Bone Metastases: A translational and clinical approach

Bone Metastases

Cancer Metastasis – Biology and Treatment VOLUME 12 Series Editors Richard J. Ablin, Ph.D., University of Arizona, College of Medicine and The Arizona Cancer Center, AZ, U.S.A. Wen G. Jiang, M.D., Wales College of Medicine, Cardiff University, Cardiff, U.K. Advisory Editorial Board Harold F. Dvorak, M.D. Phil Gold, M.D., Ph.D. Danny Welch, Ph.D. Hiroshi Kobayashi, M.D., Ph.D. Robert E. Mansel, M.S., FRCS. Klaus Pantel, Ph.D.

For further volumes: http://www.springer.com/series/5761

Bone Metastases A Translational and Clinical Approach Edited by

Dimitrios Kardamakis, M D, P hD, DM R T Department of Radiation Oncology, University of Patras Medical School, Patras, Greece

Vassilios Vassiliou, M D, P hD Department of Radiation Oncology, University of Patras Medical School, Patras, Greece and

Edward Chow, M B B S, P hD, F R CP C Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

Editors Dr. Dimitrios Kardamakis, MD, PhD, DMRT University of Patras Medical School Dept. of Radiation Oncology 265 04 Patras Greece [email protected]

Dr. Vassilios Vassiliou, MD, PhD University of Patras Medical School Dept. of Radiation Oncology 265 04 Patras Greece [email protected]

Dr. Edward Chow, MBBS, PhD, FRCPC University of Toronto Sunnybrook Health Sciences Centre Dept. of Radiation Oncology 2075 Bayview Avenue Toronto, Ontario M4N 3M5 Canada [email protected]

ISBN 978-1-4020-9818-5

e-ISBN 978-1-4020-9819-2

DOI 10.1007/978-1-4020-9819-2 Library of Congress Control Number: 2009920108 c Springer Science+Business Media B.V. 2009  No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com

To Katerina and Anastasis, whose support and patience make it possible Dimitrios Kardamakis To my family for the invaluable help they have offered and to cancer patients and researchers who struggle against cancer in their everyday life Vassilios Vassiliou To my colleagues and my patients who teach and guide me Edward Chow

Preface by Editors

Bone metastases are common in the event of malignancy and after liver and lungs, bone is the third most common site of distant metastases. Metastatic bone disease is inevitably associated with severe complications such as pain, impaired mobility, pathological fractures, spinal cord or root compression and hypercalcemia. These complications deteriorate severely the clinical and physical status of patients, affect negatively their quality of life and can also be life threatening. The understanding of the pathophysiology of bone metastases and the investigation and application of newer diagnostic and therapeutic modalities is therefore of uttermost importance. “Bone metastases: A translational and clinical approach” is intended to serve both as an introductory and reference book that focuses on the field of metastatic bone disease. All invited contributing authors are expert researchers who have prominent publications in the field of bone metastases or related topics. More specifically, the book describes thoroughly the molecular and cellular mechanisms involved in the formation of bone metastases, comments on the role of angiogenesis, presents the newer advances made in the understanding of the clinical picture and symptoms of patients, analyses the role of bone markers in research and clinical practice and deals with all aspects of imaging modalities applied for the detection and evaluation of bone metastases. Furthermore, it covers extensively the use of radiotherapy, surgery and systemic treatments for the management of metastatic bone disease, giving special attention to the role and indications of each therapeutic mode. New therapeutic approaches such as the combination of radiotherapy or radiopharmaceuticals with bisphosphonates are also commented upon. Finally, two chapters are dedicated to the assessment of the therapeutic response by applying clinical, radiological and biochemical parameters or methods. Overall the textbook presents thoroughly all aspects of metastatic bone disease, providing comprehensive and concise information that serves as a reference for researchers, oncologists, orthopaedic surgeons, clinicians and medical students alike. Moreover it can serve as a guide for the clinical and therapeutic management of patients with metastatic bone disease. The editors would like to thank all contributing authors for their scholarly efforts and complement them for their outstanding work. We also thank Dr Richard Ablin and Wen Jiang, editors of the book series on Cancer Metastasis: Biology vii

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and Treatment, for inviting us to edit a volume for the aforementioned book series. Finally, the assistance from the Publishing Editor Dr. Christina Miranda Alves dos Santos and her assistant, Ms. Melania Ruiz Esparza was more than valuable. Patras Patras Toronto, ON

Dimitrios Kardamakis Vassilios Vassiliou Edward Chow

Contents

Part I Fundamental Concepts of Bone Metastases 1 BONE ANATOMY, PHYSIOLOGY AND FUNCTION . . . . . . . . . . . . . Vassiliki Tzelepi, Athanassios C. Tsamandas, Vassiliki Zolota and Chrisoula D. Scopa

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2 PATHOPHYSIOLOGY OF BONE METASTASES . . . . . . . . . . . . . . . . 31 G. David Roodman 3 ANGIOGENESIS AND BONE METASTASIS: IMPLICATIONS FOR DIAGNOSIS, PREVENTION AND TREATMENT . . . . . . . . . . . 51 Pelagia G. Tsoutsou and Michael I. Koukourakis 4 NATURAL HISTORY, PROGNOSIS, CLINICAL FEATURES AND COMPLICATIONS OF METASTATIC BONE DISEASE . . . . . 77 Vassilios Vassiliou, Edward Chow and Dimitrios Kardamakis 5 BONE BIOMARKERS IN RESEARCH AND CLINICAL PRACTICE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Janet E. Brown and Edward Chow Part II Imaging Modalities 6 RADIOLOGIC EVALUATION OF SKELETAL METASTASES: ROLE OF PLAIN RADIOGRAPHS AND COMPUTED TOMOGRAPHY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Christina Kalogeropoulou, Anna Karachaliou and Peter Zampakis

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7 THE CONTRIBUTION OF NUCLEAR MEDICINE IN THE DIAGNOSIS OF BONE METASTASES . . . . . . . . . . . . . . . . . . 137 Andor W.J.M. Glaudemans, Marnix G.E.H. Lam, Niels C. Veltman, Rudi A.J.O. Dierckx and Alberto Signore 8 MAGNETIC RESONANCE IMAGING OF METASTATIC BONE DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Ekaterini Solomou, Alexandra Kazantzi, Odysseas Romanos and Dimitrios Kardamakis Part III Therapeutic Strategies 9 RADIOTHERAPY AND BONE METASTASES . . . . . . . . . . . . . . . . . . . 185 Jan W.H. Leer and Yvette M. van der Linden 10 BIPHOSPHONATES IN THE MANAGEMENT OF METASTATIC BONE DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Fred Saad and Arif Hussain 11 COMBINED RADIOTHERAPY AND BISPHOSPHONATES: STATE OF ART . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Vassilios Vassiliou and Dimitrios Kardamakis 12 BIPHOSPHONATES IN THE TREATMENT OF BONE METASTASES – OSTEONECROSIS OF THE JAW . . . . . . . . . . . . . . . 251 Cesar Augusto Migliorati 13 SURGICAL MANAGEMENT OF BONE METASTASES . . . . . . . . . . 263 Markku Nousiainen, Cari M. Whyne, Albert J.M. Yee, Joel Finkelstein and Michael Ford 14 THE ROLE OF CHEMOTHERAPY IN THE TREATMENT OF BONE METASTASES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 Thomas Makatsoris and Haralabos P. Kalofonos 15 HORMONOTHERAPY OF BONE METASTASES . . . . . . . . . . . . . . . . 299 Konstantinos Kamposioras and Evangelos Briasoulis 16 RADIONUCLIDE THERAPY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Giovanni Storto

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Part IV Assessment of Therapeutic Response 17 ASSESSMENT OF THERAPEUTIC RESPONSE . . . . . . . . . . . . . . . . . 345 Orit Freedman, Mark Clemons, Vassilios Vassiliou, Dimitrios Kardamakis, Christine Simmons, Mateya Trinkaus and Edward Chow 18 OUTCOME MEASURES IN BONE METASTASES CLINICAL TRIALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 Amanda Hird and Edward Chow Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

Contributors

E. Briasoulis Department of Medical Oncology, Ioannina University Medical School, Ioannina, Greece, [email protected]; [email protected] J.E. Brown Cancer Research UK Clinical Fellow/Senior Lecturer in Medical Oncology, Cancer Research UK Clinical Centre in Leeds, St James’s Hospital, University of Leeds, Leeds, UK, [email protected] E. Chow Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5, [email protected] M. Clemons Department of Medical Oncology, Princess Margaret Hospital (5-205), 610 University Avenue, Toronto, Ontario, Canada M5G 2M9, [email protected] R.A.J.O. Dierckx Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands, [email protected] O. Freedman University of Toronto, Toronto, Ontario, Canada, [email protected] J. Finkelstein Department of Surgery, Division of Orthopaedic Surgery, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., MG-361, Toronto, Ontario, Canada M4N 3M5, [email protected] M. Ford Division of Orthopaedic Surgery, Department of Surgery, Sunnybrook Health Sciences Centre 2075 Bayview Ave., MG-375, Toronto, Ontario, Canada M4N 3M5, [email protected] A.W.J.M. Glaudemans Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, 9713 GZ, The Netherland, [email protected] xiii

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A. Hird Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5, [email protected] A. Hussain Pathology and Biochemistry, Director, Medical Genito-Urinary Oncology, University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA, [email protected] H.P. Kalofonos Division of Oncology, University of Patras Medical School, 26504 Patras, Greece, [email protected] C. Kalogeropoulou Department of Radiology, University Hospital of Patras, 26500 Patras, Greece, [email protected] K. Kamposioras University General Hospital “Attikon”, Athens, Greece, [email protected] A. Karachaliou Department of Medical Physics, University of Patras Medical School, 26500 Patras, Greece, [email protected] D. Kardamakis Department of Radiation Oncology, University of Patras Medical School, 26500 Patras, Greece, [email protected] A. Kazantzi Department of Clinical Radiology, Magnetic Resonance Unit, University of Patras Medical School, 26500 Patras, Greece, [email protected] M.I. Koukourakis Radiation Oncology Department, Democritus University of Thrace, Alexandroupolis, Greece, [email protected] M.G.E.H. Lam Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands, [email protected] J.W.H. Leer Department of Radiotherapy, UMC St Radboud, Nijmegen, The Netherlands, [email protected] T. Makatsoris Division of Oncology, University of Patras Medical School, 26504 Patras, Greece, [email protected] C.A. Migliorati NSU College of Dental Medicine, 3200 S. University Drive, Fort Lauderdale, Florida 33328, USA, [email protected] M.T. Nousiainen Department of Surgery, University of Toronto, Sunnybrook Health Sciences Centre, Holland Orthopaedic and Arthritic Centre, Toronto, Ontario, Canada M4Y 1H1, [email protected]

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O. Romanos Department of Clinical Radiology, Magnetic Resonance Unit, University of Patras Medical School, 26500 Patras, Greece, [email protected] G.D. Roodman Veterans Affairs Pittsburgh Healthcare System, Department of Medicine/Hematology-Oncology, Pittsburgh, Pennsylvania; and University of Pittsburgh, Department of Medicine/Hematology-Oncology, Pittsburgh, Pennsylvania, USA, [email protected] F. Saad Division of Urology, Director, Genito-Urinary Oncology, University of Montreal Hospital Centre, U of M Endowed Chair in Prostate Cancer, University of Montreal, 1560 Sherbrooke St east, Montreal, Quebec, Canada H2L 4M1, [email protected] C.D. Scopa Department of Pathology, University of Patras School of Medicine, Patras, Greece, [email protected] A. Signore Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands; Medicina Nucleare, “Sapienza” University, 2nd Faculty of Medicine, 00189 Rome, Italy, [email protected] C. Simmons Department of Medical Oncology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5, [email protected] E. Solomou Department of Clinical Radiology, Magnetic Resonance Unit, University of Patras Medical School, 26500 Patras, Greece, [email protected] G. Storto IRCCS, CROB, Rionero in Vulture; Institute of Biostructures and Bioimages, CNR, Naples; Department of Biomorphological and Functional Sciences, University “Federico II”, Naples, SDN Foundation, Institute of Diagnostic and Nuclear Development, Naples, Italy, [email protected] M. Trinkaus Department of Medical Oncology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5, [email protected] A.C. Tsamandas Department of Pathology, University of Patras School of Medicine, Patras, Greece, [email protected] P.G. Tsoutsou Radiation Oncology Department, Democritus University of Thrace, Alexandroupolis, Greece, [email protected] V. Tzelepi Department of Pathology, University of Patras School of Medicine, Patras, Greece, [email protected]

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Y.M. van der Linden Radiation Oncologist, Radiotherapeutic Institute Friesland, Leeuwarden, The Netherlands, [email protected] V. Vassiliou Department of Radiation Oncology, University of Patras Medical School, 26500 Patras, Greece, [email protected] N.C. Veltman Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands, [email protected] C.M. Whyne Department of Surgery, University of Toronto, Orthopaedic Biomechanics Laboratory, Sunnybrook Health Sciences Centre, IBBME and IMS, Toronto, Ontario, Canada M4N 3M5, [email protected] A.J.M. Yee Department of Surgery, University of Toronto, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Rm MG 371-B, Toronto, Ontario, Canada M4N 3M5, [email protected] P. Zampakis Department of Radiology, University Hospital of Patras, 26500 Patras, Greece, [email protected] V. Zolota Department of Pathology, University of Patras School of Medicine, Patras, Greece, [email protected]

Part I

Fundamental Concepts of Bone Metastases

Chapter 1

BONE ANATOMY, PHYSIOLOGY AND FUNCTION Vassiliki Tzelepi, Athanassios C. Tsamandas, Vassiliki Zolota and Chrisoula D. Scopa Department of Pathology, Room F1-35, University of Patras Medical School, 26504 Patras, Greece, e-mail: [email protected]

Abstract:

Bone metastases depend on reciprocal interactions between malignant cells and bones that will determine the homing and growth of malignant cells in the bone microenvironment. Additionally, the final step of bone metastasis (bone destruction or production) that determines the clinical phenotype of the metastatic foci (osteolytic or osteoblastic metastasis, respectively) is actually mediated by the bone cells under the influence of various factors secreted by malignant cells. In fact, metastatic lesions are the result of disruption of the normal bone remodeling process. Thus, understanding of the normal histology and physiology of the bone is fundamental in the elucidation of bone metastasis mechanisms and the development of therapeutic interventions. This chapter presents a description of the normal structure, physiology and function of the bone, emphasizing the aspects that are most relevant to the metastatic process. It begins with a description of the anatomy and histology of normal bone and continues with a detailed discussion on the microscopic and functional characteristics of bone cells and non-cellular matrix. Finally, a discussion on embryological development of bones, comments on bone functions and a conclusion on how the different constituents of bones are involved in the highly coordinated processes of bone remodeling, mechanotransduction and mineral homeostasis, are presented. By reviewing the structure, physiology and function of the bone, the reader will be able to understand the mechanisms implicated in bone metastasis, the pathobiologic basis of the clinical phenotype and the mechanism of action of the therapeutic strategies used in clinical practice.

Key words: Osteoblast · Osteoclast · Osteocyte · Remodelling · Mechanotransduction · Mineral homeostasis · Intramembranous ossification · Enchondral ossification · Cancellous bone · Compact bone D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 1,  C Springer Science+Business Media B.V. 2009

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1.1 Introduction Bones are individual organs composed of multiple tissues including bone, cartilage, fat, connective tissue, hematopoietic tissue, nerves and vessels. The human skeleton is composed of 206 bones and is divided into the axial skeleton that includes the skull, hyoid, sternum, ribs and vertebrae and the peripheral skeleton that includes the bones of the limps and the pelvis. The acral skeleton is part of the peripheral skeleton and consists of the bones of the hands and feet [1]. Bone formation and function involves a complex coordination among multiple cell types. Additionally, bones are dynamic structures that are constantly remodeled during life in response to various mechanic and hormonic stimuli. This process requires a tightly regulated interplay among the various cell types of bone. Bones are classified according to their shape and size in cuboid bones (i.e., carpal and tarsal bones), flat bones (bones of the skull, ilium) and tubular bones. The latter are further subdivided into long (i.e., humerus, radius, ulna, femur, tibia, fibula) and short (i.e., metacarpal and metatarsal bones) tubular bones [1]. Additionally, bones are classified according to the manner of embryological development. Thus, membranous bones are formed de novo from undifferentiated connective tissue (intramembranous ossification) whereas enchondral bones are formed by enchondral ossification in which undifferentiated mesenchymal cells differentiate into chondrocytes and form a cartilaginous anlage that will subsequently be replaced by bone [1, 2]. Enchondral ossification of long bones forms the growth plate which divides bone into distinct anatomic regions. The epiphysis is the bone region located from the growth plate to the joint surface. The region on the other side of the growth plate is called metahysis, whereas the bone in the central region in between the two metaphyses is the diaphysis. Metaphysis is distinguished from diaphysis due to its higher vascularization and higher proportion of cancellous bone [2]. However, despite their differences in location, size, shape, and embryological development, bones are composed of the same cell types and in many cases they are histologically indistinguishable [1].

1.2 Bone Histology and Structure Anatomically, bones are composed of the periosteum, the cortex and the medulla. Periosteum surrounds the external surfaces of bones except in the region of articular cartilage [1] and serves as a transitional region between the bone and the adjacent soft tissues [3]. The cortex lies beneath the periosteum and is thicker along surfaces that bear greater load such as the diaphysis of long bones. The medulla represents the inner layer of bones and contains blood vessels, nerves and the hemapoietic or fatty bone marrow [1]. Periosteum is composed of two distinct layers, an outer fibrous and an inner cellular layer. The outer layer is in continuity with the overlying tissues and consists of fibroblasts, collagen, elastin fibers and a network of nerves and vessels. The inner cellular layer contains osteoprogenitor cells, fibroblasts and osteoblasts,

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along with microvessels and sympathetic nerves. Cellularity of the inner layer decreases with age since both osteoprogenitor cells and osteoblasts become fewer in number with maturity. Additionally, fibroblasts and vascular density of periosteum decrease with age. These age-related changes possibly contribute to the decline of periosteal bone formation rate and responsiveness to hormones and cytokines noted with increased age of the organism [1, 3]. The periosteum contributes to the regulation of cortical thickness and the maintenance of bone size and shape. The cortex is composed of compact bone whereas the medulla is composed of cancellous bone. Compact bone is hard and tan-white macroscopically and denser than cancellous bone on X-rays. On the contrary, cancellous bone is fenestrated. The percentage of compact and cancellous (or trabecular) bone tissue in a bone depends on the biomechanical requirements. Bones that are exposed to large torsional forces, like long bones, are composed mainly (80%) of compact bone, whereas bones that transmit weight-bearing forces, such as the vertebral bones, are predominantly composed of cancellous bone. In long bones, compact bone tissue is thicker in the middiaphysis, an area that is exposed in large torsial and weight-bearing forses, and thinner adjacent the articular surfaces where cancellous bone predominates and is responsible for the transmission of weight-bearing forces. Histologically, compact and cancellous bone tissues are made of two types of bone: woven and lamellar bone (Fig. 1.1). This categorization depends on the organization of type I collagen fibers of bones’ extracellular matrix. Both types can be found in cancellous and compact bone, but represent different phases of bone development. Woven bone is formed during periods of rapid osteogenesis as in the case of embryological development, normal bone growth, fracture repair and neoplastic bone

Fig. 1.1 Tissue section adjacent a fracture. Woven bone is deposited above lamellar bone

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formation (bone forming neoplasms, Codman’s triangle). It is an immature, disorganized type of bone that is characterized by an irregular arrangement of collagen fibers and a random distribution of cells, whose long axis is parallel to the neighboring collagen fibers. Woven bone is more cellular and more mineralized than lamellar bone. A characteristic feature of woven bone is that it is rapidly formed and resorbed and due to its structural organization can resist forces equally in all directions. Additionally, even though it is weaker than lamellar bone, it is more flexible [1, 4]. Lamellar bone is an organized type of bone tissue that is slowly fabricated and eventually replaces woven bone (Fig. 1.1). In normal adults, the entire skeleton is made of lamellar bone [1, 4]. It is organized in lamellas, which are composed of up to five sublayers of mineralized collagen with intermingled osteocytes [5]. Collagen fibers are distributed in parallel arrays and osteocytes are deposited in an organized fashion, since their long axis is parallel to the regularly deposited collagen fibers. As compared to woven bone, lamellar bone displays a decreased cellularity. Additionally, in contrast to woven bone, its mineralization occurs slowly and continues long after the initial deposition of organic matrix. Minerals are deposited almost exclusively within collagen fibers. Thus, lamellar bone is stronger and more rigid, but has less elasticity than woven bone [1, 4]. Lamellae of cortical (compact) bone follow three architectural patterns: circumferential, concentric and interstitial. Circumferential lamellae are the most common architectural pattern in the developing skeleton. They are the first lamellae to be deposited, being gradually replaced by concentric lamellae that surround the Haversian canals (Fig. 1.2). The Haversian canals and the lamellae that surround it are known as secondary osteons or Haversian systems. A few circumferential lamellae remain in the inner and outer surface of compact bone (just beneath the periosteum and along the endosteum, respectively) and are associated with bone growth during adult life, whereas the rest compact bone in adult life is made of concentric lamel-

Fig. 1.2 (A) Demineralized section of adult cortical bone. Haversian canals are surrounded by concentric lamellae; (B) Haversian canals contain blood vessels and mesenchymal cells. Bone lining cells and osteoblasts line the surface of the canal (arrow). Osteocytes reside in their lacunae (arrowhead)

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lae. The remaining spaces between the concentric lamellae are filled by interstitial lamellae [1, 2, 4]. The Haversian canals are a part of a branching interconnecting network that courses the cortex and are viewed as circular or cylindrical structures on tissue sections depending on the plan of section. They are filled with loose connective tissue stroma that contains vessels, nerves and mesenhymal cells (including stem cells) and are created by bone resorption. The process usually begins in circumferential lamellae of the endosteal surface of compact bone and rarely in lamellae of the sub-periosteal surface. As resorption proceeds, a canal is formed in which osteoclastic activity is oriented in the leading edge (cutting cone) followed by osteoblastic activity and new bone formation. Osteoblasts deposit lamellae of bone in a targetlike fashion around the canal. This action gradually decreases the diameter of the initial canal and create the concentric lamellae of compact bone. In each lamellae, collagen fibers are oriented in parallel to each other and to the long axis of the cells, a fundamental characteristic of lamellar bone. However, adjacent lamellae display slightly different pitches which enhances the strength of the bone [1, 4]. Nutritional support of the cells embedded in bone matrix depends on diffusion of oxygen and metabolites from vessels of the Haversian canal. Each Haversian canal and the lamellae that surround it comprise a relatively self-contained metabolic unit. Additionally, osteocyte communication through a complex network of cell processes is usually limited within the boundaries of a Haversian system. Cement lines define the boundaries of each Haversian system. They are thin and appear basophilic on tissue sections. Cement lines are believed to represent the remnants of mineralized substance that is secreted at the initial phase of bone formation and are characterized by reduced mineralization, absence of collagen and high concentration of sulfated mucosubstances. It has been proposed that cement lines mark the site of bone resorption that precedes bone formation. In normal bone, cement lines delineate the boundaries of the Haversian system in an orderly arranged pattern. In Paget disease of the bone, cement lines display a mosaic arrangement, representing the disorganized bone formation, characteristic of the disease [1, 6]. The space between the Haversian systems is filled up by interstitial lamellae. In contrast to the circular, target-like arrangement of the concentric lamellae, interstitial lamellae are irregularly shaped and represent remnants of previous generations of circular lamellas. Osteocytes of interstitial lamella are located far away from Haversian canals and may have no access to nutritional supplies and oxygen. Consequently they undergo necrosis leaving their lacuna empty [1, 4]. Cancellous bone consists of an interconnected network of trabeculae of lamellar bone and is located within the medullary cavity of bones. Red hematopoietic or yellow fat marrow resides between the trabeculae (Fig. 1.3). Large trabeculae may contain Haversian systems, surrounded by concentric lamellae, whereas smaller ones are composed of lamellae of bone oriented in the same direction as the trabeculae [1, 4]. Trabeculae that do not contain blood vessels are vascularized from adjacent bone marrow [2]. The surfaces of the trabeculae are lined by quiescent osteoblasts, being the areas where bone resorption begins. The large surface provided by the trabeculae of cancellous bone enables the skeleton to rapidly respond to

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Fig. 1.3 (A) Demineralized section of cancellous bone. Note the trabeculae, surrounded by yellow bone marrow (adipose tissue); (B) The trabeculae are composed of lamellae of bone oriented in the same direction as the trabeculae. Quiescent osteoblasts and bone lining cells line the surface of the trabeculae (arrow)

metabolic demands. Trabeculae are deposited in relation to the lines of mechanical stress according to Wolff’s law and distribute weight-bearing forces along a variety of different pathways [1, 4].

1.3 Bone Cell Types: Histology and Physiology Bone tissue, regardless of its type contains the same cell types: osteoblasts, osteoclasts, osteocytes and bone-lining cells.

1.3.1 Osteoblasts Osteoblasts are responsible for the synthesis and calcification of bone extracellular matrix and also regulate osteoclast maturation and activation. They derive from spindle-shaped cells known as osteoprogenitor cells that lie in the periosteum, the Haversian system and medullary canals [1, 6]. The differentiation of osteoblasts from osteoprogenitor cells during bone development and growth is not fully understood. However, some transcription factors that control osteogenesis have been identified. Runt-related transcription factor 2 (Runx2) and sex determining region Y-box 9 (Sox9) are basic regulators of osteogenesis and chondrogenesis. Osterix (Osx) is a zinc finger-containing protein that is important for osteoblastic differentiation. It appears that Runx2 regulates early cartilagous and pre-osteoblastic differentiation and plays an important role in the formation of cartilage anlage during enchondral bone formation, whereas Osx is important for commitment of preosteoblasts to osteoblastic phenotype [6]. However, regulation of osteoblast development in adult life remains largely unknown. Even though Runx2 seems to participate in the regulation of the activity of mature osteoblasts, transgenic expression of Runx2 in immature osteoblasts results in osteopenia, due to impaired osteoblastic maturation and enhanced osteoclastic activity. Thus, Runx2, apart from its role in osteoblasts, may be implicated in the regulation of osteoclastic function. Moreover, Runx2 expression in osteoblasts has

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Fig. 1.4 (A) Active osteoblasts line the surface of a trabeculae (arrows) and produce osteoid (arrowhead) (B) Multinucleated osteoclasts in resorption pits (arrows)

different effects depending on the stage of osteoblastic maturation and temporal control of Runx2 is important for the regulation of osteoblastic activity [7]. Osteoblasts line all bone surfaces and are spindle-shaped when they are metabolically inactive (Fig. 1.3) [1]. Some authors designate the metabolically inactive, spindle shaped osteoblasts as preosteoblasts [8]. Preosteoblast retain the capacity to proliferate but do not deposit bone matrix. They can produce type I collagen precursor molecules and express osteonectin, alkaline phosphatase, insulin-like growth factor, PTH-receptor and several integrins. Preosteoblasts differentiate into active osteoblasts, which are polyedral cells with abundant amphophilic to basophilic cytoplasm, eccentric nucleus with one to three nucleoli and prominent perinuclear halo (Fig. 1.4A). These cells are actively producing bone, but do not divide [8]. Ultrastructuraly, active osteoblasts have a well-developed Golgi apparatus, which corresponds to the perinuclear halo often seen in tissue sections, extensive granular endoplasmic reticulum, numerous mitochondria and abundant lysosomes [1]. The ultrastructure characteristicts of osteoblasts impart their function which is to produce a variety of extracellular matrix components [2]. Bone sialoprotein, osteocalcin, vitamin D3 receptor, vitronectin, thrompospondin, decorin and several bone morhogenetic proteins (BMP) are expressed by active osteoblasts, but not preosteoblasts and help the discrimination between the two cell types [8]. Type I collagen and alkaline phosphatase are considered markers of early osteoblastic differentiation (preosteoblast), whereas osteocalcin is a molecular marker for the late stage of osteoblastic differentiation [6]. Osteoblasts display multiple cytoplasmic processes that connect the cells with adjacent osteoblasts and osteocytes via gap junctions and mediate the propagation of signals among these cells [1, 9, 10]. Gap junctions are intercellular junctional complexes, formed by two juxtaposed hemichannels located in adjacent cellular membranes. Each hemichannel, also called connexon, is a hexameric of transmembrane proteins (connexins). This formation creates a transcellular conduit that permits the diffusion of ions, metabolites and small signaling molecules between the two cells and forms a functional syncytium that permits cell communication. Gap junction permeability and selectivity is dictated by its specific connexin composition, which allows a tight regulation of the type of signals that can be diffused.

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Signaling through gap junctions plays a critical role in osteoblast and osteocyte response to mechanic and hormonic stimuli. Mutations of gap junction proteins in mouse models and humans genetic diseases (i.e., oculodentodigital dysplasia, Charcot-Marie-Toth disease) are associated with skeleton malformations, which highlight their role in bone development and growth [9, 10].

1.3.2 Osteocytes As soon as osteoblasts become entrapped in the matrix they produce, they are called osteocytes. Osteocytes are the most common cell type of the bone, representing the 95% of all bone cells. Osteocytes’ half life is 25 years, whereas osteoblasts survive for up to three months and osteoclasts have a lifespan of only a few weeks [1, 8]. However, a small proportion of osteoblasts will become osteocytes (up to 30%). Most osteoblasts undergo apoptosis whereas others transform into inactive surface lining osteoblasts [8]. As active osteoblasts produce bone matrix (osteoid), they become embedded into their product. In this early stage of osteoblast to osteocyte differentiation, osteocytes are called large osteocytes, young osteocytes or osteoid-osteocytes. These osteocytes are larger than older osteocytes, retain their ability to synthesize collagen and their cytoplasm is characterized by a well developed Golgi apparatus. As mineralization of osteoid proceeds, osteocytes become smaller due to reduction in the endoplasmic reticulum and Golgi apparatus. Thus, protein synthesis also diminishes and these cells no longer express some of the markers of early osteocyte phenotype (osteocalcin, bone sialoprotein, alkaline phosphatase). Finally mature osteocytes reside in a lacunar space in the bone extracellular matrix (Fig. 1.2B) [8]. On histologic examination, osteocytes have small amounts of cytoplasm surrounding their nuclei in the lacunal space, but possess numerous long and delicate cytoplasmic processes (dendrites) that transverse the bone matrix through small tunnels called canaliculi. Their nucleus is not always visible in routine sections due to its small size [1]. Gap junctions are formed between their processes and the processes of neighboring osteocytes and surface osteoblasts and enable communication between cells. Thus, osteocytes are by no means isolated due to their remote location and envelopment in rigid mineralized extracellular matrix. Their long processes provide a large surface for contact with the matrix and extracellular fluid along the canaliculi and create a complex and integrated cell network. These properties are fundamental for their response to the mechanical and metabolic demands of the organism, since they represent sensors of strain stimuli. Osteocytes are stimulated by mechanical stimuli and influence the activity of osteoprogenitor cell, osteoblasts and osteoclasts, which in turn respond by remodeling bone mass according to environmental requirements (Wolff’s law) [11, 12]. Furthermore, osteocytes are fundamental in mineral homeostasis since they respond to changes in ion concentrations and stimulate exchange of ions between bone matrix and extracellular fluid [13]. Another function of osteocytes that is not characteristic of human osteocytes but has been well described in other vertebrate species, is osteocytic osteolysis.

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Osteocytes have a limited ability of bone resorption, which may be important for mineral mobilization during periods of increased requirements, such as pregnancy or lactation [8].

1.3.3 Osteoclasts Osteoclasts are multinucleated giant cells that mediate the resorption of bone matrix (Fig. 1.4B). They originate from fusion of preosteoclasts that derive from mononuclear hematopoietic progenitor cells of the granulocytic-macrophage colony-forming unit (GM-CFU) and the macrophage colony-forming unit (M-CFU) [1, 4, 14–20]. Various cytokines (interleukin -1, -3, -6, -11, -13, -18, tumor necrosis factor) and growth factors (granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor) regulate the development, differentiation and activity of osteoclasts [21]. Identification of the transcription factors implicated in osteoclastogenesis was largely based on studies of mutant mice with osteopetrosis. In fact, the first evidence of the hematopoietic origin of osteoclasts came from mice with osteopetrosis that were cured after injection of normal spleen cells [18]. A few years later and based on the results obtained from mice, a 3.5 month old girl with osteopetrosis was cured with bone marrow transplantation from her brother. The Y chromosome was present in osteoclasts but not in osteoblasts or other cells of the bone, thus establishing the hematopoietic origin of osteoclasts in humans [22]. Macrophage differentiation from progenitor cells is dependent on the transcriptional factor PU-1. Mice deficient in this factor lack not only macrophages, but also osteoclasts, due to deficiency of osteoclast progenitors. c-Fos is also required for osteoclast differentiation but its effect is distal to the activity of PU-1. Mice that lack c-Fos have decreased numbers of osteoclasts and increased number of macrophages, since c-Fos is implicated in the commitment of hematopoietic precursors to osteoclastic differentiation. NF-kB is also critical for the development of osteoclasts from macrophage precursors [15]. Farther maturation of osteoclasts is tightly regulated by adjacent cells especially osteoblasts and bone marrow stromal cells. TNF family receptors and ligands mediate a molecular cross talk between osteoclasts and osteoblasts that ensures the tight co-ordination of bone formation and resorption, that is vital to successful bone remodeling. RANK (receptor activator for nuclear factor kappa B) is a receptor expressed on preosteoclasts. Binding to its ligand (RANKL), which is located on the cell membrane of osteoblasts and bone marrow stromal cells, stimulates osteoclastogenesis. Its expression is upregulated by PTH, vitamin D, and various cytokines (PGE2, IL1a, TNF-a) that stimulate bone resorption. RANK, after binding to its ligand, activates TNF receptor-associated factors (TRAFs) which have been shown to activate NF-κB, c-jun N-terminal kinase (JNK) and c-fos [14]. These factors seem to be important for osteoclast differentiation and activity, since mice harboring mutations in their genes display osteopetrosis either due to low number of osteoclasts or due to the presence of a normal number of inactive osteoclasts [15].

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Osteoblasts and bone marrow stromal cells also produce a second factor that is fundamental for ostoclastogenesis. Macrophage colony stimulating factor (M-CSF) is produced by osteoblasts and bone marrow stromal cells and binds to its receptor on osteoclast precursors and stimulates their survival and proliferation. In fact, M-CSF enhances the proliferation of osteoclast progenitor cells which differentiate into osteoclasts under the influence of RANKL. Genetic modification of M-CSF gene in mouse results in osteopetrotic phenotype due to failure of osteoclast development. However, osteopetrosis resolves spontaneously over time as a result of enhanced expression of GM-CSF. Thus, M-CSF and GM-CSF are redundant in osteoclastogenesis [15]. Osteoprotegerin (also known as osteoclastogenesis inhibitory factor, OCIF) acts as a negative regulator of osteoclastogenesis. It is a soluble receptor of RANKL and is produced by various cells, including osteoblasts, hematopoietic bone marrow cells and immune cells. It acts as a decoy receptor that binds to RANKL and prevents activation of RANK and osteoclast development and activation [15, 23]. It is evident so far that adjacent cells regulate the differentiation and function of osteoclasts. Additionally, adjacent cells and not osteoclasts themselves are the targets of various stimuli that influence bone resorption. For example parathormone (PTH) is a hormone produced by parathyroid glands and is involved in the restoration of low calcium levels to normal. This is achieved by various mechanisms including mobilization of calcium from bone by increasing bone resorption. However, PTH does not act directly on osteoclasts and its receptors have been recognized on osteoblasts and stromal cells. Binding of PTH on its receptors, stimulates the expression of RANKL and blunts the expression of osteoprotegerin, thus enhancing osteoclastogenesis in a paracrine fashion. This mechanism possibly accounts for the osteoclastic activity of vitamin D as well [15]. However, the regulation of the development and activity of osteoclasts is far more complicated than described above and involves complex signal networks rather than linear signal transduction pathways [23]. Osteoclasts are found within resorption pits (Howship’s lacunae) which are produced by digestion of bone matrix by themselves. Histologically, they have 4–20 nuclei (usually less than 12 but occasionally up to 100) and abundant amphophilic cytoplasm. They are polarized with one side located in intimate apposition to the bone surface whereas the nuclei and Golgi apparatus tend to congregate on the other side of the cell (Fig. 1.4B). Integrins, and in particular integrin αν β3 , which has been shown to be the main type expressed by mature osteoclasts, play a key role in osteoclast activity [16]. Integrins are transmembrane heterodimeric proteins that consist of an α- and β- chain. The extracellular domain of integrins recognize specific motifs of aminoacid sequences in proteins of the extracellular matrix, the most common being the sequence Arg-Gly-Asp, known as RGB. Their intracellular domain, on the other hand, is associated with proteins of the cytoskeleton and is connected to intracellular signal transduction pathways. Thus integrins integrate (hence their name) the extracellular milieu with the cytoskeleton and eventually the cell nuclei. They have been designated as the sensory organ of the cell [24]. Mice deficient in αν β3

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display an osteosclerotic phenotype in vivo and their osteoclasts have diminished bone resorbing activity in vitro [25]. Additionally, apart from their binding properties, integrin complexes of the osteoclasts are associated with signaling molecules such as c-Src kinase and the FAK-like kinase Pyk2 [15]. c-Src kinase is essential for osteoclast function and its disruption in mouse models results in inactive osteoclasts [21]. Thus, blocking of integrin signaling by specific, high affinity ligands may be effective in reducing bone resorption in various pathologic situations such as osteoporosis [26]. Binding of integrin to RGD sequences of proteins of the extracellular bone matrix (vitronectin, osteopontin and bone sialoprotein) causes reorganization of cytoskeleton of osteoclasts and polarization of actin filaments to form a circular structure (actin ring) [16]. F-actin of the actin ring localizes in punctuate plasma membrane protrusions (podosomes) that are tightly attached to the bone matrix and form the sealing zone, which creates an extracellular area isolated from the rest microenvironment. The sealing zone ensures compartmentalization of plasma membrane in two distinct regions with distinct morphology and different protein composition. The membrane surrounded by the sealing zone displays numerous fingerlike extensions (brush border, ruffled zone) that increase its surface. The formation of the ruffled zone is regulated by the integrin αν β3 , since osteoclasts in αν β3 knock-out mice display a poorly formed ruffled zone [25]. The rest of the cell membrane is also subdivided into two distinct domains, even though no physical barrier has been found. These domains are known as the basolateral domain and the functional secretory domain. The functional secretory domain is thought to correspond to the apical membrane of epithelial cells. Even though their exact function is not known, functional secretoty domains are implicated in excretion of resorbed bone remnants [27]. The ruffled border contains proton pumps (H+ ATPase) coupled to a Cl− channel that excrete HCL into the leak proof area. As a result, the sealed area between the cell and the bone surface has a pH of 4.5. Additionally, a Cl− /HCO− 3 exchanger is located on the membrane surface that is opposite to the brush border and ensures maintenance of intracellular pH [27]. The ruffled border is linked with the nuclei by a network of interconnecting actin filaments. This actin network transmits signals produced by anchorage to the nuclei and orchestrates bone resorption [1]. The cytoplasm adjacent to the brush border contains numerous lysosomes that fuse with the membrane and release their contents into the sealing zone [27]. Additionally, osteoclasts contain numerous mitochondria in order to meet the high energy requirements of the resorption process. Osteoclasts express high levels of carbonic anhydrase that produces H+ from CO2 and H2 O and enables continuous release of protons to the resorption pit [1]. In the sealing zone, HCl dissolves the solid hydroxyapatite to Ca+2 , HPO2− 4 and H2 O, whereas proteolytic enzymes, whose activity is enhanced in the acidic microenvironment, mediate resorption of organic bone components. Cysteine proteinases (cathepsins K, B, D, L) and matrix metalloproteinases are the most important proteolytic enzymes in the resorption pit [27]. The sealing of the space between osteoclast and bone surface is very important not only because it assures the functional separation and different protein composition of the brush border membrane,

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but also due to the fact that it prevents the diffusion of the highly destructive solution to adjacent tissues [21]. Bone resorption begins with demineralization of collagen, followed by degradation of non-collagen proteins and catabolism of collagen fibers [1]. Organic and inorganic products are trancytosized to the free surface of osteoclasts (the functional secretory domain, which is located opposite to the brush border) where they fuse to the membrane and release their content to the extracellular fluid. This is very important for calcium mobilization to blood circulation [6]. Degradation of proteins seems to continue in transcytotic vesicles, even though the proportion of extracellular to intracellular degradation is not known. The widely used osteoclastic marker tartrane-resistant acid phosphatase (TRAP), is associated with the production of reactive oxygen species in transcytotic vesicles and may contribute to the degradation of organic ingredients of bones [27]. Organic remnants are subsequently removed by macrophages [1]. Osteoclasts are detached from bone surface and either target a new site or undergo apoptosis. However, the signals that arrest the process of bone resorption are not well understood. It has been hypothesized that high calcium levels in the resorption site are sensed by plasma membrane receptors of the osteoclasts and mediate their detachment from this site [21]. A negative feedback mechanism has also been proposed. RANK-induced expression of c-fos enhances activity and secretion of interferon β, which in turn inhibits activation of adjacent osteoclast precursor cells and decreases bone resorption [6]. Additionally, increasing evidence suggests that various stimuli, such as estrogen and bisphonates, stimulate intracellular pathways that result in osteoclast death (apoptosis) [21]. Deregulated function of osteoclasts results in pathologic situations, such as osteopetrosis, Paget disease of the bones and osteoporosis. Osteopetrosis is attributed to decreased resorption of the bone by osteoclasts. Mutations in the proton pump of the ruffled membrane or in the carbonic anydrase have been identified in cases of congenital human osteopetrosis [28]. Paget disease is initiated by increased bone resorption by osteoclasts followed by compensatory increase in bone formation by osteoblasts, resulting in a disorganized bone tissue. Osteoporosis results from enhanced bone resorption that cannot be compensated by bone formation. Mutations in RANK gene cause a familial type of osteoporosis, known as familial expansible osteoporosis or familial Paget disease of the bone that is characterized by focal areas of bone remodelling with osteolytic regions [6].

