Airway Syndromes
patients had COPD. Important selection criteria included placement of a temporary silicone stent first to see if patients were improved (37 of 57 were improved). If there was significant improvement and the patients were medically fit, they were then referred for operation. The median length of stay was 8 days. Surgical complications occurred in 15 patients (43%). Two patients died (6% mortality). After surgery, quality of life scores improved in 25 of 31 patients, dyspnea scores improved in 19 of 26 patients, and functional status improved in 20 of 31 patients.
term use of silicone stents for TBM because of possible late complications. I have seen mucus plugging causing cardiopulmonary arrest and problematic granulation tissue in patients with stents for only short periods of time. Due to these and other complications, I rarely recommend stent insertion as a definitive treatment for any patient with TBM, regardless of how symptomatic they are. Patients who are fit, respond well to temporary stent insertion, and are surgically minded are advised to undergo membranous wall tracheobronchoplasty. In my opinion, patients with disease limited to the trachea are better candidates than those with distal involvement.
Recommendations Placement of self-expanding metal stents does not provide lasting benefit for patients with tracheobronchomalacia and is associated with a high frequency of complications (low quality evidence). We make a weak recommendation against metallic stent insertion (Grade 2C). Placement of silicone stents may provide some benefit for a variable amount of time in patients who are poor surgical candidates with tracheobronchomalacia but is associated with a high frequency of complications (low quality evidence). We make a weak recommendation for silicone stent insertion (Grade 2C). Membranous wall tracheobrochoplasty provides some benefit for patients with tracheobronchomalacia but is associated with morbidity and mortality (low quality evidence). We make a weak recommendation for tracheobronchoplasty in patients who are good surgical candidates (Grade 2C).
Personal View of the Data Patients who present with TBM must be carefully evaluated when considering treatment, as there is uncertainty about the indications for intervention and treatment results are somewhat unpredictable. Patients with COPD, who represent the majority of evaluated patients, are the most difficult to evaluate, as their symptoms overlap with symptoms of TBM. The use of a temporary silicone stent for a diagnostic evaluation has much to recommend it. I remain concerned about the long-
Symptoms of tracheobronchomalacia can be improved with endoscopic and surgical management, although these procedures are often associated with complications (low quality evidence). We make a weak recommendation for silicone stent placement or membranous wall tracheobronchoplasty for treatment of tracheobronchial malacia in symptomatic patients (Grade 2C).
References 1. Carden KA, Boiselle PM, Waltz DA, Ernst A. Tracheomalacia and tracheobronchomalacia in children and adults. Chest. 2005;127:984–1005. 2. Kandaswamy C, Balasubramanian V. Review of adult tracheomalacia and its relationship with chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2009;15:113–119. 3. Guyatt G, Guterman D, Baumann MH, AddrizzoHarris D, Hylek EM, Phillips B, Raskob G, Lewis SZ, Schunemann H. Grading strength of recommendations and quality of evidence in clinical guidelines. Chest. 2006;129:174–181. 4. Madden BP, Loke TK, Sheth AC. Do expandable metallic airway stents have a role in the management of patients with benign tracheobronchial disease? Ann Thorac Surg. 2006;82:274–278. 5. Saad CP, Murthy S, Krizmanich G, Metha AC. Selfexpandable metallic airway stents and flexible bronchoscopy: long term outcomes analysis. Chest. 2003;124:1993–1999. 6. Chan AL, Juarez MM, Allen RP, Albertson TE. Do airway metallic stents for benign disease confer too costly a benefit? BMC Pulm Med. 2008;8:7. 7. Gaissert HA, Grillo HC, Wright CD, Donahue DM, Wain JC, Mathisen DJ. Complications of benign
366 t racheobronchial strictures by self-expanding stents. J Thorac Cardiovasc Surg. 2003;126:744–747. 8. FDA public health notification: complicatsions from metallic tracheal stents in patients with benign airway disorders. Available at: www.fda.gov/cdrh/safety /072905-tracheal.html Accessed 23 November 2009. 9. Ernst A, Majid A, Feller-Kopman D, Guerrero J, Boiselle P, Loring SH, O’Donnell C, DeCamp M, Herth FJ, Gangadharan S, Ashiku S. Airway stabilization with silicone stents for treating adult tracheobronchomalacia. Chest. 2007;132:609–616.
C.D. Wright 10. Murgu SD, Colt HG. Complications of silicone stent insertion in patients with expiratory central airway collapse. Ann Thorac Surg. 2007;84:1870–1877. 11. Wright CD, Grillo HC, Hammoud ZT, Wain JC, Gaissert HA, Zaydfudim V, Mathisen DJ. Tracheo plasty for expiratory collapse of central airways. Ann Thorac Surg. 2005;80:259–266. 12. Majid A, Guerrero J, Gangadharan S, Feller-Kopman D, Boiselle P, DeCamp M, Ashiku S, Michaud G, Herth F, Ernst A. Tracheobronchoplasty for severe tracheobronchomalacia. Chest. 2008;134:801–807.
42
Carinal Resection for Cancer Federico Venuta and Erino A. Rendina
Carinal resection and reconstruction still remains one of the most challenging areas of thoracic surgery. Both primary and metastatic lesions may involve this section of the airway; however, the most frequent scenario is represented by direct invasion by bronchogenic carcinoma (T4). Lung cancer tends to infiltrate in a cephalad direction and upper lobe tumors often extend to the proximal main bronchus, the carina, or the lateral wall of the distal trachea; this happens in particular on the right side. A spectrum of techniques has been reported for reconstructing the carina and the procedure may or may not be associated with resection of lung parenchyma, from sleeve lobectomy to pneumonectomy. All the procedures are technically demanding and hampered by potentially serious complications. However, recent reports from experienced centers with large series1–8 have clearly demonstrated that the surgical approach is safe, with an operative mortality of less than 10%, and that long term survival is encouraging in well selected groups of patients. Careful preoperative evaluation and selection, meticulous surgical technique and close postoperative monitoring are crucial for success. A literature search was performed using PubMed database; the search terms were: carinal resection, carinal reconstruction, carinal resection and reconstruction, primary tracheal tumors, tracheal resection, lung cancer and carinal resection, lung cancer and carinal involvement, T4 lung cancer; the timeframe was 1990–2009; only original articles, reviews and case reports in English were selected; papers from the same group published in different years with increasing numbers or different subsets of patients were included to evaluate the progression of
results. Series of patients undergoing carinal reconstruction mixed with other subgroups of patients (i.e. sleeve resections or tracheal resection) were reported only if a reasonable number of patients were included and it was possible to extrapolate the characteristics of the patient population, the details of the surgical procedure, operative morbidity and mortality and long-term results. Strength of recommendations and quality of evidence were ascertained according to the Report of the American College of Chest Physicians Task Force.9 Unfortunately, no randomized studies were available, and this affects grading and strength of recommendation.
Indications The most frequent indication for carinal reconstruction is direct involvement by bronchogenic carcinoma; in this setting the procedure should be considered when the tumor involves the first centimeter of the ipsilateral main bronchus, the lateral aspect of the lower trachea, the carina, or the take off of the contralateral main bronchus. This scenario is more frequent on the right side; tumors arising on the left side rarely extend up to the carina without extensively invading the subaortic region. In patients with lung cancer carinal reconstruction is associated with pneumonectomy in most of the cases. Carinal resection and reconstruction may be required also for primary airway tumors; in particular, mucoepidermoid and adenoidcystic carcinoma as well as squamous cell carcinoma may pose an indication, due to their pattern of growth. In fact, these tumors tend to extend locally in most
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of the cases, involving the airway longitudinally and circumferentially; however, they may also penetrate extraluminally to involve adjacent structures. Contraindications are mainly related to the functional status of the patients. However, some oncologic considerations also deserve attention: patients with N2 and N3 lung cancer show poor long term results; for this reason PET (positron emission tomography), CT (computed tomography) and mediastinoscopy should be included in the preoperative work up and, if positive mediastinal lymph nodes are found, this is usually considered a contraindication to surgery. Induction therapy may be considered but it increases the technical difficulty of the operation and may be associated with greater operative mortality, in particular when carinal pneumonectomy is performed. Preoperative functional work-up should be performed as for all the other patients who are candidates for major thoracic procedures.
Surgical Techniques The surgical approach is planned according to the type of carinal resection required. Carinal resection without lung parenchyma sacrifice is usually performed through a transpericardial approach via median sternotomy. If lung resection (usually a pneumonectomy) is required, an ipsilateral thoracotomy is the approach of choice. However, for left carinal pneumonectomy median sternotomy may enhance exposure8,11; also an approach through anterior or bilateral thoracotomies and clamshell incision have been reported.12,13
Isolated Carinal Resection This procedure is indicated for tumors involving only the carina and/or the origin of the right or left main bronchus. Limited resection of the carinal region can be reconstructed approximating the main bronchi fashioning a new spur that is sub sequently anastomosed to the distal trachea. If a more extended resection is indicated, end-to-end plus end-to side anastomosis are required: end-toend anastomosis between the trachea and right main bronchus with end-to-side anastomosis of the left main bronchus across the mediastinum into the bronchus intermedius14 or into the lateral wall of
the trachea15; Eschapasse inverted the Barclay technique,16 anastomosing the left main bronchus to the trachea and the right main bronchus either to the left main bronchus or to the trachea.
Right Carinal Pneumonectomy This is the most frequent type of carinal resection in patients with lung cancer. The trachea and contralateral main bronchus are divided, limiting the length of the resection to less than 4 cm. The left main bronchus is anastomosed to the distal tracheal.
Carinal Resection with Lobar Resection Lung cancer may extend proximally from the right upper lobe orifice, involving the right main bronchus to near its origin, and even the carina itself. This presentation requires distal dissection, involving the right upper lobe take off and the vascular elements of the lobar hilum, to ascertain if a sleeve lobectomy can be performed as an alternative to pneumonectomy. After removing the lobe and a sleeve of bronchus en bloc with the carina, preserving the middle and lower lobe, the left main bronchus is anastomosed to the distal trachea; the bronchus intermedius is subsequently anastomosed 1 cm below, on the medial side of the left main bronchus. Occasionally, the residual right lobes can be anastomosed on the right lateral wall of the trachea above the anastomosis with the left bronchus.
Left Carinal Pneumonectomy On the left side the aortic arch usually hampers dissection and anastomosis. A safe exposure can be accomplished through median sternotomy with a transpericardial approach. The left pleural space is entered to allow dissection of the hilum and removal of the left lung: an end–to–side anastomosis between the trachea and right main bronchus is subsequently performed.
Results The initial reports on carinal resection with or without pulmonary resection were associated with a high postoperative mortality rate.17–19 At that time focus was directed towards feasibility, technical details and immediate benefits. During
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the following years, improved patient selection, technical skills, anesthesia and ICU care have significantly contributed to improve early and long term outcome. In a quarter of century the mortality rate for carinal resection and reconstruction has significantly decreased, not exceeding 10% in most of large studies from single institutions.5,6,20,21 However, the mortality rate still exceeds that for isolated lung resection; this is particularly true for carinal pneumonectomy.4,6 The most frequent complications are ARDS and respiratory failure, cardiac events and infection. In contrast, bronchopleural fistula and other anastomotic complications have significantly decreased in frequency with the improvement of experience and technical skills.
Macchiarini and colleagues7 contributed to improving intraoperative management during carinal pneumonectomy: low tidal volumes controlled techniques are indicated; high inspiratory oxygen concentrations, repeated collapse and reexpansions of the lung, and hypoxic pulmonary vasoconstriction during hypoperfusion of the ipsilateral lung or hyperperfusion of the contralateral lung should be avoided.22–24 Also apneic techniques can be applied to improve exposure and limit airway manipulation.7 Long term results can now be addressed referring to several recent studies, many of them reporting on more than 50 patients (Table 42.1); in most of these series overall 5 year survival exceeds 40%; encouraging survival rates at 10 years have been reported.
Table 42.1. Carinal resection and reconstruction 1990–2008 and historical reference.
Author
Year
Patients
Primary airway tumors
Grillo30 Watanabe25 Tsuchiya19 Mathisen26 Muscolino13 Maeda12 Roviaro27 Dartevelle1 Mitchell6 Spaggiari28 Mitchell5 Di Rienzo29 Porhanov4 Mezzetti30 Gaissert3 Regnard2 Macchiarini7 De Perrot8 Roviaro31 Gaissert32 Yamamoto33 Yamamoto34 Rea10
1982 1990 1990 1991 1992 1993 1994 1995 1999 2000 2001 2001 2002 2002 2004 2005 2006 2006 2006 2006 2007 2007 2008
36a 15 20 37 7 42 28 55 143e 6f 60 6 231 27 61 65 50 119 53 18 14 35 49
23 2 0 0 0 0 0 0 60 0 0 0 45 0 61 0 0 19 0 18 0 1 0
Lung cancer 5 13 20 37 7 31 28 55 58 6 60 6 151 27 0 65 50 100 53 0 14 34 49
Operative Induction No pulmonary mortality therapy resection (%) NR 0 0 NR 0 11 16 12 16 6 9 0 NR 15 NR 11 18 23 23 0 5 6 19
11 2 2 9 0 6 0 0 63 0 20 0 54 0 20 5 5 13 0 18 0 1 0
13 13.1 15 8 0 9.7 3.6 7.2 13 0 15 0 16 17.4 16 7.7 4 7.6 7.5 11.1 7.1 8.5 6.1
Airway complications (%)
N0
N1
N2
19.4 26.7 0 18.9 14.3 11.9 0 5.5 17.1 0 16.7 0 25.1 7.4 NA 15.4 16 10.1 1.9 NA 28.5 11.4 4.1
NR 4 3 19 3 30 IIIA/B 14 9 NR 0 34 4 4 8 NA 10 21 14 24 – 9 16 21
NR 2 3 3 3
NR 8 12d 5 1
9 35 NR 3 13 2 8 11 NA 32 11 59 16 – 0 3 13
5 11 NR 3 11g 0 35 8 NA 23 18 27g 12 – 5 10i 15
Survival Mean ~ 40.4 monthsb 20% 4 yearsc 59% 2 years 1% 5 years ~ 55% 5 years NR Mean 29 months 40% 5 years NR Median 14.5 months 42% 5 years Median 21 months 24.7 5 years 20% 5 years 45% 5 yearsh 26.5% 5 years 51% 5 years 44% 5 years 33.4% 5 years NA 28.5% 5 years 28.3% 5 years 27.5% 5 years
NR not reported; NA not assessable; N0 no nodal involvement in patients with lung cancer; N1 hilar nodal involvement in patients with lung cancer; N2 ipsilateral mediastinal nodal involvement in patients with lung cancer a 36 resections in 31 patients b calculated in 27 patients c including one N3 d two other patients were N3 e 143 resections in 134 patients f all the resections associated with superior vena cava reconstruction g N2 + N3 h including tracheal resections i in five patients with recurrent lung cancer staging was not reported
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In all the reported studies careful patient selection is stressed to obtain reliable long term results. In lung cancer patients survival is clearly related to nodal status; the presence of N2 disease is the most important oncologic prognostic factor, reducing 5-year survival to as low as 0%.1,20 The presence of metastatic mediastinal lymph node involvement has always been considered a potential contraindication and this is particularly true in this subset of patients. However, in patients with a potential indication for carinal resection and reconstruction, induction therapy (chemo- or chemo-radiation) was never systematically emplo yed, probably for the fear of increased anastomotic complications. A study from Macchiarini and associates7 demonstrated that this approach is feasible and it is able to pathologically downstage N2 status in a significant percentage of patients without affecting postoperative morbidity and mortality. In this study a prospective algorithm was proposed, stressing the importance of PET and invasive preoperative staging of the mediastinum with mediastinoscopy. According to this report, patients with invasion of more than two mediastinal nodal stations, as well as positive stations 2R/2L or N3 disease, should not undergo surgery. Notwithstanding these restrictions, in that study N1–N2 disease demonstrated a negative impact on multivariate analysis. However, no comparison is possible with patients who do not undergo resection; in fact, patients receiving medical treatment (chemoradiotherapy) were usually unsuitable for surgery due to their clinical status or stage of the disease. The lack of randomized studies and control studies with alternative treatments necessarily result in relatively low evidence grade and strength of recommendation.
Summary A moderate amount of data are available, primarily from retrospective clinical reviews, regarding the utility of carinal resection for cancer. As such, the quality of the data is low. Our review identified a number of important points. Nodal status significantly affects long-term outcomes. Preoperative staging with PET/CT is
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mandatory for appropriate patient selection. Preoperative staging with mediastinoscopy, EBUS, or other invasive procedures is mandatory when CT shows enlarged lymph nodes and/or when mediastinal lymph nodes are PET positive. Induction chemotherapy does not importantly affect postoperative morbidity and mortality. Carinal invasion due to bronchogenic carcinoma (T4) doesn’t require induction chemotherapy per se; induction therapy should be administered only if mediastinal lymph nodes are pathologically positive (N2/3). Overall, carinal resection for malignancy improves survival in appropriately selected patients, and has an acceptable level of morbidity and mortality in the hands of experienced surgeons (evidence quality low). We make a weak recommendation for carinal resection in appropriately selected patients with primary tracheal tumors or with regionally advanced lung cancer in the absence of N2 disease (recommendation grade 2B). Carinal resection and reconstruction still remains one of the most challenging areas of airway surgery; this is certainly related to technical details but also to careful patient selection required to optimize results. Surgery should be avoided if mediastinal lymph nodes are pathologically involved. Aggressive staging is mandatory; PET and mediastinoscopy should be performed to diagnose N2/3 disease. Patients presenting with bronchogenic carcinoma and negative mediastinal nodes are considered for carinal resection without any induction therapy; if N2 disease is discovered induction therapy can be safely performed without increasing postoperative morbidity and mortality.
Carinal resection for cancer offers possible long-term survival benefits for carefully selected patients with regionally advanced lung cancer or primary tracheal tumors, and has acceptable morbidity and mortality (low quality evidence). We make a weak recommendation for carinal resection in appropriately selected patients with primary tracheal tumors or with regionally advanced lung cancer in the absence of N2 disease (recommendation grade 2B).
42. Carinal Resection for Cancer
References 1. Dartevelle PG, Macchiarini P, Chapelier A. Update of: tracheal pneumonectomy for bronchogenic carcinoma: report of 55 cases. Ann Thorac Surg. 1995;60: 1854–1855. 2. Regnard JF, Perrotin C, Giovannetti R, et al. Resection for tumors with carinal involvement: technical aspects, results and prognostic factors. Ann Thorac Surg. 2005;80:1841–1846. 3. Gaissert HA, Grillo HC, Shadner B, et al. Long term survival after resection of primary adenoid cystic and squamous cell carcinoma of the trachea and carina. Ann Thorac Surg. 2004;78:1889–1897. 4. Porhanov VA, Poliakov IS, Selvaschuk P, et al. Indications and results of sleeve carinal resection. Eur J Cardiothorac Surg. 2002;22:685–694. 5. Mitchell JD, Mathisen DJ, Wright CD, et al. Resection for bronchogenic carcinoma involving the carina: long-term results and effect of nodal status on outcome. J Thorac Cardiovasc Surg. 2001;121: 465–471. 6. Mitchell JD, Mathisen DJ, Wright CD, et al. Clinical experience with carinal resection. J Thorac Cardio vasc Surg. 1999;117:39–53. 7. Macchiarini P, Altmeyer M, Go T, et al. technical innovations of carinal resection for nonsmall-cell lung cancer. Ann Thorac Surg. 2006;82:1889–1897. 8. De Perrot M, Mercier EF, Mussot S, Chapelier A, Dartevelle P. Long term results after carinal resection for carcinoma: does the benefit warrant the risk ? J Thorac Cardiovasc Surg. 2006;131:81–89. 9. Guyatt G, Gutterman D, Baumann MH, AddrizzoHarris D, et al. Grading strength of recommendations and quality of evidence in clinical guidelines. Report from an American College of Chest Physicians task force. Chest. 2006;129:174–181. 10. Rea F, Marulli G, Schiavon M, et al. Tracheal sleeve pneumonectomy for non small cell lung cancer (NSCLC): short and long – term results in a single institution. Lung Cancer. 2008;61:202–208. 11. Pearson FG, Todd TR, Cooper JD. Experience with primary neoplasms of the trachea and carina. J Thorac Cardiovasc Surg. 1984;88:511–518. 12. Maeda M, Nakamoto K, Tsubota N, Okada T, Katsunara H. Operative approaches for left sided carinoplasty. Ann Thorac Surg. 1993;56:441–446. 13. Muscolino G, Valente M, Ravasi G. Anterior thoracotomy for right pneumonectomy and carinal reconstruction in lung cancer. Eur J Cardiothorac Surg. 1992;6:11–14. 14. Barclay RS, McSwan N, Welsh TM. Tracheal resection without the use of grafts. Thorax. 1957;12:177–180. 15. Grillo HC, Bendixen HH, Geherart T. Resection of carina and lower trachea. Ann Surg. 1963;158: 889–893. 16. Eschapasse H, Vahdat F, Gaillard J, Besso JC. Reflections on resection of the lower trachea and bronchial bifurcation. Ann Chir Thorac Cardiovasc. 1967;6:63–70.
371 17. Jensik RJ, Faber LP, Kittle CF, et al. Survival in patients undergoing tracheal sleeve pneumonectomy for bronchogenic carcinoma. J Thorac Cardio vasc Surg. 1982;84:489–496. 18. Deslauriers J, Beaulieau M, McClish A. Tracheal sleeve pneumonectomy. In: Shields TW, ed. General Thoracic Surgery. Philadelphia, PA: Lea & Fabriger; 1989: 382–387. 19. Tsuchiya R, Goya T, Naruke T, et al. Resection of tracheal carina for lung cancer. Procedure, complications and mortality. J Thorac Cardiovasc Surg. 1990; 99:779–787. 20. Dartevelle P, Macchiarini P. Carinal resection for bronchogenic cancer. Semin Thorac Cardiovasc Surg. 1996;8:414–425. 21. Roviaro G, Varoli F, Romanelli A, et al. Complications of tracheal sleeve pneumonectomy: personal experience and overview of the literature. J Thorac Cardio vasc Surg. 2001;121:234–240. 22. Fessler HE, Brown RG. Protocols for lung protective ventilation. Crit Care Med. 2005;33:S223–S227. 23. Demling RH. The modern version of adult respiratory distress syndrome. Ann Rev Med. 1995;46:193–202. 24. Jordan S, Mitchell JA, Quinlan GJ, Goldstraw P, Evans TW. The pathogenesis of lung injury following lung resection. Eur Respir J. 2000;15:790–799. 25. Grillo HC. Carinal reconstruction. Ann Thorac Surg. 1982;34:356–373. 26. Mathisen DJ, Grillo HC. Carinal resection for bronchogenic carcinoma. J Thorac Cardiovasc Surg. 1991; 102:16–23. 27. Roviaro GC, Varoli F, Rebuffat C, et al. Tracheal sleeve pneumonectomy for bronchogenic carcinoma. J Thorac Cardiovsc Surg. 1994;107:13–18. 28. Spaggiari L, Pastorino U. Combined tracheal sleeve and superior vena cava resections for non-small cell lung cancer. Ann Thorac Surg. 2000;70:1172–1175. 29. Di Renzo G, Go T, Macchiarini P. Simplified anastomotic technique for end-to-side bronchial reimplantation onto the trachea or contralateral main bronchus after complex tracheobronchial resections. J Thorac Cardiovsc Surg. 2002;124:632–635. 30. Mezzetti M, Panigalli T, Giuliani L, Raveglia F, Lo Giudice F, Meda S. Personal experience in lung cancer sleeve lobectomy and sleeve pneumonectomy. Ann Thorac Surg. 2002;73:1736–1739. 31. Roviaro G,Vergnani C, Maciocco M,Varoli F, Francese M, Despini L. Tracheal sleeve pneumonectomy: long – term outcome. Lung Cancer. 2006;52:105–110. 32. Gaissert HA, Grillo HC, Shadmehr B, et al. Ann Thorac Surg. 2006;82:268–273. 33. Yamamoto K, Miyamoto Y, Ohsumi A, Imanishi N, Kojima F. Surgical results of carinal reconstruction: an alternative technique for tumors involving the tracheal carina. Ann Thorac Surg. 2007;84: 216–220. 34. Yamamoto K, Miyamoto Y, Ohsumi A, Imanishi N, Kojima F. Results of surgical resection for tracheobronchial cancer involving the tracheal carina. Gen Thorac Cardiovasc Surg. 2007;55:231–239.
Part 6
Pleura and Pleural Space
43
Use of Sealants to Reduce Air Leak Duration and Hospital Stay After Lung Resection Antonio D’Andrilli, Federico Venuta, and Erino A. Rendina
Introduction Parenchymal air leak is the most common compli cation after lung resection. It occurs in 48%1 to 70%2 of patients in large series. Prolonged paren chymal air leaks persisting over 7 days have been reported to have an incidence of 15–18%.3–5 The risk of prolonged air leak increases when interlo bar fissures are incomplete, and in patients with emphysematous lung. Furthermore, the presence of poor predicted postoperative forced expiratory volume during the first second, pleural adhesions and upper lobe resections have been found to be predictors of prolonged air leaks in large retro spective studies.3 Persisting air leaks have a detri mental effect on the postoperative course resulting in a longer need for chest tube drainage, with asso ciated pain, reduced mobility and increased risk of further complications.6 This is associated with prolonged hospital stay and higher costs of care, with the need for additional inpatient and outpa tient resources.7 Standard methods for intraoperative control of air leaks include suture and stapling, but have the disadvantage of causing further trauma to lung tissue. The routine use of surgical staplers for divi sion of lung parenchyma has improved the pri mary closure of resection lines. Buttressing of staple line with synthetic or biological materials, including bovine pericardial strips, has been rec ommended based on the positive results achieved in emphysema surgery.8 However, this technique can only be used in selected settings, since a num ber of additional potential sources of air leak have
to be considered, especially in hilar region and on decorticated lung surface areas. For these reasons, significant efforts have been made over recent years to minimize intraoperative air leaks after lung resection, including the search for improved surgical technique and the experimentation with a number of sealants to be used as an adjuvant to surgical technique.
Search Parameters Since industrial research is currently active in this field, many experiences with the use of sealants in lung surgery have been published, but most of them are not randomized trials. The search strategy for evidence regarding the use of sealants in lung surgery for this chapter has included only randomized controlled trials pub lished between 1990 and June 2009 (electronic search using MEDLINE) using the terms [exp lung neoplasms/ OR lung neoplasm/ OR lung carci noma OR lung cancer OR tumor OR pneumonec tomy OR lobectomy OR segmentectomy OR lung resection OR pulmonary resection OR decortica tion] AND [exp suture techniques/ OR tissue adhesive OR exp fibrin tissue adhesive/ OR sealant OR fibrin glue OR vivostat OR Coseal OR tachoc omb OR tachosil OR bioglue OR focalseal OR advaseal]. A total of 13 randomized trials1,2,9–19 were available in the English literature, representing the best evidence on this topic. Most of these studies include patients undergoing lobectomy or sublo bar resection, principally for lung cancer (71–92%
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of all the patients). Only two trials were exclusively conducted in patients with lung cancer.1,15 One trial10 included a large number of pneumonectomy patients, thus investigating the efficacy of the seal ant (fibrin glue) in the prevention and treatment of both parenchymal and bronchial air leaks. Only four trials included patients exclusively undergo ing lobectomy.1,9,13,15
Search Results Clinical experience in this field has indicated that sealant materials have to display a number of characteristics. They need to be sufficiently adher ent to withstand pressure of the inflated lung, but also elastic to accommodate the volume changes of the parenchyma during respiration. Moreover these products should also fix rapidly to the lung tissue and be unalterated by the intrapleural flu ids. They also need to be nonirritating, systemati cally non toxic, and without antigenicity. A number of different products have been eval uated. Fibrin based sealants, principally including fibrin glue, have been the most studied options, being employed in seven of these trials. Conven tional fibrin sealants generally include compo nents prepared from human plasma (fibrinogen, thrombin) and, sometimes, animal-derived com ponents such as bovine aprotinin and thrombin. These components carry a theoretical risk of transmitting human or animal-borne infectious agents including hepatitis (B and C) virus, human immunodeficiency virus type 1 (HIV-1), prions responsible for diseases such as Creutzfeldt Jacob disease or bovine spongiform encephalopathy. Moreover, additional concerns of antigenic reac tions to foreign proteins and of thrombotic effects from high concentration of added thrombin have been reported.20 For this reason, more recently, an autologous fibrin sealant to be prepared intraop eratively with the patient’s blood has been devised and employed in one of these trials.15 This fibrin sealant is free from added thrombin, thus avoiding the above mentioned potential adverse effects. Among the trials utilizing fibrin based products, two studies have experimented with a combina tion of a collagen patch coated with human fibrin ogen and thrombin.1,18 When applied to wet tissue
surfaces, the coagulation factors dissolve forming a stable fibrin clot which glues the collagen fleece to the tissue. Five other trials have tested the use of polyeth ylene glycol-based sealants.2,12,13,16,19 In three of these, the polymeric sealant was photopolymer ized by visible xenon light.2,12,13 These synthetic biodegradable materials offer the advantage of avoiding antigenicity and the risk of disease trans mission associated with human and animal sour ces of materials.However,the times for reabsorption vary from 1 month up to 10–16 months13 for some products, so that potential infectious problems due to foreign body effects in the pleural cavity have to be considered. Among the polyethylene glycol based sealants only one, used in the trial by Allen and colleagues,16 also includes human components (serum albumin), although the authors emphasize that it was derived from plasma according to meth ods specified by FDA that have been designed to minimize the risk of transmitting the principal blood-born pathogens. One randomized trial used a glutaraldehydebased sealant including bovine serum albumin.17 This sealant also carries a potential risk of bloodborne disease transmission because of its bovine components, although the specific incidence of this complication is not reported in the literature.
Disparities Among Trials The large variety of products that has been uti lized makes the scientific data non homogeneous, limiting the possibility of comparing results of different studies.21, 22 Moreover, there are several other aspects besides the sealant properties, dif fering from one study to another, that should be considered. They include the number of patients enrolled, the inclusion criteria, the management of chest drains, the mode of application of the sealant, and the experience of surgeons. A fundamental aspect influencing the accuracy of the results obtained is related to the number of patients included in each study. Five randomized trials9,11,12,15,17 include patients numbering from 11 to 33 for each study arm. These group sizes are con sidered too small to enable statistical comparisons concerning the topic investigated, although it must
43. Use of Sealants to Reduce Air Leak Duration and Hospital Stay After Lung Resection
be pointed out that one of these trials17 was stopped at its halfway point, on the basis of the interim anal ysis of results, because the predefined endpoints had been reached. Only the trial by D’Andrilli19 and colleagues in the English literature includes more than 100 patients for each study group. The inclusion criteria vary among the different randomized studies. Patients were randomized in only six trials11,13,16–19 after identifying intraopera tive air leaks, thus using the sealant with therapeu tic intent. In all the other trials, the staple line and the cut surfaces of the lung were routinely covered with the sealant regardless of the presence of air leaks. In these series the sealant was therefore principally used with a prophylactic intent. This methodological aspect may have influenced the scientific significance of the results obtained, since in many studies patients without intraoperative air leaks were enrolled, thus suggesting the possi bility of different air leaks rates between the treat ment group and the control group. This possible bias has been avoided in the study by Lang and colleagues,1 because patients without air leak were identified before randomization, and were ran domized to treatment options separately from the patients with air leak, assuring their equal distri bution between the two arms of the study. An interesting methodological aspect that shows clear differences among the trials analysed regards the intraoperative treatment modalities. In most of the studies the treatment arm includes the addi tion of the sealant to standard procedures (usually suture and stapling) employed to achieve air leak cessation, and is compared to the control arm receiving the standard treatment alone. Conversely, in some studies,1 the sealant is employed alone without previous surgical attempt to control air leaks and compared with the standard treatment. When considering the management of chest drain there is still high variability among different Institutions. In particular, there is no consensus regarding the best modality of suction applica tion. Many authors have based their choice on evi dence in literature23,24 that reports a reduced length of postoperative air leaks when water seal option is used if compared with the suction modality. Conversely, in other experience, the modality of suction is established on the basis of a patient by patient evaluation, or according to specific proto cols adopted in each institution.
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Furthermore, the criteria for removing the chest drain show many differences from one institution to another. Although most authors indicate the absolute absence of air leaks as the first necessary condition for removing the drain, there are some surgeons13,17 reporting cases of drain removal in presence of air leaks, even without using a clamp ing test.13 Also, the length of time reported from the air leak disappearance to the drain removal is variable. Moreover, there is high discrepancy among the authors concerning the quantity of flu ids drainage allowed during the 24 h prior to drain removal, ranging from less than 100–150 mL19 to less than 5 mL/kg.16 Because of the marked hetero geneity of the chest drain protocols used, the dura tion of chest drain may appear sometimes as a misleading parameter for evaluating the efficacy of the sealant and for comparing results among different studies. Also, outpatient chest tube man agement with Heimlich valves, which has reached widespread in recent years, has been used in some series with the obvious result of shortening the in-hospital stay.14,16 Some other variables, such as the mode of seal ant application (spray or syringe spot) or the experience of surgeons (residents or certified sur geons), are generally considered not important in influencing study outcomes since their uniformity is usually guaranteed within each study.
Results of Randomized Trials Although slight differences have been reported among the published randomized trials concern ing the postoperative outcome measures assessed, there are principally three parameters that have been emphasized and evaluated in almost all the studies to assess the efficacy of the sealants employed: the duration of air leaks, the time of chest tube removal and the length of hospital stay.
Air Leak Duration and Incidence Patients receiving the application of sealant showed a statistically significant reduction of the mean or median duration of postoperative air leaks in six trials (Table 43.1).1,2,13,14,17,19 Among these, only one employed the fibrin glue as the
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378 Table 43.1. Randomized controlled trials assessing the efficacy of sealants on duration of air leak after lung surgery. Author (year) Country Fleischer (1990) Canada9 Mouritzen (1993) Denmark10
Sealant/surgical procedures
Air leak incidence Treatment vs. control NR
Fibrin glue/ lobectomy bilobectomy, segmentectomy, wedge, decortication pneumonectomy Fibrin glue 33 pts standard Lobectomy 33 pts stand. + fibrin segmentectomy decortication
4 vs. 5 days (median) p > 0.05
Postoperative 38.7% vs. 65.5% p < 0.05
5 vs. 4 days (median) p = 0.79
NR
Macchiarini (1999) France12
Polyethyleneglycol Lobectomy bilobectomy, wedge
13 pts standard + fibrin 11 pts standard
1.9 vs. 2.4 days (mean) p = 0.2
Porte (2001) France13
Polyethylene-
59 pts standard
33.7 vs. 63.2 h (mean) p = 0.013
Intraoperative 0 vs. 82% p = 0.001 Postoperative 23% vs. 91% p = 0.001 Postoperative day 4
glycol photopolymerized by xenon light Lobectomy
procedures + sealant 61standard proc
Polyethyleneglycol based photopolymerized by xenon light
117 pts standard techniques + sealant 55 only standard tech
39 vs. 52.3 h (mean) p = 0.006
Postoperative 61% vs. 89% p < 0.001
Postoperative 34% vs. 68% p = 0.001 Prolonged 2% vs. 16% p = 0.015 Intraoperative 23% vs. 84% p < 0.001 Postoperative 65% vs. 86% p = 0.005 48 h 34% vs. 37% p = 0.76
Wain (2001) USA2
0.14 pts treatment (sealant) 14 pts control 59 pts surgery alone 55 pts surg. + sealant
Air leak duration Treatment vs. control 2.3 vs. 3.3 days (mean) p = 0.94
Wong (1997) UK11
Fibrin glue/ lobectomy
Patients
12.8% vs. 41.5% p = 0.002
Lobectomy, segment, wedge Fabian (2003) USA14
Fibrin glue Lobectomy bilob, segment, wedge
50 pts fibrin 50 pts control
1.1 vs. 3.1 days (mean) p = 0.005
Allen (2004) USA16
Polyethyleneglycol based with human albumin Lobectomy segment, wedge, decortication
2 vs. 2 days (median) p = 0.41
Lang (2004) (four countries)1
Equine collagen fleece with human fibrinogen and thrombin
95 pts standard treat + sealant 53 pts standard treatment randomization 2:1 ratio 96 pts sealant 93 pts standard treat
Lobectomy Glutaraldehyde based with bovine albumin Lobectomy, segmentectomy, wedge D’Andrilli (2009) Polyethylene glycol based Italy19 Lobectomy, segmentectomy Tansley (2006) UK17
Pts patients; NR not reported
1.9 vs. 2.7 (mean) p = 0.01
25 pts standard treat + sealant 27 pts standard treat
1 vs. 4 days (median) p < 0.001
NR
102 pts standard technique + sealant 101 pts standard technique
3.5 vs. 4.2 days (mean) p = 0.01
Intraoperative 14.7% vs. 40.6% p < 0.001
Study characteristics/ complications Patients without AL included Small numbers No sealant related complications Pneumonectomy included Pts without AL included No sealant related complications
Decortication included Only pts with AL Single surgeon No sealant relat. compl. Not stated whether blinded Small numbers Empyema 3.8% fibrin group Patients without AL included
Only pts with AL 6 months follow-up Drain removed in p.o. day 6 in spite of AL status 6.7% empyema in treatment group Multicenter 46 pts without AL included No standardized postop management protocol 3% empyema in the treatment group Pts without AL included Operations by residents No postop drain management protocol No sealant related complications Multicenter study Only pts with AL included 1 month follow-up No sealant related complications Multicenter study Patients without AL included Non blinded study No sealant related complications Only pts with AL included Small numbers Postop assessment not blinded No sealant related complications No sealant related complications Large statistical sample Only pts with AL included
43. Use of Sealants to Reduce Air Leak Duration and Hospital Stay After Lung Resection
sealant option, three used a polyethylene-glycol based sealant, one used a glutaraldehyde based sealant and one used a collagen patch coated with fibrinogen and thrombin. Fabian and colleagues, using fibrin glue,14 reported a mean air leak dura tion of 1.1 days in the group of patients treated by the sealant compared to 3.2 days in the control group. In the three studies using polyethylene gly col based sealants by Porte,13 Wain2 and D’Andrilli,19 the mean air leak duration in the sealant group compared to the control group was 33.7 versus 63.2 h, 39 versus 52.3 h and 3.5 versus 4.2 days, respectively. In Wain’s trial, that divided patients before randomization in “low risk” and “high risk” for air leaks, the benefit of sealant application was seen in both the groups, suggesting that selection of patients based on the degree of air leak risk is not necessary. Tansley17 reported a significantly reduced median air leak duration in the group of patients treated by a glutaraldehyde based sealant with respect to the control group (1 vs. 4 days). In the study by Lang employing the fibrinogen/ thrombin coated collagen patch,1 the mean dura tion of air leak was 1.9 days in the sealant group and 2.7 days in the group without sealant. This study, including a large number (52% of the total) of patients without air leak following lobectomy, also demonstrated that prophylactic use of the sealant after achieving surgical freedom from air leak is not required, since the occurrence of sec ondary air leaks after standard lobectomy is rare. In summary, based on these data, most of the studies showing a significant reduction of the length of postoperative air leakage after the seal ant application used a polyethylene glycol based product. A reduction in air leak duration was obtained in 6 of 11 of the randomized trials avail able in literature, and when considering the most studied options, this result was observed in 50% of the polyethylene glycol based sealant trials and in 25% of the fibrin glue trials. The incidence of a postoperative air leak was not different between the two groups of random ized patients in five trials, while in two studies this data were not available.15,18 In one of these,15 the rate of patients showing air leak was significantly lower (40% vs. 80%) in the sealant group in the immediate postoperative period, while in the other study by Anegg,18 there was no significant differ ence between the two groups of patients when comparing the incidence of air leaks persisting over 7 days postoperatively.
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In most of the studies the efficacy of the sealant was also assessed by the analysis of air leaks inci dence postoperatively at various times comparing patients receiving sealants with their controls (Table 43.1). Among the ten authors reporting these data, seven2,10,12–14,16,19 observed a significantly reduced incidence of postoperative and intraop erative (when assessed) air leaks. On the contrary, the trials by Lang1 and by Anegg18 reported no sig nificant difference, while Belboul15 observed a sig nificantly reduced rate of air leak in the sealant group immediately postoperatively, but this result was not confirmed during the hospital stay. In three trials10,12,16 despite the significant reduc tion obtained in terms of postoperative air leaks incidence, there was not a shortening of the mean or median duration of the air leaks in patients receiving sealants. Conversely, in the multicenter study by Lang,1 the mean air leaks length appeared significantly reduced in the sealant group although the air leaks incidence assessed 48 h after surgery was similar to that of the control group.
Chest Tube Duration The duration of pleural drain is generally consid ered a misleading measure to assess the efficacy of a treatment for parenchymal air leaks due to a number of reasons. First, persisting air leaks are not the only clinical event dictating continued chest tube drainage; there are other important causes, such as the high volume of the pleural fluid drainage and incomplete residual lung expansion requiring prolonged drainage. Moreover there is wide discrepancy among the authors concerning the quantity of pleural fluids permitting the tube removal, as previously reported in this chapter. Second, the protocols for chest tube management are inhomogeneous when considering the timing of tube removal with respect to the air leak status. There are authors who remove the drain immedi ately after the air leak disappearance1 and authors that wait for 24 or 48 h in some patients with previ ous clamping test and radiological control. Also, there are authors who remove the drain on the same postoperative day in all patients independently from the air leak status13 and other authors who remove the drain despite persistent air leak.13,17 However, the mean or median time of chest drain removal has been reported in almost all (11 out of 13) randomized trials considered in this chapter, thus allowing an analysis on this data.
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Only three studies have reported a significant reduction of the pleural drainage time in the group of patients treated by the sealant (Table 43.2).14,17,18 One of these studies was that by Fabian, using the fibrin glue, that reported a 3.5 day mean duration of the chest tube in the sealant group compared to 5 days in the control group. Also the trial by Tansley17 with a glutaraldehyde based sealant reg istered a median drain duration of 4 days in the group treated with the product, which was signifi cantly shorter than that observed in the control group (5 days). The most recent study assessing the efficacy of a fibrinogen/thrombin coated col lagen patch18 has been the last in the literature observing a significant reduction of the chest drain duration in those patients receiving the
adhesive application (5.1 vs. 6.3 days). The remain ing eight series reporting this data have not observed any statistically significant difference in the chest drain duration, although a trend towards a reduction of the drainage time following sealant application has been registered in some of them.10,15
Postoperative Hospital Stay The duration of postoperative hospital stay has been indicated as a flawed parameter for the evaluation of postoperative air leaks, since it could be influenced by many other medical and social factors (co-morbidity, inadequate familiar sup port) and by some aspects of the chest drain
Table 43.2. Randomized controlled trials assessing the efficacy of sealants on drain duration after lung surgery. Author (year) Country Fleischer (1990) Canada9 Mouritzen (1993) Denmark10
Wong (1997) UK11 Macchiarini (1999) France12 Porte (2001) France13
Wain (2001) USA2
Fabian (2003) USA14 Allen (2004) USA16 Belboul (2004) Sweden15 Tansley (2006) UK17 Anegg (2007) Austria18
Pts patients
Sealant/ surgical procedures Fibrin glue/ lobectomy Fibrin glue/ lobectomy, bilobectomy, segmentectomy, wedge, decortication pneumonectomy Fibrin glue/ lobectomy, segmentectomy decortication Polyethylene-glycol/ lobectomy, bilobectomy, wedge Polyethylene-glycol photopolymerized by xenon light/ lobectomy Polyethylene-glycol based photopolymerized by xenon light/ lobectomy, segmentectomy, wedge Fibrin glue/ lobectomy, bilobectomy, segmentectomy, wedge Polyethylene-glycol based with human albumin/ lobectomy, segmentectomy, wedge, decortication Fibrin (autologus)/ lobectomy Glutaraldehyde based with bovine albumin/ lobectomy, segmentectomy, wedge Equine collagen with human fibrinogen and thrombin/ lobectomy, segmentectomy
Patients
Drain duration (days) Treatment vs. control
14 pts treatment (sealant) 14 pts control 59 pts surgery alone 55 pts surg. + sealant
6.1 vs. 5.9 (mean) p = 0.95 3 vs. 4 p > 0.05
33 pts standard 33 pts stand. + fibrin
6 vs. 6 (median) p = 0.8
13 pts standard + fibrin 11 pts standard 59 pts standard procedures + sealant 61standard proc
6.1 vs. 6.9 (mean) p = 0.9 6 days
117 pts standard techniques + sealant 55 only standard tech
4.5 vs. 5.2 (mean) p = 0.41
50 pts fibrin 50 pts control 95 pts standard treat + sealant 53 pts standard treatment randomization 2:1 ratio 20 pts standard treat + sealant 20 pts standard treat 25 pts standard treat + sealant 27 pts standard treat
3.5 vs. 5 (mean) p = 0.02 6.8 vs. 6.2 (median) p = 0.67
75 pts sealant 77 pts standard treatment
5.1 vs. 6.3 (median) p = 0.02
1 vs. 2 (median) p = 0.068 4 vs. 5 (median) p = 0.01
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43. Use of Sealants to Reduce Air Leak Duration and Hospital Stay After Lung Resection
management (i.e. use or no use of outpatient devices such as Heimlich valve). The length of postoperative hospitalization was registered in all but one1 the randomized trials. Among the 12 studies including this data, only three found the length of hospital stay to be significantly shorter in the group treated with sealants compared to their controls (Table 43.3).16–18 The American study16 using a polyethylene-gly col based sealant with human albumin, and the trial by Tansley17 using a gluteraldehyde based sealant reported the same median hospital stay
duration: 6 days in the treatment group and 7 days in the standard care group. More recently the Austrian study assessing the efficacy of a fibrino gen/thrombin coated collagen patch18 has shown a significant reduction of hospital stay in the group treated with the sealant (6.2 vs. 7.7 days). In all the other nine trials reporting this outcome, the length of postoperative hospitalization was not signifi cantly influenced by the sealant application, indi cating that the reduction of air leaks incidence and/or duration is frequently not sufficient to shorten the postoperative hospital stay. This may
Table 43.3. Randomized controlled trials assessing the efficacy of sealants on hospital stay after lung surgery. Author (year) Country Fleischer (1990) Canada9 Mouritzen (1993) Denmark10
Wong (1997) UK11 Macchiarini (1999) France12 Porte (2001) France13
Wain (2001) USA2
Fabian (2003) USA14 Allen (2004) USA16
Belboul (2004) Sweden15 Tansley (2006) UK17 Anegg (2007) Austria18 D’Andrilli (2009) Italy19
Pts patients
Sealant/ surgical procedures Fibrin glue/ lobectomy Fibrin glue/ lobectomy, bilobectomy, segmentectomy, wedge, decortication pneumonectomy Fibrin glue Lobectomy, segmentectomy decortication Polyethylene-glycol Lobectomy, bilobectomy, wedge Polyethylene-glycol photopolymerized by xenon light Lobectomy Polyethylene-glycol based photopolymerized by xenon light Lobectomy, segmentectomy, wedge Fibrin glue Lobectomy, bilobectomy, segmentectomy, wedge Polyethylene-glycol based with human albumin Lobectomy, segmentectomy, wedge, decortication Fibrin (autologus) Lobectomy Glutaraldehyde based with bovine albumin Lobectomy, segmentectomy, wedge Equine collagen with human fibrinogen and thrombin Lobectomy, segmentectomy Polyethylene glycol based Lobectomy, segmentectomy
Patients
Hospital stay (days) Treatment vs. control
14 pts treatment (sealant) 14 pts control 59 pts surgery alone 55 pts surg. + sealant
9.8 vs. 11.5 (mean) p = 0.21 9 vs. 10 (median) p > 0.05
33 pts standard 33 pts stand. + fibrin
8 vs. 9 (median) p = 0.57
13 pts standard + fibrin 11 pts standard 59 pts standard procedures + sealant 61standard proc
13.0 vs. 14.4 p = 0.4 9.2 vs. 8.6 p > 0.05
117 pts standard techniques + sealant 55 only standard tech
7.4 vs. 10.1 p = 0.78
50 pts fibrin 50 pts control 95 pts standard treat + sealant 53 pts standard treatment randomization 2:1 ratio
4.6 vs. 4.9 p = 0.32 6 vs. 7 p = 0.02
20 pts standard treat + sealant 20 pts standard treat 25 pts standard treat + sealant 27 pts standard treat
4 vs. 4.5 (median) p = 0.12 6 vs. 7 p = 0.004
75 pts sealant 77 pts standard treatment
6.2 vs. 7.7 p = 0.01
102 pts standard technique + sealant 101 pts standard technique
5.7 vs. 6.2 (mean)
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confirm that other clinical events play a crucial role in the postoperative outcome, especially when patients with advanced age and compromised performance status are enrolled. In conclusion, among all the 13 randomized studies analysed in this chapter, only that by Tansley,17 experimenting with a glutaraldehyde based sealant, reported in the treatment groups statistically significant benefit in terms of median air leaks duration, length of chest drain and length of hospitalization. The concomitant evidence of significant advantages in all these three parame ters was observed in no other experience.
Other Measures As the sealants investigated have variable time of absorption and adherence to tissues that modifies over time, concern about theoretical foreign body effects determining increased pleural fluids drain age have been expressed by some authors. However, none of the studies analysing this parameter14,16,19 found statistical significant difference concerning the volume of pleural fluid drainage between the two study groups.
Complications There was no clinical or laboratory evidence of sealant related complications in all but one13 of the randomized trials. In these studies the distribu tion of reported surgical and medical morbidity also was generally similar between the group treated by sealant and the control group. Con versely, in the study by Porte,13 testing a polyethyl ene glycol based sealant photopolymerized by xenon light, a 6.7% (4/59 patients) incidence of empyema was observed in the sealant group com pared to no evidence of this complication in the control group. Although this difference did not reach statistical significance, the complication was considered by the authors to be related to the seal ant application. On the basis of radiological and clinical findings, it has been hypothesized that the sealant might act as a foreign body in the chest cavity creating an impermeable pleural space lia ble to be infected, due the lack of sufficient adher ence to the lung over time. In the trial by Wain,2 3% of patients in the treatment group developed empyema compared to none in the control group,
without any statistically significant difference and any evident correlation with the sealant use. In the study by Macchiarini12 one case of pleural empy ema (3.8% incidence) was observed in the treat ment group, but the infectious complication was associated with a broncho-pleural fistula and con sidered not related to the sealant application.
Recommendation A reduction of air leak incidence was observed postoperatively after sealant application in 70% of the randomized trials reporting this data (evi dence quality moderate), but a shortening of air leak duration was observed in a lower percentage of studies (6 out of 11 analysing this measure; evi dence quality low). The reduction of air leak inci dence and/or duration did not influence the other important outcomes, including duration of chest tube drainage and length of hospital stay (evidence quality high). Sealant application is generally safe since only one study reported a possible increase in sealant related complications (evidence quality high). Despite some potential advantages, the data dictate a weak recommendation against the rou tine use of surgical sealants after lung resection (recommendation grade 2B). Further randomized controlled studies with more homogeneous patient selection criteria and methods and adequate sam ple size are required in the future in order to better define the utility of sealants and to identify the most effective option to use.
A Personal View of the Data We have experience with the use of a synthetic polyethylene-glycol based sealant in a large pro spective randomized study19 and have tested some other products during our surgical activity over the last years. Results obtained in the prospective randomized trial have indicated that the addition of the sealant to the standard surgical technique is able to significantly reduce incidence and dura tion of air leaks after lung resection but has a lim ited impact on the overall postoperative outcome, since it does not significantly reduce the length of hospital stay. This result should not be surprising
43. Use of Sealants to Reduce Air Leak Duration and Hospital Stay After Lung Resection
if we consider that air leaks are not the only nor the major cause of prolonged hospitalization, because a number of other medical and social fac tors can delay the patient discharge. Moreover, we have noted that conditions determining intraop erative air leaks can be different with respect to anatomical location and number of sites. Therefore, technical solutions usually vary case by case and also the indication for use of sealant may change. Another important aspect related to the seal ant use is the obvious increase in the costs, which at present is not offset by decreases in length of hospital stay. Different sealant options have vari able impact on hospital costs that have to be considered when evaluating the indication for a given treatment modality, especially for surgeons operating in institutions with limited economic resources. Based on the above mentioned considerations, we believe that sealants offer a useful solution to be employed as an adjuvant to the standard surgical technique in order to improve intra-operative air leaks control. However, we think that the routine use of surgical sealant in all the patients should not be recommended at present. Instead, a case-bycase decision based on the features, anatomical location, and extent of air leak is the most appro priate strategy. In particular, sealant application is not necessary when the absence of intraoperative air leak is achieved by standard techniques, and is preferred in case of large decorticated surfaces or hilar para-fissural air leaks sites where an effective surgical repair is more difficult to achieve. Pleural sealants may reduce the incidence and duration of air leak after lung resection (evi dence quality moderate) and appear safe to use (evidence quality high), but reduction of air leak incidence and duration do not influence the duration of chest tube drainage or length of hospital stay (evidence quality high). We make a weak recommendation against the routine use of surgical sealants after lung resection (recommendation grade 2B).
Acknowledgement: we wish to thank Dr. Elisabetta Grigioni for data management and editorial revision.