1.3.4 Bone Lining Cells The surface of the bone matrix not undergoing remodelling is lined by specialized cells called bone lining cells. They represent the inactive form of osteoblasts or may be derived from other mesenchymal cells. They are flat spindle-shaped cells that extend along bone surfaces and are connected to each other with gap junctions. Their roles include partitioning of bone fluid compartment (lacunae and canalliculi) from interstitial fluids, formation of bone-marrow barrier and regulation of other bone cells function [2].

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1.4 Bone Non-cellular Matrix Bone tissue is characterized by abundant extracellular matrix which can be subdivided into organic and inorganic (mineral) matrix. Cellular constituents represent 8% of bone weight, whereas organic matrix makes up for 25% and minerals for 67% of bone weight [4]. Organic matrix is mainly composed of collagen type I, which is secreted by osteoblasts and is organized in layers (lamellae) [29]. Other types of collagen that can be found in bone extracellular matrix include collagen type V, III, XI and XIII [1]. Orientation of lamellae depends on stage of development and type of bone. Adult skeleton is composed of lamellar bone. In adult compact bone, collagen fibers (and lamellae) are mainly organized in concentric layers around Haversian systems, whereas in adult cancellous bone, lamellae are organized parallel to the long axis of trabecullae. In contrast to the fine organization of lamellae in lamellar bone, newly formed bone, either during development and growth or due to pathologic stimuli, is characterized by disorganized orientation of lamellae [1, 4]. Collagen type I is composed of two a1 chains and one a2 chain. After secretion, collagen chains assemble into a triple helix by a highly orchestrated process. Defects in collagen assembly due to mutation in genes encoding collagen chains result in bone genetic disease known as osteogenesis imperfecta. Recent data supports a link of gene mutations or genetic polymorphisms in genes encoding collagen chains with abnormal mineral density, low body mass and possibly osteoporosis. However, apart from its structural function, collagen regulates the biologic functions of bone cells, including cell apoptosis, proliferation and differentiation [29]. Non-collagen proteins (glycoproteins and proteoglycans) comprise a small proportion of bone organic matrix and include osteocalcin, fibronectin, osteonectin, thrombospondin-2 and osteopontin. They are implicated in mineralization of bone matrix [2] and are produced by osteoblasts or are derived and concentrated from the serum [1]. The latter is the result of the excellent adsorbent properties of bone mineral which binds circulating growth factors and various serum proteins such as 2-HS-glycoprotein [30]. The most abundant non-collagenous protein of the bone is osteocalcin, which is produced by osteoblasts and functions as a regulator of mineralization. Its levels in blood serum are a useful clinical marker of bone formation [1]. In addition to bone mineralization, non-collagenous proteins have important functions in the regulation of bone mass and fracture healing [29, 31]. For example, fibronectin contains the RGD aminoacid sequence that binds to integrin receptors of cell surface and activates intracellular signal transduction pathways. Osteonectin, also known as Secreted Protein Acidic and Rich in Cysteine (SPARC) is an important mediator of tissue remodeling and its loss is associated with osteopenia due to impaired bone turnover [29]. Osteopontin belongs to the Small IntegrinBinding LIgand N-linked Glycoprotein (SIBLING) family of proteins. Members of this family bind to integrin receptors through RGD sequences. Osteopontin regulates bone resorption and is expressed in both osteoclasts and osteoblasts, possibly mediating coupling of osteoblastic and osteoclastic activity during bone remodelling [29, 32, 33]. SIBLING proteins are also expressed by malignant epithelial

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cells, such as cells of the highly osteotropic breast and prostate cancer [34,35]. They are thought to enhance colonization of bone by malignant cells and protect cancer cells from host defense [36]. Their role in bone metastasis is further supported by the finding that OPN-deficient mice exhibit fewer metastatic foci after injection of the melanoma cell line B16 [37]. Two transcription factors that are critical for osteoblastic differentiation seem to mediate transcription of bone matrix proteins as well. These factors are Runx2 and osterix. However, the precise mechanism of transcriptional regulation and response to extracellular systemic stimuli such as hormones and mechanic forces remains elusive [29]. The inorganic phase constitutes the largest proportion of bone matrix and accounts for the rigity and strength of the skeleton [1]. Hydroxyapatite [Ca10 (PO4)6 (OH)2 ] is the most common bone mineral. Carbonate and magnesium are also contained inside the crystals of hydroxyapatite and facilitate release of ions from bone mineral phase when needed [2]. During bone development, mineralization occurs by the production of several small vesicles that contain crystals of hydroxyapatite and amorphous calcium phosphate. Large mineral aggregates are formed and deposited in and around collagen fibers. In adult bone, mineralization is a complex process involving the osteoblasts and numerous growth factors, cytokines and extracellular matrix proteins. Mineral is deposited between the ends of adjacent collagen molecules and eventually crystals of apatite are situated within and outside collagen fibers [1]. Bone mineralization is slower than bone matrix deposition. Thus, a region of the bone matrix close to the site of active bone formation (i.e., adjacent the layer of osteblasts in trabeculae or Haversian canals) is unmineralized. Unmineralized bone matrix is called osteoid (Fig. 1.4A). The width of osteoid layer depends on the rate of bone formation. In inactive regions, osteoid layer is thin, whereas in foci of active bone formation the layer is several times thicker [1]. Defects in bone mineralization result in the deposition of excessive amounts of osteoid, a pathologic situation called osteomalacia [2].

1.5 Vascularization of Bones Blood supply of bones is provided by three main sources: (a) the principle nutrient artery, (b) the metaphyseal arteries and (c) the periosteal arterioles. The nutrient artery is usually one and occasionally, i.e., in the femur, two in number. They enter long bones in the diaphysis, transverse the cortex and divide into ascending and descending branches within the medullary cavity [1]. They are also accompanied by one or two nutrient veins [38]. Each artery gives rise to smaller branch arteries, arterioles and capillaries that nourish the fatty and hematopoietic bone marrow. Arterioles of the Haversian canals originate from the nutrient artery and supply the inner two thirds of the cortex, whereas the outer third of the cortex is nourished by the small periosteal arterioles [1]. In medullary cavities containing hematopoietic bone marrow, nutrient arteries end up in a plexus of sinusoids which drain through a

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system of venules into larger venous channels and finally through a central longitudinal veins into the nutrient veins [38]. Metaphyseal arteries are more numerous than nutrient arteries, enter the metaphyseal region of bones and provide blood supply to the metaphysis and epiphysis of bones [1]. At birth all bones contain hematopoietic bone marrow in their medullary cavities. In adult skeleton, most hematopoietic bone marrow is replaced by fat marrow except from the bone marrow of vertebrae, ribs, sternum, pelvis and skull [2]. The sinusoids of the hematopoietic bone marrow are lined by an endothelial layer and also contain an incomplete basement membrane and an incomplete layer of adventitial cells [38]. Endothelial cells of bone marrow sinusoids allow migration of maturing blood cells and present increased permeability as demonstrated after injection of Indian ink. This may have implications for the formation of metastases to bones, since metastatic cells enter bones mainly through anastomoses of the nutrient artery to the sinusoidal network of bone marrow and most metastatic foci are found at red marrow containing medullary cavities [2]. In the contrary, yellow bone marrow is less vascular. Vessels in fat marrow are located between adipose cells and are composed of a continuous endothelium which is surrounded by a well developed basement membrane. Vascular density of bone marrow seems to affect response to growth signals and bone growth. Thus, bone turnover is higher adjacent to red marrow and bone response to PTH has been shown to be greater in red marrowassociated bones than bones containing fat marrow [2].

1.6 Histogenesis of Bone Embryological development of bone begins prior to day 40 of gestation by migration of primitive mesenchymal cells from the cranial neural crest for the craniofacial skeleton, the paraxial mesoderm for the axial skeleton and the lateral plate mesoderm for the appendicular skeleton. Activation of homeobox genes results in the development of localized cellular condensations at the sites of future bones [1]. By the seventh week of gestation, mesenchymal cells of condensations mature either to chondrocytes or osteoblasts. There are two biologically distinct pathways that will result in the development of grossly and microscopically indistinguishable bones; membranous and enchondral (also known as endochondral) ossification [1, 30].

1.6.1 Enchondral Ossification Most bones develop through a cartilagous intermediate anlage. These include bones of the vertebral column, pelvis and extremities [30]. Cartilage has the advantage of exhibiting both appositional and interstitial growth, whereas bone tissue can only enlarge through apposition of new bone on its surface. Appositional growth is insufficient for rapid increase in size, thus bones that require rapid growth such as tubular bones of the extremities, vertebrae and ribs are first formed as a cartilagous anlage [1]. Cartilage has an additional advantage compared to other soft tissues.

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It is rigid enough to withstand mechanical loads. In fact, cartilage combines both elasticity and rigity. Elasticity in cartilage is strain-rate dependent. Thus, cartilage is hard when forces are loaded rapidly, but soft when forces are applied slowly. This is attributed to the small pores formed between extracellular matrix components which enable movement of the water only when forces are applied for a few minutes or longer [39]. Growing cartilage will subsequently be replaced by bone in its entirety, apart from the epiphyseal growth plate that will be responsible for longitudinal growth of bones in prepubertal children. Epiphyseal growth plate will eventually be replaced by bone after puberty, a process known as closure of the growth plates [1]. In enchondral ossification, the cartilage anlage is initially avascular and has the shape of adult bone. Its growth results from the proliferation of chondrocytes and the accumulation of extracellular matrix, which is composed of proteoglycans and collagen. Cartilagous anlage is surrounded by the perichondrium, which will develop into periosteum once ossification begins. The first step of ossification is the differentiation of mesenchymal cells of perichondrium into osteoblasts. A layer of osteoblasts is produced along the middle region of the cartilagous shaft. Osteoblasts deposit a collar of woven mineralized bone in this region which indicates the transformation of perichondrium into periosteum. The periosteum, osteoblasts and the collar of woven mineralized bone form the primary center of ossification which is located in the midportion of the cartilagous shaft and surrounds in a collarlike way the middle region of the diaphysis of the developing bone. Primary centers of ossification develop in long bones by the third month of fetal life. The creation of the periosteal collar determines the cessation of interstitial growth of diaphysis and from thereafter further expansion of the diameter of the bone can be accomplished only by appositional growth. The chondrocytes which are surrounded by the periosteal collar enlarge due to cell hypertrophy and swelling. This is followed by perichondrocyte deposition of collagen type X, matrix mineralization and finally chondrocyte apoptosis and activation of chondroclastic resorption. As mineralized cartilage undergoes resorption, it is penetrated by a capillary network originating from periosteal vessels around the primary center of ossification. The capillaries are accompanied by primitive mesenchymal cells, including osteoblast- and osteoclast-progenitor cells. Resorption of cartilagous matrix results into the formation of longitudinal struts of cartilage with their long axis parallel to the long axis of the bone. Osteoblasts derived from the perivascular progenitor cells deposit layers of osteoid along the surface of cartilagous struts. Thus trabeculae composed of a central cartilagous core and a peripheral rim of bone are formed. These trabeculae are called primary trabeculae. The space developing in between the trabeculae as a result of cartilage resorption, is the medullary cavity and will be occupied by varying amounts of adipose tissue and hematopoietic bone marrow elements. Thus in enchondral ossification, the primary center of ossification is initially formed in the central region of the developing bone and progresses towards both ends of bone [1, 30]. In the majority of long bones, a similar process of ossification develops in the middle of the epiphysis and forms the secondary center of ossification. Secondary

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centers of ossification develop much later than primary centers, usually after birth. In secondary centers of ossification chondrocyte maturation, mineralization, apoptosis and primary trabeculae formation proceed in the same sequence as in the primary center of ossification and progresses centrifugally towards the periphery of the epiphysis. Thus a cylindrical segment of cartilage anlage is entrapped between the two enlarging ossification centers [1, 30]. When enchondral ossification originating from the primary center of ossification reaches the diaphyseal–epiphyseal junction, the epiphyseal growth plate is formed and ensures continual growth of the length of the bone. Here a sequence of bone formation identical to the one that was previously described for the primary center of ossification occurs. The different stages of chondrocyte maturation and bone formation are structured into merging regions that form the epiphyseal growth plate. These regions are: a zone of resting chondrocytes, a zone of proliferating chondrocytes that are arranged in spiral columns, a zone of chondrocyte hypertrophy and a zone of chondrocyte apoptotic necrosis and matrix mineralization. The zones of the epiphyseal growth plate merge with a zone of cartilage resorption that is brought about by osteoclasts (chondroclasts), resulting in the formation of primary trabeculae [1, 30]. The epiphyseal growth plates close at different times in different persons, in different bones of the same person, in different ends of the same bone and even in different regions of the same epiphyseal growth plates. For example, closure of growth plates begins earlier in girls than boys by 1.5 to 2 years and the lateral half of the growth plate of the distal tibia closes several months after the median half of the same growth plate [40]. Longitudinal bone growth is controlled at three different levels. Systemic control, local control and mechanic control are all responsible for adult bone length [39]. Systemic control is mediated by several hormones, including parathyroid hormone, growth hormone, thyroid hormone, androgens, estrogens, and adrenal cortical hormones. Local control is mediated by a variety of factors that include Parathyroid Hormone related Protein (PTHrP), Indian hedgehog, fibroblast growth factors, bone morphogenetic proteins and VEGF [39, 41]. The most important local regulators are Indian hedgehog gene and PTHrP [1]. They are involved in a feedback loop that controls the width of the proliferating zone [39]. Indian hedgehog is produced by prehypetrophic chondrocytes and promotes production of PTHrP [41]. This is accomplished by increasing the expression of TGF-β by perichondrial cells [42]. PTHrP is produced by perichondrial cells and chondrocytes of the periarticular perichondrium in response to TGF-β and diffuses to the prehypertrophic zone of the growth plate, where concentration of PTHrP receptors is high. PTHrP inhibits differentiation of proliferating chondrocytes and ensures a continuous supply of proliferating chondrocytes which is important for bone growth. Fibroblast growth factors (FGF) inhibit chondrocyte proliferation and decrease chondrocyte hypertrophy and matrix synthesis [40]. Several chondrodysplasia phenotypes, including achondroplasia, the most common form of dwarfism in humans, result from aberrations in FGF activity due to mutations in the gene coding the FGF receptor [42].

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Mechanical control of bone growth was first proposed in the 19th century by the Hueter-Volkmann law and is extensively applied in orthopedic surgical procedures used to correct genu varum (hemi-epiphysiodesis). It is generally accepted that compression decreases bone formation whereas tension increases bone length, even though the mechanisms that mediate this effect are not known. However, mild compression has shown to increase bone growth and it must exceed a certain level in order to act negatively on bone development [39]. Bone growth in width is of paramount importance for bone strength. Enlargement of the diameter of the bone diaphysis is accomplished by subperiosteal bone deposition. Osteoblasts of the periosteum deposit cortical bone on the external surface of the bone. This process does not involve an intermediate step of cartilage anlage and is called intramembranous ossification. This is followed by endosteal bone resorption and results in enlargement of medullary cavity, while cortical thickness depends on the relative rate of bone formation to bone resorption. However the coordinated bone resorption on the inner cortical surface and bone formation on the outer cortical surface ensures preservation of bone shape and maintenance of the relative proportion of cortical thickness to marrow cavity diameter as bone enlarges [40]. The final shape of bones is dependent on a continuous adaptation process known as bone modelling. Bone modelling is active during growth and sculpts the shape of bones by adding bone in some places and removing it from other places. Bone modelling is less active after skeletal maturity [1, 30]. However when bone strains exceed a certain level, modelling can be re-activated in order to strengthen loadbearing bones. Additionally, bone modelling can be activated in pathologic settings and is involved in the shaping of the callus formed in regions of healing fractures and the periosteal new bone formation evoked by local processes including tumors and infections [43].

1.6.2 Intramembranous Ossification Most flat bones of the skull (frontal, parietal, occipital and temporal bones) develop directly from connective tissue without an intermediate cartilagous model. This process of bone development in which the tissue that will be replaced by bone is a fibrous-like membrane is called intramembranous ossification. Apart from the bones that are entirely formed by intramembranous ossification, this process participates in the development of all bones, since bone cortices are partly formed from subperiosteal osteoblast progenitor cells. Initially, condensed vascular connective tissue is deposited in the site of future bones. This tissue contains osteoblast progenitor cells that differentiate into osteoblasts and begin to synthesize bone matrix. After mineralization of the bone matrix, osteoblasts are entrapped in the growing bone and become osteocytes. Continuous deposition of bone forms primitive cortical bone, whereas if bone formation stops, primitive cancellous bone is created. The mesenchymal tissue of the fibrous membrane in between the trabeculae is gradually replaced by hematopoietic or

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adipose tissue. The primitive cortical and cancellous bone is composed of woven bone that will later be replaced by lamellar bone [1, 30].

1.7 Bone Functions Bones along with the muscles, tendons and ligands attached on them are responsible for movement and standing [2,6]. Bone development was critical for the evolution of our species, since it facilitated locomotion and bipedalism [28]. Additionally, bones surround cavities in which critical organs are protected from external mechanical forces [2, 6]. For example, skull bones form the cranial cavity where the brain resides. Pleura and thoracic vertebrae form the thoracic cage which is important for the protection of the heart and lungs. The spinal cord is located in the spinal tube. In between the trabeculae of cancellous bone resides the hematopoietic bone marrow. Apart from their protective role, bone cells have the ability to respond to signals that regulate hematopoiesis. Bone resorption increases diameter of medullary cavity when needed for example in high altitudes [28]. Apart from the obvious structural functions mentioned above, bones are more than a rigid inactive organ and exert various metabolic functions in the body, since they are critically involved in mineral homeostasis. Bones deposit and store minerals, especially calcium and phosphate, which are released when needed. Thus, bone tissue responds to changes in blood calcium and phosphate levels and is involved in restoration of their levels within normal limits [2, 6]. Additionally, bones’ large surface absorbs toxins and heavy metals, minimizing their deleterious effects on other tissues [44]. Additionally, bones play a critical role in the regulation of hematopoiesis. Bone microenvironment provides a supportive microenvironment for the development of mature blood cells from hematopoietic stem cells, known as the stem cell niche. Interactions between progenitor cells and their microenvironment determine the maturation process, providing both permissive and instructive signals for stem cell differentiation. The hematopoietic stem cell niche is composed of the osteoblasts located along the endosteal surface and the bone marrow blood vessels. It has been proposed that osteoblastic niche provides a quiescent microenvironment for stem cells whereas the vascular niche drives proliferation and further differentiation of hematopoietic stem cells [45].

1.8 Bone Physiology 1.8.1 Remodelling Bone remodelling is defined as the replacement of older bone by newer bone and takes place in all bone surfaces. These are the periosteal surface, the endosteal surface, the surfaces of Haversian canals of compact bones and the surfaces of trabeculae of cancellous bone. Bone remodelling begins in embryonal life and continues

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throughout life. In adult skeleton bone remodelling represents the 90% of bone turnover [30]. Bone remodelling is mediated by a temporary bone structure called basic multicellular unit (BMU). Osteoclasts and osteoblasts are, as expected, the major components of this unit [2]. Osteocytes and bone lining cells are also involved in bone remodelling. Changes in bone strain and release of various hormones and cytokines stimulate osteocytes or bone lining cells. These cell types are connected to each other and to osteoblasts through a complicated system of cell processes that run through the bone matrix. The bone lining cells contract and secrete collagenase that digests a protective-coating layer of matrix and combined with cell contraction, exposes the mineralized bone surface. Bone exposion, together with signals released from osteoblasts, stimulates osteoclast formation. Osteoclasts mediate bone resorption which lasts two to four weeks and is followed by the reversal phase, during which resorption remnants are cleaned up. Subsequently, new bone is formed by osteoblasts and is mineralized. Bone formation lasts about four months [28]. In cortical bone, bone remodelling forms the cutting cone, a cone-shaped structure that bores holes in the hard and compact matrix of compact bone and is the top of a cylinder. The osteoclasts are gathered in the leading edge of the cutting cone. Osteoclasts are followed by a capillary loop surrounded by mesenchymal osteoblast progenitor cells. The later differentiate into osteoblasts that mediate the formation of new bone matrix (osteoid) and its minelarization, thus refilling the gap made by osteoclastic resorption. The same sequence of events occurs during remodelling of cancellous bones. Remodelling begins at the trabecular surface, where osteoclasts are activated and start to erode the bone matrix forming a resoption cavity. After removal of remnants, osteoblasts form new bone at the same site [30]. Bone mass is completely renewed every 10 years, since each year about 10% of bone is remodelled [6]. The ratio between bone formation to bone resorption determines the total bone mass. Disruption of the balance between the two processes may lead to bone loss or gain. This disruption may be reversible, so that bone mass returns to normal when stimuli (i.e., hypocalcaemia) is eliminated or may lead to irreversible deregulation of bone mass, especially bone loss (osteopenia or even osteoporosis) [2,30]. Additionally, bone loss may occur when mechanical loads stay below a threshold range (the remodelling threshold rage) and is called disuse-mode remodelling [43]. Bone remodelling activity varies between different bones and different regions of the same bone. Activity of remodelling (measured by the frequency with which a given site on the bone surface undergoes remodelling, the activation frequency) is identical between cortical and cancellous bone. However, cancellous bone is more (5–10 times) actively remodelled than cortical bone, possibly due to its higher surface to total volume ratio [30]. Thus, when the balance between bone formation and bone resorption is negative (i.e., less bone is formed than reabsorbed), it usually takes place next or close to the bone marrow cavity. This explains why 90% of bone loss during ageing or impaired-mode remodelling comes from bone next to the marrow [46].

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In bone remodelling, resorption which is the main function of osteoclasts, is coordinated with bone formation by osteoblasts. The two processes are coupled in order to maintain bone mass and usually when one increases the other will follow and other way round. The exact mechanisms that mediate the coupling of the two processes are not fully understood. Several factors have been shown to stimulate both bone resorption and formation. These include (among others) PTH, PGE, FGF, TGF-β [7]. In fact, PTH has both anabolic and catabolic function in bone mass, depending on the pattern and duration of action [47]. Additionally, during matrix degradation from osteoclasts, factors that enhance bone formation are released, such as the insulin like growth factor (IGF) and the transforming growth factor-β (TGF-β) [7]. Estrogens are among the major regulators of bone remodelling and act by altering the production or activity of factors that regulate bone resorption and formation [44]. In addition to hormones and growth factors that determine the rate of remodelling, mechanical loads seem to determine the site of remodelling [28]. Bone remodelling serves two basic functions of human skeleton, mechanical support and mineral homeostasis [2]. The human skeleton has to adjust to alterations of mechanical stress and this is accomplished by degradation of old bone and formation of new aligned with the new environmental demands. The adaptation of bones to local mechanical forces is the basis for orthopaedic and orthodontic procedures [7]. Additionally, repair of fatigue damages and micro-fractures is largely dependent on bone remodelling. Alterations of calcium levels in blood serum elicit a response in bone cells in order to restore calcium levels to normal [30]. Thus, mechanical forces and calcium levels are the major regulators of bone remodelling. However, there is a hierarchy in bone functions with calcium homeostasis being the most important. Thus, calcium deficiency will eventually lead to bone loss in spite of the presence of mechanical demands [7]. The normal pathway of bone remodelling is exploited by inflammatory cells and tumor cells which explain the bone loss that accompanies chronic inflammatory diseases, i.e., rheumatoid arthritis, and bone loss or gain that is noted in osteolytic or osteoblastic bone metastasis [6, 21, 28, 48–50].

1.8.2 Mechanotransduction Mechanotransduction refers to the process of translating mechanical signals generated by physical forces such as tension and compression into a cellular response, via the activation of intracellular signaling pathways. In bone, mechanotransduction is a basic function of osteocytes which are capable of monitoring the physical forces and eliciting bone response by activating effector cells (osteoblasts and osteocytes). The net effect of the coordinated action of bone cells is the organization of bone tissue according to the direction of mechanical forces. This leads to mechanical adaptation of bone structure and ensures efficient bearing of load by a relatively thin and light structure [51]. The asteroid morphology of osteocytes, with their numerous dendritic processes is fundamental for mechanical adaptation and transduction of mechanical signals.

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Osteoblasts are buried in a rigid mineralized matrix, but a complex network of cell dendrites connects each cell with its neighbors and with cells of the endosteal and periosteal bone surface [11]. Dendrites are connected with gap junctions, which facilitate the integration of signals in effector cells and the activation of osteoblasts and bone-lining cells. Additionally, the bone matrix around cell bodies (around the lacunae) and cell processes (along the course of canaliculli) does not calcify and is therefore more easily penetrated by water and small molecules than the mineralized bone tissue of the lamellae. This complex structure of pores and channels, named the lacuno-canalicular porosity is the basis of mechanotransduction [51]. Since bone tissue is stiff and rigid, the strain imposed by mechanical loads is very low and 10 times less than the one needed for in vitro activation of osteocytes. Consequently, activation of osteocytes directly by the strain produced by mechanical forces seems improbable. However, squeezing of extracellular fluid present in the lacuno-canalicular system produces shear forces at the cell membrane of the osteocyte body and dendrites. Mechanical perturbation of cell membrane is the principal stimulus of the cell. Streaming potentials may be generated by fluid movements over the cell surface, but their role in cell activation remains elusive [51]. Regarding the molecular basis of mechanic activation of osteocytes, two types of cell surface receptors are involved: those that respond to changes in the solid matrix structure of the bone and those that are activated indirectly by shear stress imposed by fluid flow [11]. Integrin dimmers bind to extracellular matrix proteins and activate via adaptor proteins two intracellular pathways: the MAPK (mitogen activated protein kinase) pathway and the PLC/IP3 (phospholipase C/triphosphate inositol) pathway. Moreover, integrin intracellular domains bind through adaptor proteins to the cytoskeleton and modulate gene expression via connections of actin cytoskeleton to the nuclear envelope. The MAPK pathway results in ERK1/2 activation, which in turn enhances activation of the transcription factor AP-1. IP3 opens stores of intracellular calcium, whereas cytoskeleton modulation by integrin ensures cell stabilization against applied forces. Additionally, stretch-activated ion channels are present on the cell membrane and respond to stress stimuli, allowing extracellular calcium to flow in cells. Increases in intracellular calcium through influx from the extracellular fluid along with release from intracellular stores, activate calcium responsive proteins, such as protein kinase C, CAM kinase and calcineurin, which in turn activate various transcription factors. Integration of various pathways results in transcriptional activation of bone growth-promoting genes including c-fos, IGF-1, cycloxygenase and osteocalcin [12]. Nitric oxide (NO) and prostaglandins are other important mediators of the mechanically induced cell responses. Their role in dilatation of blood vessels is well known. Endothelial cells sense blood fluid shear stress, generated by increased blood pressure and respond by increasing the diameter of blood vessel. Several similarities between the response of endothelial cells to mechanic stimuli and that of osteocytes have been found, including up-regulation of prostaglandins, expression of ecNOS (endothelial Nitric Oxide Synthase) and release of NO. Additionally, mechanical activation of osteocytes enhances production of growth actors (i.e., IGF) and other paracrine anabolic factors (i.e., PGE2 ). These factors are transferred to the bone

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surface via the lacuno-canalicular system either through intracellular or extracellular pathways and stimulate the recruitment of osteoblasts. Furthermore, various data suggest the existence of active suppression of osteoclasts by osteocytes, even though the exact mechanisms remain unknown [51].

1.8.3 Mineral Homeostasis Bones play a major role in mineral homeostasis and are the major reservoir of most essential minerals. Almost all body’s calcium (99%) and 85% of body’s phosphorus is deposited in bone matrix. Apart from the calcium and phosphorus hemostasis that are traditionally known to be regulated by bone, other essential minerals are also harbored in bone matrix. Bones contain 95% of body’s sodium and 50% of body’s magnesium [1]. The mineralized skeleton seems to have evolved to fulfil the need for calcium homeostasis in terrestrial environments. For the marine organisms bones are not critical for calcium homeostasis since calcium is plentiful in the sea. In these organisms mineralized skeleton is probably crucial for phosphate storage. However, for mammalian species of the land, bones are crucial calcium reservoirs, providing a continuous source of calcium between meals. Serum calcium is regulated between very narrow limits (8.5 to 10.2 mg/dL, corrected for serum albumin concentration). The strict extracellular levels of calcium reflect its numerous intra- and extracellular roles in various vital processes including neuromuscular activity, blood clotting and intracellular signal transductions. The tight regulation of calcium homeostasis is achieved through a finely regulated interplay between PTH, calcitonin and vitamin D. Bone, kidney and intestine are the target organs of these hormones [28, 52]. PTH and calcitonin act primarily on bones. Additionally, even though vitamin’s D major target is the intestine, Vitamin D receptors exist in the nuclei of osteoblasts and possibly regulate indirectly osteoclastogenesis [53]. PTH is the major regulator of calcium homeostasis in humans, acting primarily on the bones and the kidneys [47]. PTH is produced by chief cells of parathyroid glands in response to low levels of calcium. On the contrary, elevation of calcium levels result in decrease of PTH production. Parathyroid cells sense extracellular levels of calcium by the calcium-sensing receptor located on their cell membrane [52]. PTH activates PTH receptor expressed in target organs. The receptor is also activated by PTHrP, a hormone implicated in regulation of bone growth during development. PTHrP is also ectopically expressed by some malignant neoplasms resulting in hypercalcaemia known as humoral hypercalcaemia of malignancy. In bone, PTH receptors are expressed by osteoblasts, osteocytes and bone-lining cells [47]. After binding to its receptor, PTH enhances the expression of RANKL which in turn binds to the RANK receptor of the osteoclast progenitor cells and enhances osteoclastogenesis [15]. Additionally, PTH stimulates the production of collagenase-3 and decreases production of type I collagen from osteoblasts [54]. Thus, PTH stimulates bone resorption and calcium release through transformation of osteoblasts from cells involved in bone formation, to cells driving bone

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resorption, both directly and indirectly [54]. Continuous exposure to elevated levels of PTH, as in the case of primary hyperparathyroidism or chronic renal failure, results in osteitis fibrosa cystica which is characterized by increased bone resorption [55]. On the contrary, intermittent increase in PTH levels are associated with anabolic effects regarding bone mass. PTH causes sub-periosteal bone formation, increases trabecular and cortical thickness and improves bone mineral density. PTH analogs have been used for the therapy of osteoporosis especially in patients not responding to other treatment modalities [47], since its use stimulates bone formation instead of simply inhibiting bone resorption [56]. Thus theoretically, PTH analogs can be used to reverse the osteoporotic phenotype. The anabolic effects of PTH are mediated by its ability to stimulate the proliferation of preosteoblasts, the promotion of the differentiation of preosteoblasts and osteoblasts and the inhibition of osteoblast apoptosis [54, 56]. The function of PTH in regard to the bone mass is regulated by several feedback loops and depends on the timing of PTH administration (continuous or pulsative) rather than the levels of PTH. It has been proposed that pulsative administration of PTH, which is characterized by a rapid increase in PTH blood levels followed by rapid decline to baseline, is associated with rapid recovery from feedback loops and gives the opportunity of new activation of downstream molecules. In that case, the balance between bone formation and bone resorption is in favor of the former. In contrast, continuous PTH administration results in a constant down regulation of the PTH receptors and other effector molecules (i.e., cAMP) due to feedback mechanisms and the lower ratio of bone formation to bone resorption [56]. Calcitonin is involved in restoration of high calcium levels. It is produced by parafollicular cells (C cells) of the thyroid gland. Calcitonin acts on bones and kidneys, decreasing calcium release and increasing calcium excretion, respectively. Calcitonin is a widely used drug for the treatment of osteoporosis due to its antiosteoclastic effects. Calcitonin acts directly on osteoclasts and inhibits bone resorption interfering with osteoclasts’ development, differentiation and motility [57]. Vitamin D is the third major regulator of calcium homeostasis. It is synthesized in the skin after conversion of 7-dehydrocholesterol to vitamin D by ultraviolet light of sunlight or can be of dietary origin. Vitamin D is subsequently hydroxylated by 25-hydroxylase of the liver and 1-hydroxylase of the kidney. These modifications produce the active form of the molecule [1,25(OH)2 D] [58]. Vitamin D regulates bone mineralization indirectly by enhancing intestinal absorption of calcium. Its deficiency results in impairment of bone mineralization. Bones are characterized by the presence of excessive amounts of unmineralized matrix. In children with vitamin D deficiency, bone growth is defective and the developing bones are not rigid resulting in severe skeletal deformation (rickets). Upon deficiency in adults, the shape of the bones is not affected, but due to impaired mineralization, bones have loose their rigity and are susceptible to fractures (osteomalakia) [42, 53]. However, vitamin D has dual functions concerning bone mass. In normal conditions it enhances bone formation indirectly, due to increased absorption of calcium from the intestine as described above. On the contrary, in supraphysiological

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doses, vitamin D induces bone resorption and releases calcium from the bone to the blood circulation. This is possibly accomplished through direct actions on bone cells especially osteoblasts which express osteoblastic vitamin D receptor in their nuclei. Activation of vitamin D receptors of osteoblasts enhances the expression of factors that stimulate osteoclastogenesis (RANK, M-CSF) and increases bone resorption [53].

References 1. Rosenberg AE, Roth SI (2007) Bone. In: Mills SE (ed.) Histology for histopathologists, 3rd edn. Lippincot Williams, Philadelphia, PA 2. Shea JE, Miller SC (2005) Skeletal function and structure: implications for tissue-targeted therapeutics. Adv Drug Del Rev 57:945–957 3. Allen MR, Hock JM, Burr DB (2004) Periosteum: biology, regulation and response to osteoporosis therapies. Bone 35:1003–1012 4. Walsh WR, Walton M, Bruce W, et al. (2003) Cell structure and biology of bone and cartilage. In: An YH, Martin KL (eds.) Handbook of histology methods for bone and cartilage. Humana Press, Totowa, NJ 5. Weiner S, Traub W, Wagner HD (1999) Lamellar bone: structure-function relations. J Struct Biol 126:241–255 6. Cohen MM Jr. (2006) The new bone biology: pathologic, molecular, and clinical correlates. Am J Med Genet A 140A:2646–2706 7. Harada S-I, Rodan GA (2003) Control of osteoblasts function and regulation of bone mass. Nature 243:349–355 8. Franz-Odendaal TA, Hall BK, Witten PE (2006). Buried alive: how osteoblasts become osteocytes. Dev Dyn 235:176–190 9. Stains JP, Civitelli R (2005) Cell–cell interactions in regulating osteogenesis and osteoblast function. Birth Def Res C 75:72–80 10. Stains JP, Civitelli R (2005) Gap junctions in skeletal development and function. Biochem Biophys Acta 1719:69–81 11. Knothe Tate ML, Adamson JR, Tami AE, et al. (2004) The osteocyte. Int J Biochem Cell Biol 36:1–8 12. Iqbal J, Zaidi M (2005) Molecular regulation of mechanotransduction. Biochem Biophys Res Commun 328:751–755. 13. Cullinane DM (2002) The role of osteocytes in bone regulation: mineral homeostasis versus mechanoreception. J Musculoskelet Neuronal Interact 2:242–244 14. Chambers TJ (2000) Regulation of the differentiation and function of osteoclasts. J Pathol 192:4–13 15. Teitelbaum SL (2000) Bone resorption by osteoclasts. Science 289:1504–1508 16. Teitelbaum SL (2000) Osteoclasts, integrins, and osteoporosis. J Bone Miner Metab 18:344–349 17. Walker DG (1972) Congenital osteopetrosis in mice cured by parabiotic union with normal siblings. Endocrinology 91:916–920 18. Walker DG (1973) Osteopetrosis cured by temporary parabiosis. Science 180:875 19. Walker DG (1975) Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells. Science 190:784–785 20. Walker DG (1975) Spleen cells transmit osteopetrosis in mice. Science 190:785–787 21. Bar-Shavit Z (2007) The osteoclast: a multinucleated, heatopoietic-origin bone-resorbing osteoimmune cell. J Cell Biochem 102:1130–1139 22. Coccia PF, Krivit W, Cervenka J, et al. (1980) Successful bone-marrow transplantation for infantile malignant osteopetrosis. N Engl J Med 302:701–708

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23. Blair HC, Robinson LJ, Zaidi M (2005) Osteoclast signalling pathways. Biochem Biophys Res Commun 328:728–738 24. Clark EA, Brugge JS (1995) Integrins and signal transduction pathways: the road taken. Science 268:233–239 25. McHugh KP, Hodivala-Dilke K, Zheng MH, et al. (2000) Mice lacking αν β3 integrins are osteosclerotic due to dysfunctional osteoclasts. J Clin Invest 104:433–440 26. Engleman VW, Nickols GA, Ross FP, et al. (1997) A peptidomimetic antagonist of the a´ vˆa3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo. J Clin Invest 99:2284–2292 27. Vaananen HK, Zhao H, Mulari M, et al. (2000) The cell biology of osteoclast function. J Cell Sci 113:377–381 28. Rodan GA (2003) The development and function of the skeleton and bone metastasis. Cancer 97:726–732 29. Young MF (2003). Bone matrix proteins: their function, regulation and relationship to osteoporosis. Osteoporosis Int 14:S35–S42 30. Steiniche T, Hauge EM (2003) Cell Normal structure and function of the bone. In: An YH, Martin KL (eds.) Handbook of histology methods for bone and cartilage. Humana Press, Totowa, NJ 31. Alford AI, Hankenson KD (2006) Matricellular proteins: extracellular modulators of bone development, remodelling and regeneration. Bone 38:749–757 32. Dodds RA, Connor JR, James IE, et al. (1995) Human osteoclasts, not osteoblasts, deposit osteopontin onto resorption surfaces: an in vitro and ex vivo study of remodelling bone. J Bone Miner Res 10:1666–1680 33. Asou Y, Rittling SR, Yoshitake H, et al. (2001) Osteopontin facilitates angiogenesis, accumulation of osteoclasts, and resorption in ectopic bone. Endocrinology 142:1325–1332 34. Bellahcene A, Castronovo V (1997) Expression of bone matrix proteins in human breast cancer: potential roles in microcalcification formation and in the genesis of bone metastases. Bull Cancer 84:17–24 35. Waltregny D, Bellahcene A, Van Riet I, et al. (1998) Prognostic value of bone sialoprotein expression in clinically localized human prostate cancer. J Natl Cancer Inst 90:1000–1008 36. Jain A, Karadag A, Fohr B, et al. (2002) Three SIBLINGs enhance factor H’s cofactor activity enabling MCP like cellular evasion of complement-mediated attack. J Biol Chem 277:13700–13708 37. Nemoto H, Rittling SR, Yoshitake H, et al. (2001) Osteopontin deficiency reduces experimental tumor cell metastasis to bone and soft tissues. J Bone Miner Res 16:652–659 38. Wickramasinghe SN (2007) Bone Marrow. In: Mills SE (ed.) Histology for histopathologists, 3rd edn. Lippincot Williams, Philadelphia, PA 39. Rauch F (2005) Bone growth in length and width: the yin and yang of bone stability. J Mucoskelet Neuronal Interact 5:194–201 40. Forriol F, Shapiro F (2005) Bone development. Interaction of molecular components and physical forces. Clin Orthop Relat Res 432:14–33 41. Adams SL, Cohen AJ, Lassova L (2007) Integration of signaling pathways regulating chondrocyte differentiation during endochondral bone formation. J Cell Physiol 213:635–641 42. Ballock RT, O’Keefe RJ (2003) The physiology and pathophysiology of the growth plate. Birth Def Res C 69:123–143 43. Frost H (2004) A 2003 update of bone physiology and Wolff’s law for clinicians. Angle Orthod 74:3–15 44. Raisz LG (1999) Physiology and pathophysiology of bone remodelling. Clin Chem 45:1353–1358 45. Kropp HG, Avecilla ST, Hooper AT, et al. (2005) The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology (Bethesda) 20:349–356 46. Frost H (2001) From Wolff’s law to the Utah paradigm: insights about bone physiology and its clinical applications. Anat Rec 262:398–319

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Chapter 2

PATHOPHYSIOLOGY OF BONE METASTASES G. David Roodman Department of Medicine/Hematology-Oncology, University of Pittsburgh School of Medicine, VA Pittsburgh Healthcare System, Research and Development 151-U, University Drive C, Rm. 2E113, Pittsburgh, PA 15240, USA, e-mail: [email protected]

Abstract:

Bone is a very common site for cancer metastasis and may be the only site of metastasis in patients with breast cancer or prostate cancer. The exact incidence of bone metastasis is unknown, but it has been estimated that approximately 300,000–400,000 people in the United States die from bone metastasis each year. Bone metastasis can involve any bone but has a predilection for areas of red bone marrow. Bone lesions are characterized as either osteolytic or osteoblastic, but this classification actually represents extremes of a continuum in which normal bone remodeling, where bone destruction and formation are balanced, is unbalanced. Increased bone destruction is characteristic of osteolytic metastasis and markedly increased bone formation results in osteoblastic metastasis. However, patients can have both osteolytic and osteoblastic metastasis as well as mixed lesions containing both elements. Bone is a frequent site of involvement in patients with prostate cancer, breast cancer and multiple myeloma (MM) because the propensity of these tumors to home to bone and the capacity of bone marrow to support the growth of the tumor. In patients with osteolytic and osteoblastic bone metastasis, both osteoclast formation and activity are increased. In osteoblastic bone metastasis osteoblast is also increased by tumor derived factors. However, the factors which enhance osteoclast or osteoblast activity differ among different tumor types. The identification and characterization of the pathophysiologic mechanisms and factors that underlying bone metastasis have provided important new therapeutic targets for treating these patients, who are currently incurable, and are reviewed in this chapter.