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References 1. Lang G, Csekeo A, Stamatis G, Lampl L, Hagman L, Marta GM, Mueller MR, Klepetko W. Efficacy and safety of topical application of human fibrinogen/ thrombin-coated collagen patch (TachoComb)for treatment of air leakage after standard lobectomy. Eur J Cardiothorac Surg. 2004;25:160–166. 2. Wain JC, Kaiser LR, Johnstone DW, Yang SC, Wright CD, Friedberg JS, Feins RH, Heitmiller RF, Mathisen DJ, Selwyn MR. Trial of a novel synthetic sealant in preventing air leaks after lung resection. Ann Thorac Surg. 2001;71:1623–1639. 3. Brunelli A, Monteverde M, Borri A, Salati M, Marasco RD, Fianchini A. Predictors of prolonged air leak after pulmonary lobectomy. Ann Thorac Surg. 2004;77:1205–1210. 4. Isowa N, Hasegawa S, Bando T, Wada H. Preoperative risk factors for prolonged air leak following lobec tomy or segmentectomy for primary lung cancer. Eur J Cardiothorac Surg. 2002;21:951–954. 5. Rice TW, Kirby TJ. Prolonged air leak. Chest Surg Clin N Am. 1992;1:802–811. 6. Keagy B, Lores M, Starek P, Murray GF, Lucas CL, Wilcox BR. Elective pulmonary lobectomy: factors associated with morbidity and operative mortality. Ann Thorac Surg. 1985;40:349–351. 7. Varela G, Jiménez MF, Novoa N,Aranda JL. Estimating hospital costs attributable to prolonged air leak in pulmonary lobectomy. Eur J Cardiothorac Surg. 2005;27:329–333. 8. Venuta F, Rendina EA, De Giacomo T, Flaishman I, Guarino E, Ciccone AM, Ricci C. Technique to reduce air leaks after pulmonary lobectomy. Eur J Cardio thorac Surg. 1998;13:361–364. 9. Fleisher AG, Evans KG, Nelems B, Finley RJ. Effect of routine fibrin glue use on the duration of air leaks after lobectomy. Ann Thorac Surg. 1990;49:133–134. 10. Mouritzen C, Dromer M, Keinecke HO. The effect of fibrin glueing to seal bronchial and alveolar leakages after pulmonary resections and decortications. Eur J Cardio Thorac Surg. 1993;7:75–80. 11. Wong K, Goldstraw P. Effect of fibrin glue in the reduction of postthoracotomy alveolar air leak. Ann Thorac Surg. 1997;64:979–981. 12. Macchiarini P, Wain J, Almy S, Dartevelle P. Experi mental and clinical evaluation of a new synthetic, absorbable sealant to reduce air leaks in thoracic operations. J Thorac Cardiovasc Surg. 1999;117: 751–758. 13. Porte HL, Jany T, Akkad R, Conti M, Gillet PA, Guidat A, Wurtz AJ. Randomized controlled trial of a syn thetic sealant for preventing alveolar air leaks after lobectomy. Ann Thorac Surg. 2001;71:1618–1622. 14. Fabian T, Federico JA, Ponn RB. Fibrin glue in pulmonary resection: a prospective, randomized, blinded study. Ann Thorac Surg. 2003;75:1587–1592. 15. Belboul A, Dernevik L, Aljassim O, Skrbic B, Radberg G, Roberts D. The effect of autologous fibrin sealant (Vivostatcparen) on morbidity after pulmonary
384 lobectomy: a prospective randomized, blinded study. Eur J Cardio Thorac Surg. 2004;26:1187–1191. 16. Allen MS, Wood DE, Hawkinson RW, Harpole DH, McKenna RJ, Walsh GL, Vallieres E, Miller DL, Nichols FC III, Smythe WR, Davis RD, Group MSSS. Prospective randomized study evaluating a biode gradable polymeric sealant for sealing intraopera tive air leaks that occur during pulmonary resection. Ann Thorac Surg. 2004;77:1792–1801. 17. Tansley P, Al-Mulhim F, Lim E, Ladas G, Goldstraw P. A prospective, randomized, controlled trial of the effectiveness of BioGlue in treating alveolar air leaks. J Thorac Cardiovasc Surg. 2006;132:105–112. 18. Anegg U, Lindenmann J, Matzi V, Smolle J, Maier A, Smolle-Juttner F. Efficiency of fleece-bound sealing (Tachosil®) of air leaks in lung surgery: a prospective randomised trial. Eur J Cardiothorac Surg. 2007;31: 198–202. 19. D’Andrilli A, Andreetti C, Ibrahim M, Ciccone AM, Venuta F, Mansmann U, Rendina EA. A prospective randomized study to assess the efficacy of a surgical sealant to treat air leaks in lung surgery. Eur J Cardiothorac Surg. 2009;35:817–821.
A. D’Andrilli et al. 20. Cederholm-Williams. Fibrin glue. Br Med J. 1994; 308:570. 21. Serra-Mitjans M, Belda-Sanchis J. Surgical sealant for preventing air leaks after pulmonary resections in patients with lung cancer [update of Cochrane Database Syst Rev 2001;(4):CD003051; PMID: 11687173]. Cochrane Database Syst Rev. 2005;(3): CD003051. 22. Rocco G, Rendina EA, Venuta F, Mueller MR, Halezeroglu S, Dienemann H, Van Raemdonck D, Hassen HJ. The use of sealants in modern thoracic surgery: a survey. Interact Cardiovasc Thorac Surg. 2009;9:1–3. 23. Cerfolio RJ, Tummala RP, Holman WL, Zorn GL, Kirklin JK, McGiffin DC, Naftel DC, Pacifico AD. A prospective algorithm for the management of alveo lar air leaks after pulmonary resection. Ann Thorac Surg. 1998;66:1726–1731. 24. Marshall MB, Deeb ME, Bleier JI, Kucharczuk JC, Friedberg JS, Kaiser LR, Shrager JB. Suction vs water seal after pulmonary resection: a randomized prospective study. Chest. 2002;121:831–835.
44
Optimal Initial Therapy for Pleural Empyema Curtis J. Wozniak and Alex G. Little
Introduction
Literature Review
Empyema thoracis has remained a persistent clinical challenge since being described in the Hippocratric corpus.1 Fundamental therapeutic goals are well established: removal of infected fluid, disruption of loculations, and lung re- expansion. Historically, surgical therapy was accomplished with chest tube drainage and/or thoracotomy. The advent of video assisted thoracic surgery (VATS), fibrinolytic agents, and image guided catheter placement techniques provides an increased array of options. Appropriate therapeutic options are based on the characteristics of the empyema. However, there is a frustrating lack of standardization in the literature relative to empyema staging. In 1962 the American Thoracic Society described three pathologic phases of empyema: exudative, fibrinopurulent, and organizing.2 We emphasize that this article described “pathologic responses” that “are not sharply defined”.2 Subsequent authors have assigned numeric values to the phases of the pathologic findings and thus have defined a “stage”, “category”, or “class” of empyema.3–5 Unfortunately, these efforts are inconsistent. “Empyema” is simplest described as pleural space infection, i.e. bacteria in the pleural space. Pleural fluid without bacteria, even in a parapneumonic setting, is not an empyema. While appreciating that some patients will not fit neatly into any staging system, we define empyema stages as shown in Table 44.1. Therapy should be directed by this type of classification system.
Methodology A MEDLINE search was conducted initially utilizing the MeSH database with the following MeSH terms: “Empyema, Pleural” or “Empyema, Pleural/surgery” or “Empyema, Pleural/therapy.” Additional standard MEDLINE searches were done to identify articles describing thoracic empyema management after 1990. Case-reports were excluded. Results were limited to humans, adults, and the English language. Articles were assigned a level of evidence quality using the following grading scale: 1. 2. 3. 4.
Randomized trial = High Large prospective trial = Moderate Observational study = Low Any other evidence = Very low
Recommendations are based both on the quality of the evidence and the balance among benefits and risks as described by Guyatt et al.6
Stage I: Exudative Empyema Stage I empyema is characterized by the presence of infected but freely flowing, relatively clear fluid within the pleural space. The challenge for appropriate treatment is early diagnosis. Therefore, the value of early fluid sampling is emphasized, especially in a patient with pneumonia and an effusion greater than 10 mm on a decubitus chest x-ray.5
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_44, © Springer-Verlag London Limited 2011
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386 Table 44.1. Empyema staging scheme. Stage I – Exudative II –Fibrinopurulent III – Fibrothorax
Fluid appearance Serous Cloudy/turbid or purulent Little or no fluid
Fluid character
pH
Free flowing Free flowing or thick –
£7.2 £7.2 –
If bacteria are seen or cultured, then the diagnosis is clear. However, in early empyema and/or after a patient has been given antibiotics, both Gram stain and culture may fail to show bacteria. In this situation, a pH < 7.2 correlates with a high likelihood of infection, which should prompt treatment. This was best demonstrated by Heffner in a metaanalysis of seven studies.7 He confirmed that the most accurate fluid characteristics for predicting the need for chest tube drainage among patients with effusion or empyema included pleural fluid pH, glucose and LDH, with an accuracy of 92%, 84% and 82%, respectively. When patients with definite empyema were excluded, pH remained the best predictor of infection and the need for chest tube drainage among patients with parapneumonic effusions. A pH < 7.21 established the criterion for patients at highest risk. The use of antibiotics as the first step in treatment of infected or possibly infected pleural fluid is standard therapy. This is not based on any particular study but simply on routine considerations of treatment of any infection.8–11 Whether to add chest drainage is the next decision challenge. The use of antibiotics alone for Stage I empyema has been reported to result in a success rate of 82%.12 However, subsequent reports have disputed these findings. In 2003, evidence-based guidelines promulgated by the British Thoracic Society (BTS) based on a literature review recommended chest tube drainage in the presence of: (1) organisms identified on Gram stain or culture; (2) purulent fluid (discussed in next section); or (3) pH < 7.2.5 Using their grading system, they assign a level B (intermediate strength) to this recommendation. Our review of the studies used as the basis for this recommendation showed them all to be observational studies and therefore amounted to low grade evidence.3,7,13,14 When drainage is performed, tube thoracostomy with standard 20F or larger diameter chest tubes is utilized almost exclusively in older studies. There are few good quality clinical series documenting the results when small, pig-tail catheters,
Gram stain/culture Positive or Negative Positive Positive
Loculations on CT No Variable (may have multiple) May have multiple
typically inserted by interventional radiologists, are used. Our review of the utilization of imageguided drainage catheters shows variable success, between 0% and 86%. Catheter sizes ranged between 8F and 14F; inclusion criteria of the reviewed studies varied widely, from uncomplicated effusion15 to Stage II empyema.16 Generally, most success was achieved in Stage I empyema. Further discussion of image-guided catheters will follow in Stage II.
Stage II: Fibrinopurulent Empyema Stage II empyema represents a spectrum of pathologic processes within the pleural space and encom passes: (1) culture-positive, unilocular turbid fluid; (2) freely flowing pus; or (3) multi-loculated, thick purulent collections. Treatment options, in addition to antibiotics, are drainage with or without the addition of fibrinolytic agents, or surgical intervention.
Drainage and Fibrinolytics A stepwise approach to this stage of empyema has historically been utilized, beginning with minimally invasive approaches, typically either an image-guided drainage catheter or chest tube, and proceeding to VATS or thoracotomy for drainage failures. There are reasonably compelling data to suggest that a more aggressive initial treatment approach should be considered if Stage II empyema is clearly established. Maier, in a small study (n = 14), focused on Stage II empyema and reported 100% failure for image-guided catheters and recommended this approach for Stage II empyema be abandoned.16 Thourani et al., in a report on cost effectiveness of empyema treatment, compared failed to successful use of initial image-guided catheter in regards to increased costs ($55,609 vs. $23, 354), length of stay (29 vs. 15 days), and mortality (22% vs. 0%).17 Other clinical features have been identified that may aid in selecting a more aggressive approach
44. Optimal Initial Therapy for Pleural Empyema
to Stage II empyema. Huang et al. reported results from a study of 123 patients with Stage I or II empyema.18 He examined factors predicting failure of chest tube drainage (i.e. incomplete drainage with fever, leukocytosis, or fatal outcome). On univariate analysis, loculations (OR 4.72; 95% CI 1.97–12.21; p = 0.0005) and large effusion size (OR 2.41; 95% CI 1.07–5.51; p = 0.03) predicted chest tube failure. On multivariate analysis, loculations continued to be predictive of chest tube failure (OR 10.29; 95% CI 2.18–79.65; p < 0.0008). Patients with chest tube failure had a significantly higher mortality (47%) compared to those with successful chest tube drainage (11%) (p = 0.0001). In their review of studies to establish consensus guidelines, the American College of Chest Physicians (ACCP) also note the high failure for chest tube alone in Stage II.4 They compared the efficacy of treatment based on the following initial intervention options: no drainage, thoracentesis, chest tube, fibrinolytics, VATS, and thoracotomy. Pooled failure rates (i.e. need for second intervention) following tube thoracostomy alone was 40%. For tube drainage with the addition of fibrinolytics the failure rate dropped to 15%. The failure rate of VATS was 0% and thoracotomy was 10%. The study concluded that “tube thoracostomy alone appears to be insufficient” for patients with a large effusion, a loculated effusion that is gram stain or culture positive, or a purulent effusion. They suggest that tube drainage with fibrinolytics, VATS and thoracotomy are equivalent interventions and that treatment should proceed utilizing one of these approaches. The purported mechanism of the fibinolytics urokinase and streptokinase is disruption of loculations, thereby facilitating complete tube drainage of all loculated collections.19,20 Reported success rates for the use of fibrinolytics vary. The Cochrane reviewers analyzed seven randomized controlled trials assessing the utility of fibrinolytics among 702 patients in which fibrinolytics were compared to saline.21 Endpoints were mortality and the need for surgical intervention. Six of the reviewed experiences found that fibrinolytic therapy decreased the need for surgical intervention (RR 0.63; 95% confidence interval 0.46–0.85).17 In the two studies that contained calculable outcome measures, mortality was not decreased by the addition of fibrinolytics to tube thoracostomy (RR 1.08; 95% confidence interval 0.69–1.68). They
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concluded that fibrinolytics may confer a benefit in reducing the need for surgical intervention. In contrast, a prospective, randomized study from Maskell et al. of 430 patients differed from the Cochrane report and found that fibrinolytics did not reduce the need for surgical intervention or mortality.22 The overall rate of either the need for surgical intervention or death was 31% in their fibrinolytic group and 27% in the placebo group (RR 1.14; 95% confidence interval 0.85 to 1.54; p = 0.43). Adverse events occurred more frequently in the fibrinolytic group (7%) compared to the control group (3%) (95% confidence interval 0.98–6.36; p = 0.08). Maskell recommended that “generally, the use of fibrinolytics should be avoided” because they did not reduce the need for surgery or death. In their discussion, the authors considered why streptokinase failed to show improvement in pleural fluid clearance. They noted that, while streptokinase may break down barriers between loculated collections, it does not decrease the viscosity of the pus. In their patients with established fibrinopurlent empyema (83% had grossly purulent fluid), streptokinase was ineffective in pleural space clearance and therefore did not lead to significant clinical improvements. Their study aids in identifying the reason for lack of efficacy of streptokinase in advanced fibrinopurlent empyema. It also suggests the potential efficacy of alternative fibrinolytic agents. They theorize that tissue plasminogen activator (tPA), due to its alternative mechanism of action, may be more effective at reducing pus viscosity.23,24 Subsequent authors have, in fact, demonstrated reasonable success utilizing chest tube drainage and tPA in Stage II. Levinson et al. reported their experience with chest drainage (tube size range 10–36F) and tPA or urokinase in a retrospective series of 27 patients with fibrinopurulent empyema.25 They placed second chest tubes for failure of radiologic resolution in 43% of their patients. No patient required surgical intervention and 88% survived. In a more recent and smaller (n = 25) prospective trial, Zuckerman et al. used a similar treatment approach utilizing tube drainage and an initial trial of tPA instillation followed by VATS for refractory cases.26 Seventy-two percent of their patients were successfully treated with drainage and tPA alone while 28% failed and required VATS. They attempted to identify pre-operative pleural fluid characteristics that would predict failure of fibrinolytics, but no significant differences were
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identified between the successful and unsuccessful fibrinolytic groups. They conclude that tPA can be used safely and effectively to assist chest tube drainage in patients with loculated pleural empyema, recognizing that VATS will be required in a modest number of treatment failures. Inclusion criteria in their study were based on clinical (evidence of pneumonia) and radiographic findings and did not document pleural fluid values, making results somewhat difficult to generalize. Furthermore, both Levinson and Zuckerman followed fairly labor intensive treatment protocols that required up to 9 tPA instillations, multiple follow-up CT scans, and frequent placement of second and third drainage tubes. The impact on length of stay, complications, and cost of these treatment approaches have yet to be fully identified. These intensive regimens ideally should be compared to VATS in a prospective, randomized fashion.
Surgical Therapy Tables 44.2 and 44.3 summarize recent experiences with thoracotomy and VATS for the treatment of empyema.27–30 Success rates were adjusted to define success for purposes of this review as no need for a second intervention and no death. Contemporary studies of thoracotomy for empyema demonstrate success rates of 93–96% with few complications and a low mortality rate (1.5–7%), as shown in Table 44.3. Diminishing the strength of these reports were inclusion of pediatric patients, poor stratification of treatment outcomes based on stage, and a low proportion of patients undergoing thoracotomy in several reports.27,31 Recognizing these caveats, the success of thoracotomy for definitive treatment of empyema appears established.
Table 44.2. Use of image-guided drainage catheters for empyema.
Author
Evidence grade
n
Stage
Type/size
ImgGuided (US/CT)
Keeling Akhan Shankar Maier
Low Low Low Low
82 93 103 14
I/II I/II Not specified II
8–12F 8–14F 10–14F 9–12F
US, CT US, CT US, CT US, CT
Required second interventions/ surgery (%) 19 7 36 100
Fibrinolytrics (%)
Complications (%)
Mortality
Success (%)
51 29 0 0
3 11 3 0
NR 2 1 0
65 86 63 0
US Ultrasound; CT Computed Tomographic Scan
Table 44.3. Studies of thoracotomy for empyema.
Author
Evidence grade
PreOpSx n (d)
Ashbaugh27
Very lowa
122
36
LeMense28
Very lowa
39
NR
Pothula29
Very lowa
90
NR
Weissberg31
Low
380
NR
Included pediatric patients d days; Sx symptoms
a
Stage
Thor as initial intervention Complications Deaths Thoracotomy (%) (%) Chest tube (d) Hospital days (%) (%) Success (%)
I–III (70% 83 (68%) stage III) I/II (some with 22 (56%) high risk fluid) I–III 71 (79%) Limited thoracotomy 19 (21%) I (72%) Decortication II (14%) 13 (3%) III (14%) Fenestration 38 (10%)
NR
7.4
23
NR
6
94
23
NR
19.8
NR
7
95
NR
NR
NR
10
4
93
0
NR
NR
NR
1.5
96
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44. Optimal Initial Therapy for Pleural Empyema Table 44.4. Studies of VATS for empyema. Author
Evidence grade
n
Landreneau32 Striffeler33 Cassina34 Luh35
Low Low Low Very lowa
Solaini36
Very lowa
76 67 45 145 89 120
PreOp 1° VATS Chest tube Complications Mortality symptoms (d) Stage (%) (d) Hospital days Conversion (%) (%) (%) Success (%) NR <3 weeks 37 NR – 33
II/III II II I II I/II
0 0 0 NR NR 32
3.3 4.1 7.1 7 NR 6
7.4 12 10.7 21 35 7
17 28 8 3.5 21 8
3 15 11 6 11 10
6.6 4 0 2.1 5.6 0
86 92 82 93 84 99
Included pediatric patients d days
a
Recent reports have focused on VATS for stage II, as shown in Table 44.4.32–36 VATS was more often used as a rescue than a primary intervention. Success rates, complications, and mortality were similar to those of thoracotomy. Conversion rates were variable, but appeared to correlate with advanced empyema stage. Compared to thoracotomy, VATS patients have fewer chest tube days, a shorter hospital stay, and lower costs.37,38 For example, Lawrence et al. found in an experience with 42 patients that those treated with VATS required fewer hospital days (18 vs. 21 days) and shorter chest tube duration (4 vs. 8.5 days).37 The role of VATS in Stage II empyema has also been evaluated in a randomized study of 20 patients, which compared VATS to chest tube drainage plus fibrinolytics.39 The authors reported a 90% success rate for VATS compared to only 44% in the chest tube/fibrinolytic group. They concluded that for large, loculated effusions, VATS is preferable to chest tube drainage with fibrinolytics, suggesting that utilization of fibrinolytics only serves to postpone definitive treatment. Timing of surgical intervention is also important. Lardinois, in an experience with 178 patients, found that the probability of conversion from VATS to thoracotomy in Stage II empyema increased from 22% to 86% after day 12, and therefore made a recommendation for earlier performance of VATS.40 Other authors have found that there was no difference in outcomes based on treatment timing.27,37,41,42 These apparently conflicting findings probably speak to the importance of the choosing the correct procedure based on the stage of disease. Our own study found that the choice of initial procedure was critical in determining outcomes.42
In this retrospective study of 104 patients, the strongest predictor of mortality was a failed first procedure, even when controlling for other patient factors. Those patients who had a successful first procedure had shorter hospital stays, fewer complications, and decreased mortality. Both VATS and thoracotomy were identified as having the least frequent failures when utilized as initial therapy. This raises the important question of whether surgical intervention should be delayed until drainage procedures fail (i.e. mainly as “rescue” therapy), or thought of as primary therapy. This study suggests that identifying the best initial therapy will achieve the best results. Supporting this conclusion, one of the few randomized studies on this issue from Wait et al. compared primary VATS to chest tube/fibrinolytics.39 VATS patients had fewer chest tube days, less hospital days, and higher success rates. The authors concluded that in large/loculated effusions, initial VATS intervention is preferable to chest tube drainage with fibrinolytics. In another study, Petrakis et al. compared 20 patients undergoing VATS after failed drainage plus urokinase with 18 patients who proceeded directly to VATS.43 Both groups had either Stage I or Stage II empyema. Similar to Wait’s findings, the patients who had primary VATS had shorter hospital stays (4.5 vs. 7.5 days, p = 0.001) and higher success rates (95% vs. 85%, p = NS). Neither group had any deaths. The primary VATS group had 86% Stage I patients, limiting the strength of their conclusion.
Stage III: Organizing Empyema Organized empyema, Stage III, is characterized by a thick, rigid pleural peel typically appearing after 4–6 weeks. Drainage alone is never sufficient because
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of the solid nature of the tissue which is firmly adherent to both pleural surfaces. Surgical decortication is a requirement. Retrospective reports demonstrate the durability and effectiveness of thoracotomy for organizing empyema.44,45 Success rates are reported between 92% and 100% with 0–4% mortality.41,44–47 An expanded role for VATS, however, is being explored by some investigators. In one study comparing VATS to thoracotomy, hospital stay was decreased from 21 days in the thoracotomy group to 16 days in the VATS group.47 Weaknesses of this study were the inclusion of 25% of patients with Stage II empyema, no clear documentation of conversion rate, and a high proportion of patients with tuberculosis (38%). Important data rarely measured in other studies were patient-reported outcomes (dyspnea, pain, return to activity). Chan found very few significant improvements in patient-reported outcomes with the use of VATS in patients with chronic empyema. Other experiences with VATS in Stage III are notable for either a very high conversion rate (42%)41 or very low utilization (7%).46 Superior success rates of thoracotomy and the limited experience with VATS illustrate the effectiveness of thoracotomy for patients with Stage III empyema.
Recommendations Accurately staging empyema and applying appropriate therapy based upon that information is critically important based on low quality data that demonstrate failed initial procedures result in higher costs, prolonged hospital stay, and increased mortality. Chest tube drainage and antibiotics is effective and safe therapy for Stage I empyema (evidence quality moderate). We make a strong recommendation for treatment of Stage I empyema with antibiotics and chest tube drainage (recommendation grade 1C). Patients whose pleural fluid is neither gram stain or culture positive but has a pH of < 7.2 should be treated as though they are in Stage I, with antibiotics and chest tube drainage. The use of small-bore catheters and antibiotics in the treatment of Stage I empyema is effective and safe (evidence quality low). We make a weak recommendation for the use of smaller catheters (with or without image-guidance) and
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antibiotics as an alternative to chest tube placement in managing Stage I empyema as long as their use is strictly confined to Stage I patients (recommendation grade 2B). Optimal therapy for patients with Stage II empyema is unsettled due to a lack of high quality evidence. If tube drainage plus fibrinolytics are attempted in Stage II, utilization of streptokinase or urokinase should be abandoned in favor of tPA. Our review suggests that earlier surgical intervention is probably preferable, but does necessitate exposure to operative risks. Surgical intervention can be either VATS or thoracotomy. VATS seems to be preferable to thoracotomy given nearly equivalent success rates and low quality data that demonstrate reductions in chest tube days, hospital stay, and cost for VATS compared to thoracotomy. Given a choice between tube drainage plus fibrinolytics (streptokinase or urokinase) in comparison to VATS, VATS is the preferable treatment modality based on moderate quality evidence. The presence of loculations in patients with Stage II empyema should prompt more aggressive intervention, either fibrinolytics or VATS, in light of low quality evidence that found loculations to be predictive of chest tube failure. Surgical intervention should occur within 12 days of symptom onset, but consistent data showing an impact on mortality is lacking. Thoracosopic management of Stage II empyema is safe and effective, and is superior to chest tube drainage with fibrinolytics and thoracotomy (evidence quality low).We make a weak recommendation for VATS decortication for management of Stage II empyema (recommendation grade 2B). Chest tube drainage with tPA is reasonably effective for management of patients with Stage II empyema and is safer than VATS or open decortication in patients who have medical contraindications to surgery. We make a weak recommendation for chest tube drainage with tPA in patients with Stage II empyema who are not good candidates for surgical intervention (recommendation grade 2B). We again emphasize that matching initial intervention with stage is one of the most important factors in predicting positive outcome. Once Stage III empyema is established, surgical intervention by thoracotomy and open decortication is most likely to be successful and is safe; VATS has been applied on a limited basis in Stage III and results have shown the necessity of high
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conversion rates (evidence quality low). We make a strong recommendation for open decortication for patients with Stage III empyema (recommendation grade 1C).
Chest tube drainage and antibiotics is effective and safe therapy for Stage I empyema (evidence quality moderate). We make a strong recommendation for treatment of Stage I empyema with antibiotics and chest tube drainage (recommendation grade 1C).
A Personal View of The Data Our practice, based on our own experience and this review of the literature, is as follows: Stage I: Patients are treated with antibiotics and tube drainage, preferably with a chest tube as it is more likely to result in complete pleural fluid evacuation. Stage II: Unless there are significant contraindications to operative intervention, our experience is that definitive treatment provided by either VATS or thoracotomy is the most effective initial therapy. We reserve tube drainage and fibrinolytics for patients for whom there are medical or other contraindications for surgical intervention. Stage III: These patients have firm material adherent to pleural surfaces and require thoracotomy for adequate exposure and treatment. The majority of evidence addressing treatment for empyema consists of retrospective reviews and therefore is low quality. Few randomized studies have been conducted, and they are notable for either few patients39 or methodologic flaws.22,48 Controversy exists regarding optimal treatment of patients with Stage II empyema. Unfortunately, the low grade evidence currently available contains a number of challenges that impede development of unequivocal recommendations. Lack of clear staging standards for empyema, in our view, contributes to confusion. Many reports publish results of patients with “empyema” without reporting stage-based outcomes. Rigorous staging standards akin to those for cancer should be adopted to at least ensure that investigators are addressing similar patients. Trials comparing primary VATS to tube drainage plus tPA among patients with Stage II parapneumonic empyema would be of considerable value. Earlier investigation in a small study suggests primary VATS is superior.39 Data from a larger trial to clearly define patients in whom primary surgical intervention is most beneficial is a needed addition to our understanding of this complex disease.
Thoracosopic management of Stage II empyema is safe and effective, and probably is superior to both chest tube drainage with fibrinolytics and thoracotomy (evidence quality low). We make a weak recommendation for VATS decortication for management of Stage II empyema (recommendation grade 2B).
Chest tube drainage with tPA is reasonably effective for management of patients with Stage II empyema and is safer than VATS or open decortication in patients who have medical contraindications to surgery (evidence quality low). We make a weak recommendation for chest tube drainage with tPA in patients with Stage II empyema who are not good candidates for surgical intervention (recommendation grade 2B).
Surgical intervention by thoracotomy and open decortication is the most successful treatment and is safe for Stage III empyema (evidence quality low). We make a strong recommendation for open decortication for patients with Stage III empyema (recommendation grade 1C).
References 1. Christopoulou-Aletra H, Papavramidou N. “Empyemas” of the thoracic cavity in the hippocratic corpus. Ann Thorac Surg. 2008;85:1132–1134. 2. Andrews N, Parker E, Shaw R, et al. Management of nontuberculous empyema: a statement of the subcommittee on surgery. Am Rev Resp Dis 1962; 85:935–936. 3. Light RW. A new classification of parapneumonic effusions and empyema. Chest. 1995;108:299–301. 4. Colice GL, Curtis A, Deslauriers J, et al. Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline. Chest. 2000;118:1158–1171.
392 5. Davies CW, Gleeson FV, Davies RJ, Pleural Diseases Group, Standards of Care Committee, British Thoracic Society. BTS guidelines for the management of pleural infection. Thorax. 2003;58(Suppl 2): ii18–ii28. 6. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest. 2006;129:174–181. 7. Heffner JE, Brown LK, Barbieri C, DeLeo JM. Pleural fluid chemical analysis in parapneumonic effusions. A meta-analysis. Am J Respir Crit Care Med. 1995; 151:1700–1708. 8. Rahman NM, Chapman SJ, Davies RJ. The approach to the patient with a parapneumonic effusion. Clin Chest Med. 2006;27:253–266. 9. Sahn SA. Diagnosis and management of parapneumonic effusions and empyema. Clin Infect Dis. 2007;45:1480–1486. 10. Chapman SJ, Davies RJ. The management of pleural space infections. Respirology. 2004;9:4–11. 11. Hampson C, Lemos JA, Klein JS. Diagnosis and management of parapneumonic effusions. Semin Respir Crit Care Med. 2008;29:414–426. 12. Berger HA, Morganroth ML. Immediate drainage is not required for all patients with complicated parapneumonic effusions. Chest. 1990;97:731–735. 13. Light RW, Girard WM, Jenkinson SG, George RB. Parapneumonic effusions. Am J Med. 1980;69: 507–512. 14. Potts DE, Levin DC, Sahn SA. Pleural fluid pH in parapneumonic effusions. Chest. 1976;70:328–331. 15. Keeling AN, Leong S, Logan PM, Lee MJ. Empyema and effusion: outcome of image-guided small-bore catheter drainage. Cardiovasc Intervent Radiol. 2008;31:135–141. 16. Maier A, Domej W, Anegg U, et al. Computed tomography or ultrasonically guided pigtail catheter drainage in multiloculated pleural empyema: a recommended procedure? Respirology. 2000;5:119–124. 17. Thourani VH, Brady KM, Mansour KA, Miller JI, Jr, Lee RB. Evaluation of treatment modalities for thoracic empyema: a cost-effectiveness analysis. Ann Thorac Surg. 1998;66:1121–1127. 18. Huang HC, Chang HY, Chen CW, Lee CH, Hsiue TR. Predicting factors for outcome of tube thoracostomy in complicated parapneumonic effusion for empyema. Chest. 1999;115:751–756. 19. Park JK, Kraus FC, Haaga JR. Fluid flow during percutaneous drainage procedures: an in vitro study of the effects of fluid viscosity, catheter size, and adjunctive urokinase. AJR Am J Roentgenol. 1993;160: 165–169. 20. Simpson G, Roomes D, Reeves B. Successful treatment of empyema thoracis with human recombinant deoxyribonuclease. Thorax. 2003;58:365–366. 21. Cameron R, Davies HR. Intra-pleural fibrinolytic therapy versus conservative management in the treatment of adult parapneumonic effusions and
C.J. Wozniak and A.G. Little empyema. Cochrane Database Syst Rev. 2008;(2): CD002312. 22. Maskell NA, Davies CW, Nunn AJ, et al. U.K. controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med. 2005;352:865–874. 23. Light RW, Nguyen T, Mulligan ME, Sasse SA. The in vitro efficacy of varidase versus streptokinase or urokinase for liquefying thick purulent exudative material from loculated empyema. Lung. 2000; 178:13–18. 24. Simpson G, Roomes D, Heron M. Effects of stre ptokinase and deoxyribonuclease on viscosity of human surgical and empyema pus. Chest. 2000;117: 1728–1733. 25. Levinson GM, Pennington DW. Intrapleural fibrinolytics combined with image-guided chest tube drainage for pleural infection. Mayo Clin Proc. 2007;82:407–413. 26. Zuckerman DA, Reed MF, Howington JA, Moulton JS. Efficacy of intrapleural tissue-type plasminogen activator in the treatment of loculated parapneumonic effusions. J Vasc Interv Radiol. 2009;20:1066–1069. 27. Ashbaugh DG. Empyema thoracis. Factors influencing morbidity and mortality. Chest. 1991;99:1162–1165. 28. LeMense GP, Strange C, Sahn SA. Empyema thoracis. Therapeutic management and outcome. Chest. 1995;107:1532–1537. 29. Pothula V, Krellenstein DJ. Early aggressive surgical management of parapneumonic empyemas. Chest. 1994;105:832–836. 30. Rosenthal D, Chrisant MR, Edens E, et al. International Society for Heart and Lung Transplantation: practice guidelines for management of heart failure in children. J Heart Lung Transplant. 2004;23: 1313–1333. 31. Weissberg D, Refaely Y. Pleural empyema: 24-year experience. Ann Thorac Surg. 1996;62:1026–1029. 32. Landreneau RJ, Keenan RJ, Hazelrigg SR, Mack MJ, Naunheim KS. Thoracoscopy for empyema and hemothorax. Chest. 1996;109:18–24. 33. Striffeler H, Gugger M, Im Hof V, Cerny A, Furrer M, Ris HB. Video-assisted thoracoscopic surgery for fibrinopurulent pleural empyema in 67 patients. Ann Thorac Surg. 1998;65:319–323. 34. Cassina PC, Hauser M, Hillejan L, Greschuchna D, Stamatis G. Video-assisted thoracoscopy in the treatment of pleural empyema: stage-based management and outcome. J Thorac Cardiovasc Surg. 1999;117: 234–238. 35. Luh SP, Chou MC, Wang LS, Chen JY, Tsai TP. Videoassisted thoracoscopic surgery in the treatment of complicated parapneumonic effusions or empyemas: outcome of 234 patients. Chest. 2005;127: 1427–1432. 36. Solaini L, Prusciano F, Bagioni P. Video-assisted thoracic surgery in the treatment of pleural empyema. Surg Endosc. 2007;21:280–284. 37. Lawrence DR, Ohri SK, Moxon RE, Townsend ER, Fountain SW. Thoracoscopic debridement of empyema thoracis. Ann Thorac Surg. 1997;64:1448–1450.
44. Optimal Initial Therapy for Pleural Empyema 38. Angelillo Mackinlay TA, Lyons GA, Chimondeguy DJ, Piedras MA, Angaramo G, Emery J. VATS debridement versus thoracotomy in the treatment of loculated postpneumonia empyema. Ann Thorac Surg. 1996;61:1626–1630. 39. Wait MA, Sharma S, Hohn J, Dal Nogare A. A randomized trial of empyema therapy. Chest. 1997;111: 1548–1551. 40. Lardinois D, Gock M, Pezzetta E, et al. Delayed referral and gram-negative organisms increase the conversion thoracotomy rate in patients undergoing video-assisted thoracoscopic surgery for empyema. Ann Thorac Surg. 2005;79:1851–1856. 41. Waller DA, Rengarajan A. Thoracoscopic decortication: a role for video-assisted surgery in chronic postpneumonic pleural empyema. Ann Thorac Surg. 2001;71:1813–1816. 42. Wozniak CJ, Paull DE, Moezzi JE, et al. Choice of first intervention is related to outcomes in the management of empyema. Ann Thorac Surg. 2009;87:1525–1531.
393 43. Petrakis I, Katsamouris A, Drossitis I, Bouros D, Chalkiadakis G. Usefulness of thoracoscopic surgery in the diagnosis and management of thoracic diseases. J Cardiovasc Surg (Torino). 2000;41:767–771. 44. Martella AT, Santos GH. Decortication for chronic postpneumonic empyema. J Am Coll Surg. 1995;180: 573–576. 45. Andrade-Alegre R, Garisto JD, Zebede S. Open thoracotomy and decortication for chronic empyema. Clinics (Sao Paulo). 2008;63:789–793. 46. Melloni G, Carretta A, Ciriaco P, et al. Decortication for chronic parapneumonic empyema: results of a prospective study. World J Surg. 2004;28:488–493. 47. Chan DT, Sihoe AD, Chan S, et al. Surgical treatment for empyema thoracis: is video-assisted thoracic surgery “better” than thoracotomy? Ann Thorac Surg. 2007;84:225–231. 48. Heffner JE. Multicenter trials of treatment for empyema–after all these years. N Engl J Med. 2005;352: 926–928.
45
Management of Malignant Pleural Effusion: Sclerosis or Chronic Tube Drainage Leslie J. Kohman and Todd L. Demmy
Introduction The optimal palliative management for patients with symptomatic malignant pleural effusion (MPE) is not well understood. This is largely because of the difficulty in studying heterogeneous, advanced diseases in individuals with little remaining quality life. Because the benefits of thoracentesis are short-lived, these patients often proceed to more durable forms of palliative therapy, primarily obliteration of the pleural space by irritant chemicals or intermittent external drainage by a chronic indwelling pleural catheter. The indwelling catheter method is gaining popularity because it has the advantage of not requiring inpatient hospitalization and avoids the pain and inflammatory complications caused by pleurodesis.1 Its downsides include fewer data regarding its effectiveness, longer time until pleurodesis occurs, possible increased nutritional loss that can occur with ongoing pleural fluid drainage, and increased risk of pleural infection from prolonged pleural drainage. Furthermore, patients may be displeased by the inconvenience caused to them or their caregivers by taking responsibility for drainage as well as any discomfort or impaired body image caused by an indwelling device. Pleurodesis is appealing because of its history of effectiveness and, if successful, the duration of therapy is relatively brief and often yields permanent control. Talc is used most frequently because it is inexpensive, and several laboratory and clinical studies have demonstrated its equivalency or advantages over other more expensive sclerosants
like bleomycin or doxycycline.2–4 A randomized prospective comparison (CALGB 9334) showed no advantages of intraoperative talc poudrage over talc slurry infusion done at the bedside.5 That study showed a high failure of complete lung reexpansion before the administration of talc as well as a high mortality within the first 30 days related to the pleurodesis therapy and patient disease. Indwelling tunneled pleural catheters have been used with increasing frequency in the past decade because they do not require hospitalization and they avoid the use of sclerosing agents, which have all had complications associated with them. This chapter will attempt to answer the question of which method of managing MPE is superior – chemical pleurodesis or indwelling drainage catheter. Superiority is defined by a high percentage of successful pleurodesis, low rate of complications, freedom from recurrence or retreatment, and reduced hospital stay. We will cite current literature regarding the effectiveness of chronic indwelling pleural catheter in the management of malignant pleural effusion in comparison to chest tube with chemical sclerosis. Although other types of tunneled pleural catheters have been described for this use, most notable the Tenckhoff catheter, by far the most used and the best described catheter is the PleurX® (CareFusion, San Diego, CA). One similar tube has been on the market recently, the Aspira® catheter (Bard Access Systems, Inc) which uses a low-vacuum siphon pump mechanism rather than a vacuum bottle. However, this system has never been described in the peer-reviewed literature and so will not be addressed here.
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_45, © Springer-Verlag London Limited 2011
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Methods of Identifying Relevant Literature The literature was searched via Ovid Medline, PubMed and Scopus using search terms including PleurX®, tunneled pleural catheter, and malignant pleural effusion (management). The Cochrane database was also queried. The search was limited to references in English and in humans and there were no relevant sources prior to 1999. Papers describing fewer than five patients were not included, and reports of a few cases using Tenckhoff or other catheters were also excluded. Studies were included if they reported results of PleurX® catheters either in stand-alone analysis or in comparison to another method of management of MPE, primarily standard chest tube and sclerotherapy. The definition of success varied among the reports, as did the classification of complications.
Results The results of the search are listed in Table 45.1, which describes 4 reports: one prospective, randomized trial of PleurX® versus doxycycline sclerosis,1 one prospective, randomized trial of PleurX® versus talc sclerosis,6 one prospective comparison of PleurX® versus video-assisted thoracoscopic surgery (VATS) plus talc insufflation,7 and one retrospective comparison of PleurX® versus talc or doxycycline sclerosis.8 Eleven additional reports were reviewed; they are all retrospective, single-institution case series lacking comparison groups and will not be further discussed.
Summary of Prospective Studies In 1999 Putnam1 published the first and still the largest prospective comparison of PleurX® catheter versus chest tube and doxycycline pleurodesis. Patients were randomized in a 2:1 fashion (45
doxycycline, 99 PleurX®). When treatment results were analyzed, only 135 patients who received the appropriate treatment without protocol violations were included (41 doxycycline, 94 PleurX®). Demographics were similar but the mean initial size of the effusions in the PleurX® group was significantly larger. Doxycycline patients had a 68% initial success rate versus 97% in the PleurX® group and a 21% recurrence rate in the successful patients versus a 13% recurrence rate in the PleurX® group (NS). PleurX® patients had a 14% rate of local complications versus none in the doxycycline group. At 30 days, the dyspnea score was better in the PleurX® group. All other measures of dyspnea were no different. Median hospital stay was 6.5 days in the doxycycline group versus 1 day in the PleurX® group (p < 0.001). The authors concluded that the PleurX® catheter is an effective treatment for MPE and when compared with doxycycline pleurodesis, it requires a shorter hospitalization, and it can be placed and managed on an outpatient basis. The authors noted that the measures of success were different in the two groups, and that patients with trapped lung would be considered failures in the doxycycline group but not in the PleurX® group. In 2003 Ohm and colleagues7 published a prospective study of 41 patients with MPE. Those with a normally expanding lung had thoracoscopy with talc pleurodesis and those with a “trapped” lung (83% in this series by the authors’ definition) had a PleurX® catheter. Two patients in the VATS/talc group had prolonged parenchymal-pleural fistulae and prolonged hospital stay. These authors preferred to achieve pleural symphysis without a foreign device, but preferred the PleurX® in patients with a trapped lung (a vast majority in their estimation). The PleurX® patients had a significantly shorter hospital stay. They concluded that the PleurX® is safe and effective and has a role in the
Table 45.1. Results of studies comparing indwelling catheters to sclerosis for management of malignant pleural effusion. Author
Year
Putnam1
1999
Demmy6
2010
Ohm7
2003
Putnam8
2000
Study design Prospective, randomized 2:1 PleurX® vs. doxy Prospective, randomized PleurX® vs. talc Prospective comparison vs. VATS/talc Retrospective comparison, PleurX® vs. talc or doxy
Patients 144 58 41 168 (100 PleurX®, 68 tube + talc)
Results Pleural cath effective, marked reduction in LOS (6.5 days to 1) 5× improved odds ratio of “success” PleurX® efficacious in patients with trapped lung Effective and safe, reduced hospital stay from 7 days to 0
Pleurodesis (%)
Evidence quality
46%, mean 29 days
High
68% vs. 83% in talc sclerosis arm 12% (trapped lung patients only) 21%
Moderate Moderate Low
45. Management of Malignant Pleural Effusion: Sclerosis or Chronic Tube Drainage
treatment of patients with trapped lung. Patients with a performance status of 2 or better and those first evaluated on an ambulatory basis were likely to benefit the most. The third prospective study, comparing PleurX® catheters to talc sclerosis via chest tube, has been presented in abstract form.6 This summarized 58 eligible patients from a trial (CALGB 30102) which originally planned for 530 patients to accept a hypothesis of equivalence, but the study was closed early due to insufficient accrual. The composite primary endpoint of technical “success” was: lung re-expansion (at least 90%) after drainage, talc pleurodesis completion or PleurX® reliable function by 2 weeks, and survival without recurrent effusion 30 days from the initial procedure. Results showed that the groups were balanced and the talc pleurodesis group had more deaths or effusion recurrences within 30 days (47%) compared to the PleurX® group (18%, p = 0.026). Overall technical success was higher with PleurX® (62% vs. 45%) with logistic regression showing a fivefold increase in the likelihood of success for PleurX® over talc pleurodesis (OR = 5, 95% CI:1–27, p = 0.049). Patients achieving initial expansion success also had a fivefold increase in the likelihood of success (OR = 5, 95% CI: 1–27, p = 0.041) and scored better on multiple QOL scales including overall change in function than those not achieving initial good expansion. Multivariate regression analysis revealed that patients treated with PleurX® had better dyspnea scores (8.5 vs. 6.1, p = 0.047) especially in the subgroup with poor expansion (9.0 vs. 4.9, p = 0.033). The authors concluded that PleurX® catheters provide better palliation for MPE than talc pleurodesis.
Limitations of Studies Ideally, there would be a large, multiinstitutional randomized trial comparing best practice (chest tube and talc sclerosis) to PleurX® catheter. This may not be possible with the current popularity of the PleurX® catheter. The study by Demmy,6 as yet unpublished, describes results based on 58 patients from a trial that was designed to have 530 patients. The trial was closed early due to poor accrual, with a postulation that there was no longer equipoise among surgeons and patients regarding the superiority of the PleurX® catheter. Therefore, it is unlikely that such a definitive trial will ever take place.
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Inclusion criteria for patients discussed in the reports in the table varied widely; at a minimum, the basic inclusion criterion was a pleural effusion in a cancer patient requiring treatment. Some series limited the PleurX® to patients who had high- volume drainage, or to those who had trapped lung, or to those considered unsuitable for other methods because of high-risk factors. Some required prior thoracentesis. Endpoints also varied widely: length of hospital stay, relief of dyspnea, quality of life, need for further interventions, ease of use and patient acceptance, efficacy and cost. The method and location of insertion varied somewhat among studies. Locations included outpatient clinic, hospital bedside, and operating room. Most of the papers make no mention of the use of prophylactic antibiotics, although the Demmy trial6 required prophylactic antibiotics. One may assume that those catheters placed in the office did not include IV antibiotics. The procedure-related complication reporting was non-standardized and was done in inconsistent formats. Most authors stated that the complication rate was “low” or “acceptable.” There were no reported major immediate complications of the procedures. One report7 utilized the PleurX® only in cases of trapped lung. This bias accounts for the rather low percentage of pleural sclerosis in that study. Demmy6 reports the highest sclerosis rate, 63%, which may reflect the inclusion of patients with lungs that expanded fully as well as those that might be trapped. Indeed, patients whose lung fully expanded had a much higher success rate. Demmy also reported that physicians had a poor ability to judge the chance of full expansion and this criterion should be dropped from consideration when treatment is planned since it does not influence overall relief of dyspnea and quality of life. Most patients with symptomatic malignant pleural effusion have a limited life expectancy and many die with their catheters in place. The rate of sclerosis at the time of death may not be accurate, since some patients decide that it is not worth the pain or trouble to have the catheter removed even if it is no longer functioning. Later series have attempted to limit this intervention to patients with a life expectancy of at least 3 months, but physicians are not accurate in their determination of this parameter either. Although complete cost and cost-effectiveness data are not published anywhere, the fact that a
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PleurX®catheter can be inserted on an outpatient basis (compared to 6–7 days in the hospital for chest tube placement and chemical sclerosis5,8) suggests that there will be significant cost savings. Nonetheless, the cost of the drainage bottles is significant and has not been measured over the total time the catheter is in place and being drained.
Summary of Published Results Both talc pleurodesis and PleurX® catheter are effective in the management of malignant pleural effusion. PleurX® is clearly superior to any other method when measured by hospital length of stay and is more effective in cases of trapped lung. It has a higher rate of local complications (e.g. cellulitis) but a lower rate of systemic complications (e.g. ARDS). PleurX® has a lower rate of pleurodesis but an equal or higher rate of relief of dyspnea compared to talc pleurodesis because pleurodesis is not required for relief of dyspnea. It has a lower rate of recurrent effusion. It may have a higher rate of patient satisfaction. Talc is the most effective and possibly the most widely used sclerosant. However, talc has been associated with severe and even fatal respiratory complications.9–11 Kuzniar and associates12 reviewed talc sclerosis patients retrospectively, and concluded that oxygen supplementation, recent chemotherapy, and presence of peripheral edema were independent predictors of a combined outcome of acute lung injury or severe hypoxemia after VATS talc pleurodesis. Such patients should be considered strongly for intra-pleural catheter management. Large-particle talc, which is the type in the product commercially available from the Bryan Corporation (4 Plympton Street, Woburn, MA) is reported to have less deposition in the lung and liver than normal- or mixed-particle talc, which in turn has less acute systemic response and a greater deposition in organs than talc of mixed particles in rabbit experiments.13–15 Maskell and associates16 noted similar negative effects from smaller particle talc in humans: mixed talc (including small particles) worsened gas exchange versus graded talc (small particles removed) and induced more systemic inflammation than graded talc. Even largesized talc particles are deposited in both lungs very early after pleurodesis, and inflammatory pulmonary changes appear bilaterally.17
Conclusion and Recommendations In the management of malignant pleural effusion, both chronic tube drainage (PleurX® catheter) and talc pleurodesis provide symptom relief and acceptable quality of life for patients with symptomatic malignant pleural effusion. Talc pleurodesis is associated with a low but definite incidence of systemic complications such as ARDS. PleurX® catheter is superior to talc in cases of trapped lung, has the advantage of a shorter length of hospital stay, and provides greater freedom from recurrence (evidence quality moderate). We make a weak recommendation for chronic tube drainage in the management of malignant pleural effusion (recommendation grade 2B). PleurX® catheter should be recommended to patients with trapped lung and to those who wish to avoid hospitalization. Those who choose talc sclerosis should be warned of potential serious pulmonary and systemic complications.
Personal Perspective My algorithm for managing symptomatic malignant pleural effusion is presented in Fig. 45.1. Talc is the favored sclerosant because of its greater effectiveness than other agents and its low cost, though it does have a risk of significant systemic complications.11 I don’t use Bleomycin because it is less effective than talc except perhaps in effusions associated with breast cancer.18 Bleomycin is less likely to clog a very small catheter (less than 12 F) than talc and does not carry the risk of pulmonary complications that talc does. PleurX® is preferred for patients who appear to have a Algorithm for MPE Tap to assess symptom relief* No relief No tube
Relief of dyspnea Full expansion
Chest tube and â talc or PleurX
Trapped Lund*
PleurXâ
Figure 45.1. Suggested algorithm for managing malignant pleural effusion. *indicates circumstances in which pleural manometry may help in decision making.
45. Management of Malignant Pleural Effusion: Sclerosis or Chronic Tube Drainage
trapped lung. Pleural manometry may be used to assess for potentially trapped lung thus avoiding a failed attempt at sclerosis.19–22 For outpatients, I favor the PleurX® approach, regardless of whether the lung expands fully, as it avoids hospitalization completely. I also prefer the PleurX® catheter for inpatients whose insurance will cover the drainage kits and who would be ready for discharge shortly after the effusion is drained. For inpatients who will be hospitalized for several days, and who do not have a trapped lung, chest tube and sclerosis will complete the therapy during the hospital stay and there is no advantage to a PleurX®. Future investigations should address the need for prophylactic antibiotics and the appropriate schedule of drainage (does daily drainage shorten the interval to pleural sclerosis?). The role of pleural manometry in assessing for trapped lung should be explored in a multiinstitutional trial. Because of acknowledged dangers of talc administered intrapleurally, new sclerosing agents should be explored, such as silver nitrate.23–25 Acknowledgment We acknowledge the able assistance of Shahryar Mousavi MD, Linda Veit and Christine Feliu, Department of Surgery, Upstate Medical University, Syracuse, NY, in the preparation of this manuscript.
Both chronic tube drainage (PleurX® catheter) and talc pleurodesis provide symptom relief and acceptable quality of live for patients with symptomatic malignant pleural effusion, but talc pleurodesis carries a higher risk of important complications (evidence quality moderate). We make a weak recommendation for chronic tube drainage in the management of malignant pleural effusion (recommendation grade 2B).
References 1. Putnam JB Jr, Light RW, Rodriguez RM, et al. A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions. Cancer. 1999;86: 1992–1999. 2. Bresticker MA, Oba J, LoCicero J, III, et al. Optimal pleurodesis: a comparison study. Ann Thorac Surg. 1993;55:364–366. 3. Hartman DL, Gaither JM, Kesler KA, et al. Comparison of insufflated talc under thoracoscopic guidance with standard tetracycline and bleomycin pleurodesis for control of malignant pleural effusions. J Thorac Cardiovasc Surg. 1993;105:743–747.