Key words: Metastasis · Bone · Pathogenesis of Bone Metastasis · Osteoclast · Osteoblast D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 2,  C Springer Science+Business Media B.V. 2009

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2.1 Introduction Bone is a very common site for cancer metastasis and may be the only site of metastasis in patients with breast cancer or prostate cancer. The exact incidence of bone metastasis is unknown, but it has been estimated that approximately 300,000– 400,000 people in the United States die from bone metastasis each year [1]. Bone metastasis is frequently seen in patients with breast cancer and prostate cancer with up to two-thirds to three-fourths of the patients developing bone metastasis [2], and 15–30% of patients with lung, bladder, uterine, rectal, thyroid or renal cancer developing bone metastasis during the course of their disease (Table 2.1). The development of bone disease has a major impact on the survival of patients with cancer. In a study by Saad et al. [3] in which 3,049 patients with MM, breast cancer, prostate cancer, lung cancer or other solid tumors were analyzed, patients with MM have the highest fracture incidence at 43%, followed by breast cancer and prostate cancer, with lung cancer and other solid tumors only having 17% (Table 2.2). Further, the occurrence of fractures has a major effect on survival for these patients. An increased risk of death was significantly associated with both nonvertebral and vertebral fractures for all tumor types. The risk of death in patients with breast cancer for example was increased 24% in patients with nonvertebral fractures and 19% in patients with vertebral fractures. Similarly, an increase risk of death was seen in patients with nonvertebral fractures who have prostate cancer. In Table 2.1 Bone metastasis is a frequent complication of cancer. Myeloma is the most frequent cancer to involve bone followed by breast cancer and prostate. Once cancer metastasizes to bone, it is incurable for the overwhelming majority of patients. The incidence of bone metastasis and median survival of patients with bone metastasis is depicted in this table

Myeloma Melanoma Bladder Thyroid Lung Breast Prostate

Incidence of Bone Metastases (Thousands)a,b

Median Survival (Months)b−d

70–95 20–25 14–45 40 60 30–40 65–75 65–75

6–54 12 6 6–9 48 6–7 19–25 12–53

a

Mathers, et al. [88]. Coleman [89]. c American Cancer Society [90]. d Zekri, et al. [91]. b

Table 2.2 Percentage of cancer patients presenting with fractures Multiple Myeloma Breast Cancer Prostate Cancer Lung Cancer and Other Solid Tumors Adapted from Saad, et al. [3].

n

Percent

513 1130 640 766

43 35 19 17

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MM patients, there was a 20% increase risk of death in patients who sustained a fracture compared to patients who did not. Further, the economic burden of metastastic bone disease is tremendous [4]. The mean medical cost for patients with metastatic bone disease was $75,329 compared to $31,082 from patients without bone involvement and similar tumors. The incremental cost for all cancer types studied with bone involvement was $44,442 with the highest increment seen in patients with MM ($63,455). These authors estimated that the national cost burden for patients with metastatic bone disease was 12.6 billion dollars. These results clearly demonstrate that metastatic bone disease has a tremendous impact both on the well-being of patients, the survival of patients, and the cost of their care. In addition, the morbidity that is associated with bone metastasis can be devastating. Patients can have severe bone pain, pathologic fractures, nerve compression syndrome including spinal cord compression [5], and if they have high levels of bone resorption, life-threatening hypercalcemia.

2.2 Clinical Manifestations of Bone Metastasis Bone metastasis can involve any bone but has a predilection for areas of red bone marrow. Bone lesions are characterized as either osteolytic or osteoblastic (Fig. 2.1), but this classification actually represents extremes of a continuum in which normal bone remodeling, where bone destruction and formation are balanced, is unbalanced. Increased bone destruction is characteristic of osteolytic metastasis and markedly increased bone formation results in osteoblastic metastasis. However, patients can have both osteolytic and osteoblastic metastasis as well as mixed lesions containing both elements. For example, patients with MM have pure lytic lesions, while patients with prostate cancer have predominantly osteoblastic lesions. Patients with breast cancer also have osteolytic lesions, but at least 15–25% of these patients may have skeletal disease, which is predominantly osteoblastic in nature [6]. Because there still is reactive new bone formation in response to the bone destruction in patients with bone metastasis from solid tumor, bone scans can identify these sites of new bone formation. However, in MM where bone formation is markedly suppressed or even absent, bone scans can underestimate the extent of the bone disease [7]. Even in patients who have predominantly osteoblastic metastasis there is still ongoing bone destruction. This has been shown by studies of Coleman and others in prospective trials of bisphosphonates for the treatment of bone metastasis [8]. These studies clearly demonstrate that patients with prostate cancer can have very high levels of bone resorption markers in their urine and serum. Further, agents that block bone resorption can decrease bone pain and pathologic fractures in patients with prostate cancer [9].

2.3 Bone as a Preferential Site for Bone Metastasis Bone is a frequent site of involvement in patients with prostate cancer, breast cancer and MM because the propensity of these tumors to home to bone and the capacity of bone marrow to support the growth of the tumor. The metastatic process, which

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(A)

(B)

(C)

Fig. 2.1 Osteoclasts and osteoblasts in normal bone and bone metastasis. (A) Osteoclasts and osteoblasts in normal bone. The large osteoclast (arrow) is actively resorbing bone. Osteoblasts are small cuboidal shaped cells that actively lay down bone matrix. Magnification 100× (generously provided by Dr. Hua Zhang, Helen Hayes Hospital, New York). (B) Osteolytic bone metastasis. Renal carcinoma cells are seen invading the bone marrow, and osteoclasts (arrows) are actively resorbing bone adjacent to the tumor cells. Magnification 200× (courtesy of Dr. Brendan Boyce, University of Rochester, New York). (C) Osteoblastic metastasis. Thickened trabeculae and large numbers of osteoblasts are seen next to the bone surface. Tumor cells from adenocarcinoma of the lung are easily seen between the two large trabeculae. Magnification 200× (courtesy of Dr. Brendan Boyce, University of Rochester, New York)

involves bone destruction and/or formation, enhances both the growth of the tumor due to the release of activated growth factors from bone during the bone resorptive process and the production by bone marrow stromal cells and osteoblasts of growth factors and cytokines, which enhance the survival and growth of the tumors. Many of these stromal cell-derived growth factors and cytokines are upregulated due to adhesive interactions between tumor cells and bone marrow stromal cells (Fig. 2.1, Table 2.3) [10]. In addition, soluble factors produced by tumors themselves further enhance the production of cytokines by bone marrow stromal cells, which also

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Table 2.3 Adhesive Interactions Involved in Bone Metastases Tumor ∗

Breast CA Breast CA Myeloma ∗

Receptor

Integrin

Effect

Urokinase Bone sialoprotein VCAM1, fibronectin

β1 Integrin αv β5 α4 β1 , α5 β1

Tumor progression Adhesion and progression Growth factor production

CA: carcinoma. Table 2.4 Stromal/Osteoblast-Derived Factors that may Affect Bone Metastases PDGF

RANKL

VEGF FGFs IGFs TGF-β

IL-6 BMPs SDF-1 MCP-1

PDGF: platelet-derived growth factor; RANKL: ligand of the receptor activator for nuclear factor κB; VEGF: vascular endothelial growth factor; IL-6: interleukin 6; FGFs: fibroblast growth factors; BMPs: bone morphogenic proteins; IGFs: insulin-like growth factors; SDF-1: stromal cell-derived factor 1; TGF-β: transforming growth factor β; MCP-1: monocyte chemoattractant protein 1.

increase tumor survival and growth. Cytokines that have been shown to be active in this process are listed in Table 2.4 [10]. In addition, blood flow is high in areas of red marrow [11], which may account for the predilection of metastasis to these sites. Further, bone is the largest repository of immobilized growth factors in the body, including transforming growth factorβ (TGF-β), insulin-like growth factors (IGF)-1 and -2, fibroblast growth factors (FGF), platelet-derived growth factors (PDGF), bone morphogenetic proteins, and calcium [12], which make bone a perfect site for metastasis. These growth factors, which are released and activated during bone resorption [13], provide fertile ground in which tumor cells can grow. This “seed-and-soil hypothesis” of the mechanism of bone metastasis was first advanced by Stephan Paget in 1889 [14], and is supported by animal models of bone metastasis. Recently, the bone marrow has also been shown to play a major role in maintaining tumor cells in a dormant state, so they can be reactivated at later states. Tumor stem cells can home to bone via cytokines and chemokines, in particular, SDF-1 expressed by osteoblasts and stromal cells in the marrow microenvironment, and its cognate receptor, CXCR4, on tumor cells. SDF-1 is chemotactic for tumor cells and directs these cells toward the marrow. The marrow microenvironment maintains normal hematopoiesis through production of cytokines and chemokines that enhance the growth and differentiation of hematopoietic stem cells (HSCs) and directs their homing to the marrow. However, HSCs are not distributed uniformly throughout the bone marrow, but are highly localized in “niches” that allow the HSCs to remain in a dormant state. Upon release from the “niche,” stem cells enter the cell cycle and proliferate and differentiate to the formed elements of blood [15].

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Cancers that metastasize to bone appear to use a similar mechanism to either usurp the HSC niche or use a similar type of niche to grow within the marrow and to maintain “cancer stem cells” in a dormant state that are resistant to chemotherapeutic agents. Like normal HSCs, cancer stem cells can lay dormant for long periods of time until they are activated to differentiate and proliferate into malignant cells [16]. The cellular composition of the stem cell niche is an area of active investigation, and its components are just beginning to be identified. Osteoblasts are an important component of the stem cell niche, and form the “endosteal niche” [17]. Cytokines and chemokines produced by osteoblasts as well as adhesive interactions between osteoblasts and HSCs maintain HSCs in G0 and provide a signal for homing of HSCs to the bone marrow. Prostate cancer cells like HSCs utilize a similar mechanism to home to the bone marrow and lodge there [18]. As noted above, several chemokines play critical roles in homing of HSC and cancer cells to the marrow. SDF-1, which is expressed by osteoblasts and endothelial cells, acts as a chemoattractant for both HSCs and cancer cells including MM cells to home to the bone marrow [19]. Recently, annexin II (AXII) has been identified as important in HSC and cancer cell lodgment in the bone marrow and the mobilization of HSCs and cancer cells to the peripheral blood [18]. Recent evidence suggest that other cells in the bone microenvironment the osteoclasts (OCLs), which are responsible for the bone destructive process, may also be involved in tumor cell mobilization. Kollet and coworkers examined the contribution of OCL to the mobilization of immature hematopoietic progenitors, and showed that OCLs secrete MMP-9 and cathepsin K, which cleave SDF-1, OPN and stem cell factor in the surrounding extracellular matrix [20]. This in turn weakens HSC anchorage provided by the endosteal niche. These results show that OCLs are involved in stem cell mobilization. Whether OCLs are also involved in tumor stem cell mobilization to increase bone metastasis or permit metastasis to solid organs remains to be determined.

2.4 The Role of Adhesive Interactions to Bone Metastasis Interactions between specific cell surface molecules on bone cells, bone marrow cells, and tumors are critical to both tumor invasion and the metastatic process. The importance of these interactions has been demonstrated by studies in human breast carcinoma, MM, and prostate carcinoma. Van der Pluijm and coworkers [21] found that the urokinase receptor and β1 integrins formed functional adhesion complexes at distinct sites at the cell surface of metastatic human breast carcinoma cells and that the urokinase receptor is capable of regulating the adhesive function of integrins on breast carcinoma cells. They showed that the addition of a blocking peptide for the urokinase-integrin complex inhibits the attachment of breast carcinoma cells to vitronectin. Using a mouse model of breast carcinoma metastasis, those authors reported that transplantation of nude mice with MDA-231 breast carcinoma cells that overexpress this blocking peptide, results in a significant reduction in tumor progression in bone compared with empty vector-transfected cells. Furthermore, mice

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that were transplanted with MDA-231 cells and received continuous administration of the peptide for 28 days had significantly reduced tumor progression in bone compared with animals that were treated with a scrambled control peptide. These results show that breast carcinoma progression in bone requires adhesive interactions between molecules that are expressed in the bone and molecules that are expressed in tumor cells. Similarly, Sung and coworkers [22] have shown human breast carcinoma cells adhere, proliferate, and migrate to bone through the interactions between αv β3 and αv β5 integrins and bone sialoprotein. In patients with MM, adhesive interactions between the α4 β1 and α5 β1 integrins and vascular cell adhesion molecule 1 (VCAM-1) or fibronectin appear to play an important role in upregulating the expression of cytokines and growth factors by bone marrow stromal cells, further enhancing tumor growth and chemotherapy resistance of the tumor. Damiano and Dalton [23] have shown that these adhesive interactions play an especially important role in the capacity of MM cells to resist standard chemotherapeutic agents, including doxorubicin and melphalan. It is very likely that adhesive interactions between a variety of tumor cells and bone marrow stromal cells result in the release of growth factors by stromal cells and osteoblasts, which also further enhance tumor growth. Similarly, in MM blocking α4 β1 binding to marrow stromal cells affects both the bone destructive process and tumor growth. Adhesive interactions between MM cells, for example, and marrow stromal cells enhanced both tumor growth and production of the factors such as RANKL and TNF-α (discussed below), which enhance OCL formation and activity and further amplify the bone destructive process. Thus, adhesive interactions between tumor cells and stromal cells play a critical role in the homing of the tumor to the bone, the growth of the tumor in the bone, and the upregulation of growth factor production by stromal cells required for tumor cell survival.

2.5 Regulation of Normal Bone Remodeling The adult skeleton is continually being remodeled to replace defective bone as well as to release calcium for various metabolic processes. This occurs through coordinated activity between the osteoblast and the OCL. In the normal bone remodeling sequence, osteoclastic bone resorption is followed by new bone formation at the site of new bone formation and then the process is balanced. However, in bone metastasis this process is either severely imbalanced or even uncoupled, so that bone resorption may be followed by inadequate bone formation, or exuberant bone formation, or no bone formation at all. In patients with bone metastasis, bone destruction is mediated by the OCL, the normal bone resorbing cells, rather than by tumor cells. The RANKL signaling pathway plays a critical role in both normal and malignant bone remodeling by regulation of OCL activity. RANK is a transmembrane signaling receptor, which is a member of the tumor necrosis receptor superfamily. It is found on the surface of OCLs precursors [24, 25]. RANK ligand

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(RANKL) is expressed as a membrane-bound protein on marrow stromal cells and osteoblasts, and secreted by activated lymphocytes. Its expression is induced by cytokines that stimulate bone resorption [26] such as PTH, 1,25 OH Vitamin D3 and prostaglandins [27, 28]. RANKL binds to RANK receptor on OCL precursors and induces OCL formation. Rank signals through the NF-κB and JunN terminal kinase pathways and induces increased osteoclastic bone resorption and enhanced OCL survival [29]. The important role of RANKL in normal osteoclastogenesis has been clearly demonstrated in RANKL or RANK gene knockout mice. These animals lack OCLs and as result develop severe osteopetrosis [30, 31]. OPG is a soluble decoy receptor for RANKL and is a member of the TNF receptor superfamily [32]. It is produced by osteoblasts as well as other cell types and blocks the interactions of RANKL with RANK, thereby limiting osteoclastogenesis. In normal subjects, the ratio RANKL/OPG is very low. Studies using knockout mice for the OPG gene have shown the importance of OPG. OPG deficient mice develop severe osteopenia and osteoporosis [30, 32–35]. Osteoblasts are bone-forming cells that arise from mesenchymal stem cells [36]. The factors controlling osteoblast differentiation are less well understood than for OCLs. The one transcription factor that has been clearly linked to osteoblast differentiation is core binding factor alpha 1 (Cbfa1), also known as Runx-2. Cbfa1 is responsible for the expression of most genes associated with osteoblast differentiation [37]. In mice lacking the Cbfa1 gene bone does not develop [38, 39]. Many extracellular factors can enhance the growth and differentiation of osteoblasts, including PDGF, FGF, and TGF-β.

2.6 Factors Involved in Osteolytic Bone Metastasis In patients with osteolytic bone metastasis, both OCL formation and activity are increased. However, the factors which enhance OCL activity differ among different tumor types. A common mediator of many effects of these tumor-derived factors on OCL formation is RANKL, which is increased in the bone microenvironment in patients with MM and plays an important role in the bone destructive process in breast cancer and prostate cancer as well (Fig. 2.2).

2.6.1 RANKL RANKL expression is increased when MM cells or breast cancer cells bind to marrow stromal cells [40]. RANKL then induces osteoclastogenesis, which results in the release of growth factors that further enhance the growth and survival of tumor cells. In addition, factors produced by tumor cells directly enhance RANKL expression. Using the 5T2 model of MM, Oyajobi and co-workers [41] showed that MIP-1α can induce RANKL expression in bone marrow stromal cells. In addition, IL-6, which is induced when murine MM cells bind to bone marrow stromal cells, also enhances RANKL production. IL-6 also enhances the survival of MM cells.

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Fig. 2.2 The vicious cycle involved in osteolytic metastasis. Tumor cells, in particular breast cancer, secrete parathyroid hormone related peptide as the primary stimulator of osteoclastogenesis. In addition, tumor cells produce other factors that increase osteoclast formation including IL-6, PGE2, tumor necrosis factor, and M-CSF. These factors increase RANK ligand expression, which directly act on osteoclast precursors to induce osteoclast formation and bone resorption. The bone resorption process releases factors such as TGF-β, which increase parathyroid hormone related peptide production by tumor cells as well as growth factors that increase tumor growth. This symbiotic relationship between bone destruction and tumor growth further increases bone destruction and tumor growth Source: Adapted from Roodman NEngl J Med.2004,350.1655.

RANKL has no direct effects on the growth of tumor cells, although its increased production enhances bone destruction, which further enhances the bone metastatic process. A recent study has reported that RANKL can also act as a chemoattractant for tumor cells expressing RANK [42]. A human antibody to RANKL, Denosumab, has been developed, which is in clinical trial for osteoporosis, arthritis and bone metastasis. The antibody has a similar action to OPG and lowers bone receptor markers in patients and is in phase III trials either being compared to placebo or to zoledronic acid, the most potent bisphosphonate used to treat patients with bone metastasis [43]. In MM, several other OCL-inducing factors have been identified in addition to RANKL, which appear to play an important role in the bone destructive process in these patients. These include IL-6, MIP-1α and IL-3.

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2.6.2 MIP-1α MIP-1α is a chemokine that is produced by MM cells in 70% of MM patients, and is a potent inducer of human OCL formation. MIP-1α can increase OCL formation independently of RANKL and can potentiate both RANKL and IL-6 stimulated OCL formation [44]. Bataille et al. reported that gene expression profiling of MM cells from patients demonstrated that MIP-1α is the gene most highly correlated with bone destruction in MM [45]. Further, Abe and coworkers have shown that elevated levels of MIP-1α also correlate with an extremely poor prognosis in MM [46]. In vivo models of MM have demonstrated that MIP-1α can induce OCL formation and bone destruction. Blocking MIP-1α expression in MM cells injected into SCID mice or treating the animals with a neutralizing antibody to MIP-1α results in decreased tumor burden and bone destruction [47,48]. MIP-1α also plays an important role in homing of MM cells to the bone marrow. MIP-1α increases adhesive interactions between MM cells and marrow stromal cells by increasing expression of β1 integrins. This results in production of RANKL, IL-6, VEGF and TNFα by marrow stromal cells, which further enhances MM cell growth, angiogenesis and bone destruction. Masih-Khan et al. reported that the t4:14 translocation in MM results in a constitutive expression of the FGFR3 receptor, which in turn results in high levels of MIP-1α [49]. Patients with the t4:14 translocation have a very poor prognosis, which may reflect the increased MIP-1α production in this patient population.

2.6.3 Interleukin-3 Interleukin-3 (IL-3) in addition to RANKL and MIP-1α, is also significantly elevated in bone marrow plasma of MM patients as compared to normal controls [50]. IL-3 can induce OCL formation in human bone marrow cultures at levels similar to those measured in MM patient samples, and OCL formation induced by marrow plasma from MM patients can be inhibited by using a blocking antibody to IL-3 [50]. IL-3 also indirectly influences osteoclastogenesis by enhancing the effects of RANKL and MIP-1α on the growth and development of OCLs. It also stimulates MM cell growth directly [50]. IL-3 also inhibits osteoblast formation through a factor produced by macrophages in the marrow microenvironment [51].

2.6.4 Interleukin-6 Interleukin-6 (IL-6) has been long recognized as a proliferative factor for plasma cells, but is unclear if IL-6 levels correlate with disease status [52]. IL-6 is a potent inducer of human OCL formation [53]. Levels of IL-6 are elevated in MM patients with osteolytic bone disease when compared to MM patients without bone disease, as well as in patients with monoclonal gammopathy of unknown significance (MGUS) [54]. Most studies support the finding that IL-6 is produced by

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cells in the bone marrow microenvironment through direct contact with MM cells rather than MM cells themselves. These cells most likely are OCLs and stromal cells. Increased osteoblast production of IL-6 has been also reported in cocultures of human osteoblasts with MM cells [55]. Although the precise role of IL-6 in MM bone disease is yet to be determined, IL-6 production by OCLs can increase tumor burden leading to enhanced bone destruction as well as act as an autocrine/paracrine factor to increase OCL formation [56].

2.6.5 PTHrP and TGF-β In breast cancer, other factors which can enhance RANKL production appear to be involved. One of the major factors produced by breast cancer cells is parathyroid hormone related peptide (PTHrP), which induces osteoclastic bone resorption through induction of RANKL by marrow stromal cells. Breast cancer cells also produce IL-6, IL-8, prostaglandin E2, M-CSF, IL-1 and tumor necrosis factor-α, which may increase OCL formation in bone metastasis [57–59]. The increased levels of PTHrP produced by breast cancer cells appear to be due to release of TGF-β in the bone microenvironment. Several laboratories have shown that, when breast carcinoma cells metastasize to bone and induce bone resorption, TGF-β is released in active form from bone. In particular, Chirgwin and Guise [57] have reported that breast carcinoma cells produce parathyroid hormone-related peptide (PTHrP), which induces osteoclastic bone resorption and releases TGF-β from the bone matrix. TGF-β then increases PTHrP production further, creating a vicious cycle in which tumor cells induce bone destruction and, through this process, release growth factors that enhance the growth of the tumor (Fig. 2.2). TGF-β is a potent, multifunctional cytokine that is produced by many cells, including osteoblasts and bone marrow stromal cells that can regulate cell growth and stimulate matrix production. TGF-β is a major factor in bone remodeling, and tumor-derived agents that enhance TGF-β production have been associated with increased bone formation [60]. TGF-β normally functions as a suppressor of tumor growth. Lang and coworkers [61] have shown that mice lacking TGF-β due to haploinsufficiency are more susceptible to tumors. Furthermore, TGF-β is immunosuppressive, which can increase tumor survival further by suppressing the immune system. TGF-β also can stimulate normal stromal cells and osteoblasts to secrete growth factors that enhance tumor growth. In patients with MM, Brown and coworkers [62] reported that TGF-β can depress dendritic cell function in these patients, further enhancing the growth of these tumors and protecting them from immune surveillance. Guise and coworkers [63] reported that the administration of a neutralizing monoclonal antibody to PTHrP inhibited the development of breast carcinoma bone metastasis by MDA-MB-231 cells in nude mice. It is noteworthy that those authors also showed that inhibiting TGF-β responsiveness of the tumor by using a dominant negative TGF-β receptor also reduced bone metastasis.

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Because of the importance of TGF-β in osteolytic bone metastasis, inhibitors of TGF-β type 1 receptor kinase have been explored in preclinical models of skeletal metastasis. Bandyopadhyay and coworker [64] have shown that systemic administration of a TGF-β receptor 1 kinase inhibitor reduced the number and the size of lung metastasis and bone metastasis in a model of metastatic breast cancer. Similarly, Ehata and coworkers [65] have also shown that a novel TGF-β type 1 receptor kinase inhibitor blocked bone metastasis by human breast cancer cells in preclinical mouse models. The inhibitor decreased the invasion of the breast cancer cells induced by the TGF-β in vitro and suppressed transcription of PTHrP, and IL-11 mRNA in the breast cancer cells. Thus, blocking TGF-β signaling is an important area of investigation for inhibiting bone metastasis in patients with breast cancer. Kang and coworkers [66] have shown that TGF-β induced signaling by means of the Smad transcription factor and plays an important role in breast cancer bone metastasis. These investigators demonstrated active Smad signaling in both human and mouse bone metastatic lesions. Further, Smad4 contributed to the formation of osteolytic bone metastasis and was essential for the induction of IL-11, a gene implicated in bone metastasis in mouse systems. Javelaud and coworkers [67] have also demonstrated the importance of TGF-β in melanoma bone metastasis. These investigators reported in a mouse model of melanoma metastasis to bone that overexpression of the inhibitory Smad7, which blocked TGF-β signaling, impaired bone metastasis. Thus, TGF-β plays a major role in the bone metastatic process for many solid tumors. Kang and coworker [68] have used gene expression profiling to identify the genes required for breast cancer bone metastasis. They found that IL-11, osteopontin (OPN), CXCR4 and CTGF were the genes required for bone metastasis, and that overexpression of IL-11 and OPN with either CTGF or CXCR4 was sufficient for bone metastasis. The results suggest that for a tumor to be metastatic to bone, it must express a set of genes that includes genes for homing (CXCR4), angiogenesis (CTGF) and osteolysis (IL-11 and OPN). CTGF and IL-11 are TFG-β responsive genes, which once the tumor metastasizes to bone and increases TGF-β release from bone, further amplify the bone destructive process.

2.6.6 Platelet-Derived Growth Factor Platelet-derived growth factor (PDGF) is a polypeptide produced by osteoblasts in the bone microenvironment that shares extensive sequence homology with the oncogene c-Cis. PDGF increases cell replication, bone resorption, collagen degradation, and collagenase expression as well as inhibiting osteoblast function. The mitogenic activity of PDGF increases the growth of tumor cells as well as enhances OCL activity. Yi and coworkers used MCF-7 cells in a model of breast carcinoma metastasis to bone in nude mice [69] and reported that, breast carcinoma cells that overexpressed HER-2-NEU produced large amounts of PDGF and showed an enhanced propensity

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of these cells to metastasize to bone. Furthermore, they suggested that PDGF played a causative role in the development of osteosclerotic bone metastasis in this model. Thus, upregulation of PDGF may enhance osteoblast formation and activity in bone metastasis and may enhance the growth of tumor cells through its mitogenic effects on tumors.

2.6.7 Vascular Endothelial Growth Factor Vascular endothelial growth factor (VEGF) induces the growth of vascular endothelial cells as well as enhances OCL formation and activity. Investigators in Japan have shown that VEGF can rescue the osteopetrotic phenotype of the op/op mouse, suggesting that VEGF is an OCL stimulatory factor [70]. VEGF is produced by marrow stromal cells rather than by the vascular endothelium of bone. FGF, TGF-β, and the insulin growth factors increase VEGF production by several cell types, and VEGF production is upregulated by MM cells when they bind to bone marrow stromal cells [71]. This upregulation of VEGF results in increased angiogenesis that enhances the proliferation of MM cells. Thus, VEGF appears to be an important cytokine regulating the growth of MM cells and probably the growth of other tumor cells that bind to bone marrow stromal cells. Gupta and coworkers [71] have shown in cocultures of MM cells with bone marrow stromal cells that VEGF significantly increased interleukin 6 (IL-6) secretion by bone marrow stromal cells and that stromal cells from MM patients and normal donors secreted VEGF, FGF, and IL-6. Thus, VEGF produced by bone marrow stromal cells has multiple effects on tumor growth, including increased angiogenesis, increased growth of tumor cells, upregulation of IL-6 (another growth and survival factor for MM cells), as well as increased OCL formation.

2.6.8 Insulin-Like Growth Factors Insulin-like growth factors (IGFs) are produced by osteoblastic cells and are regulated by a number of factors produced by bone marrow stromal cells in the bone marrow microenvironment. These include TGF-β, FGF, PDGF, and prostaglandins. IGFs induce proliferation of osteoblasts and play a major role in stimulating differentiation of osteoblasts [72]. In addition, IGFs increase bone resorption by stimulating the formation of OCLs and activating preexisting OCLs. IGFs can also regulate OCL activity through their regulation of RANKL and RANK levels in bone [73]. IGFs are potent mitogens for tumor cells. For example, Ferlin and coworkers [74] showed that IGFs induce the survival and proliferation of MM cells independent of IL-6 production by bone marrow stromal cells. These authors found that IGF acts as a potent survival/proliferation factor for MM cells, and strongly suggested a role for IGFs in the pathophysiology of MM.

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2.7 Factors Increasing Osteoblast Activity in Bone Metastasis In patients with osteoblastic bone metastasis, osteoblast formation and activity are increased although there is still underlying bone destruction. Prostate cancer is the cancer which has predominantly osteoblastic bone metastasis with increased numbers of irregular bone trabeculae [69]. Risk factors responsible for increased osteoblast activity in prostate cancer are just beginning to be defined.

2.7.1 Endothelin-1 Endothelin-1 has been identified as a possible factor involved in the development of osteoblastic metastases [75]. In vitro studies of samples from patients with breast cancer showed that endothelin-1 can stimulate bone formation and osteoblast proliferation [76]. Recent studies suggest that endothelin-1 may increase osteoblast activity by inhibiting expression of DKK1 by marrow stromal cells [77]. In addition, serum endothelin-1 levels are increased in patients with osteoblastic metastases from prostate cancer [78]. Use of a selective endothelin-1 receptor antagonist decreased both osteoblastic metastases and tumor burden in an animal model, although it had no effect on tumor growth at orthotopic sites [75]. These observations suggest that blocking osteoblastinducing activity by tumors may decrease tumor growth in bone. Consistent with these observations are recent studies using an endothelin-1 receptor antagonist, Atrasentan, in clinical trials in patients with prostate cancer and bone metastasis. The basis for this trial was that endothelin-1 levels are increased in advanced prostate cancer, endothelin-1 is produced by prostate cancer cells and that blocking endothelin-1 activity in preclinical models of osteoblastic bone metastasis had beneficial effects on tumor burden. However, in clinical trials with Atrasentan, Caraduchi and coworkers [79] showed no effect of Atrasentan on progression-free survival or overall survival of patients. However, there was a significant decrease in cancer-induced bone pain and bone alkaline phosphatase, a marker of bone formation. Further, progression of tumor was decreased in patients who only had bone metastasis but no other sites of metastasis. Hall and coworkers [80] have shown that the Wnt signaling pathway plays an important role in the osteoblastic metastasis in prostate cancer. The Wnt signaling pathway promotes the proliferation, expansion and survival of pre and immature osteoblastic cells [81]. Osteoblasts produce several soluble inhibitors of the canonical Wnt pathway; including Dickkopf (DKK1), secreted frizzled related proteins (sFRP), and Wnt inhibitor factor (Wif-1). Hall and coworkers showed that blocking expression of the Wnt signaling pathway antagonist DKK1 in an osteolytic prostate cancer cell line resulted in increased osteoblast activity in the metastasis. In contrast, expressing DKK1 in a prostate cancer cell line that induced both osteoblastic and osteolytic metastasis when injected into tibia of mice, resulted in conversion of the tumor to a highly osteolytic tumor. Recently, Li and coworkers [82] showed that

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normal prostate cells do not express the Wnt stimulator Wnt-7b, but high grade prostate cancer cells do. Further, 16 of 38 bone metastases from patients with breast cancer also expressed Wnt-7b by gene array. DKK1 was not expressed in normal prostate cancer cells but was expressed in 2 of 3 specimens from osteolytic bone metastasis from patients. They interpreted these results to show that DKK1 expression is low in most prostate cancers, and thus allows enhanced Wnt signaling and results in increased osteoblast activity. In contrast to prostate cancer, osteoblast activity is suppressed in MM. Tian and co-workers reported the production of the Wnt antagonist, DKK1, by primary CD138+ MM cells but not by plasma cells from MGUS patients. They demonstrated that levels of DKK1 mRNA correlated with focal bone lesions in patients with MM [83, 84]. In contrast, patients with advanced disease as well as some human MM cell lines did not express DKK1, suggesting that these inhibitors may mediate bone destruction only in the early phases of disease [83]. Anti-DKK1 antibody administration to SCID-hu mice injected with 1◦ MM cells, inhibited MM cell growth and increased bone formation in the implanted fetal bone [85]. MM cells also produce sFR2 [58], another Wnt antagonist, which suppresses osteoblast differentiation in MM. In addition to inhibition of osteoblastogenesis, elevated DKK1 levels can also enhance osteoclastogenesis. Wnt signaling in osteoblasts increases expression of OPG [86] and downregulates the expression of RANKL [87], suggesting a possible mechanism by which inhibition of Wnt signaling in osteoblasts would indirectly increase osteoclastogenesis. Taken together, these studies indicate that DKK1 is a key regulator of bone remodeling in both physiological and pathological conditions and that blocking Wnt signaling may contribute to both stimulation of osteoclastogenesis and inhibition of osteoblasts in myelomatous bones. Thus, multiple stimulators of OCL activity and suppressors of osteoblast differentiation are present in patients with bone metastasis and together result in the devastating bone disease present in these patients.

2.8 Summary The identification and characterization of the pathophysiologic mechanisms underlying bone metastasis have provided important new therapeutic targets for treating these patients, who are currently incurable. Bone metastasis takes a tremendous toll on patients both physically, financially and impacts their survival. Current therapies using intravenous bisphosphonates have greatly improved the outlook of the patients with bone metastasis, but only slow the progression of the disease rather than completely eradicating it [8]. The identification of RANKL as a major mediator of the bone destructive process in bone metastasis for multiple tumor types has led to phase III clinical trials of a human antibody to RANKL, Denosumab, which prevents skeletal-related events in patients with bone metastasis from a variety of tumors. Similarly, endothelin-1 receptor antagonists, TGF-β, receptor kinase antagonists and antibodies to DKK1 are in preclinical or clinical trials. Thus, the future

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appears much brighter for patients with bone metastasis, and the availability of these new agents along with bisphosphonates to prevent development of metastasis or eradicate metastasis and decrease the tumor burden in bone is an exciting possibility.

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20. Kollet O, Dar A, Lapidot T (2007) The multiple roles of osteoclasts in host defense: bone remodeling and hematopoietic stem cell mobilization. Annu Rev Immunol 25:51–69 21. van der Pluijm G, Sijmons B, Vloedgraven H, et al. (2001) Urokinase-receptor/integrin complexes are functionally involved in adhesion and progression of human breast cancer in vivo. Am J Pathol 159:971–982 22. Sung V, Stubbs JT III, Fisher L, et al. (1998) Bone sialoprotein supports breast cancer cell adhesion proliferation and migration through differential usage of the alpha(v)beta3 and alpha(v)beta5 integrins. J Cell Physiol 176:482–494 23. Damiano JS, Dalton WS (2000) Integrin-mediated drug resistance in multiple myeloma. Leuk Lymphoma 38:71–81 24. Hsu H, Lacey DL, Dunstan CR, et al. (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A 96:3540–3545 25. Nakagawa N, Kinosaki M, Yamaguchi K, et al. (1998) RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun 253:395–400 26. Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342 27. Yasuda H, Shima N, Nakagawa N, et al. (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 95:3597–3602 28. Hofbauer LC, Heufelder AE (1998) Osteoprotegerin and its cognate ligand: a new paradigm of osteoclastogenesis. Eur J Endocrinol 139:152–154 29. Roodman GD (2007) Treatment strategies for bone disease. Bone Marrow Transplant 40:1139–1146 30. Dougall WC, Glaccum M, Charrier K, et al. (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13:2412–2424 31. Tsukii K, Shima N, Mochizuki S, et al. (1998) Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha, 25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Biochem Biophys Res Commun 246:337–341 32. Lacey DL, Timms E, Tan HL, et al. (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176 33. Bucay N, Sarosi I, Dunstan CR, et al. (1998) osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268 34. Li J, Sarosi I, Yan XQ, et al. (2000) RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A 97:1566–1571 35. Simonet WS, Lacey DL, Dunstan CR, et al. (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319 36. Aubin JE (1998) Bone stem cells. J Cell Biochem Suppl 30–31:73–82 37. Yang X, Karsenty G (2002) Transcription factors in bone: developmental and pathological aspects. Trends Mol Med 8:340–345 38. Komori T, Yagi H, Nomura S, et al. (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764 39. Otto F, Thornell AP, Crompton T, et al. (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771 40. Mancino AT, Klimberg VS, Yamamoto M, et al. (2001) Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells. J Surg Res 100:18–24 41. Oyajobi BO, Williams PJ, Story B, et al. (2001) Myeloma bone disease and tumor burden reversed by a neutralizing antibody to macrophage inflammatory protein (MIP 1-α/CCL3) in vivo. J Bone Miner Res 16:S192

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42. Jones DH, Nakashima T, Sanchez OH, et al. (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692–696 43. Roodman GD, Dougall WC (2008) RANK ligand as a therapeutic target for bone metastases and multiple myeloma. Cancer Treat Rev 34:92–101 44. Han JH, Choi SJ, Kurihara N, et al. (2001) Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood 97:3349–3353 45. Magrangeas F, Nasser V, Avet-Loiseau H, et al. (2003) Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease. Blood 101:4998–5006 46. Hashimoto T, Abe M, Oshima T, et al. (2004) Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with multiple myeloma. Br J Haematol 125:38–41 47. Alsina M, Boyce B, Devlin RD, et al. (1996) Development of an in vivo model of human multiple myeloma bone disease. Blood 87:1495–1501 48. Choi SJ, Oba Y, Gazitt Y, et al. (2001) Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. J Clin Invest 108:1833–1841 49. Masih-Khan E, Trudel S, Heise C, et al. (2006) MIP-1alpha (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma. Blood 108:3465–3471 50. Lee JW, Chung HY, Ehrlich LA, et al. (2004) IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. Blood 103:2308–2315 51. Ehrlich LA, Chung HY, Ghobrial I, et al. (2005) IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood 106:1407–1414 52. Solary E, Guiguet M, Zeller V, et al. (1992) Radioimmunoassay for the measurement of serum IL-6 and its correlation with tumour cell mass parameters in multiple myeloma. Am J Hematol 39:163–171 53. Roodman GD, Kurihara N, Ohsaki Y, et al. (1992) Interleukin 6. A potential autocrine/paracrine factor in Paget’s disease of bone. J Clin Invest 89:46–52 54. Sati HI, Apperley JF, Greaves M, et al. (1998) Interleukin-6 is expressed by plasma cells from patients with multiple myeloma and monoclonal gammopathy of undetermined significance. Br J Haematol 101:287–295 55. Karadag A, Oyajobi BO, Apperley JF, et al. (2000) Human myeloma cells promote the production of interleukin 6 by primary human osteoblasts. Br J Haematol 108:383–390 56. Abe M, Hiura K, Wilde J, et al. (2004) Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood 104:2484–2491 57. Chirgwin JM, Guise TA (2000) Molecular mechanisms of tumor-bone interactions in osteolytic metastases. Crit Rev Eukaryot Gene Expr 10:159–178 58. Oshima T, Abe M, Asano J, et al. (2005) Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 106:3160–3165 59. Park BK, Zhang H, Zeng Q, et al. (2007) NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med 13:62–69 60. Festuccia C, Bologna M, Gravina GL, et al. (1999) Osteoblast conditioned media contain TGF-beta1 and modulate the migration of prostate tumor cells and their interactions with extracellular matrix components. Int J Cancer 81:395–403 61. Lang SH, Clarke NW, George NJ, et al. (1999) Scatter factor influences the formation of prostate epithelial cell colonies on bone marrow stroma in vitro. Clin Exp Metastasis 17:333–340 62. Brown RD, Pope B, Murray A, et al. (2001) Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10. Blood 98:2992–2998

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63. Guise TA, Yin JJ, Taylor SD, et al. (1996) Evidence for a causal role of parathyroid hormonerelated protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 98:1544–1549 64. Bandyopadhyay A, Agyin JK, Wang L, et al. (2006) Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor. Cancer Res 66:6714–6721 65. Ehata S, Hanyu A, Fujime M, et al. (2007) Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci 98:127–133 66. Kang Y, He W, Tulley S, et al. (2005) Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci U S A 102:13909–13914 67. Javelaud D, Mohammad KS, McKenna CR, et al. (2007) Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis. Cancer Res 67: 2317–2324 68. Kang Y, Siegel PM, Shu W, et al. (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3:537–549 69. Yi B, Williams PJ, Niewolna M, et al. (2002) Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. Cancer Res 62:917–923 70. Niida S, Kaku M, Amano H, et al. (1999) Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption. J Exp Med 190:293–298 71. Gupta D, Treon SP, Shima Y, et al. (2001) Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 15:1950–1961 72. Shinar DM, Endo N, Halperin D, et al. (1993) Differential expression of insulin-like growth factor-I (IGF-I) and IGF-II messenger ribonucleic acid in growing rat bone. Endocrinology 132:1158–1167 73. Wang Y, Nishida S, Elalieh HZ, et al. (2006) Role of IGF-I signaling in regulating osteoclastogenesis. J Bone Miner Res 21:1350–1358 74. Ferlin M, Noraz N, Hertogh C, et al. (2000) Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway. Br J Haematol 111:626–634 75. Guise TA, Yin JJ, Mohammad KS (2003) Role of endothelin-1 in osteoblastic bone metastases. Cancer 97:779–784 76. Kasperk CH, Borcsok I, Schairer HU, et al. (1997) Endothelin-1 is a potent regulator of human bone cell metabolism in vitro. Calcif Tissue Int 60:368–374 77. Clines GA, Mohammad KS, Bao Y, et al. (2007) Dickkopf homolog 1 mediates endothelin-1stimulated new bone formation. Mol Endocrinol 21:486–498 78. Nelson JB, Hedican SP, George DJ, et al. (1995) Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med 1:944–949 79. Carducci MA, Saad F, Abrahamsson PA, et al. (2007) A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 110:1959–1966 80. Hall CL, Bafico A, Dai J, et al. (2005) Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res 65:7554–7560 81. Westendorf JJ, Kahler RA, Schroeder TM (2004) Wnt signaling in osteoblasts and bone diseases. Gene 341:19–39 82. Li ZG, Yang J, Vazquez ES, et al. (2008) Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone. Oncogene 27:596–603 83. Tian E, Zhan F, Walker R, et al. (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349: 2483–2494

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84. Politou MC, Heath DJ, Rahemtulla A, et al. (2006) Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation. Int J Cancer 119:1728–1731 85. Yaccoby S, Ling W, Zhan F, et al. (2007) Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 109:2106–2111 86. Glass DA II, Bialek P, Ahn JD, et al. (2005) Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764 87. Spencer GJ, Utting JC, Etheridge SL, et al. (2006) Wnt signalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro. J Cell Sci 119:1283–1296 88. Mathers, et al. (2000) IARC Globocon. http://wwwlpubmedcedntral.nih.gov. Accessed March 2006 89. Coleman (2001) Cancer Treat Rev. 27:165 90. American Cancer Society (2005) Cancer Facts and Figures. At: http://www.cancer.org/ docroot/STT/content/STT 1x Cancer Facts Figures 2005.asp. Accessed March 2006 91. Zekri, et al. (2001) Int J Oncol 19–379

Chapter 3

ANGIOGENESIS AND BONE METASTASIS: IMPLICATIONS FOR DIAGNOSIS, PREVENTION AND TREATMENT Pelagia G. Tsoutsou and Michael I. Koukourakis Radiation Oncology Department, Democritus University of Thrace, Medical School, Dragana 68 100, Alexandroupolis, Greece, e-mail: [email protected]

Abstract:

Angiogenesis consists of the mechanism by which new blood vessels are formed within the tumor to sustain its development and growth. This “angiogenic switch” is mediated by various molecules deriving from the cancer cell and/or the tumor-associated stroma and is promoted either by oncogene activation or by the physiological response of any cell to the hypoxic stress. The angiogenic switch is governed by the balance between angiogenic inducers and inhibitors. There is a certain affinity between tumors sites and metastatic sites; that is the theory of “seed and soil”: certain tumor cells (the “seed”) have a specific affinity for the milieu of certain organs (the “soil”). Metastases result only when the seed and soil are compatible. The pathophysiology of bone metastasis is complex, involving different cell populations and regulatory proteins. The traditional idea that bone metastases are either osteoblastic or osteolytic represents in fact a continuum. There is a multiplicity of reasons for a tumors’ propensity to metastasize to bone: Increased blood flow in red marrow and the presence of adhesive molecules on tumor cells are the most important. Adhesion triggers the secretion of angiogenic factors and bone resorbing factors from tumor cells that enable cancer cell survival and growth. The unique bone environment characterized by the continuous remodelling through osteoclast and osteoblast activity on trabecular surfaces provides cancer cells a soil rich in growth factors, such as transforming growth factor –β (TGF-β), fibroblast growth factor (FGF), plateletderived growth factor (PDGF)), and insulin growth factors (IGFs). Physical factors within the bone microenvironment, including low oxygen levels, acidic pH, and high extracellular calcium concentrations, may also enhance tumor growth. Bone-derived chemokines such as osteopontin, bone sialoprotein, and stromal-derived factor also act as chemoattractants for cancer cells.