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4. Zimmer PW, Hill M, Casey K, et al. Prospective randomized trial of talc slurry vs bleomycin in pleurodesis for symptomatic malignant pleural effusions. Chest. 1997;112:430–434. 5. Dresler CM,Olak J,Herndon JE,et al.Phase III Intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion. Chest. 2005;127:909–915. 6. Demmy TL, Gu L, Toloza E, et al, Optimal catheter based therapy of pleural effusions in cancer patients. Abstract submitted to ASCO 2010. 7. Ohm C, Park D, Vogen, M, et al. Use of indwelling pleural catheter compared with thorascopic talc pleurodesis in the management of malignant pleural effusions. Am Surg. 2003;69:198–202. 8. Putnam JB, Walsh, GL, Swisher, SG, et al. Outpatient management of malignant pleural effusion by a chronic indwelling pleural catheter. Ann Thorac Surg. 2000;69:369–375. 9. Brant A, Eaton T. Serious complications with talc slurry pleurodesis. Respirology. 2001;6:181–185. 10. Light RW. Talc should not be used for pleurodesis. Am J Respir Crit Care Med. 2000;162:2024–2026. 11. Froudarakis ME, Klimathianaki M, Pougounias M. Systemic inflammatory reaction after thoracoscopic talc poudrage. Chest. 2006;129:356–361. 12. Kuzniar TJ, Blum MG, Kasibowska-Kuzniar K, Mutlu GM. Predictors of acute lung injury and severe hypoxemia in patients undergoing operative talc pleurodesis. Ann Thorac Surg. 2006;82:1976–1981. 13. Ferrer J, Montes JF, Villarino MA, Light RW, GarciaValero J. Influence of particle size on extrapleural talc dissemination after talc slurry pleurodesis. Chest. 2002;122:1018–1027. 14. Genofre EH, Vargas FS, Acencio MM, Antonangelo L, Teixeira LR, Marchi E. Talc pleurodesis: evidence of systemic inflammatory response to small size talc particles. Respir Med. 2009;103:91–97. 15. Rossi VF, Vargas FS, Marchi E, Acencio MM, Genofre EH, Capelozzi VL, Antonangelo L. Acute inflammatory response secondary to intrapleural administration of two types of talc. Eur Respir J. 2010;35: 396–401. 16. Maskell NA, Lee YC, Gleeson FV, Hedley EL, Pengelly G, Davies RJ. Randomized trials describing lung inflammation after pleurodesis with talc of varying particle size. Am J Respir Crit Care Med. 2004;170: 377–382. 17. Stamatelopoulos A, Koullias G, Arnaouti M, Donta I, Perrea D, Dosios T. Malignant pleural effusion and talc pleurodesis. Experimental model regarding early kinetics of talc particle dissemination in the chest after experimental talc pleurodesis. J BUON. 2009;14:419–423. 18. Shaw PHS, Agarwal R. Pleurodesis for malignant pleural effusions. Cochrane Database Syst Rev. 2004; Issue 1. Art. No.: CD002916. doi: 10.1002/14651858. CD002916.pub2. 19. Doelken P, Huggins JT, Pastis N J, Sahn SA. Pleural manometry: technique and clinical implications. Chest. 2004;126:1764–1769.
400 20. Feller-Kopman D, Walkey A, Berkowitz D, Ernst A. The relationship of pleural pressure to symptom development during therapeutic thoracentesis. Chest. 2006;129:1556–1560. 21. Huggins JT, Doelken P. Pleural manometry. Clin Chest Med. 2006;27:229–240. 22. Huggins JT, Sahn SA, Heidecker J, Ravenel JG, Doelken P. Characteristics of trapped lung: pleural fluid analysis, manometry, and air-contrast chest CT. Chest. 2007;131:206–213. 23. Antonangelo L, Vargas FS, Teixeira LR, Acencio MM, Vaz MA, Filho MT, Marchi E. Pleurodesis induced by talc or silver nitrate: evaluation of collagen and elastic
L.J. Kohman and T.L. Demmy fibers in pleural remodeling. Lung. 2006;184: 105–111. 24. Marcheix B, Brouchet L, Renaud C, Lamarche Y, Mugniot A, Benouaich V, Berjaud J, Dahan M. Videothoracoscopic silver nitrate pleurodesis for primary spontaneous pneumothorax: an alternative to pleurectomy and pleural abrasion? Eur J Cardiothorac Surg. 2007;31:1106–1109. 25. Paschoalini M da S, Vargas FS, Marchi E, Pereira JR, Jatene FB, Antonangelo L, Light RW. Prospective randomized trial of silver nitrate vs talc slurry in pleurodesis for symptomatic malignant pleural effusions. Chest. 2005;128:684–689.
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The Role of VATS Pleurodesis in the Management of Initial Primary Spontaneous Pneumothorax John C. Kucharczuk
Introduction “Initial primary spontaneous pneumothorax” refers to a first time pneumothorax occurring in a patient with no known lung disease in the absence of a precipitating event. Historically, the ageadjusted incidence of primary spontaneous pneumothorax is 7.4/100,000/year for males and 1.2/100,000/year for females, with a male-to-female incidence of 6.2:1.1 Smoking appears to significantly increase the risk in young men by as much as a factor of 20.2 In reality, most patients with primary spontaneous pneumothorax have some underlying lung disease that is unrecognized at the time of clinical presentation. The abnormality most commonly found at the time of surgery is a subpleural bleb. Those patients with underlying diseases that predispose them to pneumothorax are best described as having “secondary spontaneous pneumothorax” and are further subclassified as having underlying airways disease, infectious disease, interstitial lung disease, or connective tissue disorder. The subclassification and distinction of patients with secondary spontaneous pneumothorax is clinically relevant, as these patients require not only treatment of their acute pneumothorax but also recognition and management of their underlying disease. Because the underlying causes of secondary spontaneous pneumothorax vary greatly in their treatment and surgical management, these patients are not the focus of this chapter. Patients with initial primary spontaneous pneumothorax typically present with pleuritic chest
pain and/or dyspnea. Most present to an emergency room or their primary care physician’s office. Generally, a number of medical providers including primary care physicians, emergency room physicians, and pulmonologists are involved in their care, with surgeons seldom included in the early decision making process. Many patients are appropriately treated by observation, aspiration and/or small bore chest tube placement without any surgical involvement. While there is relative consensus in regards to surgical intervention in patients with a second episode of spontaneous pneumothorax, there continues to be ongoing debate about what role surgery, and specifically video assisted thoracoscopic surgery (VATS), plays in the management of initial primary pneumothorax. Unfortunately, specific diagnostic and therapeutic treatment approaches to this patient population are often based on local, institutional, and specialty biases because there is little evidenced based literature. The purpose of this chapter is to review the available data for the surgical management of those patients who fail initial treatment of their spontaneous pneumothorax and specifically review the application of VATS pleurodesis in this patient population. It is hoped that this chapter will provide the surgeon with a guide for appropriately timed and selected surgical intervention. To achieve this, the five most common clinical issues facing the surgeon are emphasized: (1) timing of surgical evaluation for consideration of surgical intervention; (2) whether or not routine preoperative CT scanning should be performed; (3) what surgical approach should be
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selected (VATS vs. axillary thoracotomy); (4) what specific operative procedure should be performed – bullectomy and/or pleurodesis; and (5) what the post operative chest tube management strategy should be. The clinical recommendations given are graded according to the guidelines set forth by the ACCP Physicians Task Force on Grading Recommendations and Quality of Evidence in Clinical Guidelines.3
Methods The current clinical management of spontaneous pneumothorax is heavily influenced by clinical guidelines published by the American College of Chest Physicians (ACCP) in 20014 and the British Thoracic Society (BTS) in 2003.5 Neither set of guidelines has been updated since its initial publication. In this chapter the guidelines served as the basis for formulating the relevant clinical question surrounding the use of thoracoscopic pleurodesis for the treatment of initial primary spontaneous pneumothorax. In order to locate more recent data which could modify the recommendations, two Pubmed searches were performed. For the first, the search term “spontaneous pneumothorax and surgery” was limited to items with: Humans, Clinical Trial, MetaAnalysis, Practice Guideline, Randomized Con trolled Trial, Review, Comparative Study, Consensus Development Conference, English, and published between 2000 and 2009. The Search resulted in 72 manuscripts. The list was manually sorted to identify 21 articles specifically addressing surgery for primary pneumothorax. The second search used the Mesh heading “Pneumothorax/surgery and clinical trials” limited to publications between 2000 and 2009. This search resulted in 19 manuscripts which were manually sorted to identify 12 articles specifically addressing surgery for primary pneumothorax. The resulting articles served as the core reference literature for this chapter. References were selected from the core literature to illustrate, refute or clarify a point made in the ACCP or BTS clinical guidelines with respect to the clinical questions raised in this chapter.
Clinical Issues Timing of Surgical Consultation Should surgical intervention be considered in patients with initial primary spontaneous pneumothorax and, if so, when should the surgical evaluation be obtained? In 2001, the American College of Chest Physicians (ACCP) published a Delphi consensus statement on the management of spontaneous pneumothorax (consensus statement based on expert consensus opinion and literature search).4 The panel recommended that patients with air leak continuing beyond 4 days should be evaluated for surgical intervention and that additional chest tubes or attempts at chest tube sclerosis should not be used in this subset of patient unless a significant contraindication to surgery is present. The 2003 British Thoracic Society (BTS) guidelines likewise recommend that a thoracic surgical opinion should be obtained early (3–5 days) in patients with persistent air leak or failure of lung re-expansion (consensus statement based on expert consensus opinion and literature search).5 The reluctance of some physicians to consider surgical evaluation stems from observational studies suggesting that, if one waits long enough, nearly all air leaks will self-resolve. This rationale fails on two accounts. First, it does not acknowledge that appropriately timed surgical intervention can decrease chest tube duration and length of hospital stay, and facilitate earlier return to work or school. In fact, a recent comparative study investigating salvage treatments for failed aspiration of primary spontaneous pneumothorax comparing VATS to chest tube drainage suggested that the VATS patients had lower complication rates, shorter hospital stays and lower rates of overall failure (evidence quality low, observational study).6 Second, it does not acknowledge the additional morbidity that arises when conservative management does fail or is complicated by infection or the formation of bronchopleural fistulae. In such cases, definitive surgical management becomes more complex, costly and ultimately riskier to the patient. Some have even advocated consideration of immediate VATS for first presentation. An interesting
46. The Role of VATS Pleurodesis in the Management of Initial Primary Spontaneous Pneumothorax
Japanese decision analysis paper explored the appropriateness of VATS for the first episode of spontaneous pneumothorax based on qualityadjusted life expectancy analysis.7 The authors found that VATS could be considered the treatment of choice for first episode of pneumothorax as long as the perioperative mortality rate remained less than 0.3%. Although interesting, this single decision analysis alone lacks sufficient weight to deviate from the current ACCP and BTS guidelines. Thus, based on the consensus statements from both the ACCP and the BTS, timely surgical consultation should be requested in patients with failed lung reexpansion or air leak persisting more than 4 days following chest tube drainage.
Routine CT Scanning Should routine CT scanning be performed prior to surgery in patients with initial primary spontaneous pneumothorax? The 2001 ACCP panel consensus opinion is that routine CT scanning is not indicated in patients presenting with their first episode of primary spontaneous pneumothorax (high quality of evidence high, consensus statement).4 No consensus was reached as to the value of CT scanning in patients with persistent air leaks who were undergoing surgery. The 2003 BTS guidelines suggest that CT scanning is appropriate when differentiating pneumothorax from complex bullous lung disease, when aberrant chest tube placement is suspected, and when the plain chest radiograph is obscured by subcutaneous emphysema (high quality of evidence high, consensus statement).5 Again, no specific recommendation is given as to the role of routine preoperative CT scanning. Nevertheless, many surgeons request a CT scan looking for “blebs” prior to surgery. A prospective longitudinal study demonstrated that CT scanning can accurately predict the presence of contralateral bullae in patients presenting with unilateral primary spontaneous pneumothorax (evidence quality low, based on observational study).8 The authors suggest that CT scan results can be used to predict the future risk of contralateral pneumothorax and suggest a potential role for preemptive surgical intervention on the contralateral side. At present there are no additional data to support the use of CT scanning in this
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manner, and no data support the performance of prophylactic contralateral surgical intervention for patients with blebs. Thus, there is no evidence base to recommend for or against routine CT scanning in the patient with initial spontaneous pneumothorax; the decision to scan patients should be based on individual clinical judgment and patient characteristics.
Surgical Approach What is the optimal surgical approach to patients with primary spontaneous pneumothorax who require intervention? The 2001 ACCP guidelines state that a thoracoscopic approach is preferred for the surgical management of primary spontaneous pneumothorax with a persistent air leak.4 The guidelines stipulate that a muscle sparing axillary thoracotomy is an acceptable alternative, whereas standard thoracotomy and sternotomy are not. In contrast, the 2003 BTS guidelines name thoracotomy as the gold standard yielding the lowest recurrence rates; thoracoscopy is considered an alternative therapy.5 The evidence supporting the selection of VATS over thoracotomy is confusing and somewhat contradictory. A systematic review of randomized clinical trials of VATS surgery, which included six randomized trials comparing VATS with conventional methods (two versus chest tube drainage and four versus conventional thoracotomy) in 327 patients, concluded that VATS was associated with better outcomes and a lower complication profile for the treatment of primary spontaneous pneumothorax (evidence quality high – based on meta analysis of randomized trials).9 The major outcomes examined were pain and recurrence rate. A contradictory meta-analysis reviewed four randomized trials and 25 non-randomized trials (evidence quality moderate, based on multiple randomized studies but question of up to date source information).10 This analysis concluded that VATS was associated with a 4% recurrence rate as compared to a 1% rate for open techniques, and suggested that open techniques remain the standard. Critics argue that the inclusion of both randomized and non randomized trials, as well as the inclusion of trials early in the VATS experience,
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may have adversely influenced the analysis.11 A more recent prospective trial comparing quality of life measures after VATS versus anterolateral thoracotomy for primary spontaneous pneumothorax suggests that VATS is associated with higher quality of life scores, in particular a decrease in thoracic pain (evidence quality moderate, prospective study).12 Based on the above evidence, taking into particular consideration recurrence rates, age of source data and qualitative measures of improvement, VATS is the preferred approach to primary spontaneous pneumothorax, although axillary thoracotomy is an acceptable alternative.
Intraoperative Pleurodesis Should pleurodesis be added to bullectomy at the time of surgery? Although a number of methods have been described to address a ruptured bulla at the time of VATS, stapled bullectomy remains the most commonly used procedure (evidence quality low, observational study).13 Bullectomy alone, however, is associated with a high rate of recurrence. A comparative retrospective study demonstrated recurrence rates as high as 16% for bullectomy alone as compared to a recurrence rate of 1.9% for those patients undergoing bullectomy with pleurodesis (evidence quality low, retrospective comparative study).14 Whether pleurodesis should be achieved by mechanical means (e.g. pleurectomy or pleural abrasion) or through the use of adjuvant sclerotic agents (e.g. talc) remains unclear. The ACCP guidelines suggest apical pleural abrasion is the procedure of choice, with pleurectomy being an acceptable alternative; no consensus was reached on the use of talc poudrage.4 The use of thoracoscopic pleural abrasion appears to be associated with lower postoperative complication rates, specifically a decreased rate of hemothorax. This was recently illustrated in a randomized trial which showed a hemothorax rate of 7.4% for apical pleurectomy versus 0.9% for pleural abrasion (evidence quality high, randomized study).15 No difference between the long term recurrence rates of these two procedures was noted. One randomize trial investigated whether or not the use of adjuvant agents (chemical) sclerosis to supplement VATS mechanical pleurodesis
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could reduce long term recurrence rates (evidence high, randomized trial).16 This study randomized patients following VATS stapled bleb resection and mechanical pleurodesis to postoperative bedside chest tube administration of minocycline versus standard chest tube management. The authors found a slight decrease in the recurrence rate but significant increase in pain, suggesting that the benefit of thoracoscopy was lost when adjuvant minocycline was used. Whether or not patient characteristics can be identified to predict future recurrence to support the use of adjuvant chemical sclerosis remains unclear. At present there is not enough evidence to support the adjuvant use of chemical sclerosis agents. Significant geographic differences exist regarding the adjuvant use of talc poudrage for pleurodesis. The BTS guidelines suggest that talc poudrage alone can be used for patients with primary spontaneous pneumothorax; however, based on higher rates of failure (9% greater than those associated with surgical abrasion/stripping procedures) and lingering questions on the instillation of a foreign body, it should not be considered as the initial treatment. In the United States talc is generally reserved for patients who fail initial attempts at mechanical pleurodesis and is used only sparingly after other agents have failed. In contrast, several recent European retrospective institutional reviews have suggested talc poudrage is a safe and effective method of achieving pleurodesis at the time of thoracoscopy (evidence quality low, observational study).17 A large single-institutional experience including 861 patients compared VATS talc poudrage alone in primary spontaneous pneumothorax to VATS stapled bleb resection with adjuvant talc poudrage (evidence quality low, observational study).18 Although the study inclu ded patients with both initial and recurrent spontaneous pneumothorax, they found a long term recurrence rate of only 1.73% in patients who underwent VATS with stapled bleb resection and adjuvant talc poudrage compared to 2.41% VATS talc poudrage alone. These findings suggest that VATS talc poudrage may be acceptable as an adjuvant or even primary treatment for primary spontaneous pneumothorax; however, based on the lack of additional studies and on the current ACCP clinical guidelines, adjuvant talc poudrage cannot
46. The Role of VATS Pleurodesis in the Management of Initial Primary Spontaneous Pneumothorax
be recommended without further study. At present, the best approach to patients with initial primary spontaneous pneumothorax requiring surgical intervention is VATS stapled bullectomy with mechanical pleurodesis.
Chest Drain Management Should the chest tube be placed to suction or water seal following a VATS procedure for spontaneous pneumothorax? Much controversy has surrounded the management of chest tubes following thoracic surgical procedures. Clearly pleural apposition is required to effect pleurodesis; however, when the lung is fully expanded and the pleural surfaces are opposed, one can question whether continued negative chest tube suction is necessary and if conversion to water seal could decrease the time to chest tube removal. Neither the ACCP nor the BTS guidelines provide any comment on chest tube management following VATS for primary spontaneous pneumothorax. One single authored, single institution, randomized trial of suction versus water seal in patients following VATS for pneumothorax has been reported (evidence quality moderate, randomized study but with limitations).19 Following surgery all patients were initially place on suction. Once the patients were fully recovered and transferred to the ward, they were then randomized to suction versus water seal. The results suggest that water seal is associated with a shorter mean chest tube duration compared to the suction group (2.7 vs. 3.8 days; p = 0.004), as well as a significantly shorter hospital stay compared to that of the suction group (3.7 vs. 4.8 days; p = 0.004). There are no other direct data available to address this specific chest tube management question in patients undergoing VATS for spontaneous pneumothorax. There are, however, multiple randomized studies suggesting that the chest tube duration after pulmonary resection is shortened by placing the chest tube on water seal (evidence quality moderate, randomized study but with limitations.20-22 The data suggest that, following VATS for primary spontaneous pneumothorax, the chest tube should be placed to water seal as long as the lung is fully expanded.
405
Conclusions and Recommendations VATS stapled bullectomy with mechanical pleurodesis provides benefit for patients presenting with an initial primary pneumothorax if they have a continued air leak at 4 days or if the lungs fails to re-expand with tube thoracostomy, and is safe (moderate quality of evidence). A strong recommendation is made for VATS stapled bullectomy with mechanical pleurodesis in patients who fail initial therapy for primary spontaneous pneumothorax (recommendation grade 1B). This guideline can be applied to most patients with initial spontaneous pneumothorax and a persistent air leak at 4 days, a failure of lung expansion or both.
A Personal View of the Data The thoracic surgical unit at the hospital of the University of Pennsylvania sees a relatively large volume of young patients with primary spontaneous pneumothorax. The referral pattern is related to the large number colleges and universities within close proximity and our position as a regional referral center for general thoracic surgery. In conjunction with our colleagues in emergency medicine and pulmonary medicine we have formalized a pathway for patients presenting with initial spontaneous pneumothorax which is in general keeping with the ACCP recommendations. Those patients with small asymptomatic pneumothorax are observed in the emergency room for a short interval and, if stable, are discharged with follow up to either their primary care physician or the pulmonary medicine clinic. Patients with larger or symptomatic primary spontaneous pneumothorax undergo initial aspiration followed by observation. Those who develope an expanding pneumothorax following aspiration or remain symptomatic receive a small bore percutaneous chest tube and are admitted to the thoracic surgical service. Patients who present with large symptomatic primary spontaneous pneumothorax receive a small bore percutaneous chest tube and are admitted to the thoracic surgical service. All patients admitted to our hospital with a diagnosis of primary spontaneous pneumothorax are admitted to our service and are managed by the thoracic
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surgical team in a dedicated thoracic surgical unit. Patients with failure of lung expansion or a persistent air leak after 48–72 h are taken to the operating room for video-assisted thoracoscopy. Our standard procedure is thoracoscopy with apical wedge resection and mechanical pleurodesis. In general, formal pleurectomy is avoided due to the increased postoperative bleeding complication rates. Likewise, adjuvant sclerotic therapy such as talc and chemical pleurodesis are not used. Chest tubes are placed to suction in the operating room. A chest radiograph is obtained in the postanesthesia recovery area. The patients are transferred back to the thoracic surgical unit. At present we did not have consensus among our eight general thoracic surgeons as to when the tube should be placed to water seal. I favor early use of water seal for the chest tubes and convert from suction to water seal within the first 8 h as long as the initial postoperative film shows that the lung is fully expanded. If there is no air leak and lung is expanded, the chest tubes are removed at 48 h and the patient is discharged to home.
VATS stapled bullectomy with mechanical pleurodesis provides benefit for patients presenting with an initial primary pneumothorax if they have a continued air leak at 4 days or if the lungs fails to re-expand with tube thoracostomy, and is safe (moderate quality of evidence). A strong recommendation is made for VATS stapled bullectomy with mechanical pleurodesis in patients who fail initial therapy for primary spontaneous pneumothorax (recommendation grade 1B).
References 1. Melton LJ III, Hepper NGG, Offord KP. Incidence of spontaneous pneumothorax in Olmsted County, Minnesota: 1950 to 1974. Am Rev Respir Dis. 1979;120:1379–1382. 2. Gobbel WG Jr, Rhea WG Jr, Nelson IA, Daniel RA Jr. Spontaneous pneumothorax. J Thorac Cardiovasc Surg. 1963;46:331–345. 3. Guyatt G. Gutterman D, Baumann M, AddrizzoHarris D, Hylek E, Phillips B, Raskob G, Lewis S, Schunemann H. Grading strength of recommendations and quality of evidence in clinical guidelines. Chest. 2006;129;174–181.
J.C. Kucharczuk 4. Baumann MH, Strange C, Heffner JE, Light R, Kirby TJ, Klein J, Luketich JD, Panacek EA, Sahn SA; AACP Pneumothorax Consensus Group. Management of spontaneous pneumothorax: an American College of Chest Physicians Delphi consensus statement. Chest. 2001;119:590–602. 5. Henry M, Arnold T, Harvey J, on behalf of the BTS Pleural Disease Group, a subgroup of the BTS Standards of Care CommitteeThorax 2003;58:ii39 © 2003 BMJ Publishing Group & British Thoracic Society. BTS guidelines for the management of spontaneous pneumothorax. Thorax. 2003;58(Suppl 2): ii39–ii52. 6. Chen JS, Hsu HH, Tsai KT, Yuan A, Chen WJ, Lee YC. Salvage for unsuccessful aspiration of priamry pneumothorax: thoracoscopic surgery or chest tube drainge? Ann Thorac Surg. 2008;85:1908–1913. 7. Morimoto T, Fukui T, Koyama H, Noguchi Y, Shimbo T. Optimal strategy for the first episode of primary spontaneous pneumothorax in young men. A decision analysis. J Gen Intern Med. 2002;17:193–202. 8. Sihoe A, Yim A, Lee T, Wan S, Yuen I, and Arifi A. Can CT scanning be used to select patients with unilateral primary spontaneous pneumothorax for bilateral surgery? Chest. 2000;118:380–383. 9. Sedrakyan A, van der Meulen J, Lewsey J, Treasure T. Video assisted thoracic surgery for treatment of pneumothorax and lung resections: systematic review of randomised clinical trials. BMJ. 2004;329:1008. doi:10.1136/bmj.38243.440486.55. 10. Barker A, Maratos EC, Edmonds L, Lim E. Recurrence rates of video-assisted thoracoscopic versus open surgery in the prevention of recurrent pneumothoraces: a systematic review of randomised and nonrandomised trials. Lancet. 2007;370:329–335. 11. Treasure T. Minimal access surgery for pneumothorax. Lancet. 2007;370:294–295. 12. Balduyck B, Hendricks J, Lauwers P, Van Schill P. Quality of life evolution after surgery for primary or secondary spontaneous pneumothorax: a prospective study comparing different surgical techniques. Interact CardioVasc Thorac Surg. 2008;7:45–49. 13. Hatz RA, Kaps MF, Meimarakis G, Loehe F, Müller C, Fürst H. Long-term results after video-assisted thoracoscopic surgery for first-time and recurrent spontaneous pneumothorax. Ann Thorac Surg. 2000; 70:253–257. 14. Horio H, Nomori H, Kobayashi R, Naruke T, Suemasu K. Impact of additional pleurodesis in video-assisted thoracoscopic bullectomy for primary spontaneous pneumothorax. Surg Endosc. 2002;16:630–634. 15. Rena O, Massera F, Papalia E, Della Pona C, Robustellini M, Casadio C. Surgical pleurodesis for Vanderschueren’s stage III primary spontaneous pneumothorax. Eur Respir J. 2008;31:837–841. 16. Chen JS, Hsu HH, Chen RJ, Kuo SW, Huang PM, Tsai PR, Lee JM, Lee YC. Additional minocycline pleurodesis after thoracoscopic surgery for primary spontaneous pneumothorax. Am J Respir Crit Care Med. 2006;173:548–554.
46. The Role of VATS Pleurodesis in the Management of Initial Primary Spontaneous Pneumothorax 17. Gyorik S, Erni S, Studler U, Hodek-Wuerz R, Tamm M, Chhajed P. Longterm follow up of thoracoscopic talc pleurodesis for primary spontaneous pneumothorax. Eur Respir J. 2007;29:757–760. 18. Cardillo G, Carleo F, Giunti R, Carbone L, Mariotta S, Salvadori L,Petrella L,Martelli M.Videothoracoscopic talc poudrage in primary spontaneous pneumothorax: A single-institution experience in 861 cases. J Thorac Cardiovasc Surg. 2006;131:322–328. 19. Ayed A. Suction versus water seal after thoracoscopy for primary spontaneous pneumothorax: prospective randomized study. Ann Thorac Surg. 2003; 75:1593–1596.
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20. Marshall MB, Deeb ME, Bleier JL, Kucharzcuk JC, Friedberg JS, Kaiser LR, Shrager JB. Suction vs water seal after pulmonary resection: a randomized prospective study. Chest. 2002;121:831–835. 21. Cerfolio RJ, Bass C, Katholi CR. Prospective randomized trial compares suction versus water seal for air leaks. Ann Thorac Surg. 2001;71:1613–1617. 22. Alphonso N, Tan C, Utley M, Cameron R, Dussek J, Lang-Lazdunski L, Treasure T. A prospective randomized controlled trial of suction versus non-suction to the under-water seal drains following lung resection. Eur J Cardiothorac Surg. 2005;27:391–394.
47
Malignant Pleural Mesothelioma: Patient Selection for Pleurectomy Raja M. Flores and Naveed Z. Alam
Introduction Although primary pleural tumors had been reported since the eighteenth century, the epidemiology of mesothelioma first came to light in 1960 with the report by Wagner and colleagues of 33 asbestos mine workers from South Africa who developed mesothelioma.1 Malignant pleural mesothelioma (MPM) is a rare tumor. Although the geographical distribution of the disease is diverse, taken as a whole the United States has an incidence just under 1 per 100,000.2 The incidence has been rising since the 1970s. The male to female ratio is 5:1 which is likely due to the occupational exposure of asbestos. Surgery has a well defined role in the diagnosis of MPM and in its palliative management. It is in the arena of curative therapy where the controversy begins. This chapter focuses on the evidence for pleurectomy in the treatment of MPM, and specifically on radical pleurectomy and decortication (P/D) for debulking or resection rather than a limited pleurectomy for palliative pleurodesis. Indications for P/D can be thought of as being patient related or tumor related. Perhaps the least controversial statement one can make about P/D is that it can be offered to patients who do not have the cardiopulmonary reserve to tolerate pneumonectomy. For patients who can tolerate pneumonectomy, the choice of operation becomes less clear. Some centers perform P/D for patients with early stage disease, confined to the parietal pleural “capsule” (Butchart I, IMIG T1a or T1b), the reasoning being that, if no lung parenchyma is involved, the inherent morbidity and mortality
risk of adding a pneumonectomy is not warranted. Others disagree, feeling that in cancer you only have one chance to eradicate the disease and, furthermore, the absence of lung parenchyma facilitates the administration of post-operative adjuvant therapy, in particular radiation therapy. If one accepts that MPM is a disease for which true R0 resection is a theoretical possibility, then the goal of surgery is to remove all gross tumor and serve as a springboard for adjuvant therapy. The choice of operation can then be made based on the extent of resection required and the extent of resection that the patient will tolerate. Some clinicians feel that, with newer methods of radiation administration and ongoing attempts at other local and systemic therapies, the argument that residual lung parenchyma hinders appropriate adjuvant therapy may be less of a factor than it once was. The debate continues.
Methodology A Medline search was performed using Pubmed and the search terms “pleurectomy” and “mesothelioma”. Limits were set to English language publications in between 1989 and 2009.
Results The evidence relating to P/D for mesothelioma is almost all of low quality. There is no randomized data and the studies are either case series or
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retrospective comparisons of prospectively collected data. It is evident that P/D is generally well tolerated with a mortality limited to approximately 1–2% when performed at high volume centers, with the most common complication being prolonged air leak occurring in 10% of patients. Hemorrhage, pneumonia, and empyema are less common complications.3
Pre-operative Evaluation All patients undergoing consideration for P/D need thorough imaging and cardiopulmonary evaluation. At a minimum, pulmonary function testing should be performed. Quantitative ventilation perfusion scans may also be indicated if associated lung resections are anticipated or to evaluate the possibility of extra-pleural pneumonectomy (EPP). CT of the thorax and upper abdomen is required imaging and MRI may be superior in assessing discrete foci of chest wall invasion or diaphragmatic muscle involvement.4 FDG-PET scanning in MPM can be used to provide stage and prognostic information. In addition to helping to determine the extent of tumor, PET can be used to detect N3 or M1 disease in 10% of patients.5,6 The standardized uptake value (SUV) can also be used to predict the presence of N2 lymphatic spread.6 High SUV has also been shown to correlate with poor survival in MPM.7 Mediastinoscopy is useful in determining the N stage of most patients and is more accurate than CT.8 However, up to 25% of patients have lymph node involvement confined to areas of the hemithorax inaccessible by mediastinoscopy such as the peridiaphragmatic or internal mammary regions.9
P/D Alone The results of studies examining P/D alone are summarized in Table 47.1. Median survival ranges from nine to 20 months in the literature. All of these studies are observational and hence the quality of this evidence is low. Few if any centers would offer P/D without some form adjuvant therapy any longer for patients who are not on a purely palliative track.
Table 47.1. Studies of pleurectomy alone for malignant pleural mesothelioma. Source Chahinian Brenner11 Law12 Chailleux13 Ruffie14 Brancatisano15 Rusch16 Soysal17 Ceresoli18 10
Year
Patients
Median survival (months)
Mortality (%)
1982 1982 1984 1988 1989 1991 1991 1997 2001
30 69 28 29 63 45 26 100 38
13 15 20 14 10 16 10 17 13
0 N/A 11 N/A 0 2 N/A 1 N/A
N/A not available. Adapted from Van Ruth S, Baas P, Zoetmulder FA. Surgical treatment of malignant pleural mesothelioma.45
Combined Modality Therapy Since the results of surgery alone are poor, most recent studies have combined P/D with some form or combination of adjuvant therapies. These have included external radiation, brachytherapy, systemic chemotherapy, intrapleural chemotherapy, and photodynamic therapy. It is important to note that these studies are almost uniformly observational in nature, and once again constitute low quality evidence. When comparisons are performed, they are by and large across inhomogeneous groups, thereby limiting the conclusions that can be drawn about efficacy. There have been a number of studies comparing P/D to EPP, shown in Table 47.2. The largest of these was recently reported by one of us (RF).23 A comparison of 663 consecutive patients that underwent resection between 1990 and 2006 was performed. There were 278 P/D procedures and 385 EPPs. Median survival and operative mortality were 16 months and 4% for P/D and 12 months and 7% for EPP. Patients in both arms received various regimens of neoadjuvant and adjuvant therapies based on clinical trials that were running concurrently over the 17 years. There were important differences in the two groups, with the P/D group having older patients and higher proportion of early stage disease, whereas the EPP group had more patients with epitheliod histology. A study comparing palliative decortication versus P/D in patients who were also planned to
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47. Malignant Pleural Mesothelioma: Patient Selection for Pleurectomy Table 47.2. Non-randomized comparative studies of surgical therapy for malignant pleural mesothelioma. Source Allen Pass20 Martin-Ucar21 Okada22 Flores23 Luckraz24 19
Therapies
Year
Patients
Survival (months)
P/D vs. EPP P/D vs. EPP P/D vs. EPP P/D vs. EPP P/D vs. EPP P/D vs. EPP
1994 1997 2007 2008 2008 2009
56 vs. 40 39 vs. 39 12 vs. 45 34 vs. 31 278 vs. 385 90 vs. 49
9.0 vs. 13.3 14.5 vs. 9.4 16 vs. 15 17 vs. 13 16 vs. 12 10.1 vs. 10.3
P value
Evidence quality low Low Low Low Low Low
N/A 0.012 0.4 0.9 <0.001 0.09
P/D pleurectomy/decortication; EPP extrapleural pneumonectomy; N/A not available.
receive adjuvant chemotherapy showed that the P/D group had improved survival.25 There were important differences in the groups with more patients receiving the planned adjuvant chemotherapy in the P/D group. Studies using various forms of radiation therapy are summarized in Table 47.3. The earliest experience with combined therapy for MPM was reported by McCormack et al.,26 at Memorial Sloan-Kettering Cancer Center (MSKCC). The combination of P/D with external radiation and systemic chemotherapy in 18 patients with epithelial mesothelioma produced a median survival of
16 months. In the subsequent 33 patients, brachytherapy was added and the median survival was 21 months. A Finnish study comprising 100 patients evaluated five different adjuvant radiation schedules and chemotherapy regimens following pleurectomy.28 The median survival was 8 months and the 2-year survival was 20%. They found no differences among the groups. Studies focused primarily on P/D with chemotherapy (systemic or intrapleural) are summarized in Table 47.4. Rusch and colleagues from MSKCC evaluated P/D followed by intrapleural cisplatin
Table 47.3. Studies of pleurectomy with radiation with or without other therapies. Source McCormack Alberts27 Mattson28 Lee29 Gupta30 Lucchi31 Bolukbas32
26
Therapy
Year
Patients
Median survival (months)
Mortality (%)
S,R,C S,R,B S,R,C S,R,±C S,R,± B I,S,I,R,C S,C+R
1982 1988 1992 2002 2005 2007 2009
18 26 100 26 123 49 35
16 11 8 18 13.5 26 30
2 N/A N/A 1.6 0 5.8
S surgery; R external radiation; B brachytherapy; C systemic chemotherapy; N/A not available. Adapted from Van Ruth S, Baas P, Zoetmulder FA. Surgical treatment of malignant pleural mesothelioma.45
Table 47.4. Studies of pleurectomy with chemotherapy for malignant pleural mesothelioma. Source Rusch Rice34 Sauter35 Lee36 Colleoni37 Hasturk38 Ceresoli39 Sugarbaker40 33
Therapy
Year
Patients
Median survival (months)
S,I,C S,I,C S, I, C S,I S,I,C S,C S,C S,I
1994 1994 1995 1995 1996 1996 2001 2003
28 9 13 15 20 20 16 44
18 13 9 12 12 12 14 9
S surgery; C systemic chemotherapy; I intrapleural chemotherapy; N/A not available. Adapted from Van Ruth S, Baas P, Zoetmulder FA. Surgical treatment of malignant pleural mesothelioma.45
Mortality (%) 4 5 8 0 0 N/A N/A 11
R.M. Flores and N.Z. Alam
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and mitomycin followed by systemic cisplatin and mitomycin given 3–5 weeks postoperatively.33 There were 28 patients who underwent P/D and received intrapleural chemotherapy. There was one postoperative death and two patients who developed grade 4 nephrotoxicity. The median survival was 18 months and significant morbidity was present in 53% of patients. Local failure was high, with 16 local relapses in 27 patients. The authors were concerned about the potential for serious toxicity. In a more recent report, and the only one to date to incorporate pemetrexed with P/D, Bolukbas and colleagues performed P/D on 35 patients followed by administration of cisplatin/pemetrexed and radiotherapy.32 They had 5.8% mortality from the trimodality therapy and a median survival of 30 months, despite only 51% of patients having a macroscopic complete resection. This suggests there is some promise with this regimen. The search for effective therapies to achieve local control in MPM has sparked interest in a number of other areas. Hyperthermia has been investigated in combination with surgery. Ratto et al. gave hyperthermic cisplatin (41.5 C) for 60 min following P/D (three patients) or EPP (four patients).41 Patients also received 55 Gy to chest wall incisions. There was no death or toxicity and the treatment was well tolerated. An interesting finding was that systemic cisplatin levels were significantly higher in the group that had P/D, indicating that the remaining lung plays an important role in the absorption of intrapleural cisplatin. In a dose escalation study, Sugarbaker and colleagues performed P/D on 44 patients followed by intraperitoneal and ipsilateral hemithoracic lavage with cisplatin at 42 C.40 They reported postoperative mortality of 11% and median survival of 9 months. Photodynamic therapy (PDT), a modality used to enhance local control, has also been investigated in conjunction with P/D with studies shown in Table 47.5. A photosensitizer is administered systemically and then target areas are illuminated
with laser to effect cell kill. No recent studies of this technique have been published, however.
Recommendations All the available evidence is of low quality, with the vast majority of papers being case series. The few comparative papers are retrospective comparisons of inhomogeneous groups. P/D alone is safe but does not improve survival in MPM (low quality evidence). We strongly recommend against P/D performed in isolation for MPM (recommendation grade 1C). P/D as part of a multimodality treatment protocol including systemic chemotherapy and radiation has acceptable morbidity and mortality and improves survival over supportive care alone (low quality evidence). We make a weak recommendation that P/D be performed in patients with good performance status in whom gross macroscopic clearance of disease can be achieved as part of multimodality treatment (recommendation grade 2C).
Personal View of the Data The question as to whether or not any surgical intervention should be performed outside of palliation in mesothelioma is in and of itself a controversial one. There is no high or even moderate evidence to suggest that it should be performed, but for those who treat this disease, surgery is generally part of the treatment algorithm. The evidence suggests that surgery in isolation is of no value. In that context, the choice of operation is affected by myriad factors. Apart from the risks and benefits of the procedure alone, the influence on subsequent treatment modalities needs to be considered. More extensive surgery may make it
Table 47.5. Studies of pleurectomy with photodynamic therapy for malignant pleural mesothelioma. Source
Therapy
Year
Patients
Median survival (months)
Mortality (%)
Pass Moskal43
S,P,C,I S,P
1997 1998
25 40
14 15
4 7
42
S surgery; C systemic chemotherapy; I intrapleural chemotherapy; P photodynamic therapy. Adapted from Van Ruth S, Baas P, Zoetmulder FA. Surgical treatment of malignant pleural mesothelioma.45
47. Malignant Pleural Mesothelioma: Patient Selection for Pleurectomy
more difficult for patients to tolerate adjuvant chemotherapy. Lung sparing surgery (P/D) may make it more difficult to give external beam radiation to the affected hemithorax. Unfortunately, the current evidence does not guide us in an unequivocal direction. Our feeling is that the role of surgery is to reduce as effectively as possible the tumor burden with removal of all macroscopic disease. If gross macroscopic clearance can be achieved with P/D, we feel that should be the operation that is performed. The reported trials on multimodality therapy using newer agents and techniques have been by and large confined to protocols where EPP has been mandated. As noted above, Bolukbas and colleagues are the only ones to have reported on P/D in a protocol including pemetrexed.32 In terms of newer radiation techniques, no studies have yet reported on outcomes of intensity modulated radiation therapy (IMRT) along with P/D. These studies will likely be published in the near future, as more and more centers are applying these techniques and protocols to their mesothelioma patients. The higher quality evidence that is needed may never be available. The study required to answer all the questions would be a triple randomization to chemotherapy and radiation versus chemo/ radiation and P/D versus chemo/radiation and EPP. This trial will, of course, never be performed. Future trials should include novel agents and techniques with or without P/D to define the role of surgery in mesothelioma more clearly. P/D alone is safe but does not improve survival in MPM (low quality evidence). We strongly recommend against P/D performed in isolation for MPM (recommendation grade 1C). P/D as part of a multimodality treatment protocol including systemic chemotherapy and radiation has acceptable morbidity and mortality and improves survival over supportive care alone (low quality evidence). We make a weak recommendation that P/D be performed in patients with good performance status in whom gross macroscopic clearance of disease can be achieved as part of multimodality treatment (recommendation grade 2C).
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References 1. Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J In Med. 1960;17:260–271. 2. Verschraegen C. Mesothelioma: incidence and survival rates in the United States. Proc Am Soc Clin Oncol. 2003;22:869. 3. Pass HI, Pogrebeniak HW. Malignant pleural mesothelioma. Curr Probl Surg. 1993;30:921–1012. 4. Heelan RT, Rusch VW, Begg CB, Panicek DM, Caravelli JF, Eisen C. Staging of malignant pleural mesothelioma: comparison of CT and MR imaging. Am J Roentgenol. 1999; 172:1039–1047. 5. Benard F, Sterman D, Smith RJ, Kaiser LR, Albelda SM, Alavi A. Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography. Chest. 1998;114:713–722. 6. Flores RM, Akhurst T, Gonen M, Larson SM, Rusch VW. Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma. J Thor CV Surg. 2003;126:11–15. 7. Flores RM, Akhurst T, Gonen M, et al. FDG-PET predicts survival in patients with malignant pleural mesothelioma. Proc Am Soc Clin Oncol. 2003;22:620. 8. Schouwink JH, Kool LS, Rutgers EJ, Zoetmulder FA, van Zandwijk N, v d Vijver MJ, Baas P. The value of chest computed tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma. Ann Thor Surg. 2003;75:1715–1719. 9. Rusch VW, Venkatraman ES. Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically. Ann Thorac Surg. 1999; 68:1799–1804. 10. Chahinian AP, Pajak TF, Holland JF, Norton L, Ambinder RM, Mandel EM. Diffuse malignant mesothelioma: prospective evaluation of 69 patients. Ann Intern Med. 1982;96:746–755. 11. Brenner J, Sordillo PP, Magill GB, Golbey RB. Malignant mesothelioma of the pleura: review of 123 patients. Cancer. 1982;49:2431–2435. 12. Law MR, Gregor A, Hodson ME, Bloom HJ, TurnerWarwick M. Malignant mesothelioma of the pleura: a study of 52 treated and 64 untreated patients. Thorax. 1984;39:255–259. 13. Chailleux E, Dabouis G, Pioche D, de Lajarte M, de Lajarte AY, Rembeaux A, Germaud P. Prognostic factors in diffuse malignant pleural mesothelioma: a study of 167 patients. Chest. 1988;93:159–162. 14. Ruffie P, Feld R, Minkin S, Cormier Y, Boutan-Laroze A, Ginsberg R, Ayoub J, Shepherd FA, Evans WK, Figueredo A, Pater JL, Pringle JF, Kreisman H. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol. 1989;7:1157–1168. 15. Brancatisano RP, Joseph MG, McCaughan BC. Pleurectomy for mesothelioma. Med J Aust. 1991;154: 455–457.
414 16. Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in malignant pleural mesothelioma: lung cancer study group trial. Thorac Cardiovasc Surg. 1991;102:1–9. 17. Soysal O, Karaoglanoglu N, Demiracan S, Tupcu S, Tastepe I, Kaya S, Unlu M, Cetin G. Pleurectomy/ decortication for palliation in malignant pleural mesothelioma: results of surgery. Eur J Cardiothorac Surg. 1997;11:210–213. 18. Ceresoli GL, Locati L, Ferreri AJ, Cozzarini C, Passoni P, Melloni G, Zannini P, Bolognesi A, Villa E. Therapeutic outcome according to histologic subtype in 121 patients with malignant pleural mesothelioma. Lung Cancer. 2001;34:279–287. 19. Allen KB, Faber LP, Warren WH. Malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy. Chest Surg Clin N Am. 1994;4:113–126. 20. Pass HI, Kranda K, Temeck BK, Feuerstein I, Steinberg SM. Surgically debulked malignant pleural mesothelioma: results and prognostic factors. Ann Surg Oncol. 1997;4:215–222. 21. Martin-Ucar AE, Nakas A, Edwards JG, Waller DA. Case-control study between extrapleural pneumonectomy and radical pleurectomy/decortication for pathological N2 malignant pleural mesothelioma. Eur J Cardiothorac Surg. 2007;31:765–770. 22. Okada M, Mimura T, Ohbayashi C, Sakuma T, Soejima T, Tsubota N. Radical surgery for malignant pleural mesothelioma: results and prognosis. Interact Cardiovasc Thorac Surg. 2008;7:102–106. 23. Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, Bains MS, Rusch VW. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg. 2008;135:620–626. 24. Luckraz H, Rahman M, Patel N, Szafranek A, Gibbs AR, Butchart EG. Three decades of experience in the surgical multi-modality management of pleural mesothelioma. Eur J Cardiothorac Surg. 2009 Aug 28. [Epub ahead of print]. 25. Nakas A, Trousse DS, Martin-Ucar AE, Waller DA. Open lung-sparing surgery for malignant pleural mesothelioma: the benefits of a radical approach within multimodality therapy. Eur J Cardiothorac Surg. 2008;34:886–891. 26. McCormack PM, Nagasaki F, Hilaris BS, Martini N. Surgical treatment of pleural mesothelioma. Thorac Cardiovasc Surg. 1982;84:834–842. 27. Alberts AS, Falkson G, Goedhals L, Vorobiof DA, Van der Merwe CA. Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers. J Clin Oncol. 1988;6:527–535. 28. Mattson K, Holsti LR, Tammilehto L, Maasilta P, Pyrhonen S, Mantyla M, Kajanti M, Salminen US, Rautonen J, Kivisaari L. Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation. Int J Radiat Oncol Biol Phys. 1992;24:643–650.
R.M. Flores and N.Z. Alam 29. Lee TT, Everett DL, Shu HKFiglin RA, Holmes EC. Radical pleurectomy/decortication and intra-operative radiotherapy followed by conformal radiation with or without chemotherapy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2002;124: 1074–1077. 30. Gupta V, Mychalczak B, Krug L, Flores R, Bains M, Rusch VW, Rosenzweig KE. Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys. 2005;63:1045–1052. 31. Lucchi M, Chella A, Melfi F, Dini P, Tibaldi C, Fontanini G, Mussi A. Four-modality therapy in malignant pleural mesothelioma: a phase II study. J Thorac Oncol. 2007;2:237–242. 32. Bolukbas S, Manegold C, Eberflein M, Bergmann T, Fisseler-Eckhoff A, Schirren J. Survival after trimodality therapy for malignant pleural mesothelioma: radical pleurectomy, chemotherapy with cisplatin/ pemetrexed and radiotherapy. Lung Cancer. 2009 Sept 16. [Epub ahead of print]. 33. Rusch VW, Saltz L, Venkatraman E, Ginsberg R, McCormack P, Burt M, Markman M, Kelsen D. A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol. 1994; 12:1156–1163. 34. Rice TW, Adelstein DJ, Kirby TJ, Saltarelli MG, Murthy SR, Van Kirk MA, Wiedemann HP, Weick JK. Aggressive multimodality therapy for malignant pleural mesothelioma. Ann Thor Surg. 1994;58: 24–29. 35. Sauter ER, Langer C, Coia LR, Goldberg M, Keller SM. Optimal management of malignant mesothelioma after subtotal pleurectomy: revisiting the role of intrapleural chemotherapy and postoperative radiation. J Surg Oncol. 1995;60:100–105. 36. Lee JD, Perez S, Wang HJ, Figlin RA, Holmes EC. Intrapleural chemotherapy for patients with incompletely resected malignant mesothelioma: the UCLA experience. J Surg Oncol. 1995; 60:262–267. 37. Colleoni M, Sartori F, Calabro F, Nelli P, Vicario G, Sgarbossa G, Gaion F, Bartolotti L, Toniolo L, Manente P. Surgery followed by intracavitary plus systemic chemotherapy in malignant pleural mesothelioma. Tumori. 1996;82:53–56. 38. Hastürk S, Tastepe I, Unlu M, Cetin G, Baris YI. Combined chemotherapy in pleurectomized malignant pleural mesothelioma patients. J Chemother. 1996;8:159–164. 39. Ceresoli GL, Locati L, Ferreri AJ, Cozzarini C, Passoni P, Melloni G, Zannini P, Bolognesi A,Villa E. Therapeutic outcome according to histologic subtype in 121 patients with malignant pleural mesothelioma. Lung Cancer. 2001;34:279–287. 40. Sugarbaker D, Richards WG, Zellos LS. Feasibility of pleurectomy and intraoperative bicavitary hyperthermic cisplatin lavage for mesothelioma: a phase I-II study. Proc Am Soc Clin Oncol. 2003;22:620.
47. Malignant Pleural Mesothelioma: Patient Selection for Pleurectomy 41. Ratto GB, Civalleri D, Esposito M, Spessa E, Alloisio A, De Cian F, Vannozzi MO. Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: a feasibility and pharmacokinetic study. Thorac Cardiovasc Surg. 1999;117: 759–765. 42. Pass HI, Temeck BK, Kranda K, Thomas G, Russo A, Smith P, Friauf W, Steinberg SM. Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma. Ann Surg Oncol. 1997;4:628–633.
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43. Moskal TL, Dougherty TJ, Urschel JD, Antkowiak JG, Regal AM, Driscoll DR, Takita H. Operation and photodynamic therapy for pleural mesothelioma: 6-year follow-up. Ann Thorac Surg. 1998;66:1128–1133. 44. Guyatt G, Gutterman D, Baumann MH, AddrizzoHarris D, EHylek EM, Phillips B, Raskob G, Lewis SZ and Schünemann H. Grading strength of recommendations and quality of evidence in clinical guidelines. Chest. 2006;129;174–181. 45. van Ruth S, Baas P, Zoetmulder FAN. Surgical treatment of malignant pleural mesothelioma. Chest. 2003;123;551–561.
48
Malignant Pleural Mesothelioma: Patient Selection for Extrapleural Pneumonectomy David A. Waller
Introduction The selection of patients with malignant pleural mesothelioma (MPM) for extrapleural pneumonectomy (EPP) can be considered in two areas: resectability and operability. Resectability refers to the ability to achieve macroscopic tumor clearance. Operability refers to the patient’s fitness to tolerate the operation. There is a relative paucity of evidence to support either of these criteria. However, it is reasonable to apply the criteria for fitness for pneumonectomy learned from surgery for NSCLC. The criteria for resectability must be considered separately. The original TNM staging system for MPM is thought to be outdated by many and is actively under revision. Debate surrounds the prognostic significance of extrapleural nodal metastases particularly the adopted nomenclature of N0-2. Consequently the roles of mediastinoscopy and laparoscopy in patient selection for EPP are controversial. The role of non-invasive imaging is more established but the exact role of positron emisssion tomography (PET) is not yet determined. Finally, the histological subtype of MPM has been proposed as an important selection criterion, but some dispute its importance.
Methodology A Pubmed search was performed using the terms: [malignant pleural mesothelioma] AND [extrapleural pneumonectomy OR pneumonectomy]
AND [patient selection OR prognostic factors]. The search was limited to articles published in English during the period 1999–2009.
Published Data Resectability: Tumor Characteristics Do MRI or CTPET Add Anything to CT in Patient Selection? The limitations of computed tomography in initial evaluation are its difficulties in assessing (1) chest wall involvement, (2) mediastinal lymph nodes, (3) transdiaphragmatic extension of tumor, and (4) peritoneal studding and solid organ metastases less than 2 mm in size.1 MRI imaging has been found to be superior to CT in revealing invasion of the diaphragm or endothoracic fascia or solitary resectable foci of chest wall invasion, but it is unlikely to contribute significantly to nodal staging.2,3 It remains a valuable adjunct in the selection of patients for radical surgery The routine use of positron emission tomography [PET] in assessment is not mandatory since sensitivities of only 19% and 11% for tumor and nodal status, respectively, are reported.4 The SUVmax of the primary tumor may have prognostic significance: in a multivariable analysis, high standard uptake value tumors were associated with a 1.9 times greater risk of death than low standard uptake value tumors, and a high standard uptake value in the primary tumor correlated with the presence of N2 disease.5
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_48, © Springer-Verlag London Limited 2011
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How Useful Are EBUS/EUS or Mediastinoscopy in Excluding Patients for EPP? Lymph node size on CT does not predict malignant involvement,6 thus routine tissue biopsy is recommended to exclude N2 disease. Sensitivity and negative predictive value for mediastinoscopy have been found to be inferior to endobronchial ultrasound [EBUS]: 28% and 49% versus 59% and 57%, respectively.7 N2 disease, but not mediastinoscopy, has been shown to have a significant impact on survival. The proportion of patients with N2 disease and longterm survival were similar regardless of whether preoperative mediastinoscopy yielded a negative result.8 This may be explained by the finding that positive N2 nodes inaccessible by mediastinoscopy were present in almost half of all cases.9
Should Patients with N2 Disease Be Denied EPP? In one of the earliest large case series of EPP extrapleural nodal metastases were identified as a poor prognostic factor (OR 2.0, CI 1.3–3.2; P = 0.0026).10 Two more recent case series8,11 have also found that N2 disease is associated with reduced survival with a hazard ratio for survival of 1.7. Survival appears to be influenced by the number of involved N2 stations rather than their anatomical location. Further evidence against EPP in patients with N2 disease comes from a nonrandomized comparison which found that preservation of the lung during radical surgery for N2 positive MM did not compromise survival, even in an older group population.12
What Characteristics of the Primary Tumor Are Important in Selection? The existing TNM staging system has inaccuracies, but local tumor invasion into chest wall [T3] or mediastinum [T4] is associated with poor survival; stages III and IV had a 1.8 times greater risk of death than stages I and II.13 In addition, preresection tumor volume is representative of T status in malignant pleural mesothelioma and can predict overall survival.14 Tumor volumes associated with negative nodes were significantly smaller and progressively higher stage disease was associated with higher median preoperative volumes.
Is Laparoscopy a Required Selection Tool? Peritoneal disease progression is frequently seen after EPP and limited series have explored the use of laparoscopy to exclude this preoperatively. Positive evidence of transdiaphragmatic or peritoneal involvement was found in around 10% of cases assessed for EPP.15,16 What is not apparent is how many of these patients also had mediastinal lymph node metastases and may have been excluded from consideration for EPP following EBUS or mediastinoscopy.
Should Patients with Non-Epithelioid MPM Be Denied EPP? Sugarbaker reported a threefold relative risk of death for nonepithelial cell type after EPP10; Flores13 found a similar 2.9 times greater risk of death for mixed histology compared to epithelioid tumors (OR 3.0, CI 2.0–4.5; P < 0.0001). Following trimodality therapy epithelial tumors have a better survival than patients with sarcomatoid and mixed tumors, with median survivals of 21.9 versus 11.1 months, respectively,17 and others confirm that epithelial histologic subtype and EPP are independent predictors for 18-month survival.18 Furthermore in sarcomatoid disease the extent of surgical excision has no effect on survival unlike in epithelioid disease.19
Is Induction Chemotherapy a Valuable Selection Process? In two prospective trials17,20 a significant proportion (30 of 77 and 45 of 61) of patients became inoperable during induction chemotherapy prior to EPP due to disease progression. These patients were arguably spared inappropriate surgery. The survival benefit of EPP as part of multi-modality therapy, rather than in isolation, has been repeatedly demonstrated10,13; thus, patients must be fit to undergo chemotherapy as part of EPP selection.
Are Biomarkers of Any Current Use in Patient Selection? Serum tumor markers, i.e. mesothelin, may have value in diagnosis of MPM21 but there is as yet no correlation with prognosis and therefore no role
48. Malignant Pleural Mesothelioma: Patient Selection for Extrapleural Pneumonectomy
in patient selection. Expression data for four genes were collected from tumor specimens, and three ratios of gene expression (TM4SF1/PKM2, TM4SF1/ARHGDIA, and COBLL1/ARHGDIA) were determined by quantitative reverse transcriptasepolymerase chain reaction.22 Patients were assigned to good or poor outcome groups by the gene ratio test. The test predicted overall survival on multivariable analysis and may have a future role in selecting those patients who will benefit most from surgery.
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postoperative morbidity risk of around 60% including a 9% risk of technical complications.25 These may be increased by neoadjuvant chemotherapy particularly acute lung injury.26 There is a relatively lower operative risk from P/D with reported operative mortality of 4%.13 Treatment related mortality from extended systemic chemotherapy is low and in selected younger patients with epithelioid disease and good performance status median survival is over 18 months and is comparable to EPP.27
Operability: Patient Characteristics The lack of published evidence for EPP necessitates extrapolating the criteria for assessing fitness for pneumonectomy for NSCLC23 to mesothelioma surgery. The most useful tests of cardiorespiratory fitness are spirometry and gas transfer. If the FEV1 is >80% predicted or >2 L and there is no evidence of either undue dyspnea on exertion or interstitial lung disease, the patient is suitable for EPP without further physiologic evaluation. In patients with either a predicted postoperative (ppo) FEV1 of <40% or a ppoDLCO of <40% there is an increased risk for perioperative death and cardiopulmonary complications, and whilst preoperative exercise testing can be undertaken, alternative treatment should be considered. Patients who are being considered for surgery who have a VO2max of <15 mL/kg/min and both a ppoFEV1 and a ppoDLCO of <40% should not be considered for EPP. Scintigraphy can be used to assess split lung function24 and is particularly useful to confirm that the affected lung is contributing little to overall function.
What Are the Relative Risks and Benefits of EPP? Any patient selection process should include an assessment of the risks and benefits of a treatment in comparison to the therapeutic alternatives. In the selection for EPP the two main alternative treatments are systemic chemotherapy or radical pleurectomy/decortication. The risk of operative mortality from EPP has decreased with increasing experience and improved post operative care with a current risk of over 5%.13 Nevertheless there remains a significant
Summary and Recommendations Patient selection for extrapleural pneumonectomy should include assessment of stage and histological subtype of MPM utilising at least video assisted thoracoscopy, CT of the chest and abdomen and mediastinal node biopsy using endobronchial ultrasound or mediastinoscopy (but not routine CT/PET or laparoscopy) in order to exclude those with extrapleural nodal metastases and non-epithelioid cell type. Patients in whom ppoFEV1 or ppoDLCO <40% after assessment of differential lung function and/or whose mean pulmonary artery pressure exceeds 35 mmHg or who have evidence of moderate right ventricular dysfunction should be considered for alternative treatment. Patients who are not suitable to be considered for pre or postoperative systemic chemotherapy or whose disease progresses during induction chemotherapy should not be considered for EPP. In light of the higher operative morbidity and mortality of EPP, other lower risk treatment strategies including radical pleurectomy/decortication or extended courses of systemic chemotherapy should be discussed with the patient (Table 48.1). EPP in patients with epithelioid histology, without mediastinal nodal involvement or extrathoracic disease, and with adequate cardiopulmonary function is safe in experienced, high-volume centers and may offer prolonged survival as part of multimodality therapy (evidence quality moderate). A weak recommendation is made for EPP as part of multimodality therapy in highly selected patients with malignant pleural mesothelioma (recommendation grade 2B).
D.A. Waller
420 Table 48.1. Data from studies of surgical therapy for mesothelioma. Study
Study format
Flores13 Sugarbaker10
EPP vs. PD retrospective multi-institutional EPP, prospective single institutional
Martin-Ucar12
EPP vs. PD in N2 positive disease, retrospective case-control
Study conclusion Increased HR (1.4) for EPP related to operative mortality Prognostic factors: epithelioid cell type; negative margins; extrapleural nodal metastases No difference in mean survival between EPP and PD
Patients
Quality of evidence
EPP 385 vs. PD 278 EPP 183
Low Moderate
EPP 45 vs. PD 12
Moderate
EPP extrapleural pneumonectomy; PD pleurectomy/decortication; N2 ipsilateral mediastinal lymph nodes; HR hazard ratio
A Personal View of the Data The case for EPP in the radical treatment of MPM is weakening as the objective of surgery has been refocused on achieving complete macroscopic tumor clearance, which may now be attained by lung sparing total pleurectomy (LSTP). EPP is associated with higher morbidity and mortality than LSTP but the only long term survivors from MPM have undergone EPP as part of multimodality therapy. The risks of EPP can only be justified in those with the most to gain (best prognosis tumors) and least to lose (best performance status). Thus, EPP should only be offered to younger patients (arbitrarily under 50 years of age) whose ppoFEV1 > 50% who have epithelioid MPM which is negative on mediastinoscopy and who can tolerate chemoradiotherapy. Mediastinoscopy may not be able to exclude all mediastinal nodal disease, of course, but it does provide a representative sample. The classical anatomic locations are not as important as the scatter of nodal involvement. Every effort should be made to obtain biopsy specimens from as many stations as possible before undertaking extrapleural pneumonectomy for malignant mesothelioma. The argument against routine laparoscopy, similar to that against routine cerebral imaging in early stage NSCLC assessment, is that in the presence of negative CT/PET and mediastinoscopy a positive result is unlikely. In the majority of other patients who should be offered LSTP there may be a situation in which complete macroscopic tumor clearance is not possible due to lung parenchymal invasion. In these situations the surgeon should resist the compulsion to perform EPP since the most morbid and high risk procedure should not be reserved for
those with the more advanced disease and therefore the worst prognosis. The situation is akin to performing pneumonectomy for metastatic multifocal non-small cell lung cancer. The default option in this scenario should be surgical debulking sufficient only to achieve lung mobilization, re-expansion and symptom relief. Conversely, some would argue against EPP for stage I MPM and instead promote lung sparing pleurectomy. As stated earlier, there is an argument for using the most aggressive surgical option in the earliest disease stage with the best prognosis. To continue the NSCLC analogy, would one advocate wedge resection for stage I NSCLC in favor of an anatomical resection? The timing of multimodality therapy remains open to debate. There are sound reasons why systemic chemotherapy should be given prior to EPP including maximal compliance with the intended regimen. However, there are persuasive reasons for avoiding perioperative complications associated with induction chemotherapy. Importantly, one of the most feared reservations about this regimen is tumor progression in non-responders to the point of unresectability, which may actually be one of the best patient selection criteria. Future prospective randomized data are desperately needed in the field of surgery for MPM. We are at present in a virtually evidence–free zone. Fundamental questions, including the potential benefit of radical surgery plus chemotherapy over chemotherapy alone, remain to be answered. The MARS trial in UK has shown the feasibility of conducting a randomized trial of EPP versus chemotherapy28 but results of a sufficiently powered larger study are awaited. Only then can the mode of radical surgery (EPP) or lung sparing total pleurectomy be further investigated.
48. Malignant Pleural Mesothelioma: Patient Selection for Extrapleural Pneumonectomy
EPP in patients with epithelioid histology, without mediastinal nodal involvement or extrathoracic disease,and with adequate cardiopulmonary function is safe in experienced, high-volume centers and may offer prolonged survival as part of multimodality therapy (evidence quality moderate). A weak recommendation is made for EPP as part of multimodality therapy in highly selected patients with malignant pleural mesothelioma (recommendation grade 2B).
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422 20. Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJ, Rosenzweig KE, Flores R, Friedberg JS, Pisters K, Monberg M, Obasaju CK, Vogelzang NJ. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol. 2009;27:3007–3013. 21. Creaney J, Yeoman D, Demelker Y, Segal A, Musk AW, Skates SJ, Robinson BW. Comparison of osteopontin, megakaryocyte potentiating factor, and mesothelin proteins as markers in the serum of patients with malignant mesothelioma. J Thorac Oncol. 2008;3: 851–857. 22. Gordon GJ, Dong L, Yeap BY, Richards WG, Glickman JN, Edenfield H, Mani M, Colquitt R, Maulik G, Van Oss B, Sugarbaker DJ, Bueno R. Four-gene expression ratio test for survival in patients undergoing surgery for mesothelioma. J Natl Cancer Inst. 2009; 101:678–686. 23. Colice GL, Shafazand S, Griffin JP, Keenan R, Bolliger CT; American College of Chest Physicians. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidencedbased clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):161S–177S. 24. Win T, Tasker AD, Groves AM, White C, Ritchie AJ, Wells FC, Laroche CM. Ventilation-perfusion scintig-
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raphy to predict postoperative pulmonary function in lung cancer patients undergoing pneumonectomy. AJR Am J Roentgenol. 2006;187:1260–1265. 25. Sugarbaker DJ, Jaklitsch MT, Bueno R, Richards W, Lukanich J, Mentzer SJ, Colson Y, Linden P, Chang M, Capalbo L, Oldread E, Neragi-Miandoab S, Swanson SJ, Zellos LS. Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg. 2004;128:138–146. 26. Stewart DJ, Martin-Ucar AE, Edwards JG, West K, Waller DA. Extra-pleural pneumonectomy for malignant pleural mesothelioma: the risks of induction chemotherapy, right-sided procedures and prolonged operations. Eur J Cardiothorac Surg. 2005;27:373–378. 27. Hillerdal G, Sorensen JB, Sundström S, Riska H, Vikström A, Hjerpe A. Treatment of malignant pleural mesothelioma with carboplatin, liposomized doxorubicin, and gemcitabine: a phase II study. J Thorac Oncol. 2008;3:1325–1331. 28. Treasure T, Waller D, Tan C, Entwisle J, O’Brien M, O’Byrne K, Thomas G, Snee M, Spicer J, Landau D, Lang-Lazdunski L, Bliss J, Peckitt C, Rogers S, Marriage Nee Denholm E, Coombes G, Webster-Smith M, Peto J. The mesothelioma and radical surgery randomized controlled trial: the MARS feasibility study. J Thorac Oncol. 2009 Aug 5. [Epub ahead of print].
Part 7
Mediastinum
49
Thymectomy for Myathenias Gravis Joshua Sonett
Introduction Perhaps one of the longest unresolved issues in thoracic surgery is the role of thymectomy in the treatment of myasthenia gravis (MG). Persistent questions and issues involve not only the surgical approach to thymectomy, but even the role of thymectomy itself in the treatment of myasthenia gravis. Many of these issues remain unclear because there is no high quality data, and even limited moderate quality data, available to compare and analyze comparable study populations. Results of many studies are not reported using appropriate Kaplan– Meier methodology, making analysis of the results even more challenging or ineffective.1 Additionally, myasthenia gravis is an entity with varying degrees of severity, time courses and self remissions. Review of the relevant literature, which dates back to at least the 1930s,2,3 is thus very challenging and open to bias given the intersection of data results presented as crude survival curves, differing patient populations of myathenias gravis (that have differing responses to non-surgical and surgical therapy), and even definitions of treatment success that vary widely. In this chapter defined endpoints and clear data analysis will be offered in a subject that has no prospective randomized studies to define strong recommendations.
Search Methods Search methods were performed primarily in Pubmed using the search terms “thymectomy” and “surgical outcomes”. Relevant results were
limited to studies reporting results with Kaplan– Meier life table analyses; studies reporting only crude calculation of results of remission were omitted. Only studies that also adequately reported preoperative Osserman category and postoperative assessments of complete stable remission were deemed admissible.
Thymectomy Versus Medical Treatment To help understand the role of thymectomy in MG, Gronseth performed an evidence-based review the published literature on thymectomy in non-thymomatous MG between 1953 and 1998. In 310 articles discussing MG and thymectomy, 28 articles, involving 8,490 patients, were found to be consistent with high level observational studies.4 Results indicated an overall benefit for patients undergoing thymectomy versus medical treatment. Patients undergoing thymectomy were twice as likely to attain medication-free remission than non-operated patients, with median relative rates of medication-free remission: 2.1; absence of symptoms: 1.6; and symptom improvement: 1.7. Overall crude uncorrected results of patients undergoing thymectomy resulted in a median rate of remission of 25%, asymptomatic state of 39%, and an overall “improvement” rate of 70%. However, significant confounding differences in baseline characteristics of prognostic importance existed between thymectomy and non-thymectomy patient groups. The final conclusion, based on the level of available evidence, was the benefit of
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_49, © Springer-Verlag London Limited 2011
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thymectomy in nonthymomatous autoimmune MG has not been established conclusively, and that thymectomy is recommended as an option to increase the probability of improvement. Thus, as we in the surgical community debate and analyze the actual different methods and techniques of thymectomy, the debate must be viewed in the context that conclusive evidence of the efficacy of thymectomy is itself still lacking many years after it was introduced as a therapeutic modality. To help define conclusively the role of thymectomy in non-thymomatous MG, a prospective multi-institutional international trial,approved for funding by the NIH, is in progress to randomize patients to thymectomy versus medical treatment beginning in 2006.5
Surgical Approaches to Thymectomy The surgical approaches to thymectomy are varied and reflect the desire to perform a complete resection weighed against the magnitude and morbidity of the procedure. All approaches enable complete resection of the capsular thymus; what differentiates the approaches are the extent of peri-thymic mediastinal and cervical tissue that are excised. To help understand the different approaches to thymectomy and categorize the extent of resections, the Myasthenia Gravis Foundation of America (MGFA) has broadly classified varying techniques of resection based on the operative approach and extent of surgical resection (Table 49.1).6,7 In the ever dynamic surgical field, robotic approaches (T-2a) are evolving as well as bilateral
Table 49.1. The MGFA thymectomy classification. T-1 transcervical thymectomy (a) Basic (b) Extended T-2 videoscopic thymectomy (a) VATS (b) VATET T-3 transsternal thymectomy (a) Standard (b) Extended T-4 transcervical and transsternal thymectomy From.6, 7
thoracoscopic approaches (T-2b). Overall, individual case series have reported data that support the validity and success of all the approaches; however, the lack of prospective case controlled studies do not provide a reliable level of evidence that one thymectomy technique is superior.4 Given the lack of definitive case controlled and prospective studies, this evidence-based review will highlight selective studies that are reported by established centers in the long-term treatment of myasthenia gravis. All data presented represent moderate quality evidence. Additional literature review will examine the failure of thymectomy procedures, morbidity, and results of anatomic studies of thymic resection. Simple comparison of reported remissions rates and partial remission rates or “improvement” can be and are misleading when evaluating treatment results. Many patients with myasthenia gravis will improve with time, thus any true reflection of surgical results should include time after thymectomy. Unfortunately, the majority of the literature does not accommodate for time and is reported as simple “crude” calculations of remissions (improvement divided by the number of thymic resections). The best method for comparing and understanding results of the literature is life table analysis using the Kaplan– Meier method.8–10
Extended Transsternal Thymectomy Akira Masoaoka11 of Nagoya University in Japan and Alfred Jaretzki12 of Columbia University in New York have been amongst the most articulate and persistent leaders in regards to the role extended or complete thymectomy in myasthenia gravis. In 1996 Masaoka and colleagues reported a 20 year review of their experience with extended thymectomy for myasthenia gravis.11 This procedure involves en bloc resection of the anterior mediastinal fat tissue form phrenic to phrenic laterally and the diaphragm and the thyroid gland caudally and cephalad. All adipose tissues in this region is meticulously resected, including around the brachiocephalic veins, thyroid and pericardium. Cervical neck dissection is performed via the sternotomy incision, but aggressive dissection near the recurrent nerves is avoided. In a cohort of 286 patients, remission rates (RR) in nonthymomatous MG
427
49. Thymectomy for Myathenias Gravis Table 49.2. Extent of thymic tissue recovered in perithymic mediastinal fat tissue. Author Jaretzki et al. Masaoka et al.12 Zielinski et al.13 Ashour14 Scelsci et al.15 Mineo et al.16 11
Surgical approach
Extracapsular thymic tissue
Maximal Extended Extended Extended VATET VATS
50 pts 98% 18 pts 72% 58 pts 56.0% 38 pts 39.5% 27 pts 37% 31 pts 32%
VATET video assisted thoracoscopic extended thymectomy; VATS video assisted thoracic surgery.
were 45.8% (5 years), 55.7% (10 years), and 67.2% at 15 years. Similar results have been consistently documented in other series of extended thymectomy. Analysis of multiple publications utilizing extended thymectomy consistently find pathologic evidence of thymic tissue within the mediastinal fat outside the capsule of the “primary thymus” (Table 49.2).11–16
Transcervical Thymectomy Basic transcervical thymectomy (T-1a) as an alternative to transsternal thymectomy was introduced on a large scale by Kirschner and colleagues in the late 1960s.17 However, widespread acceptance of the procedure only followed the introduction of a more extended and facilitated technique as presented by Cooper: “I do not like to get up and present a paper and look like a blithering idiot by telling people you can take out something through the neck when it is obvious to everybody that it is much easier to take it out through the chest.”18 Utilizing the Cooper sternal retracter to improve visualization and dissection of the thymus as well as perithymic fat, a series of 65 patients were presented with a 52% crude complete remission rate. These results have been consistently repeated by other groups (Defilippi 50% RR19; Calhoun 44% RR20) combined with reports of minimal morbidity and length of hospital stay of less than 1.5 days.21
VATS Thymectomy, Extended VATS Procedures (VATET) More recently, evolution of videoscopic techniques has enabled excellent visualization and minimally invasive techniques for thymic resection. Early results were initially presented by a consortium of
minimally invasive centers, describing the technique and safe encouraging initial results. Mack et al.22 described 33 thymectomies (either left or right VATS) performed at three institutions with an 18.6% RR at 23 months follow up. Yim and colleagues recently presented the most comprehensive experience, with VATS thymectomy in 38 patients at a single institution. In this limited study, a crude RR of 22% was achieved and the RR was 75% as measured by Kaplan–Meier survival curve.23 In an effort to mimic the approach of the maximal thymectomy as described by Jaretzki, Novellino has described the VATET (Video Assisted Thoracoscopic Extended Thymectomy) approach, utilizing a small cervical incision and then bilateral thoracoscopic procedures.24 In a very well controlled series presented by Mantegazza, 159 patients underwent VATET; at 6 years the complete stable remission rate by life table analysis was 50.6%.25
Morbidity and Failures Results of the evidence-based review by Gorsenth indicate a remarkably low mortality rate for any of the surgical procedures.4 Operative mortality rates were found to be higher prior to 1970, but after that time reported rates were found to consistently less than 1%. Additionally, with present day techniques of extended transsternal thymectomy including avoidance of the recurrent nerves, morbidity for the various methods are not significantly different. What is clear is that patients receiving transcervical and thoracoscopic thymectomy procedures can be discharged earlier and have earlier return to daily activities and function. Importantly, limited but significant data can be found documenting the failure of initial thymectomy secondary to retained thymic tissue missed at initial exploration Table 49.3.26–41 The table refers to a collection of limited case reports that include a total of 70 patients. In this small cohort, 50 of 70 patients, or 71%, had an improvement their symptoms of myathenia gravis after resection of residual thymic tissue, addressing the importance and significance of complete resection. Additionally, given the challenge of completely resecting all ectopic thymic tissue, Ponseti argues that it many patients, the presence of ectopic thymic tissue may represent an important prognostic sign, helping to identify patients in
J. Sonett
428 Table 49.3. Surgical resection of persistent thymic tissue after initial thymectomy. Author/series
Patients
Original procedure
Henze26 Masaoka27 Miller28 Rosenberg29 Zielinski40 Poompeo41
20 6 6 13 21 8
Transcervical Transcervical Tanscervical 3 Basic transternal 3 Transcervical Transcervical 19 Transsternal 2 Transcervical 6 Transternal 2
Pathologic thymus Improvement 20/20 6/6 5/6 11/13 17/21 8/8
19/20 3/6 5/6 6/13 11/17 6/8
whom more aggressive immunotherapy may be necessary postoperatively.42
Summary and Recommendations Table 49.4 summarizes the best available retrospective series of thymectomy in myasthenia gravis for studies using accurate survival analysis.30–39 These series were selected as the few trials that used Kaplan–Meier analysis for reporting and carefully reported rates of patient follow up and loss of data. Included in the summaries is symptom severity at the time of presentation of myasthenia, so that this can be taken into account as part of the analysis of the data. Although the data, in a prospective manner, do not definitely prove one method as being superior to others, a strong case is building that, regardless of the approach, a more complete thymectomy is important to optimize long term results and medication free remission. Unfortunately, it is clear that many answers and approaches to the treatment of myasthenia gravis remain unanswered based on a critical analysis of the data. The recent NIH supported randomized trial of medical therapy versus thymectomy in the treatment of MG highlights the uncertainty of the evidence to date. Although conclusive evidence does not definitively support the role of thymectomy in myasthenia gravis, a preponderance of data supports the role of thymectomy as safe and effective in the treatment paradigm of MG (low quality evidence). A weak recommendation is made for the use of
thymectomy as a component of multimodality therapy for non-thymomatous myasthenia gravis (recommendation grade 2C). In terms of the different surgical approaches to thymectomy, the literature does not definitively support any one particular surgical procedure. This must be taken in the context of the preponderance of data being reported as crude data in generally small single center experiences. These equivocal results must be weighed against clear pathologic evidence of extracapsular thymic tissue in the majority of patients and limited but defined reports of retained thymic tissue being the cause of some initial surgical failures. Thus, some form of complete or “extended” thymectomy should be the goal of any surgical approach; this has been shown to be feasible by all the approached described. A complete or extended thymectomy is safe and provides better long-term outcomes than less extensive resections (evidence quality low). A weak recommendation is made for a complete or extended thymectomy in the treatment of MG, regardless of the approach used (recommendation grade 2C).
Personal View and Clinical Practice I strongly believe that the evidence to date supports the role of thymectomy in the treatment of myasthenia gravis. This recommendation and practice is bolstered by the modern day ability to perform the procedure with a very low morbidity and mortality, thus fulfilling the basic surgical tenant of risk versus benefit. Given that recommendation and practice, I clearly understand the limits of the data to date, and would support the randomized trial of thymectomy versus medical therapy. But, as with any trial, I would have to bow to some of my biases, and would be reluctant to enter patients into the trial who present with significant respiratory failure. In terms of surgical approach, my bias is toward some type of maximal or extended thymectomy. I believe this can be accomplished best by bilateral VATS with possible cervical exploration, or other minimally invasive approaches that clearly visualize both phrenic nerves, diaphragmatic-pericardial reflections, and the superior poles of the thymus. However, this
429
49. Thymectomy for Myathenias Gravis Table 49.4. Comparative Kaplan–Meier remission rates of 11 thymectomy techniques (all low quality evidence observational studies). Class (% of patients)
Rodriguez M.
Post-OP FU (% CSR)
Ocu
Mild
Mod
Severe
Preop (dura) Mean years
5 years
7.5 years
No thymectomy (Spontaneous remissions in children) 149 9 Nonea
16
73
2
–
15
18
Thym (type)
Series
N
Transcervical thymectomy Papatestas A.E. Shrager J.B. Durelli L. dePerrot M.
T-1ab T-1bc T-1cd T-1de
651 78 300 120
– 15 0 11
– 32 27 32
– 39 56 37
– 14 17 20
– – 2.5 0.8
23 43 33 30
33 – – 55
36 159 92
22 12 7
41 31 34
14 45 43
23 12 16
3.0 2.6 2.2
13 51 20
20 – 32
73 47 98
– 0 18
– 30 41
– 59 23
– 11 18
5.5 2.0 2.3
40 44 30
50 – 41
0
18
52
30
2.8
50
81
Videoscopic thymectomy Manlula A. Novellino L. Ruckert JC.
T-2af T-2bg T-2ch Transsternal thymectomy
Lindberg C. Novellino L. Park I.K.
T-3bi T-3bj T-3bk
Transcervical–transsternal thymectomy Jaretzki A.
T-4l
72
This analysis compares the Kaplan–Meier life table analyses of 11 thymectomy reports and one report of spontaneous remissions. In addition, the severity and duration of the MG is recorded. See text “Comparative Results Following Thymectomy” for an analysis of this data. Type of thymectomy: a None – Spontaneous remissions in children (30). b T-1a – Basic transcervical thymectomy (31). c T-1b – Extended transcervical thymectomy (32). d T-1c – Extended transcervical thymectomy + partial sternal split (33). e T-1d – Extended transcervical thymectomy + thoracoscopy (34). f T-2a – Classic VATS (unilateral thoracoscopy) (23). g T-2b – VATET (bilateral thoracoscopy) (35). h T-2c – Unilateral thoracoscopy + robotic technology (36). i T-3b – Extended transsternal thymectomy (37). j T-3b –Extended transsternal thymectomy (35). k T-3b – Extended transsternal thymectomy (38). l T-4 – Combined transcervical–transsternal thymectomy (12). Preop (dura): Pre-operative (duration); Post-OP FU (% CSR): Post-operative Follow up (Complete Stable Remission); N: number; Ocu: Ocular; Mod: moderate; Sev: severe Table reprinted with permission from.39
practice paradigm must be viewed with the understanding that the published results to date do not clearly support any one particular approach, and transcervical or unilateral VATS resection are used by many accomplished thoracic surgeons. In the final analysis, the onus is on the thoracic surgical community to definitively determine whether there is a benefit of thymectomy for myasthenia gravis. This benefit, if proven, will allow us to proceed with further studies to best define the appropriate and perhaps best approaches to resection as well as refine indications in terms of symptoms, and timing of surgery. I thus would
encourage and support the impending trial of thymectomy versus medical therapy in the treatment of myasthenia gravis.
The preponderance of data supports the role of thymectomy as safe and effective in the treatment of MG (low quality evidence). A weak recommendation is made for the use of thymectomy as a component of multimodality therapy for non-thymomatous myasthenia gravis (recommendation grade 2C).
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A complete or extended thymectomy is safe and provides better long-term outcomes than less extensive resections (evidence quality low). A weak recommendation is made for a complete or extended thymectomy in the treatment of MG, regardless of the approach used (recommendation grade 2C).
References 1. Jaretzki A, Steinglass KM, Sonett JR. Thymectomy in the management of myasthenia gravis. Semin Neurol. 2004;24:49–62. 2. Blacock A, Mason MF, Morgan HJ, Riven SS. Myasthenia gravis and tumors of the thymic region: report of a case in which the tumor was removed. Ann Surg. 1939;110:544–561. 3. Clagett OT, Eaton LM. Surgical treatment of myasthenia gravis. J Thorac Surg. 1947;16:62–80. 4. Gronseth SG, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review). Neurology. 2000:55:7–15. 5. Wolfe GI, Kaminski HJ, Jaretzki A III, Swan A, Newsom-Davis J. Development of a thymectomy trial in nonthymomatous myasthenia gravis patients receiving immunosuppressive therapy. Ann N Y Acad Sci. 2003;998:473–480. 6. Jaretzki A III, Barohn RJ, Ernstoff RN, et al. Myasthenia gravis: recommendations for clinical research standards. Neurology. 2000;55:16–23. 7. Myasthenia Gravis Research Foundation. Myasthenia Gravis: recommendations for clinical research standards. Availabe at: http://www.myasthenia.org/docs/ ClinicalResearchStandards.pdf. Accessed 1 March 2010. 8. Masaoka A. Extended trans-sternal thymectomy for myasthenia gravis. Chest Surg Clin N Am. 2001; 11:369–387. 9. Jaretzki A III. Thymectomy for myasthenia gravis: an analysis of the controversies regarding technique and results. Neurology. 1997;48(suppl 5):S52–S63. 10. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958; 53:457–481. 11. Masaoka A, Nagaoka Y, Kotake Y. Distribution of thymic tissue at the anterior mediastinum. Current procedures in thymectomy. J Thorac Cardiovasc Surg. 1975;70:747–754. 12. Jaretzki A III, Wolff M. “Maximal” thymectomy for myasthenia gravis. Surgical anatomy and operative technique. J Thorac Cardiovasc Surg. 1988;96: 711–716. 13. Zielinski M, Kusdsal J, Szlubowski A, Soja J. Comparison of late results of basic transsternal and extended thymectomies in the treatment of myasthenia gravis. Ann Thorac Surg. 2004;78:253–258.
J. Sonett 14. Ashour M. Prevalance of ectopic thymic tissue in myasthenia gravis and its clinical significance. J Thorac Cardiovasc Surg. 1995;109:632–635. 15. Scelsi R, Ferro T, Novellino L, Mantegazza R, Cornelio F, Porta M, Longoni C, Pessuoli G. Detection and morphology of thymic remnants after video-assisted thoracoscopic extended thymectomy (VATET) in patients with myasthenia gravis. Int Surg. 1996;81: 14–17. 16. Mineo CT, Pompeo E, Lerut T, Bernardi G, Coosemans W, Nofroni I. Thoracoscopic thymectomy in autoimmune myasthenia: results of left-sided approach. Ann Thorac Surg. 2000;69:1537–1541. 17. Kirschner PA, Osserman KE, Kark AE. Studies in myasthenia gravis. JAMA. 1969;209:906–910. 18. Cooper JD, AL-Jilaihawa AN, Pearson FG, Humphrey JG, Humphrey HE. An improved technique to facilitate transcervical thymectomy for myasthenia gravis. Ann Thorac Surg. 1988;45:242–247. 19. DeFilippi VJ, Richman DP, Ferguson MK. Transcervical thymectomy for myasthenia gravis. Ann Thorac Surg. 1994;57:194–197. 20. Calhoun RF, Ritter JH, Guthrie TJ, Pestronk A, Meyers B, Patterson GA, Pohl MS, Cooper JD. Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients. Ann Surg. 1999;230:555–561. 21. Ferguson MF. Transcervical thymectomy. Semin Thorac Cardiovasc Surg. 1999;11:59–64. 22. Mack MJ, Landreneau RJ, Yim AP, Hazelrigg SR, Scruggs GR. Results of video-assisted thymectomy in patients with myasthenia gravis. J Thorac Cardio vasc Surg. 1996;112:1352–1360. 23. Manalulu A, Lee TW, Wan I, Law CY, Chang C, Garzon JC, Yim AP. Video-assisted thoracic surgery thymectomy for nonthymomatous myasthenia gravis. Chest. 2005;128:3454–3460. 24. Novellino L, Longoni M, Spinelli L, Andretta M, Cozzi M, Faillace G. Extended thymectomy without sternotomy performed by cervicotomy and thoracoscopic technique in the treatment of myasthenia gravis. Int Surg. 1994;79:378–381. 25. Mantegazza R, Fulvio B, Bernasconi P, Antozzi C, Confalonieri P, Novellino L, Spinelli L, Ferro MT, Beghi E, Cornelio F. Video-assisted thoracoscopic extended thymectomy and extended transsternal thymectomy (T-3b) in non-thymomatous myasthenia gravis patients: remission after 6 years of followup. J Neurol Sci. 2003;212:31–36. 26. Henze A, Biderfeld P, Chrisensson B, Matell G, Pirsanen R. Failing transcervical thymectomy in myasthenis gravis. An evaluation of transsternal re-exploration. Scan J Thorac Cardiovasc Surg. 1984; 18:235–238. 27. Masaoka A, Monden Y, Seike Y, Tanioka T, Kagotani K. Reoperation after transcervical thymectomy for myasthenia gravis. Neurology. 1982;32:83–85. 28. Miller RG, Filler-Katz A, Kiprov D, Roan R. Repeat thymectomy in chronic refractory myasthenia gravis. Neurology. 1991;41:923–924.
49. Thymectomy for Myathenias Gravis 29. Rosenberg M, Jauregui WO, De Vega M, Herrera MR, Roncoroni AJ. Recurrence of thymic hyperplasia after thymectomy in myasthenia gravis. Its importance as a cause of failure of surgical treatment. Am J Med. 1983;74:78–82. 30. Rodriguez M, Gomez MR, Howard FM Jr, Taylor WF. Myasthenia gravis in children: long term follow-up. Ann Neurol. 1983;13:504–510. 31. Papatestas AE, Genkins G, Kornfeld P, Horowitz S, Kark AE. Transcervical thymectomy in myasthenia gravis. Surg Gynecol Obst. 1975;140:535–540. 32. Shrager JB, Deeb ME, Mick R, Brinster CJ, Childers HE, Marshall MB, Kucharczuk JC, Galetta SL, Bird SJ, Kaiser LR. Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy. Ann Thorac Surg. 2002;74:320–327. 33. Durelli L, Maggi G, Casadio C, Ferri R, Rendine S, Bergamini L. Actuarial analysis of the occurrence of remission following thymectomy for myasthenia gravis in 400 patients. J Neurol Neurosurg Psychiatr. 1991;54:406–411. 34. dePerrot M, Bril V, McRae K, Keshavjee S. Impact of minimally invasive transcervical thymectomy on outcome in patients with myasthenia gravis. Eur J Cardiothorac Surg. 2003;24:677–683. 35. Mantegazza R, Confalonieri P, Antozzi C, Novellino L, Ferrò MT, Porta M, Pezzuoli G, Cornelio F. Videoassisted thoracoscopic extended thymectomy (VATET) in myasthenia gravis two-year follow-up in 101 patients and comparison with the transsternal approach. Ann N Y Acad Sci. 1998;841:749–752. 36. Rückert JC, Ismail M, Swierzy M, Sobel H, Rogalla P, Meisel A, Wernecke KD, Rückert RI, Müller JM.
431 Thoracoscopic thymectomy with the da Vinci robotic system for myasthenia gravis. Ann N Y Acad Sci. 2008;1132:329–335. 37. Lindberg C, Andersen O, Larsson S, Odén A. Remission rate after thymectomy in myasthenia gravis when the bias of immunosuppressive therapy is eliminated. Acta Neurol Scand. 1992;86:323–328. 38. Park IK, Choi SS, Lee JG, Kim DJ, Chung KY. Complete stable remission after extended transsternal thymectomy in myasthenia gravis. Eur J Cardiothorac Surg. 2006;30:525–528. 39. Sonett JR, Jaretzki A 3rd. Thymectomy for nonthymomatous myasthenia gravis: a critical analysis. Ann N Y Acad Sci. 2008;1132:315–328. 40. Zielinski M, Kuzudzai J, Staniec B, Harazda M, Nabialek T, Pankowski J, Szlubowski A, Narski M. Extended rethymectomy in the treatment of refractory myasthenia gravis: original video-assisted technique of resternotomy and results of the treatment in 21 patients. Interact Cardiovasc Thorac Surg. 2004;3:376–380. 41. Pompeo E, Nofroni I, Iavicoli N, Mineo TC. Thoracoscopic completion thymectomy in refractory nonthymomatous myasthenia. Ann Thorac Surg. 2000;70:918–923. 42. Ponseti JM, Gomez J, Vilallonga R, Ruiz C, Azem J, Lopez-Cano M, Armengol M. Influence of ectopic tissue on clinical outcome following extended thymectomy in generalized seropositive nonthymomatous myasthenia gravis. Eur J Cardio-Thorac Surg. 2008;34:1062–1067.
50
Optimal Surgical Approach and Extent of Resection of the Thymus in Patients with Myasthenia Gravis Mitchell J. Magee
Since Blalock et al.1,2 reported improvement in at least half of the patients with myasthenia gravis (MG) in whom they performed thymectomy, the role of thymectomy in the treatment of non- thymomatous MG as well as the optimal surgical approach and extent of resection has been debated. Central to this debate is the lack of randomized controlled trials comparing surgery, medical therapy, and the natural history of the disease and disagreement among surgeons as to what constitutes the best surgical therapy. Further adding to the controversy, until recently, has been the lack of universally accepted classifications, grading systems, and methods of analysis for patients undergoing surgical therapy for MG.3,4 Most surgeons agree in concept that improved clinical outcomes correlate with completeness of thymectomy, and currently the majority of surgeons utilize the median sternotomy approach, removing the encapsulated thymus with varying extents of adjacent mediastinal fat. Anatomic reports on the common presence of widely distributed ectopic thymic tissue,5–7 coupled with reports of complete responses to excision of residual thymic tissue after failed initial thymectomy,27 corroborate the premise that complete thymectomy is preferred, prompting some surgeons to advocate a more extensive combined cervical and trans-sternal mediastinal dissection aimed at more complete removal of all thymic tissue. In contrast, other surgeons favor less invasive approaches to thymectomy, citing similar response rates with less radical removal of thymic associated tissue. As summarized in the recommendations for clinical research standards in myasthenia
gravis, the debate is not resolved regarding which of the multiple techniques that have been described for removal of the thymus in MG is ideal.3,4 Although, classically, “total thymectomy” is considered the goal of surgery, it has not been demonstrated unequivocally that this is necessary, nor is it clear to what extent each of the resectional techniques achieve this goal. When assessing outcomes in MG patients treated with various surgical approaches to thymectomy in retrospective analyses, including meta-analyses perhaps even to a greater extent, there are numerous factors that preclude accurate comparisons including: incompletely defined or disparate patient populations in the treatment groups compared and associated selection bias; incompletely defined or inconsistencies in the extent of thymus resected within treatment groups; differences in continued medical therapy following thymectomy and the relative contributions of surgery and medical therapy to the reported outcome; and lastly, a lack of consistent objective criteria used to assess preoperative disease severity and postoperative response to therapy within an adequate period of long-term follow-up. The MGFA (Myasthenia Gravis Foundation of America) Thymectomy Classification was proposed as an attempt to apply objectivity and consistency in reporting of the various approaches and techniques employed when removing thymus tissue in patients with myasthenia gravis (Table 50.1). This chapter compares the various surgical approaches to thymectomy and their associated less well defined and inconsistent extents of resection currently employed in the surgical treatment
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434 Table 50.1. Thymectomy classification.3,4 T-1 Transcervical thymectomy (a) Basic (b) Extended T-2 Videoscopic thymectomy (a) “Classic” (b) “VATET” T-3 Transsternal thymectomy (a) Standard (b) Extended T-4 Transcervical & transsternal thymectomy
of patients with non-thymomatous myasthenia gravis, incorporating the MGFA Classification scheme. The relevant published data supporting the use of each of these approaches will be contrasted and provide the basis for recommending the optimal surgical approach and extent of resection of the thymus in patients with MG.
Transcervical Thymectomy The basic transcervical thymectomy, as it was first described as a suitable alternative for thymectomy in patients with MG by Crile and subsequently substantiated by Kirschner et al.,8–10 is now universally considered inadequate and has been abandoned. The accepted technique now defined as extended transcervical thymectomy, described and popularized by Cooper, has been used successfully with reports of satisfactory results by several groups.11–14 In most cases the completely encapsulated thymus gland is removed intact with both upper poles and both lower poles in continuity.11,14,15 Proponents of the transcervical approach site similar remission rates with less morbidity and shorter mean length of hospital stay when compared to transsternal approaches. Shrager and colleagues reported their experience in 78 patients in 2002 and again in 151 patients in 2006.12,13 Cited concerns with the transcervical approach include: a comparatively less radical resection of thymic tissue due to limited access to the most caudal and lateral extents of the anterior mediastinum, which is conceptually less desirable due to an association with poorer outcomes; the unique nature of this approach makes it difficult to teach, learn, and
consistently reproduce and therefore has limited adoption; and the neck incision may not be considered as cosmetically acceptable.
VATS Thymectomy The “classic” videoscopic thymectomy or VATS thymectomy has several permutations including left-sided, right-sided, bilateral, and subxyphoid. The right-sided approach is generally favored due to relative increased working space absent the left ventricle, and because the superior vena cava serves as an excellent landmark for initial dissection and identification of the innominate vein. Similar to the transcervical approach, the completely encapsulated thymus gland is removed intact with both upper poles and both lower poles in continuity along with all mediastinal adipose tissue within the borders of the phrenic nerves, diaphragm and cervical border of the anterior mediastinum cephalad to the innominate vein, achieving a similar extended thymectomy as that described in the transsternal approach. Tomulescu and colleagues compared the right and left sided approaches to VATS thymectomy and found similar operating times, length of hospitalization, and rates of remission.16 No differences in operative complications were noted. In their experience, the left side approach is preferred due to the majority of mediastinal fat being located on the left side of the anterior mediastinum, making dissection of the thymus on the contralateral side safer and easier. They further believe that the risk of injury to the right phrenic nerve is decreased due to its location outside the surgical field and that the left side affords needed access to the aortopulmonary window. Several centers, including our own, have reported intermediate term MG remission rates comparable to more invasive approaches to thymectomy.17–19 Cited advantages of the VATS approach include decreased blood loss, decreased length of hospital stay, improved cosmetic results, faster recovery and social reintegration, and less pain. As opposed to the skills needed to obtain the unique exposure required for transcervical thymectomy, a VATS thymectomy can be easily learned and performed safely and effectively by most thoracic surgeons experienced in advanced
50. Optimal Surgical Approach and Extent of Resection of the Thymus in Patients with Myasthenia Gravis
videothoracoscopy. Similar to the transcervical approach, but to a lesser extent, VATS potentially achieves a less radical resection of thymic tissue, which debatably is less desirable due to the potential for poorer outcomes. We recently retrospectively reviewed our experience in 48 patients with myasthenia gravis who underwent VATS thymectomy between March, 1992 and June, 2006.20 Patients were assessed utilizing MGFA guidelines with clinical visits or by telephone interview and follow-up was greater than 90% complete with a mean postoperative period of follow-up of 6 years. Mean hospital postoperative length of stay was 1.9 days. Complete stable remission was seen in 34.9%, minimal manifestations seen in an additional 55.8%, and two patients (4%) were worse postoperatively. These results were similar to those observed in a “comparable” group of 47 MG patients who underwent extended transsternal thymectomy during the same time period. Mantegazza published a follow-up report on a technique described by Novellino as VATET, videoassisted thoracoscopic extended thymectomy, consisting of bilateral thoracoscopy and open cervical exploration.21,22 VATET essentially combines elements of the VATS and transcervical approaches to achieve a more thorough extirpation of thymic tissue. Two hundred and six MG patients underwent either the VATET or extended transsternal thymectomy and were followed for 6 years. The 159 patients that underwent the VATET procedure had comparable complete stable remission (CSR) rates to the 47 patients that had an extended transsternal thymectomy (50.6% vs. 48.7%).23 Shigemura et al. prospectively studied the contribution of the transcervical exploration to the VATET procedure and concluded that additional thymus tissue can be removed through a cervical incision following bilateral VATS thymectomy, although the clinical significance of this has not been demonstrated.24
Robotic-Assisted Thymectomy The incorporation of complete robotic surgical systems, such as the da Vinci (Intuitive Surgical Inc.), has been proposed by some to enhance precision maneuverability in the mediastinum when
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compared to conventional VATS thymectomy. Augustin and others recently published a review of the 32 institutional reported robotic thymectomies, including their own experience, and compared Robotic-Assisted Thoracoscopic Surgery (RATS) to VATS thymectomy.25 The left-sided operative approach is preferred. While the feasibility and safety of RATS thymectomy with the daVinci system has been proven, the benefits of, or value added by, the robotic-assisted thoracoscopic surgical approach to thymectomy, compared with the conventional VATS approach have not yet been demonstrated. Proponents of robot-assisted thymectomy opine that robotic surgery is more suitable than VATS for an extended thymectomy due to easier dissection of the upper horns, more controlled ligation of the thymic veins, and improved unilateral access to the entire anterior mediastinum.25,26
Transsternal Thymectomy Transsternal thymectomy is the most common approach used in the surgical treatment of MG. The basic transsternal thymectomy, as it was originally performed by Blalock, has been abandoned in favor of more extensive resections that can be easily achieved through the same or a smaller incision, e.g. upper partial sternotomy, with similar or less morbidity. Masaoka and colleagues identified thymic tissue in adipose tissue located outside the thymic capsule in the anterior mediastinum in 13 of 18 MG patients undergoing thymectomy.7 Based on this observation, they recommended removal of all adipose tissue in the anterior mediastinum along with the gross thymus via an extended thymectomy. A detailed description of the procedure along with their 20-year experience was subsequently reported.27 286 patients with nonthymomatous MG underwent extended transsternal thymectomy between 1973 and 1993. Remission rates were 36.9% at 3 years, 45.8% at 5 years, 55.7% at 10 years, and 67.2% at 15 years. Venuta reported their experience with 232 thymectomies performed between 1970 and 1997.28 One hundred and one patients with nonthymomatous MG had an extended thymectomy through a partial upper sternotomy. After a mean postoperative follow-up of 119 months, 25% of the patients were in complete remission and an
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additional 46% were clinically improved. There were two operative deaths (0.9%) due to respiratory failure in patients with postoperative bleeding requiring reoperation and seven patients (4.5%) in the nonthymomatous group died from MG (mean survival: 34.3 ± 3.6 months). Minor complications included arrhythmia (1.8%) and infection (1.8%) and mean postoperative hospital stay was 6.4 days. Allowing for differences in severity of disease and methods of reporting outcomes, the results of extended transsternal thymectomy appear to be comparable to other approaches but are associated with significant morbidity.
Transcervical and Transsternal (“Maximal”) Thymectomy The primary proponent and practitioner of this approach are Jaretzki and colleagues.6,33 Wide exposure in the neck and mediastinum is achieved through a complete median sternotomy incision and separate collar incision. The skin incisions are occasionally connected to create a “T”, but the subcutaneous and deeper planes of dissection in the neck and mediastinum are always confluent. All thymus, suspected thymus, and mediastinal fat, including both mediastinal pleural sheets, are removed en bloc utilizing sharp dissection on the pleurae and pericardium. The entire dissection is performed and completed “as if it was an en bloc dissection for a malignant tumor”.29 This radical extirpation is associated with the most morbidity and least desirable cosmetic result. Advocates for this approach, believing it the most effective in achieving a durable complete remission, also believe that the end results justify the means. However, in the absence of controlled prospective clinical trials showing a clear benefit to more radical complete removal of all gross and microscopic thymic tissue, a more balanced approach between procedure-related morbidity and “complete” thymectomy is warranted.
Recommendations There are no randomized trials comparing any of the various surgical techniques, nor are there any
Table 50.2. Outcomes for representative surgical approaches to thymectomy for non-thymomatous myasthenia gravis. Author/series Shrager13 Mack20 Masaoka27 Jaretzki33
Resection approach Transcervical VATS Trans-sternal “Maximal”: combined trans-sternal/cervical
Patients
Complete response rate (%)
Evidence quality
151 48 286 95
37 34.9 36.9 46
Low Low Low Low
prospective comparisons. Most of the retrospective observational studies are small, the few larger studies lack consistency in their comparisons to alternative approaches and reported outcomes, and all of the retrospective reports are limited in quality due to imprecision, inconsistency, or bias in patient selection and/or toward a specific technique. A group from Berlin30 performed a retrospective, matched-pair comparison of extended median sternotomy, left thoracotomy, and leftsided unilateral VATS, and found no difference in MG remission rates between groups and less morbidity observed in the VATS group. Three additional studies comparing sternotomy and VATS thymectomy,31–32 including our own,20 demonstrated equivalent outcomes. None of the various surgical approaches to thymectomy, or any associated defined extent of extracapsular resection, has proven superior in providing benefit to patients with myasthenia gravis (evidence quality low) (Table 50.2). Less invasive approaches are associated with better cosmesis and fewer complications. Based on these data, a weak recommendation is made for VATS or extended transcervical thymectomy for management of non-thymomatous MG (Grade 2C).
A Personal View of the Data Without strong evidence to support consistently improved outcomes with more invasive approaches to potentially achieve more radical resections, I favor an approach that is: more likely to be accepted by patients and referring neurologists due to decreased morbidity and improved cosmesis, easily learned and reproducible to achieve a consistent extent of resection and provides exposure that most
50. Optimal Surgical Approach and Extent of Resection of the Thymus in Patients with Myasthenia Gravis
closely approximates the more invasive incisional techniques. Based on this rationale of balancing procedural morbidity with extent of resection, I recommend VATS thymectomy for management of non-thymomatous MG. No specific surgical approach has proven superior in providing benefit to patients with myasthenia gravis; less invasive approaches are associated with better cosmesis and fewer complications (evidence quality low). A weak recommendation is made for VATS or extended transcervical thymectomy for management of non-thymomatous MG (Grade 2C).
References 1. Blalock A, Harvey AM, Ford FR, Lilientha JL Jr. The treatment of myasthenia gravis by removal of the thymus gland. Preliminary report. JAMA. 1945; 127:1089–1096. 2. Blalock A. Thymectomy in the treatment of myasthenia gravis. Report of twenty cases. J Thorac Surg. 1944;13:316–339. 3. Jaretzki III A, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis: recommendations for clinical research standards. Neurology. 2000;55:16–23. 4. Jaretzki III A, Barohn RJ, Ernstoff RM, et al. Myasthenia gravis: recommendations for clinical research standards. Ann Thor Surg. 2000;70:327–334. 5. Jaretzki III A, Bethea M, Wolff M, et al. A rational approach to total thymectomy in the treatment of myasthenia gravis. Ann Thorac Surg. 1977;24:120–130. 6. Jaretzki A III, Wolff M. “Maximal” thymectomy for myasthenia gravis: surgical anatomy and operative technique. J Thorac Cardiovasc Surg. 1988;96:711–716. 7. Masaoka A, Nagaoka Y, Kotake Y. Distribution of thymic tissue at the anterior mediastinum: current procedures in thymectomy. J Thorac Cardiovasc Surg. 1975;70:747–754. 8. Crile G Jr. Thymectomy through the neck. Surgery. 1966;59:213–215. 9. Kirschner PA, Osserman KE, Kark AE. Studies in myasthenia gravis: transcervical total thymectomy. JAMA. 1969;209:906–910. 10. Kark AE, Kirschner PA. Total thymectomy by the transcervical approach. Br J Surg. 1971;58:323–326. 11. Cooper JD, Al-Jilaihawa AN, Pearson FG, Humphrey JG, Humphrey HE. An improved technique to facilitate transcervical thymectomy for myasthenia gravis. Ann Thorac Surg. 1988;45:242–247. 12. Shrager JB, Deeb ME, Mick R, et al. Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy. Ann Thorac Surg. 2002;74:320–327.