D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 3,  C Springer Science+Business Media B.V. 2009

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Therefore, the most important angiogenic molecules in bone metastasis are VEGF, heparenase, TGF-β, IGF, PDGF, Interleukin- 8 (IL-8) and IL-6. Angiogenesis opens up a whole era of new treatment modalities for bone metastases: biphosphonates can act as anti-angiogenic agents and a field of targeted anti-angiogenic therapies for bone metastases is also emerging. Key words: Angiogenesis · Angiogenic factors · Bone metastasis · Cancer · Therapy

3.1 Introduction Angiogenesis has emerged as an important chapter in our understanding of tumor biology. New blood vessels formation within the tumor is essential to sustain its survival and growth. The pioneer work of the recently deceased Judah Folkmann and subsequent laborious work from various research groups all over the world during the past 20 years, revealed the role of angiogenesis as an essential part of tumor pathogenesis. Angiogenesis also became a major target for therapy and, indeed, the development of a large number of antiangiogenic agents in the recent years has opened a new era of therapeutics. Angiogenesis is fundamental to reproduction, development, and repair; it mainly consists of growth of blood vessels that can “turn on” and “turn off” within a brief period. Although a fundamental physiological procedure, angiogenesis can become pathologic and lead to the progression of many neoplastic and non-neoplastic diseases [1]. This “angiogenic switch” within a previously non- angiogenetic tumor is mediated by various molecules deriving from the cancer cell itself and/or the tumor-associated stroma fibroblasts and infiltrating macrophages and lymphocytes. Once a cancer cell becomes refractory to the normal regulatory mechanisms of division and differentiation, its progression and survival depend on its proximity to a vascular supply [2]. In fact, data of human lung cancer brain metastases indicate that tumor cell division takes place within 75 μm of the nearest blood vessel, whereas tumor cells residing beyond 150 μm from a vessel undergo programmed cell death [2]. These data are in accordance with the diffusion coefficient of oxygen in tumor tissue, which is approximately 120 μm [3]. Therefore, this explains the notion supported by Folkmann, that a tumor without any newly formed vessels can be no bigger than 1 mm in diameter. This early theory [4] suggested that tumors can persist in situ for months to years without neovascularization, when they are no more than 2–3 mm large but then become vascularized when a subgroup of cells in the tumor “switches” to an angiogenic phenotype. In the prevascular phase, cells, or even dormant micrometastases may replicate rapidly as well, but without the angiogenetic procedure their rate of proliferation reaches equilibrium with their rate of death [5]. To grow larger than that, the tumor needs new vessel supplies, therefore the angiogenetic process needs to be “switched on”. This is promoted either by oncogene activation or by the physiological response of any cell to the

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hypoxic stress by up-regulating hypoxia-dependent transcription factors that trigger the overexpression of angiogenic factors, such as VEGF [6–8]. The angiogenic switch is governed by the balance between angiogenic inducers and inhibitors [9]. The essential evidence for this assumption comes from in vitro bioassays, where both bFGF and VEGF can elicit a positive response from capillary endothelial cells, but if an inhibitor such as TSP-1 (thrombospondine 1) is added, the response is blocked [9]. As Hanahan points out: “a net balance of inhibitors over activators would maintain the switch in the off position, whereas a shift to an excess of activating stimuli would turn on angiogenesis” [9]. This raises the question how are all these regulators combined to produce a certain angiogenic result in a given tissue. Manipulation of this balance would find important therapeutic applications in oncology. The whole concept of the “angiogenic switch” along with the interplaying cells is described in Fig. 3.1.

osteoblasts

new bone

osteoclast

BONE development of metastasis macrophage Angiogenesis switch on: inducers

Angiogenesis switch off: inhibitors

Angiogenesis: induction of new blood vessel to support tumor growth

fibroblast endothelial cell

vessel Inducers of angiogenesis: bFGF, VEGF Inhibitors of angiogenesis: TSP-1

cancer cell

fibroblast

osteoblasts

osteoclast

switch on

lymphocyte

new bone

BONE switch off

Fig. 3.1 Interplay of tumor cells to support tumor growth through induction of angiogenesis. These are the basic cells interplaying in the angiogenetic procedure to support metastatic growth. Cancer cells travel through normal blood vessels. Those surviving this “trip” finally exavasate through a rupture of the basement membrane of the vessel and interact with the host environment (stroma, cells) in order to promote angiogenetic loops that will allow them to survive and proliferate. A cluster of tumor cells cannot grow beyond 2–3 mm, if not sustained by the growth of a newly formed vessel, a process called neovascularization. This newly formed blood vessel is formed by endothelial cells, that interact with the tumor cells and promote, both of them, the secretion of angiogenesis inducers (basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β) and others). This is the angiogenesis “switch on” that is in balance with an angiogenesis “switch off”, promoted by angiogenesis inhibitors, also secreted by these cells. Though the endothelial-cancer cell interplay is the basic feature of the angiogenetic process, other cells, such as the fibroblast, the lymphocytes, the osteoblasts and the osteoclasts interplay as well through the angiogenetic swith on/off, as previously described

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The neovascularization supports tumor growth through a “perfusion” effect, a “paracrine” effect [1] and an “autocrine” effect. Perfusion allows nutrients and oxygen to enter and catabolites to exit. The paracrine effect results from the production of growth factors by cells employed in the tumor microenvironment, mainly fibroblasts and infiltrating macrophages and lymphocytes [1]. The autocrine effect refers to the role of angiogenic proteins produced by cancer cells to stimulate the survival and proliferation of the cancer cell by binding to proper receptors [10–17]. Quantification of angiogenesis in a biopsy specimen may have a prognostic as well as a predictive value. There is a common positive association between tumor angiogenesis and the risk of metastasis, recurrence, or death with regard to many tumor types. High microvessel density might be a predictor of metastatic risk because high density increases the area of the vascular surface, thus increasing the possibility for a metastatic cell to escape into the circulation [1]. On the other hand, the angiogenesis “potential” of the tumor might preclude its response to radiotherapy or chemotherapy, while anti-angiogenic agents may reverse this effect, as seen in clinical studies with agents such as bevacizumab [Avastin] [18, 19].

3.2 The Process of Angiogenesis The basic cell that forms a blood vessel is the endothelial cell. The endothelial cells are among the cells with the longest life in the body (apart from the central nervous system), that is in a normal adult vessel, only 1 in every 10,000 endothelial cells (0.01%) happens to be in the cell division cycle at any given time [20]. However, in special circumstances intense endothelial cell proliferation, thus angiogenesis occurs. Figure 3.2 describes the process of neovascularisation through the interplay of endothelial-tumor cell. Inducers of angiogenesis – interplay of cancer and endothelial cell

cancer cell

• • • • • • • •

Neovascularization: Perfusion (O2) Paracrine effect (tumor growth) Autocrine effect: growth factors (fibroblasts, macrophages, lymphocytes) • Autocrine (proteins from tumor cell to itself for survival and proliferation)

blood vessel

endothelial cell

endothelial cell

Fig. 3.2 Interplay between endothelial and cancer cell

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The process of angiogenesis is complex. The basement membrane that surrounds endothelial cells is locally degraded, and they in turn change shape and invade into surrounding stroma and start proliferating [9]. A region of differentiation then appears, where the endothelial cells connect to each other and form a lumen of a new capillary tube. These tubes fuse and coalesce into loops leading to blood circulation. The classical proof of angiogenesis came from experiments whereby tumor fragments or cultured tumor cells were placed in an avascular site, the cornea of a rabbit eye [21]. The implants attracted new capillaries that grew to vascularize the expanding tumor mass. If the capillary formation was blocked tumor growth was dramatically impaired. Further experiments confirmed this result and showed that in the absence of an adequate vasculature, tumor cells either become necrotic and/or apoptotic [5, 22], restraining the increase in tumor volume that should result from continuous cell proliferation, the hallmark of cancer [9]. The blood vessels of tumors are known to be chaotic, leaky and inefficient [23]. The difference between immature tumor vessels and mature normal ones found in healthy tissues is the topic of current research. Vascular morphogenesis requires that endothelial cells undergo morphological changes such as activation, migration, alignment, proliferation, tube formation, branching, anastomosis, and maturation of intercellular junctions and basement membrane [24]. Each of these stages is either known or suspected to depend on VEGF and TGF-β morphogenetic protein signaling pathways [24]. VEGF is essential for initiation of angiogenic sprouting, and also regulates migration of capillary tip cells, proliferation of trunk cells, and gene expression in both. TGF-β regulates cell migration and proliferation, as well as matrix synthesis. These pathways develop an essential interplay in vascular morphogenesis [24]. Moreover, the inflammatory cytokine interleukin-1β has been recently identified as an essential trigger of VEGFdependent angiogenesis and is thought to play a considerable role in tumor vessels maturation [23].

3.3 Angiogenesis and Metastasis The process of cancer cell metastasis is by large obscure but it seems that there are key steps in its pathogenesis. After the initial event that confers the malignant phenotype, cancer cells continue to grow with nutrients supplied by simple diffusion from adjacent normal vessels. As soon as the tumor mass reaches 1–2 mm in diameter, angiogenesis is needed to sustain an adequate supply of nutrient and oxygen to the inner sectors of the growing mass. The onset of this process depends on the synthesis and secretion of proangiogenic factors by tumor cells. As already underlined, the newly growing vessels are immature, with thin often discontinuous walls so that tumor cells, having activated genes controlling cell-cell adhesion disruption and cellular motility, may penetrate in the lumen and reach the systemic circulation. The majority of circulating tumor cells are rapidly destroyed. Some of

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them will be trapped in the capillary beds of organs. Surviving cancer cells can start an intra-capillary growth or extravasate into the parenchyma through disruption of the capillary walls forming a micrometastasis. This micrometastases must in its turn survive and grow through development of a vascular network (angiogenesis). This provides the micrometastasis the ability to invade, penetrate newly formed blood vessels, and enter the circulation, therefore producing “metastasis from metastasis” [25]. It has been made evident early in clinical studies that there is a certain affinity between tumors sites and metastatic sites, i.e., certain tumors metastasize to specific organs [26]. Historically, it was Stephen Paget in 1889 that first developed the theory of “seed and soil” [27]. He proved that certain tumor cells (the “seed”) had a specific affinity for the milieu of certain organs (the “soil”). Metastases result only when the seed and soil are compatible [27]. In 1928, Ewing challenged this theory by implying that metastasis is the result of purely mechanical factors deriving from anatomical re-arrangements of the vascular system within the tumor; a theory that, however, has not gained uniform acceptance [28]. Later on, Zeidman and Buss demonstrated that tumor cells from different tumors interact differently with the capillary bed of a given organ [29]. Sugarbaker proved that each type of tumor provokes a specific pattern of metastases even when injected to the same site [30], while Fisher and Fisher demonstrated that tumor cells can traverse different organs at different rates [31]. Cancer metastasis depends on the interplay of tumor cells with various host factors. The cancer cells consist of multiple genetically unstable cell populations with diverse karyotypes, growth rates, cell-surface properties, antigenicities, immunogenicities, sensitivity to various cytotoxic drugs, and abilities to invade and produce metastasis [25, 26, 32, 33]. It has been shown that the expression of proangiogenic cytokines by malignant cells is under the regulation of the tissue microenvironment [25]. Microenvironmental factors influence expression levels of basic fibroblast growth factor (bFGF), a growth factor that controls the angiogenic switch of some tumors [34]. All this evidence suggests an important role of the microenvironment to a tissues’ ability to promote or inhibit angiogenesis, therefore regulating its metastatic potential. Figure 3.3 describes the interplay between tumor cell and host factors (the seed and soil hypothesis). On the other hand, a tumor can be “hostile” to the implantation of a certain metastasis, due to the function of the tissue microenvironment as a negative regulator of tumor cell growth [25]. Recently, the molecular basis of tumor dormancy has become the topic of research interest [25]. This is a very important aspect of cancer pathogenesis, especially in certain tumor types, such as breast cancer that can recur or metastasize after a long lag period. Cell cycle arrest and immune surveillance have been implicated in tumor dormancy [35, 36]. Interestingly, this dormant cell can become metastatically active if removed from the inhibitory influences of the organ microenvironment [37]. This can be attributed to the inhibition of angiogenesis taking place at this negatively regulatory environment [21].

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Seed and soil hypothesisOsteotropism Bone colonizing tumor cells express: • MMP-1 (proteolysis) • IL-11 (osteoclastogenesis) • Osteopontin (osteoclastogenesis) • Connective tissue growth factor (angiogenesis) • Chemokine receptor CXCR4 (homing to bone) • Bone chemokines, • O2 pressure, • Acidic pH, • Calcium tumor growth • Osteopontin, sialoprotein, stromal-derived factors serve as chemoattractants for cancer cells

cancer Cancer cell

Tumor cells interplay with host factors through: • proangiogenic cytokines • bFGF

osteoblasts osteoclast

• blood flow in the bone marrow • Adhesive molecules on tumor cells to stromal cells and matrix • Secretion of angiogenic and bone resorbing factors cancer survival and growth

Bone remodelling through osteoclast and osteoblast FGF PDGF IGF Bone chemokines

Fig. 3.3 The seed and soil hypothesis-osteotropism

3.4 Bone Metastases – Osteotropism In the United States alone, more than 350,000 individuals die each year with evidence of skeletal metastasis, mainly arising from breast or prostate tumors and to a lesser extent from lung and kidney cancers [38, 39]. The pathophysiology of bone metastasis is complex, involving different cell populations and regulatory proteins [25]. Bone metastases have been classified as either osteolytic or osteoblastic, depending on which cell types are involved, however, in clinical practice, most patients hospit both types. Mainly breast cancer provokes osteolytic metastases, whereas most prostate tumors form osteoblastic lesions [38]. This traditional idea that bone metastases are either osteoblastic or osteolytic represents in fact a continuum [40]. Although bone scanning detects only osteoblastic metastases, in most bone scans of patients even harboring mainly osteolytic metastases, some osteoblastic element is present and therefore is imaged. The advent of new molecular techniques, namely DNA microarray platforms has enlightened the genetic determinants that are critical for tumor cell survival in bone. Kang et al. has studied an underlying gene expression signature in bone-colonizing variants that explained the organ tropism to bone [41]. Compared to the parental tumor population, the bone-colonizing tumor cells expressed significantly more matrix metalloproteinases-1 (MMP-1), interleukin-11 (IL-11), osteopontin, connective

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tissue growth factor, and the chemokine receptor CXCR-4, which accounted for homing to bone (CXCR-4), proteolysis (MMP-1), angiogenesis (connective tissue growth factor), and osteoclastogenesis (IL-11 and osteopontin) [25, 41]. There is a multiplicity of reasons for a tumors’ propensity to metastasize to bone: Increased blood flow in red marrow and the presence of adhesive molecules on tumor cells recognizing the marrow stromal cells and matrix enhance cancer cell entrance and installation in the bones. Adhesion per se triggers the secretion of angiogenic factors and bone resorbing factors from tumor cells that enable cancer cell survival and growth. The unique bone environment characterized by the continuous remodelling through osteoclast and osteoblast activity on trabecular surfaces provides cancer cells a soil rich in growth factors, such as transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and IGFs. Physical factors within the bone microenvironment, including low oxygen levels, acidic pH, and high extracellular calcium concentrations, may also enhance tumor growth [42]. Bone-derived chemokines such as osteopontin, bone sialoprotein, and stromal-derived factor also act as chemoattractants for cancer cells [43–46]. Such interactions are described in Figs. 3.3 and 3.4. The predilection of some tumors to metastasize to the bones, for example breast cancer, was described more than 50 years ago by Walther in 1948 [47]. He found in an autopsy study (when adjuvant chemotherapy did not exist) that 64% of 186 patients who died of breast cancer had metastases to bone. Two more recent studies Osteotropism •

•

Avβ3 integrin: adhesion molecule of cancer cell binds to bone matrix protein

Cancer cells decorate themselves with • bone sialoprotein (BSP) • Osteopontin and bone cells expressing integrins trap them → preferential adhesion

cancer cell

Osteopontin: →ανβ3 integrin: blocks apoptosis

blood vessel

osteoblasts

osteoclast

Fig. 3.4 The role of integrins and ostopontin in osteotropism

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reported that 62–71% of breast cancer patients had bone metastases at autopsy, suggesting that chemotherapy was not a preventive factor as far as bone metastases are considered [48, 49]. Breast, lung and prostate cancer have a definitive predilection to bone metastasis [50, 51]. Stromal interactions are important for cancer osteotropism. Through cell-surface adhesion molecules, such as the ανβ3 integrin, present in cancer cells, they bind to bone matrix proteins. Osteopontin (OPN) binding and signaling through ανβ3 integrins on breast cancer cells blocks apoptosis, providing a survival advantage to breast cancer cells in bone [52, 53]. Then, cancer cells decorate themselves with bone matrix proteins, such as bone sialoprotein (BSP) and OPN [52, 54, 55] enabling bone stromal cells expressing integrins to trap them. This adhesion of cancer cells to the bone marrow vasculature is preferential and depends on the phenotypic differentiation of endothelial cells across organs [56–59].

3.5 Angiogenic Molecules in Bone Metastasis 3.5.1 VEGF As already described, VEGF is a fundamental angiogenesis inducer secreted by cancer cells and by activated tumor- associated fibroblasts contributing to the growth of the primary and secondary tumors. VEGF expression is directly dependent on the transcriptional activity of hypoxia inducible factors 1 and 2 (HIF 1 and 2) [60]. Hypoxia decelerates the degradation for the HIF1a and HIF2a subunits of HIFs, leading to the accumulation of HIFs in the cytoplasm of cancer cells, entrance in the nuclei and binding to the hypoxia responsible element of VEGF-A and of genes involved in angiogenesis, anaerobic metabolism and apoptosis inhibition. VEGF binds to receptors on endothelial cells that are transmembrane tyrosine kinases and are coupled to the cellular regulatory network [9]. VEGF receptors are highly expressed on endothelial cells but also in cancer cells. VEGF acts by binding to three distinct VEGF receptors: VEGFR1 (Flt-1), VEGFR2 (KDR/Flk-1), and VEGFR3 (Flt-4) [60–62]. VEGFA isoforms are the basic angiogenic molecules since they induce most of angiogenesis steps (migration, protease production, and proliferation). Moreover, VEGF increases the permeability of blood vessels by stimulating the functional activity of vesicular-vacuolar organelles, clusters of cytoplasmic vesicles and vacuoles located in microvascular endothelial cells [62]. This is thought to facilitate tumor progression by generating an extravascular fibrin gel that acts as a substrate for endothelial and tumor cell growth [63]. VEGF also mediates endothelial cell survival by upregulating the phosphatidylinositol-3 kinase/Akt signal transduction pathway [64] and stimulating expression of the antiapoptotic proteins Bcl-2 and A1 [65]. VEGF has been proven to promote osteoblast activity and to induce initial differentiation of osteoblasts; however, it requires other factors to induce mineralization [66]. Furthermore, it has been shown to contribute to prostate cancer–induced osteoblastic activity in vivo [66].

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3.5.2 Heparenase Other growth-regulatory factors, involved in bone metastasis are heparan sulfates [67]. They are present within the tumor microenvironment as components of heparan sulfate proteoglycans or as free heparan sulfate chains. They act to fine-tune the activities of growth factors and chemokines and therefore regulate tumor cell growth, angiogenesis, and osteoclastogenesis [68]. One of them, syndecan-1, is a major heparan sulfate proteoglycan of breast cancer cells which is also found in the bone marrow, that correlates with poor prognosis [69]. Syndecan-1 is also induced in reactive stroma responding to breast cancer [70]. Interestingly, the heparan sulfate of tumors of the breast is substantially different from that found in normal breast tissues [67]. This may be due in part to the action of heparan sulfate–modifying enzymes, such as heparanase. Heparanase cleaves heparan sulfate chains with an endo-´ι-D-glucuronidase activity releasing activated fragments of heparan sulfate that mediate its growth and angiogenic effects by acting on tumor and endothelial cells [68]. These fragments interact with growth factors, while the cleavage of heparan sulfate contributes to erosion of basement membrane barriers, thereby facilitating invasion and metastasis [71, 72]. Indeed, heparanase has been directly implicated in promoting invasiveness, angiogenesis, and metastasis [73–76]. Heparanase is an important factor of breast carcinomas, correlating with greater metastatic potential [77]. It has been shown that the expression of heparanase in myeloma cells implanted in immunodeficient mice promotes tumor metastasis to bone [78]. Furthermore, that same effect has been shown in breast cancer, where a marked enhancement of osteoclastogenesis and bone turnover was discovered in animals bearing tumors that expressed heparanase compared with controls, suggesting a role for heparanase in promoting bone resorption even when tumors are not evident in the bone [67]. The underlying mechanism is the stimulation of osteoclastogenesis. Heparanase might hold a role in mediating the release of osteolytic agents into the circulation that then travel to act on bone [67]. This has also been shown in other studies emphasizing the role of heparan sulfate proteoglycans, such as syndecan-1, interleukin (IL)-8, hepatocyte growth factor, FGF, and osteoprotegerin [68, 79–84]. Interestingly, these findings are consistent with the fact that treatment with heparin, a highly sulfated form of heparan sulfate, causes bone resorption and decreased bone density [85]. It has further been hypothesized that tumors condition the bone marrow for metastases by first stimulating osteoclastogenesis and bone resorption and by releasing various factors stored in the bone that fuels further tumor growth, thereby leading to continued stimulation of osteoclasts [86, 87]. Functional interactions between metastatic cancer cells and bone cells are essential, that are being mediated by soluble stimulators of osteoclast activity [86, 87]. Anyhow, expression of heparanase by a tumor distal to the bone can have a dramatic impact on bone turnover by affecting skeletal integrity, preparing a growth-enriching bone microenvironment that will support metastatic tumor cells once they invade the bone.

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Thus, the use of heparanase inhibitors as an early therapeutic approach to impede progression of breast cancer as well as other bone-homing tumors, might prove a useful approach [67].

3.5.3 TGF-β TGF is an important molecule deriving from the bone extracellular matrix that activates PTHrP-independent osteolytic pathways. It acts through a Smad-dependent signaling pathway and leads to the induction of increased synthesis and secretion of IL-11 by bone-homing breast cancer cells. IL-11 is a known cytokine with powerful osteolytic activity, which is thought of playing a critical role in the molecular signature of bone metastasizing breast carcinoma cells [41]. TGF-β is present in high concentrations in bone matrix [88] and is expressed by some breast cancers and cancer-associated stromal cells [89]. TGF-β is stored in bone and is released and activated during osteoclastic bone resorption [90]. Therefore, it is suggested that TGF-β is an important factor for bone metastasis of breast cancer through the TGF-β receptor- mediated signaling pathway and that its interaction to PTHrP accounts for the osteolytic matastases seen in breast cancer patients [91]. Fibroblasts are now being considered as critical players in tumor growth by regulating the phenotype of the tumor cells as well as the angiogenic response that supports them [92]. Fibroblasts and their activated counterpart, the myofibroblast, synchronize these events through the expression of extracellular matrix molecules, growth factors and morphogens, including FGF and TGF-β [92]. TGF-β also participates into smooth muscle cell accumulation during normal angiogenesis [93]. It has already been mentioned that TGF-β is an important factor considering vascular morphogenesis: while VEGF is essential for initiation of angiogenic sprouting, TGF-β regulates cell migration and proliferation and regulates extracellular matrix [24]. Overexpression of TGF-β is associated with metastasis and poor prognosis, and TGF-β antagonism has been shown to prevent metastasis in preclinical models with surprisingly little toxicity [94]. The efficacy of the anti-TGF-β antibody 1D11 in suppressing metastasis was shown to be dependent on a synergistic combination of effects on both the tumor parenchyma and microenvironment through enhancement of the CD8+ T-cell-mediated antitumor immune response, but also through the innate immune response and angiogenesis. This study suggested that elevated TGF-β expression in the tumor microenvironment modulates a complex network of intercellular interactions that promote metastasis, while TGF-β antibodies reverse this effect, and produce no major effect of TGF-β antagonism on any cell compartment, thus letting authors of the study to suggest there might exist a good therapeutic window and autoimmune complications could be avoided [94]. Moreover, TGF-β has been suggested to depend on cyclooxygenase-2, which displays a proangiogenic activity, mediated principally through its metabolite PGE2.

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A novel signalling route through which PGE2 activates the Alk5-Smad3 pathway in endothelial cells, involving the release of active TGF-β, through a process mediated by the metalloproteinase MT1-MMP has been recently identified [95].

3.5.4 IGF Bone expresses large amounts of insulin-like growth factor IGF ligands, and the IGF system is required for normal bone physiology. In a study, high IGF-IR-expressing neuroblastoma cells have been shown to adhere tightly to bone stromal cells, flatten, and extend processes [96]. The IGF/IGF-IR system plays a major role in the pathogenesis and progression of Ewing’s sarcoma [97–99]. Moreover, a central role for IGF-1 in the pathophysiology of multiple myeloma has been established. IGF-I deriving from the tumor-microenvironment interaction may facilitate the migration, survival and expansion of the multiple myeloma cells in the bone marrow [100, 101]. Moreover, the inhibition of the IGF-1R-mediated signalling pathway has been suggested to be a possible new therapeutic principle in multiple myeloma. Targeting the IGF-1R using picropodophyllin has both antitumor activities and also influences the bone marrow microenvironment by inhibiting both angiogenesis and bone disease [100, 102]. Even more interestingly, evidence suggests that IGF family is a multi-component network of molecules involved in the regulation of both physiological and pathological growth processes in the prostate [103]. Their roles include participation in cellular metabolism, differentiation, proliferation, transformation and apoptosis, during normal development and malignant growth [103]. They also are essential in prostate cancer bone metastases, angiogenesis and androgen-independent progression. Therapeutic interventions in men with androgen independent progression targeting the IGF family are currently under intense research, such as reduction of IGF-I levels (growth hormone-releasing hormone antagonists, somatostatin analogs), reduction of functional IGF-I receptor levels (antisense oligonucleotides, small interfering RNA), inhibition of IGF-IR and its signalling (monoclonal antibodies, small-molecule tyrosine kinase inhibitors) and IGF Binding Proteins [103]. VEGF is produced by many cell types, including osteoblasts. IGF-I is a known osteogenic factor and it modulates VEGF expression in osteoblasts [104]. Therefore, IGF-I may enhance osteoblast synthesis of VEGF, which may then act locally on endothelium to stimulate angiogenesis [104]. Moreover, IGF-I has a local regulatory role in bone remodelling, regulates proliferation of bone-derived endothelial cells and has a role in skeletal angiogenesis. IGF-I induces growth and chemotactic responses in bone endothelium acting through the type-I IGF receptor, which might be part of a generalized response of bone cells to IGF-I that facilitates cell migration [105]. Nevertheless, the transcription factor runt-related gene 2 (RUNX2)/core binding factoralpha-1/acute myeloid leukemia 3/polyoma enhancer-binding protein 2alphaA/osteoblast-specific transcription factor 2 regulates osteoblast differentiation through cascades involving IGF [106]. RUNX2 might be important in IGF-I and extracellular matrix-regulated endothelial cell migration and differentiation [106].

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3.5.5 PDGF Another family of genes activated in response to HIF-1α signaling is this encoding the polypeptide chains of platelet-derived growth factor (PDGF) [107]. PDGF is a family of cationic homo-and heterodimers of disulfide-bonded A- and B-chains, which are synthesized as precursor molecules that assemble into dimers and undergo proteolytic processing [108,109]. To date, five PDGF isoforms have been identified: PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. These isoforms act by binding to two tyrosine kinase receptors, PDGF-Rα and PDGF-Rβ. What is interesting about PDGF is that its functional activity depends, to a large extent, on the anatomical location of the tumor in question. Tyrosine kinase receptors can play different roles in different vascular beds. Imatinib (STI571 or Glivec; Novartis Oncology), that selectively inhibits activation of PDGF-R signal transduction has changed the field in the treatment of chronic myelogenous leukemia [110]. In an orthotopic murine model of hormone-refractory human prostate cancer metastasis to the bone, enhanced tumor cell expression of PDGF-BB, and its receptor PDGF-Rβ has been noted [25]. The expression of these proteins was enhanced in lesions growing adjacent to bone. In contrast, these angiogenic proteins were poorly expressed in surrounding tissues, such as muscle [9]. They also noted that PDGF-Rβ was activated on both the prostate tumor cells and the tumor-associated endothelium, while phosphorylated PDGF-Rβ was not found in either of them, thus suggesting a paracrine as well as an autocrine action for PDGF-BB. This expression pattern of PDGF-Rβ suggested that it might be a good target for therapy because its inhibition could affect the malignant cell population as well as the blood vessels that support tumor growth. Indeed, treatment of mice with imatinib or the combination of imatinib plus paclitaxel led to induction of significant apoptosis of both tumor cells and tumor-associated endothelial cells, resulting in smaller tumors, fewer lymphatic metastases, and a significant reduction in bone lysis. These experiments demonstrated that tumor-associated endothelial cells express phosphorylated PDGF-R when confronted with tumor cells that secrete PDGF ligands and that inhibition of this activation, particularly in combination with chemotherapy, can produce a significant therapeutic effect.

3.5.6 Interleukin-8 (IL-8) IL-8 is a member of the alpha chemokine family of cytokines originally identified as a neutrophil chemoattractant. IL-8 has been shown to stimulate osteoclastogenesis and bone resorption and is characteristically expressed by tumors that tend to metastasize to bone [87]. Expression of IL-8 is significantly enhanced by lysophosphatidic acid, which is a product of activated platelets [111]. Breast cancer cells have been proven to induce platelet aggregation and stimulate the secretion of lysophosphatidic acid. It has been reported that elevated levels of IL-8 correlated with increased bone metastasis in breast cancer [87].

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IL-8 is thought of playing a major role in VEGF-independent tumor angiogenesis [112]. Induction of IL-8 preserved the angiogenic response in HIF1-α-deficient colon cancer cells, suggesting that IL-8 mediates angiogenesis, independently of VEGF [113]. IL-8, a member of the CXC chemokine family exerts its angiogenic properties on endothelial cells through interaction with its receptors CXCR1 and CXCR2 [114, 115]. Overexpression of IL-8 is associated with advanced disease, poor prognosis and tumor recurrence in several cancer types [116, 117]. The synthesis and secretion of IL-8 depends, among others, on EGFR signalling [118]. In addition, activation of endothelial growth factor receptor EGFR is involved in the pathogenesis of bone metastases, through stimulation of bone marrow stromal cells to produce osteoclastogenic factors and to sustain osteoclast activation [118].

3.5.7 Interleukin-6 (IL-6) Mesenchymal stem cells (MSC) are a predominant fibroblast cell population within the bone marrow and are among the first cell types to encounter metastatic breast cancer cells. Hormone-responsive (i.e., estrogen receptor- alpha (ERα)-positive) tumors have a much stronger metastatic predilection for bone than their ERα-negative counterparts [119–121]. Although hormone-responsive breast cancer patients tend to have a more favorable clinical prognosis than hormone unresponsive patients, those presenting with bone metastasis and increased serum IL-6 levels face high mortality rates [122, 123]. Elevated IL-6 serum levels directly correlate with disease staging and unfavorable clinical outcomes in women with metastatic breast cancer [124]. Activated fibroblasts produce elevated levels of IL-6 [125]. The pleiotropic cytokine IL-6 has many homeostatic functions and serves as a growth factor for several cancers including multiple myeloma and prostate cancer [124, 126]. Among other cytokines exerting an important role in multiple myeloma, interleukin 6 (IL-6), IGF-1, VEGF and others are the most critical. They are secreted from stromal, endothelial cells and/or osteoclasts, and promote myeloma cell growth as well as paracrine cytokine secretion and angiogenesis in the bone marrow [101]. IL-6 is considered among the major osteoclastogenic cytokines, along with IL-1β and TGF-β. In multiple myeloma, B-cell plasmacytomas stimulate bone resorption and angiogenesis, resulting in osteolytic lesions. An interaction between multiple myeloma cells and mesenchymal stem cells from bone marrow stroma results in the formation of osteolytic metastases. It has been shown that an IL-6-neutralizing antibody blocks this effect [127]. There is a mutual stimulation between VEGF and IL-6, suggesting paracrine interactions between myeloma and marrow stromal cells [128]. Breast cancer cells interact with bone marrow cells and result in increased production of IL-6 that enhances bone destruction and angiogenesis within the bone [129, 130]. IL-6 is produced by macrophages, T cells, B cells, endothelial cells and

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tumour cells. It promotes tumour growth by upregulating anti-apoptotic and angiogenic proteins in tumour cells [131]. In a recent study it was shown that serum IL-6 levels have independent prognostic value in patients with metastatic breast cancer and that they are correlated with the extent of disease [131].

3.6 General Principles of Antiangiogenic Therapy Early in the mid ‘90s, when antiangiogenic therapy first became a realistic option in cancer treatment, some first guidelines where proposed by Folkmann: “(i) since antiangiogenic therapy is directed at specific targets of angiogenesis (migrating and proliferating endothelial cells), it is not likely to cause bone marrow suppression, gastrointestinal symptoms, or hair loss, as observed with chemotherapy. (ii) antiangiogenic therapy needs to be administered for several months to a year or more, since it down-regulates neovascularization by inhibiting the proliferation and migration of endothelial cells rather than by killing them and this is a much slower process than the lysis of tumor cells. (iii) antiangiogenic agents are not likely to cause resistance phenomena similar to those observed with classic chemotherapeutic agents. (iv) combining antiangiogenic and cytotoxic therapy or radiotherapy may be more effective than either type alone. (v) antiangiogenetic therapy does not have to cross the blood–brain barrier” [1]. Understanding the regulatory mechanisms of the angiogenic process allows for the development of compounds and monoclonal antibodies suitable for antiangiogenic therapy. Monoclonal antibodies that bind and block the actions of VEGF have been developed, as well as compounds interfering with signal transduction of VEGF receptors. Moreover, the knowledge of morphogenesis of new vessels provides important targets for antiangiogenic treatment. For example, sprouting capillaries express the integrins alpha-v-beta-3 αv β3 or alpha-v-beta-5 αv β5 . Abrogation of these integrins evokes programmed cell death (apoptosis) of the new endothelial cells and dramatically impairs neovascularization of tumors [132,133]. Anti-integrin antibodies and interfering RDG peptides are in development as candidates for antiangiogenic therapy [9]. Another biological principle is the interrelationship between tumor angiogenesis and modulation of cell death. The vasculature has been suggested to be a paracrine regulator of apoptosis [9]. Therefore, not only does inadequate vasculature promote necrotic cell death, but it also can elicit tumor cell apoptosis. Therefore, angiogenesis obtains a pivotal role in anticancer treatment. Angiogenesis inhibitors are already an important component of therapeutic strategies targeting metastatic tumors. Moreover, antiangiogenic treatments already emerge as efective adjuvant treatments as they may prolong the dormant state of micrometastasis improving the progression- free survival. Finally, as methods for early cancer detection improve, interference to cancer growth through downregulation of the angiogenic switch can become another option of both cancer treatment and prevention [9].

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3.6.1 Treatment of Bone Metastases with Anti-Angiogenetic Agents 3.6.1.1 Biphosphonates as Anti-Angiogenic Agents Skeletal complications of bone metastases increase the risk of death and undermine patients’ quality of life [134]. The role of biphosphonates, which are essential in the symptomatic palliation of bone metastasis is currently being investigated in the prevention of bone metastases. Recent evidence indicates that benefits of bisphosphonates may extend beyond the treatment of metastatic bone lesions and, through their potential anti-tumour activity, they may prevent bone metastasis. This antitumor activity is thought to be due to induction of apoptosis, inhibition of tumour cell invasion and tumour growth reduction [134]. Therefore, it is currently being suggested that patients with early-stage disease may benefit from early bisphosphonate therapy, before bone metastasis develops [134]. Part of the antitumor activity of bisphosphonates may be attributed to an antiangiogenic effect [135]. Treatment of endothelial cells with biphosphonates reduced proliferation, induced apoptosis, and decreased capillary-like tube formation in vitro, while reducing the quantity of blood vessels in bone biopsy specimens from patients with Paget’s disease [136]. It is possible that biphosphonates, particularly zoledronic acid and pamidronate, could represent a powerful tool for angiogenesis inhibition. However, these findings are still preliminary and cannot be affirmed unless properly tested in prospective clinical trials. Nitrogen-containing bisphosphonates lead to caspase-dependent apoptosis, inhibit matrix metalloproteinases and downregulate αv β3 and αv β5 integrins suppressing angiogenesis [137]. It has been shown that zolendronic acid at therapeutic dose levels markedly inhibits in vitro proliferation, chemotaxis and capillarogenesis of bone marrow endothelial cells of patients with multiple myeloma [138]. Zoledronic acid also reduces angiogenesis in the in vivo chorioallantoic membrane assay [138]. These effects are partly sustained by gene and protein inhibition of VEGF and VEGFR2 in an autocrine loop. At the clinical level, it has been shown that this antiangiogenic activity of zolendronic acid could be attributed, at least patially, to a transient reduction of VEGF, bFGF and MMP-2 circulating levels after infusion [139]. In another study the changes in VEGF and markers of bone resorption were assessed in a cohort of patients with metastatic bone disease following a single infusion of zoledronic acid [140]. The majority of patients developed a significant reduction in circulating levels of beta-CTX at just 1 day after the single zoledronic acid infusion and a statistically significant correlation between median VEGF and beta-CTX was noted. In another study, after a single dose infusion of zolendronic acid, the MMP-2, VEGF and bFGF basal values showed a statistically significant decrease in their circulating levels [139]. Even more interestingly, the VEGF- related zolendronic acid modifications were shown to correlate with time to- first skeletal-related event, time to- bone progression disease, and time to- worsening of performance status, thus suggesting that the VEGF modifications may represent a surrogate marker [141]. Alendronate also possesses an antiangiogenic effect, possibly deriving from its direct antiangiogenic effects on intra-tumor endothelial cells [142]. Moreover,

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neridronate was shown to have antiangiogenic properties in vitro [143]. In a recent study, treatment with clodronate encapsulated in liposomes (clodrolip) efficiently depleted tumor-associated macrophages in the murine F9 teratocarcinoma and human A673 rhabdomyosarcoma mouse tumour models resulting in significant inhibition of tumour growth [144]. Tumour inhibition was accompanied by a substantial reduction in blood vessel density in the tumour tissue and the strongest effects were observed with the combination therapy of clodrolip and a VEGF-neutralising antibody, whereas free clodronate was not significantly active. Minodronate inhibited melanoma growth and improved survival in nude mice by suppressing the tumorassociated angiogenesis and macrophage infiltration [145]. After treating patients with disodium pamidronate infusion, basal VEGF levels decreased significantly, while interferon-gamma (IFN-γ) and IL-6 levels increased [146]. 3.6.1.2 Targeted Anti-Angiogenic Therapies VEGF-A and its receptors play a role in both osteoclastogenesis and tumor growth. In a study, systemic (i.v.) treatment of nude mice bearing intrafemoral prostate (PC-3) tumors with the vascular ablative agent VEGF121 /recombinant gelonin (rGel) strongly inhibited tumor growth. Thus, VEGF121 /rGel inhibits osteoclast maturation in vivo and is probably important in the suppression of osteolytic lesions. This is a novel mechanism of action for this class of agents, suggesting a potentially new approach for treatment or prevention of tumor growth in bone [147]. Megavoltage irradiation and anti-VEGF monoclonal antibodies have been shown to have a beneficial effect on bone destruction [148]. Renal cancer is another disease with a known predilection to bone metastasis and interferon- α (IFN-α) -based therapies are among the standard agents used in the treatment of metastatic renal cell cancer. IFN-α has, among others, antiangiogenic properties; it has been implied there could be an effect of IFN-α on tumorinduced osteoclast differentiation and bone angiogenesis. In a recent study, it was shown that IFN-α has a wide spectrum of activities on renal cancer-induced bone disease, in addition to its recognized role as a cytotoxic and immunomodulatory agent, namely its ability to reduce bone resorption and to impair tumor-associated angiogenesis [149]. Vitronectin receptor, an ανβ3 integrin, is required for osteoclasts to adhere to the bone surface. Interactions between vitronectin receptor and the Arg-Gly-Asp tripeptide sequence found in several bone matrix proteins lead to osteoclast attachment, activation, and the release of cathepsins into the resorption lacuna [150]. Several small-molecule inhibitors of the vitronectin receptor specifically reduce the angiogenic activity and also inhibit bone resorption in vitro and in vivo, which makes them candidates for clinical testing [150–152]. Endothelin-1 binds to the G-protein–coupled endothelin-A receptor and initiates signaling pathways that lead to vasoconstriction, cell proliferation, and angiogenesis. Endothelin-1 is highly secreted from prostate cancer cells and stimulates osteoblast proliferation, leading to osteoblastic bone metastases. Inhibiting the endothelin-A receptor may prevent the formation of osteoblastic metastasis in patients with

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prostate cancer. Atrasentan (ABT-627) is an inhibitor of the endothelin-A receptor that promotes bone formation in vitro and inhibits osteoblastic metastases in mice [153]. Atrasentan is in phase III trials in patients with prostate cancer and bone metastases [154,155], as well as in patients with increasing prostate-specific antigen levels who are expected to develop bone metastases. c (Pfizer, The receptor tyrosine kinase (RTK) inhibitor SU11248 (sutent malate ), Inc.) is a multitargeted kinase inhibitor that inhibits VEGF receptor (R)-1, 2 and 3, PDGFR-α and β, Flt3, RET, and Kit [156]. Its inhibitory effects against osteoclast formation have been reported, suggesting that it may be an effective and tolerated therapy to inhibit growth of breast cancer bone metastases, with the additional advantage of inhibiting tumor-associated osteolysis [157]. In another experimental model of bone metastasis, an angiogenesis inhibitor, angiostatin, was showed to produce a marked inhibition in the extent of skeletal lesions through a direct inhibition of osteoclast activity and generation, suggesting that, besides its anti-angiogenic activity, angiostatin must also be considered as a very effective inhibitor of bone resorption, broadening its potential clinical use in cancer therapy [158]. Neovastat (AE-941), a naturally occurring multi-functional inhibitor of angiogenesis was also tested with respect to its antimetastatic bone cancer properties [159]. Neovastat prevented the degradation of osteoid-like radiolabeled extracellular matrices, while it inhibited the gelatinolytic activity of matrix metalloproteinase, producing, however a small decrease in the number of osteolytic lesions. c an inThe systemic administration of STI571 (imatinib mesylate, Gleevec ), hibitor of phosphorylation of PDGFR, in combination with paclitaxel, produced apoptosis of tumor cells and bone- and tumor-associated endothelial cells. Thus, by inhibiting angiogenesis, a decrease in tumor incidence and weight, and a decrease in incidence of lymph node metastasis were shown [160]. This therapeutic activity was correlated with inhibition of osteoclast function, inhibition of tumor cell proliferation, and induction of apoptosis in tumor-associated endothelial cells and tumor cells. The molecular players (angiogenic molecules) in bone metastasis and the possible emerging agents with anti-metastatic properties to bone are described in Fig. 3.5.

•

• • • • • • •

Interplaying molecules of angiogenesis in bone metastasis: VEGF Heparanase TGF-β IGF PDGF IL-8 IL-6

Agents with possible anti-metastatic properties to bone • • • • • • • • •

Anti-integrin antibodies (interfering RGD peptides) Biphosphonates (zolendronic acid, alendronate, nerindronate, clondronate, minodronate, disodium pamidronate) Vascular ablative agent VEGF 121 recombinant gelonin (rGel) IFN-α Vitronectin receptor (ανβ3 integrin) Endothelin-1 (atresentan ABT-627) Receptor tyrosine kinase (RTK) inhibitor, SU 11248 (sutent malate) Neovastat (AE-941) STI 571 (imatinib mesylate (Gleevec©), inhibitor of PDGFR

Fig. 3.5 Angiogenic molecules and emerging agents with antimetastatic properties to bone

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Chapter 4

NATURAL HISTORY, PROGNOSIS, CLINICAL FEATURES AND COMPLICATIONS OF METASTATIC BONE DISEASE Vassilios Vassiliou, Edward Chow and Dimitrios Kardamakis Department of Radiation Oncology, University of Patras Medical School, 26504 Patras, Greece, e-mail: [email protected]

Abstract:

The survival and prognosis of patients with metastatic bone disease varies widely and depends on many factors including the histologic type and grade of the primary tumor, performance status and age of patients, presence of extraosseus metastases, level of tumor markers and extend of skeletal disease. Bone metastases are inevitably associated with considerable morbidity and suffering, and severe complications such as pain, pathological fractures, spinal cord or nerve root compression, impaired mobility, bone marrow infiltration and hypercalcemia of malignancy. All aforementioned complications are thoroughly discussed, giving emphasis to associated symptomatology, clinical features and patient evaluation. The last part of the chapter deals with symptom clusters that occur in patients with bone metastases before and after treatment. Such symptoms are pain, depression, fatigue, drowsiness, anxiety, shortness of breath, nausea, poor sense of well being and poor appetite.

Key words: Bone metastases · Natural history · Prognosis · Morbidity · Complications · Clinical features · Symptom clusters · Hypercalcemia

4.1 Introduction Bone metastases are not only common in the event of malignancy, but their development is of particular clinical importance, since they can bring about severe complications such as pain, pathological fractures, spinal cord compression and hypercalcemia [1]. These events can be detrimental not only for the quality of life and performance status of cancer patients, but may also be life threatening [2]. In D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 4,  C Springer Science+Business Media B.V. 2009

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the current chapter we discuss the natural history, prognosis, clinical picture and complications of metastatic bone disease. Symptom clusters occurring in cancer patients with metastatic bone lesions are also presented.

4.2 Natural History and Prognosis Due to the high prevalence, marked osteotropism and the relatively long clinical course of breast and prostate cancer, bone metastases are most often seen in patients with such malignancies. Bone metastases are also frequent in other tumors such as lung, kidney and thyroid. The survival from the time of development of bone metastases varies considerably among the different types of tumors. In the case of prostate and breast cancer, the median survival from the time that bone metastases are diagnosed is measured in years [3, 4], whereas the corresponding survival in patients with advanced lung cancer is measured in months [5]. Through several studies it has been shown that certain tumor characteristics were associated with an increased risk of developing either bone or extaosseus metastases. In breast cancer patients the incidence of metastases to bone was found to be significantly higher in tumors which produce parathyroid hormone related peptide (PTHrP) [6] and are either estrogen receptor positive [7] or well differentiated [3,8]. A significant association between histological high grade tumors and a development of intrapulmonary, liver and para-aortic lymph node metastases has also been reported [8]. In a different study by James et al., a significant correlation between the development of bone metastases and the degree of lymph node involvement by the primary tumor was also found [9]. In a trial involving 2,240 consecutive patients with localized breast carcinoma, 30% relapsed after a median follow up period of 5 years, with 8% developing metastasis to bone. The median survival after the recurrence in bone was 20 months, whereas the survival in women who developed metastasis to liver was only 3 months [3]. The survival of patients with bone metastases from breast cancer was also influenced by the subsequent formation of extraosseus metastases. The median survival of such patients was shown to be 1.6 years as compared to 2.1 years for patients with metastases confined to the skeleton [10]. In the same study it was found that older, post menopausal women with lobular carcinoma or ductal grade III tumors were more likely to have disease that remains confined to skeleton [10]. The same was true for women with minimal axillary lymph node involvement [10]. Survival in women with bone metastases is also dependent on other clinical and histopathological factors such as the metastasis free survival interval, additional sites of metastatic disease other than bone, estrogen receptor status and serological tumor marker levels. Multivariate analysis has shown that all of these factors independently contributed to survival from the time of bone metastases formation [9]. In a different study by Coleman et al., multivariate analysis showed that age, menopausal status, bone disease at initial presentation and histological grade and type, were also important prognostic factors after the diagnosis of metastatic bone disease [10]. Important factors of good prognostic significance were lobular or ductal grade I or

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Table 4.1 Prognostic factors in patients with metastatic breast or prostate cancer Primary cancer

Breast

Prostate

Extraosseus metastases Estrogen receptor status Metastasis free survival Performance status Age Serological tumor marker levels Histologic type (lobular vs ductal) Histologic grade (ductal) Bone metastases at presentation

Performance status Histologic grade Baseline prostatic specific antigen Hemoglobin level Alkaline phosphatise Lactate dehydrogenase AST Extent of bone disease Age

Data from James et al. [9], Coleman et al. [10], Robson and Dawson [11], Sabbatini et al. [12], Eisenberger et al. [13], Matzkin et al. [14], Armstrong et al. [15]

II carcinomas, age < 70 years, disease free interval ≥ 3 years, bone disease at presentation and positive estrogen receptor status [10]. Established prognostic factors in women with bone metastases from breast cancer are presented in Table 4.1. Patients with prostatic carcinoma also have a relatively long clinical course. In men with metastases confined to the axial skeleton, good performance status and under androgen blockade, the duration of disease control was found to be 4 years [11]. Survival in patients with metastatic prostatic cancer is dependent on several prognostic factors such as tumor grade, baseline prostate specific antigen (PSA), PSA doubling time, hemoglobin, alkaline phosphatase (ALP), aspartate aminotranferase (AST), lactate dehydrogenase (LDH), performance status, number of metastatic sites and extent of metastatic bone disease (Table 4.1) [11–15]. It may be worth to note that the extent of metastatic bone disease in prostatic cancer may be quantified by using the bone scan index (BSI). In this system each bone is evaluated individually and assigned a numeric score. The score represents the product of the percentage of the involved bone with tumor times the known weight of the bone that is derived from the reference man [16]. It has been shown that in patients with BSI values <1.4, 1.4–5.1% and >5.1%, median survivals were 18.3, 15.5 and 8.1 months respectively [12]. Survival in patients with multiple myeloma ranges from a few months to more than a decade [17]. With modern, intensive therapy involving autologous hematopoietic stem cell transplantation, the median survival is approximately 5 years [18]. Many prognostic factors have been reported in the scientific literature, the most important ones being albumin, beta2-microglobulin, chromosomal karyotype, renal function, hemoglobin, performance status, calcium, interleukin 6 (IL6), C-reactive protein (CRP), low plasma cell percentage in bone marrow and a positive response to treatment [17–19]. Renal cell cancer also shows remarkable osteotropism. Metastases from renal carcinoma are usually lytic in type, highly vascular and are associated with severe morbidity [20]. In a series with 209 patients with renal cell carcinoma, bone metastases developed in 22% of patients and bone was the second commonest site of metastases after lung (37%) [21]. In a recent study by Toyoda Y et al. it was reported

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that median survival in patients with bone metastases from renal carcinoma was 12 months and overall survival at 2 years was 37%. In the same study it was found that clinical features correlating with longer survival were a long interval between the time of diagnosis and development of bone metastases (greater than 24 months) and the absence of extraosseus metastatic disease [22]. The median survival of patients with none of the above favorable factors was 5 months and for those with both factors 30 months [22].

4.3 Morbidity and Complications of Metastatic Bone Disease Bone metastases are accompanied by considerable morbidity and suffering. About two thirds of patients with breast cancer and metastases to bone will subsequently develop complications such as pain, pathological fractures, spinal cord or nerve root compression, impaired mobility, bone marrow infiltration and hypercalcemia of malignancy [23–25]. Table 4.2 summarizes the potential complications associated with bone metastases. From the presented complications (Table 4.2), pathological fractures, hypercalcemia of malignancy, spinal cord compression, surgery to bone and radiation to bone are known as skeletal related events (SREs). These events are composite end points used in the majority of trials involving treatment with bisphosphonates. Pain and impaired mobility are evident in 65–75% of patients with bone metastases [26] and metastatic bone lesions have been reported to be the commonest cause of cancer-related pain [27]. Bone pain may be nociceptive [28, 29], or neuropathic [28–30]. In the former case pain is produced via simulation of nociceptors in the endostium by chemical mediators such as prostaglandins, leukotrienes, substance P, bradykinine, interleukins 1 and 6, endothelins and tumor necrosis factor-a (TNF-a). Nociceptive pain may also result due to stretching of periostium resulting from tumor infiltration or increase in size, or fracture. Neuropathic pain may result from direct infiltration and destruction of nerves by tumors. In two recent trials pain was found to be the major factor affecting the quality of life and performance status of cancer patients with bone metastases [31, 32]. The level of morbidity differed between patients with different types of metastatic bone lesions (lytic, mixed, sclerotic) [31]. Figures 4.1–4.3 present typical examples Table 4.2 Complications that may accompany metastatic bone disease Pathological fracture Bone pain Hypercalcemia of malignancy Nerve root compression Impaired mobility Surgery to bone Radiation to bone Spinal cord compression Infiltration of bone marrow

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Fig. 4.1 Lytic bone metastases in the right (a) and left (b) iliac bones in two patients with renal carcinoma. This figure is reprinted from Clin. Exp. Metastasis 24:49–56, Fig. 3, copyright 2007, with kind permission of Springer Science + Business Media B

of lytic, mixed and sclerotic bone metastases. Patients with osteolytic lesions had the highest mean pain scores with 8.1 points (visual analogue scale, 0–10) and the least mean scores for quality of life (QOL-EORTC C30, physical functioning scale, 0–100) and Karnofsky performance status (KPS, 0–100) with 31.4 and 58.6 points respectively. This group of patients was also found to have the highest percentage and mean opioid consumption (measured in daily oral morphine equivalents, mg) and the least mean bone density with 116.3 Hounsfield Units (HU, measured by Computer Tomography). On the contrary the group with osteosclerotic bone lesions had the least mean pain score with 4.6 points, the highest mean scores for QOL and

Fig. 4.2 Typical mixed bone lesions in the second (a) and fifth (b) lumbar vertebrae, due to metastatic breast carcinoma in two separate patients. The above figure is reprinted from Clin. Exp. Metastasis 24:49–56, Fig. 4, copyright 2007, with kind permission of Springer Science + Business Media B

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Fig. 4.3 Osteosclerotic bone metastases in two different breast cancer patients, in the eighth thoracic (a) and fourth cervical (b) vertebrae. This figure is reprinted from Clin. Exp. Metastasis 24:49–56, Fig. 5, copyright 2007, with kind permission of Springer Science + Business Media B

KPS with 61.1 and 66.6 points respectively, the least percentage and mean opioid requirement and the highest mean bone density with 444 HU. Table 4.3 presents the mean values of the clinical and radiological evaluations of the 3 groups of patients taking part in the study [27]. Interestingly, this study also showed that bone density had a strong, negative, statistically significant correlation with pain and a strong, positive, statistically significant correlation with QOL (partial correlation coefficients −0.57 and 0.64 respectively) (Table 4.4). These results showed that Table 4.3 Summary of results of clinical and radiological evaluations Pts with lytic bone Pts with mixed bone Pts with sclerotic p value : lesions (n = 32) lesions (n = 30) bone lesions (n = 18) Pain score (0–10): Quality of life (0–100): Performance status (0–100): Bone density: (Hounsfield units) Opioid consumption: (%)

8.1 ± 2.2 31.4 ± 14.6

6.6 ± 1.7 45 ± 10.9

4.6 ± 1.3

<0.05a

61.1 ± 15.5

<0.05a

66.6 ± 10

< 0.05a

58.6 ± 9.7

64.6 ± 7.3

116.3 ± 40.4

240.7 ± 69.4

444 ± 86.6

<0.05a

100%

86.6%

55.5%

<0.05b

Data presented as mean values ± standard deviation. Abbreviations: Pts = patients. This table is reprinted from Clin Exp Metastasis 24:49–56, Table 1, copyright 2007, with kind permission of Springer Science + Business Media B. a ANCOVA test: All pair wise comparisons between groups were statistically significant, apart from performance status between the mixed and sclerotic groups. b 2 X test, followed by the Holm’s sequential Bonferroni method.

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Table 4.4 Partial correlation coefficients between pain score, quality of life, performance status and bone density Variables

Bone density:

Pain:

Quality of life:

Pain: Quality of life: Performance status:

−0.57a 0.64a 0.39a

– −0.78a −0.51a

– – 0.49a

The above table is reprinted from Clin Exp Metastasis 24:49–56, Table 2, copyright 2007, with kind permission of Springer Science + Business Media B. a Statistically significant after controlling for type I error.

there is a clear correlation between the clinical status of patients and the type of bone metastases and that the level of bone resorption at sites of bone metastasis is a major determinant of the level of morbidity and suffering [31]. A link between pain and the level of resorption in patients with metastatic bone disease has also been demonstrated in other studies [33]. Not only the type but also the location of bone metastases affects the clinical picture and level of suffering. Patients with vertebral metastases typically present with neck or back pain that may be exacerbated by palpation or local application of pressure or movement. Ten percent of such patients suffer from pain due to spinal instability. In such cases pain may be excruciating, worsening upon patient movement. Base of skull involvement can result in nerve palsies, neuralgias or headache [5]. Finally, hip or femoral metastases commonly cause back or lower limb pain [5] and are associated with marked movement impairment. Bone metastases are frequently complicated by pathologic fractures and are the second most common cause of such fractures after osteoporosis. Pathologic fractures are a result of bone destruction at metastatic bone sites and are most commonly seen in osteolytic metastases involving the cortex. Bone lysis and the loss of structural integrity at metastatic sites inevitably lead to a reduction of the loading capabilities of the affected bone and ultimately to fracture. Rib fractures and vertebral collapses are especially frequent [5], but the most detrimental fracture in terms of patient’s QOL and performance status are the fractures of weight bearing long bones. Such fractures occur in 10–20% of patients with metastases to bone [26] and the most commonly affected site is the proximal femur [34]. Many authors have tried to study and reveal the risk factors for pathologic fractures. A number of studies have reported that such fractures appear in patients with lesions that exceed 50% of the diameter of the affected bone [35, 36]. Other studies have shown that lesions >2.5 cm are at greater risk to fracture as compared to metastatic lesions ≤2.5 cm [37]. Bertin and co-workers have also shown that avulsion of the lesser trochanter is another important risk factor for pathologic fractures in the femur [38]. A set of criteria have been proposed for prophylactic internal fixation in patients with peritrochanteric femoral lesions. These criteria are as follows: (a) lesion size >2.5 cm (b) lesion diameter greater than 50% of the diameter of the affected bone and (c) avulsion of the lesser trochanter [39]. Mirels H has proposed a scoring system for impending pathologic fractures of long bones that is to our opinion very useful. The system incorporates variables such

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as size of lesion, radiographic appearance, level of suffering (pain), and location of metastasis. Through the assessment of patients, each variable is assigned a score. It was shown that lesions that scored greater than 7 points generally required internal fixation and lesions with scores equal or greater than 10 had an estimated risk to fracture greater than 50% [40]. The probability of undergoing a pathologic fracture increases with the duration of metastatic bone disease and this complication is more common in patients with metastases confined to bone. This is rather paradoxical since such patients have a relatively good prognosis as compared to patients with extraosseus metastases [1, 10]. Special attention should be given to the evaluation of patients with impending pathologic fractures in order to prevent this severe complication. Risk factors should be carefully evaluated and patients at risk should be referred to orthopedic surgeons for prophylactic surgery. This need is of uttermost importance if we take into consideration that it was recently reported that pathologic fractures not only deteriorate the QOL of patients, but also correlate with a reduced survival [41]. Bone marrow infiltration by tumor cells is favored by the high blood flow in the red marrow [42], the adhesive molecules of tumor cells that bind them to marrow stromal cells and bone matrix [43] and the large repository of immobilized growth factors that are released during the process of bone resorption [44]. Such factors serve as a fertile ground for tumor cell growth and proliferation [43]. It is worth noticing that not all patients with bone marrow infiltration develop bone metastases. It has been shown that 25% of breast cancer patients were found to have tumor cells in their bone marrow prior to surgery. After a median follow up of 76 months only 48% of the above patients (patients with bone marrow infiltration) developed bone metastases. Metastatic bone disease was also diagnosed in 25% of patients who were free of bone marrow tumor cell infiltration prior to surgery [44, 45]. Bone marrow infiltration and tumor growth into the marrow space is in most cases accompanied by extensive fibrosis and may result in reduced haemopoiesis and pain. Useful diagnostic signs are leukoerythroblastosis with immature white and red cells in peripheral blood smears. This is seen in about 50% of patients with bone marrow infiltration and is a result of extramedullary haemopoiesis [29]. Early detection of bone marrow metastases enables earlier therapy [46] that may result in alleviation of pain [47] and prevention of complications of metastatic bone disease [48, 49]. Both magnetic resonance imaging (MRI) and bone marrow scintigraphy have proved to be effective in detecting bone marrow metastases, MRI being superior in terms of sensitivity and specificity [50]. Spinal cord compression is a medical emergency that calls for an urgent evaluation and treatment [5], since neurological recovery is probable only in the case that compression is relieved within 24 to 48 h from the time of diagnosis [51]. This complication generally occurs late in the natural history of cancer and is considered as a pre-terminal event since upon its occurrence prognosis is rather poor. The thoracic spine is most commonly affected. Local pain and tenderness over the affected cord lesion is the commonest initial symptom in patients with spinal cord compression due to metastatic bone disease and usually precedes neurological manifestations by weeks or months. Pain is more

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intense with activities such as coughing or straining that increase intradural pressure and may worsen at night time [5]. Metastases with a more lateral localization involving nerve roots bring about radiculopathy with focally sited segmental pain, dermatomal sensory disturbances such as numbness and tingling and weakness in muscles innervated by the affected root. At diagnosis of spinal cord compression, patients typically present with leg weakness. In most cases both sensory and motor loss is seen and defects of both power and sensation occur at and below the involved level. Sphincter or bladder function loss occurs late and is associated with poor prognosis. Vertebral metastases below the L1 or L2 level may produce the cauda equina syndrome that involves bladder or bowel dysfunction (retention or incontinence), severe low back pain with motor weakness, sensory loss or pain in one or more commonly both legs, saddle anesthesia and sexual dysfunction. In a retrospective study by Hill ME et al. that involved 70 patients with spinal cord compression secondary to breast cancer, it was found that at the time to diagnosis all patients had radiological evidence of bone metastases and the most common symptoms were motor weakness (96%), followed by pain (94%), sensory (79%) and sphincter (61%) disturbances. The majority of patients (91%) had at least one symptom for more than a week prior to diagnosis [52]. A detailed history taking and physical and neurological examination is critical for diagnosing spinal cord compression in cancer patients. Any patient with a history of cancer and back pain should be investigated for spinal cord compression. In a prospective study involving cancer patients it was shown that there was a 30% probability of spinal cord compression at the presence of any of the following risk factors: back pain, abnormal neurological findings at neurological examination, or detection of vertebral metastases through radiologic assessment (plain X-rays). In the case that two factors were present, the likelihood of spinal cord compression was between 60 and 70% and in the presence of all three factors the probability was greater than 90% [53]. MRI is very useful in the evaluation of possible malignant cord compression providing detailed information on the extent and the number of epidural compressions [54, 55]. Patients are generally managed with either decompressive surgery or radiotherapy or a combination of the two therapeutic modalities. Surgery is usually reserved for younger patients with a good performance status, patients with a single site of cord compression and in cases of fracture dislocations and spinal instability [56]. Ambulation is the most important factor for response to therapy prior to treatment and the most important post treatment survival factor [52,57]. In the study by Hill and co-workers 96% of patients who were ambulant prior to therapy maintained their ability to walk post therapy and from patients who were unable to walk prior to treatment, only 45% regained ambulation. The results suggest that that earlier diagnosis and intervention can improve the therapeutic outcome. Additionally, there was no evidence of survival benefit from surgery over radiotherapy as primary treatment [52]. Overall post therapy 20% of patients improve neurologically, 30% remain stable and about half of patients deteriorate. The median survival is 7 months for patients who are able to walk post treatment and 1.5 months for non ambulatory patients [58].

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4.4 Metabolic Complications: Hypercalcemia of Malignancy Hypercalcemia is one of the commonest metabolic complications seen in patients with metastatic bone disease, occurring in 3–30% of cancer patients during the course of their disease [59]. It is most typically seen in patients with lung (squamous cell carcinoma), breast, kidney, ovarian and head and neck tumors [5, 59]. The occurrence of hypercalcemia in breast cancer patients ranges between 30 and 40%, but is rather uncommon in patients suffering from colorectal and prostate cancer [59]. This complication is also manifested in patients with hematological malignancies such as multiple myeloma and lymphoma. In multiple myeloma up to a third of patients develop hypercalcemia [60]. Calcium serum concentration is closely regulated by a complex homeostatic mechanism, involving organs such as bone, liver, parathyroid glands, kidneys and gastrointestinal tract. Parathyroid hormone (PTH) has a key role in the whole mechanism. When calcium serum levels are low, PTH is secreted from the parathyroid glands. PTH acts on bone by enhancing osteoclastic resorption with accompanied calcium release and on kidney by reducing urinary calcium excretion and increasing phosphate excretion. Parathyroid hormone-related peptide (PTHrP) is secreted by a variety of tumors [61, 62] and it has been shown that its actions parallel those of PTH [59, 62]. The level of PTHrP is elevated in up to two thirds of patients with metastatic bone disease and hypercalcemia and in the vast majority of patients with humoral hypercalcemia. It was also demonstrated that impaired hepatic function in women with liver metastases from breast cancer is associated with hypercalcemia [63]. This could be explained by the fact that impaired hepatic function may result in a reduced PTHrP metabolism and consequently enhanced bone resorption. Increased calcium serum level also interferes with the action of anti-diuretic hormone (ADH) at the distal nephrone, causing polyuria and polydipsia, a syndrome like diabetes insipitus. This results in dehydration that further exacerbates hypercalcemia [59]. Three distinct syndromes have been described in hypercalcemia of malignancy: (a) the humoral hypercalcemia of malignancy, (b) hypercalcemia associated with skeletal metastases, and (c) hypercalcemia accompanying hematological malignancies. Humoral hypercalcemia of malignancy (HHM) is manifested in patients with elevated serum calcium in the absence of skeletal metastases. The syndrome is a result of circulating PTHrP released from tumor cells. In patients with evidence of osteolytic metastases, bone resorption is stimulated by the local release of PTHrP. During the process of bone resorption local factors such as the transforming growth factor alpha (TGF-a), TGF-b, epidermal growth factor and interleukin 1 are released, promoting the secretion of PTHrP from tumor cells [64,65]. A viscous cycle is therefore formed enhancing bone resorption and calcium release. There is evidence for a humoral contribution in this syndrome, since in breast cancer patients the extent of metastatic bone disease does not correlate with the level of hypercalcemia [66]. The third syndrome is the one in which hypercalcemia is manifested in patients with hematological malignancies. Hypercalcemia is rather uncommon in patients with Hodgkins and non-Hodgkins lymphoma, but as mentioned before it occurs

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in about one third of multiple myeloma patients [60]. In a study with 165 patients admitted to a Hematology Department, hypercalcemia was documented in 9 patients with myeloma, in 5 patients with high grade B-cell non-Hodgkins lymphoma and in one with myeloid neoplasia [67]. In the cases with B-cell non-Hodgkins lymphoma, circulating levels of PTHrP were detected [67] and the same was true for one third of patients with elevated calcium serum level and multiple myeloma [67]. The above findings indicate that PTHrP mediated hypercalcemia is not only seen in patients with solid tumors, but also in patients with hematological malignancies. The clinical picture of patients with hypercalcemia is in many cases nonspecific and clinicians should have a high index of suspicion. Asymptomatic patients turn out to have fatigue and malaise or signs of hypertension or renal failure. In symptomatic patients common symptoms are polyuria, polydipsia, anorexia, nausea, vomiting, constipation and bone pain. Patients may also present with abdominal pain (due to peptic ulcer or pancreatitis) or loin/ureteric pain due to urinary tract stones. Mental disturbances include confusion, depression, psychosis, alteration in the level of consciousness and in severe cases coma. In case that hypercalcemia is not corrected, renal function and mental status deteriorate and death may result from renal failure and cardiac arrhythmias. Symptoms and signs of hypercalcemia are presented in Table 4.5. The prognosis of hypercalcemic patients is poor and treatment is effective in improving the symptomatology but not in prolonging survival [59]. Patient rehydration, bisphosphonates [68, 69], calcitonin [70], and diuretics such as frusemide [71] are important in the overall management of symptomatic hypercalcemia that is a metabolic emergency and calls for immediate patient evaluation and treatment.

Table 4.5 Clinical features and symptoms in patients with hypercalcemia Non specific symptoms Malaise Fatigue Gastrointestinal Nausea and vomiting Anorexia Constipation Abdominal pain Mental disturbances Confusion Depression Psychosis Drowsiness Apathy Coma Renal Polyuria Polydipsia Signs of dehydration Ureteric or loin pain

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4.5 Symptom Clusters in Cancer Patients with Bone Metastases Studies in cancer symptom research have mainly focused on the management and severity of individual symptoms [72]. This approach has advanced our understanding of a particular symptom. However symptoms seldom occur in isolation in patients with advanced cancer. It is therefore important to focus on evaluating multiple symptoms, using cross-sectional and longitudinal study designs. The term “symptom cluster” was first quoted by Dodd et al. [73] in their research with pain, fatigue, and sleep disturbances. They defined symptom clusters as three or more concurrent symptoms that are related to each other, which may or may not have the same etiology. A subsequent paper published in 2005 described symptom clusters as two or more symptoms that are related to each other, occur together, are a stable group and are relatively independent of other clusters [74]. The relationship, strength and time frame needed for these clusters to present have not been specified. Symptom clusters may have an adverse effect on patient outcomes and a synergistic effect as a predictor of patient morbidity. Palliative radiotherapy has been well established for the treatment of symptomatic bone metastases. Although pain might have improved, patients in some clinical trials reported no significant improvement in quality of life (QOL). Failure to improve QOL significantly after palliative radiotherapy can be due to multiple bone metastases in patients. Pain relief in one irradiated site may unmask pain in other bony metastatic sites. It is important to explore whether bone pain “clusters” with other common symptoms in advanced cancer. There is suggestion that pain, depression, and fatigue may occur in combination. Failure to recognize these symptom clusters may result in failure to improve overall QOL. During initial consultation at Rapid Response Radiotherapy Program, Odette Cancer Centre, patients with bone metastases were asked to rate their symptom distress using the Edmonton Symptom Assessment Scale (ESAS) with an 11-point categorical scale (0–10; 0 = absence of symptom and 10 = worst possible symptom) [74]. The ESAS evaluates nine symptoms: pain, fatigue, nausea, depression, anxiety, drowsiness, appetite, sense of well-being, and shortness of breath. This questionnaire has been successfully validated in cancer patients [75, 76]. Patients were asked to rate the item “pain” in the ESAS as bone pain at the irradiated site. Patient demographics, cancer history, disease status, and analgesic consumption during the previous 24 h were recorded at the first visit. Patient demographics included age, gender, inpatient or outpatient status, weight loss of greater than 10% over the previous 6 months and KPS. All primary assessments and questionnaires were completed before radiation simulation. At weeks 1, 2, 4, 8, and 12 post-radiation, ESAS scores were obtained by telephone interview. Responders to radiation treatment were defined as complete or partial response. The International Bone Metastases Consensus Working Party defines complete response to be a pain score of zero at the irradiated site with no concomitant increase in analgesic intake (stable or reducing analgesics in daily oral morphine equivalents) [77]. Partial response was defined as a pain reduction of 2 or more at the

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irradiated site on a 0–10 scale without analgesic increase or analgesic reduction of 25% or more from baseline without an increase in pain [77]. Between January 1999 and January 2002, 518 patients (280 male and 238 female) with bone metastases provided complete baseline data on ESAS at the time of consultation. The median age was 68 years and the median KPS was 60. The most common primary cancer sites were lung, breast and prostate. The median total daily oral morphine equivalent consumption was 30 mg (range 0–3,600 mg). Three clusters were identified and accounted for 66% of the total variance: Cluster 1 included fatigue, pain, drowsiness and poor sense of well being and accounted for 44% of the total variance. Cluster 2 included anxiety and depression and accounted for 12% of the total variance. Cluster 3 included shortness of breath, nausea and poor appetite and accounted for 10% of the total variance [78]. Percentage of patients who responded to radiotherapy at weeks 1, 2, 4, 8 and 12 was 49, 50, 50, 47 and 51% respectively. In comparing the pattern of symptom cluster dynamics in the responders, pain clustered out in weeks 8 and 12; breathlessness clustered out in week 2. Only two symptom clusters remained in weeks 2, 8, and 12. In nonresponders, symptom clusters prevailed in all weeks, except for week 8 with breathlessness clustering out. Over time, symptom components of the symptom clusters changed. However, some symptoms often appeared in the same cluster. Fatigue and drowsiness remained together for all weeks in both groups; anxiety and depression also followed each other. The mean symptom severity of most of the ESAS items significantly decreased over time (baseline to week 12) except for nausea, depression, and shortness of breath. Opioid consumption changed significantly over time as well. When comparing responders and nonresponders over time (weeks 1 to 12), all ESAS items and opioid consumption intakes were significantly different, except for shortness of breath. For the opioid consumption in responders and nonresponders through weeks 1 to 12, there is an obvious difference between the mean morphine equivalency of opioid consumption between the two groups. Nonresponders to treatment had a higher intake of analgesics than responders. Analgesic consumption in responders decreased. In conclusion, it is important for health care professionals to take a detailed history especially the commonly encountered symptoms in patients with advanced cancer in addition to pain. It is also of interest to follow the research in symptom cluster which is still in its infancy stage.

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55. Jacobson H, Goran H (1992) Radiological detection of bone and bone marrow metastases. Med Oncol Tumor Pharmacother 8:25 56. Sundaresan N, Sachdev VD, Holland JF, et al. (1995) Surgical treatment of spinal cord compression from epidural metastasis. J Clin Oncol 13:2330–2335 57. Maranzano E, Latini P (1995) Effectiveness of radiation therapy without surgery in metastatic spinal cord compression. Final results from a prospective trial. Int J Radiat Oncol Biol Phys 32:959–967 58. Helweg-Larsen S, Sorensen PS, Kreiner S (2000) Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients. Int J Radiat Oncol Biol Phys 46:1163–1169 59. Grill V, Martin J (2000) Hypercalcemia of malignancy. Rev Endocr Metab Disord 1:253–263 60. Mundy GR, Raisz LG, Cooper RA, et al. (1974) Evidence for secretion of an osteoclast stimulation factor in myeloma. N Engl J Med 291:1041–1046 61. Moseley JM, Gillespie MT (1995). Parathyroid hormone-related protein. Crit Rev Clin Lad Sci 32:299–343 62. Danks JA, Ebeling PR, Hayman JA, et al. (1989) Parathyroid hormone-related protein: immunocytochemical localization in cancers and in normal skin. Bone Min Res 4:273–278 63. Coleman R, Fogelman I, Rubens R (1988) Hypercalcemia and breast cancer: an increased humoral component in patients with liver metastases. Eur J Surg Oncol 14:423–428 64. Kak¨onen SM, Mundy GR (2003) Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer 97(3 Suppl):s834–s839 65. Mundy GR, Guise TA (1997) Hypercalcemia of malignancy. Am J Med 103:134–145 66. Ralston SH, Fogelman I, Gardner MD, et al. (1984) Relative contribution of humoral and metastatic factors to the pathogenesis of hypercalcemia of malignancy. Br Med J 288:1405–1408 67. Firkin F, Seymour JF, Watson AM, et al. (1996) Parathyroid hormone-related protein in hypercalcemia associated with hematological malignancy. Br J Haematol 94:486–492 68. Coleman RE (1998) Pamidronate disodium in the treatment and management of hypercalcemia. Rev Contemp Pharmaco 9:147–164 69. Major PP, Lortholary A, Hon J, et al. (2001) Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy-a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 19:558–567 70. Hosking DJ, Stone MD, Foote JW (1990) Potentiation of calcitonin by corticosteroids during the treatment of malignancy. Eur J Clin Pharmacol 38:37–41 71. Suki WN, Yium JJ, von Minden M, et al. (1970) Acute treatment of hypercalcemia with frusemide. N Eng Med 283:836–840 72. Dodd MJ, Miaskowski C, Paul SM. (2001) Symptom clusters and their effect on the functional status of patients with cancer. Oncol Nurs Forum 28:465–470 73. Kim HJ, McGuire DB, Tulman L, Barsevick AM. (2005) Symptom clusters: concept analysis and clinical implications for cancer nursing. Cancer Nurs 28:270–282 74. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. (1991) The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 7:6–9 75. Chang VT, Hwang SS, Feuerman M. (2000) Validation of the Edmonton Symptom Assessment Scale. Cancer 88:2164–2171 76. Moro C, Brunelli C, Miccinesi G, Fallai M, Morino P, Piazza M, Labianca R, Ripamonti C. (2006) Edmonton symptom assessment scale: Italian validation in two palliative care settings. Support Care Cancer 14:30–37 77. Chow E, Wu JS, Hoskin P, Coia LR, Bentzen SM, Blitzer PH. (2002) International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases. Radiother Oncol 64:275–280 78. Chow E, Fan G, Hadi S, Filipczak L. (2007) Symptom clusters in cancer patients with bone metastases. Support Care Cancer 15: 1035–1043

Chapter 5

BONE BIOMARKERS IN RESEARCH AND CLINICAL PRACTICE Janet E. Brown1 and Edward Chow2 1 Cancer Research UK Clinical Fellow/Senior Lecturer in Medical Oncology, Cancer Research UK Clinical Centre in Leeds, St James’s Hospital, University of Leeds, Leeds LS9 7TF, UK, e-mail: [email protected] 2 Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada, e-mail: [email protected]

Abstract:

Biochemical markers (biomarkers) are increasingly being used in clinical practice. Bone biomarkers have been developed from collagen metabolism and other pathways which report on different aspects of the status of bone formation, bone resorption and bone remodelling. Simple assays for these markers in blood and urine have been developed. Markers for both bone resorption and formation have been correlated with the presence of metastatic bone disease and with its associated skeletal complications, such as pain and fracture and predictive models have been developed which are able to assess the risk of such complications in individual patients. Bone biomarkers are also very useful in monitoring therapy using bisphosphonates and other bonespecific drugs and trials are underway to assess the possible role of bone biomarkers in directing anti-resorptive therapy. Bone biomarkers have played and continue to play a role in development of new bonespecific therapies, such as RANK-ligand inhibitors and cathepsin K. Further novel and more specific bone markers may be anticipated as modern techniques such as proteomics are increasingly applied in this field.