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13. Shrager JB, Nathan D, Brinster CJ, et al. Outcomes after 151 extended transcervical thymectomies for myasthenia gravis. Ann Thorac Surg. 2006;82:1863–1869. 14. Calhoun RF, Ritter JH, Guthrie TJ, et al. Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients. Ann Surg. 1999;230:555–561. 15. Meyers BF, Cooper JD. Transcervical thymectomy for myasthenia gravis. Available at: www.ctsnet.org/ sections/clinicalresources/thoracic/expert_tech-23. html, 2002. Accessed 25 November 2009. 16. Tomulescu V, Ion V, Kosa A, Sgarbura O, Popescu I. Thoracoscopic thymectomy mid-term results. Ann Thorac Surg. 2006;82:1003–1007. 17. Mack MJ, Landreneau RJ, Yim AP, Hazelrigg SR, Scruggs GR. Results of video-assisted thymectomy in patients with myasthenia gravis. J Thorac Cardiovasc Surg. 1996;112:1352–1360. 18. Savcenko M, Wendt GK, Prince SL, Mack MJ. Videoassisted thymectomy for myasthenia gravis: an update of a single institution experience. Eur J Cardiothorac Surg. 2002;22:978–983. 19. Manlulu A, Lee TW, Wan I, Law CY, Chang C, Garzon JC, Yim A. Video-assisted thoracic surgery thymectomy for nonthymomatous myasthenia gravis. Chest. 2005;128:3454–3460. 20. Meyer DM, Herbert MA, Magee MJ, Sobhani NC, Tavakolian P, Duncan A, Bruns M, Korngut K, Williams J, Prince SL, Huber L, Wolfe GI, Mack MJ. Comparative clinical outcomes of thymectomy for myasthenia gravis performed by extended transsternal and minimally invasive approaches. Ann Thorac Surg. 2009;87:385–391. 21. Mantegazza R, Confalonieri P, Antozzi C, Novellino L, Ferro MT, Porta M, Pezzuoli G, Cornelio F. Videoassisted thoracoscopic extended thymectomy (VATET) in myasthenia gravis two-year follow-up in 101 patients and comparison with the transsternal approach. Ann NY Acad Sci. 1998;841:749–752. 22. Novellino L, Longoni M, Spinelli L, Andretta M, Cozzi M, Faillace G, et al. “Extended” thymectomy, without sternotomy performed by cervicotomy and thoracoscopic technique in the treatment of myasthenia gravis. Int Surg. 1994;79:378–381. 23. Mantegazza R, Baggi F, Bernasconi P, Antozzi C, Confalonieri P, Novellino L, Spinelli L, Ferrò MT, Beghi E, Cornelio F. Video-assisted thoracoscopic extended thymectomy and extended transsternal thymectomy (T-3b) in non-thymomatous myasthenia gravis patients: remission after 6 years of followup. J Neurol Sci. 2003;212(1–2):31–36. 24. Shigemura N, Shiono H, Inoue M, Minami M, Ohta M, Okumura M, Matsuda H. Inclusion of the transcervical approach in video-assisted thoracoscopic extended thymectomy (VATET) for myasthenia gravis: a prospective trial. Surg Endosc. 2006;20: 1614–1618. 25. Augustin F, Schmid T, Sieb M, Lucciarini P, Bodner J. Video-assisted thoracoscopic surgery versus roboticassisted thoracoscopic surgery thymectomy. Ann Thorac Surg. 2008;85:S768–S771.
438 26. Savitt MA, Gao G, Furnary AP, Swanson J, Gately HL, Handy JR. Application of robotic-assisted techniques to the surgical evaluation and treatment of the anterior mediastinum. Ann Thorac Surg. 2005;79:450–455. 27. Masaoka A, Yamakawa Y, Niwa H, et al. Extended thymectomy for myasthenia gravis patients: a 20-year review. Ann Thorac Surg. 1996;62:853–859. 28. Venuta F, Rendina EA, Giacomo TD, Rocca GD, Antonini G, Ciccone AM, et al. Thymectomy for myasthenia gravis: a 27-year experience. Eur J Cardiothorac Surg. 1999;15:621–625. 29. Sonett JR, Jaretzki III A. Thymectomy for nonthymomatous myasthenia gravis: a critical analysis. Ann NY Acad Sci. 2008;1132:315–328. 30. Ruckert JC, Sobel HK, Gohring S, Einhaupl KM, Muller JM. Matched-pair comparison of three different approaches for thymectomy in myasthenia gravis. Surg Endosc. 2003;17:711–715. 31. Lin T, Tzao C, Lee S, Wu C, Shy C, Lee C, Chou M. Comparison between video-assisted thoracoscopic
M.J. Magee thymectomy and transternal thymectomy for myasthenia gravis (analysis of 82 cases). Int Surg. 2005; 90:36–41. 32. Bachmann K, Burkhardt D, Schreiter I, Kaifi J, Busch C, Thayssen G, Izbicki JR, Strate T. Long-term outcome and quality of life after open and thoracoscopic thymectomy for myasthenia gravis: analysis of 131 patients. Surg Endosc. 2008;22:2470–2477. 33. Jaretzki A, Penn AS, Younger D, Wolff M, Olarte MR, Lovelace RE, Rowland LP. “Maximal” thymectomy for myasthenia gravis. J Thorac Cardiovasc Surg. 1988;95:747–757. 34. Guyatt G, Gutterman D, Baumann MH, AddrizzoHarris D, Hylek EM, Phillips B, Raskob G, Lewis SZ, Schünemann H. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest. 2006;129:174–181.
51
The Optimal Approach for Resection of Encapsulated Thymoma: Open Versus VATS Shaf Keshavjee and Christian Finley
Introduction The appropriate use of video assisted thoracic surgery (VATS) in the treatment of thymoma is not clearly defined. Recently, increasing numbers of case series have reported the use of VATS in the resection of encapsulated thymomas and subsequently even in more advanced disease. These results have lead to the increasing adoption of this technique, which has not been clearly studied. For more advanced thymomas, many practitioners are adopting the use of neoadjuvant and adjuvant therapies, while for encapsulated thymomas, the standard therapy is resection. For many years, the standard of care for thymomas has been open resection, most commonly via sternotomy. However, with the maturing and rapid proliferation of VATS resection techniques it has been intuitive to examine its applicability to thymomas. Since its first description,1 there has been much debate as to whether this approach would increase the rate of recurrence and hence result in increased morbidity and or mortality.2 Thus, the question remains as to the appropriate use of this technique in the resection of thymomas. Thymomas are a fascinating tumor of the mediastinum. Their location, close margins and penchant for even the most benign appearing of lesions to recur or metastasize make their management challenging. Thymomas also present the challenge of local recurrence. Thymomas are unique in their tumor biology in two aspects, first in their strong and well documented propensity to spread by droplet metastases locally in the mediastinum and in the pleural space3–5; and secondly in the relative
infrequency of development of disseminated lymphatic or hematogenous spread.6 With relatively low numbers in most series, even the most dedicated of practitioners is challenged to conduct studies providing the highest quality evidence. Hence, most treatment decisions are based on expert opinion and those studies that do exist are mostly retrospective observational studies, resulting in weak recommendations at best. In this context, this chapter strives to help the surgeon address the challenge of whether a VATS approach should be used in the resection of encapsulated thymomas (Masaoka Stage 1). This chapter will examine this issue by addressing the following questions: • Is VATS resection of the thymus technically feasible and what are its complications? • What is the evidence surrounding the recurrence rate of thymoma in VATS thymectomy? • Is there any operative or long-term survival data? • What are the technical considerations? What is the significance of an incomplete resection? • With the VATS resection of the thymoma is the whole thymus gland completely removed? • Are we able to effectively gauge encapsulation preoperatively?
Published Data English literature papers were obtained by a Medline search from 1950 to present for “VATS” procedures with related terms and “thymectomy” and “thymus”
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resulting in 205 publications. These were reviewed for their relevance. Journals reporting resection of multiple mediastinal tumors were included if they reported greater than five thymomas.
for non-invasive thymomas. Most authors make a disclaimer regarding these complications as occurring “early” in their experience, implying a considerable learning curve. While complications can also occur using the open approach, in most large series the morbidity rate ranges from 6.8% to 18%.3–5,13–17 These studies included all stages and were more comprehensive in reporting minor complications, such as atrial fibrillation and respiratory complications, that largely were not mentioned in the VATS literature.1,7–12 Thus, direct comparison is difficult. Conceivably, small thymomas in experienced hands could reach the level of length of stay (LOS) and complication profile of the non-thymomatous myasthenia gravis outcomes as shown in Table 51.3.8,18–21 The overall quality of evidence in Table 51.3 is low. In a small study of 30 patients with noninvasive thymomas, the conversion rate was 10%,22 one of which was for massive bleeding. In another larger trial of multiple mediastinal masses, the conversion rate was 4.2%.9 The greatest body of published literature specific to the issue of VATS resection of thymoma comes from Cheng, who has published on resection of
Technical Feasibility and Safety Minimally Invasive Thymoma Resection Versus Open Resection Studies of minimally invasive resection for thymomas are universally small retrospective case series. Despite this limitation, the literature that does exist suggests that resection is safe in experienced hands as shown in Table 51.1.1,7–12 Results of open resection, the standard of care, are reported in Table 51.2.3–5,13–17 Importantly, in almost all of the series, significant complications occurred using VATS resection. There were reports of: vascular injury, chylothorax, phrenic nerve injury, prolonged air leak and diaphragm injury, resulting in a morbidity rate of 5.1–10%1,7–12 Table 51.1. Studies of minimally invasive resection for thymoma. Mortality (%)
LOS (days)
32 mediastinal masses, 9 thymoma 118 mediastinal masses, 22 thymoma 24 thymoma, 13 by Vats, 1 Masoaka Stage 1 40 mediastinal masses, 7 thymoma
0
6
0
6
0
4.5
0
7.5
44 thymoma, 27 Stage 1
0
7.6
Study
Year
Number of patients
Augustin8
2008
Roviaro9
1994
Chetty10
2004
Cirino12
2000
Cheng7
2007
Complications
Complete resection
Follow up (months)
Recurrence Level of (%) evidence
3 conversions 1 transient recurrent nerve palsy 5 conversions 1 prolonged ventilation 1 chylothorax
100%
25
0
Low
–
1–75
0
Low
2 R1 resections in a Masoaka 2a and 3
–
0
Low
1 prolonged airleak 1 phrenic nerve injury 1 stellate ganglia injury 1 diaphragm injury 0 “Major” complications
–
80
0
Low
100%
39.6
0
Low
Table 51.2. Studies of resection of thymoma by open surgical technique. Study
Year
Number of Stage 1 patients
Mortality (%)
LOS (days)
Complications (%)
Kondo14 Regnard3 Strobel13 Blumberg4 Wright5 Rea15 Moore17
2005 1996 2004 1995 2005 2004 2001
496 135 75 25 64 44 33
– 1.6 0 0 1.1 0 1.4
– – – 8 – – 5
– 6.9 – – – 6.8 18
Stage 1 complete resection (%) 100 100 – 100 100 100 100
Study follow up 0–120 months 8 years 60 months 3.7 years 115 months 92 months 7 years
Stage 1 recurrence (%) 1.2 3.7 2 4% 0% 0% 6%
Level of evidence Moderate Moderate Moderate Moderate Moderate Moderate Moderate
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51. The Optimal Approach for Resection of Encapsulated Thymoma: Open Versus VATS Table 51.3. Studies of minimally invasive resection of the thymus in non-thymomatous myasthenia gravis. Study
Year
Method
Number of patients
Mortality (%)
LOS (days)
Manlulu
2005
VATS
38
0
3
De Perrot19
2003
Transcervical
120
–
2
Shrager20
2002
Transcervical
78
0
1.5
Bril21 Augustin8
1998 2008
Transcervical Robotic
52 32 (9 thymoma)
– 0
– 6
18
Stage 1, Stage 2 and even “encapsulated” thymic carcinoma. In his report on early encapsulated thymoma, Cheng showed that it was possible to resect without conversion, death or “major” complication in 44 patients, 27 of whom had Stage 1 disease. This study included resection of tumors up to 18 cm in size.7 Cheng23 also reported in his non-randomized non-matched study – comparing four VATS to four tran-sternal resections of encapsulated WHO C thymic carcinomas – that VATS was safe. He reported a lower length of stay (LOS), blood loss and pleural drainage for the VATS group. The study is limited by significant differences in the comparison groups. However, it highlights that the resection is technically possible. It also demonstrated that not all lesions that appear encapsulated are necessarily Stage 1 thymomas. This concept is explored later. With the DaVinci robot, Bodner et al.12 showed that they could safely resect thymomas with no mortality or intraoperative complications in six thymomas. In these studies on minimally invasive resection of encapsulated thymoma, the length of stay ranged from 4.5 to 7.6 days. The LOS for the open procedures varied from 5 to 8 days with many of the largest studies not reporting their LOS. These values are similar to those reported in the VATS papers as shown in Table 51.1.
Minimally Invasive Resection in Non-Thymomatous Myasthenia Gravis Certainly, there are a number of larger studies in the setting of non-thymomatous myasthenia gravis that show that minimally invasive thymectomy,
Complications 2 conversions for bleeding 2 reintubations 23 conversions 4 patients complications 2 pneumothorax 1 atrial Fibrillation 1 vocal cord injury 0 3 conversions 1 diaphragm injury 1 transient recurrent nerve palsy
Level of evidence Low Low Low Low Low
whether transcervical, transthoracic, or robotic assisted, is feasible, results in low mortality, low length of stay, and improved pain and morbidity as shown in Table 51.3.8,18–21 The LOS varied from 1.5 to 6 days with an operative mortality rate of 0%. The conversion rate was 5.3–19% with low 3.3–5.1% morbidity rates. Clearly, these procedures are not as complex as resection of encapsulated thymomas, but they do show that the thymus gland can be safely resected via a minimally invasive approach. In the case of smaller thymomas located within the gland itself, the procedure should not vary much.
Recurrence Examining the recurrence rate of Masaoka Stage 1 thymoma is very difficult as the recurrence rate is reported in the open literature is low – in the range of only 1–6%.3–5,13–17 Compounding the challenge in evaluating this is the protracted timeframe of the disease, with most authors suggesting following patients for more than 10 years. To show even a doubling of recurrence rate with a power of 80% would require a sample size of approximately 480 patients followed for >10 years. In all published case series on VATS resection for Stage 1 thymomas there are no recurrences. However, the cumulative published experience is only 72 Stage 1 tumors followed for 1–80 months. Clearly, with these low numbers, short follow up, and the potential for publication and selection bias, we must withhold judgment. Nonetheless, at present, there are few reported recurrences after VATS resection for encapsulated thymoma in these series. In one paper with multiple resection techniques,
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only two patients with Stage 1 thymomas were resected by VATS. In this study, one of two recurred while 0 of 28 open procedures recurred.27
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the robotic techniques.12 No authors in the VATS literature comment on pathologic completeness of thymic resection. Cheng7 states all residual thymic tissue was removed but, at times, this was done after the tumor was resected.
Operative or Long Term Survival Data There is no reported early or late mortality data for VATS encapsulated thymoma resections. In the case of open surgery, the operative mortality is low, at 0–1.6%, with a long term mortality of 0–4.9%.3–5,13–17 However, similar to disease recurrence data, the small sample size and limited follow-up tempers these results.
Significance of Incomplete Resections In the literature on open resection of Stage 1 thymoma, the complete resection rate is 100% in almost all large series.3–5,13–17 On multivariate analysis, completeness of resection is the only factor predictive of long-term survival in the largest studies on thymoma.3,14 This result speaks to the importance of a complete operation and places the pressure on surgeons attempting minimally invasive procedures to ensure they reach the high bar set by the open procedure. Certainly, as surgeons improve in the VATS approach, their techniques will become further refined, but given both the learning curve and the infrequent operator variables, there is an increased chance of failing to meet this standard.
Complete Thymectomy Most institutions performing large volumes of thymomas recommend completely excising the thymus3,24 because of the risk of multicentric disease.3,25 They are almost universally successful at this. This raises the question of the VATS approach’s ability to completely excise the thymus, in particular, into the neck. In one early series, incomplete thymectomy was performed on 11 of 30 patients.22 However, Bodner describes a pathologically confirmed complete thymectomy, including the upper pole, with
Failure to Predict Encapsulation Even with CT scans reporting encapsulation, pathologic findings not infrequently show Stage 2 disease (transgression of tumor cells into the thymic tissue). With a 5 year survival of 70–90%,3–5,13–17 this has a significantly worse prognosis than Masoaka Stage 1 disease. This issue makes the appeal of resection via VATS even more suspect. In one paper on robotic removal, three of nine thymomas considered Stage 1 preoperatively were resected and found to be 2a disease pathologically.8 In another series 1 of 6 patients were Masoaka Stage 2 when initially thought to be encapsulated.12 In the largest study reported by Cheng,7 despite having rigid preoperative criteria including encapsulation on CT scan, 17 of 44 patients were Stage 2 disease. Overall, this lack of accuracy of current imaging modalities to predict important staging parameters, such as extracapsular invasion, raises the level of risk when undertaking a VATS resection of thymomas.
Conclusions and Recommendations The level of evidence for VATS resection of encapsulated thymoma is low. With the propensity of thymoma to recur locally via droplet metastasis, the importance of complete resection is paramount, thus technical considerations are extremely important in this disease. While safe, it is not clear that VATS thymectomy is complete or effective. The accumulated literature favors that VATS resection of encapsulated thymoma should not be performed outside a clinical trial. We make a weak recommendation against VATS thymectomy for encapsulated thymomas (grade of recommendation 2C). All efforts at VATS resection should be directed at a well designed prospective clinical trial to better evaluate the risk and benefits of this approach.
51. The Optimal Approach for Resection of Encapsulated Thymoma: Open Versus VATS
Our Approach to Encapsulated Thymomas The author’s personal view of the evidence is that it provides the initial outcomes of an intuitively appealing new surgical approach. Nonetheless, the data are limited, making the integration of this technique into common practice difficult. Future research will likely show VATS resection of encapsulated thymomas to have low morbidity, with length of stays comparable to MIS resection of nonthymomatous myasthenia gravis. Certainly the issue of local and droplet metastasis demand the highest technical considerations, but with the relatively large numbers needed to prove noninferiority of the VATS approach, it seems unlikely that it will be shown with higher levels of evidence. Therefore, our current standard approach for thymomas, even those presumed to be encapsulated on preoperative evaluation, is to resect them via median sternotomy if technically feasible. We look forward to future research and remain hopeful that continued evaluation of this approach gains a higher level of evidence.
VATS thymectomy is safe, but there is insufficient evidence that it is complete or effective (evidence quality low). We make a weak recommendation against VATS thymectomy for encapsulated thymomas (recommendation grade 2C).
References 1. Landreneau RJ, Dowling RD, Castillo WM, et al. Thoracoscopic resection of an anterior mediastinal tumor. Ann Thorac Surg. 1992;54:142–144. 2. Acuff TE, Mack MJ, Ryan WH, et al. Thoracoscopic thymoma resection. [Comment]. Ann Thorac Surg. 1993;55:562–563. 3. Regnard J-F, Magdeleinat P, Dromer C, et al. Prognostic factors and long-term results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg. 1996;112:376–384. 4. Blumberg D, Port J, Weksler B, Delgado R, MD, Rosai J, Bains M, Ginsberg R, Martini N, McCormack P, Rusch V, Burt M. Thymoma: a multivariate analysis of factors predicting survival. Ann Thorac Surg. 1995;60:908–913. 5. Wright CD, Wain JC, Wong DR, et al. Predictors of recurrence in thymic tumors: importance of inva-
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sion, World Health Organization histology, and size. J Thorac Cardiovasc Surg. 2005;130:1413–1421. 6. Kondo K, Monden Y. Lymphogenous and hematogenous metastasis of thymic epithelial tumors. Ann Thorac Surg. 2003;76:1859–1865. 7. Cheng YJ, Hsu JS, Kao EL. Characteristics of thymoma successfully resected by videothoracoscopic surgery. Surg Today. 2007;37:192–196. 8. Augustin F, Schmid T, Sieb M, Lucciarini P, Bodner J. Video-assisted thoracoscopic surgery versus roboticassisted thoracoscopic surgery for thymectomy. Ann Thorac Surg. 2008;85:S768–S771. 9. Roviaro G, Rebuffat C, Varonli F, et al. Video thoracoscopic excision of mediastinal masses: indications and techniques. Ann Thorac Surg. 1994;58: 1679–1684. 10. Chetty G, Khan O, Onyeaka C, Ahmad F, Rajesh P, Waller D. Experience with video-assisted surgery for suspected mediastinal tumours. Eur J Surg Oncol. 2004;30:776–780. 11. Bodner J, Wykypiel H, Greiner A, Kirchmayr W, Freund M, Margreiter R, Schmid T. Early experience with robot-assisted surgery for mediastinal masses. Ann Thorac Surg. 2004;78:259–265. 12. Cirino L, Milanez de Campos J, Fernandez A, Samano M, Fernandez P, Filomeno L, Jatene F. Diagnosis and treatment of mediastinal tumors by thoracoscopy. Chest. 2000;117:1787–1792. 13. Ströbel P, Bauer A, Puppe B, et al. Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis. J Clin Oncol. 2004;22:1501–1509. 14. Kondo K, Monden Y. Thymoma and myasthenia gravis: a clinical study of 1089 patients from Japan. Ann Thorac Surg. 2005;9:219–224. 15. Rea F, Marullia G, Girardia R, Bortolottia L, Favarettob A, Galligionic A, Sartoria F. Long-term survival and prognostic factors in thymic epithelial tumours. Eur J Cardiothorac Surg. 2004;26:412–418. 16. Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg. 2004;77:1860–1869. 17. Moore K, McKenzie P, Kennedy C, McCaughan B. Thymoma: trends over time. Ann Thorac Surg. 2001; 72:203–207. 18. Manlulu A, Lee TW, Wan I, et al. Video-assisted thoracic surgery thymectomy for nonthymomatous myasthenia gravis. Chest. 2005;128:3454–3460. 19. de Perrot M, Bril V, McRae K, Keshavjee S. Impact of minimally invasive transcervical thymectomy on outcome in patients with myasthenia gravis. Eur J Cardiothorac Surg. 2003;24:677–683. 20. Shrager JB, Deeb ME, Mick R, et al. Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy. Ann Thorac Surg. 2002;74:320–327. 21. Bril V, Kojic S, Ilse W, Cooper J. Long-term clinical outcome after transcervical thymectomy for myasthenia gravis. Ann Thorac Surg. 1998;65:1520–1522.
444 22. Sakamaki Y, Kido T, Yasukawa M. Alternative choices of total and partial thymectomy in video-assisted resection of noninvasive thymomas. Surg Endosc. 2008;22:1272–1277. 23. Cheng YJ. Videothoracoscopic resection of encapsulated thymic carcinoma: retrospective comparison of the results between thoracoscopy and open methods. Ann Surg Oncol. 2008;15:2235–2238. 24. Okumura M, Miyoshi S, Takeuchi Y, et al. Results of surgical treatment of thymomas with special reference to the involved organs. J Thorac Cardiovasc Surg. 1999;117:605–613.
S. Keshavjee and C. Finley 25. Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer. 2003;105:546–551. 26. Cheng YJ, Kao EL, Chou SH. Videothoracoscopic resection of stage II thymoma. Chest. 2005;128: 3010–3012. 27. Singhal S, Shrager JB, Rosenthal DI, et al. Comparison of stages I-II thymoma treated by complete resection with or without adjuvant radiation. Ann Thorac Surg. 2003;76:1635–1642.
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Management of Residual Disease After Therapy for Mediastinal Germ Cell Tumor and Normal Serum Markers Heather D. Riggs, Lawrence H. Einhorn, and Kenneth A. Kesler
Introduction Five to 10% of germ cell tumors originate in the anterior mediastinum. Fewer than 10–20% of anterior mediastinal masses are found to be primary mediastinal germ cell tumors, the majority consisting of thymic or thyroid pathologies or lymphomas. Germ cell tumors have three histologic categories: pure teratoma or pure seminoma with no other germ cell elements and nonseminomatous germ cell tumors. Sixty to 70% of all mediastinal germ cell tumors are teratomas, which are typically mature but occasionally demonstrate immature elements. Mature teratomas are almost always cured with surgical resection alone. Immature teratomas can grow more rapidly and also can degenerate into non-germ cell histologies, such as sarcomas and epithelial cancers, that are resistant to chemotherapy. Mediastinal seminomas have a high rate of cure with cisplatin-based chemotherapy alone. Unlike primary mediastinal nonseminomatous germ cell tumors (PMNSGCT), mediastinal seminomas have a prognosis similar to seminomas that originate in the testes or retroperitoneum.1 The vast majority of residual masses following chemotherapy for mediastinal seminoma represent complete tumor necrosis without viable neoplasm. Seminomas are therefore classified as favorable prognosis germ cell tumors. Nonseminomatous germ cell tumors (NSGCT), the focus of this chapter, are the primary type of malignant germ cell tumor originating in the mediastinum. Three different histological subtypes may be found, alone or in combination, including yolk sac cancer, embryonal carcinoma,
and choriocarcinoma. Frequently, these are mixed tumors with elements of teratoma, immature teratoma, or seminoma. PMNSGCT are poor risk germ cell tumors, as categorized by the International Germ Cell Cancer Collaborative Group.2 The 49% overall survival of patients with PMNSGCT contrasts significantly with the 80% long-term survival of patients with NSGCT originating in the testis and 63% survival for NSGCT originating in the retroperitoneum.1 Several aspects of PMNSGCT biology are thought to explain the poorer prognosis. At the time of diagnosis, 25% or more of PMNSGCT patients demonstrate metastatic disease to the lungs, cervical nodes, liver, bone or central nervous system. The tendency of immature teratomatous elements to degenerate into chemotherapy-refractory “non-germ cell” cancers significantly contributes to the aggressive biology of PMNSGCT.3 PMNSGCT have an unusual association with hematologic malignancies.4 In a large international series, 17 of 287 PMNSGCT patients developed a hematologic malignancy.1 These most commonly were poor-prognosis entities such as acute megakaryoblastic leukemia, with 5 month median survival. Finally, PMNSGCT have been found to be poorly responsive to second-line chemotherapy. Primary testis or retroperitoneal NSGCT can achieve cure rates in more than 60% of cases requiring second-line salvage chemotherapy.5 In contrast, cure rates for PMNSGCT with second-line chemotherapy are less than 10%.6,7 Given the aggressive behavior of PMNSGCT, surgery to remove residual disease after chemotherapy has played a significant role in improving long-term survival. The evidence to support the
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role of surgery for PMNSGCT patients consists of retrospective series from referral centers that evaluate a relatively large number of patients with this rare but important neoplasm. This chapter provides the most current evidence related to an aggressive surgical approach to remove any residual mediastinal mass following cisplatin-based chemotherapy in patients with PMNSGCT.
Diagnosis and Initial Therapy PMNSGCT typically presents as a rapidly growing anterior mediastinal mass in young adult males. The tumor commonly invades the adjacent lung, pericardium, great vessels, and occasionally cardiac chambers. Although pleural and pericardial effusions are seen, they are usually not malignant.8 Serum tumor markers (STMs), which include alpha fetoprotein (AFP) and b-human chorionic gonadotropin (b-hCG), are elevated in up to 90% of patients with PMNSGCT. In patients with an elevated AFP or a markedly elevated b-hCG (e.g., >1,000 mIU/mL), a biopsy is unnecessary. However, in patients in whom STMs are normal or a minimally elevated b-hCG is present, a CT-guided FNA biopsy is necessary to differentiate seminoma from PMNSGCT.8 Because the rate of cure with surgery alone is extremely poor, PMNSGCT are initially treated with cisplatin-based chemotherapy. BEP (bleomycin, etoposide, and cisplatin) given for four cycles has been the standard approach for poor-risk NSGCT, including PMNSGCT. A randomized trial comparing VIP (etoposide, ifosfamide, and cisplatin) to BEP demonstrated equivalent survival, but different toxicity.9 Although VIP was associated with more nausea, vomiting and myelosuppression, no pulmonary toxicity was noted. In a series of 158 patients from Indiana University who underwent surgical resection of residual disease after chemotherapy, post-operative pulmonary failure occurred in 14% of patients, and 47% of these patients died.10 Pulmonary toxicity attributable to bleomycin is thought to significantly increase the risk of post-operative respiratory failure, particularly if a lobectomy is required.11 Since 2007, 21 patients have been treated with VIP as an alternative to BEP at Indiana University, decreasing the
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rate of rates of post-operative pulmonary failure to 0%.8 It has therefore been our preference to administer four cycles of VIP chemotherapy after diagnosis. After chemotherapy, residual masses remain in the majority of patients with a significant chance that the residual disease pathologically contains persistent NSGCT or degenerative non-germ cell cancer. Many have attempted to improve survival with alternative, more intensive chemotherapy regimens. MD Anderson reported results of an intensive regimen that contained eight different chemotherapeutic agents given to 20 PMNSGCT patients, in some cases as second-line chemotherapy. In this series, 2-year survival was 58% with high chemotherapy-related morbidity.12 A German phase II study evaluated high-dose VIP followed by autologous stem-cell rescue in the first-line setting for poor-risk NSGCT. Twenty-eight PMNSGCT patients were included, and 2-year survival was 68%.13 This concept was further evaluated in a multi-institution randomized trial of 219 patients with poor-risk NSGCT comparing four cycles of BEP to two cycles of BEP followed by high-dose carboplatin-based chemotherapy followed by autologous stem cell transplant. Fifty-eight patients with PMNSGCT were included, and the trial found no survival benefit for the more intensive regimen.14
Normal Serum Tumor Markers After Chemotherapy Unfortunately PET cannot distinguish between residual masses that contain complete necrosis from those that contain teratoma or microscopic foci of persistent NSGCT or degenerative nongerm cell cancer. PET therefore has not been helpful in selecting patients in whom surgery could potentially be avoided. Cutoff levels of postchemotherapy serum tumor markers have been advocated to assist with decision-making regarding surgery; however, this strategy also has significant limitations. Surgical series of PMNSGCT have reported that normal STMs are relatively poor predictors of benign pathology in resected residual masses.10,15 Forty-five percent to 90% of PMNSGCT patients exhibit normalization of STMs
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after chemotherapy.1,10 An analysis of an Indiana University series found that 32% of patients presenting to surgery with normal STMs after chemotherapy were nonetheless found to have pathologic evidence of viable malignancy in the residual mass.16 Memorial Sloan Kettering reported outcomes in 49 PMNSGCT patients, 32 of whom underwent postchemotherapy resection of residual disease.15 Nineteen patients had normal STMs at the time of surgery, yet 58% of these patients had pathologic evidence of viable malignancy in the residual mass. Teratoma, which is refractory to chemotherapy and is found in up to 33% of residual masses following chemotherapy, typically generates normal or very low elevation of STM’s. This concept is demonstrated by the socalled “growing teratoma syndrome” in which a mediastinal mass continues to enlarge during chemotherapy, despite a rapid decline in STMs.17 In this scenario, which is estimated to occur in less than 5% of PMNSGCT cases, no further chemotherapy should be given, and expeditious surgical resection is recommended. While considered “benign,” teratoma has not only local growth potential but, more importantly, significant potential to degenerate into non-germ cell cancer; therefore resection of teratoma is necessary.
STMs reported in an Indiana University series, only 57% had pathologic evidence of malignancy.16 In this same series, of the patients with documented rising STMs preoperatively, only 67% had pathologic evidence of persistent NSGCT in the residual mass. In another retrospective study from Indiana University, 8 of 32 patients survived longterm who presented to surgery with documented rising STMs.10,19 Prior to surgery in these cases, an MRI of the brain and CT of the abdomen were obtained to rule out additional sites of disease. In an Indiana University series of 158 patients, although the subset of patients with rising STMs had a hazard ratio of 2.25 (95% CI 1.10–4.60, p = 0.03) for inferior survival, surgery appeared to have more curative potential than current secondline chemotherapy regimens in these cases.10 Of note, in this study, analysis of patient survival if STMs were elevated but not rising at the time of surgery found elevated STMs did not predict inferior survival as compared to patients whose STMs were normal preoperatively. Post-operatively, two additional cycles of adjuvant cisplatin-based chemotherapy should be considered for patients with pathologic evidence of viable NSGCT but who do not have rising STMs at the time of surgery indicative of cisplatin-refractory disease.8
Elevated or Rising Serum Tumor Markers After Chemotherapy
Surgical Management
Management of patients whose STMs remain elevated or continue to rise after chemotherapy has been controversial. Second-line chemotherapy is effective for patients with testicular NSGCT refractory to first-line chemotherapy and, in this setting, plays an important treatment role.18 PMNSGCT patients, however, not only have a higher incidence of cisplatin-refractory disease, but NSGCT originating in the mediastinum has been found to be an independent predictor of a poor response to second-line chemotherapy.6,7 Similar to the relatively poor correlation of normal STMs to benign residual disease after chemotherapy, elevated STMs have not been found to be highly specific for the presence of residual malignancy. Of PMNSGCT patients who underwent surgery for postchemotherapy residual masses with elevated
Although removal of residual masses following chemotherapy frequently requires complex and sometimes extensive resections, the reported morbidity and mortality has been acceptable. PMNSGCT most commonly occurs in young healthy adult males without significant comorbid risk factors for surgery. Surgical resection is typically delayed for 4–6 weeks after completing chemotherapy to allow for functional and hematologic recovery. Surgery is technically challenging as preoperative chemotherapy renders surrounding mediastinal tissues fibrotic, obscuring normal anatomic planes. How ever, the effectiveness of cisplatin-based chemotherapy often results in extensive tumor necrosis that is more marked around the periphery. This finding usually allows a complete resection, which minimizes operative morbidity by preserving critical structures that abut but are not densely
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adherent to or directly involved with the residual mass such as lung, great vessels, phrenic nerves, and occasionally cardiac chambers. Frozen section confirmation of tumor-free surgical margins are necessary in these cases. In an Indiana University surgical series, operative morbidity was reported to be 23%.10 Postoperative complications in these patients included respiratory failure requiring more than 48 h of mechanical ventilation in 12% of the series with occasional prolonged alveolar air leaks and delayed pericardial effusion. Rates of respiratory failure were significantly higher in patients who underwent lobectomy or pneumonectomy compared with those who did not (21% vs. 8%, p = 0.02). Operative mortality was 6% in this series. Ninety percent of operative mortality was associated with respiratory failure. Risk of mortality also correlated with the extent of pulmonary resection and was 12% in patients requiring lobectomy or pneumonectomy compared with 3% in patients requiring less than a lobar resection (p = 0.04). As previously discussed, respiratory failure has not been observed in more recent patients who received non- bleomycin containing chemotherapy regimens preoperatively, regardless of the magnitude of pulmonary resection required. The use of VIP chemotherapy appears to further reduce postoperative morbidity and mortality with equivalent oncologic outcomes. STMs are commonly measured prior to hospital discharge, at 1 month, then every 2 months for the first postoperative year, every 4 months during year 2, every 6 months for years 3–5, and then annually. Chest x-rays are also obtained every 6 months for the first 5 years. Patients with pathologic evidence of teratoma in the resected mass are followed with CT scans, rather than chest x-rays, every 4 months for years 1 and 2 postoperatively and then every 6 months during years 3–5. When recurrent teratoma is detected early, patients may be cured with surgical resection.
Survival Published retrospective reviews of treatment approaches and outcomes for PMNSGCT patients from single and multi-institution data, are listed
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in Table 52.1. The majority of the patients in these series were treated between the late 1970s and the 1990s. During this time period, several aspects of the approach to treating PMNSGCT patients changed significantly. In the era prior to cisplatinbased combination chemotherapy, patients were typically offered surgical resection or radiation as primary therapy, a practice that persisted at some institutions until the late 1980s. After the widespread acceptance of initial cisplatin-based chemotherapy, some institutions did not routinely offer resection of residual masses to patients whose STMs normalized. More recently, the greatest challenge is determining the role of “salvage” surgery for patients with persistently elevated or rising STMs. Many institutions initiate salvage chemotherapy regimens to include high-dose therapy with stem cell support in an attempt to normalize STMs prior to surgical resection of residual masses. Others proceed directly to surgery, if the patient is operable, regardless of the STM status. Therefore, interpreting the implications of published retrospective series is complicated by the considerable heterogeneity in the specific treatment offered. Walsh and colleagues published a 5-year series of 20 PMNSGCT patients treated at MD Anderson, nine of whom were referred for salvage therapy after prior chemotherapy and, in some cases, attempted resection.12 Patients were treated with an intensive chemotherapy regimen, consisting of alternating courses of four cisplatin-based combinations with a total of eight different agents. Three chemotherapy-related deaths occurred. Patients were offered resection of residual masses only if their STMs normalized after chemotherapy. Eleven patients were resected, one of whom received surgery as “salvage” treatment in the setting of rising STMs and died of recurrent disease several months after surgery. The overall 2-year survival in this series was 58%. Memorial Sloan Kettering reviewed the results of 32 of 49 patients with PMNSGCT who had surgical resection of residual disease after chemotherapy.15 Although the overall 2-year survival for the entire series was 40%, patients who had pathologic findings of teratoma or necrosis (34% of the patients in this series) had an overall survival of 81%, while those with viable NSGCT or non-germ cell tumor had an overall survival of only 19%.
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52. Management of Residual Disease After Therapy for Mediastinal Germ Cell Tumor and Normal Serum Markers Table 52.1. Published retrospective surgical series of PMNSGCT treated with chemotherapy followed by surgery of residual disease. References
PMNSGCT (n)
Years
Patients resected n (%)
Preoperative normal STMs n (%)
Lemarie Goss22 Gerl23 Hidalgo24 Bacha25 Fizazi26 Walsh12 Vuky15 Bokemeyer1 Takeda27 Kesler10
45 10c 12 27c 14c 38c 20 49 287c 21c 158
1983–1990 1978–1993 1981–1994 1978–1995 1979–1995 1976–1993 1993–1998 1979–1999 1975–1996 1951–2000 1981–2006
22 (49%) 9 (90%) 12 (100%) 6 (22%) 14 (100%) 15 11 (55%) 32 (65%) 143 (49%) 6 158 (100%)
ND ND ND 6 (100%) 8 (57%) 15 10 (91%) 19 (59%) 124 (87%) ND 96 (61%)
21
c
Post-operative pathology n (%) Benigna
Malignantb
Overall survival
ND 6 (67%) ND 3 (50%) 5 (36%) 5 (33%) 7 (63%) 13 (34%) 90 (63%) ND 89 (56%)
ND 3 (33%) ND 3 (50%) 9 (64%) 10 (67%) 4 (36%) 21 (66%) 51 (36%) ND 59 (37%)
2-year, 53% 5-year, 47% 5-year, 57% 5-year, 32% 5-year, 48% 2-year 45% 2-year, 58% 2-year, 40% 5-year, 45% 5-year, 24% 58%
Teratoma or necrosis. Persistent NSGCT or non-germ cell tumor. c Series included patients treated with primary surgery. ND no data; STMs serum tumor markers. a
b
Thirteen of the patients in this series had elevated or rising STMs preoperatively. Ten of these patients had complete surgical resection. The overall survival for this group was 31%, but 17% for those with rising STMs. In 2002, the results of an international, multicenter review of extragonadal germ-cell tumors were published.1,20 Of the 635 patients included, 287 had PMNSGCT. Forty-nine percent of PMNSGCT patients underwent post-chemotherapy surgery, and overall survival at 5 years was 45%. Of the resected patients, the majority (87%) had normal STMs preoperatively. The resected residual mass was found to pathologically contain mature teratoma or complete necrosis in 26% and 37% of patients respectively. Indiana University recently published a 25-year institutional experience managing PMNSGCT patients during the cisplatin era.10 Over the most recent decade, institutional practice has changed to resect residual disease if deemed amenable to complete surgical removal after first-line chemotherapy, regardless of STM status. This practice has been based on the lack of sensitivity and specificity of STMs to predict pathology in the residual mass as well as the poor efficacy of second-line chemotherapy for PMNSGCT. All of the 158 patients in this series underwent post-chemotherapy resection of residual masses. Survival was 58% at a median follow-up of 34 months.
Besides differences in treatment strategies, there are other sources of bias which should be considered when comparing reported series. Series that include operated patients exclusively may result in overly optimistic survival data, as inoperable patients would not be included. Conversely, given that these series primarily originate from referral centers, many of the patients included were referred for surgical treatment of chemotherapy refractory disease, which predictably would negatively bias overall outcome.
Prognostic Variables Visceral Metastases The presence of visceral metastases at the time of PMNSGCT diagnosis was predictive of inferior 2-year survival (34% vs. 60% in patients without visceral metastases, p < 0.01) in a large multicenter series.20 Reports from single institutions have also noted a trend toward inferior survival for patients who present with extramediastinal metastases.10,15 Postchemotherapy residual disease at extrathoracic sites may require metastasectomy either concurrently or sequentially after resection of residual anterior mediastinal disease. In an
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Indiana University series, 46 of 158 patients presented with extramediastinal disease. Nineteen of these patients required pulmonary metastasectomy following chemotherapy and 16 underwent extrathoracic metastasectomy of either bone, cervical lymph node, or CNS disease.10
Serum Tumor Markers Choriocarcinoma is the rarest subtype of nonseminomatous germ cell cancer but has the highest propensity of the three subtypes for the development of hematogenous, and specifically pulmonary, metastases. Elevated b-hCG levels most commonly indicate the presence of choriocarcinoma in NSGCT patients. A negative prognostic impact of elevated pre-treatment b-hCG (HR 1.48, 95% CI 1.06–2.08, p = 0.02) on survival was noted by Hartmann and colleagues.20 An Indiana University series however, reported a HR of 1.35 (95% CI 0.79–2.32, p = 0.27) for overall survival when b-hCG was elevated at the time of diagnosis. Rising STMs preoperatively and persistently elevated STMs post-operatively have been identified as adverse prognostic indicators. In contrast, STMs that are elevated, but not rising, at the time of surgery have not been strongly predictive of shortened survival. Vuky et al.15 reported similar survival outcomes for patients with elevated STMs as compared with those with normal STMs at the time of resection (p = 0.33). Patients with rising STMs, on the other hand, demonstrated a trend to shorter survival (p = 0.09) in this same series. Kesler and colleagues also reported no statistically significant difference in survival for patients with elevated STMs compared with those with normal STMs at the time of surgery (HR 1.69, 95% CI 0.90–3.20, p = 0.10).10 Rising STMs, however, negatively impacted survival with a HR 2.25 (95% CI 1.10–4.60, p = 0.03). In this same series, elevated STMs after surgery (HR 4.65, 95% CI 2.31–9.38, p < 0.01) was also negatively predictive.
Pathology of Resected Residual Mass Of all variables studied, the “worst” pathology present in the resected residual mass has been reported to be most predictive of survival. Kesler and coworkers found three significantly different survival rates for patients pathologically demonstrating complete necrosis, teratoma, and
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persistent NSGCT or degenerative non-germ cell cancer in order of increasing severity. Although often considered benign, persistent teratoma associated with PMNSGCT not infrequently contains immature elements that can transform into malignant histologies, including sarcomas, epithelial cancers and even hematologic malignancies. Hematologic malignancies often involve the megakaryocyte lineage, such as acute megakaryoblastic leukemia, and some series have identified germ-cell tumor marker chromosomal abnormalities, such as isochromosome i(12p), in the leukemic blasts. These findings imply that the leukemia originated from a common progenitor, and differentiation to leukemia may result when neoplastic germ cells invade the sternal bone marrow environment. Chromosomal markers typically associated with secondary, or therapy-related leukemia (e.g., 11q23 abnormalities and alterations in chromosomes 5 or 7) are not consistently noted. In the Indiana University series, three deaths secondary to leukemia occurred in patients with teratoma found in the residual mass, which in part, explains the survival decline noted in this group. Vuky and colleagues also found a significant impact of residual mass pathology on survival.15 In this series, findings of teratoma or complete necrosis were associated with an 81% 2-year survival compared with a 19% survival for patients found to have residual NSGCT or malignant transformation in the residual mass (p < 0.01). A trend to longer survival may additionally be predicted by the percentage of the residual mass found to contain viable malignancy. Kesler et al. noted that the overall survival of the group of patients found to have persistent NSGCT or non-germ cell cancer present in the residual mass was 39%. However, patients with more than 50% of the resected residual mass involved with viable malignancy had an overall survival of 33% compared with 59% if less than 50% of the residual mass contained viable malignancy (p = 0.22).10
Conclusion and Recommendations PMNSGCT has a distinct biology and treatment strategy compared to NSGCT originating in the retroperitoneum and testis. Knowledge regarding the biologic behavior and outcomes following available therapeutic modalities has been gained
52. Management of Residual Disease After Therapy for Mediastinal Germ Cell Tumor and Normal Serum Markers
from retrospective series for this rare but important neoplasm. Postchemotherapy STMs, unfortunately, have relatively poor sensitivity and specificity to predict pathology of residual mediastinal abnormalities. The majority of PMNSGCT patients with normal STMs following chemotherapy will have pathologic evidence of teratoma, viable NSGCT, or degenerative non germ cell cancer in residual mediastinal abnormalities, all of which require surgical removal for successful outcomes. The patients with pathologic evidence of complete tumor necrosis after chemotherapy have excellent survival; however, they represent a distinct minority of patients. Postchemotherapy surgery could potentially be avoided in this subset; however, the pathologic finding of necrosis cannot be predicted by current imaging modalities or STMs. The incidence of cisplatin-refractory disease is much higher in PMNSGCT, and existing salvage chemotherapeutic regimens have limited efficacy. In this setting, salvage surgery, if technically feasible, results in poor but possible longterm survival; however, survival following surgery is superior to salvage chemotherapy including high-dose chemotherapy with peripheral blood stem cell transplant. Surgery to remove residual mediastinal masses following cisplatin-based chemotherapy is indicated in the multimodality treatment strategy of PMNSGCT patients who are considered operable regardless of STM status. Resection after chemotherapy for PMNSGCT offers improved long-term survival compared to second-line chemotherapy and has acceptable morbidity and mortality (low quality evidence). We make a weak recommendation for resection of residual disease in patients with abnormal mediastinal imaging after initial chemotherapy for PMNSGCT, regardless of the status of serum tumor markers (recommendation grade 2B). Resection after chemotherapy for PMNSGCT offers improved long-term survival compared to second-line chemotherapy and has acceptable morbidity and mortality (low quality evidence). We make a weak recommendation for resection of residual disease in patients with abnormal mediastinal imaging after initial chemotherapy for PMNSGCT, regardless of the status of serum tumor markers (recommendation grade 2B).
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References 1. Bokemeyer C, Nichols C, Droz J, et al. Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. J Clin Oncol. 2002;20:1864–1873. 2. International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol. 1997;15: 594–603. 3. Reuter V. The pre and post chemotherapy pathologic spectrum of germ cell tumors. Chest Surg Clin N Am. 2002;12:673–694. 4. Nichols C, BJ R, NA H, et al. Hematologic neoplasia associated with mediastinal germ cell neoplasms. N Engl J Med. 1990;322:1425–1429. 5. Einhorn L, Williams S, Chamness A, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med. 2007;357:340–348. 6. Saxman S, Nichols C, Einhorn L. Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: the Indiana University Experience. J Clin Oncol. 1994;12:1390–1393. 7. Hartmann J, Einhorn L, Nichols C, et al. Second-line chemotherapy in patients with relapsed extragonadal non-seminomatous germ cell tumors: results of an international multicenter analysis. J Clin Oncol. 2001;19:1641–1648. 8. Kesler K, Einhorn L. Multimodality treatment of germ cell tumors of the mediastinum. Thorac Surg Clin. 2009;19:63–69. 9. Hinton S, Catalano P, Einhorn L, et al. Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer. 2003;97: 1869–1875. 10. Kesler K, Rieger K, Hammoud Z, et al. A 25-year single institution experience with surgery for primary mediastinal nonseminomatous germ cell tumors. Ann Thorac Surg. 2008;85:371–378. 11. Andrade R, Kesler K, Wilson J, et al. Short and longterm outcomes after large pulmonary resection for germ cell tumors following bleomycin-combination chemotherapy. Ann Thorac Surg. 2004;78:1224–1229. 12. Walsh G, Taylor G, JC N, et al. Intensive chemotherapy and radical resections for primary nonseminomatous mediastinal germ cell tumors. Ann Thorac Surg. 2000;69:337–343. 13. Bokemeyer C, Schleucher N, Metzner B, et al. Firstline sequential high-dose VIP chemotherapy with autologous transplant for patients with primary mediastinal nonseminomatous germ cell tumours: a prospective trial. Br J Cancer. 2003;89:29–35. 14. Motzer R, Nichols C, Margolin K, et al. Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol. 2007;25: 247–256.
452 15. Vuky J, Bains M, Bacik J, et al. Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum. J Clin Oncol. 2001;19:682–688. 16. Kruter L, Kesler K, Yu M, et al. The predictive value of serum tumor markers for pathologic findings of residual mediastinal masses after chemotherapy for primary mediastinal nonseminomatous germ cell tumors [abstract]. Proc Am Soc Clin Oncol. 2008:5087. 17. Afifi H, Bosl G, Burt M, et al. Mediastinal growing teratoma syndrome. Ann Thorac Surg. 1997;64: 359–362. 18. Loehrer P, Gonin R, Nichols C, et al. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol. 1998;16: 2500–2504. 19. Radaideh S, Cook V, Kesler K, et al. Outcome following resection for patients with primary mediastinal nonseminomatous germ cell tumors and rising serum tumor markers post-chemotherapy [abstract]. Proc Am Soc Clin Oncol. 2008:5038. 20. Hartmann J, Nichols C, Droz J, et al. Prognostic variables for response and outcome in patients with extragonadal germ-cell tumors. Ann Oncol. 2002;13: 1017–1028.
H.D. Riggs et al. 21. Lemmarie E, Assouline P, Diot P, et al. Primary mediastinal germ cell tumors: results of a French retrospective study. Chest. 1992;102:1477–1483. 22. Goss P, Schwertfeger L, Blackstein M, et al. Extragonadal germ cell tumors: a 14-year Toronto experience. Cancer. 1994;73:1971–1979. 23. Gerl A, Clemm C, Lamerz R, et al. Cisplatin-based chemotherapy of primary extragonadal germ cell tumors. Cancer. 1996;77:526–532. 24. Hidalgo M, Paz-Ares L, Rivera F, et al. Mediastinal non-seminomatous germ cell tumours (MNSGCT) treated with cisplatin-based combination chemotherapy. Ann Oncol. 1997;1997:555–559. 25. Bacha E, Chapelier A, Macchiarini P, et al. Surgery for invasive primary mediastinal tumors. Ann Thorac Surg. 1998;66:234–239. 26. Fizazi K, Culine S, Droz J, et al. Primary mediastinal nonseminomatous germ cell tumors: results of modern therapy including cisplatin-based chemotherapy. J Clin Oncol. 1998;16:725–732. 27. Takeda S, Miyoshi S, Ohta M, et al. Primary germ cell tumors in the mediastinum: a 50-year experience at a single Japanese institution. Cancer. 2003;97: 367–376.
53
Symptomatic Malignant Pericardial Effusion: Surgical or Percutaneous Drainage? M. Blair Marshall
Up to 21% of patients dying of cancer will have a malignant pericardial effusion, and malignant disease is one of the most common causes of pericardial effusion.1,2 These data are somewhat dependent upon geographic location and institution, as institutions dealing primarily with cancer will have a skewed population and certain locations around the world will differ in their spectra of pathology.3,4 Pericardial effusions in patients with malignant disease are thought to occur through three mechanisms: pericardial metastases, direct invasion of the tumor or nodal metastases into the pericardium, or obstruction of the lymphatic draining from either tumor or radiation induced fibrosis with no malignancy involving the pericardium.5 The latter is not necessarily associated with an active malignancy; this is an important issue, as life expectancy will vary significantly between patients with and without malignant pericardial involvement. Symptoms associated with malignant pericardial effusions range from dyspnea and fatigue to tamponade. Regardless of the severity of symptoms, the symptomatic patient needs to be treated. How best to treat patients with symptomatic pericardial effusions is a challenging problem. Historically, an open surgical approach was used to treat this often life threatening problem. With advances in technology and the introduction of 2-D echocardiography, percutaneous approaches have become more common over the past 2 decades. Initial reports of percutaneous pericardiocentesis, when done blindly, were associated with significant morbidity and mortality.6 With the addition of 2-D echocardiographic guidance, this has become a much safer procedure.
Given the frequency of occurrence of this pathology and the excellent outcomes associated with traditional surgical approaches, one might expect that this would provide a prime opportunity for a randomized prospective study comparing surgical and percutaneous techniques in the management of malignant pericardial effusions. This would have involved an unbiased evaluation of each technique with respect to morbidity, mortality, limitations, effectiveness and cost; it would have provided us with high quality evidence. As a result, management of malignant pericardial effusion would no longer be a “difficult decision in thoracic surgery”; however, no such study has been done.
Published Data In attempting to decide whether a surgical or percutaneous approach is best, a review of the literature was conducted searching PubMed under the MeSH headings “pericardial effusion” and “management”. The search was limited to the English language, humans, clinical trials and the publication period from 1995 through 2009. This yielded 128 abstracts and selected biographies from several of these studies; when appropriate, additional studies that were absent from the search were added for review. This search identified no prospective randomized studies and only one prospective study.2 For the most part, published studies do not address this issue directly. The majority of studies are retrospective reviews that do a poor job at comparing
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techniques due to several flaws in the methodology: (1) mixed patient populations, including those with malignant disease and benign disease; (2) mixed levels of symptoms: those requiring emergent procedures versus elective drainage; and (3) mixed techniques. The techniques used to treat these patients generally were not randomized but were based upon clinical indications, local expertise and physician preference. A summary of these studies and the level of evidence that their data provide is in Table 53.1.2–4,7–15
Impact of Patient Populations on Outcomes Patients with malignant disease clearly differ from those with benign disease. The majority of studies reviewed included patients who were symptomatic from both benign and malignant conditions. Many studies report results from an extended time period, during which the spectrum pathology evidently changed. There were also important variations among geographic regions and individual institutions. Even when the patient population is limited to those with malignancy, there continues to be considerable differences within this population. Because these studies are not randomized to focus on the issues discussed in this chapter, the data present a gross bias in evaluating these techniques and comparing one study to the next, which affects the level of evidence as highlighted in Table 53.1.
The risk factors associated with the underlying pathology affects patient outcomes in these studies. In one study of medical patients with and without a history of malignancy, the 1 year mortality was 76.5% in patients with malignancy versus 13.3% in those with non-malignant disease. However, the in-hospital mortality was not different between these two groups.2 One might wonder, given the previous study, how this could be, but the severity of benign disease affects acute outcomes, especially in patients with advanced HIV or postoperative low cardiac output syndrome. Again, these risk factors are not stratified.9 There also are biases in studies that report only on patients with malignancy. Patients with a history of being treated for a malignancy mediastinal radiation, for example, may present with a benign pericardial effusion and no active malignancy. Such patients will likely behave better than those with a pericardial effusion secondary to metastatic spread of disease, even though they are grouped in the same “malignant disease” category.16 In those with an active malignancy, the type of malignancy has a major impact on survival. For example, the median survival for patients with a malignant effusion due to breast cancer is much higher than the survival of those with an effusion due to lung cancer.4 These issues have an impact not only on the survival of patients undergoing these procedures, but the complications and risk of recurrence as well. Since these are the critical factors risk factors that should be stratified in evaluating which
Table 53.1. Treatment of symptomatic pericardial effusions. Procedures Author Cornily2 Becit3 O’Brein7 Liberman8 Dosios9 Cullinane4 McDonald10 Tsang11 Tsang12 Vayre13 Allen14 Moores15
Years
Pts.
Type
SX
1996–2005 1990–2003 1992–2002 1992–2002 1991–2001 1991–2001 1995–1999 1979–2000 1979–1998 1982–1998 1986–1994 1988–1993
114 368 71 191 104 63 246 977 275 110 117 155
M, B M, B M, B M, B M, B M M, B M, B M M, B M, B M, B
34 368 56 78 104 14 150
VT
AT
15 3
110
30
19
PC
94 155
Level of evidence
80
Low Low Low Low Low Low Low Low Low Low Low Low
96 a
275
PA
139 41 23
1127 118 69
M malignant; B benign; SX subxiphoid; VT video thoracoscopy; AT anterior thoracotomy; PC percutaneous catheter; PA percutaneous aspiration (pericardiocentesis). a Study reported on pericardiocentesis and catheter placement together.
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technique is better, one should be skeptical of the risks and mortality reportedly associated with each technique in these series.
Impact of Technique: Approaches and Procedures Dividing approaches into surgical versus percutaneous ignores the variability within these general techniques. A technique is best categorized by determining whether it is percutaneous or surgical, and then more specifically by the subsequent procedure. The majority of studies report on a mix of procedures performed. Some include a variety of percutaneous approaches, or a variety of surgical approaches, or even a combination of both. For the percutaneous approach, the subtypes include pericardiocentesis or aspiration, and pericardial catheter drainage. Some studies report on a single approach for the intervention such as “percutaneous”, but include patients who underwent aspiration and/or catheter placement.11 In addition, some studies include patients who underwent pericardial sclerosis but included these patients with the other percutaneous subtypes.12 Due to the recurrent nature of malignant disease when compared with more acute causes of tamponade, such as cardiac surgery, percutaneous aspiration was inferior to the surgical approach. In patients with malignant effusions percutaneous aspiration alone results in an increased need of either subsequent repeat procedure or surgical intervention.12,13 The surgical techniques often include multiple types of procedures without accounting for variations in approach: subxiphoid drainage under local anesthesia or general anesthesia, video assisted thoracoscopy under general anesthesia, or even an open limited or standard thoracotomy. These techniques have not been evaluated in any randomized clinical trials. Usually, the decision to use a particular technique is based on surgeon preference, local expertise, or a clinical indication such as a concomitant pleural effusion or other factors.4,7 The rationale for using one approach or another was frequently not described. Theoretically, an effusion related to metastatic cancer in the pericardial space is a recurring
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problem. The theory held by some is that the creation of a “window” between the pericardium and the pleural space or between the pericardium and the preperitoneal space allows a more permanent effluent out of the pericardial space. There is little objective evidence that this actually occurs. The surgical subxiphoid drainage is done through a small incision overlying the xiphoid, with excision of a piece of pericardium and placement of a thoracostomy tube into the pericardial space. This was misnamed “subxiphoid window” in some series, although there is no “window” created.4,8,14 This misconception is still prevalent among many cardiothoracic surgeons. There is no data to suggest that the creation of a “window” is more effective than tube drainage alone in the majority of patients, but these types of procedures are still performed.7 If creation of a window were the mechanism of success, than subxiphoid drainage and percutaneous catheter drainage would have a much higher recurrence rates. When prolonged drainage is performed, the algorithm for how long the drainage tube should be left in place is not typically reported. Surgically placed tubes are commonly put on suction, whereas percutaneously placed pericardial drains are allowed to drain via gravity or even are clamped and intermittently opened. In the majority of publications reviewed, variability in the length of the drainage period was not accounted for although it seems that most agree on 4–5 days.2,7
Which Drainage Technique Is Best? Both surgical and percutaneous drainage of malignant pericardial effusions are safe and effective. Because the data are plagued with the previously mentioned limitations, the conclusions from individual studies supporting one approach or the other should be interpreted with caution. In Table 53.1 the data are parsed where possible to identify morbidity, mortality, and re-intervention rates associated with each technique, but given the haphazard reporting, accurate categorization often was not possible. Some papers reported only morbidity, others only mortality. Mortality was not uniformly defined, with some discussing 30-day mortality and others discussing in-hospital mortality, etc. These outcomes will be separately discussed.
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Benefits Relief of Symptoms In many studies, both techniques demonstrate the ability to effectively drain the pericardium and relieve a patient’s symptoms, and the benefit of this is clearly substantial. For patients with acute tamponade, percutaneous catheter based drainage is a more expeditious procedure and is effective. When a percutaneous approach is not possible due to loculated effusions or other reasons, surgical drainage is effective and safe in the management of tamponade (evidence quality low).14 For managing symptoms from a malignant effusion, both pericardial catheter drainage and surgical drainage are highly effective and safe. Among the surgical techniques, including subxiphoid drainage, video assisted drainage, limited and extended thoracotomy, there are no data to suggest that one therapy is more effective than another (evidence quality low).4,7
Diagnosis For patients with symptomatic malignant effusions, is the ability to diagnose malignant involvement of the pericardium through biopsy or cytology an added benefit of the procedure? In one series, pericardial involvement was the first sign of malignancy in 31% of patients presenting with a malignant effusion.2 Given this and the fact that histopathology and pericardial biopsy can be performed with a surgical technique, is there a diagnostic benefit to surgical drainage and what is the relative importance of this? Even with this ability, in up to 10% of patients the etiology will remain unknown.2 One series showed similar rates of confirming a malignant diagnosis in patients suspected of having malignancy, 61% for surgical and 59% for percutaneous drainage.10 In a more recent surgical series of 368 patients undergoing subxiphoid surgical drainage, pericardial biopsies were taken in all patients and only 14% of patients had a malignant etiology. Cytology of the pericardial fluid was negative for malignancy but positive on histology in 18 of 51 patients (35%). In 10% of patients with cancer, neither the pericardium nor histopathology showed evidence of malignancy.3 Lastly, in another
study of 63 patients presenting with symptomatic effusions associated with malignancy, cytology was available for 58 patients and pathology was available for 56. In 15 patients both the cytology and histopathology were positive. Interestingly, 13 patients had positive cytology alone without positive histopathology, and no patients had positive histopathology without positive cytology.4 This latter series suggests that there is no additional benefit of pericardial biopsy and provides probably the most reliable data. Thus, both percutaneous and surgical techniques share the same ability to obtain a diagnosis (evidence quality low).
Freedom from Further Intervention Studies that incorporated pericardiocentesis as a percutaneous technique compared with surgical drainage demonstrated significant differences in the risk of recurrence and the need for additional intervention favoring surgical drainage, 27% versus to 14%.11 In one series of patients presenting with tamponade, surgical drainage had to be performed in 17% of patients who failed a pericardiocentesis, and 21% of these were done emergently for failure of the primary procedure to relieve tamponade within a few hours of drainage.13 A more recent series demonstrated a 10% early failure rate of pericardiocentesis in a mixed patient population. Given these data, pericardiocentesis should not be performed for tamponade because a significant proportion of patients will require an urgent secondary procedure (evidence quality low). Due to high recurrence rates, pericardiocentesis alone should not be performed in patients suspected of having a malignant effusion.Percutaneous catheter placement adds little to the morbidity of pericardiocentesis and significantly decreases the need for reintervention in patients with malignant disease (evidence quality low).12 As part of the transition from pericardiocentesis to catheter based therapy, several institutions reported on the use of varying sclerosing agents in increasing the likelihood of success and decreasing the need for further intervention. Many reported on the safety of the use of these agents but demonstrated limited benefit to their use. The most recent of these, a randomized prospective study, failed to demonstrate a benefit of intrapericardial Bleomycin in the management of patients with malignant
53. Symptomatic Malignant Pericardial Effusion: Surgical or Percutaneous Drainage?
effusion from lung cancer.17 Thus, the routine use of sclerosants in patients with malignant effusions offers no benefit (evidence level low). In a comparison between percutaneous catheter placement and surgical drainage, the rate of recurrence requiring re-intervention was 0% in patients undergoing subxiphoid drainage or video thoracoscopic window in one surgical series.7 In an additional series looking at patients with malignancy alone, recurrence rates for pericardial aspiration, pericardial catheter, and surgical drainage were 36.4%, 11.5% and 0% respectively.12 In another study comparing pericardial catheter to subxiphoid drainage, recurrence rates requiring additional intervention were 15.6% and 4.7%, respectively. In this same series, the 1 year freedom from recurrence was 81% for the catheter group and 95% for the surgical group, even though there were more patients with malignant disease in the surgical group.14 A recent European series showed that 10% of patients required an additional intervention following subxiphoid drainage, 60% of which were due to uremic pericarditis and 30% of which were due to tuberculous pericarditis. These data are not reflective of the US population, as in the US studies the majority of pericardial effusions are due to malignancy or previous surgery.3 Surgical drainage appears to offer improved freedom from re-intervention compared to percutaneous drainage. However, this does not take into consideration additional issues such as morbidity, mortality, burden and cost.
Morbidity and Mortality As none of these studies provide pre-procedural risk stratification, one has to interpret the data regarding risk cautiously. Some studies of percutaneous drainage compared their results to older surgical studies, demonstrating increased morbidity and mortality for surgical drainage, but these do not reflect the modern surgical approach.7 The severity of complications in these study populations are not all equal, as a cardiac laceration requiring a median sternotomy is different from an asymptomatic pneumothorax requiring no intervention, and not all studies separate out complications according to severity. One series of 110 patients undergoing echocardiography guided approaches reported a 10% early mortality within
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24 h, with six deaths occurring during the procedure. The majority of these patients demonstrated rupture of the free ventricular wall in an area of infarct at the time of autopsy.13 This is from an older study, and these results appear distorted when compared with more recent reports.11 Major complications associated with the surgical and percutaneous approaches are rare. The subxiphoid, video assisted and limited anterior approaches are low risk.7,10 Some series do not report complications but only provide mortality data associated with a given procedure.2,15 It is difficult to compare data form one study to the next because of lack of consensus regarding reporting of risk and mortality: in-hospital mortality is used by some and 30-day mortality by others. Mortality in these studies is predominantly related to the patient’s underlying condition and not to individual techniques.4,7 Many of these patients with either benign or malignant disease can be extremely sick. Studies that report on both surgical and percutaneous techniques describe an increased mortality associated with one or the other technique or no difference.2,11,14 Without stratifying these patients according to risk, it is not possible to draw any conclusions regarding risks of procedure-related mortality. Overall, survival in patients with an active malignancy and symptomatic pericardial effusion is poor, with a median survival of 2–4.5 months, and this is not dependent upon technique of drainage.4,10,11 In-hospital survival may be dependent upon technique when that technique is not done perfectly and additional interventions must be done to correct technical error, be it percutaneous or surgical. The morbidity and mortality associated with both percutaneous and surgical approaches is low, and there are not enough valid data to differentiate these two approaches based upon risk and mortality (evidence quality low).
Burden In several studies, the decision to use one technique over another was based upon the need for a synchronous intervention, such as the management of a concomitant pleural effusion. In one study comparing two surgical approaches, subxiphoid versus video thoracoscopic drainage, 39% of patients
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underwent additional procedures including drainage of pleural effusion, talc pleurodesis, lung biopsy, mediastinal biopsy, tube thoracostomy, and transesophageal echocardiography at the time of surgery.7 In this setting, it appears that the lower recurrence rate associated with subxiphoid drainage and need for a concomitant intervention warrants a surgical approach (evidence quality low). One can argue that there is decreased pain and decreased need for prolonged recovery from a percutaneous approach compared to a surgical approach. This is true, although there are few data on the topic. Based upon pain and length of recovery, percutaneous catheter drainage is the preferred treatment (evidence quality low).
Cost There are no studies that compare the cost of a percutaneous catheter based approach to a surgical approach. However in today’s environment, cost and comparative effectiveness need to be taken into consideration. There are data that can be extrapolated from other studies, where a procedure could be performed in a monitored setting or intensive care unit versus in the operating room, such as in percutaneous core needle breast biopsy versus open biopsy or percutaneous tracheostomy versus open tracheostomy. In these studies, the cost savings offered by the percutaneous procedure are significant.18,19 For patients undergoing percutaneous drainage of a malignant pericardial effusion, the likelihood of recurrence requiring an additional intervention is high enough that the need for repeat interventions must be taken into consideration when attempting to consider costs. The only way to formally answer this is with a randomized trial so that the relative risks and impact of recurrence on burden and cost can be taken into consideration. Initial treatment of a malignant pericardial effusion is less expensive using percutaneous catheter drainage than with surgical drainage (evidence quality very low).
Summary and Recommendations All of the aforementioned issues come into play in the management of patients with malignant
pericardial effusions, but based upon these data alone, there is no significant benefit of the more invasive surgical approaches over percutaneous approaches. Both therapies are effective. When performed in patients with malignant pericardial effusion, catheter based therapies are more effective that pericardiocentesis alone. When the expertise is available, percutaneous catheter based therapy is the treatment of choice due to the decreased costs, reduced pain, and quicker recovery associated with this technique. In addition, these patients have a decreased life expectancy and the majority will require no further intervention. The recurrence rate is lower following surgical drainage, but the negative impact of a need for a trip to the operating room, increased pain, prolonged recovery, and greater cost likely negate this benefit in the majority of patients. Among surgical techniques, there are no data demonstrating that one technique is more effective than another, although the subxiphoid approach is more commonly performed. This approach also has the added benefit of being able to be performed under local anesthesia. This benefit may be mitigated by the need for additional intrathoracic procedures and a thoracoscopic or limited anterior approach may be preferable in such situations. In patients with malignant effusions requiring surgical drainage and no additional interventions, a subxiphoid approach is the better approach. In patients with an uncomplicated symptomatic malignant pericardial effusion, both percutaneous catheter techniques and surgical drainage provide good relief of symptoms and are safe (evidence quality low). Percutaneous techniques are likely less costly and better tolerated. A weak recommendation is made for percutaneous catheter drainage rather than surgical drainage of symptomatic malignant pericardial effusions (recommendation grade 2C). When the percutaneous approach is not possible or when there other clinical considerations indicate, surgical drainage is appropriate.
A Personal View of the Data At my institution, the thoracic surgeons perform both techniques and, given the benefits of the percutaneous approach, that is the procedure of choice
53. Symptomatic Malignant Pericardial Effusion: Surgical or Percutaneous Drainage?
for our patients in this setting. The increased incidence of failure of this technique is acknowledged and should be discussed with patients prior to selecting the optimal therapy. Some patients may prefer a more definitive approach even though it may be more invasive, and this is not unreasonable.
In patients with an uncomplicated symptomatic malignant pericardial effusion, percutaneous catheter techniques provide good relief of symptoms and are safe (evidence quality low). A weak recommendation is made for percutaneous catheter drainage rather than surgical drainage of symptomatic malignant pericardial effusions (recommendation grade 2C).
References 1. Theologides A. Neoplastic cardiac tamponade. Semin Oncol. 1978;5:181–192. 2. Cornily JC, Pennec PY, Castellant P, Bezon E, Le Gal G, Gilard M, Jobic Y, Boschat J, Blanc JJ. Cardiac tamponade in medical patient: a 10-year follow-up survery. Cardiology. 2008;111:197–201. 3. Becit N, Unlü Y, Ceviz M, Koçogullari CU, Koçak H, Gürlertop Y. Subxiphoid pericardiostomy in the management of pericardial effusions: case series analysis of 368 patients. Heart. 2005;91:785–790. 4. Cullinane CA, Paz B, Smith D, Carter N, Grannis FW. Prognostic factors in the surgical management of pericardial effusion in the patient with concurrent malignancy. Chest. 2004;125:1328–1334. 5. Karam N, Patel P, deFilippi C. Diagnosis and management of chronic pericardial effusions. Am J Med Sci. 2001;322:79–87. 6. Buzaid AC, Garewal HS., Greenberg BR Managing malignant pericardial effusion. West J Med. 1989; 150:174–179. 7. O’Brein PK, Kucharczuk JC, Marshall MB, Freidberg JS, Chen Z, Kaiser LR, Shrager JB. Comparative Study of subxiphoid versus video-thorascopic pericardial “window”. Ann Thorac Surg. 2005;80:2013–2019. 8. Liberman M, Labos C, Sampalis JS, Sheiner NM, Mulder DS. Ten-year surgical experience with nontraumatic pericardial effusions: a comparison
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between the subxiphoid and transthoracic approaches to pericardial window. Arch Surg. 2005; 140:191–195. 9. Dosios T, Theakos N, Angouras D, Asimacopoulos P. Risk factors affecting the survival of patients with pericardial effusion submitted to subxiphoid pericardiostomy. Chest. 2003;124:242–246. 10. McDonald JM, Meyers BF, Guthrie TJ, Battafarano RJ, Cooper JD, Patterson GA. Comparison of open subxiphoid pericardial drainage with percutaneous catheter drainage for symptomatic pericardial effusion. Ann Thorac Surg. 2003;76:811–815. 11. Tsang TS, Enriquez-Sarano M, Freeman WK, Barnes ME, Sinak LJ, Gersh BJ, Bailey KR, Seward JB. Consecutive 1127 therapeutic echocardiographically guided pericardiocenteses: clinical profile, practice patterns, and outcomes spanning 21 years. Mayo Clin Proc. 2002;77:429–436. 12. Tsang TS, Seward JB, Barnes ME, Bailey KR, Sinak LJ, Urban LH, Hayes SN. Outcomes of primary and secondary treatment of pericardial effusion in patients with malignancy. Mayo Clin Proc. 2000;75:248–253. 13. Vayre F, Lardoux H, Pezzano M, Bourdarias JP, Dubourg O. Subxiphoid pericardiocentesis guided by contrast two-dimensional echocardiography in cardiac tamponade: experience of 110 consecutive patients. Eur J Echocardiogr. 2000;1:66–71. 14. Allen KB, Faber LP, Warren WH, Shaar CJ. Pericardial effusion: subxiphoid pericardiostomy versus percutaneous catheter drainage. Ann Thorac Surg. 1999; 67:437–440. 15. Moores DW, Allen KB, Faber LP, Dziuban SW, Gillman DJ, Warren WH, Ilves R, Lininger L. Subxiphoid pericardial drainage for pericardial tamponade. J Thorac Cardiovasc Surg. 1995;109:546–551. 16. Martin RG, Ruckdeschel JC, Chang P, Byhardt R, Bouchard RJ, Wiernik PH. Radiation-related pericarditis. Am J Cardiol. 1975;35:216–220. 17. Kunitoh H, Tamura T, Shibata T, Imai M, Nishiwaki Y, Nishio M, Yokoyama A, Watanabe K, Noda K, Saijo N. A randomised trial of intrapericardial bleomycin for malignant pericardial effusion with lung cancer (JCOG9811). Br J Cancer. 2009;100:464–469. 18. Anania G, Bazzocchi M, di Loreto C, Risaliti A, Terrosu G, Donini A, Zuiani C, Puglisi F, Bresadola F. Percutaneous large core needle biopsy versus surgical biopsy in the diagnosis of breast lesions. Int Surg. 1997;82:52–55. 19. Oliver ER, Gist A, Gillespie MB. Percutaneous versus surgical tracheotomy: an updated meta-analysis. Laryngoscope. 2007;117:1570–1575.
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Bronchogenic and Pericardial Cysts: Resect or Observe Kemp H. Kernstine and Peace Eneh
Introduction
Signs, Symptoms and Complications
Bronchogenic cysts are the most common cystic lesions in the mediastinum representing 15–25% of all mediastinal masses.1 They are the most common congenital foregut cyst and comprise 60% of mediastinal cysts.2 The prevalence of bronchogenic cysts is 1:68,000 admissions.3 They arise from abnormal budding of the tracheobronchial tree4 and, thus, are found along the anterior aspect of the esophagus, around the trachea, and in the mediastinum, hilum and lung. Depending upon when the cyst separates from the developing foregut it can be found in the neck, along the vertebrae, pericardium, subdiaphragmatic space and in other sites. Bronchogenic cysts can develop infection, compress and/or irritate adjacent vital structures and spontaneously hemorrhage. Fistulae have been reported to be as high as 43% in symptomatic patients,5 accounting for 53% of the major complications associated with cysts.6 Fifty-five percent of bronchogenic cysts have significant pericystic adhesions to mediastinal structures7; their presence makes surgical resection difficult. In contrast, pericardial cysts are most frequently located at the lateral inferior border of the pericardium and are the second most common mediastinal cyst.2 They are most commonly congenital, but may also be acquired from trauma or surgery. They occur in 1:100,000 admissions and make up 7% of all mediastinal tumors.8 The cysts arise from the mesenchymal lacunae failing to fuse normally to form the pericardial sac.2 Bronchogenic and pericardial cysts present in all age groups and may be challenging to diagnose and treat.
Although many of these cysts are found on routine chest radiographs, two-thirds of patients are found to be symptomatic.9 The most common presenting complaints are related to compression of adjacent structures such as chest pain, dyspnea, fever, and cough.6,9,10 Malignancy may present as more serious sequelae such as hoarseness, chylothorax, Horner’s syndrome, diaphragmatic paralysis, and superior vena caval syndrome.9 A bronchogenic cyst may abruptly increase in size due to intra-cyst bleeding or infection.11 A more gradual size increase may represent malignancy or malignant degeneration. Infants are particularly sensitive to the acute size change, developing dyspnea from the airway distortion or compression and pulmonary shunting.12 Other sudden catastrophes include cyst rupture or erosion into adjacent structures such as the airway, the pericardium, and the heart,13,14 potentially resulting in acute respiratory distress, hemodynamic failure, arrhythmias, and potentially bleeding, and may lead to sudden death. In contrast to bronchogenic cysts, pericardial cysts are unlikely to develop malignancy and rarely erode or bleed, although there has been a case report of erosion into the right ventricular wall.15
Literature Search Technique Within the search engine Scopus™ (Elsevier B.V., Radarweg 29,1043 NX Amsterdam,The Netherlands, Reg. No. 33156677, BTW No. NL005033019B01), we
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_54, © Springer-Verlag London Limited 2011
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searched the terms bronchogenic cyst and pericardial cyst and within those headings searched terms: case series, management to include resection, surgical resection, excision and observation or conservative; complications, morbidity, review, Cochrane, consensus and English. We excluded the array of congenital cystic lung lesions.
K.H. Kernstine and P. Eneh
reported.40 The authors of these reports recommended that both symptomatic and asymptomatic cysts should be resected owing to the unpredictable behavior of theses cysts. Rarely, pericardial cysts may result in life-threatening complications.41 With the current methods of resection and quality of anesthesia, the risk of observing bronchogenic cysts may be greater than the risk of resection.7,42,43
Data That Impact on Decision Making There are many factors that influence the decision to resect or observe an apparent bronchogenic or pericardial cyst. Benign cysts are more commonly asymptomatic,5 malignant or infected cysts are more likely symptomatic. Conservative management has been advocated for asymptomatic cysts.16 However, nearly three-quarters will become symptomatic with long-term observation.6,10,17–20 In children, resection of all cysts often is recommended because of the tendency for the cysts to increase in size over time and the potential for acute airway obstruction, given that the diameter of their airways are smaller and more pliable than adults and thus more likely to become acutely obstructed and the potential affect on proper vital organ development.21–23 Table 54.1 summarizes the retrospective reported case series that comprise 15 or more patients with bronchogenic cysts, a number we chose that would represent a sufficient experience to make a recommendation.3,5,6,10,17,18,24–33 All 16 reports recommend resection of bronchogenic cysts in both symptomatic and asymptomatic patients in adults and children. Patel et al.10 and St. George et al.,6 in particular, found that the strategy of waiting for symptoms to develop increased the rate of intra- and post-operative complications compared with patients who were asymptomatic at the time of resection. Resection of asymptomatic cysts may prevent future complications.6 There have been reports of serious life-threatening complications that have occurred in adults, patients who were observed rather than resected. In a few representative case reports there were lifethreatening complications of cyst rupture and airway obstruction.19,34–37 There have been reports of acute paroxysmal atrial fibrillation associated with dyspnea.38,39 Pain and dysphagia have been
Surgical Treatment Modalities Surgically removing these cysts ensures accu rate diagnosis and a definitive treatment.3,18,32,33,43 Whether in the lung, pleural space or mediastinum, thoracotomy has been the method most commonly utilized to resect thoracic cysts or masses. In the last 2 decades, there has been an increase in the use of minimally invasive techniques. Weber et al.44 reported the use of videoassisted thoracoscopic surgery (VATS) in 12 patients with bronchogenic cysts. There were no postoperative complications. One patient required conversion to open thoracotomy due to extensive pleural adhesions. In another patient, the cyst could not be completely resected, a small portion being left attached to vital structures. There were no recurrences or complications during the mean follow-up of 40.5 months. Hazelrigg and colleagues45 published their experience in nine thoracoscopically-resected cysts. They too reported no complications or recurrences. The technology is continuing to improve enabling resection,45 but there are still challenges: pericystic adhesions, tracheal or bronchial fistulas, and the possibility of malignant transformation.46 Cysts that are severely adherent to vital structures can be partially excised with complete obliteration of the remaining cyst endothelium to reduce the likelihood of recurrence.7,45,47 Robotic surgery is another minimally invasive technique to resect cysts. Although robotic resection of mediastinal masses has been reported to be a safe and practical,48,49 the experience is early. Using the da Vinci robot (Intuitive Surgical, Sunnyvale, California), Yoshino et al.50 removed a 2-cm bronchogenic cyst in a 28-year old woman. The authors noted that the cyst would have been
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54. Bronchogenic and Pericardial Cysts: Resect or Observe Table 54.1. Published series of bronchogenic cysts. Years of Study
Patients
Symptomatic at Diagnosis (%)
Surgically Resected
St. George6
1969–1989
86
72
86
NR
Suen17
1962–1991
42
50
40
2–12 cm (5.3 cm)
Patel10
1975–1992
18
44
18
3–10 cm (6 cm)
Ribet3
1967–1993
69
64
69
2–15 cm (4.5 cm)
Cuypers24
1975–1993
20
30
20
2–12 cm (4.4 cm)
Aktogu5
1975–1994
31
81
30
NR
Ribet18
1967–1993
41
80
37
3.5–10 cm (5.5 cm)
Cioffi25 Kanemitsu26
1976–1996 1966–1996
16 17
56.2 29
16 17
2–10 cmb 2–9 cm (4.2 cm)
Sarper27
1985–2002
22
82
22
NR
Takeda33
1951–2000
47
39
47
NR
Limaiem28
2000–2006
33
94
33c
2–16 cm (5.7 cm)
Gursoy29
2000–2007
28
NR
28
2–12 cm (6.2 cm)
De Giacomo30
1995–2008
30
37
30
3–10 cm (5.2 cm)
Kosar31
1990–2005
29
86
29
2–12 cm (4.7 cm)
Liu32
1983–2007
50
66
50d
2–15 cm (5.1 cm)
Author
Summary
1951–2008
579
Mean values in parentheses. Includes 11 esophageal duplication cysts. c 31 total excision, 2 subtotal excision. d 47 complete resection, 3 subtotal resection. a
b
61 (range 29–94%)
572 (98.8%)
Size of Cystsa
2–15 cm (5.1 cm)
Adults (% of Total)
Authors’ Remarks
86 (100%) Resect all bronchogenic cysts, more hazardous operation in symptomatic patients. – Complete excision in most cases to avoid complications and malignant degeneration. 18 (100%) Resection of bronchogenic cyst in all operable patients 45 (65%) Resection because of uncertainties in diagnosis and in evolution 20 (100%) All cases of bronchogenic cyst should be surgically resected due to their potential of becoming malignant or developing complications 30 (97%) Bronchogenic cysts should be treated surgically and a conservative approach is not recommended 20 (49%) Resect symptomatic and asymptomatic as preventive measure 16 (100%) Resect all cysts 16 (94% Cyst should be resected in most patients to relieve symptoms and to prevent complications 10 (45%) Bronchogenic cyst in operable patients should be surgically resected 41 (87%) Diagnosis of symptomatic cyst is an indication for complete extirpation; preventive resection in asymptomatic patients 33 (100%) Complete surgical resection for all to establish diagnosis, alleviate symptoms and prevent complications 28 (100%) Resection in all cases is recommended to aid diagnosis and prevent operative difficulty and complications 30 (100%) Considering the low conversion and complication rate, thoracoscopic excision should be considered the primary therapeutic option 16 (55%) Treatment of all bronchogenic cyst is recommended 50 (100%) Surgical resection in both symptomatic and asymptomatic patients, surgical resection is the best way for diagnosis 501 (87%)
Evidence Quality Low
Low
Low Low Low
Low
Low
Low Low
Low
Low
Low
Low
Low
Low Low
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very challenging to remove by VATS, where instead robotic technology enabled the resection. Bacchetta and his coworkers51 robotically resected a 5 × 6 cm symptomatic pericardial cyst from a 43-year-old man. Partial decompression by needle aspiration was required for safe removal. Given the current technology for both VATS and robotics, thoracotomy is preferable when the cyst: (a) is too large to be completely resected using minimally invasive techniques, (b) is located in difficult to access locations, and (c) is suspicious of infection or malignancy.7,47–50 Perhaps robotic technology will prove to overcome the VATS shortcomings.
Other Treatment Modalities Alternatives to surgical resection include percutaneous and endoscopic aspiration and thoracoscopic or mediastinoscopic partial cyst resection. The theoretical frequency of recurrence, and the potential for bleeding and/or infection make cyst aspiration much less appealing.52,53 However, the nature of the cyst might have a significant role in influencing the appropriate treatment modality. Cysts containing thin fluid might benefit more from aspiration, especially those densely adherent to vital structures. There is controversy over whether biopsy or aspiration is preferable to achieve a diagnosis. There are a variety of techniques for both tissue biopsy and aspiration of these cysts. Percutaneous CT-guided needle biopsy serves as a good biopsy tool. Endoscopic ultrasonography (EUS) is particularly beneficial in that aspiration can be performed under a direct vision.9 In either case, needle aspiration may present some complications, such as bleeding, perforation and infection.54 Viemann and Puri55 argued that EUS-FNA is a safe and effective diagnostic tool with sensitivity of 90% and specificity of 100%, but Weirsema et al.56 and others54 argued against the use of EUSFNA for cystic lesions due to the 14% infection rate and potential for bleeding. EUS-FNA provides minimally invasive approach that may be more accurate than CT-guided FNA and other imaging modalities for the diagnosis of benign mediastinal cysts, but can result in life-threatening
K.H. Kernstine and P. Eneh
infections. Wildi et al. recommended that FNA of anechoic (cystic) lesions should be avoided because of risk of infections.54 Prophylactic antibiotics and minimizing needle passage are measures to reduce the risk of infection.54,56–58 The total EUS-FNA nonfatal complication rate is 1.6%, something to be considered when deciding to perform the procedure.58 Bronchoscopy-directed transtracheal aspiration has been used to partially or completely obliterate cysts. Kramer et al. aspirated 50 mL from a 5-cm bronchogenic cyst, reducing its diameter to 1 cm, with no enlargement after 2 years.59 Ultrasound-guided endobronchial needle aspiration (EBUS-FNA) appears to improve the accuracy and yield of aspiration. Gallucio et al.60 aspirated a 4-cm, 20 HU recurrent cyst previously treated by VATS, complicated by pericystic adhesion. After complete aspiration there was no recurrence noted after 18 months. In another case, Roos-Hesselink and colleagues61 aspirated a 100 mL serous fluid from a 9-cm smooth margined cyst with no recurrence at 3 years. There appears to be some cysts that may be treated with simple aspiration with excellent long-term results. The method of aspiration and selection of the appropriate cyst is undefined.6,59–62
Cyst Characteristics Indicative of Malignancy Cyst criteria that imply a greater likelihood of malignancy include size >3 cm, outer border irregularity, irregular shape, septations, multiple densities, enlarged regional lymph nodes and increasing size.63,64 If malignancy is suspected, alternative imaging methods, such as CT, MR or EUS, may provide further information to better discern cyst characteristics needed for further management. Biomarkers in the serum and cyst have not been found helpful in discerning the presence of malignancy. Although there have been reports of malignant bronchogenic cysts having elevations of both serum and cyst fluid CA 19–9 and CEA,65–67 fluid tumor marker levels of CEA, CA 15–3, CYFRA 21–1, CA 19–9 and CA 125 have been inconsistent in predicting malignancy.43 The role of biomarkers
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54. Bronchogenic and Pericardial Cysts: Resect or Observe
in the evaluation and management of mediastinal cysts remains to be determined. Aspirated cyst fluid should be sent for cytology, microbiological analysis, and cell differential examination. If the cytology appears malignant, the cyst should oncologically staged and resected as indicated. However, a negative cytology does not exclude the presence of cancer. If a cyst is infected, then surgery should be delayed until a course of antibiotic treatment has been completed.11 There are case reports in which malignancy developed in a congenital bronchogenic cyst. Suen et al.17 reported a case of adenocarcinoma arising from a bronchogenic cyst in an 8½-year-old girl. Tanita et al.68 also reported the case of a 46-year-old man with recurrent malignant melanoma that arose from a cutaneous bronchogenic cyst in the left scapular area.
Observation as Management Method Pugatch et al. reported no development of symptoms in 4 asymptomatic patients after follow up with CT for period ranging from 6 months to 3 years.69 Ribet and colleagues followed two patients with bronchogenic cysts who refused surgery for 15 years and found that one patient remained free of symptoms and the other died of a malignancy of unknown origin.3 Bouzas-Mosquera et al. followed a 55 × 40 mm pericardial cyst for 9-months and observed no development of symptoms in the patient.70 Cyst observation in asymptomatic patients certainly has precedence, but may have greater risk for some patients. On the other hand, St. George et al. reported that 24/37 (65%) of their asymptomatic patients required surgery when the bronchogenic cyst enlarged or became symptomatic over a period of 6 months to several years of observation.6 Patel et al. also reported that all three of their asymptomatic patients who were followed-up for 1½–10 years eventually required surgery due to development of symptoms or enlargement of the cyst.10 There has been no formalized study of the natural history of bronchogenic or pericardial cysts. As a result, management information is based on relatively small retrospective studies and anecdotal information. There are numerous questions that
need to be addressed: For lesions managed by observation, how long these cysts should be followed? How frequently and what tests should be performed? Should care costs be considered in the management decision-making?
Summary and Recommendations Lesions suspicious for bronchogenic or pericardial cyst should undergo a high resolution computed tomogram. Patients with an apparent bronchogenic or pericardial cyst should undergo a thorough history and physical examination to assess for signs and symptoms of the cysts. Patients in whom the diagnosis of a bronchogenic or pericardial cyst is inconclusive should undergo chest magnetic resonance imaging. Endoscopic bronchial ultrasound (EBUS) and esophageal ultrasound (EUS) may be performed to provide further diagnostic information. EBUS, EUS and CT-guided needle aspiration may be performed to assist diagnosis and potentially palliate patients. Administration of prophylactic antibiotics prior to cyst aspiration and minimizing needle passes is recommended. Bronchogenic cysts 2–3 cm or greater in diameter in healthy asymptomatic adult patients should undergo resection because three-quarters will become symptomatic and will become more difficult to remove with a greater likelihood for postoperative complications once removed. Symptomatic cysts in adults should be excised for symptom control. Cysts in children, whether or not symptomatic at diagnosis, are highly likely to enlarge and/or become symptomatic if observed. Excision of cysts is safe, controls symptoms, and prevents future complications (evidence quality low). We make a weak recommendation for excision of symptomatic, suspicious and/or enlarging cysts in adults and all cysts in children unless there are prohibitive medical conditions (recommendation grade 2B). Resection of asymptomatic pericardial cysts is safe and controls symptoms; however, asymptomatic pericardial cysts in adults generally do not enlarge or become symptomatic (evidence quality low). We make a weak recommendation for observation of asymptomatic pericardial cysts in adults (recommendation grade 2C).
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For higher risk or elderly patients, cyst aspiration or unroofing techniques with or without instillation/application of a sclerosing agent may be used for definitive therapy. In cases where cysts are aspirated, unroofed or incompletely resected, routine follow-up must be performed with chest computed tomogram every 3–6 months depending on the level of suspicion for malignancy or recurrence. For cysts that are aspirated, cytology may be helpful in establishing the presence of malignancy, but in cases where the cytology shows no malignant cells, malignancy in the cyst is not excluded. Currently available serum and cyst biomarkers provide no assistance in determining the presence of malignancy in the cyst. Cyst aspiration may be used as a temporizing measure to treat acute, possibly life-threatening symptoms, or to make the surgical resection easier. Bronchogenic cysts may acutely, but rarely hemorrhage, fistulize, enlarge or become infected, and may develop life-threatening events that warrant emergent intervention. Patients who have decided to undergo observation should be informed of these aspects and should be prepared to take appropriate measures should any change in symptoms develop. Thoracotomy is the standard-ofcare approach for resecting mediastinal cysts. Ideally, cysts should be completely resected. For those that cannot, the wall of the cyst should be either debrided or coagulated to reduce the likelihood of recurrence. Minimally invasive techniques that provide equivalent resection include VATS and robotics.
A Personal View of the Data In my practice, patients suspicious for a mediastinal mass or cyst undergo a high resolution computed tomogram. Pericardial cysts are unlikely to be malignant or to develop symptoms and can be more frequently observed rather than resected. For bronchogenic cysts, if there is a high suspicion of malignancy, then a FDG-PET is performed. Any suspected metastatic lesions outside of the mediastinum are biopsied. If metastatic cancer is found, treatment is directed according the malignancy discovered. If there is still high suspicion of malignancy, needle aspiration of the primary lesion is
K.H. Kernstine and P. Eneh
performed and again treatment directed according to the findings on biopsy. For patients with cystic lesions that are symptomatic or those found in children, resection is performed dependent upon the co-morbidities present. For high risk, terminal or the very elderly, other options for symptomatic or particularly large cysts are to aspirate or surgically unroof the cyst. We have not used the injection of sclerosant to treat cysts after aspiration. We approach cyst aspiration cautiously, as we have had an experience of EUS-directed cyst aspiration resulting in an infected and life-threatening cyst enlargement. We tend to resect all cysts larger than 2–3 cm. Our approach is to resect mediastinal and intralobar cysts robotically given the visibility and dexterity afforded by the technique. For intralobar cysts, we attempt to perform a parenchymal sparing procedure. For those cysts where there are dense adhesions or particularly large, a thoracotomy is performed. As necessary, a portion of the cyst may be left attached to vital structures and either debrided or cauterized. In asymptomatic patients, especially patients with cysts smaller than 2–3 cm and who have lesions unlikely to be malignant or to be involved with infection or bleeding, less aggressive measures can be undertaken. There is insufficient evidence to guide us precisely. With the reports of acute hemorrhage and risk of developing symptoms, potential of malignancy and increasing the difficulty if resection is required, patients are provided with the information concerning the risk of continued observation. Most patients choose to have a resection. For those that choose observation, we repeat the CT every 3 months for a year and then every 6 months for the next 2–3 years and then on a yearly basis for the next 10–15 years, realizing that there is no evidence to support this plan.
Excision of bronchogenic cysts is safe, controls symptoms, and prevents future complications (evidence quality low). We make a weak recommendation for excision of symptomatic, suspicious and/or enlarging cysts in adults and all cysts in children unless there are prohibitive medical conditions (recommendation grade 2B).
54. Bronchogenic and Pericardial Cysts: Resect or Observe
Resection of asymptomatic pericardial cysts is safe and controls symptoms; however, asymptomatic pericardial cysts in adults generally do not enlarge or become symptomatic (evidence quality low). We make a weak recommendation for observation of asymptomatic pericardial cysts in adults (recommendation grade 2C).
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468 32. Liu HS, Li SQ, Cao ZL, Zhang ZY, Ren H. Clinical features and treatment of bronchogenic cyst in adults. Chin Med Sci J. 2009;24:60–63. 33. Takeda S, Miyoshi S, Minami M, Ohta M, Masaoka A, Matsuda H. Clinical spectrum of mediastinal cysts. Chest. 2003;124:125–132. 34. De Nunzio MC, Evans AJ. Case report: the computed tomographic features of mediastinal bronchogenic cyst rupture into the bronchial tree. Br J Radiol. 1994;67:589–590. 35. Le Guen Y, Hureaux J, Gagnadoux F, Gourdier AL, Racineux JL. Treatment of a compressive bronchogenic cyst by computed tomography-guided needle aspiration. Rev Mal Respir. 2005;22:481–484. 36. Anderson PG, Anderson M, Allen G. A bronchogenic cyst causing respiratory distress. Aust NZ J Surgery. 1992;62:752–753. 37. Zikri MA, Rice TW. Subcarinal foregut cysts. A unique clinical problem. J Cardiovasc Surg. 2000;41: 137–141. 38. Johnston SR, Adam A, Allison DJ, Smith P, Ind PW. Recurrent respiratory obstruction from a mediastinal bronchogenic cyst. Thorax. 1992;47:660–662. 39. Rodriguez R, Boiselle PM, DeCamp Jr MM. What caused this man’s dyspnea, chest pain, and atrial fibrillation? J Respir Dis. 2006;27:539–544. 40. Pages ON, Rubin S, Baehrel B. Intra-esophageal rupture of a bronchogenic cyst. Interact Cardiovasc Thorac Surg. 2005;4:287–288. 41. Nijveldt R, Beek AM, van Gorp JM, van Rossum AC. Pericardial cyst. Lancet. 2005;365(9475):1960. 42. Shitrit D, Zingerman B, Shitrit AB, Shlomi D, Kramer MR. Diagnostic value of CYFRA 21–1, CEA, CA 19–9, CA 15–3, and CA 125 assays in pleural effusions: analysis of 116 cases and review of the literature. Oncologist. 2005;10:501–507. 43. Tecce PM, Fishman EK, Kuhlman JE. CT evaluation of the anterior mediastinum: spectrum of disease. Radiographics. 1994;14:973–990. 44. Weber T, Roth TC, Beshay M, Herrmann P, Stein R, Schmid RA. Video-assisted thoracoscopic surgery of mediastinal bronchogenic cysts in adults: a single-center experience. Ann Thorac Surg. 2004; 78:987–991. 45. Hazelrigg SR, Landreneau RJ, Mack MJ, Acuff TE. Thoracoscopic resection of mediastinal cysts. Ann Thorac Surg. 1993;56:659–660. 46. Kernstine K, Van Natta T, Burkhart T, DeArmond D. Congenital lung diseases, Chapter 9. In: Sellke FW, Del Nido PJ, Swanson SJ, Sabiston DC, Spencer FC, eds. Sabiston & Spencer Surgery of the Chest. 7th ed. Philadelphia, PA.: Elsevier Saunders; 2005:119–139. 47. Michel JL, Revillon Y, Montupet P, et al. Thoracoscopic treatment of mediastinal cysts in children. J Pediatr Surg. 1998;33:1745–1748. 48. Bodner J, Wykypiel H, Greiner A, et al. Early experience with robot-assisted surgery for mediastinal masses. Ann Thorac Surg. 2004;78:259–266.
K.H. Kernstine and P. Eneh 49. Meehan JJ, Sandler AD. Robotic resection of mediastinal masses in children. J Laparoendosc Adv Surg Tech. 2008;18:114–119. 50. Yoshino I, Hashizume M, Shimada M, Tomikawa M, Sugimachi K. Video-assisted thoracoscopic extirpation of a posterior mediastinal mass using the da Vinci computer enhanced surgical system. Ann Thorac Surg. 2002;74:1235–1237. 51. Bacchetta MD, Korst RJ, Altorki NK, Port JL, Isom OW, Mack CA. Resection of a symptomatic pericardial cyst using the computer-enhanced da Vinci Surgical System. Ann Thorac Surg. 2003;75:1953–1955. 52. Konstantinov IE, Saxena P, vanden Driesen R, Newman MA. Large bronchogenic cyst: diagnosis and surgical management. Heart Lung Circ. 2008;17:146–148. 53. Rice DC, Putnam JB Jr. Recurrent bronchogenic cyst causing recurrent laryngeal nerve palsy. Eur J Cardiothorac Surg. 2002;21:561–563. 54. Wildi SM, Hoda RS, Fickling W, et al. Diagnosis of benign cysts of the mediastinum: the role and risks of EUS and FNA. Gastrointest Endosc. 2003;58: 362–368. 55. Vilmann P, Puri R. The complete “’medical”’ mediastinoscopy (EUS-FNA + EBUS-TBNA). Minerva Med. 2007;98:331–338. 56. Wiersema MJ, Vilmann P, Giovannini M, Chang KJ, Wiersema LM. Endosonography-guided fine-needle aspiration biopsy: diagnostic accuracy and complication assessment. Gastroenterol. 1997;112:1087–1095. 57. Barawi M, Gottlieb K, Cunha B, Portis M, Gress F. A prospective evaluation of the incidence of bacteremia associated with EUS-guided fine-needle aspiration. Gastrointest Endosc. 2001;53:189–192. 58. O’Toole D, Palazzo L, Arotcarena R, et al. Assessment of complications of EUS-guided fine-needle aspiration. Gastrointest Endosc. 2001;53:470–474. 59. Kramer MR, Shitrit D, Grubstein A. Endobronchial aspiration of bronchogenic cyst: a first report of long-term follow-up. Eur J Cardiothorac Surg. 2005; 27:151. 60. Galluccio G, Lucantoni G. Mediastinal bronchogenic cyst’s recurrence treated with EBUS-FNA with a long-term follow-up. Eur J Cardiothorac Surg. 2006; 29:627–629. 61. Roos-Hesselink JW, Verhoeven GT, Stoker J. Bronchogenic cyst mimicking an intracardiac mass: diagnosis by magnetic resonance imaging and treatment by needle aspiration. Heart. 1996;75:639. 62. Kuhlman JE, Fishman EK, Wang KP, Zerhouni EA, Siegelman SS. Mediastinal cysts: diagnosis by CT and needle aspiration. AJR. 1988;150:75–78. 63. Glazer HS, Siegel MJ, Sagel SS. Low-attenuation mediastinal masses on CT. AJR. 1989;152:1173–1177. 64. Palazzo L, Landi B, Cellier C, Cuillerier E, Roseau G, Barbier JP. Endosonographic features predictive of benign and malignant gastrointestinal stromal cell tumours. Gut. 2000;46:88–92.
54. Bronchogenic and Pericardial Cysts: Resect or Observe 65. Oto T,Ando A,Aoe M, Date H, Shimizu N. Bronchogenic cyst with high serum carcinoembryonic antigen. Jpn J Thorac Cardiovasc Surg. 2003;51:34–36. 66. Takeda N, Nakajima J, Yamada N, Hiroi Y, Hirata Y, Nagai R. Rupture of bronchogenic cyst in the pericardium with high carbohydrate antigen 19–9 production. Respir Med Extra. 2007;3:76–78. 67. Tokuchi Y, Ukita H, Tsuneta Y, et al. Bronchogenic cyst with high carbohydrate antigen 19–9 in the cyst fluid and the serum. Intern Med. 1998;37:86–90.
469 68. Tanita M, Kikuchi-Numagami K, Ogoshi K, et al. Malignant melanoma arising from cutaneous bronchogenic cyst of the scapular area. J Am Acad Dermatol. 2002;46(2 Suppl):S19–S21. 69. Pugatch RD, Faling LJ, Robbins AH, Spira R. CT diagnosis of benign mediastinal abnormalities. AJR. 1980;134:685–694. 70. Bouzas-Mosquera A, Alvarez-Garcia N, Peteiro J, Castro-Beiras A. Pericardial cyst. Intern Med. 2008; 47:1819–1820.
55
Patient Selection and Optimal Extent of Surgery for Hyperhidrosis Stephen R. Hazelrigg, Ibrahim Bulent Cetindag, and Melita L. Viegas
Hyperhidrosis presents a challenge to both the patient as well as the physician. It has a significant negative impact on quality of life, causing impairments in social and occupational activities. A 2004 survey of 150,000 households in the United States revealed focal hyperhidrosis to be present in 2.9% of the general population. Of these patients, the axilla was affected in 51%, palms in 25%, and the face in 20%. Only 38% of these patients had sought medical help at the time of the survey.1 Once non-surgical modalities have been exhausted, surgical intervention is the next step. Even though the success of surgical treatment is well documented for eliminating hyperhidrosis from the primary site, the side effect of compensatory sweating (CS) remains a significant problem after surgery. Sympathectomy has been a treatment modality since the late nineteenth century for several diverse indications including glaucoma, trigeminal neuralgia, and seizures.2 In 1951 Kux described thoracoscopic sympathectomy for duodenal ulcer, angina pectoris, hypertension, and diabetes mellitus. This article did not discuss the level of sympathectomy; however, it did mention gustatory sweating after angina treatment which implies a high level of sympathectomy.3 Following this initial work, thoracoscopic sympathectomy was used for vascular insufficiencies and cardiac arrhythmias in the 1980s and 1990s. However, other less invasive treatments, such as beta blockers, have supplanted sympathectomy for the treatment of cardiac arrhythmias. The durability of benefits for peripheral vascular problems has not been consistently demonstrated.4–5
Today, thoracoscopic sympathectomy is used mostly for hyperhidrosis and occasionally for complex pain syndromes.
Sympathetic Chain Physiology The sympathetic chain is a paired bundle of nerves that runs just parallel to the vertebral bodies down to the second lumbar level. In the chest, they are located over the costovertebral junctions posteriorly and the stellate ganglion located at the T1 level. The stellate ganglion mostly innervates the face and pupils. This level must be preserved to avoid Horner’s Syndrome after sympathectomy. Currently, the second and third thoracic levels are felt to primarily innervate the upper extremities and are considered the appropriate level for palmar hyperhidrosis, while T3 and T4 are levels felt primarily to involve the axilla.6 The sympathetic ganglion cells are activated mainly by stimuli received through afferent preganglionic neurons in the spinal cord. The activated sympathetic stimulus is conducted from the spinal cord to the sympathetic ganglion via the intercostal nerves sequentially.7 Sympathetic nervous fibers originate from the intermediolateral horns of the spinal cord between T1 and L2. Each pathway consists of pre- and post-ganglionic neurons. The nerve fibers distributing to the sweat glands are post-ganglionic fibers arising from the ganglia in the sympathetic trunks. These nerves then come together with the corresponding spinal
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nerves in the target organ. In the sympathetic trunks, signals may travel up or down before exiting and distributing to the target organ. Therefore, distributions will overlap and are not necessarily to the same part of the body from the corresponding spinal segment. The autonomic nervous system functions through positive and negative feedback mechanisms. First, the hypothalamus is triggered by a stimulus and sends signals to the sweat glands through the autonomic nervous system. Nervous impulses from the target organs are transmitted as afferent negative feedback signals to the hypothalamus by way of the sympathetic trunk. It is hypothesized that if the T2 level is interrupted by sympathectomy, the negative signals cannot reach the central nervous system, which results in preponderance of uninterrupted positive signals from hypothalamus to the target organ. Therefore, efferent positive feedback signals to the sweat gland are strong, thus causing more severe compensatory sweating to occur.8,9 If the interruption is in lower levels such as T4, negative signals coming from T2 and T3 are preserved to create some negative signals in the hypothalamus, which results in less potent positive stimulus to the target organ resulting in less severe compensatory sweating. As will be discussed in this review, the literature now advocates the interruption of the sympathetic chain at lower levels in order to decrease the incidence of compensatory sweating.9 Based on current data, the optimal level of operation for different areas of hyperhidrosis were investigated for procedural success, longterm satisfaction and complications.