Key words: Bone metastases · Bisphosphonates · Bone markers · Radiotherapy

5.1 Introduction – Why Bone Biomarkers? Biomarkers are increasingly being used in the management of patients across a wide range of medical specialties. A biomarker is an objective measurement that acts as an indicator of normal biological processes or pathological processes or pharmacological response to therapeutic intervention. Biomarkers are valuable tools for D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 5,  C Springer Science+Business Media B.V. 2009

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aiding diagnosis, for identifying groups of patients at risk, for monitoring response to treatment and for use as surrogate end points in development of new therapies. Ideally, a biomarker should be capable of rapid and simple quantitative measurement in easily obtained biological fluids such as blood or urine. As such, they can often give valuable information on the change of disease status (for example in indicating response to therapy), before such changes become clinically evident. Biomarkers are often proteins or peptides and their practical value is increased when they can be routinely and accurately measured in biological fluids. Whilst biomarkers are often discovered empirically, the confidence that such a biomarker will prove to be clinically useful is increased if it is biologically plausible, i.e., if there is a logical, scientific rationale that it should be increased (or reduced) in the relevant disease state. Bone biomarkers (often simply called bone markers) are assuming increasing importance in the management and understanding of conditions which involve disturbance of normal bone metabolism, such as osteoporosis and metastatic bone disease. Pathological changes in bone are often slow to become apparent symptomatically or to become evident by imaging, for example on plain X-ray, but there is growing evidence that bone marker changes reflect underlying changes in pathology or response to treatment, well in advance of such changes being detectable by imaging methods. Thus, bone marker measurements are complementary to imaging methods and therefore can potentially be used to influence therapeutic and other patient management decisions at an early stage. However, the most appropriate applications of bone markers are still being evaluated and therefore they are not yet established in routine clinical practice. In this Chapter we consider the bone biomarkers which are most developed in terms of clinical utility and their applications in different aspects of metastatic bone disease.

5.2 Bone Turnover and Effects of Bone Metastases During adult life, normal bone undergoes a continuous remodeling process of resorption of old bone by osteoclasts and new bone formation by osteoblasts. Up to 25% of cancellous bone is remodeled annually, compared to only 3% of cortical bone [1]. The process occurs in discrete packets throughout the skeletal system, known as bone remodeling units [2]. Within these units, the remodeling sequence begins with bone resorption via activation of osteoclasts, which resorb bone by the production of proteolytic enzymes and hydrogen ions [2]. This process takes place over about 10 days [3] and is followed by bone formation to repair the defect. The whole remodeling process is normally under tight control, responding to a wide variety of local and systemic factors, as well as mechanical loading [4–6]. This results in a fine balance between bone formation and bone resorption, so that the total amount of bone remains approximately constant [2]. The normal processes of bone resorption and formation result in shedding of proteins, protein fragments and mineral components directly involved in bone structure

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or metabolism into the blood and urine and this represents a rich source of potential bone markers for the processes of bone turnover. Such biomarkers are often classified according to whether they are produced from the bone resorption process (resorption markers) or the bone formation process (formation markers) [6, 7]. Metastatic tumour development in bone is thought to follow the occupation of the bone erythropoietic stem cell niche by cancer stem cells and results from complex interactions between tumour cells and the bone microenvironment [8, 9]. Tumour-derived factors attract and stimulate osteoclasts, increasing bone turnover and releasing bone-derived growth factors and cytokines which facilitate cancer cell proliferation in a vicious cycle of tumour growth and bone destruction [9, 10]. The acute changes in bone turnover associated with metastatic bone disease might be expected to be reflected in bone turnover markers and, as will be seen from the sections below, this turns out to be the case. Indeed, bone biomarkers may provide an excellent quantitative tool in the management of metastatic bone disease.

5.3 Biomarkers of Bone Formation 5.3.1 Collagen Biosynthesis Under the control of osteoblasts, collagen biosynthesis is a complex process and includes several post-translational modifications. Osteoblasts first secrete type I procollagen, a protein rich in the hydroxylated amino acids hydroxyproline and hydroxylysine and formed by combination of two α1 and one α2 polypeptide chains [11]. Conversion of procollagen into native collagen requires cleavage of both the Nterminal and C-terminal regions. Intermolecular crosslinks are then formed rendering the protein insoluble and the collagen fibrils are formed by precise spatial alignment of the collagen chains. These processes give rise to several molecules which can be used as markers of bone formation. The characteristics of the main bone formation markers are shown in Table 5.1. Table 5.1 Biomarkers of bone formation and bone resorption Biomarker

Abbreviation

Function

Type I procollagen N-terminal propeptide Type I procollagen C-terminal propeptide Bone alkaline phosphatase Osteocalcin Calcium Hydroxyproline N-terminal cross-linked telopeptide of Type I collagen C-terminal cross-linked telopeptide of Type I collagen Pyridinoline cross links of Type I collagen and Deoxypyridinoline cross links of Type I collagen Bone sialoprotein Osteoprotogerin Tartrate-resistant acid phosphatase serum Type 3b

PINP PICP BALP Osteocalcin Ca2+ Hydroxyproline NTX CTX PYD DPD BSP OPG TRACP5b

Bone formation Bone formation Bone formation Bone formation Bone resorption Bone resorption Bone resorption Bone resorption Bone resorption Bone resorption Bone resorption Bone resorption Bone resorption

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5.3.2 Propeptides of Type I Procollagen During the conversion of procollagen into native collagen through the action of specific proteases, both the N-terminal fragment, known as Type I procollagen N-terminal propeptide (PINP) and the C-terminal fragment, known as Type I procollagen C-terminal propeptide (PICP) are released into the circulation and can therefore be used as serum bone formation markers for collagen formation. Molecular characterization of both PICP and PINP has been carried out and reviewed by Brandt et al. [12]. Care is needed in analysis because of different molecular forms but analysis may be carried out by electroimunoassays, ELISA techniques and radioimmunoassay [12]. PINP is increasingly thought to be useful as a bone formation marker because, not only does it appear to accurately reflect changes in bone metabolism, but also because it appears to be a stable molecule and is less sensitive to diurnal variation and dietary intake than some other markers [12, 13]. More studies are now using P1NP as a formation marker, for example the studies by Brasso et al. [14] and Jung et al. [15] discussed in Section 6 which showed that high levels of serum PINP was associated with poor outcome in prostate cancer, with multivariate Cox analyses showing that P1NP was an independent predictor of survival. A similar study by Jung et al. [15] showed that prostate cancer patients with bone metastases who had high PINP levels had significantly shorter survivals than patients with low PINP levels.

5.3.3 Bone Alkaline Phosphatase (BALP) Osteoblasts are rich in a particular isozyme of alkaline phosphatase (BALP), which has been used for many years as a serum bone formation marker. In early studies, it was difficult or impossible to distinguish alkaline phosphatase activity arising from bone from that arising from liver and other organs. However, more recently, immunoassay methods relying on monoclonal antibodies specific for the bone isozyme have been developed and have improved both the sensitivity and the specificity of the assay [16]. The release of the enzyme into the circulation from osteoblasts corresponds predominantly to the matrix maturation phase of bone formation and therefore reports on an intermediate phase of osteoblast activity compared with PINP and PICP, which report on the earlier phase of osteoblast proliferation. Elevated BALP levels occur in Paget’s disease, renal rickets, osteomalacia, celiac disease and in bone cancers [7]. BALP levels are also often increased in metastatic bone disease and may be correlated with bone resorption. This is because increased bone formation may occur as a response to accelerated bone resorption caused by bone metastases. The use of BALP in clinical studies in bone metastases is illustrated in the later sections of this Chapter.

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5.3.4 Osteocalcin Osteocalcin is a small protein synthesized by mature osteoblasts and serum osteocalcin is considered a marker of the late phase of bone formation [17, 18]. Although the protein binds strongly to bone mineral, small levels appear in serum and may be measured by radioimmunoassay or ELISA techniques, though there are multiple isoforms and different assays detect different forms [19]. It has advantages in that it is bone-specific, it correlates with changes in bone turnover and assays are widely commercially available. However, it is subject to diurnal variation, has poor sample stability and there is wide variation in assays using different kits [17].

5.4 Biomarkers of Bone Resorption Under the action of osteoclasts, bone resorption involves the breakdown of collagen and other components of the skeleton and it is from these breakdown products that most established or ‘conventional’ bone resorption markers are derived. Many such products released into the blood and the urine have been investigated for marker utility. A list of the bone resorption markers which have been most studied is included in Table 5.1.

5.4.1 Early Biomarkers of Bone Resorption Urinary calcium excretion, expressed relative to urinary creatinine, has been widely used as an indicator of bone resorption for more than 25 years [20, 21]. Provided that measurements are made on early morning urine samples after overnight fasting, urinary calcium can be a convenient and reproducible marker for quantifying calcium excretion [22] and for monitoring response to treatment [20, 23]. However, relating urinary calcium excretion to the specific events occurring in bone turnover is more complex because it reflects net turnover (i.e., the difference between formation and resorption) and is also influenced by dietary factors as well as the levels of parathyroid hormone and parathyroid hormone-related protein [24]. Other studies have shown that calcium excretion was not elevated in patients with metastatic bone disease relative to controls [25] nor did calcium excretion levels correlate with response to bisphosphonate treatment [26]. Since hydroxyproline is an amino acid which is found in collagen but in few other proteins, its metabolic levels are dominated by collagen breakdown. However, it is not a specific bone marker, since around 50% of human collagen is extra-skeletal [27]. Most collagen is metabolized through the liver, but there is sufficient renal clearance (around 15%) to enable useful urinary measurements [27, 28]. Urinary excretion of hydroxyproline is also strongly influenced by diet, age, and soft tissue destruction of tumor. Additionally, there is a circadian rhythm, with a peak between midnight and 8 am [27]. Although urinary hydroxyproline is a useful indicator of

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accelerated collagen breakdown in metastatic bone disease, it is not particularly useful or reliable for documenting disease progression or response to therapy [28].

5.4.2 Collagen Breakdown After initial work on calcium and hydroxyproline, it became clear that there was a need for additional biomarkers which more specifically reflected bone resorption. Much attention in the last decade has been focused on the potential of more bone-specific collagen breakdown products in this context. Type I collagen is helical except for regions at the N-terminus and C-terminus, which are known as N-telopeptide and C-telopeptide. Within these regions, side chains of three hydroxylysine or lysine residues from three different collagen molecules combine to form a pyridinium ring such that the three collagen chains become cross-linked, stabilising the collagen structure [11]. Pyridinoline crosslinks (PYD) result from the post-translational combination of three hydroxylysine residues, whereas deoxypyridinoline crosslinks (DPD) result from the post-translational combination of two hydroxylysine residues with one lysine residue [29]. PYD crosslinks are found in collagen in bone, cartilage and other connective tissues, whilst DPD is almost exclusive to bone [30] Following collagen breakdown with the enzyme cathepsin K, the crosslinks are found in both peptide bound (N-terminal cross-linked telopeptide of Type I collagen, NTX and C-terminal cross-linked telopeptide of Type I collagen CTX) forms and free (PYD and DPD) forms where breakdown is more complete. All of these have been evaluated as potential bone biomarkers in metastatic bone disease and are considered below.

5.4.3 N-telopeptide (NTX) and C-telopeptide (CTX) Although these peptides may be formed from collagen-containing tissues other than bone, the peptides derived from osteoclast action may occur in different forms from those derived from other tissues [7]. In the case of NTX for example, the bone-derived peptide is a so-called alpha-2 isoform, whereas that derived from non-skeletal tissue is a different isoform, designated alpha-1 [31]. CTX can exist in either alpha or beta isoforms, with the beta isoforms predominating in the peptides derived from bone [7]. Assay of NTX and CTX is now straightforward and reproducible, using ELISA assays. Commercial assay kits are readily available but, currently, routine measurements are generally only available in specialist centres which have sufficient throughput to run the assays as a service to other centres. This often therefore involves freezing and storing of samples for bulking up and later assay. Because of the growing potential of bone marker measurement on directing patient therapy, there is some interest in developing point of care devices for NTX and CTX assay, so that

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sample assay and patient management decisions can be made at the same outpatient visit. A hand held point of care device has been described by Hannon et al. [32] which is able to measure NTX on a spot of urine in the outpatient setting. A similar point of care device has been described for assay of CTX in urine, which uses a dipstick approach [33] with a second dipstick assay which measures creatinine for urine volume correction. Although not currently available, it can confidently be predicted that such devices could be quickly developed commercially, if bone marker measurements become part of routine clinical practice. For NTX the monoclonal antibody for the assay is against the alpha-2 isoform and was originally derived against urinary collagen cross links from a patient with Paget’s disease [11]. Although NTX can be measured in serum, this is rarely used, preference being given to measurement in urine, with standardisation relative to creatinine. However, there is a marked diurnal variation in NTX release through the kidneys and assays should be carried out on the second morning voided urine sample. For CTX, the monoclonal antibody used in the assay is against the beta isoform. Both serum and urinary CTX can be measured using an assay called Crosslaps. This does not measure cross links directly, but measures an octapeptide sequence of the CTX region of the alpha-1 chain [34]. Serum is generally preferred because of better precision throughout the concentration range. There is an additional C-telopeptide assay in serum which recognises a different domain in the C-telopeptide region to the CTX assay, lying between the two alpha-1 chains. This bone collagen product, known as ICTP is probably derived from non-osteoclast mediated bone resorption, utilising matrix metalloproteinases derived from the underlying pathological process, rather than the cathepsin-K mediated pathway associated with physiological bone resorption. ICTP appears to be not sufficiently sensitive for use in osteoporosis, but it may have potential value in metastatic bone disease [35]. Some studies have shown increased levels of ICTP in metastatic bone disease, for example in lung cancer patients [36] and in multiple myeloma [37, 38], although relatively little use has so far been made of this marker. This may be due, in part, to problems with the current antibody-linked assay, where it has been shown that, whilst metalloproteinase-induced collagen breakdown leaves the antigenic site of ICTP unchanged, cathepsin-K cleaves collagen at the antigenic site [39].

5.4.4 Pyridinoline Cross Links (PYD) and Deoxypyridinoline Cross Links (DPD) These molecules are released in an approximately 3:1 ratio during bone resorption and are excreted via the kidneys [1]. Bone accounts for the majority of release of these markers both because bone is their major reservoir, but also because bone has a higher turnover rate than most connective tissues [7]. Nevertheless, soft tissues may

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make a significant contribution to total urinary PYD especially and, because they may be less specific than the telopeptide markers, results must be interpreted with care. In a study of the metabolic effects of pamidronate in patients with metastatic bone disease, DPD was been found to be a more sensitive indicator of bone resorption that PYD [26]. A number of ELISA systems are now available for the measurement of PYD and DPD [40–42].

5.4.5 Bone Sialoprotein (BSP) Bone sialoprotein is a non-collagenous protein of the bone extracellular matrix and is one of the most abundant proteins in bone. BSP is also secreted by non-skeletal cells and has been classified as a member of the integrin-binding SIBLING family, which also contains osteopontin and several other proteins expressed in the skeleton [43]. The assay for bone sialoprotein is not currently widely available, but is based on immunoassay, including a competitive ELISA assay [43]. However it has been shown that BSP (and OPN) binds to complement factor H in serum and the complex needs to be disrupted, before accurate BSP assay is possible [43]. In conditions such as osteoporosis, bone sialoprotein appears to be a sensitive biomarker of bone turnover [6] probably mainly relating to bone resorption. Elevated levels of BSP have been reported in patients with multiple myeloma [44], while multivariate Cox proportional hazards regression showed that BSP was an independent prognostic factor for survival in prostate cancer patients with bone metastases [15]. In one especially interesting study in 388 patients with primary breast cancer without metastasis at baseline, increased levels of BSP (above 24 ng/mL) appeared to correlate with the subsequent development of bone metastases in breast cancer patients [45]. This has been followed up by more recent work in which tissue BSP was shown to be predictive of bone metastases in resectable non-small cell lung cancer in a retrospective case study. These observations merit further study, but suggest that BSP levels may have a role in the prediction of which cancer patients will develop bone metastases.

5.4.6 The RANK/RANK-L System and Osteoprotogerin Osteoclasts control bone resorption and the biology of this process and the factors controlling the production of osteoclasts have been intensively investigated. These studies have revealed the importance of receptor activator of nuclear factor-κB (RANK) and its ligand (RANK-L) in osteoclastogenesis [46, 47]. Osteoprotogerin (OPG) is a decoy receptor cytokine, which binds to RANKL and is a powerful inhibitor of the RANKL/RANK interaction, thereby preventing the simulation of osteoclastogenesis [47]. Experimental studies have shown that OPG halted further bone damage and diminished the skeletal pain associated with tumour-induced bone destruction [48].

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Such studies have led to new therapeutic strategies and the development of novel anti-resorptive drugs either through synthetic analogues of OPG or through the production of monoclonal antibodies to RANK-L, which exists in both membranebound and soluble forms [49]. Such drugs are now in advanced Phase III clinical trials. These findings suggested that OPG and RANK-L might be useful biomarkers for osteoclastogenesis and therefore for bone resorption. Immunoassays have been developed for OPG and for both isoforms of RANK-L. In multiple myeloma [13], the RANK-L:OPG ratio was found to be an independent prognostic factor for survival. However, in other studies to date in both post-menopausal osteoporosis and in metastatic bone disease, results have been variable and the utility of these proteins as bone resorption biomarkers remains uncertain [50, 51].

5.4.7 Tartrate-Resistant Acid Phosphatase Serum Type 3b (TRACP5b) This is an inactive, metalloprotein, pro-enzyme associated with osteoclasts, requiring proteolytic cleavage via cathepsin κ or L before the active enzyme form can be secreted into the circulation when the osteoclasts attach to the bone surface. A second isoform of the enzyme (TRACP5a) is secreted into serum by macrophages. Circulating TRACP5b activity is derived exclusively from osteoclasts and the activity of active enzyme in the circulation therefore reflects recently released enzyme as a result of bone resorption [7]. Immunoassays have been developed for the measurement of this enzyme [52]. Many recent studies have evaluated this resorption marker in both osteoporosis and metastatic bone disease. Halleen et al. [53] showed that the marker was significantly elevated in patients with osteoporosis and changes in TRACP5b (but not TRACP5a) correlated well with changes in other resorption markers and also correlated negatively with change in bone mineral density. In metastatic bone disease, whilst several recent studies have found positive correlations between TRACP5b levels and occurrence of bone metastases, especially in breast cancer [54, 55] and prostate cancer [56–58], other studies have found no difference in TRACP5b levels between renal cancer patients with bone metastases and controls [59]. In metastatic bone disease, further investigation of TRACP5b is needed to establish its role as a resorption marker.

5.5 Correlation of Bone Biomarkers Levels and Presence of Metastatic Bone Disease Can bone biomarkers be used for diagnosis of metastatic bone disease? Certainly, many studies have now shown a positive relationship between levels of various bone markers and the presence of metastatic bone disease. Early studies showed that both

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urinary calcium [20, 23] and hydroxyproline [23, 60] may be elevated in patients with metastatic bone disease. Urinary calcium may be derived from many sources and has been shown to be unsuitable as an indicator of bone metastases, particularly in patients receiving concomitant bisphosphonates [24, 26]. Similarly, as well as skeletal breakdown, diet and soft tissue destruction by tumour influence hydroxyproline levels, which are therefore not well correlated with presence of metastatic bone disease, with progression or with response to therapy. More recently, attention has been focused on the more specific markers of bone turnover. Many studies over the last 15 years have shown elevated bone markers in patients with bone metastases, compared to cancer patients without bone metastases and to healthy subjects [7, 25, 61–67]. In one example, using radiographic and bone scan findings, 127 cancer patients were divided into three groups. Group A contained 83 patients with no bone metastases, Group B contained 22 patients with one or two bone metastases and Group C contained 22 patients with three or greater. In both groups with bone involvement PYD, NTX and CTX were significantly increased indicating a high level of specificity and sensitivity of these markers [68,69]. Another study compared breast cancer patients with bone metastases with healthy pre-menopausal women. The percentage of elevated values for the cancer group were 47% for urinary calcium, 74% for hydroxyproline, 83% for CTX and 100% for each of the collagen crosslinks PYD and DPD. BALP, but not urinary calcium, correlated significantly with the other four bone markers [70]. Other examples are considered in further sections of this Chapter. Whilst bone metastases are primarily osteosclerotic in prostate cancer, nevertheless increased bone resorption also occurs with a corresponding increase in resorption markers. For example, one study of 39 prostate cancer patients with metastatic bone disease showed an approximate doubling in urinary CTX compared with healthy age-matched men [64]. In the same study, no increases in bone resorption markers were observed in prostate cancer patients without bone metastases (N = 9) or in patients with benign prostatic hyperplasia (N = 9). Formation markers, including BALP, P1NP and P1CP have also been shown to be correlated with bone metastases in patients with prostate cancer [71, 72]. Metastatic bone disease results in increased bone resorption, leading to increased remodeling, a process which also results in increased bone formation and a corresponding elevation in bone formation markers may therefore be expected. However, compared with bone resorption markers, there are much less data available. Osteoblastic metastases and a response to healing [18] induce the highest levels of BALP, corresponding to new bone formation, whilst increased levels of serum osteocalcin are primarily associated with bone metastases resulting from breast and prostate cancer [23]. Osteocalcin levels [23] and bone specific alkaline phosphatase levels [73] have both been shown to be significantly raised in patients with metastatic bone disease from breast cancer compared with normal controls. In such patients, levels of these two formation markers are significantly higher in those with blastic rather than lytic metastases [30]. Neither of these markers, however, appears to be useful for early detection of bone metastases.

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As well as correlating with the presence of bone metastases, it would be useful if markers could give an indication of the extent of bone disease. There is evidence from several studies that a range of markers including PYD, DPD and bone specific alkaline phosphatase (BALP) correlated with the number of skeletal areas involved [74, 75]. With a choice of both formation and resorption markers, how do investigators choose the most appropriate marker for their studies? Lipton et al. [76] have attempted to determine which marker best correlated with skeletal metastases and concluded that NTX was the most predictive for the presence of bone metastases, but this may depend upon the cancer type and other factors. It should be emphasised that bone markers are not specific for malignant disease and can be elevated in a number of benign bone diseases. Currently, however, bone biomarkers are not used routinely for diagnosis of bone metastases and there is still a need for skeletal imaging to diagnose bone metastases with certainty.

5.6 The Role of Bone Biomarkers in Predicting Skeletal Complications and Survival The severe bone pain and other skeletal complications (skeletal related events, SRE) associated with metastatic bone disease are often the most significant factors limiting quality of life in these patients. Details of these complications (which include hypercalcaemia, bone pain requiring radiotherapy, pathological fracture and spinal cord or nerve root compression) and their treatment are given in other chapters of this book. Identification of patients with bone metastases who are at high risk of developing SREs may be valuable in patient management, especially in decisions as to when to apply therapeutic interventions such as bisphosphonates and other bone specific therapies. A study by Lipton et al. [77] investigated the fracture rate in 21 cancer patients with bone metastases who received intravenous pamidronate and whose baseline NTX levels were above the normal range. In the 12 patients who normalised NTX on the bisphosphonates only 5 (42%) developed fractures, whereas in the 9 patients who failed to normalise, 8 patients (89%) developed fractures. Although this small study fell just short of statistical significance, it illustrated the link between marker levels and SREs and pointed to the importance of normalisation of markers as a therapeutic goal. Ali et al. [78] investigated serum NTX levels in 250 post-menopausal metastatic breast patients with bone-only metastases. 24% of patients had elevated serum NTX levels and median survival time was significantly shorter in patients with elevated baseline serum NTX (663 days) compared with patients with low baseline NTX (941 days, p < 0.001). The prognostic potential of bone markers in multiple myeloma was highlighted by Abildgaard et al. [79], who showed that elevated pre-treatment values of serum ICTP and urinary NTX were predictive of early progression of bone disease during standard chemotherapy.

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The first study to examine the possible correlation between the rate of bone resorption, as measured by a bone marker, and the frequency of skeletal complications across a range of SREs in metastatic bone disease was carried out in 121 patients, mainly with breast and prostate cancer [80]. Data were available for 121 patients over the first 3 month period of monitoring (0–3 months) and for 95 patients over the second 3 month period of monitoring (4–6 months). The results showed that patients with NTX values ≥100 nmol/mmol creatinine were almost 20 times more likely to experience a SRE/death during the following 3 month period, than those patients whose NTX value at the beginning of the 3 month period was <100 nmol/mmol creatinine (p < 0.001 for both 0–3 month and 4–6 month periods). In a multivariate logistic regression model, NTX was highly predictive for SREs/death. This initial work has been developed and expanded in very large retrospective analyses of bone markers and skeletal complications/survival from the randomised Phase 3 trials of zoledronic acid in patients with bone metastases from a variety of primary cancer types. In patients with bone metastases from prostate cancer (N = 203), lung cancer or other solid tumours (other than breast (N = 238), in the placebo arm of these studies, elevated bone marker levels correlated with negative clinical outcomes [66]. High NTX levels (≥100 nmol/mmol creatinine) were associated with a 4.6 fold increased rate of death on study in patients with prostate cancer and a 2.7 fold increased risk of death on study in patients with non small cell lung cancer and other solid tumours, compared with patients in these groups with low NTX levels (<100 nmol/mmol creatinine), with p < 0.001 in both cases. The relative risk of SREs was 3.25 times higher (p < 0.001) and 1.79 times higher (p = 0.010) for patients with high NTX in the prostate and non small cell lung cancer and other solid tumour groups respectively, compared with the corresponding patients with low NTX (see Table 5.2). The above analysis refers to updated marker values, though baseline marker values were also significantly predictive. In a combined analysis of 1,824 bisphosphonate-treated patients with metastatic bone disease (breast, prostate, non small cell lung, myeloma, other), an exploratory analysis grouped patients by baseline levels of NTX as low (<50 nmol/mmol creatinine, moderate (50–99 nmol/mmol creatinine) and high (≥100 nmol/mmol creatinine) and by baseline levels of BALP as low (< 146 U/L) or high (≥ 146 U/L) [67]. Patients with high and moderate NTX levels had 2-fold increases in risk of skeletal complications and disease progression compared with those with low NTX levels (p < 0.001 in all cases) and high NTX levels in each solid tumour category were Table 5.2 Relative risk of death and skeletal complications for patients with high NTX compared with patients with low NTX Clinical outcome

Prostate cancer

Non small cell lung cancer and other solid tumours (excluding breast)

Relative risk

p

Relative risk

P

Death on study Occurrence of SREs

4.6 3.25

p < 0.001 P < 0.001

2.7 1.79

p < 0.001 P = 0.010

Data refer to the placebo arm of the phase III zoledronic acid trials (Brown et al. [92]).

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associated with a 4–6 fold increased risk of death on study (p < 0.001 in all cases). Although BALP levels also showed some correlation with risk of negative clinical outcomes, it was not a strong prognostic indicator. Further analyses of the zoledronic acid trials data have shown a strong positive association between zoledronic aid treatment and survival in patients with high baseline levels of NTX. For example, in non small cell lung cancer, the reduction of risk of death was 35% (p = 0.024) [81]. In these prognostic studies, NTX has been shown to be the most consistently reliable bone marker, but other markers have also been studied in a range of tumour types. In a trial of 2 mg monthly IV ibandronate versus placebo in patients with multiple myeloma, Menssen et al. [82] found that the occurrence of SREs per patient year and the time to first SRE were not significantly different between the two groups. However, ibandronate patients with strongly suppressed bone markers (CTX and osteocalcin) developed significantly less bone morbidity. This is a relatively low dose of ibandronate compared with that used in breast cancer. Also in multiple myeloma patients, Woitge et al. [44] showed that BSP could be a useful marker for survival, demonstrating that survival was increased in patients with normal BSP levels compared to patients with elevated BSP levels (p < 0.001). P1NP is also proving interesting in the prognostic setting. Brasso et al. [14] showed that, in 153 metastatic prostate cancer patients, serum P1NP was associated with poor outcome, with multivariate Cox analyses showing that P1NP was an independent predictor of survival. Interestingly P1NP was elevated (compared to health male controls) in 87% patients compared to elevated BALP in 55% and elevated CTX-I in 33%. A study by Jung et al. [15] showed that prostate cancer patients with bone metastases who had high P1NP levels, had significantly shorter survivals than patients with low P1NP levels. In the same study, elevated levels of OPG, BALP, BSP, NTX and CTX also correlated with shorter survival.

5.7 Role of Bone Biomarkers in Monitoring and Directing Bisphosphonate Therapy Objective assessment of response in bone metastases from breast cancer takes up to 6 months using radiological techniques and bone markers have been studied with the aim of providing an earlier indication of response. There is currently major interest in using bone markers as fast and convenient surrogate end points for clinical efficacy (primarily reduction in skeletal complications). Whilst it is now well accepted that bone-targeted systemic therapy, particularly the use of the bisphosphonates, can substantially reduce morbidity of skeletal metastases, the optimisation and timing of these therapies remains to be established. Bone markers potentially offer a powerful and relatively simple tool to assist the clinician in developing the most appropriate treatment strategies. Moreover, there is the prospect that it may be possible to use bone markers to tailor treatment to the individual patient. There are many studies which show rapid and substantial decrease in bone marker levels following initiation of bisphosphonates therapy, with initial decreases

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of up to 60–70% in NTX and CTX being demonstrated and maintained [83, 84]. However, a key question in using bone markers in patient management is whether targeting therapy to achieve reduction of marker values into the normal range is associated with clinical benefit. Early, relatively small studies have suggested that this is the case for pain [85] and fracture rate [78], but the zoledronic acid trial data have allowed retrospective assessment of this question very recently in much larger patient groups. In breast cancer, analyses suggested that early normalisation of elevated baseline NTX while receiving zoledronic acid is associated with longer event-free and overall survival times than in patients with persistently elevated NTX levels [86]. In all tumours studied (breast cancer, prostate cancer, non small cell lung cancer and other solid tumours, the analyses suggested that breaking the cycle of bone destruction and tumour growth in bone with bisphosphonates can produce profound benefits [87]. Normalisation of elevated baseline NTX within 3 months was associated with significant improvements in survival compared with persistent NTX elevation and zoledronic acid normalized NTX in the majority of patients, so normalisation would seem a reasonable and achievable therapeutic target. Trials using this approach are considered below. However, normalisation did not appear to represent a particular threshold and NTX reductions were associated with benefit, regardless of whether normal NTX levels were reached. Whilst it is clear that bisphosphonates can reduce the levels of bone markers, as well as producing clinical benefit, caution is needed in over-generalising the correlation between bone marker levels and clinical advantage. This has recently been illustrated by Coleman et al. [7] in the analyses from the large zoledronic acid trials, where zoledronic acid was more effective than pamidronate in reducing SREs in breast cancer patients and this was mirrored by reductions in NTX, but no differences were observed in changes in BALP. Such data suggest that correlations between bone markers and clinical benefit may depend upon both the marker and the tumour type and that establishment and wider acceptance of bone markers as surrogates for skeletal complications will require more specific trials such as the SWOG study, a prospective trial which is currently under way (expected completion in 2015) to compare clinical efficacy of oral ibandronate with zoledronic acid, where a comparison across SRE endpoints is the primary objective [7, 88]. The dependence of bone marker levels on circadian rhythm has been studies by Generali et al. [89] who showed that the circadian rhythm of biomarkers of bone resorption is synchronized in breast cancer patients with lytic bone metastases, independently of tumour load. An interesting question in terms of bisphosphonate therapy is whether its effectiveness can be altered by matching the dosing to the circadian rhythm. Very recent work in breast cancer patients with bone metastases has shown that administration of zoledronic acid at two opposite phases of the circadian cycle causes similar changes in bone turnover marker levels, with no difference in effect on NTX and CTX (p < 0.001), [90]. There do not appear to have been any studies assessing the differential effects of night versus day administration on skeletal complications. Since bone marker levels are reduced by bisphosphonates, the possibility arises of using bone marker measurements to direct the dosing and scheduling of therapy,

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effectively tailoring the therapy to the individual patient. In practical terms, the minimum dosing intensity would be used which would bring the marker level into a target range. The feasibility of this approach was demonstrated by a study of clodronate in patients with advanced prostate and breast cancer, metastatic to bone [91,92]. Patients were initially given the standard 1,600 mg daily oral clodronate dose, which was escalated at 6 weekly intervals, through 2,400 mg, 3,200 mg and 1,500 mg intravenously until NTX levels fell below 67 nmol/mmol creatinine. Patients whose NTX still did not normalise were given zoledronic acid infusion. An incremental proportion of patients normalised at each stage of escalation, although 24 weeks to reach the maximum dose was felt to be too long. These studies were followed up with further investigations in breast cancer patients, which showed that patients with either progressive bone metastases or SREs while on clodronate or pamidronate can have relevant palliative benefits with a switch to zoledronic acid [93] or oral ibandronate [94] reflected by improvement in pain control and bone turnover markers [95]. The marker directed approach is currently being assessed in ongoing trials, including the BISMARK trial, which is a large (N = 1,500) prospective study comparing NTX directed therapy to a standard dosing schedule in breast cancer patients with bone metastases [7, 96, 97]. Patients are being randomised to receive either zoledronic 4 mg every 3 to 4 weeks (standard schedule) or zoledronic acid 4 mg on a marker-directed schedule based on changes of NTX from baseline. The primary endpoint is the frequency and timing of SREs. The study is expected to be complete in 2010.

5.8 Effect of Radiotherapy for Bone Metastases on Markers of Osteoclast Activity Radionuclides have been employed in the treatment of bone metastases. Papatheofanis [98] measured serum PICP concentrations as a semi-quantitative index of bone turnover in patients with bone metastatic prostate cancer before and following palliative 89Sr chloride therapy. Two groups of 10 patients each were studied: one group received irradiation, whereas the other group received 89Sr chloride therapy. The concentration of serum PICP rose from 649 ± 279 ng/mL before treatment with external beam radiotherapy to 927 ± 157 ng/mL 4 months after therapy (p < 0.05). However, the results demonstrated a four-fold decrease (p < 0.001) in serum PICP in clinical responders to 89Sr chloride therapy versus baseline, four months after the completion of treatment. The clinical non-responders demonstrated no significant change in PICP concentrations during that interval. These data demonstrate that serum PICP concentration correlates with clinical response to 89Sr chloride therapy and may also be extremely useful in predicting a therapeutic response to such intervention. Papatheofanis [99] also investigated the production of urinary PYD and DPD in prostate cancer patients with bone metastases who were and were not treated

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with 89Sr-chloride therapy. Patients were monitored for PYD and DPD production for a 6-month interval. The urinary production of these compounds remained unchanged for 6 months after 89Sr-chloride therapy for symptomatic osseous metastases. However, the patients who were not treated with 89Sr-chloride therapy exhibited a two-fold increase in PYD and a four-fold increase in DPD above controls during the interval. The author concluded that PYD and DPD are sensitive and specific bone resorption markers which demonstrate a slowing of bone resorption after palliative 89Sr-chloride therapy in patients with bone metastases. Papatheofanis also studied whether 89Sr-chloride decreased the production of cell adhesion molecules (E-selectins) that participate in the metastatic process [100]. Sera were collected from 25 men with metastatic prostate carcinoma who received 89Sr-chloride palliative therapy and from 5 patients who received 2 courses of radionuclide therapy. A 2.8-fold decrease in serum E-selectin concentration occurred within 2 months of radionuclide therapy (p < 0.0001). At 10 months, however, the concentration increased to a mean (± SD) of 151.2 ± 51.3 ng/mL, surpassing the baseline concentration. This pattern coincided with symptomatic improvement and subsequent health status deterioration. For patients who received 2 courses of radionuclide therapy, a second fall in serum E-selectin concentration followed the second radionuclide treatment. The author concluded that a significant decrease in serum E-selectin concentration was observed after systemic radionuclide therapy. This finding suggests that expression of cell adhesion molecules, an important determinant of metastatic progression, may be inhibited by 89Sr-chloride. External beam palliative radiotherapy is well established for the treatment of symptomatic bone metastases [101]. The exact mechanism of its action is still uncertain, although tumor cell kill may be an important reason. However, the absence of a dose-response relation, rapid responses, and poor correlation of efficacy with radiosensitivity suggest that an effect on host mechanisms of pain could also be important. Markers of bone remodeling have been shown to be suppressed by anti-resorptive therapy, and the response of these bone markers has been applied to monitoring therapy for bone metastases. In the UK Bone Pain Radiotherapy Trial [102], 22 patients were entered into a supplementary study to establish the effects of local radiotherapy for metastatic bone pain on markers of osteoclast activity, particularly the PYD and DPD, the latter being specific for bone turnover [103, 104]. Urine samples were collected before and one month after radiotherapy. Patients were treated with either a single 8 Gy or 20 Gy in 5 daily fractions. Pain response was scored with validated pain charts completed by patients. Urinary pyridinium concentrations were compared with pain response (Fig. 5.1). In the non-responding patients, baseline concentrations of both PYD and DPD were higher than responders, and rose further after treatment, whereas in responders, the mean values remained unchanged. This resulted in significant differences between responders and non-responders for both indices after treatment (p = 0.027). The authors conclude that radiotherapy-mediated inhibition of bone resorption, and thus osteoclastic activity, could be a predictor for pain response. They also propose either that tumor cell killing reduces the production of osteoclast activating factors, or

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A Pyridinoline (nmol/mmol creatinine)

Before radiotherapy (SE)

4 weeks after radiotherapy (SE)

650 600 550 500 450 400 350 300 250 200 150 100 50 0 Responder

B

Before radiotherapy (SE)

Deoxypyridinoline (nmol/mmol creatinine)

109

Non-Responder 4 weeks after radiotherapy (SE)

140 120 100 80 60 40 20 0 Responder

Non-Responder

Total: 22 patients, 8 with breast cancer and 14 with prostate cancer; 5 patients showed no response, 9 a partial response and 8 a complete response

Fig. 5.1 Effect of radiotherapy on urinary markers of osteoclast activity related to pain response (A). Pyridinoline; (B). Deoxypridinoline

that there is a direct effect upon osteoclasts within the radiation volume, distant from tumor shrinkage. Their study supports the results from randomized trials that high dose radiotherapy is not necessary for pain relief, and that single low-doses of treatment are more than adequate for most patients. However, their study is limited by a small sample size.

5.9 Current and Future Directions Bone biomarkers have played and continue to play a key role in the research and development of new bone specific therapies including bisphosphonates and, more

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recently, RANK-L inhibitors and other agents such as cathepsin-K. All agents which have proved to be useful in bone specific therapy have demonstrated a reduction in bone resorption markers and this currently has become a requisite for development of new agents for clinical success. For example, the novel, fully human monoclonal antibody specific to RANK-L, denosumab, is being investigated in multiple trials for the prevention and treatment of bone metastases [105]. In the Phase I and II trials of denosumab, bone markers have a clear role in determining dose and schedule to be taken forward in large Phase III studies [86]. However, in these Phase III studies the primary endpoint remains a clinical one based on skeletal complications rather than bone markers. With this exciting phase of development which is likely to result in approval of several new bone specific agents for routine therapy, bone markers may also have an important role in directing choice of therapy or, indeed, switch from one agent to another at different stages of a patient’s illness. This possibility is illustrated by a randomised phase II study in 111 patients with bone metastases from prostate, breast and other cancers, among patients with elevated urinary NTX (>50 nmol/mmol creatinine) despite previous intravenous bisphosphonates therapy, denosumab normalised NTX significantly more frequently than ongoing bisphosphonate therapy [106] suggesting that a switch of agent could add benefit to patients with particularly aggressive metastatic bone disease. Most work with bone biomarkers in cancer relates to existing bone metastases and therapies to reduce skeletal complications and, although there is some work suggesting that increases in bone resorption markers may represent an early indication of impending macroscopic bone metastases which are not yet detectable using imaging techniques [68, 75, 107], there are currently no biomarkers which are able to predict individual risk of developing metastatic bone disease. Such markers are urgently needed since it will be important on cost and safety grounds to direct adjuvant anti-metastatic therapy to those patients who are most likely to benefit. This is especially topical, since a recent study [108] and other ongoing studies have highlighted the likely adjuvant use of zoledronic acid and other agents in preventing bone metastases. For such studies, newer, more sensitive technologies such as proteomics present exciting opportunities in novel biomarker discovery. Matrix metalloproteinases, cathepsin K and other proteases derived from both the invading cancer cells and the bone microenvironment play key roles in the metastatic process suggesting a rich source of protein fragments for proteomic studies. However, at present, proteomic approaches remain relatively unexploited in bone metastasis. The relatively sparse existing body of proteomic knowledge regarding bone cancer and the potential for the future has been reviewed by Suva and colleagues [109]. Several research groups are now focusing in this area. In conclusion, although the development of bone metastases is generally regarded as indicating that curative management is no longer feasible, developments in bone specific therapies and the parallel development of accurate and meaningful bone biomarker measurements such as NTX have improved clinical care for these patients. New bone specific therapies may be expected to continue to emerge, complementing and enhancing the bisphosphonates. In parallel, novel bone markers such

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as BSP, TRACP5b, RANK-L and OPG still require further study and verification in particular tumour types and their usefulness remains to be determined. In practice, however, full validation and exploitation of biomarkers requires extensive prospective clinical trials and this is likely to limit the number of bone biomarkers which will enter routine clinical practice. Acknowledgement We thank Cancer Research UK for the award of a Clinician Scientist Fellowship (to JEB).