Method A search of medical literature using PubMed was performed. All randomized controlled trials as well as observational studies conducted on human subjects in English language from 1990 to 2009 were reviewed. Different combinations of keywords, including “sweating, hyperhidrosis, level, sympathectomy, compensatory, satisfaction, outcomes” were used to reach the relevant articles. Once relevant articles were identified, manuscripts and abstracts were reviewed. Papers describing
sympathectomy operations for other or mixed indications and those with very low number of subjects were excluded.
Palmar Hyperhidrosis Excessive sweating from the palms and soles can be quite debilitating both socially and professionally. Sympathectomy has been performed on individuals with disabling, recalcitrant palmar hyperhidrosis since 1920. Sympathectomy typically involves the surgical destruction of the second and/or third thoracic ganglia. Cauterization and/or clipping at these levels leads to a satisfaction rate of 94–98%.10 Complications and side effects of thoracoscopic sympathectomy include recurrence of hyperhidrosis, gustatory sweating, and compensatory sweating. Rarely one can see a Horner’s syndrome, neuralgia, or a pneumothorax. Of all the complications and side effects associated with sympathectomy, compensatory sweating is the most common problem that leads to patient dissatisfaction. There has been much debate and study regarding the appropriate level for the sympathectomy to be performed. Yazbek and Wolosker et al. studied 60 patients in a prospective randomized controlled study, comparing the results of T2 versus T3 transection. Sympathectomy included transection as well as thermoablation. The patients in both groups had palmar anhydrosis on return visits at 1 month and 6 months. One month after the operation, compensatory sweating was observed in 26 of 30 patients in the T2 group and in 27 of the T3 group. Six months after the operation all the patients in the T2 group had some degree of compensatory sweating as did all but one patient in the T3 group.11 In their follow up publication at 20 months, all patients exhibited compensatory sweating. The degree of severity was recorded and, overall, the patients in the T3 group presented with a lower degree of compensatory sweating at each assessment level. Quality of life assessments were also performed at each time interval and the quality of life for all patients was much improved postoperatively. There was no significant difference between the two groups (p = 0.76).12 Yoon and Rim, in a prospective study, compared transection at T2–3 (Group A) to level T3 only
55. Patient Selection and Optimal Extent of Surgery for Hyperhidrosis
(Group B). Their mean follow up was 17.8 months in group A versus 16.6 months in group B. Compensatory sweating was present in 45% of Group A patients versus 16% in group B. At the end of the study 66% of T2–3 (Group A) patients versus 87% of T3 only (Group B) patients were satisfied with their results. This difference was statistically significant.13 In a similar study, Katara et al., performed a prospective randomized blinded study, comparing ablation of the T2 ganglion on one side with ablation of T2 and T3 on the other in each patient. The mean follow up was 23 months. There was no difference in the results with regard to efficacy (100% success), recurrence (no cases), frequency of compensatory sweating (80%), severity of the compensatory sweating (no severe cases, 20% moderate cases, no interference with the quality of life), and satisfaction subsequent to the procedure (>80%).14 Miller et al. retrospectively analyzed 282 patients who underwent sympathectomy at the T2 level or T2 through T4 for palmar hyperhydrosis. Ninetynine percent of the cases experienced therapeutic success. The patients in the multilevel group had significantly worse compensatory sweating than the T2 level only group. Multivariate logistic regression analysis showed that higher BMI, multiple levels of sympathectomy, and older age were the three factors most predictive of compensatory sweating. Satisfaction rate were similar between the groups. These findings suggest that a multi level sympathectomy resulted in more compensatory hyperhidrosis than single level sympathectomy.15 In a retrospective review of 234 patients, 86 patients were treated by T2 level sympathectomy, 70 patients by endoscopic thoracic sympathectomy (ETS) at T3, and 78 patients by T4 level sympathectomy. Overly dry hands were reported in 36% at T2, 39% at T3 and 8.6% at T4. Overall, 88.5% of patients noted compensatory sweating and the incidence in each group was 92%, 92%, and 80% respectively (p < 0.05). The most common region for compensatory hyperhidrosis was the back, occurring in 56.3%, 75%, and 42.9%, respectively. The group having the T4 sympathectomy had the lowest incidence and least severe compensatory sweating of the three groups. Most patients were satisfied with the results of surgery, especially in groups T3 and T4. Generally, the higher the level of transection, the greater the incidence of compensatory
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sweating. No one in the T3 group or the T4 group expressed regret for having undergone the surgery, while 11 people in the T2 group expressed some unhappiness. The incidence of overly dry hands was significantly higher in T2 and T3 groups compared to the T4 group. It seemed that T4 ETS for palmar hyperhidrosis had the least post-operative complications, including palmar over dryness, presence of CS, and regions of CS. These results led the authors to suggest T4 as the ideal level for sympathectomy.6 Yazbek and Wolosker also investigated lower levels of sympathectomy for palmar hyperhidrosis in another prospective study comparing the T3 level to the T4 level. They failed to achieve anhydrosis in all patients. After 6 months, hyperhidrosis improved in all patients, but anhydrosis was achieved in only 26/35 patients in the T3 group and 8/35 patients in the T4 group. All patients had significant reduction in sweating, however, and compensatory sweating at 6 months was 100% in the T3 group versus 71% in the T4 group (P < 0.05). Quality of life assessments were similar in both groups. The authors concluded that the T4 level is acceptable for palmar hyperhidrosis as long as the patient is made aware that their hyperhidrosis will improve but not be eliminated.16 Yang et al., in a prospective randomized study, compared T3 sympathectomy to T4 sympathectomy in 163 patients with palmar hyperhidrosis. All patients were cured, and there was no recurrence of palmar hyperhidrosis in a mean followup of 13.8 months. The rate of mild compensatory sweating was not statistically different; however, the incidence of more severe compensatory sweating was significantly lower in the T4 group.17 As a result, it appeared that the lower level sympathectomy (T4) led to a reduction in major compensatory sweating (Table 55.1). As can be appreciated from the above review of the literature, the appropriate level of sympathectomy has been a hot topic of debate. Several studies have evaluated the clinical outcomes at each level. Initially, it was recommended that a T2 or T2–3 sympathectomy is the appropriate level for palmar hyperhidrosis. However, there is a growing body of evidence that suggests lower levels of sympathectomy for palmar hyperhidrosis may produce better patient satisfaction as a result of less compensatory sweating. It is our finding, after
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474 Table 55.1. Summary for palmar hyperhidrosis. Author
Year
Yazbek Yazbek11 Yoon13 Yoon13 Katara14 Katara14 Miller15 Miller15 Chang6 Chang6 Chang6 Wolosker16 Wolosker16 Yang17 Yang17 11
2005 2005 2003 2003 2007 2007 2009 2009 2007 2007 2007 2008 2008 2007 2007
Level T2 T3 T2–3 T2 T2 T2–3 T2 T2–4 T2 T3 T4 T3 T4 T3 T4
Dry (%) 100 96.6 100 100 100 100
74.4 92.3 77.1
100 100
CH (%)
Satis (%)
86 90 45 16 80 80 13* 34* 92 92* 80* 100* 71* 23* 7.1*
Regret (%)
66* 87*
9.3* 3.8* 0*
Number 30 30 24 30 25 25 179 103 86 78 70 35 35 78 85
F/U 6 months 6 months 17.8 months 17.8 months 23 months 23 months 1 months 1 months 60.9 months 35.6 months 43.1 months 6 months 6 months 13.8 months 13.8 months
Type Pros Pros Pros Pros Pros Pros Retro Retro Retro Retro Retro Pros Pros Retro Retro
Statistically significant. Pros Prospective; Retro Retrospective; Satis Satisfaction.
*
reviewing the literature, that a single level T2, T3 or T4 sympathectomy will produce excellent results in eliminating palmar hyperhidrosis and is safe; however, those done at T3 or T4 will limit the severity of compensatory sweating and avoid overly dry hands after surgery (evidence quality high).9–21 We strongly recommend a T3 or T4 level sympathectomy for palmar hyperhidrosis, with the T4 level producing less anhydrosis but also less compensatory sweating (recommendation grade 1B).
Axillary Hyperhidrosis Over the last 2 decades the technique for treating axillary hyperhidrosis has evolved. Higher success rates are attributed to technique as well as careful patient selection. Complications and side effects of sympathectomy are similar to those for palmar hyperhidrosis, and compensatory sweating continues to be an important concern after surgery. In addition, recurrent hyperhidrosis is more prevalent for axillary problems than for palmar hyperhidrosis.22 In a retrospective cohort study, Hsu et al. reviewed their experience with 171 patients treated for axillary hyperhidrosis. They divided patients into three groups: T3–T4 sympathectomy in Group 1, T4
sympathectomy in Group 2, and T4-T5 sympathectomy in Group 3. The incidence of overly dry hands was significantly higher in the T3–T4 group. A 70% compensatory sweating incidence was noted in the T3–T4 group compared to 29% in the T4 and T4–T5 groups. In s questionnaire satisfaction was rated as excellent, good and poor. The poor result rate was 32%, 30%, and 15% respectively. This result suggested a significant role for preservation of the T3 level in the prevention of compensatory sweating, thus resulting in superior outcomes.23 This same group of authors published another report in 2003, 2 years after their first study, and re-evaluated the T3–4 level sympathectomy. This time they added “fair” between “good” and “poor” in their questionnaire. This time the “poor” rate was 9%, and the “fair” rate was 21%. In both studies the success rate was significantly lower than seen in palmar hyperhidrosis cohorts.24 Munia et al. performed a randomized, prospective study to compare the results of sympathectomy at T3–T4 versus T4 for axillary hyperhidrosis. The study reviewed the efficacy of treatment, presence and severity of compensatory sweating, and patient satisfaction over a 1 year time period. There were no treatment failures at 1 year follow up. A total of 64 patients with pure axillary hyperhidrosis were randomized between the two treatment levels. In the T3–T4 group, sympathectomy was performed
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55. Patient Selection and Optimal Extent of Surgery for Hyperhidrosis
on the bodies of the third, fourth, and fifth ribs, followed by a thermoablation of the segment between them. Patients in the T4 group underwent resection of the chain at the fourth and fifth ribs, with thermoablation of the segment between them. The incidence of compensatory sweating was lower in the T4 group at 1, 6 and 12 months follow-up. The T4 group experienced compensatory sweating in 57.6%, while the T3–T4 group experienced it in 93.5% at 1 year. Sites of compensatory sweating were the abdomen, back, and/or legs. Compensatory sweating was less severe in the T4 group and there were no severe cases by the final follow-up at 12 months. Thirty-five percent of the T3–T4 patients showed moderate to severe compensatory sweating, while only 12.5% of the T4 group had this same problem. The incidence and severity of compensatory hyperhidrosis in patients who underwent T3–T4 resection remained constant over the 12 month follow-up interval, while there was decrease in the incidence in the T4 group from 6 to 12 months (p < 0.05). Overall, patients in the T4 group reported higher post-operative satisfaction than those of the T3–T4 group (p < 0.05). It must be noted, however, that both groups showed that the procedure improved their quality of life. Munia et al. concluded that sympathectomy from the upper margin of the fourth rib to the lower margin of the fifth rib followed by thermoablation of the chain, resulted in good success and acceptable compensatory sweating.25 Montessi et al. performed a retrospective review of 521 cases comparing different levels of ablation. These patients were divided into three groups: sympathectomy extending superiorly to T2 (Group I),
to T3 (Group II), or to T4 (Group III). Post-operative control of axillary hyperhidrosis was achieved in 82% of group I, 89% of group II, and 80% of group III. Severe compensatory sweating occurred in 32% of group I, 9% of group II and 4% of group III. While patient satisfaction was high across the board, there was a decrease in incidence and severity of compensatory sweating with lower levels of ablation. They also performed an extensive review of the literature and concluded that the T4–T5 level for axillary hyperhidrosis was preferred.26 Doolabh et al., in their retrospective study, reported a 98% success rate for axillary hyperhidrosis by removing the T4 level. This was inconsistent with many prior reports and may be because the majority of the patients also had a palmar component to their disease that was relieved, resulting in a higher satisfaction rate than is typically seen in axillary hyperhidrosis alone27 (Table 55.2). Overall, the literature on axillary hyperhidrosis is not as consistent as it is for palmar hyperhidrosis. There is a considerable failure rate in many publications, especially the ones with isolated axillary hyperhidrosis.22–28 Fewer surgeons offer sympathectomy for axillary hyperhidrosis, and this results in a smaller number of studies to analyze.2 An alternative treatment for axillary hyperhidrosis is the removal of the axillary sweat glands. Sympathectomy is much less invasive and typically is tried first for patients with axillary hyperhidrosis. While the precise level to recommend is still not proven, the recent body of evidence supports that sympathectomy at the T4 and T5 levels is reasonably effective and is safe (evidence quality low). We make a weak
Table 55.2. Summary of axillary hyperhidrosis. Author
Year
Level
HSU23 HSU23 HSU23 Hsia24 Munia25 Munia25 Montessi26 Montessi26 Montessi26 Dooblah27
2001 2001 2001 2003 2008 2008 2007 2007 2007 2004
T3–4 T4 T4–5 T3–4 T3–4 T4 T2 T3 T4 T4
Dry (%)
82 89 80 99
CH (%)
Satis (%)
Regret (%)
Number
70 29 29 65 54* 93* 32* 9* 4*
68* 70* 85*
32 30* 15* 9 16* 0*
40 56 75 262 31 33 99 total 99 total 99 total 55
F/U
Type
42 months 12 months 12 months
Retro Retro Retro Retro Pros Pros Retro Retro Retro
17 months
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recommendation for T4 or T5 sympathotomy for management of axillary hyperhidrosis (recommendation grade 2B).
Craniofacial Hyperhidrosis and Blushing Craniofacial hyperhidrosis can be quite debilitating for many patients. Sympathectomy has been used as a viable approach to the problem; however, it has also been reported to be associated with higher levels of patient dissatisfaction compared to palmar and axillary hyperhidrosis. Evidence of effectiveness of sympathectomy is weak due to the lack of randomized trials.29 Several studies have evaluated methods to decrease the incidence of compensatory sweating; however, due to the close proximity and association of the T2 ganglion with the T1 ganglion, this has been difficult to achieve. In 2004, Kim et al., reviewed a total of 44 sympathectomies for facial sweating. Twenty-two underwent T2 clipping (Group 1) and 22 underwent division of the T2 rami-communicates (Group 2). The goal of raminectomies was to preserve the sympathetic trunk and eliminate compensatory sweating after surgery. They retrospectively analyzed the rate of satisfaction, facial dryness, and grade of compensatory sweating. Both groups were similar with respect to facial dryness (P = 0.099). Group 1: excessive dryness occurred in 5 patients (22.7%) and dryness in 17 patients (77.3%); Group 2: excessive dryness occurred in three patients (13.6%), dryness in 15 patients (68.1%), and persistent sweating in four patients (18.3%). The rate of satisfaction was 77.3% in Group 1 and 63.6% in Group 2, which was not statistically significant (P > 0.05). The rate of compensatory sweating in Group 2 (72.7%) was significantly lower than in Group 1 (95.4%) (P = 0.039). The chance of embarrassing and disabling compensatory sweating was lower in Group 2 (76.5% overall; embarrassing in eight patients, disabling in nine) than in Group 1 (36.4% overall; embarrassing in seven patients, disabling in one; P = 0.006). They concluded that conservation of the sympathetic trunk and performing raminectomies causes less compensatory hyperhidrosis after surgery, which could translate into a higher level of patient satisfaction.30
S.R. Hazelrigg et al.
Kao and coworkers evaluated their results with 30 patients who were operated on for facial hyperhidrosis. They all underwent T2 level ablations with electrocautery. One patient had ptosis that resolved at 2 months. The mean follow up was 15 months. All patients were satisfied with the results. Most patients experienced CS of some degree. Doolabh et al. reported a similar success rate in their small series of 39 patients with facial hyperhidrosis, with a 95% satisfactory rate.31 Severe facial blushing is usually brought on by emotional or social stimuli and can often have a serious negative impact on the individual. These patients may experience both facial blushing and upper limb hyperhidrosis. Adair et al. retrospectively reviewed 59 patients with complaints of facial blushing and/or upper limb hyperhidrosis. Twelve of these patients experienced only facial blushing. All patients had T2–T3 level sympathectomies. Overall, the level of facial blushing score was reduced from 78 to 26 on a 100-point visual analog scale. Only 29% of the patients reported complete resolution of their symptoms. Ninetyone percent of the facial blushing group experienced compensatory sweating. All 12 patients with facial blushing alone noted improvement in their blushing post-operatively, with four experiencing complete resolution of symptoms. Sixty-three percent of the patients reported their overall quality of life to be much better, while 13% reported their quality of life to be worse. This study, along with several others, recommended that careful selection of patients and conversations regarding the high likelihoods of compensatory sweating are keys to success.32 The results were similar to the those of a large retrospective study by Drott and coworkers. They analyzed results in 1314 consecutive patients treated for facial blushing by resection of the T2 level only. They followed 891 of these patients for mean of 29 months, and facial blushing scores dropped from 8.8 to 2.5 (10-point visual analog scale). Six percent regretted the procedure because of severe compensatory sweating, and 15% of the patients were not satisfied after the procedure33 (Table 55.3). Lower sympathectomy levels and their impact on facial sweating and hyperhidrosis have not been studied in detail. The majority of the articles emphasize a high incidence of compensatory sweating resulting in many patients having regrets
477
55. Patient Selection and Optimal Extent of Surgery for Hyperhidrosis Table 55.3. Summary of facial blushing and hyperhidrosis. Author
Year
Level
Kim Kim30 Kao31 Adair32 Drott33
2004 2004 1996 2005 2003
T2 T2 rami T2 T2–3 T2
30
Dry
CH (%)
Satis (%)
76.5 36.4
77 63* 100 63 6
91 85
after surgery. This is consistent with T2 level resections, as was discussed earlier in this chapter. Chou et al. reviewed their experience with sympathectomy at the T3 level for facial sweating in 33 patients. After surgery minor facial sweating function was preserved, but the compensatory sweating incidence was only 27.3%. Three patients (9%) expressed regret. The authors also assessed facial sweating function in their patients who had T4 level removed for palmar or axillary hyperhidrosis. They found that at this level (T4) the facial sweating function was entirely preserved.9 Overall these studies on facial sweating and blushing have demonstrated that sympathectomy is quite safe and associated with low complication rates. The nagging problem remains the high incidence of compensatory sweating which lowers patient satisfaction rates. At the facial level, because of this lower success rate and higher incidence of compensatory sweating, patient selection is important. Psychologically stable, well informed patients with debilitating facial sweating and blushing are reasonable candidates. Risks should be carefully discussed prior to surgery. The success rate is in the 70–90% range according to the literature; however, more data are needed for an adequate evaluation of surgery for facial hyperhidrosis. Clipping instead of dividing the sympathetic chain may be a better solution for facial hyperhidrosis because of its reversibility. Chou et al. reported successful reversal of compensatory hyperhidrosis by removing clips in severely regretful patients.34 Sympathectomy at the T2 or T3 level for facial hyperhidrosis provides reasonable improvement in original symptoms and is safe, but results in a moderate level of patient dissatisfaction owing to compensatory sweating (evidence quality low). We make a weak recommendation for T2 or T3 sympathectomy for facial hyperhidrosis in carefully selection patients (recommendation grade 2C).
Regret
*
13%
Number 22 22 30 59 891
F/U
15 months 20 months 29 months
Type Pros pros Retro Retro
Single level T2, T3 or T4 sympathectomy produces excellent results in eliminating palmar hyperhidrosis and is safe; those done at T3 or T4 limit the severity of compensatory sweating and avoid overly dry hands after surgery (evidence quality high).9–21 We strongly recommend a T3 or T4 level sympathectomy for palmar hyperhidrosis (recommendation grade 1B).
Recent evidence demonstrates that sympathectomy at the T4 or T5 levels for isolated axillary hyperhidrosis is reasonably effective and is safe (evidence quality low). We make a weak recommendation for T4 or T5 sympathotomy for management of axillary hyperhidrosis (recom mendation grade 2B).
Sympathectomy at T2 or T3 for facial hyperhidrosis provides reasonable improvement in symptoms and is safe, but results in a moderate level of patient dissatisfaction owing to compensatory sweating (evidence quality low). We make a weak recommendation for T2 or T3 sympathectomy for facial hyperhidrosis in carefully selection patients (recommendation grade 2C).
References 1. Strutton D. Kowalski J, Glaser D, Stang PE. US Prevalence of hyperhidrosis and impact on Individuals with axillary hyperhidrosis: results from a national survey. J AM Acad Dermatol. 2004;51:241–248. 2. Baumgartner FJ. Surgical approaches and techniques in the management of severe hyperhidrosis. Thorac Surg Clin. 2008;18:167–181. 3. Kux E. The endoscopic approaches to the vegetative nervous system and its therapeutic possibilities. Dis Chest. 1951;20:139–147.
478 4. Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A Jr. The long QT syndrome: a prospective international study. Circulation. 1985;71:17–21. 5. Sayers RD, Jenner RE, Barrie WW. Transthoracic endoscopic sympathectomy for hyperhidrosis and Raynaud’s phenomenon. Eur J Vasc Surg. 1994;8:627–631. 6. Chang Y-T, Li H, Lee JY, Lin PJ, Lin CC, Kao EL, Chou SH, Huang MF. Treatment of palmar hyperhidrosis T4 level compared with T3 and T2. Ann Surg. 2007;246:330–336. 7. Gray H. The sympathetic nerves. In: Lewi WH, ed. Anatomy of the Human Body. 20th ed. Philadelphia, PA: Lea & Febiger; 2000:1292–1299. 8. Dumont P. Side effects and complications of surgery for hyperhidrosis. Thorac Surg Clin. 2008;18:193–207. 9. Chou SH, Kao EL, Lin CC, Chang YT, Huang MF. The importance of classification in sympathetic surgery and a proposed mechanism for compensatory hyperhidrosis: experience with 464 cases. Surg Endosc. 2005;20:1749–1753. 10. Reisfeld R, Nguyen R, Pnini A. Endoscopic thoracic sympathectomy. Surg Laparosc Endosc Percutan Tech. 2000;10:5–10. 11. Yazbek G, Wolosker N, Campos JRM, Kauffman P, Ishy A, Puech-Leão P. Palmar hyperhidrosis - which is the best level of denervation using video assisted thoracoscopic sympathectomy: T2 or T3 ganglion? J Vasc Surg. 2005;42;281–285. 12. Yazbek G, Wolosker N, Kauffman P, Campos JRM, Leao PP, Jatene FB. Twenty months evolution following sympathectomy on patients with palmar hyperhidrosis: sympathectomy at T3 level is better than T2 level. Clinics (Sao Paulo). 2009;64;8:743–749. 13. Yoon SH, Rim DC. The selective T3 sympathectomy in patients with essential palmar hyperhidrosis. Acta Neurochir. 2003;145:467–471. 14. Katara AN, Domino JP, Cheah WK, So JB, Ning C, Lomanto D. Comparing T2 and T2-T3 ablation in thoracoscopic sympathectomy for palmar anhydrosis: a randomized control trial. Surg Endosc. 2007;21: 1768–1771. 15. Miller DL, Bryant AS, Force SD, Miller JI Jr. Effects of sympathectomy level on the incidence of compensatory hyperhidrosis after sympathectomy for palmar hyperhidrosis. J Thorac Cardiovasc Surg. 2009;138: 581–585. 16. Wolosker N,Yazbek G, Ishy A, de Campos JR, Kauffman P, Puech-Leão P. Is sympathectomy at T4 level better than at T3 level for treating palmar hyperhidrosis? J Laparoendosc Adv Surg Tech. 2008;18:102–106. 17. Yang JJ, Tan JJ, Ye GL, Gu WQ, Wang J, Liu YG. T3/T4 thoracic sympathectomy and compensatory sweating in treatment of palmar hyperhidrosis. Chin Med J. 2007;120:1574–1577. 18. Bonjer HJ, Hamming JF, du Bois NAJJ, van Urk H. Advantage of limited thoracoscpic sympathectomy. Surg Endosc. 1996;10:721–723. 19. Riet M, Smet AA, Kuiken H, Kazemier G, Bonjer HJ. Prevention of compensatory hyperhidrosis after thoracoscopic sympathectomy for hyperhidrosis. Surg Endosc. 2001;15:1159–1162.
S.R. Hazelrigg et al. 20. Neumayer C, Zacherl J, Holak G, Függer R, Jakesz R, Herbst F, Bischof G. Limited endoscopic thoracic sympathetic block of hyperhidrosis of the upper limb: reduction of compensatory sweating by clipping T4. Surg Endosc. 2004;18:152–156. 21. Choi BC, Lee YC, Sim SB. Treatment of palmar hyperhidrosis by endoscopic clipping of the upper part of the T4 sympathetic ganglion. Clin Auton Res. 2003; 13:48–51. 22. Naumann M, Hamm H. Treatment of axillary hyperhidrosis. Br J Surg. 2002;89:259–261. 23. Hsu CP, Shia SE, Hsia JY, Chuang CY, Chen CY. Experiences in thoracoscopic sympathectomy for axillary hyperhidrosis and osmidrosis: focusing of extent of sympathectomy. Arch Surg. 2001;136: 1115–1117. 24. Hsia JY, Chen, CY, Hsu CP, Shai SE, Yang SS, Chuang CY. Outpatient thoracoscopic sympathectomy for axillary osmidrosis. Eur J Cardiothorac Surg. 2003;24: 425–427. 25. Munia MAS, Wolosker N, Kaufmann P de Campos JR, Puech-Leão P. Sustained benefit lasting one year from T4 instead of T3-T4 sympathectomy for isolated axillary hyperhidrosis. Clinica. 2008;63:771–774. 26. Montessi J, de Almedia P, Vieira JP, Abreu Mda M, Souza RL, Montessi OV. Video-assisted sympathectomy in the treatment of primary hyperhidrosis: a retrospective study of 521 cases comparing different levels of ablation. J Bras Pneumol. 2007;33:248–254. 27. Dooblah N, Horswell S, Williams, Huber L, Prince S, Meyer DM, Mack MJ. Thoracoscopic sympathectomy for hyperhidrosis: indications and results. Ann Thorac Surg. 2004;77:410–414. 28. Licht PB, Jorgensen OD, Ladegaard L, Pilegaard HK. Thoracoscopic sympathectomy for axillary hyperhidrosis: the influence of T4. Ann Thorac Surg. 2005; 80:455–460. 29. Malmiwaara A, Kuukasjarvi P, Autti-Ramo I, Kovanen N, Mäkelä M. Effectiveness and safety of endoscopic thoracic sympathectomy for excessive sweating and facial blushing: A systematic review. Int J Technol Assess Health Care. 2007;23:54–62. 30. Kim DH, Paik HC, Lee DY. Comparative analysis of T2 selective division of rami-communicantes (ramicotomy) with T2 sympathetic clipping in treatment of craniofacial hyperhidrosis. Eur J Cardiothorac Surg. 2004;26:396–400. 31. Kao MC, Chen, YL, Lin JY, Hsieh CS, Cheng LC, Huang SJ. Endoscopic sympathectomy treatment for craniofacial hyperhidrosis. Arch Surg. 1996;131: 1091–1094. 32. Adair A, George ML, Camprodon R, Broadfield JA, Rennie JA. Endoscopic sympathectomy in the treatment of facial blusing. Ann R Coll Surg Engl. 2005; 87:358–360. 33. Drott C, Claes G, Rex L. Facial blushing treated by sympathetic denervation - long lasting benefits in 831 patients. J Cosmet Dermatol. 2003;1:115–119. 34. Lin TS, Chou MC. Needlescopic thoracic sympathetic block by clipping for craniofacial hyperhidrosis. Surg Endosc. 2002;16:1055–1058.
Part 8
Chest Wall
56
Pectus Excavatum in the Adult: Current Treatment Modalities Dawn E. Jaroszewski, Jason D. Fraser, and David M. Notrica
Introduction
Methods
Pectus excavatum (PE) is a posterior depression of the sternum and adjacent costal cartilages accounting for more than 90% of congenital chest wall deformities.1,2 With inward compression and decreased chest volume, PE can be more than a cosmetic deformity. Severe cases frequently result in exercise intolerance and physiologic cardiopulmonary impairment. Often patients with PE are dismissed by their physicians as having an inconsequential cosmetic problem. This misconception has resulted in many patients reaching adulthood with uncorrected severe defects. With the advent of internet-based information sources and the lure of less invasive repair techniques, many adult patients with uncorrected PE are now seeking surgical repair. There is some evidence that a true physiologic impairment associated with the defect may worsen as the patient ages. Cardiopulmonary symptoms may develop in the adolescent; however, others may only develop symptoms with aging. The physiologic data documenting improved cardiopulmonary function and psychosocial function after repair in adults is limited by small sample sizes. Although many studies and a meta-analysis now support repair of PE in the adolescent, only a few studies in adults document physiologic impairment. This chapter reviews the available adult literature regarding treatment of PE in the adult patient.
A literature search was performed using Pubmed, EMBASE and OVID for English publications relevant to pectus excavatum deformity, surgical repair, and surgical repair of the adult patient. Articles were restricted to the English language and publication dates 1980–2009.
Effects of PE Symptomatic PE presents in a variety of ways. Exercise intolerance, fatigue, dyspnea on exertion, and compensatory tachypnea are noted in the majority of symptomatic patients.1,3–9 Many patients are asymptomatic at a younger age but start experiencing symptoms as they age.10–19 Despite multiple studies, demonstration of a correlation of physiological impact with the symptoms of PE has been inconsistent. An increased work of breathing may result from a mildly or segmentally restricted chest wall combined with impaired oxygen delivery. Sternal compression is suspected to decrease the thoracic volume, which can reduce the SVO2, exercise tolerance, tidal volume and vital capacity. The decreased volume may cause subjective dyspnea, decreased endurance, and compensatory tachypnea during exercise.20–24 An impaired ability to increase cardiac output may also result from PE
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_56, © Springer-Verlag London Limited 2011
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due to a decreased venous return to the right heart. Direct cardiac compression has been shown to reduce stroke volume and cardiac output in severe deformities, causing accelerated fatigue and compensatory tachycardia.21–24 Poor body image and impaired psychosocial function are additional important concerns for surgical repair.3 Visible physical differences may increase the PE patient’s risk for body image and interpersonal difficulties.25–27 Physicians need to consider the physiologic and psychological implication of PE just as they would any other physical deformity.
Patient Evaluation The presentation of a patient with clinically symptomatic PE warrants a thorough workup to access the significance of the defect and determine whether the patient should be considered for repair. A complete history and physical examination, including auscultation of the heart for murmurs and examination for physical findings suggestive of Marfan syndrome is critical. A systolic cardiac murmur is sometimes heard and mitral valve prolapse is found in as many as 25–44% of patients.1,7,9,20,23 The percentage of pectus patients with mitral valve prolapse appears to increase with age.1,23 Other useful tools for evaluation include a noncontrast computerized tomographic (CT) scan of the chest for evaluation of the severity of the defect, cardiac compression or displacement and other potential pathology. The normal pectus index after maturity is 2.2 +/–0.1 in males and 2.4 +/– 0.1 in females and an index of 3.2 or greater is considered severe.20,28 In adult patients, a 12-lead electrocardiogram is necessary to exclude intracardiac conduction abnormalites, dysrhythmias (first-degree heart block, right bundle block and Wolff Parkinson-White syndrome), or evidence for ischemia. A transthoracic or transesophageal echocardiogram is useful to document the effect of the depressed sternum on the right atrium and right ventricle as well as associated interference with diastolic filling.1,5,7,8 Identifying valvular abnormalities, including mitral valve prolapse and evaluation of the aortic root and
D.E. Jaroszewski et al.
valve is especially critical in suspected or confirmed Marfan syndrome. Both static and exercise pulmonary function tests in the adult patients may demonstrate depressed pulmonary function, whether from poor cardiac function or from the extrinsic compression and resultant loss of lung volume. Static pulmonary function tests are the least sensitive but may show restrictive airway disease or obstructive airway disease with decreases in forced vital capacity and maximal ventilatory volumes.1,5,21 Despite significant symptoms and severe PE, many patients will have a normal or low normal static pulmonary function test. Cardiopulmonary exercise testing (CPET) has been very useful in the evaluation of PE and may show an O2 pulse (mL/beat) and amount of delivered oxygen (VO2 L/min and VeL/min) significantly below predicted values in patients with PE.3,6,21,29 CPET testing allows for examination of the integrative responses of the cardiovascular and ventilatory response to maximal incremental exercise.30 Impairment of oxygen transport or cardiac performance can result in decreased exercise tolerance.30,31 Low normal and below normal values may indicate that surgical correction could benefit the patient. Unfortunately, CPET use and interpretation relating to PE is not widely available.
Current Controversies Regarding PE Repair in the Adult Consideration of surgical treatment of the adult PE patient should be given for severe anatomic deformities and patients with symptoms attributable to PE. Patients demonstrating two or more of the criteria listed in Table 56.1 are considered for surgical correction.1,3–5 The two most common methods for repair include modifications of the open chondrectomy approach and the minimally invasive repair of pectus excavatum (MIRPE). Modifications of the open repair as described by Ravitch have been used for decades and are still used.13,14,32–36 The open repair involves, to varying degrees, resection of the deformed costal cartilage. Usually an incision is made over the sterum and subpectoral muscle flaps are created bilaterally
56. Pectus Excavatum in the Adult: Current Treatment Modalities Table 56.1. Indications for surgical correction of pectus excavatum. Symptomatic progression of the deformity Paradoxical movement of the chest wall with deep inspiration CT with severity index greater than or = 3.2 Cardiac compression or displacement Pulmonary compression Abnormal pulmonary function studies showing significant restrictive lung disease Mitral valve prolapsed Any cardiac pathology secondary to compression of the heart Significant body image disturbance Abnormal cardiopulmonary testing
over the affected ribs. The deformed costal cartilage along the length of the pectus defect is freed from the perichondrium and resected. Additional options include sternal osteotomy with or without sternal turnover in an anterior-to-posterior manner or the use of mesh. The majority of procedures include placement of a metal strut to support the sternum, which may be left in place for 6 months to a year. Proponents of the open technique claim lower cost, shorter hospitalization and less post operative pain.13,14,33–36 It is ideal for patients who have a combination of PE and carinatum, significant asymmetry, or extensive defects involving the upper ribs and cartilage. In the adult patient with a fixed, calcified chest wall this may be the best surgical option. MIRPE was described by Nuss et al. in 1998.37 This method of repair involves positioning a bar behind the sternum. The curved bar is passed in a U-position under the sternum and rotated into an inverted-U position to elevate the sternum outward The bar is supported by the anterior ribs on either side of the depression and fixed to the lateral ribs to avoid displacement. The advantages of the Nuss approach include shorter operative time, lower blood loss, avoidance of anterior chest scar, avoidance of rib cartilage resection, and avoidance of the sternal osteotomy. Incorporation of thoracoscopic techniques has made the operation safer, allowing visualization of the heart when the bar is passed between the sternum and heart. The major issues regarding management of PE in the adult that need to be addressed are: (1) does corrective surgery improve cosmesis; (2) does corrective surgery improve cardiopulmonary function; and (3) does MIRPE or open chondrectomy provide better results?
483
Cosmetic Results in the Adult Undergoing PE Repair Several recent publications have shown that MIRPE is readily performed in the adult population.9,11–12,14–19 The age at which MIRPE is no longer a good surgical option is unknown. In adults, placement of a second bar is often necessary and desirable to achieve optimal cosmetic results and to fully elevate the chest. Using two bars may also distribute the pressure between the bars so there is less risk of displacement.38 Reoperation for insertion of a second pectus bar to correct the development of a post operative depression of the upper sternum or for bar displacement was required in up to 14% of patients.9,10,15,19 Achieving 100% correction of the chest is best achieved with MIRPE in patients with symmetric deformities.12 In most series, the majority of the patients experienced a correction of >80% of their deformity and results are reported as good to excellent in 85–95% of adult patients repaired.9,12,19,36 Long-term results with follow up and risk for recurrences however have not been reported to date. The advantages of MIRPE include shorter operative time and avoidance of rib cartilage resections, sternal osteotomies, and conspicuous anterior chest scars. Patient satisfaction with the cosmetic results of the open repair are as good as or better than that of the MIRPE, with 90–95% of patients responding to questionnaires indicating that they considered the result following repair to be very good or excellent and would highly recommend repair of pectus to other patients.13,14,36 Adult patients with significant asymmetry associated with their deformity may benefit from open correction. However, many patients with an asymmetrical deformity prefer the minimal residual asymmetry rather than the larger, more conspicuous chest scar of the open operation.
Physiologic Improvement After PE Repair in Adults Whether surgical repair of the PE corrects physiologic performance is controversial in the pediatric population and virtually unknown for the
D.E. Jaroszewski et al.
484
adult.6,20,22 The adult patient’s perception of significant improvement of symptoms after repair has been the most convincing evidence for repair. Publications documenting post operative improvement in the adult are limited to quality of life surveys, subjective satisfaction reports and a small number of patients with documented relief of cardiac compression.6–9,13,20,22,25–27 Relief of symptoms is described in the vast majority of patients whether they were corrected by open repair or MIRPE. Resolution of the mitral valve prolapse and release of the chest wall entrapment is seen in most patients evaluated both pre-and post operative with either the MIRPE or the open surgery.6–9,13 There is a single case report showing improved CPET function post-open repair in a 78 year old PE patient with heart failure.6 Neither surgical procedure has been shown to be superior for improving physiologic impairment.
Complications after chondrectomy in adults with PE are similar to those of MIRPE without the associated incidents of bar displacement or rotation and include infection, effusion, pneumothorax, bleeding and pericarditis. Recurrence rates after repair of PE using the open technique have been reported in 1.3–6% of patients.13,14,33–3639 No high-quality reports comparing MIRPE to chondrectomy in adults have been published. A published comparison of surgical methods is limited to a small group of patients with complications reported for the MIRPE patients significantly higher than the Ravitch (35.7% vs. 14.3%).36 This comparison included a >28% rate of bar displacement that is nearly triple the rate incurred at other experienced centers. Tables 56.2 and 56.3 summarize the majority of publications for PE repair in the adult.
Conclusions and Recommendations Complications After PE Repair in Adults MIRPE in the adult patient has a significant learning curve with a high incidence of complications and recurrence reported in early series of patients.9,10,36 These complications included bar displacement, bar rotation, abscess formation, pneumothorax, effusions, pericarditis and bleeding. In a limited number of adult patients, increased infection rates, bar displacement and recurrence were reported for the adult population compared to the pediatric patients10,36 The incorporation of thoracoscopic techniques has made the operation safer in all age groups by allowing visualization of the heart when the bar is passed behind the sternum.17,19,20,38 Utilizing more than one support bar, the addition of lateral stabilizers and increasing post-operative time before bar removal to greater than 2 years seems to have significantly reduced frequency of complications. Recurrence rates as low as 2–5% have been reported for the MIRPE adult patients, however, follow up is on a small number of patients for limited time periods.11,12,16–19 The true rate of recurrence may not be known until further follow up results are available and will likely be close to those reported for open repair.
The treatment of PE deformity in adults continues to evolve as more data and surgical experience accrue. Both the MIRPE and open repair with chondrectomy appear to provide symptomatic relief, improved cardiovascular performance and good cosmetic results in appropriately selected patients. Based on the limited published literature, MIRPE in the adult has an acceptable and equivalent low complication rate in the adult patient compared to the open technique (evidence quality low).11–12,15–19 Although the data available are limited, we make a weak recommendation for surgical correction of PE in adult patients who have symptoms or documented cardiopulmonary insufficiency (recommendation grade 2B). Patients with life-long body image disturbance should also be considered for repair if the deformity is a significant deviation from normal (recommendation grade 2C).
A Personal View of the Data Although patients often have symptoms without documented impairment on static cardiac and pulmonary testing, we continue to advocate repair when the patient meets the above criteria because of the documented subjective improvement in
485
56. Pectus Excavatum in the Adult: Current Treatment Modalities Table 56.2. Surgical outcomes for repair of pectus excavatum in adults. Reference
Years of study
Mansour Coln9 Kim10
1971–2001 1998–2001 1999–2003
14
Schalamon11 Hebra12 Krueger8 Krasopoulos26 Jaroszewski13 Aronson15 Pilegaard16 Cheng17 Teh18 Olbrecht19 Antonoff36
2000–2005 1998–2006 1999–2004 2003–2004 1986–2007 1999–2005 2001–2007 2005–2007 1999–2004 1997–2006 2004–2008
Jaroszewski6
2007
Number of patients 77 8 27 12 12 43 30 17 20 279 35 180 96 19 107 56 Ravitch 14 Nuss 22 Leonard 1
Ages (years) 16–68 median 22 19–32 mean 24 <12 13–19 ³20 18–39 mean 22 18–32 mean 23 17–54 Mean 28 14–37 mean 18 19–67 mean 27 18–47 mean 23 18–43 mean 22 18–42 mean 24.5 17–42 mean 19.5 18–30 mean 23 23.4 Ravitch 19.5 Nuss 20.7 Leonard 78
Mean operative times (minutes)
Mean hospital stay (days)
No times 79.2 52.0 ± 22.9 80.4 ± 27.4 127.3 ± 44.9 70 60% of cases 1–2 h No times No times reported 191 65 41 80 126 82 110 ± 4 109 ± 8 111 ± 4
4 4 4.9 8.0 10 9.3 Not reported Not reported 6 2.9 7 5 7.2 5.8 3 2.2 3.9 1.5
No times reported
4
Table 56.3. Long-term outcomes of pectus excavatum repair in adults. Reference
Years of study
Patients with 2+ struts placed (%)
Mansour14
1971–2001
None
N/a
Coln9
1998–2001
None
4 of 8
Kim10
1999–2003
Ages: ≤12 0 13–19 75% ³20 92%
Patients followed with struts removed
23 9 4
Schalamon11 Hebra12
2000–2005 1998–2006
19 16
15 of 43 No follow up reported
Krueger8
1999–2004
N/a
No follow up reported
Krasopoulos26
2003–2004
5
No follow up reported
Results of study 90.9% relief of symptoms and excellent patient satisfaction. In 12 month follow-up, 1 recurrence. Complications occurred in 14.3% Relief of symptoms and increase in activity obtained in all patients. Relief of cardiac compression in 6 (all) patients. In 22 month follow-up, no recurrences Chest pain for more than 6 months was reported in 54.5% of adults. In follow up of 16.9 months, no adult recurrences. Significantly longer operating time and increased complication rate in adults compared to young patients In follow up of 5.4 months no, recurrences The complication rate appears to be similar to previously reported series of pediatric patients, and the results obtained were considered very good or excellent in the great majority of cases Intraoperative trans-esophageal echocardiography was performed before and after surgery. End-diastolic right ventricular diameter, area, and volume and left ventricular ejection fraction all significantly increased after surgical repair of pectus excavatum Confirmed the positive impact that the Nuss procedure had on physical and physiological well-being in the young adults in the study
Type of study
Evidence quality
Retrospective review of modified Ravitch
Low
Retrospective review of MIRPE
Low
Retrospective review of MIRPE with classification into 3 age groups
Low
Prospective review of MIRPE Low Retrospective review of author’s Low experience and collection of survey from American Pediatric Surgical Association with MIRPE Prospective study of cardiac Moderate function by trans-esophageal echocardiogram during open repair
Nuss Evaluation Questionnaire Moderate modified for adults and Single Step Questionnaire used to measure disease-specific quality-of-life changes after MIRPE
D.E. Jaroszewski et al.
486 Table 56.3 (continued) Reference
Years of study
Patients with 2+ struts placed (%)
Patients followed with struts removed
Jaroszewski13
1986–2007
N/a
N/a
Aronson15
1999–2005
3
14 of 35
Pilegaard16
2001–2007
33
46 of 180
Cheng17
2005–2007
23
7 of 96
Teh18
1999–2004
37
6 of 19
Olbrecht19
1997–2006
6
52 of 107
Antonoff36
2004–2008
Not reported
Not reported
Jaroszewski6
2007
N/a
N/a
Results of study 98% of patients reported considerable improvement in exercise tolerance, 5 patients recurred over mean 26 month follow-up Incidence of bar slips equal but more stabilizers used. Operating times equal. Longer use of analgesia in adults, incidence of wound abscess higher but same recovery time. All but one patient achieved excellent results. Operating time in adults 41 vs. 35 min in pediatrics. Hospital stay same as pediatrics. Only 1 month follow-up after removal of bars Bilateral thoracoscopic MIRPE allowed no mediastinal injury or bleeding complications. 6 patients were re-do from recurrences after Ravitch 2 patients with bars removed at 2 years had mild recurrence at 6 month follow-up No statistical differences in adult vs. pediatric MIRPE as seen except for higher blood loss and use of more than one bar in adults. At 1 year follow up, 3.9% recurred after bars removed at 2 years. Bar displacement was still high at 7.7% Length of stay, fees, analgesic needs, and complication rate were highest in MIRPE patients with 28% bar displacements, bars removed mean of only 27 months Pre- and post-operative echocardiogram and cardiopulmonary testing showed significant improvement in function of heart failure patient after pectus repair
exercise tolerance and function. The general consensus by both the pediatric and thoracic surgical communities also supports surgical repair of the significant PE. Patient testimony after surgical repair continues to encourage correction of the defect. Our results indicate that adults whose defects are corrected with either the open or MIRPE do extremely well, with no intraoperative complications, short operative time, minimal blood loss, short hospital stays and low rates of early and late postoperative complications. A full discussion of both types of surgical correction is provided for the patient and requires the patient to have an understanding of the limited long-term data available for the adult patient after MIRPE. Even with significant asymmetry which may benefit greater
Type of study
Evidence quality
Retrospective review with non-validated questionnaire on open repair pectus patients
Low
Retrospective review of MIRPE with comparison to 141 pediatric patients
Low
Retrospective review of patients undergoing MIRPE compared with pediatrics
Low
Retrospective review of patients undergoing MIRPE with use of bilateral thoracoscopy
Low
Retrospective review of adults undergoing MIRPE procedure Retrospective review of MIRPE with comparison to 80 pediatric patients
Low
Retrospective review of patients undergoing 3 types of PE repair
Low
Prospective single case report
Very low
Low
from open repair, we allow the patient to choose the procedure. In our experience, the majority of patients select the MIRPE for their repair. Both minimally invasive repair and open chondrectomy provide symptomatic relief, improved cardiovascular performance, and good cosmetic results in appropriately selected adult patients with pectus excavatum, and are safe (evidence quality low). We make a weak recommendation for surgical correction of PE in adult patients who have symptoms or documented cardiopulmonary insufficiency associated with a substantial anatomic deformity (recommendation grade 2B).
56. Pectus Excavatum in the Adult: Current Treatment Modalities
References 1. Kelly RE Jr. Pectus excavatum: historical background, clinical picture, preoperative evaluation and criteria for operation. Semin Pediatr Surg. 2008;17:181–193. 2. Fokin AA, Steuerwald NM, Ahrens WA, Allen KE. Anatomical, histologic, and genetic characteristics of congenital chest wall deformities. Semin Thorac Cardiovasc Surg. 2009;21:44–57. 3. Jaroszewski DE, Notrica DM, McMahon L, et al. Current management of pectus excavatum: a review and update of therapy and treatment recommendations. J Am Board Fam Med. 2010;23:230–239. 4. Jaroszewski DE, Fonkalsrud EW. Pectus deformity in the adult patient: cardiopulmonary symptoms as an indication for repair. Chest. 2006;130:282S–283S. 5. Colombani PM. Preoperative assessment of chest wall deformities. Semin Thorac Cardiovasc Surg. 2009;21:58–63. 6. Jaroszewski D, Steidley E, Galindo A, Arabia F. Treating heart failure and dyspnea in a 78-year-old man with surgical correction of pectus excavatum. Ann Thorac Surg. 2009;88:1008–1010. 7. Coln E, Carrasco J, Coln D. Demonstrating relief of cardiac compression with the Nuss minimally invasive repair for pectus excavatum. J Pediatr Surg. 2006;41:683–686. 8. Krueger T, Chassot P, Christodoulou M, et al. Cardiac function assessed by transesophageal echocardiography during pectus excavatum repair. Ann Thorac Surg. 2010;89:232–239. 9. Coln D, Gunning T, Ramsay M, Swygert T, Vera R. Early experience with the Nuss minimally invasive correction of pectus excavatum in adults. World J Surg. 2002;26:1217–1221. 10. Kim do H, Hwang JJ, Lee MK, Lee DY, Paik HC. Analysis of the Nuss procedure for pectus excavatum in different age groups. Ann Thorac Surg. 2005; 80:1073–1077. 11. Schalamon J, Pokall S, Windhaber J, Hoellwarth ME. Minimally invasive correction of pectus excavatum in adult patients. J Thorac Cardiovasc Surg. 2006; 132:524–529. 12. Hebra A, Jacobs JP, Feliz A, Arenas J, Moore CB, Larson S. Minimally invasive repair of pectus excavatum in adult patients. Am Surg. 2006;7:837–842. 13. Jaroszewski DE, Fonkalsrud EW. Repair of pectus chest deformities in 320 adult patients: 21 year experience. Ann Thorac Surg. 2007;84:429–433. 14. Mansour KA, Thourani VH, Odessey, et al. Thirtyyear experience with repair of pectus deformities in adults. Ann Thorac Surg. 2003;76:391–395. 15. Aronson DC, Bosgraaf RP, van der Horst C, Ekkelkamp S. Nuss procedure: pediatric surgical solution for adults with pectus excavatum. World J Surg. 2007;31:26–30. 16. Pilegaard HK, Licht PB. Routine use of minimally invasive surgery for pectus excavatum in adults. Ann Thorac Surg. 2008;86:952–956.
487 17. Cheng YL, Lee SC, Huang TW, Wu CT. Efficacy and safety of modified bilateral thoracoscopy-assisted Nuss procedure in adult patients with pectus excavatum. Eur J Cardiothorac Surg. 2008;34:1057–1061. 18. Teh SH, Hanna AM, Pham TH, Lee A, Deschamps C, Stavlo P, Moir C. Minimally invasive repair for pectus excavatum in adults. Ann Thorac Surg. 2008;85: 1914–1918. 19. Olbrecht VA, Arnold MA, Nabaweesi R, et al. Lorenz bar repair of pectus excavatum in the adult population: should it be done? Ann Thorac Surg. 2008; 86:402–409. 20. Kelly RE Jr, Shamberger RC, Mellins RB, Mitchell KK, Lawson ML, Oldham K, Azizkhan RG, Hebra AV, Nuss D, Goretsky MJ, Sharp RJ, Holcomb GW 3rd, Shim WK, Megison SM, Moss RL, Fecteau AH, Colombani PM, Bagley TC, Moskowitz AB. Prospective multicenter study of surgical correction of pectus excavatum: design, perioperative complications, pain, and baseline pulmonary function facilitated by internet-based data collection. J Am Coll Surg. 2007;205:205–216. 21. Malek MH, Fonkalsrud EW, Cooper CB. Ventilatory and cardiovascular responses to exercise in patients with pectus excavatum. Chest. 2003;124:870–882. 22. Malek MH, Berger DE, Housh TJ, et al. Cardiovascular function following surgical repair of pectus excavatum: a meta-analysis. Chest. 2006;130:506–516. 23. Raggi P, Callister TQ, Lippolis NJ, Russo DJ. Is mitral valve prolapse due to cardiac entrapment in the chest Cavity? A CT view. Chest. 2000;117:636–642. 24. Jaroszewski D, Steidley E, Galindo A, Arabia F. Cardiopulmonary testing for documentation of symptomatic pectus excavatum patients. Chest. 2009;136:144S–b. 25. Kelly RE Jr, Cash TF, Shamberger RC, Mitchell KK, Mellins RB, Lawson ML, Oldham K, Azizkhan RG, Hebra AV, Nuss D, Goretsky MJ, Sharp RJ, Holcomb GW 3rd, Shim WK, Megison SM, Moss RL, Fecteau AH, Colombani PM, Bagley T, Quinn A, Moskowitz AB. Surgical repair of pectus excavatum markedly improves body image and perceived ability for physical activity: multicenter study. Pediatrics. 2008;122: 1218–1222. 26. Krasopoulos G, Dusmet M, Ladas G, Goldstraw P. Nuss procedure improves the quality of life in young male adults with pectus excavatum deformity. Eur J Cardiothorac Surg. 2006;29:1–5. 27. Lam MW, Klassen AF, Montgomery CJ, LeBlanc JG, Skarsgard ED. Quality-of-life outcomes after surgical correction of pectus excavatum: a comparison of the Ravitch and Nuss procedures. J Pediatr Surg. 2008;43:819–825. 28. Daunt SW, Cohen JH, Miller SF. Age-related normal ranges for the Haller index in children. Pediatr Radiol. 2004;34:326–330. 29. Malek MH, Coburn JW. Strategies for cardiopulmonary exercise testing of pectus excavatum patients. Clinics Sao Paulo. 2008;63:245–254.