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59. Jung K, Lein M, Ringsdorf M, et al. (2006) Diagnostic and prognostic validity of serum bone turnover markers in metastatic renal cell carcinoma. J Urol 176:1326–1331 60. Coombes RC, Dady P, Parsons C, et al. (1983) Assessment of response of bone metastases to systemic treatment in patients with breast cancer. Cancer 52:610–614 61. Massidda B, Ionta MT, Foddi MR, et al. (1996) Usefulness of pyridinium crosslinks and CA 15–3 as markers in metastatic bone breast carcinoma. Anticancer Res 16:2221–2224 62. Lipton A, Demers L, Daniloff Y, et al. (1993) Increased urinary excretion of pyridinium crosslinks in cancer patients. Clin Chem 39:614–618 63. Walls J, Assiri A, Howell A, et al. (1999) Measurement of urinary collagen crosslinks indicate response to therapy in patients with breast cancer and bone metastases. Br J Cancer 80:1265–1270 64. Garnero P, Buchs N, Zekri J, et al. (2000) Markers of bone turnover for the management of patients with bone metastases from prostate cancer. Br J Cancer 82:858–864 65. Kanakis I, Nikolaou M, Pectasides D, et al. (2004) Determination and biological relevance of serum cross-linked type I collagen N-telopeptide and bone-specific alkaline phosphatase in breast metastatic cancer. J Pharm Biomed Anal 34:827–832 66. Brown JE, Cook RJ, and Major P (2005) Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97:59–69 67. Coleman RE, Major P, Lipton A, Brown JE, Lee KA, Smith M, Saad F, Zheng M, Hei YJ, Seaman J, and Cook R (2005) Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 23:4925–4935. 68. Demers LM, Costa L, Chinchilli VM, et al. (1995) Biochemical markers of bone turnover in patients with metastatic bone disease. Clin Chem 41:1489–1494 69. Vinholes JJ, Coleman R, Lacombe, et al. (1999) Assessment of bone response to systemic therapy in an EORTC trial: preliminary experience with the use of collagen cross-link excretion. Br J Cancer 80:221–228 70. Body JJ, Dumon JC, Gineyts E, et al. (1997) Comparative evaluation of markers of bone resorption in patients with breast cancer-induced osteolysis before and after bisphosphonate therapy. Br J Cancer 75:408–412 71. Garnero P (2001) Markers of bone turnover in prostate cancer. Cancer Treat Rev 27:187–192 72. Koizumi M, Yonese J, Fukui I, et al. (2001) The serum level of the amino-terminal propeptide of type I procollagen is a sensitive marker for prostate cancer and metastasis to bone. BJU Int, 87:348–51 73. Berruti A, Panero A, Angelli A, et al. (1996) Different mechanisms underlying bone collagen resorption in patients with bone metastases from prostate and breast cancer. Br J Cancer 73:1581–1587 74. Berruti A, Torta M, Piovesan A, et al. (1995) Biochemical picture of bone metabolism in breast cancer patients with bone metastases. Anticancer Res 15:2871–2876 75. Costa L, Demers LM, Gouveia A, et al. (1999) Biochemical markers of bone turnover correlate with the extent of metastatic bone disease. Proc ASCO Abstr 18:2375 76. Lipton A, Costa L, Suhail A, et al. (2001) Use of markers of bone turnover for monitoring bone metastases and the response to therapy. Semin Oncol 28:54–59 77. Lipton A, Demers L, Curley E, et al. (1998) Markers of bone resorption in patients treated with pamidronate. Eur J Cancer 34:2021–2026 78. Ali SM, Demers LM, Leitzel K, et al. (2004). Baseline serum NTx levels are prognostic in metastatic breast cancer patients with bone-only metastasis. Ann Oncol 15:455–459. 79. Abildgaard N, Brixen K, Kristensen JE, et al. (2003) Comparison of five biochemical markers of bone resorption in multiple myeloma: elevated pre-treatment levels of S-ICTP and U-Ntx are predictive for early progression of the bone disease during standard chemotherapy. Br J Haematol 120:235–242 80. Brown JE, Thomson C, and Ellis S (2003). Bone resorption predicts for skeletal complications in metastatic bone disease. Br J Cancer 89:2031–2037

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81. Hirsch V, Major P, Lipton A, et al. (2008) Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclasts activity. J Thorac Oncol 3:228–236 82. Menssen HD, Sakalova A, Fontana A, et al. (2002) Effects of long term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol 20:2353–2359 83. Brown JE, McCloskey EV, Dewar JA, et al. (2007) The use of bone markers in a 6-week study to assess the efficacy of oral clodronate in patients with metastatic bone disease. Calcif Tissue Int 81:341–351 84. Rosen LS, Gordon G, Kaminski M, et al. (2003) Long term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a double-blind, multicentre, comparative trial. Cancer 98:1735–1744 85. Vinholes JJ, Purohit OP, Abbey ME, et al. (1997) Relationship between biochemical and symptomatic response in a double blind trial of pamidronate for metastatic bone disease. Ann Oncol 8:1243–1250 86. Lipton A, Cook RJ, Major P, et al. (2007) Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclasts activity. Oncologist 12:1035–1043 87. Lipton A, Cook R, Saad F, et al. (2008) Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer 113:193–201 88. Rivkin S (2006) Oral ibandronate versus intravenous zoledronic acid for breast cancer patients with skeletal complications: the swog trial. Bone 38:S82. Abstract 101 89. Generali D, Berruti A, Tampellini M, et al. (2007) The circadian rhthym of biochemical markers of bone resorption is normally synchronized in breast cancer patients with bone lytic metastases independently of tumor load. Bone 40:182–188 90. Generali D, Dovio A, Tampellini M, et al. (2008) Changes of bone turnover markers and serum PTH after night or morning administration of zoledronic acid in breast cancer patients with bone metastases. Br J Cancer 98:1753–1758. 91. Brown JE, Ellis S, Gutcher S, et al. (2002) The bone resorption marker NTX is strongly correlated with skeletal events in metastatic bone disease and is influenced by dose escalation of clodronate. Am Soc Clin Oncol 21:385a 92. Brown JE, Ellis S, Gutcher S, et al. (2005) Using bone turnover markers to direct bisphosphonate therapy. Is this a feasible approach? Cancer Treat Reviews, 31:44–57 93. Clemons M, Dranitsaris G, Ooi W, et al. (2006) Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal related event or progressive bone metastases despite first-line bisphosphonate therapy. J Clin Oncol 24:4895–4900 94. Clemons M, Dranitsaris G, Ooi W, et al. (2008) A phase II trial evaluating the palliative benefit of second-line oral ibandronate in breast cancer patients with either a skeletal related event (SRE) or progressive bone metastases (BM) despite standard bisphosphonates (BP) therapy. Breast Cancer Res Treat 108:79–85 95. Simmons C, Broom RJ, Cole DEC, et al. (2007) Urinary N-telopeptide is a rapid predictor of response to and palliative benefit from bisphosphonates therapy in patients with metastatic breast cancer. Support Cancer Ther 4:182–187 96. US National Institutes of Health. Clinical trials: randomized study of bone marker-directed schedule versus standard schedule of zoledronic acid in patients with advanced breast cancer metastatic to the bone. Available at http://www.cancer.gov/clinicaltrials/NCRI-BISMATK. Accessed October 31, 2007 97. UK Clinical Research Network: Portfolio Database. Cost-effective use of BISphosphonates in metastatic bone disease – a comparison of bone MARKer directed zoledronic acid therapy to a standard schedule – the BISMARK trial. Available at http://pfsearch.ukcrn.org.uk/ StudyDetail.aspx?TopicID=1&StudyID=1737. Accessed October 31, 2007

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98. Papatheofanis FJ (1997) Serum PICP as a bone formation marker in 89Sr and external beam radiotherapy of prostatic bony metastases. Br J Radio 70:594–598 99. Papatheofanis FJ (1997) Quantitation of biochemical markers of bone resorption following strontium-89-chloride therapy for metastatic prostatic carcinoma. J Nucl Med 38:1175–1179. 100. Papatheofanis FJ (2000) Decreased serum E-selectin concentration after 89Sr-chloride therapy for metastatic prostate cancer bone pain. J Nucl Med 41:1021–1024 101. Chow E, Harris K, Fan G, et al. (2007) Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 25:1423–1436 102. Bone Pain Trial Working Party (1999) 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Radiother Oncol 52:111–121 103. Hoskin PJ, Stratford MRL, Folkes LK, et al. (2000) Effect of local radiotherapy for bone pain on urinary markers of osteoclast activity. Lancet 355:1428–1429 104. Abbiati G, Bartucci F, Longoni A, et al. (1993) Monitoring of free and total urinary pyridinoline and deoxypyridinoline in healthy volunteers: sample relationships between 24-h and fasting early morning urine concentrations. Bone Miner 21:9–19 105. Lipton A and Jun S (2008) RANK-L inhibition in the treatment of bone metastases. Curr Opin Support Palliat Care 2:197–203 106. Faizazi K, Lipton A, Mariette X, et al. (2008) Denosumab in patients with bone metastases from prostate, breast and other cancers and elevated urinary N-telopeptide (UNtx) during intravenous (IVBp) therapy: final results of a randomised phase 2 study. J clin Oncol 26: 3596 107. Lipton A, Costa L, Ali SM, et al. (2001b) Bone markers in the management of metastatic bone disease. Cancer Treat Rev 27:181–185 108. Gnant M, Mlineritsch B, Schippinger W, et al. (2008) Adjuvant ovarian suppression combined with tamoxifen or anastrazole alone, or in combination with zoledronic acid in premenopausal women with hormone responsive stage I and II breast cancer: first efficacy results from ABCSG/12. J clin Oncol 26:4BA4 109. Bhattacharyya S, Epstein J, and Suva LJ (2006) Biomarkers that discriminate multiple myeloma patients with or without skeletal involvement detected using SELDI-TOF mass spectrometry and statistical and machine learning tools. Dis Markers 22:245–255

Part II

Imaging Modalities

Chapter 6

RADIOLOGIC EVALUATION OF SKELETAL METASTASES: ROLE OF PLAIN RADIOGRAPHS AND COMPUTED TOMOGRAPHY Christina Kalogeropoulou1 , Anna Karachaliou2 and Peter Zampakis1 1 University Hospital of Patras, 26500 Patras, Greece, e-mail: [email protected] 2 Department of Medical Physics, University of Patras Medical School, Patras, Greece, e-mail: [email protected]

Abstract:

The diagnosis and confirmation of bone metastasis, especially in asymptomatic patients, can be a difficult and challenging task. Bone scintigraphy is a very sensitive method and continues to be the primary choice for detection of bony metastases. Radiography is not generally recommended as a screening method and it is commonly used such scintigraphy. Computed Tomography (CT) can be used to further delineate the nature of a scintigraphically positive osseous region and to evaluate the extent and pattern of bone destruction of the metastasis as well as the presence of a soft tissue mass. This is very important in planning radiation ports or biopsy sites. The application of Multislice Computed Tomography (MSCT) gives a rapid and excellent survey of the axial skeleton and contributes to the evaluation of the stability of skeletal metastases with the use of multiplanar and three-dimensional reconstructions. CT can also quantify the therapeutic effect on bone metastases by measuring the differences in attenuation values between pre and post treatments cans. Moreover Computed Aided diagnosis (CAD) schemes for the quantification/characterization of metastatic bone disease on CT data and for monitoring tumor response to therapy are currently emerging.

Key words: Skeletal metastasis · Plain radiographs · Multislice computed tomography · Lytic lesion · Bone destruction D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 6,  C Springer Science+Business Media B.V. 2009

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6.1 Introduction Metastases to the skeleton represent the commonest type of malignant bone tumors. Notably, the most common tumors (breast, lung, and prostate) also show a marked osteotropism. Skeletal metastases are clinically important due to the associated disabling symptoms, severe complications and the deterioration of quality of life of affected patients [1–3]. Furthermore, associated complications such as spinal cord compression, pathologic fractures and hypercalcemia may even threaten life. The imaging characteristics of skeletal metastases are highly variable and are influenced by several factors including the histological type of the tumor, location of metastatic deposits, age of the patient, timing of radiologic evaluation and applied imaging modality. Therefore, the diagnosis and confirmation of a bone metastasis, especially in asymptomatic patients, can be a difficult and challenging task. Bone Scintigraphy (BS), plain films, CT and Magnetic Resonance Imaging (MRI) are today the most commonly used imaging methods for the detection of osseous metastases. Additionally, PET (Possitron Emisssion Tomography) and PET/CT have been recently introduced as very promising imaging modalities. BS continues to be a reasonable screening examination method and is used as the first choice for detection of bony metastases, especially in asymptomatic patients [4]. This is mainly because it is very sensitive (95%), cost effective and can image the whole skeleton. Moreover, problems of specificity can often be resolved by using plain films, CT or MRI [5]. Over the last years the introduction of MRI, has somehow altered the scenery of skeletal imaging, since numerous studies have shown that early bone marrow involvement by tumor cells can be detected with MRI, long before scintigraphic detection is possible [6, 7]. Although MRI is considered to be a highly sensitive and specific technique for the evaluation of bone marrow metastases, and provides a better soft-tissue contrast than CT, there are several limitations and drawbacks in its application that cannot be ignored, especially in patients with a poor clinical status [8–11]. Due to its high spatial and temporal resolution, CT is more sensitive than BS and plain X-rays for the detection of bone metastases. CT can readily demonstrate the extent and pattern of bone destruction and the presence of accompanied soft tissue mass, especially in complex anatomic areas such as the spine and pelvis. Since CT scanning is currently extensively used for staging and follow up of oncologic patients, the detection of bone metastases can be done simultaneously. Apart from providing an excellent survey of the axial skeleton, the use of multidetector computed tomography (MDCT) and multiplanar and three-dimensional reconstructions can contribute to the evaluation of the stability of skeletal metastases [12, 13]. Furthermore, CT is an imaging modality that is available in almost every hospital and therefore from the practical point of view, an easily applicable method.

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6.2 Radiologic and Pathologic Correlation Skeletal metastases have a tendency to develop in haematopoietic active bone marrow, which in adults is predominantly found in the axial skeleton including the skull and the proximal portion of the humerus and femur [14]. Evidence of multiple lesions (commonly of variable size) is the rule regarding the distribution of skeletal metastases, although solitary lesions can be seen in patients with carcinoma of the kidney and thyroid. In the latter case the radiographic differentiation from primary bone tumors can be difficult. Variability in size can differentiate metastatic disease from hematologic malignancies, which show a more uniform pattern of bone involvement. There are three main routes of spread of metastatic disease to the skeleton that bring about distinct radiological characteristics. The routs of spread are the direct extension, lymphatic spread and hematogenous dissemination [15]. Direct extension to the skeleton may occur when a primary tumor located in soft tissues invades adjacent bones. A typical example of direct extension is a carcinoma of the apex of the lung (Pancoast’s tumor) invading adjacent ribs or cervical vertebrae, or a carcinoma of the bladder or rectum invading pelvic bones. Through the lymphatic spread, metastatic tumor deposits from regional lymph nodes may secondarily involve adjacent osseous structures. This type of tumoral spread to bone occurs for example in metastatic pelvic tumors, with imaging studies typically depicting a paravertebral soft tissue mass (representing enlarged lymph nodes) and scalloped erosions of one or more vertebral bodies. The blood is the major route of metastatic skeletal involvement. The venous rather than the arterial route appears more significant, especially the vertebral plexus of Batson. The distribution of Batson’s venous plexus, as well as the overall skeletal vascularity results in a predilection for hematogenous spread to the axial skeleton and the proximal long bones. In the case of hematogenous dissemination, a soft tissue mass is an unusual finding. Regardless of the mechanism of bone involvement, at the site of skeletal metastasis bone resorption or bone formation are observed. A skeletal metastasis is classified as osteolytic when bone resorption is dominant, osteosclerotic when bone formation is mainly evident, or mixed in the case that none of the two processes predominates. It should be though noted that regardless of the type of a metastatic skeletal lesion, both resorption and formation are histologically present. Purely osteolytic lesions typically arise from carcinomas of the kidney, thyroid, uterus or gastrointestinal tumors (Figs. 6.1 and 6.2), mixed metastases generally occur in carcinomas of the lung, breast, cervix, ovaries and testicles and purely osteosclerotic lesions are commonly seen in patients with carcinoma of the prostate. On plain X-rays, osteolytic lesions may be well circumscribed (geographic bone destruction) or poorly defined (moth-eaten or permeative bone destruction). Geographic bone destruction is considered to be the result of a less aggressive tumor that is slowly growing. In such cases a smooth or irregular margin may be present, sometimes with a sclerotic rim of variable thickness. On the other hand moth-eaten bone destruction is a pattern of bone loss that indicates a more aggressive process.

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Fig. 6.1 X-ray of the chest demonstrating a painful metastasis destructing the cortex of the posterior part of 9th rib, in this 35 years old patient with pancreatic cancer

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Fig. 6.2 CT of the chest: (a and b) Multiple osteolytic metastases are demonstrated at the vertebrae and the ribs in this 80 years old patient with lung cancer. (c) Image reconstruction (MIP) of the chest well permits better appreciation of the osseous destruction

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In such lesions margins are poorly defined and the transitional zone from normal to abnormal bone is relatively larger than that observed in geographic pattern. The permeative bone destruction represents the most aggressive pattern of bone destruction. Its characteristic feature is the poor demarcation from the surrounding normal bone. Osteosclerotic lesions may be nodular or diffuse. Typically, nodular osteosclerotic lesions lack the speculated appearance of a bone island [15]. The CT imaging patterns of bone metastases are similar to those depicted with radiography. The diagnosis of an osteolytic lesion on CT is based on detection of destructive changes of the trabecular architecture or the cortex, which are replaced by a mass of soft tissue density (Fig. 6.3). Osteoblastic lesions are diagnosed with a greater difficulty. The findings suggestive of malignancy are ill defined areas of increased bone density, with loss of definition of trabecular pattern. Sclerotic metastases may become densely sclerotic and occasionally may have sharply defined margins. In this case differentiation of malignant lesion from a benign process may be impossible. Multiplicity of osteoblastic lesions is suggestive of metastatic bone disease [16]. Imaging findings on X-rays or CT evidencing bone reaction due to the presence of metastatic deposits consist of periosteal reaction, expansive remodeling, and pathologic fracture. Periosteal reaction is either absent or limited in metastatic lesions, in contrast to primary malignant tumors that are accompanied by an extensive reaction. However severe periosteal reaction leading to bone speculation and a sunburst appearance is evident in some cases of metastases especially those arising from prostate carcinoma, gastrointestinal tumors (Fig. 6.4), retinoblastoma and neuroblastoma. Expansive remodeling is seen in patients with carcinomas of the kidney, thyroid and hepatomas. In some of these cases a distinctive septated appearance accompanies the osseous expansion. Large expansive osteoblastic lesions may mimic Paget’s disease or osteosarcoma. Metastases to the skeleton lead to osseous weakening and subsequent pathologic fracture. This complication is well recognized in the spine where compression or collapse of a tumor containing vertebral body is commonly seen (Fig. 6.5).

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Fig. 6.3 CT of the pelvis depicting metastasis in the right pubic bone of a 75 years old female patient suffering from carcinoma of the external genitalia. An osteolytic lesion is presented that is accompanied by a soft tissue mass (a and b). The iodine contrast uptake by the metastatic lesion is as high as that of the as the primary tumor (b)

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Fig. 6.4 Carcinoma of the Vater, metastatic to the right mandibular condyle. Axial (a) and coronal (b) CT demonstrates an osteosclerotic lesion in the right condyle with fracture and extensive periosteal reaction

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Fig. 6.5 Coronal (a) and sagittal (b) reconstructions of the spine: Pathologic fracture is evidence at the level of L1 vertebra in a patient presented with lumbar pain. Multiple osteolytic and osteoblastic metastases along the vertebrae bodies are also demonstrated

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Pathologic fractures accompanying metastases in tubular bones are evident most frequently in the proximal portion of the femur, although other bones may be involved as well. The majority of pathologic fractures in long bones occur when more than 50% of the cortical surface has been destroyed or the lesion is larger than 3 cm in diameter. The above mentioned findings suggest a pathologic fracture, even in the absence of pain. It should be though noted that lesions that do not meet or exceed the aforementioned radiographic criteria can still lead to pathologic fractures.

6.3 Specific Sites of Osseous Involvement 6.3.1 Spine The spine represents the commonest site of skeletal metastasis. Spinal involvement is more frequent in the lumbar region, followed by the thoracic and cervical segments. Metastases most commonly involve the vertebral bodies than the posterior parts of the vertebra. Routine radiography can detect vertebral body lysis only when a large part of the bone is destroyed. More specifically, for a lesion to be radiographically detected it should exceed 2 cm and involve a bone loss of more than 50% of the bone mineral content. Of diagnostic assistance to such cases may be an indistinct posterior vertebral body margin. The collapse of a vertebral body may be the presenting consequence of skeletal metastases. Findings suggestive of a collapsed vertebral body due to metastatic disease include involvement of an upper thoracic vertebra (a spine level that is infrequently osteoporotic), the presence of a soft tissue mass, pediculate destruction and angular or irregular deformity of the vertebral endplates. If no specific radiographic pattern is evident indicating a malignant vertebral collapse, then additional diagnostic methods such as CT or MRI should be applied for further evaluation. The presence of inhomogeneous or homogeneous sclerotic areas in one or more vertebral bodies in the elderly is highly suggestive of metastatic disease. A totally radio-dense vertebral body (the ivory vertebra) (Fig. 6.6) should be differentiated from the so-called corduroy vertebral body (which shows accentuated vertical striations) seen in hemangiomas, or the rugger-jersey vertebral body (radiodense stripes at the top and bottom), characteristic of renal osteodystrophy. Pedicle destruction is the commonest finding in plain films (Fig. 6.7). It usually occurs as a result of extension of a metastatic deposit within the posterior part of the vertebral body. It is a well known radiographic finding of skeletal metastasis, seen in antero-posterior radiographs as an absence of one or both “eyes” of the vertebral body [15].

6.3.2 Skull Single or multiple osteolytic lesions of variable size may be evident in the skull. Lesions involving bone destruction are usually associated with the presence of a

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Fig. 6.6 CT of the spine shows an ivory vertebra, in a patient with prostate cancer

Fig. 6.7 X-ray of the lumbar spine: Osseous destruction of the pendicles and the lamina of the L4 vertebra is seen in this patient with lung cancer

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Fig. 6.8 CT brain: Large osteolytic metastasis to the skull along with a soft tissue mass

soft tissue mass and commonly originate from renal or breast cancer (Fig. 6.8). Differential diagnosis includes eosinophilic granuloma, epidermoid tumor, hemangioma, sarcoid etc. Osteosclerotic metastases usually arise from carcinoma of the prostate. Sclerotic lesions of the base of the skull are a well known manifestation of nasopharygeal carcinomas and may be accentuated following radiotherapy.

6.3.3 Long Tubular Bones As already mentioned the femur and humerus are long bones frequently involved by metastatic disease. Metaphyseal localization predominates, although diaphyseal or epipheseal lesions may also be evident. Medullary bone is initially affected, while cortex involvement occurs at a later stage. The latter is more readily evident on radiographs. A solitary metastatic lesion in a long tubular bone may have a similar radiographic appearance with that of a primary tumor. In such cases the absence of extensive periosteal reaction and a prominent soft tissue mass favor the diagnosis of a metastatic deposit.

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6.3.4 Sternum and Sacrum These two bones are relatively common sites of metastasis. In both locations routine radiographs are often suboptimal and CT or MRI imaging is required for adequate imaging.

6.4 The Role of Radiography and CT in the Detection of Skeletal Metastases Radiography is commonly used to evaluate symptomatic sites and to investigate further bone scintigraphy findings. Certain features of plain radiographs may help the differential diagnosis of bone metastases from other conditions and may also aid the identification of the primary tumor. Plain radiographs may also be used to assess the risk of pathologic fractures in long bones, which is said to be high if 50% of the cortex is destroyed [17]. There is a general consensus that radiographic surveys should be performed in conjunction with bone scintigraphy; in fact, the latter examination is more appropriately to be obtained first and depending on the results to be used as a guide for specific radiographic projections. The major limitation of conventional X-ray diagnosis is that osteolytic changes are first recognized once 30–50% of the cancellous bone of vertebral bodies or long bones is resorbed [18]. Consequently it is not generally recommended as a screening method due to its low sensitivity (as compared to skeletal scintigraphy) [19]. For this reason inconclusive X-ray findings, as well as lesions in anatomically complex regions must be further investigated by using cross-sectional diagnostic methods. CT is an imaging modality that is readily available in almost every hospital and therefore from the practical point of view, an easily applicable method. It is far more sensitive than conventional radiography and BS for the detection of osteolytic lesions, providing a higher spatial resolution. Similarly, high-resolution axial CT images allow an exact depiction of the complex bone structure, without overlap. Furthermore CT can be used to measure marginal differences of bone density and consequently small lesions can not escape detection. However a limitation of the CT is that it does not image the entire skeleton [3]. CT can also depict the extent and pattern of bone destruction (lytic or sclerotic) and the presence of a soft tissue mass extending from the metastatic lesion, especially in those sites that are not easily evaluated by conventional imaging techniques, such as the vertebral column and pelvis. Similarly, CT may successfully asses paravertebral or intraspinal extensions, transarticular tumor spread and soft tissue involvement with violation of neurovascular structures. Its ability to readily depict the radial extent of metastasis gives CT an important role in planning radiation ports or biopsy sites. Another application of CT is the evaluation of the nature of scintigraphically positive osseous regions, especially if radiographs fail to document the existence

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Fig. 6.9 CT of proximal femora demonstrates a soft tissue mass which replaces the medullary bone in a patient with hepatocellular carcinoma

of a metastatic focus. For the radiological assessment of the spine CT appears to be more sensitive than conventional radiography in detecting metastatic lesions and it may also be more specific. Interestingly enough, in tubular bones of the appendicular skeleton, CT can detect subtle changes in the attenuation coefficient of the marrow, which may indicate tumor infiltration. The presence of tumor cells within the marrow causes an increase in attenuation due to fat replacement (Fig. 6.9). An attenuation difference of more than 20 Hounsfield Units between the two extremities has been reported to be abnormal [20]. It should be though noted that such findings are subtle and may be overlooked by the radiologists, since they are far less apparent than the marrow changes seen on MRI. A point that needs to be discussed is that in many oncologic centers patients are followed up by CT of the thorax, abdomen and pelvis. Consequently in parallel to the evaluation of the chest and thorax, by calculating the bone window the axial and appendicular skeleton are also assessed for the presence of bone metastases. Moreover, there are investigators that propose the omission of BS in the case that chest, abdomen and pelvis are routinely scanned by CT. Since the implementation of multi-detector computed tomography (MDCT) in routine radiological evaluations, multiplanar reconstructions allow a more rapid survey of the entire skeletal system, especially of the whole spine [12]. MDCT units are currently widely available, and are in general less expensive than MRI and PET evaluations. In respect to the assessment of patients with metastatic bone disease, MDCT does not only provide an excellent survey of the axial skeleton, but it also contributes to the evaluation of the stability of skeletal metastases (Fig. 6.10). In addition, data acquired with the MDCT technique enable sagittal and coronal two-dimensional reconstructions, as well as the calculation of three-dimensional images which are very useful for surgical planning. An example of the advanced technical characteristics of MDCT is that a 16-detector CT scanner can image from the vertex to the knee at sub-minute speeds with a z-axis spatial resolution of less

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Fig. 6.10 CT of the upper thoracic spine, sagittal reconstruction: There is bone destruction and a large soft tissue mass along the posterior elements of the T4 vertebra causing spinal cord compression in this 44 years old female with breast cancer

than 1 mm. The improvement in resolution and the resulting formation of isometric voxels allows high quality multi-planar reconstructions. The skeletal system may be hence assessed for the presence of metastatic disease by using high resolution MDCT images in parallel to routine staging or follow up [21]. A recent study involving metastatic breast cancer patients has shown a good correlation between BS and MDCT of the thorax, abdomen and pelvis for the detection of bone metastases [13]. MDCT was very accurate in determining weather patients had bone metastases or not. The authors of this paper suggested that according to their findings, routine BS of patients presenting with metastatic breast cancer is not required if a CT of the thorax abdomen and pelvis is performed. These results were similar to those of another study which recommended whole body MDCT (vertex to knee) in replacement of BS in patients investigated for bone metastases [21]. It has also been shown that MDCT reduces the duration of the examination time, (three times less than that necessary for performing standard radiography) and allows a complete diagnostic evaluation in a single examination without having to reposition the patients (a procedure that is necessary in conventional studies). CT scanning of the spine may be hence applied as an alternative to radiographic survey for patients with suspected metastatic bone lesions, especially for those who are in poor general condition [15]. Several image fusion techniques have evolved in recent years, providing an improved diagnostic accuracy that may also take into consideration metabolic tumor activity. Typical examples of such techniques are PET/CT or single photon emission computed tomography (SPECT), with CT providing the precise anatomic

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localization that is necessary for high diagnostic accuracy. As shown in the study by Utsunomiya and colleagues, fused SPECT/CT images increased the diagnostic confidence significantly as compared to separate sets of scintigraphic or CT images in differentiating malignant from benign bone lesions [22]. In a different study by Nakamoto et al. [23], CT images obtained as part of PET/CT scanning were useful in yielding the precise location of bone lesions and thus contributed significantly in avoiding misdiagnosis of metastatic bone disease. However, CT had revealed morphologic changes in only half of the lesions assigned as definitely or possible definitely positive for bone metastasis by using PET. Furthermore in another study PET/CT proved to have a very high positive predictive value (ppv) for bone metastases (98%) when the findings of PET and CT were concordant. On the contrary, in cases with discordant PET and CT findings, the ppv of the integrated imaging modalities was markedly diminished [24].

6.5 The Use of CT in Guiding Bone Interventions CT allows for high precision biopsies performed either in a minimally invasive manner or with a biopsy punch. CT guidance is essential in determining the safest and shortest route to the lesions and significantly improves precision, especially when dealing with small and deep seated lesions. The use of CT scanning for guidance has greatly increased the safety and applicability of needle biopsy for skeletal metastases. The increased ease and safety of access to lesions located in different anatomical regions has also opened up therapeutic possibilities, including ablative techniques for palliation and potentially cure. Radiofrequency (RF) ablation under CT guidance has been widely used in the last years for palliation of patients with bone metastases. Several studies have shown that RF ablation provides an effective and safe alternative method of pain palliation in patients with osteolytic lesions [22, 25, 26].

6.6 Radiologic Monitoring of Tumor Response to Treatment The healing response of a purely osteolytic lesion to chemotherapy or radiation therapy starts as a faint sclerotic rim in its periphery. Later on, continued healing is manifested as a progressively developing bone sclerosis starting from the lesion periphery toward its center. As the healing process goes on, it leads to the conversion of the osteolytic focus to one that is uniformly or predominantly osteosclerotic, and finally there is an eventual shrinkage and almost disappearance of the osteosclerotic area. In some cases the response to therapy is manifested as zones of sclerosis in regions of bone that was initially radiographically normal. On the other hand, signs of disease progression are an increase in the size of the osteolytic area, or the development of new zones of osteolysis. Mixed lesions show a different pattern of successful response to therapy, with a gradual conversion to a uniform sclerotic area. In such lesions signs of tumor

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progression include increasing osteolysis in sclerotic portions of the lesion and an increase in the overall size of the metastatic focus. Overall, a decrease in size or complete disappearance of an osteoblastic lesion is a favourable prognostic sign, whereas increasing size of the osteosclerotic lesion and the development of osseous destruction within a sclerotic area are signs of tumor progression [15]. Radiation therapy itself is also associated with a number of osseous alterations, such as osteopenia, coarsening of the trabecular pattern, insufficiency fractures, ischemic necrosis of bone and more rarely, secondary neoplasia. Inevitably, these changes may complicate the accurate radiographic appraisal of the metastatic process. Quantitative methods to evaluate bone response to treatment have been elusive. Bone density of metastatic lesions measured by CT can be used to evaluate the radiologic response to treatment. More specifically CT may be applied to evaluate the changes in attenuation values between pre and post treatment scans, thus giving an objective indicator of osseous response to treatment [27–29].

6.7 Computer-Aided Detection (CAD) of Bone Lesions Computer-Aided detection and diagnosis systems (CADe and CADx) aim to improve radiologic interpretation by providing “a second opinion” for the radiologist concerning lesion identification (CADe) and lesion characterization (CADx) [30, 31]. The concept of these schemes is based on the formulation of the clinical diagnostic problem into the context of quantitative image feature extraction and pattern classification for the automatic identification and characterization/quantification of disease signs. Computerized image analysis approaches have been proposed for the quantification of osteoporosis severity on radiographs and CT image data [32, 33] as well as for assessing osteoarthritis severity on radiographs [34]. Histogram analysis of digitized radiographs has also been employed for assessing the response of metastatic osteolytic disease to radiotherapy in conjunction with disodium pamidronate [35]. CT based CADe/x schemes have recently been developed for the quantification/characterization of metastatic bone disease and monitoring response to therapy. O’Connor et al. [36] evaluated a CADe system for the detection of lytic thoracolumbar spine lesions on CT image data. The system initially carries out a spinal segmentation, followed by identification of suspected metastatic regions by means of a watershed algorithm; subsequently, shape, density and location features are extracted from the suspected metastatic regions and fed into a support vector machine classifier to reduce false positive results (i.e., to distinguish between metastasis and non-metastasis regions). The reported CADe system achieved a sensitivity of 0.94, with a false-positive rate of 4.5 per patient, on a testing dataset of 21 patients. Whyne et al proposed a computerized CT based method for the volumetric characterization of spinal metastatic disease and for evaluating tumor response to treatment [37]. The method is based on the automatic segmentation of the trabecular centrum by means of an atlas-based deformable registration technique, combined with a level-set method, and on a histogram based analysis of the vertebral centrum

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intensity distributions of CT scans that quantified the extent and distribution of disease. Using a patient-specific healthy vertebra histogram as baseline, the method is capable of quantifying volumes of lytic and blastic lesions and to further assess disease severity and temporal progression. Image registration algorithms [38] that align anatomical structures in follow-up image data (by eliminating serial image differences due to patient position and exposure settings) can further improve the computerized assessment of disease progression and treatment outcome in skeletal metastases. Furthermore, texture analysis approaches that have successfully dealt with the assessment of osteoporosis [32,33] and osteoarthritis severity [34], have not been exploited for evaluating treatment response in metastatic bone disease. Image texture features such as grey level cooccurrence matrices based [39] that are capable of characterizing the trabecular bone microstructure, could be employed for the quantification of bone re-growth and resorption in metastatic lesions. An example of application of image texture analysis of a follow-up CT image data of an osteolytic metastasis managed with combined ibandronate and radiotherapy treatment is provided [28]. Figure 6.11 illustrates a pair of CT regions of interest (ROIs) depicting a lytic lesion in a lumbar vertebra before (a) and 3 months after treatment (b). Using a rigid registration algorithm [38], the pretreatment CT ROI was transformed [Fig. 6.11(c)] to match to the post-treatment CT ROI. Figure 6.12 depicts manually identified pre-treatment [Fig. 6.11(c)] and post-treatment [Fig. 6.11(b)] ROIs subjected to texture feature extraction. Five grey level co-occurrence matrices features were investigated: Angular Second Moment, Local Homogeneity, Contrast, Entropy and Difference Entropy (using a distance of one pixel and four orientations: 0◦ , 45◦ , 90◦ and 135◦ ) [39]. The first two features reflect image homogeneity, while the remaining three reflect image heterogeneity.

Fig. 6.11 CT ROIs depicting lytic-type metastatic disease in a lumbar vertebra before (a) and 3 months after treatment with combined radiotherapy and bisphosphonates (b). (c) Transformed pre-treatment CT ROI using a rigid registration algorithm

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Fig. 6.12 The treatment outcome is evident through the differences between pre-treatment (a) and post-treatment (b) texture feature values extracted from manually identified ROIs (solid black line)

The difference between pre- and post-treatment texture feature values illustrates the treatment effect. Specifically, the increased heterogeneity demonstrated in the post-treatment ROI reflects re-ossification of the metastatic area.

6.8 Summary Plain films have a supplementary role in the detection of metastatic bone disease and can be used to evaluate symptomatic skeletal sites or to confirm findings of BS. Both CT and MDCT play an important role in the routine follow up of oncologic patients, providing simultaneously an excellent survey of the axial skeleton for the presence of metastatic bone lesions. CT also provides significant information regarding the stability of the spine and serves as guidance in performing percutaneous biopsies and palliation therapies. Furthermore CT has been successfully applied for monitoring the radiologic response after radiotherapy or systemic treatments. Finally, CTbased CADe/x schemes have recently evolved for the quantification/characterization of metastatic bone disease and for monitoring response to treatment.