488 30. Wasserman K, Hansen JE, Sue DY, et al. Principles of exercise testing and interpretation: including pathophysiology and clinical applications. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. 31. Oren A, Sue DY, Hansen JE. The role of exercise testing in impairment evaluation. Am Rev Respir Dis. 1987;135:230–235. 32. Davis JT, Weinstein S. Repair of the pectus deformity: results of the Ravitch approach in the current era. Ann Thorac Surg. 2004;78:421–426. 33. Fonkalsrud EW, Mendoza J. Open repair of pectus excavatum and carinatum deformities with minimal cartilage resection. Am J Surg. 2006;191:779–784. 34. Fonkalsrud EW. Open repair of pectus excavatum with minimal cartilage resection. Ann Surg. 2004; 240:231–235. 35. Fonkalsrud EW. 912 open pectus excavatum repairs: changing trends, lessons learned: one surgeon’s experience. World J Surg. 2009;33:180–190.
D.E. Jaroszewski et al. 36. Antonoff MB, Erickson AE, Hess DJ, Acton RD, Saltzman DA. When patients choose: comparison of Nuss, Ravitch, and Leonard procedures for primary repair of pectus excavatum. J Pediatr Surg. 2009;44: 1113–1119. 37. Nuss D, Kelly RE Jr, Croitoru DP, Katz ME. A 10-year review of a minimally invasive technique for the correction of pectus excavatum. J Pediatr Surg. 1998; 33:545–552. 38. Nuss D, Kuhn A, Obermeyer RJ. Our approach: MIS repair of pectus excavatum. Contemp Surg. 2007;63: 444–451. 39. Fonkalsrud EW, Beanes S, Hebra A, Adamson W, Tagge E. Comparison of minimally invasive and modified Ravitch pectus excavatum repair. J Pediatr Surg. 2002;37:413–417.
57
Traumatic Rib Fracture: Conservative Therapy or Surgical Fixation? John C. Mayberry and Paul H. Schipper
Introduction Rib fractures are a common problem affecting injured patients, and the vast majority of patients heal their rib fractures without surgical intervention. Patients with severe rib fracture syndromes such as flail chest, traumatic chest wall defects, or pulmonary hernias are selectively recommended for rib fracture fixation, but the practice is not uniform and is controversial. Proponents of operative intervention contend rib fracture fixation in select patients will diminish the risk of respiratory complications and improve long-term pain and disability. Skeptics argue that operative intervention is applicable to a very small subset of injured patients with severe chest wall injuries and unnecessary or meddlesome in the rest. The literature describes the following rib fracture syndromes as potential indications for operative intervention: 1. 2. 3. 4.
Flail chest Chest wall defect/pulmonary herniation Intractable acute pain Thoracotomy for other indications (“on the way out”) 5. Rib fracture non-union In this chapter we follow the above injury classification and describe and grade the evidence supporting rib fracture fixation for each indication separately. Prior to 1995 the literature on rib fracture fixation consists exclusively of uncontrolled case series and thus we have chosen 1995 as the starting point for our review. We include studies
cited under the key words flail chest, rib fracture, and rib fracture operative reduction internal fixation (ORIF) available in English and focus on studies which describe ten or more operative patients. Sternal fractures can and often do accompany traumatic rib fractures but are not addressed in this review.
Flail Chest The literature describing the benefits of flail chest operative fixation is limited to retrospective reviews of case series,1–3 uncontrolled or matched contemporary non-operative comparisons,4–8 and two small, randomized trials.9,10 Among these studies, flail chest is not consistently nor rigorously defined. Definitions of flail chest in these reports include “obvious,”4 “instability,”5 “respiratory insufficiency or failure,”1,2 and “failure to wean from ventilator”3 without mention of the number nor pattern of rib fractures. Several studies include a variety of clinical scenarios including “thoracotomy from intrathoracic injury” (“stabilization on retreat”),2,6 “severe deformity of the chest wall” (“stove-in chest”),6 and “progressive dislocation of the fractured ribs.”2 One study defines flail chest as “>6 ribs fractured and requiring mechanical ventilation.”9 Only two studies define flail chest consistent with textbook definitions, i.e. “3 or more ribs fractured in at least 2 locations with para doxical motion.”7,10 Table 57.1 describes the outcomes reported for flail chest patients receiving operative fixation
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0_57, © Springer-Verlag London Limited 2011
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490 Table 57.1. Summary of relevant reports of the operative fixation of flail chest since 1995. Study
Year
Ahmed
1995
Karev5
1997
Voggenreiter6
1998
Tanaka9
2002
Balci7
2004
Granetzny10
2005
4
Outcome classification Mechanical Ventilation ICU stay “Chest infection” Tracheostomy Mortality Mechanical Ventilation Pneumonia Mortality Mechanical Ventilation No Pulmonary Contusion With Pulmonary Contusion Pneumonia Mortality Mechanical Ventilation ICU stay Pneumonia Return to work (6 months) Mechanical Ventilation Tracheostomy Mortality Mechanical Ventilation “Chest infection” Post-op deformity Mortality
Operative fixation
Non-operative
Quality of evidence
3.9 days 9 days 15% 11% 8% 2.3 ± 0.6 days 15% 22.5% 6.5 ± 7.0 days 31 ± 34 days 40% 15%
15 days 21 days 50% 37% 29% 6.3 ± 1.2 days* 34%* 46%* 27 ± 29 days* NA 28% 39%
Low; retrospective study of 26 pts with uncontrolled contemporary comparisons
10.8 ± 3.4 days 16.5 ± 7.4 days 24% 61% 3.1 days None 11% 2 days 10% 5% 10%
18 ± 7.4 days* 27 ± 13 days* 77%* 5%* 7.2 days 19% 27% 12 days* 50%* 45%* 15%
Moderate; randomized trial of 18 operative pts compared to 19 non-operative patients with 6 month follow-up Low; retrospective study of 27 pts with
Low; retrospective study of 40 pts with uncontrolled contemporary Low; retrospective study of 20 pts with uncontrolled contemporary comparisons
Moderate; randomized trial of 20 operative patients compared to 20 non-operative patients with 2 month follow-up
*Indicates p < 0.05 operative fixation cohort compared to non-operative cohort.
compared to non-operative treatment and our opinion regarding the quality of evidence in the studies which attempted to make such a comparison. Most of these studies are of low quality because they are retrospective reviews with unmatched non-operative controls. No explanation is given for how patients were chosen for operative versus non-operative treatment. In our opinion the quality of the two randomized trials, Tanaka et al. and Granetzny et al., is moderate rather than high because the number of patients randomized is low (£40) and because the high pneumonia rates among the non-operative controls (77% and 50%) calls the quality of intensive care into question.9,10 Long-term follow-up of flail chest fixation patients is also sparse and of low quality. Mouton and colleagues reported that 95% of 23 operated patients were back to full work in a mean of 28 months.1 A later report from the same group
adding 43 consecutive patients over an additional 3 years indicated that 100% of operated patients were back to work within 3–16 weeks following discharge.2 These outcomes are so impressive that we speculate that their patient selection criteria for operative fixation were too liberal. Tanaka and colleagues reported a 6 month return to work of 61% among the operative group versus 5% among the non-operative group.9 While this study shows a significant reduction in long term disability demonstrated by the ability to return to work, the 6 month return to work rate of 5% in the non-operative group is much lower than expected from historical controls. Another retrospective study compared an operative cohort with reference groups from the literature including chronic medical patients, orthopedic trauma patients, and the general population and demonstrated that operative patients have equivalent or superior long-term pain and disability
57. Traumatic Rib Fracture: Conservative Therapy or Surgical Fixation?
outcomes.3 This report suffers from a low response rate among operative patients but does validate more specific measures of long-term outcome of rib fracture patients including the RAND 36 Health Survey and the McGill Pain Questionnaire.11,12 A unique subset of flail chest is the “chest wall implosion syndrome”.13 This severe chest wall injury is caused by a posterolateral (side) impact to the shoulder/ upper thorax and is characterized by multiple, displaced rib fractures along the medial edge of the scapula, a clavicle fracture/dislocation, and often a scapular fracture. Although this injury does not meet the anatomic definition of flail chest, these patients are physiologically similar to patients with anterolateral flail chest, i.e. nearly all will require mechanical ventilation for respiratory failure. Compared with a historical cohort of similar patients treated non-operatively (n = 7), an operative cohort (n = 9) demonstrated less time on mechanical ventilation and had improved outpatient shoulder function.13 The quality of evidence in this report is low because of the small number of patients and the uncontrolled, retrospective nature of the study, but the authors are to be commended for devising an ingenious surgical approach which does not require entrance into the pleural space.
Chest Wall Defect/Pulmonary Herniation This category of chest wall injury consists of patients that have an open wound with exposed rib fractures or a frank herniation of lung between fractured ribs. A portion of the chest wall may be missing or operative debridement of devitalized tissue may leave a defect. These are rare injuries, much more rare than flail chest, and have been reported as single case reports or small case series.3,14–21 Operative repair including rib fracture fixation and closure of the defect, either primarily or with a biologic patch, is recommended except for selected pulmonary herniations in children which have been observed to spontaneously close.20 The quality of evidence is low, but the rarity of these injuries makes it unlikely that higher quality evidence will ever be available.
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Intractable Acute Pain Of all the proposed indications for rib fracture fixation for intractable acute pain has the least support in the literature. Patients who would potentially fall into this category are in-patients with displaced rib fractures who fail several days of pain management, e.g. epidural pain control, and who are unable to mobilize or make other clinical progress because of acute pain directly attributable to the rib fractures. The rationale to offer these patients rib fracture fixation is they could have their acute pain controlled sooner and be back to work/usual activities sooner than they would otherwise. In addition, it has been proposed that these patients would have less long-term pain and disability.22 Three publications include this indication among larger case series without a specific non-operative comparison group.3,8,23 A successful case report of the thorascopic resection of the intruding ends of several displaced rib fractures illustrates the potential benefit of surgery for these patients.24
Thoracotomy for Other Indications (“on the Way Out”) This indication is mentioned in several case series of rib fracture fixation but has not been specifically studied and therefore the quality of evidence is very low.2,3,6,8 Examples of patient scenarios where rib fracture fixation has been performed “on the way out” include retained hemothorax, pulmonary laceration, and diaphragm repair.
Rib Fracture Non-Union The incidence of rib fracture non-union (pseudoarthrosis) is unknown, but if it parallels the incidence of bony non-unions in other body regions it is probably 1–5% and is dependent on the severity of the fracture and patient co-morbidities.25–27 Failure to heal by 3 months post-injury is the standard orthopedic definition of a fracture non-union. There are several case reports of successful
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operative intervention for rib fracture non-union, but the quality of evidence is very low.23,28–32 Patients with symptomatic rib fracture non-unions complain of pain exacerbated by activity and may or may not describe fracture movement. Whether the non-union can be resected and allowed to re-heal without a plate or whether a plate is necessary for re-healing is unknown. In addition, the size of the gap between resected bony ends that is acceptable with rigid fixation is unknown. The use of a bone graft in the space between the rib ends in conjunction with rigid fixation has been described.31
Recommendations Rib fracture fixation improves ventilator weaning, lessens the risk of pulmonary complications, and improves return to function for patients with flail chest, and is safe (moderate quality evidence). We make a strong recommendation for rib fracture fixation in patients with flail chest who manifest delayed ventilator weaning (5–7 days post injury) (recommendation grade 1B). Rib fracture fixation restores chest wall integrity in patients with traumatic chest wall defect or pulmonary herniation and is safe (low quality evidence). We make a strong recommendation for operative repair with rib fracture fixation and closure of defect primarily or with biologic patch in patients with chest wall defect or pulmonary herniation (Grade 1C). Operative intervention may not be necessary in pediatric patients with acute traumatic pulmonary herniation (low quality evidence). Rib fracture fixation may offer improved pain control and return to function in select patients with displaced rib fractures who fail an initial trial of aggressive pain management (low quality evidence). Rib fracture fixation may be beneficial in patients with displaced rib fractures who require operative thoracotomy for other traumatic indications and is safe (very low quality evidence). Operative resection with or without rigid fixation may improve pain associated with a rib fracture non-union (pseudo-arthrosis) (very low quality evidence). Because of a paucity of evidence, no recommendation for operative intervention can be made for these clinical situations.
Rib fracture fixation improves ventilator weaning, lessens the risk of pulmonary complications, and improves return to function for patients with flail chest, and is safe (moderate quality evidence). We make a strong recommendation for rib fracture fixation in patients with flail chest who manifest delayed ventilator weaning (5–7 days post injury) (recommendation grade 1B).
Rib fracture fixation restores chest wall integrity in patients with traumatic chest wall defect or pulmonary herniation and is safe (low quality evidence). We make a strong recommendation for operative repair with rib fracture fixation and closure of defect in patients with chest wall defect or pulmonary herniation (Grade 1C).
References 1. Mouton W, Lardinois D, Furrer M, Regli B, Ris HB. Long-term follow-up of patients with operative stabilisation of a flail chest. Thorac Cardiovasc Surg. 1997;45:242–244. 2. Lardinois D, Krueger T, Dusmet M, Ghisletta N, Gugger M, Ris HB. Pulmonary function testing after operative stabilisation of the chest wall for flail chest. Eur J Cardiothorac Surg. 2001;20:496–501. 3. Mayberry JC, Kroeker AD, Ham LB, Mullins RJ, Trunkey DD. Long-term morbidity, pain, and disability after repair of severe chest wall injuries. Am Surg. 2009;75:389–394. 4. Ahmed Z, Mohyuddin Z. Management of flail chest injury: internal fixation versus endotracheal intubation and ventilation. J Thorac Cardiovasc Surg. 1995; 110:1676–1680. 5. Karev DV. Operative management of the flail chest. Wiad Lek. 1997;50(Suppl 1 Pt 2):205–208. 6. Voggenreiter G, Neudeck F, Aufmkolk M, Obertacke U, Schmit-Neuerburg KP. Operative chest wall stabilization in flail chest – outcomes of patients with or without pulmonary contusion. J Am Coll Surg. 1998;187: 130–138. 7. Balci AE, Eren S, Cakir O, Eren MN. Open fixation in flail chest: review of 64 patients. Asian Cardiovasc Thorac Ann. 2004;12:11–15. 8. Nirula R, Allen B, Layman R, Falimirski ME, Somberg LB. Rib fracture stabilization in patients sustaining blunt chest injury. Am Surg. 2006;72:307–309. 9. Tanaka H, Yukioka T, Yamaguti Y, et al. Surgical stabilization of internal pneumatic stabilization? A prospective randomized study of management of severe flail chest patients. J Trauma. 2002;52:727–732.
57. Traumatic Rib Fracture: Conservative Therapy or Surgical Fixation? 10. Granetzny A, Abd El-Aal M, Emam E, Shalaby A, Boseila A. Surgical versus conservative treatment of flail chest. Evaluation of the pulmonary status. Interact Cardiovasc Thorac Surg. 2005;4:583–587. 11. Medical Outcomes Study: 36-Item Short Form Survey. Available at: http://www.rand.org/health/ sur veys_to ols/mos/mos_core_36item.ht m l. Accessed September 29, 2008. 12. Melzack R. The McGill pain questionnaire: from description to measurement. Anesthesiology. 2005; 103:199–202. 13. Solberg BD, Moon CN, Nissim AA, Wilson MT, Margulies DR. Treatment of chest wall implosion injuries without thoracotomy: technique and clinical outcomes. J Trauma. 2009;67:8–13. 14. May AK, Chan B, Daniel TM, Young JS. Anterior lung herniation: another aspect of the seatbelt syndrome. J Trauma. 1995;38:587–589. 15. Francois B, Desachy A, Cornu E, Ostyn E, Niquet L, Vignon P. Traumatic pulmonary hernia: surgical versus conservative management. J Trauma. 1998; 44:217–219. 16. Filosso PL, Oliaro A, Donati G, Rena O. Posttraumatic hernia of the lung. Eur J Cardiothorac Surg. 2001;19:360. 17. Lang-Lazdunski L, Bonnet PM, Pons F, Brinquin L, Jancovici R. Traumatic extrathoracic lung herniation. Ann Thorac Surg. 2002;74:927–929. 18. Ayers DE, LeFeuvre A, Barker P. Surgical repair of intercostal pulmonary hernia secondary to cough induced rib fracture. J R Nav Med Serv. 2002;88:55–56. 19. Weissberg D, Refaely Y. Hernia of the lung. Ann Thorac Surg. 2002;74:1963–1966. 20. Patel MB, Nathan JD, Frush DP, Rice HE. Nonoperative management of asymptomatic traumatic pulmonary hernia in a young child. J Trauma. 2007;62:234–235. 21. Khalil MW, Masala N, Waller DA, Cardillo G. Surgical repair of post-traumatic lung hernia using a video-
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assisted open technique. Interact Cardiovasc Thorac Surg. 2008;7:506–507. 22. Kerr-Valentic MA, Arthur M, Mullins RJ, Pearson TE, Mayberry JC. Rib fracture pain and disability: can we do better? J Trauma. 2003;54:1058–1064. 23. Richardson JD, Franklin GA, Heffley S, Seligson D. Operative fixation of chest wall fractures: an underused procedure? Am Surg. 2007;73:591–597. 24. Sing RF, Mostafa G, Matthews BD, Kercher KW, Heniford BT. Thoracoscopic resection of painful multiple rib fractures: case report. J Trauma. 2002; 52:391–392. 25. Jones GL, McCluskey GM, 3rd, Curd DT. Nonunion of the fractured clavicle: evaluation, etiology, and treatment. J South Orthop Assoc. 2000;9:43–54. 26. Gaston MS, Simpson AH. Inhibition of fracture healing. J Bone Joint Surg Br. 2007;89:1553–1560. 27. Court-Brown CM, McQueen MM. Nonunions of the proximal humerus: their prevalence and functional outcome. J Trauma. 2008;64:1517–1521. 28. Cacchione RN, Richardson JD, Seligson D. Painful nonunion of multiple rib fractures managed by operative stabilization. J Trauma. 2000;48:319–321. 29. Ng AB, Giannoudis PV, Bismil Q, Hinsche AF, Smith RM. Operative stabilisation of painful non-united multiple rib fractures. Injury. 2001;32:637–639. 30. Slater MS, Mayberry JC, Trunkey DD. Operative stabilization of a flail chest six years after injury. Ann Thorac Surg. 2001;72:600–601. 31. Cho YH, Kim HK, Kang DY, Choi YH. Reoperative surgical stabilization of a painful nonunited rib fracture using bone grafting and a metal plate. J Orthop Trauma. 2009;23:605–606. 32. Anavian J, Guthrie ST, Cole PA. Surgical management of multiple painful rib nonunions in patient with a history of severe shoulder girdle trauma: a case report and literature review. J Orthop Trauma. 2009;23:600–604.
Index
A ACCP. See American College of Chest Physicians Achalasia, optimal initial therapy clinical characteristics, 276 dilators, 269 Dor and Nissen fundoplication, after Heller myotomy, 273 epidemiology and pathophysiologic considerations, 269–270 initial therapy, 272–273 mechanical dilation, 271–272 median direct medical costs, comparison of, 273 pharmacotherapy, 271 recommendations and, 276 response to treatment, 270–271 surgical treatment candidates for, 272 esophagitis, development of, 275 issues, 273–276 myotomy and fundoplication, 275 outcomes, comparison of, 275 post-myotomy esophageal acid exposure, prevalence of, 274 symptom improvement and post-treatment GERD, 275 Adjuvant therapy, 83 Air leak duration and incidence, 375–377 American College of Chest Physicians (ACCP), 136, 165, 166, 385, 400–403 Amiodarone, for perioperative arrhythmia prophylaxis, 174–176
Analytic techniques. See Decision analytic model (DAM) Anastomosis, 244–245 Anterior mediastinotomy, 72 Antireflux procedure, distal esophageal pulsion diverticula, 308 surgery for non-acid reflux, 260, 261 prophylactic, in lung transplantation, 263–266 Antiseptic techniques, 5 Aperistaltic esophagus, fundoplication, 252–253 Arrhythmia. See Perioperative arrhythmia prophylaxis, for lung resection Arterial-venous carbon dioxide removal (AVCO2R), 189 Atrial fibrillation (AF), 172 Axillary hyperhidrosis, 472–474 B Barrett esophagus (BE) management, with HGD, 200 cryotherapy, 199 data search for, 197 efficacy and safety, 198 EMR, 198 endoscopic modalities, 197 issues, 199 outcome data for, 199 PDT, 198 recommendations for, 199–200 RFA, 198–199 Barrett mucosa, cervical remnant after esophagectomy, 241–246 columnar lined metaplasia, incidence of, 242
M.K. Ferguson (ed.), Difficult Decisions in Thoracic Surgery, DOI: 10.1007/978-1-84996-492-0, © Springer-Verlag London Limited 2011
factors affecting anastomosis, level of, 244–245 medical therapy, 245–246 pyloric drainage procedure, 244 reconstruction, route of, 245 methods, 241–242 prevalence of development of, 244 endoscopic, 242–243 mucosal damage, histologic evidence of, 243–244 neoplastic transformation, 244 recommendations and, 246 surveillance endoscopy, 246 with/without pyloroplasty, evidence based reports, 242 Bayes’ formula, 29 Bayesian meta-analysis, DAM, 34 Benign airway obstruction, stents literature search, 347 plastic stents, 348–349 recommendations, 350 SEMS, 351 fully covered, 350 uncovered/partially covered, 349–350 silicone stent, 351 Dumon stent, 348 Montgomery T-tubes, 347–348 results of, 348 b-Blockers, for perioperative arrhythmia prophylaxis, 174, 176 Botulinum toxin (Botox), 271 British Thoracic Society (BTS), 384, 400 Bronchioloalveolar carcinoma (BAC), 129 495
Index
496 Bronchogenic and pericardial cysts decision making, 460, 461 Endoscopic bronchial ultrasound (EBUS), 463 endoscopic ultrasonography (EUS), 462 literature search technique, 459–460 malignancy, cyst characteristics indicative of, 462, 463 management method, 463 signs, symptoms and complications, 459 surgical treatment modalities, 460, 462 Bronchogenic carcinoma (T4), 367–370. See also Carinal resection for cancer BTS. See British Thoracic Society C Cardiac complications, VATS vs. open lobectomy, 80 Carinal pneumonectomy, 368 Carinal resection for cancer indications, 367–368 isolated carinal resection, 368 left carinal pneumonectomy, 368 with lobar resection, 368 and reconstruction, historical reference, 369–370 right carinal pneumonectomy, 368 Cervical mediastinoscopy (CM), 69–70 Cervical remnant. See Barrett mucosa, cervical remnant Chemoradiation therapy, salvage esophagectomy evidence for, 233–234 randomized controlled trials of, 234 with/without surgery, 234–235 Chemoradiotherapy induction, for resectable esophageal cancer chemotherapy vs., 207 French 9703 Trial, 206 Intergroup Trial 113, 206 Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, 206 Medical Research Council (MRC) OEO2, 205
meta analyses, 206–207 radiotherapy, 207 Chemotherapy induction, for resectable esophageal cancer vs. chemoradiotherapy, 207 meta analyses, 205 randomised trials, 205–206 pulmonary function alterations, 106 Chest tube duration, 377–378 Chest tube management, after lung resection, 158–159 air leaks, 157, 158 alternate suction, 158 placing of, 155 recommendations, 158 study design, differences in, 156 suction vs. water seal, 156 trial designs, 156 Circumferential defect, in tracheal reconstruction, 353–356 Cochrane systematic review, 46 Collis gastroplasty, 290, 291 Columnar metaplasia, 243 Computed tomography scanner, in data collection, 8 Computerized tomographic (CT) scans, 62 mediastinal nodal involvement on high probability of, 69 low probability of, 68 Conservative therapy/surgical fixation chest wall defect/pulmonary herniation, 487 flail chest, 485–487 intractable acute pain, 487 recommendations of, 488 rib fracture non-union, 487–488 thoracotomy for, 487 Cost-effectiveness analysis (CEA), 27 Craniofacial hyperhidrosis and blushing, 474–475 Cricopharyngeal diverticula, optimal therapy endoscopic techniques diverticulostomy, 297–298 rigid vs. flexible, 298 septum dividing, techniques for, 297 Weerda diverticuloscope, 296
history, 293–294 open surgery diverticulectomy vs. diverticulopexy, 295–296 UES myotomy, 294–295 open vs. endoscopic approaches, 298–300 pharyngeal pouches, 293 recommendations, 299–300 recurrent Zenker’s diverticula, treatment of, 299 study selection criteria, 294 symptoms, 293 Cryotherapy, 199 D Database, 8–9 Decision analytic model (DAM) clinical decision analysis in, 31 elements of alternative actions, 24 Bayes formula, 29 chance node, 28 cost analysis, 26–27 cost-effectiveness analysis (CEA), 27 decision analysis, 30 decision node, 27–28 mortality risk, 28 outcomes analysis, 26 patients, clinical conditions and demographics of, 25–26 patient’s preferences, 25 probability parameter, 29 sensitivity analysis, 30–31, 33 structure for, 27–28 time frame of, 26 utility analysis, 26 expected utility theory, 23–24 issues in Bayesian meta-analysis, 34 information analyses, 34–35 Markov models, 32, 33 probabilistic analysis, 32–33 solitary pulmonary nodule, 24 thoracotomy and watchful waiting clinical decision, decision-tree to, 25 information on parameters for, 30 Diaphragm closure, synthetic reinforcement (see Large hiatal hernia repairs, diaphragm closure)
497
Index dysfunction, 329 stimulation, 329–330 Diaphragm pacing (DP) for acute respiratory failure evidence and recommendations, 332–333 laparoscopic implantation of, 330 for spinal cord injured patients, 330–331 temporary use of mechanical ventilation, 331–332 spinal cord injury (SCI), 331 Diffusion capacity of lung for carbon monoxide (DLCO), 106 Diltiazem, for perioperative arrhythmia prophylaxis, 174–176 Distal esophageal pulsion diverticula, management, 309–310 antireflux procedure, indications for, 308 diverticulectomy, need for, 304, 307 esophagomyotomy, role for, 307–308, 310 fundoplication, 310 mid-esophageal diverticula, 303 operation, indications for, 303–304 operative approach leak rates, literature, 309 minimal access approach, 308 outcomes, non-operative management, 305 recommendations and, 309 reviewed literature, operative details and outcomes, 306 Diverticula cricopharyngeal, 293–300 distal esophageal pulsion, management, 303–310 Diverticulectomy cricopharyngeal diverticula vs. diverticulopexy, 295–296 distal esophageal pulsion diverticula, 304, 307 Diverticulopexy, 295–296 Diverticulostomy, 297–298 Dumon stent, 348 Dysphagia, fundoplication, 249–250 E Early surgical decision making, 4–5 Emphysema, 180, 181
Empyema, 5, 6. See also Pleural empyema Encapsulated thymoma, resection of complete thymectomy, 438 failure to predict encapsulation, 438 incomplete resections, significance of, 438 operative/long term survival data, 438 published data, 435–436 recurrence, 437–438 surgical approach, 439 technical feasibility and safety in non-thymomatous myasthenia gravis, 437 vs. open resection, 436–437 Endobronchial ultrasound guided needle aspiration (EBUS-NA), 70–71 Endoscopic mucosal resection (EMR), 198 Endoscopic techniques, for cricopharyngeal diverticula, 296–298 Endoscopic ultrasound guided needle aspirate (EUS-NA), 71 EPP. See Extrapleural pneumonectomy Esophageal cancer lymph node dissection (see Lymph node dissection, in esophageal cancer) for resectable, induction therapy, 203–209 Esophageal diverticular disease, 303 Esophageal lengthening procedure, in giant paraesophageal hernia (PEH), 319, 321–322 Esophageal lymphatics mural lymphatics anatomy, 223, 224 lamina propria, 223 regional lymphatics and lymph nodes, 224–225 Esophageal perforation and anastomotic leak, stents clinical practice, impact on, 283 discontinuity of, etiology, 279 disease, 281 esophagogastrostomy, 284 iatrogenic perforations, 283 outcomes of, 282
published data, 283 removal, 282–283 supportive therapy, 281–282 symptoms and diagnosis of, 280 treatment and complications, 281, 282 types of, 280–281 Esophageal reconstruction, 241 Esophagectomy, Barrett mucosa in cervical remnant, 241–246 Esophagectomy, optimal surgical approach methods, 213–214 minimally invasive esophagectomy (MIE) operative techniques and learning curve, 217–218 patient selection, 218 recommendations, 220 short- and long-term outcome, clinical effects on, 218–219 open, transthoracic vs. transhiatal Dutch trial, 215, 216 long-term outcome, 217 meta-analysis, 214, 216, 217 nonrandomized comparative studies, 215 RCTs, 214–215 short-term outcome, 216 staging, effect on, 214 Esophagomyotomy, distal esophageal pulsion diverticula, 307–308, 310 Esophagus, gastroplasty for, 287–291 Evidence-based approach thymectomy, 421–425 Evidence-based clinical practice (EBCP). See Evidencedbased medicine (EBM) Evidence-based surgical decisions, 5–6 Evidenced-based medicine (EBM) current evidence, obtaining, 14 definition, 13 direct review of, 14 interactive learning, 14 levels of GRADE system, 16–17 hierarchy of, 14–15 physiologic studies, 15 randomized clinical trials (RCT), 15
Index
498 Evidenced-based medicine (EBM) (cont.) principles of, 13 recommendation, systems of GRADE and modified GRADE systems of, 18–20 Oxford Centre for, 16, 18 and pre-processed evidence, limitations of, 19–20 steps, for practitioner, 13 Extended transsternal thymectomy, 422–423 Extended VATS procedures, 423 Extracorporeal membrane oxygenation (ECMO) adult, 188 neonates, 187–188 pediatric, 188 Extrapleural pneumonectomy (EPP), 408 methodology, 415 operability, 417 patient selection, 415–417 risks and benefits, 417 Exudative empyema British Thoracic Society (BTS), 384 image-guided drainage catheters, 384, 385 F Fibrin based sealants, 374 Fibrinopurulent empyema drainage and fibrinolytics, 384–386 pleural space and encompasses, 384 surgical therapy thoracotomy, 386 VATS, 387 Fluorodeoxyglucose positron emission tomography (FDG PET), 61 Forced vital capacity (FVC), 106 Fundoplication for GERD aperistaltic esophagus, outcomes in, 252–253 impaired esophageal motility and post-fundoplication dysphagia, 249–250 Nissen, 251, 254 partial, 251, 254 peristalsis, 250, 251 randomized controlled trials, 251–252
recommendations, 253 tailored approach, 250 prophylactic antireflux surgery, in lung transplantation early vs. late, 264 pre-operative assessment and perioperative care for, 264–265 G Gastroesophageal reflux disease (GERD), 274, 275 fundoplication, 249–254 gastroplasty for, 287–291 Gastroplasty, 290–291 Collis gastroplasty, 290, 291 lengthening, history and variations of, 287–288 literature, 287 outcomes of, 289 recommendations, 289–290 shortened esophagus, incidence of, 288 techniques, 289 Giant paraesophageal hernia (PEH) Collis gastroplasty, 324 definition and types, 315 diagnosis and elective surgery, 318, 325 emergency surgery, 316, 318 esophageal lengthening procedure in, 319, 321–322, 325 gastroplasty for, 287–291 hiatus, 322, 324, 325 laparoscopic surgery for, 319–321 open surgery for, 317 operative approaches and techniques, 324 prosthetic material in, 323 transthoracic/transabdominal approach, 318–319 Gore-tex® mesh, 340 Grading of recommendations, assessment, development and evaluation (GRADE) factors, 17 and modified systems, of recommendation, 18–19 quality assessment criteria, 17 quality of evidence and categories, 16 H Heparin, VTE prophylaxis, 166 Hiatal hernias
diaphragm closure (see Large hiatal hernia repairs, diaphragm closure) gastroplasty, 287 Hiatal herniation, 322, 324 High-grade dysplasia (HGD). See Barrett esophagus (BE) management, with HGD Hyperhidrosis axillary hyperhidrosis, 472–474 craniofacial hyperhidrosis and blushing, 474–475 method, 470 palmar hyperhidrosis, 470–472 sympathetic chain physiology, 469–470 I Immunologic effects, VATS vs. open lobectomy, 83–84 Incremental cost-effectiveness ratio (ICER), 27 Induction therapy, 63. See also Positron-emission tomography (PET), for mediastinal restaging lobectomy, for stage IIIA NSCLC, 111–115 pneumonectomy, stage IIIA NSCLC, 119–123 pulmonary function alterations, 105–109 for resectable esophageal cancer, 209 chemoradiotherapy, 206–207 chemotherapy, 205–206 evidence, methods for, 204, 212 histology and tumor location, 204 principles, 204 recommendations, 208 response to, 204 stage, 203–204 surgery without therapy, outcome and radicality, 203 thoracotomy vs. VATS, 145–151 Information. See Medical information Information analyses, in decision analytic model (DAM), 34–35 Initial primary spontaneous pneumothorax chest drain management, 403 clinical issues
499
Index intraoperative pleurodesis, 402–403 routine CT scanning, 401 surgical approach, 401–402 timing of surgical consultation, 400–401 methods, 400 recommendations of, 403 Insurance companies, 9 Intensity modulated radiation therapy (IMRT), 411 International PtDA Standards Collaboration, 47 Intralobar satellite tumors, 129 Intraoperative pleurodesis, 402–403 K Kaplan–Meier remission rates, 424–425 L Laparoscopic antireflux surgery (LARS), 257, 260 Large hiatal hernia repairs, diaphragm closure biologic mesh, 342 literature search, 337–338 mesh-related complications, 340–341 radiographic recurrence rate, 341 randomized clinical trials, 338–339 recommendations, 341–342 retrospective cohort studies, 339–340 steps, 342 use of mesh, 341, 342 Lobectomy and complete mediastinal lymphadenectomy, 77 induction therapy, for stage IIIA NSCLC, 115 N2 disease, classification of, 112 outcomes of resection for, 113 pneumonectomy, 112, 114 RCTs, 112 recommendations, 114–115 Lobectomy vs. segmentectomy, for stage I lung cancer CALGB 140503 and JCOG0802 trials, 130 clinical trials, 130 definitions and approach, 125–126
limited resection histological classification, 129 intralobar satellite tumors, 129 meta-analysis, 126 observational studies, 127–128 preoperative imaging, 129–130 randomized control trial, 126 surgical approach, 130 tumor location, 128–129 tumor size, 128 recommendations and, 131 Lung cancer marginal lung function and peripheral stage I, optimal therapy for classification, 135–136 guidelines, 136 postoperative FEV1 (ppoFEV1), 136 preoperative COPD/ emphysema influence, on postoperative FEV1, 139 radiofrequency ablation (RFA), 140 recommendations, 140–141 searches, 135 segmentectomy, 137, 138, 141 stereotactic radiotherapy, 138–140 sublobar resection, 137–138 VATS lobectomy, 137 and wedge resection, 137 optimal initial pathologic mediastinal staging anterior mediastinotomy, 72 authors’ approach, 73–74 cervical mediastinoscopy, 69–70 comparative studies, 71–72 EBUS-NA, 70–71 EUS-NA, 71 high probability of, on CTCT-PET, 69 intermediate probability of, on imaging, 68–69 low probability of, on CTCT-PET, 68 occult N2 disease, predictors of, 69 VATS nodal assessment, 72–73 segmentectomy vs. lobectomy, for stage I, 125–131 Lung failure, support therapy AVCO2R, 189 ECMO, 187–188
mechanical support methods, characteristics of, 191 recommendations, 191–192 total artificial lung (TAL), 189–191 VVCO2R, 189 Lung resection chest tube management, 155–159 perioperative arrhythmia prophylaxis, 171–176 venous thrombo-embolism, perioperative prophylaxis, 165–168 Lung sparing total pleurectomy (LSTP), 418 Lung transplantation, prophylactic antireflux surgery, 263–266 Lung volume reduction (LVR) surgery, 183–184 bilateral, 182, 183 emphysema, 180, 181 Medicare, 182 NETT, 182, 183 prognostic factors, 182 RCTs, clinical results of, 180 recommendations, 183 search strategy, 179 unilateral, 183 Lung volume reduction surgery (LVRS), 39 Lymphadenectomy, extent of anatomic, 226–227 number of resected lymph nodes, 225–226 three-field, 227 transhiatal esophagectomy, 227 yield, improvement of, 227–228 Lymph node dissection, in esophageal cancer cT3, cN1, and cN2 cancers, 229 high-grade dysplasia (HGD) and T1a cancers, 228 literature search, methodology of, 225 lymphadenectomy, extent of anatomic, 226–227 number of resected lymph nodes, 225–226 three-field, 227 transhiatal esophagectomy, 227 yield, improvement of, 227–228 metastatic, prognostic importance of, 225 recommendations, 228
Index
500 Lymph node dissection, in esophageal cancer (cont.) survival improvement, mechanism of, 228 T1b and T2 cancers, 229 M Malacic airway syndromes, optimal management membranous wall tracheobronchoplasty, 364–365 recommendations, 365 searches for, 363 tracheobronchomalacia (TBM), 363 self-expanding metallic stents, 363–364 silicone stents for, 364, 365 Malignant pleural effusion management algorithm for, 396 limitations of studies, 395–396 methods of identifying relevant literature, 394 PleurX catheter vs. chest tube and doxycycline pleurodesis, 394–395 PleurX vs. talc/doxycycline sclerosis, 394 PleurX vs. VATS, 394 Malignant pleural mesothelioma (MPM) lung sparing total pleurectomy (LSTP), 418 methodology, 407, 415 operability, 417 pleurectomy with chemotherapy, 409 and decortication (P/D), 408 non-randomized comparative studies, 406–407 with photodynamic therapy, 410 with/without radiation, 409 pre-operative evaluation, 408 recommendations, 417–418 results, 407–408 tumor characteristics, patient selection biomarkers of, 416–417 chemotherapy, 416 computed tomography, 415 EBUS/EUS/mediastinoscopy, 416
EPP extrapleural nodal metastases, 416 laparoscopy, 416 non-epithelioid MPM, 416 primary tumor, 416 Markov models, in decision analytic techniques, 32, 33 Maxwell Box, pleural space management, 161, 162 Mechanical dilation, achalasia, 271–272 Mechanical ventilation, 329, 331–332 Mediastinal germ cell tumor chemotherapy elevated or rising serum tumor markers, 443 normal serum tumor markers, 442–443 diagnosis and initial therapy, 442 prognostic variables resected residual mass, pathology of, 446–447 serum tumor markers, 446 visceral metastases, 445–446 surgical management, 443–444 survival, 444–445 Mediastinal lymphadenectomy, 77 Mediastinal lymph node dissection, 82 Mediastinal restaging. See Lung cancer; Positron-emission tomography (PET), for mediastinal restaging Mediastinotomy, anterior, 72 Medical information, 6–9 Medico-legal environment, in surgical decision-making process, 43 Membranous wall tracheobronchoplasty, 364–365 Memorial Sloan-Kettering Cancer Center (MSKCC), 409 Minimally invasive esophagectomy (MIE) operative techniques and learning curve, 217–218 patient selection, 218 recommendations, 220 short- and long-term outcome, clinical effects on, 218–219 Mural esophageal lymphatics, 223–224 Myasthenia Gravis Foundation of America (MGFA), 422, 429
Myathenias gravis (MG) extended transsternal thymectomy, 422–423 Kaplan–Meier remission rates, 424–425 morbidity and failures, 423–424 patients with, 429–433 search methods, 421 surgical approaches, 422 thymectomy vs. medical treatment, 421–422 transcervical thymectomy, 423 video assisted thoracoscopic extended thymectomy (VATET), 423 Myocutaneous flaps, 355–356 N National Emphysema Treatment Trial (NETT), 8, 182, 183 National Institute for Health and Clinical Excellence (NICE), 165, 166 National Surgical Quality Improvement Project (NSQIP), 42 N2 disease, lobectomy, classification of, 112 N2 disease, thoracotomy, 98 alternative treatment approaches, 91 planned treatment, delivery of, 91–92 preoperative and postoperative QOL measures, 90 short-term and functional outcomes, 90–91 survival of, 92 categories of ignored, 92–93 incidental, 93–94 outcomes of, 93 underappreciated, 93 methods, 89 prognostic factors geographic variation, 95–96 multivariate analyses of, 94 negative and positive, survival of, 96 VATS, 98 Neoadjuvant chemoradiotherapy, pulmonary function alterations, 107 Neoadjuvant chemotherapy, pulmonary function alterations, 106–107
501
Index Neoadjuvant therapy, pulmonary function alterations, 105 Neoplastic transformation, 244 Nissen fundoplication, 249, 251 Non-acid reflux, surgical management antireflux surgery for, MII-pH monitoring, 260, 261 definitions and evaluation, 257–258 multichannel intraluminal impedence (MII) testing, 258 NERD, 258–259 studies of, 259–260 Non-erosive reflux disease (NERD), 258–259 Nonseminomatous germ cell tumors (NSGCT). See Mediastinal germ cell tumor Non-small cell lung cancer (NSCLC). See also N2 disease, thoracotomy marginal function and peripheral early stage, 140–141 for mediastinal restaging, PET (see Positron-emission tomography (PET), for mediastinal restaging) pneumonectomy, for stage IIIA, 119–123 VATS vs. open lobectomy cardiac complications, 80 and complete mediastinal lymphadenectomy, 77 complication rate, 78–79 high-risk patients, 82 immunologic effects, 83–84 intraoperative outcomes, 78 length of stay, 80–81 literature search, 77–78 morbidity, 78 oncologic efficacy, 82 operative mortality, 79 quality-of-life, 81–82 recommendations, 84–85 respiratory complications, 79–80 survival rates, 84 O Oncologic efficacy, VATS vs. open lobectomy, 82 Open esophagetomy, 214–217 Open laparotomy, giant paraesophageal hernia (PEH), 319
Open lobectomy vs. VATS, for NSCLC. See Non-small cell lung cancer (NSCLC) Open vs. VATS minimally invasive resection in non-thymomatous myasthenia gravis, 437 minimally invasive thymoma resection vs. open resection, 436–437 Ottawa Personal Decision Guide, for early stage breast cancer, 56–57 Oxford Centre for Evidence-based Medicine Grades of Recommendations, 16, 18 P Palmar hyperhidrosis, 470–472 Paraesophageal hernia (PEH), 3–4. See also Giant paraesophageal hernia (PEH) Partial fundoplication, 251, 254 Patient decision aids (PtDA) information and risk communication, 48–49 major elective operations, effects of, 51 quality of, 50, 51 steps, 49 structured guidance/coaching in, 49 SURE screening test, 49, 50 values clarification, 49 Patient selection EPP biomarkers of, 416–417 chemotherapy, 416 computed tomography, 415 EBUS/EUS/mediastinoscopy, 416 EPP extrapleural nodal metastases, 416 laparoscopy, 416 non-epithelioid MPM, 416 primary tumor, 416 hyperhidrosis, 469–475 pleurectomy, 407–411 Patient’s preferences, in decision making current approach, 48 decisional conflict, 45, 49 findings, 47–48 patient decision aids (PtDA)
information and risk communication, 48–49 major elective operations, effects of, 51 quality of, 50, 51 steps, 49 structured guidance/coaching in, 49 SURE screening test, 49, 50 values clarification, 49 preferencevalues sensitive, 45 primary data sources, 46 randomized controlled trials, criteria for, 46 shared decision making (SDM), 45–46 strategies for steps in, 51–52 systematic reviews, 52 Pectus excavatum (PE) complications after, 480–482 cosmetic results, 479 effects of, 477–478 methods, 477 patient evaluation, 478 physiologic improvement, 479–480 repair, 478–479 Percutaneous drainage, 451–457 Pericardial cysts. See Bronchogenic and pericardial cysts Perioperative arrhythmia prophylaxis, for lung resection atrial fibrillation (AF) incidence and clinical outcome, 172 clinical significance of, 172 efficacy of, 175 prevention strategies amiodarone, 174 diltiazem and verapamil, 174 magnesium, 174–175 partial sympathectomy, epidural analgesia, 174 recommendations for, 175–176 risk factors for age and gender, 173 serum markers, 173 VATS, 173 search strategy, 171 Peristalsis, fundoplication, 250, 251 Photodynamic therapy (PDT), 198, 410 Plastic stents, benign airway obstruction, 348–349
Index
502 Pleural empyema antibiotics and tube drainage, 389 empyema staging scheme, 383, 384 methodology exudative empyema, 383–384 fibrinopurulent empyema, 384–387 organizing empyema, 387–388 recommendations, 388–389 VATS, 383 Pleural space management, after pneumonectomy balanced drainage system, 164 chest tube, 161 Maxwell Box, 161, 162 methods, 162 recommendations, 163–164 results of, 162–163 three chamber drainage system, 162 Pleurectomy with chemotherapy, 409 and decortication (P/D), 407–408 methodology, 407 non-randomized comparative studies, 408, 409 patient selection for, 409–410 with photodynamic therapy, 410 pre-operative evaluation, 408 with radiation therapies, 409 recommendations, 410 Pleurodesis role, VATS. See Video assisted thoracoscopic surgery Pneumonectomy, 112, 114 after induction therapy, stage IIIA NSCLC early and long-term outcomes, 120–122 literature, searching methods, 119–120 observational studies of, 120 published evidence, 119–122 quality of life and residual function, 122 radiotherapy and chemotherapy combination, 123 randomized trials of, 121 recommendations, 122 pleural space management, 161–164 thoracotomy vs. VATS, 148, 150, 151
Polyflex stent, 348, 349 Positron-emission tomography (PET), for mediastinal restaging, 68, 69 benefits of, 65 clinical data, 64 and CT, reviewed studies, 62 issues, 64 methods, 61–62 N2 metastases response, to induction therapy, 63 recommendations, 65 study quality induction therapy, 63 vs. integrated PET/CT, 62 positive nodes, definition of, 62–63 timing of, 63 Post-fundoplication dysphagia, 249–250 Primary anastomosis, 359 Primary mediastinal nonseminomatous germ cell tumors (PMNSGCT), 441–448 Probabilistic analysis, in decision analytic model (DAM), 32–33 Prophylactic antireflux surgery, in lung transplantation fundoplication early vs. late, 264 pre-operative assessment and perioperative care for, 264–265 indications for, 264 methodology, 263 procedure selection, 265 quality of life, 265 recommendations, 265–266 safety of, 265 timing of, 263–264 Proton pump inhibitor (PPI), 245 Pulmonary function alterations, induction therapy chemotherapy and radiotherapy, effects of, 106 literature search strategy, 105 neoadjuvant chemoradiotherapy impact, on postoperative complications, 107, 108 neoadjuvant chemotherapy impact, on postoperative complications, 106–108 neoadjuvant therapy, role of, 105 operative intervention, optimal timing of, 107–108
recommendation, 108–109 research areas, 109 Pulmonary resection, induction therapy, 146 Pyloric drainage procedure, 244 Q Quality-adjusted life-years (QALYs), 26 Quality of life, 122 prophylactic antireflux surgery, in lung transplantation, 265 Quality-of-life, 81–82 Quality of life (QOL) weight, 26 R Radiofrequency ablation (RFA), 140, 141, 198–199 Radiotherapy induction, for resectable esophageal cancer, 207 Radiotherapy, pulmonary function alterations, 106 Regional lymphatics and lymph nodes, 224–225 Respiratory complications, VATS vs. open lobectomy, 79–80 Robotic-assisted thymectomy, 431 S Salvage esophagectomy, for persistent disease definitive chemoradiation therapy evidence for, 233–234 randomized controlled trials of, 234 with/without surgery, 234–235 methods, 233 outcome, 236–237 patient selection, 235 personal approach to, 237–238 recommendations and, 237 retrospective reviews of, 235 surgical resection, 236 toxicity of, 236 Sclerosis/chronic tube drainage. See also Malignant pleural effusion management methods of, 394 recommendation for, 396 Sealants use after lung resection air leak duration and incidence, 375–377
503
Index chest tube duration, 377–378 disparities among trials, 374–375 postoperative hospital stay, 378–380 randomized controlled trials, 373–374 pleural fluid drainage, 380 recommendation, 380 synthetic polyethylene-glycol based sealant, 381–382 Segmentectomy vs. lobectomy, for stage I lung cancer clinical trials, 130 considerations,in limited resection, 128–130 definitions and approach, 125–126 evidence for, limited resection, 126–128 recommendations and, 131 marginal lung function and peripheral stage I, optimal therapy for, 137, 138, 141 Self-expandable metallic stents (SEMS), 281, 284 benign airway obstruction fully covered, 350 uncovered/partially covered, 349–350 Self-expandable plastic stents (SEPS), 281 Self-expanding metallic stents, (TBM), 363–364 Serum tumor markers (STMs), 446 Shared decision making (SDM), 45–46, 52 Silicone stents benign airway obstruction, 347–348, 351 Silicone stents, for tracheobronchomalacia (TBM), 364 Society of Thoracic Surgeons (STS), 43 Spinal cord injured patients, diaphragm pacing (DP), 330–331 Standardized uptake value (SUV), 408 Statins, for perioperative arrhythmia prophylaxis, 174–176 Stents for benign airway obstruction, 347–351
for esophageal perforation and anastomotic leak, 279–284 Stereotactic radiotherapy (SRT), 138–141 Sublobar pulmonary resection, 137–138, 141 Surgeons, in decision making clinical process, surgeon factors age, 41 gender, 41 risk-taking attitude, 41 specialty training, 42 healthcare system factors medico-legal environment, 43 political environment, 42–43 practice environment, 42 methodology for, factors evaluation, 40 surgeon-patient relationship, models of, 39–40 Surgical/percutaneous drainage. See Percutaneous drainage Surgisis® mesh, 339, 340 Symptomatic malignant pericardial effusion approaches and procedures, 453 cost, 456 diagnosis, 454 drainage technique, 453 morbidity and mortality, 455 outcomes, patient populations, 452–453 published data, 451–452 relief of symptoms, 454 treatment of, 454 T Thoracotomy vs. VATS, after induction therapy, 145–151 Thymus, extent of resection MGFA, 429 non-thymomatous myasthenia gravis, 432 recommendations, 432 recommendations for, 432 robotic-assisted thymectomy, 431 thymectomy classification, 429–430 transcervical and transsternal (“maximal”) thymectomy, 431–432 transcervical thymectomy, 430 transsternal thymectomy, 431–432 VATS thymectomy, 430–431
Total artificial lung (TAL), 189–191 pulmonary artery to left atrium (PA-LA), 190 right atrium to pulmonary artery (RA-PA), 190 Toxicity, of salvage resection, 236 Tracheal reconstruction with autologous and engineered tissues circumferential defect aortic autograft, 355 immunosuppressive therapy and indirect revascularization, 355 myocutaneous flaps, 355–356 primary anastomosis, 353–354 end-to-end, 353 non-circumferential defect, 356–357 non end-to-end, 353 partial, 358, 359 pericardial patch reconstruction, 357, 358 primary anastomosis, 359 recommendations, 357–358 techniques, outcomes of, 358 Tracheobronchomalacia (TBM) self-expanding metallic stents, 363–364 silicone stents for, 364 Tracheobronchoplasty, membranous wall, 364–365 Transcervical and transsternal (“maximal”) thymectomy, 432 Transcervical extended mediastinal lymphadenectomy (TEMLA), 70 Transcervical thymectomy, 423, 430 Transhiatal esophagectomy (THE), 227 vs. transthoracic, 214–217 Transsternal thymectomy, 431 Transthoracic esophagectomy (TTE) vs. transhiatal, 214–217 Traumatic rib fracture chest wall defect, 487 flail chest, 485–487 intractable acute pain, 487 pulmonary herniation, 487 recommendations of, 488 rib fracture non-union, 487–488 thoracotomy for, 487
Index
504 Tumor, in limited resection location, 128–129 size, 128 U Ultraflex stents, 349 Upper esophageal sphincter (UES) myotomy, 294–295 Utility/quality of life (QOL) weight, 26 V VATS. See Video assisted thoracoscopic surgery VATS thymectomy, 430–431 Venous thrombo-embolism (VTE) prophylaxis, in lung resection evidence, 165, 166 heparin extended use of, 166 use, timing of, 166 mechanical and pharmacologic, 168 methods, 165
recommendations, 168 thoracic surgical patients heparin prophylaxis, 166 intermittent compression devices in, 166 studies on, 167 Venovenous carbon dioxide removal (VVCO2R), 189 Ventilator induced diaphragm dysfunction (VIDD), 329 Video assisted thoracoscopic surgery (VATS), 383, 387, 388 lobectomy, 137, 141 nodal assessment, 72–73 vs. open lobectomy, for NSCLC (see Non-small cell lung cancer (NSCLC)) pleurodesis role chest drain management, 403 clinical issues, 399–400 intraoperative pleurodesis, 402–403 methods, 400 routine CT scanning, 401 surgical approach, 401–402
timing of surgical consultation, 400–401 postoperative supraventricular arrhythmias, 173 vs. thoracotomy, after induction therapy chemotherapy, 148 lobectomy, 150, 151 lung resection, 147, 149 mortality of, 148, 149 nodal involvement, 151 pneumonectomy, 148, 150, 151 pulmonary resection, risks of, 146 radiation, 149 rationale and use of, 145–146 studies on, 147 W Wallstent stents, 349 Z Zenker’s diverticula. See Cricopharyngeal diverticula, optimal therapy