References 1. Cote RJ, Hawes D, Chaiwun B, et al. (1998) Detection of occult metastases in lung carcinomas: progress and implications for lung cancer staging. J Surg Oncol 69:265–274 2. Janni W, Gastroph S, Hepp F, et al. (2000) Prognostic significance of an increased number of micrometastatic tumor cells in the bone marrow of patients with first recurrence of breast carcinoma. Cancer 88:2252–2259 3. Yamashita K, Denno K, Ueda T, et al. (1993) Prognostic significance of bone metastases in patients with metastatic prostate cancer. Cancer 71:1297–1302

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4. Hamaoka T, Madewell JE, Podolof DA, et al. (2004) Bone imaging in metastatic breast cancer. J Clin Oncol 22:2942–2954 5. Jacobson AF and Fogelman I (1998) Bone scanning in clinical oncology: does it have a future? Eur J Nucl Med 25:1219–1223 6. Altehoefer C, Ghanem N, Hogerle S, et al. (2001) Comparative detectability of bone metastases and impact on therapy of magnetic resonance imaging and bone scintigraphy in patients with breast cancer. Eur J Radiol 40:16–23 7. Layer G, Steudel A, Schuller H, et al. (1999) MRI to detect bone marrow metastases in the initial staging of small cell lung carcinoma and breast carcinoma. Cancer 85:1004–1009 8. Lauenstein TC, Goehde SC, Herborn CU, et al. (2004) Whole-body MR imaging: evaluation of patients for metastases. Radiology 233:139–148 9. Haubold-Reuter BG, Duewell S, Schilcher BR, et al. (1993) Musculoskeletal radiology: fast spin echo MRI and bone scintigraphy in the detection of skeletal metastases. Eur Radiol 3:316–320 10. Neumann K, Hosten N, Venz S (1995) Screening for skeletal metastases of the spine and pelvis: gradient-echo opposed-phase MRI compared with bone scintigraphy. Eur Radiol 5:276–284 11. Yamaguchi T (2001) Intertrabecular vertebral metastases: metastases only detectable on MR imaging. Semin Musculoskelet Radiol 5:171–175 12. Antevil JL, Sise MJ, Sack DI, et al. (2006) Spiral computed tomography for the initial evaluation of spine trauma: a new standard of care? J Trauma; 61:382–387 13. Bristow AR, Agrawal A, Evans AJ, et al. (2008) Can computerised tomography replace bone scintigraphy in detecting bone metastases from breast cancer? A prospective study. Breast 17:100–105 14. Edelstyn GA, Gillespie PJ, and Grebbell FS (1967) The radiological demonstration of osseous metastases. Experimental observations. Clin Radiol 18:158–162 15. Resnik D and Kransdorf MJ (2005) Skeletal metastasis. In: Resnik D and Kransdorf MJ (eds.) Bone and Joint Imaging, 3rd edn. Elsevier Saunders, Philadelphia, Pensylvania, p. 1245 16. Raffi M, Firooznia H, Kramer E, et al. (1988) The role of computed tomography in evaluation of skeletal metastases. Clin. Imaging 12:19–24 17. Rybak LD and Rosenthal DI (2001) Radiological imaging for the diagnosis of bone metastases. Q J Nucl Med 45:53–64 18. Ghanem N, Uhl M, Brink I, et al. (2005) Diagnostic value of MRI in comparison to scintigraphy, PET, MS-CT and PET/CT for the detection of metastases of bone. Eur J Radiol 55:41–55 19. McKillop JH (1987) Bone scanning in clinical practice. Springer, Berlin 20. Helms CA, Cann CE, Brunelle FO, et al. (1981) Detection of bone marrow metastases using quantitative computed tomography. Radiology 40:745–750 21. Groves AM, Beadsmoore CJ, Cheow HK, et al. (2006) Can 16-detector multislice CT exclude skeletal lesions during tumour staging? Implications for the cancer patient. Eur Radiol 16:1066–1073 22. Utsunomiya D, Shiraishi S, Imuta M, et al. (2006) Added value of SPECT/CT fusion in assessing suspected bone metastasis: comparison with scintigraphy alone and nonfused scintigraphy and CT. Radiology 238:264–271 23. Nakamoto Y, Cohade C, Tatsumi M, et al. (2005) CT appearance of bone metastases detected with FDG PET as part of the same PET/CT examination. Radiology 237:627–634 24. Taira AV, Herfkens RJ, Gambhir SS, et al. (2007) Detection of bone metastases: assessment of integrated FDG PET/CT imaging. Radiology 243:204–211 25. Goetz MP, Callstrom MR, Charboneau JW, et al. (2004) Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol 22:300–306 26. Thanos L, Mylona S, Galani P, et al. (2008) Radiofrequency ablation of osseous metastases for the palliation of pain. Skeletal Radiol 37:189–194

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27. Vassiliou V, Kalogeropoulou C, Giannopoulou E, et al. (2007) A novel study investigating the therapeutic outcome of patients with lytic, mixed and sclerotic bone metastases treated with combined radiotherapy and ibandronate. Clin Exp Metastasis 24:169–178 28. Vassiliou V, Kalogeropoulou C, Christopoulos C, et al. (2007) Combination ibandronate and radiotherapy for the treatment of bone metastases: clinical evaluation and radiologic assessment. Int J Radiat Oncol Biol Phys 67:264–272 29. Quattrocchi CC, Santini D, Dell’aia P (2007) A prospective analysis of CT density measurements of bone metastases after treatment with zoledronic acid. Skeletal Radiol 36:1121–1127 30. Summers RM (2003) Road maps for advancement of radiologic computer-aided detection in the 21st century. Radiology 229:11–13 31. Costaridou L (ed.) (2005) Medical Image Analysis Methods. Taylor & Francis Group LCC, Boca Raton, FL 32. Genant HK, Engelke K, and Prevrhal S (2008) Advanced CT bone imaging in osteoporosis. Rheumatology (Oxford) 47:9–16 33. Lespessailles E, Chappard C, Bonnet N, et al. (2006) Imaging techniques for evaluating bone microarchitecture. Joint Bone Spine 73:254–261 34. Boniatis I, Costaridou L, Cavouras D, et al. (2006) Quantitative assessment of hip osteoarthritis based on image texture analysis. Br J Radiol 79:232–238 35. Kouloulias V, Matsopoulos G, Kouvaris J, et al. (2003) Radiotherapy in conjunction with intravenous infusion of 180 mg of disodium pamidronate in management of osteolytic metastases from breast cancer: clinical evaluation, biochemical markers, quality of life, and monitoring of re-calcification using assessments of gray-level histogram in plain radiographs. Int J Radiat Oncol Biol Phys 57:143–157 36. O’Connor SD, Yao J, and Summers RM (2007) Lytic metastases in thoracolumbar spine: computer-aided detection at CT-preliminary study. Radiology 242:811–816 37. Whyne C, Hardisty M, Wu F, et al. (2007) Quantitative characterization of metastatic disease in the spine. Part II. Histogram-based analyses. Med Phys 34:3279–3285 38. Pluim JP, Maintz JB, and Viergever MA (2003) Mutual-information-based registration of medical images: a survey. IEEE Trans Med Imaging 22:986–1004 39. Haralick RM, Shanmugam K, and Dinstein I (1973) Textural features for image classification. IEEE Trans Syst Man Cybern SMC-3:610–621

Chapter 7

THE CONTRIBUTION OF NUCLEAR MEDICINE IN THE DIAGNOSIS OF BONE METASTASES Andor W.J.M. Glaudemans1 , Marnix G.E.H. Lam2 , Niels C. Veltman1 , Rudi A.J.O. Dierckx1 and Alberto Signore3 1 Nuclear Medicine, S. Andrea Hospital, 2nd Faculty of Medicine, University of Rome “Sapienza”, Via di Grottarossa 1035, 00189 Rome, Italy Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, GZ, The Netherland, e-mail: [email protected] 2 Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, CX, The Netherlands, e-mail: [email protected] 3 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, GZ, The Netherlands; Medicina Nucleare, 2nd Faculty of Medicine. “Sapienza” University, Rome, Italy, e-mail: [email protected]

Abstract:

Nuclear medicine plays a relevant role in the diagnosis and therapy of bone metastases. Imaging of the bone has been one of the first nuclear medicine techniques applied in humans and still is one of the major requests from physicians. Indeed the sensitivity of this technique is such (>90%) that it is superior to any other available imaging method. On the other hand the specificity is rather low and interpretation of scans needs to be carefully evaluated by expert physicians together with other biological, anatomical and clinical information. In this chapter we will briefly start by describing bone physiology and pathophysiology as these are basic aspects for nuclear medicine imaging of bone metastases and their therapy with radiopharmaceuticals. This is followed by a short overview of epidemiology and distribution of bone metastases. The basics of nuclear medicine imaging and the different cameras and techniques will be explained. We will then review all available radiopharmaceuticals for diagnostics with particular regard to metastases from prostate, breast and lung cancer. The last paragraph presents the use of radiopharmaceuticals for the palliation of metastatic bone disease.

D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 7,  C Springer Science+Business Media B.V. 2009

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Key words: Nuclear medicine · Bone metastases · Diagnostics · Therapy · Radionuclides

7.1 Introduction Nuclear medicine plays an important role in the diagnosis of bone metastases, with bone imaging being one of its first applications in humans. The sensitivity of nuclear medicine techniques is remarkably high, exceeding 90%. On the other hand the specificity is rather low and interpretation of scans needs to be carefully evaluated by expert physicians in combination with other biological, anatomical and clinical information or other imaging modalities. In this chapter we will start by briefly discussing bone anatomy and physiology and pathophysiology and epidemiology of metastatic bone disease. We will then review all available radiopharmaceuticals used for diagnostic and therapeutic purposes, giving emphasis to bone metastases from prostate, breast and lung cancer.

7.2 Anatomy and Physiology of Bone and Pathophysiology and Epidemiology of Bone Metastases 7.2.1 Anatomy of Bone A typical long bone consists of the following parts: the diaphysis (the shaft of the bone), the epiphysis (the bone located from the growth plate to the articular surface), the metaphysis (the region where the diaphysis joins the epiphysis), the articular cartilage, the periosteum (fibrous covering around the surface of bone), the medullary cavity and the endosteum (a layer of progenitor cells and osteoblasts that lines the medullar cavity and also contains scattered osteoclasts). Bone is an organ consisting mainly of minerals (roughly 65%) and organic matrix (35%), being the storehouse for the body’s calcium, phosphorus, sodium, magnesium and calcium. Mineralised bone is called osteoid. The organic part of matrix is mainly composed of type I collagen (90–95%), and also contains various growth factors (like cytokines and growth factors) that play a role in modulating the bone turnover. The bone-forming cells include the osteoprogenitor cells, osteoblasts and osteocytes, whereas the bone-re-absorbing cells are the osteoclasts.

7.2.2 Bone Physiology and Remodelling In normal healthy bone, continuous remodelling takes place in response to mechanical stress via dynamic interactions of osteoclasts and osteoblasts. Osteoclasts are responsible for bone resorption and osteoblasts for bone formation. The mineralized bone matrix contains numerous growth factors that are released during this process, stimulating osteoblasts to form new bone. Systemic factors, such as the parathyroid hormone, and local factors such as cytokines, promote osteoclastic activity.

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7.2.3 Pathophysiology of Bone Metastases Tumour cells colonise bone by a multi-step process and grow avidly because of the very favourable microenvironment. Numerous factors are involved in the different steps of the development of metastases. Before spreading, tumour growth at the primary is influenced by growth factors, tyrosine kinase signalling pathways, loss of tumour suppressor gene expression and angiogenetic factors. Spread of tumour cells from the primary site begins with the cellular detachment from primary neoplasm, a process that is influenced by down-regulation of cell adhesion molecules (CAM) and production of serine-proteinases, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). MMP and TIMP are also involved in angiogenesis. It has been recently suggested that chemokines and chemokine receptors expression in tumor cells and peripheral tissues play an important role in tumor cell spreading and metastasis [1]. Once tumor cells reach the circulation, cell adhesion molecules such as integrins and chemokines enable them to attach themselves to the endothelial cells at the metastatic site. The disruption of the basement membrane by photolytic enzymes (type IV collagenases) is followed by tumour cell migration across the basement membrane by a process of chemotactic migration and an increased random movement by chemokinesis [2]. The bone matrix is rich in growth factors and this fertile microenvironment promotes the growth of tumour cells that have migrated to bone. Once tumour cells have colonized the bone matrix, they secrete soluble mediators that stimulate the activity of osteoclasts and/or osteoblasts and disrupt normal bone remodelling. The activation of osteoclasts and bone re-absorption causes further release of bone-derived growth factors and prostaglandins that enhance survival and proliferation of the tumour cells. The normal homeostasis of bone is consequently totally disrupted and excess bone re-absorption follows. Tumour cells can induce either an osteolytic or an osteoblastic or a mixed type response. Osteolytic bone lesions are characterised by an abnormally high rate of bone destruction/resorption as a result of increased osteoclastic activity. On the contrary, osteoblastic or osteosclerotic bone lesions are characterised by an increased bone formation around tumour-cell deposits. Pure osteolytic and pure osteoblastic bone lesions are two extreme situations. In most patients, bone metastases have a mixed appearance with both osteolytic and osteoblastic elements, one of the two being more dominant.

7.2.4 Epidemiology and Distribution of Bone Metastases The skeleton is the commonest organ to be affected by metastatic cancer. Tumours arising from the prostate, breast, lung, kidney, bladder and thyroid have a marked preference to spread to bone. Other cancer types that show osteotropism are multiple myeloma and melanoma. The prevalence of skeletal involvement is greatest in multiple myeloma, breast and prostate carcinoma (see Table 7.1). The latter two cancers account for about 80% of bone metastases and cause the greatest morbidity [3]. Tumour cells commonly metastasise to highly vascularised parts of the skeleton,

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Table 7.1 Incidence of metastatic skeletal lesions among different tumors and survival after the development of metastatic bone disease Cancer type

Frequency of skeletal lesions (%)

Median survival (Months)

5-year survival (%)

Multiple myeloma Renal cell cancer Melanoma Bladder cancer Thyroid cancer Lung cancer Breast cancer Prostate cancer

70–95 20–25 14–45 40 60 30–40 65–75 65–75

20 6 <6 ∼12 48 <6 24 40

10 10 <5 – 40 <5 20 25

which are the skull, vertebral column, the upper and lower limbs (humerus and femur), the pelvic bones and to a lesser extent the ribs. As presented in Table 7.1 the survival of patients after the development of bone metastases varies considerably among the different tumor types.

7.3 Basics of Nuclear Medicine Imaging: Radiopharmaceuticals, Isotopes, Cameras, Techniques and Precautions 7.3.1 Radiopharmaceuticals and Isotopes A radiopharmaceutical is a synthesized compound formed by a radioactive isotope and a drug. The signal is provided by the isotope that must not detach from the drug and the biodistribution and targeting characteristics are determined by the drug that must not be altered by the presence of the isotope. The drug is commonly known as a tracer. For example, the ligand hydroxymethylene-diphosphonate (HDP) is preferentially taken up by bone. Consequently, by chemically attaching 99m Tc to HDP, the radioactive isotope is transported to bone for imaging. An isotope is an atom with an unstable nucleus, which undergoes a radioactive decay, emitting gamma rays which can be imaged on a gamma camera. Isotopes that emit beta rays can be used for therapy. For example 99m Technetium (99m Tc) that is a commonly used bone scan isotope emits gamma rays. On the other hand, 153 Samarium is both a gamma- and a beta-emitter and can be used for therapy.

7.3.2 Camera’s The camera’s that are being used in Nuclear Medicine to visualize the radiopharmaceuticals are the gamma-camera (Fig. 7.1) and the Positron Emission Tomography (PET) scan camera (Fig. 7.2). A decaying isotope sends photons in all directions. Different isotopes produce different characteristic photons of a specific energy.

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Fig. 7.1 Gamma-camera with two heads

Technetium for instance predominantly sends photons of 140 keV energy, whereas I-131 sends predominantly 364 keV energy photons. A gamma-camera consists of one, two, or three heads with a detector which registers the impact of these photons.

Fig. 7.2 PET/CT camera with the gantry of the CT at the front and the gantry of the PET at the back (Siemens Medical, BiographTM True Point PET-CT)

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The gamma-camera also consists of a collimator, which is made up of parallel strips of lead axially positioned in respect to the detector surface and is located directly in front of the detector. The collimator filters tangentially the incoming photons. By this arrangement only photons that are originating directly below the detector will cause impacts that would be registered. With a gamma-camera it is also possible to acquire images from different angles (64◦ –128◦ ) in a circular manner around a patient and subsequently reconstruct a 3D-image. This is called ‘Single Photon Emission Tomography’ (SPET). The resolution of a modern gamma-camera is in ideal circumstances 8 mm. The same resolution can be expected from a SPET image. The PET-camera registers only photons that originate from a specific process called ‘annihilation’. From the nucleus of the used isotope a positively charged particle with the same weight as an electron is ejected. Thus its nucleus losses some energy and gets a smaller proton/neutron ratio, rendering it more stable. This positron will react with an electron from a nearby electron-cloud (proximity in the order of 1–2 mm). This reaction is called annihilation and the masses of the positron and electron are transformed into energy (E = mc2 ), forming two photons that eject in exactly opposite directions. The energy of each photon is exactly 511 keV. This phenomenon is registered by a PET-camera by using a ring detector around a patient and registering only coincidental impacts in opposite parts of the ring detector. The resolution of a modern PET-camera is in ideal circumstances 2 mm.

7.3.3 Techniques Bone scintigraphy images the distribution of a radioactive isotope in the skeletal system and can be performed as: a. limited bone scintigraphy or spot views (planar images of a preselected portion of the skeleton); b. whole-body bone scintigraphy (planar images of the entire skeleton in both anterior and posterior views); c. Single photon emmision tomography (SPET) d. multiphase bone scintigraphy (immediate and delayed images are aquired in order to study blood flow). In oncology the standard technique of bone scintigraphy is whole-body scanning. SPET is a nuclear medicine procedure in which a gamma camera rotates around the patient and takes pictures from many angles. A computer then uses all acquired planar images to form tomographic (cross-sectional) images. The Positron Emission Tomography is a nuclear medicine procedure in which a positron-emitter is used for imaging. The PET camera rotates around the patient and a computer forms tomographic images.

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7.3.4 Basic Precautions The use of radioactive materials means that not only the patient or tumour endures radiation, but also healthy organs and tissues. Furthermore, nearby persons should be protected from the radiation exposure. To put this in perspective, the annual radiation burden from background radiation by natural radiation sources of the general public in the Netherlands is 1.7 mSv. The radiation burden of a bone-scan by using 500 MBq radiopharmaceutical is 2.3 mSv. For an 18 F-FDG PET-scan involving a radiopharmaceutical of 400 MBq the radiation burden is 7.6 mSv. However, in contrary to the natural background radiation that is continuously present in our environment, the activity rate from diagnostically injected amount of a radiopharmaceutical decreases exponentially over time. It should be noted that the radiation burden for nearby people is calculated at 1 m distance and overall exposure is marginal as compared to the natural background radiation. Another consideration when referring to the radiation exposure is the age of a person. The added risk/mSv decreases with age. Consequently young children are most susceptible to DNA-damage due to irradiation exposure.

7.4 Bone Metastases from the Nuclear Medicine Point of View Several diagnostic modalities are available for the detection of metastatic bone lesions. These include plain X-rays, CT scan and MRI scan. All of these diagnostic modalities are based on the anatomical characteristics of bone metastases and do not provide any information concerning the physiology or metabolic activity of evaluated lesions. Therefore, nuclear imaging modalities can be valuable in the differential diagnosis between bone metastases and other bone lesions/pathology. By applying specific nuclear radiopharmaceuticals, different biophysical and biochemical characteristics of bone metastases are depicted, helping physicians to establish an accurate diagnosis. In the following subchapters the characteristics of different radiopharmaceuticals are described and their role in detecting bone metastases is commented upon.

7.4.1 Bone Specific SPET Radiopharmaceuticals: The 99m Tc-phosphate Derivates The most commonly used radiopharmaceutical for the detection of bone metastases is 99m Tc labelled with phosphates. Different forms exist, such as 99m TcHydroxymethylenediphosphonate (99m Tc-HDP) and 99m Tc-Methyldiphosphate (99m Tc-MDP) with slightly different kinetic qualities, with both being incorporated into bone (hydroxyapatite deposition) by the activity of osteoblasts. The two main factors that control accumulation of phosphonates in bone are the blood flow and the extraction efficiency, which in turn depend on capillary permeability, acid-base

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balance, parathyroid hormone levels, etc. Overall about 50% of the activity injected accumulates in the skeletal system. The maximum bone accumulation takes place 1 h after injection and remains practically constant for up to 72 h. The sensitivity of bone scans is determined by the level of the osteoblastic activity. This means that in the case of osteoblastic metastases a bone scan will reveal highly intense hot spots. However, in the case of osteolytic metastases normal bone tissue surrounding metastatic lesions will normally respond with compensatory osteoblastic activity, which will also leads to highly intense radionuclide uptake. Only in the case of slowly growing osteolytic metastases there can be absence of an osteoblastic reaction that would render the metastases undetectable through bone scanning. This is typically observed in patients with multiple myeloma or patients with large osteolytic lesions that are depicted as ‘cold spots’ i.e., focal absence of activity on the bone scan. A problem with the interpretation of bone scans is their low specificity. This means that it can be difficult to distinguish bone metastases from degenerative changes, inflammatory processes, trauma, mechanical stress, Paget’s disease, fibrous dysplasia or primary benign or malignant bone tumours [4]. Even-Sapir et al. reported that for the detection of bone metastases in patients with high-risk prostate cancer (Gleason score ≥ 8 or PSA ≥ 20 ng/mL or non-specific sclerotic lesions on CT) bone scintigraphy had a sensitivity of 70%, a specificity of 57% and a positive and negative predictive value of 64% and 55% respectively. By using SPET,

Fig. 7.3 Images of a superscan indicative of extensive metastatic disease. Notice the absence of activity in kidneys and bladder. Typical heterogeneously distributed activity over the vertebrae

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the sensitivity was improved to 92%, the specificity to 82%, and the positive and negative predictive values reached 86% and 90% respectively [5]. Langsteger and co-workers reported similar results in three other published studies [4]. Figure 7.3 presents bone scan images of a patient with extensive, widespread metastatic bone disease.

7.4.2 Non-specific Bone SPET Radiopharmaceuticals These radiopharmaceuticals are unspecific for bone metastases. They are specific for certain tumor types, depicting also metastatic bone disease if present. Because of their non-specificity to bone, it can be difficult to distinguish metastatic bone lesions from localization in surrounding soft-tissues. For all three radiopharmaceuticals discussed in this section this can be an important diagnostic problem, especially for iodine. To enable high specificity in localization, it can be helpful to acquire SPET images, i.e., 3D representation of the area suspected for bone metastases and perform image fusion with CT or MRI images. Pitfalls of using this approach are the misalignment due to the different positioning of the patient during the different studies and movement artefacts resulting for example during breathing movements. This problem may be overcome by using an integrated SPET-CT if available. This improves significantly the reliability of the fusion technique through correct patient positioning and controlling breathing movement by specific instructions or respiratory gated acquisition. 7.4.2.1 123

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I or 131 I accumulates in the thyroid where it is built into thyroid hormone and stored for later secretion. Because of this characteristic it can be used for identification of well-differentiated thyroid tumours and their metastases (see Fig. 7.7). Theoretically a high treatment dose provides a better sensitivity as compared to the low diagnostic dose of 123 I or 131 I, but several researchers found no difference between the diagnostic accuracy of 123 I pre-treatment scanning and 131 I post-treatment scanning [6, 7]. In the Netherlands according to the national guidelines, 123 I or 131 I scanning are no longer part of the initial diagnostic work-up for thyroid cancer or nodule investigation, with FNA being the standard diagnostic procedure. Similarly, the follow up of recurrent disease is done by following thyroglobulin levels instead of 123 I scanning. Nevertheless according to guidelines, after treatment with 131 I, a post-treatment scan is carried out (Fig. 7.4). Even though these radiopharmaceuticals are highly specific for thyroid tumours, scintigraphy is associated with a poor signal to noise ratio. Upon injection there is some physiological accumulation in some organs such as saliva glands, liver, spleen, intestines, kidneys and bladder, but there is little to none accumulation in structural tissue which makes it often difficult to identify the exact localization of metastases. The use of SPET-CT can be very helpful in establishing metastatic bone disease in patients with thyroid tumours.

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Fig. 7.4 Post-therapy 131 I scan with multiple metastases involving also the skull and humeri

7.4.2.2

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I and 131 I-MIBG

Metaiodobenzylguanidine (MIBG) is a noradrenalin analogue which accumulates in neurosecretory granules of adrenergic tissue. This makes it suitable for imaging apudomas, such as pheochromocytomas and paragangliomas. In children it is used for the diagnosis of neuroblastoma. The advantage of 123/131 I-MIBG is its high specificity for tissue characterisation [8]. As in the previously described radiopharmaceutical there is no accumulation in structural tissue, rendering the exact local¨ ization of metastases difficult. Ozer et al. reported on the improved diagnostic value resulting from fusion of 131 I-MIBG with a morphological imaging modality (SPETCT). The main advantage was the identification of normal distribution of 123 I-MIBG in organs such as the intestines and renal system (23 out of 31 patients), bringing about a reduction in false positive test results. Concerning the differentiation of bone metastases from a local recurrence of a phaeochromocytoma, this was possible in two patients [8]. 123/131 I-MIBG is sometimes used as an imaging modality for the identification/localization of carcinoid tumors of which bone metastases are mainly associated with bronchial primaries. However Zuetenhorst et al. found that in the direct comparison between 123/131 I-MIBG and bone scan, the latter outperformed in the detection of carcinoid tumour metastases. More specifically, in 9 patients with proven bone metastases the bone scan identified multiple bone lesions in all 9 patients, whereas 123/131 I-MIBG identified bone metastases in only 2 out of 9 [9]. Figure 7.5 presents a 131 I-MIBG scan of a patient with metastatic pheochromocytoma. 7.4.2.3

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In-Octreotide

As compared to normal tissue somatostatin subtype receptors are expressed at a higher level in neuroendocrine tumours. This characteristic is used to image neuroendocrine tumours by using radionuclide labelled octreotide derivates such as

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Fig. 7.5 131 I-MIBG scan with multiple metastases including bones in a patient with pheochromocytoma 111

In-Pentetreotide. As in the case of 123/131 I-MIBG and 123 I/131 I, 111 In-Pentetreotide lacks accumulation in structural tissue, making it difficult to identify bone metastases. In a study involving patients with neuroendocrine tumors, Hillel et al. reported that functional anatomic mapping by using SPET/CT (using 111 In-Pentetreotide) established a previously unknown tumor location in 7/11 of patients or change in the tumor location in 4/11 of patients [10]. However, as with 123/131 I-MIBG, 111 In-Pentetreotide failed to detect a large proportion (50%) of metastatic bone lesions that were detected by bone scintigraphy [9]. The added value of using 111 InPentetreotide was the identification of liver and lymphatic metastases.

7.4.3 PET Radiopharmaceuticals An advantage of PET over scintigraphy is the possibility of quantification (both in absolute numbers and semi-quantitatively), which enables an improved sensitivity of the follow-up of metastatic lesions. Consequently, PET imaging allows the possibility to monitor not only the number and size of pathologic lesions, but also the uptake intensity per lesion. In PET imaging the uptake intensity is quantified by using the ‘Standard Uptake Value’ (SUV). It represents the tissue activity within a region of interest corrected for the injected activity and for patient weight or lean body mass. This quality makes PET imaging useful for monitoring response to treatment and/or disease progression [4]. 7.4.3.1 Bone Specific PET Radiopharmaceuticals 18 18

F-fluoride

F-fluoride is a positron emitter-non-specific bone radiopharmaceutical since it images any form of calcification (also outside bone). The radiopharmaceutical itself

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was used since 1962, but was replaced by 99m Tc labelled diphosphonate after the introduction of the gamma cameras. Since the introduction of high resolution PET-cameras, 18 F-fluoride is reintroduced into nuclear medicine imaging. Indeed 18 F-fluoride provides a much higher resolution imaging than the traditional bone scan and achieves this independently from the acquisition time per bed position. Fluoride ions enter the extra cellular fluid of bone by diffusion through capillaries, leading to a slow exchange with hydroxyapatite crystals and the formation of fluoroapatite [4]. In a study by Even-Sapir et al. that was also mentioned before, 18 F-fluoride PET was reported to achieve a sensitivity of 100%, a specificity of 62%, a positive predictive value of 74% and a negative predictive value of 100%. By applying 18 F-fluoride PET/CT all aforementioned parameters were improved to 100% (Fig. 7.6) [5]. Interestingly, due to the worth noticing results shown before, researchers such as Langsteger et al. believe that 18 F-fluoride PET/CT will

Fig. 7.6 18 F-fluoride PET. Coronal and sagittal view of a patient with skeletal metastases from prostate carcinoma

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soon replace bone scanning, becoming the standard modality for bone imaging [4]. However, preliminary results of studies carried out in the Netherlands (not published yet) seem to be less convincing about this belief. 7.4.3.2

18

F-FDG

This radiopharmaceutical is useful for imaging processes with high glucose turnover, because of its intracellular accumulation. FDG is a glucose analogue that enters cells by using several glucose transporters (mainly the GLUT-1 and GLUT-3) that are located on cellular membranes. After phosphorylation glucose-6-phosphate is formed that is further metabolised by glycolysis. However FDG cannot be glycosylated and is phosphorylated by hexokinase to FDG-6-phosphate, which is retained in the cell. It is known that malignant cells have an increased glucose turnover, which is related to a higher density of GLUT-1 and GLUT-3 receptors on the cell membrane and to a higher concentration of hexokinase. This accounts for the favourable signal-to-noise ratio which has rendered 18 F-FDG a popular radiopharmaceutical for malignancies. The high glucose metabolism is related to growth, which makes 18 F-FDG especially useful for the more aggressive, fast growing, less differentiated tumour types, such as lung cancer, melanoma, lymphoma, breast cancer, sarcomas, etc. Less FDG-avid tumours are in the category of the slow growing, well-differentiated tumours, such as prostate carcinoma, carcinoid tumours, well-differentiated thyroid cancer and low-grade astrocytomas. However, every form of these well-differentiated tumours can turn into FDG-avid tumours once they dedifferentiate. The major advantage of 18 F-FDG PET over bone scan is the higher resolution and the improved sensitivity (Figs. 7.7 and 7.8). As with bone scans specificity is the limiting factor in its

Fig. 7.7 18 F-FDG scan in a patient with melanoma and diffuse bone metastases. Notice the extreme high intensity of the metastases as compared for instance with the physiologic high uptake in brain

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Fig. 7.8 18 F-FDG scan in a patient with dedifferentiated medullary thyroid carcinoma. Bone metastases are depicted in Th3-Th5, Th10, L4 and right femur

accuracy since different benign processes can have a high glucose metabolism as well. Such processes may include infections, abrasion with prosthesis, loosening of prosthesis or giant cell tumours. The advantages of 18 F-FDG PET over bone scintigraphy is that it provides information on soft-tissue metastases. Secondly by the use of SUV-values a higher specificity for the differential diagnosis between malignant and benign disease is achieved [4]. In a study by Shie et al. involving patients with metastatic breast cancer, both bone scintigraphy and 18 FDG-PET were applied for the detection of bone metastases. Through this study it was shown that by using 18 FDG-PET the patient-based sensitivity was 81% (lesion-based sensitivity was 69%) and the specificity was 93% (lesion-based specificity was 98%). The application of bone scintigraphy resulted in a patient-based sensitivity of 78% (lesion-based sensitivity was 88%) and in a specificity of 79% (lesion-based specificity was 87%). It was concluded that there was no clear benefit of imaging bone metastases with either modality, with 18 FDGPET providing a better specificity that would probably enable it to be used as a confirmatory imaging modality. Further more it was reported that 18 FDG-PET could be used to monitor response to therapy [11].

7.4.3.3

18

F-FLT

The nucleoside analogue 3-deoxy-3-[18F]-fluorothymidine (FLT) can be used for the imaging of tumour cell proliferation. The uptake of FLT is relying on the thymidine kinase 1 (TK1) enzymatic activity and thus on DNA synthesis. In direct comparison with 18 F-FDG, it was shown to have a reduced tumour uptake and because

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of the physiological high uptake in bone marrow and liver, its success in identifying metastases in these regions was limited. For identifying brain metastasis it could possibly be a better alternative than 18 F-FDG, because of the low physiologic uptake in the brain. The gold standard for brain metastasis however is 11 C-methionine (mentioned later on). For imaging bone metastases FLT is outperformed by 18 FFDG PET [12].

7.4.3.4

11

C-Choline

11

C-Choline is used in the imaging of nodal metastases from prostate cancer as well as metastatic bone disease. It was found that in malignancies there is a high intracellular trapping of phosphatidylcholine (PC) together with an up regulation of choline kinase, an enzyme that is responsible for the synthesis of PC. Consequently, by labelling choline with 11 C, it enables imaging of PC trapped in malignant cells. One of the main reasons for its superiority over 18 F-FDG in imaging prostate cancer is the low urinary clearance and therefore its low concentration in the bladder. It should be noted that the use of 18 F-FDG is associated with a higher urinary clearance and a high bladder activity that obscure the imaging of prostate; secondly there is often a low FDG uptake in prostate cancer. However, imaging with 11 C-Choline involves problems of specificity, since benign prostatic hypertrophy also gives a high choline activity. Moreover, it was reported that by using SUV values the discrimination between benign and malignant lesions is not possible. For patients with biochemical recurrences after initial treatment of the primary tumour, 11 C-Choline identifies more abnormalities that are suspicious for recurrent disease than 18 F-FDG (47% versus 27%) [13] (see Fig. 7.9).

Fig. 7.9 PET scan with 11 C-Choline (transaxial and coronal views of the pelvic region and upperlegs) in a patient with metastatic prostate cancer. Notice the bone metastasis in the right proximal femur. Bone marrow activity, as seen in the left femur and os ilium, is physiologic

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Fig. 7.10 11 C-Methionine scan showing a small bone metastasis in Th10

7.4.3.5

11

C-Methionine

11

C-Methionine has a place in prostate cancer metastases imaging. It reflects increased amino acid transportation and partially protein synthesis, as well as cellular proliferation activity. It therefore depicts viable tumour tissue. It is mainly used for imaging brain metastases, since its role in prostate cancer is less clear. In a study involving only a small group of patients it was reported that both sensitivity and specificity for imaging metastases from prostate cancer was 70% (both higher than 18 F-FDG) [13] (Fig. 7.10).

7.4.3.6 18

18

F-DOPA

F-DOPA is a radiopharmaceutical that is mainly used for the imaging of neuroendocrine tumours such as carcinoid disease. Dihydroxyphenylalanine is a precursor of the neurotransmitter dopamine. Neuroendocrine tumours are capable of taking up amino acids. Premedication with the decarboxylase inhibitor carbidopa is used to reduce the urinary extraction, that results in lower renal and bladder activity and a higher availability of DOPA for the neuroendocrine tumour cells. With the application of 18 F-DOPA all metastatic lesions, including bone lesions, are imaged with a sensitivity ranging between 65% and 100% and a specificity of 75–100% [14]. In cases of dedifferentiation of the tumour and its metastases the intensity of the lesions by using 18 F-DOPA may decrease, whereas the intensity increases when 18 F-FDG PET is applied (see Fig. 7.11).

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Fig. 7.11 18 F-DOPA scan showing bone metastases in Th4 and Th7. The hot-spot in the brain is physiological striatal activity

7.5 Typical Nuclear Medicine Imaging Characteristics of Bone Metastases from Prostate, Breast and Lung Primaries 7.5.1 Prostate Cancer Prostatic cancer cells metastasize mainly through the haematogenous route, and despite dissemination to multiple organs, growth preferentially occurs in the bone and particularly in the red marrow of the axial skeleton. The vertebral column is the commonest site for prostate tumour cells deposition. Other common sites of metastatic disease is the pelvis, ribs and to a lesser extent the skull and extremities. Prostatic cancer cells release prostate specific antigen (PSA), a serine protease that cleaves the parathyroid hormone-related peptide that is responsible for tumourinduced bone resorption. PSA may also activate osteoblastic growth factor release in the bone microenvironment during the process of bone metastases formation. Increased bone turnover is also caused by bone-derived factors such as bone morphogenetic proteins (BMPs). Moreover there is a focal imbalance between osteoblastic and osteoclastic activity. All this may lead to a vicious cycle which results in the development of osteoblastic metastases. The vicious cycle may be described as follows: prostate cancer cells invade the bone matrix, signalling between these cells and osteoblastic cells causes the release of BMPs that trigger new bone formation. This allows further release of growth factors that bring about new bone formation and more osteosclerosis and so on [15].

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For nearly 30 years bone scintigraphy with 99m Tc labelled MDP or HDP has been the ‘reference standard’ for detecting skeletal metastases. It is readily available at a low cost. Although bone scintigraphy has a high sensitivity for skeletal metastases, it is not specific. A ‘hot spot’ may also reflect trauma, infection, inflammation and so on. This can create diagnostic uncertainties that may necessitate further radiological investigation [15]. There are certain indications for the use of bone scintigraphy in patients with prostatic cancer. More specifically, routine use of a bone scan is omitted when the serum PSA level is <10 ng/mL and may also not be necessary for those with PSA levels between 10 and 20 ng/mL, when they have T1 disease and Gleason scores of 6 or lower [16]. Almost all patients with a PSA > 100 ng/mL have a widespread skeletal involvement. Similarly, bone scintigraphy should be performed when ALP levels are >90 U/L [17]. Therefore, bone scintigraphy should be carried out in patients with high-risk cancer, elevated serum ALP levels, bone pain, or equivocal bone lesions on other imaging modalities. Serial scans are often used to assess the extent of bony involvement and the effectiveness of therapy. Another modality that can detect bone metastases is of course the PET-scan, which has a higher resolution than the bone scintigraphy. Additionally, fused with a CT-scan it provides a better anatomical localisation. The most commonly used PET-radiopharmaceutical, 18 F-FDG, has been challenging in the imaging of prostate cancer. The glucose utilization in well-differentiated prostate cancer is often lower than in other tumour types. Moreover, the uptake in the primary tumour is difficult to be visualized, also due to its proximity to the bladder that shows intense physiological accumulation of FDG. The slow rates of prostatic tumour growth are associated with low rates of glycolysis and therefore a low tumour uptake, which is also evident in metastatic bone disease [18]. 18 F-FDG PET was shown to be less specific than planar bone scintigraphy in prostatic bone metastases. Prostate cancer is now established as the “classic” cancer with false-negative results on FDG-PET [19]. Other PET radiopharmaceuticals used for the assessment of patients with bone metastases from prostate cancer are 11 C- or 18 F-labelled fluorocholine and 18 Ffluoride. The latter was reported to be highly sensitive in detecting bone metastases [20, 21]. Increased 18 F-fluoride uptake in malignant bone lesions reflects the increase in regional blood flow and bone turnover characterizing these lesions. 18 F-fluoride PET has been shown to be more sensitive and specific than the bone scanning in detecting bone metastases [5]. Increased cell proliferation in tumours and up regulation of choline kinase in cancer cells are suggested as two possible mechanisms for increased choline uptake in prostatic cancer cells. 18 F-fluorocholine PET may be superior for early detection of metastatic bone disease (i.e., bone marrow involvement) [4]. This statement should be though corroborated by other studies. In patients with negative suspicious sclerotic lesions (after 18 F-fluorocholine PET), a second bone-seeking agent such as 18 F-fluoride is recommended [22].

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7.5.2 Breast Cancer Bone is the commonest of metastases in patients with breast cancer, representing the first site of metastasis in 26% to 50% of patients [23]. Similarly, 30% to 85% of patients with metastatic breast cancer will develop bone metastases during the course of the disease [24]. In most cases of metastatic bone lesions from breast cancer, both osteolytic and osteoblastic activity is evident. Interestingly, up to half of the bone metastases from breast cancer are lytic in type [25]. Breast cancer preferentially metastasizes to vertebrae and the pelvis, followed by ribs, skull and femur [26]. The detection rate of metastatic bone disease by using bone scintigraphy is 0.82% in patients with stage I disease, 2.55% for those with stage II disease, 16.75% for stage III, and 40.52% for stage IV breast cancer [27, 28]. On the basis of these results routine screening with a bone scintigraphy in early stage breast cancer (stage I or II) is not recommended. The assessment of the response of bone metastases to therapy by solely following the changes in the intensity of bone scans is also not recommended [29]. For this purpose other imaging modalities, like CT or MRI, may be applied. As noted earlier, in a recent meta-analysis the value of bone scintigraphy and FDG-PET was evaluated in detecting bone metastases in patients with breast cancer. FDG-PET was shown to have a higher specificity than a bone scan and proved to be superior to bone scintigraphy when used as a confirmatory imaging modality [30]. In a different study it was reported that the morphologic appearance of metastases influences their detection. Patients who had either lytic or a mixed type metastases had a higher number of lesions identified by using FDG-PET, whereas in patients with sclerotic lesions bone scintigraphy revealed a greater number of metastases [31]. As in the case of prostate carcinoma, in the following years 18 Ffluoride PET may replace bone scan for routine patient assessment of breast cancer patients [32].

7.5.3 Lung Cancer The role of bone scintigraphy in patients with lung cancer has changed over the course of time. Advances in other imaging techniques have resulted in an improved accuracy of staging newly diagnosed lung malignancies. In the past bone scintigraphy was commonly used as a routine staging evaluation for non small cell lung cancer (NSCLC) patients. The percentage of such patients with positive scans ranged between 34% and 49% [33]. Since the routine availability of CT imaging, evidence of metastatic disease is often first identified in lymph nodes (hilar of mediastinal) or in distant organs (liver, adrenal glands), thereby obviating the need for bone scintigraphy. Maron and co-workers designed a study to compare FDG-PET with conventional imaging modalities for the staging of NSCLC patients. They evaluated 100 patients,

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of whom 90 had undergone isotope bone scans. Overall twelve patients were diagnosed with metastatic bone disease. FDG-PET identified bone metastases in 11 out of 12 patients (92%), whereas bone scanning revealed metastatic bone lesions in only 6 (50%) patients. The bone metastasis that was missed by using FDG-PET, was a lesion located in the distal femur, a part of the body which was not to be assessed during the study. The authors stated that the use of bone scintigraphy for staging NSCLC patients can be replaced by FDG PET [34]. Additionally, studies performed by Bury and Gayed concluded that both techniques had similar sensitivity for the detection of bone metastases, with FDG PET being more specific [35, 36]. Thus when taking into account the more recent studies that compared FDG PET to bone scanning, FDG-PET showed to be superior in depicting metastatic bone disease [19].

7.6 The Use of Radiopharmaceuticals for the Palliation of Metastatic Bone Disease Bone metastases from most tumours will excite a certain level of osteoblastic response in bone, leading to an increased uptake of bone seeking radiopharmaceuticals. In this way therapeutic doses of radionuclides may be localized close to the tumour by utilizing uptake mechanisms in adjacent non-tumour tissue. Bone seeking radiopharmaceuticals have been traditionally used to image tumours in bone, but depending on the carrier ligand and energy of the radioactive label, these agents can also be used to treat primary or metastatic tumours in bone. The use of radiopharmaceuticals as a palliative treatment is indicated in patients with widespread painful metastases which do not respond to analgesics. Similarly, their application is useful in patients with symptomatic metastases that have already been treated with radiotherapy. External beam radiotherapy is though preferred in localised metastatic bone lesions and in cases with spinal cord compression [37, 38]. The degree of radiopharmaceutical uptake by bone metastases is determined by the level of their osteoblastic activity. The level of osteoblastic activity must be verified by a recently (within 8 weeks) performed skeletal scintigraphy (99m Tc-HDP). The palliative effect starts within days or weeks after injection and usually lasts for months. Patients are treated in outpatient clinics or in day-care units, where the radiopharmaceutical is injected through an intravenous running line. After injection a rapid uptake at sites of increased bone turnover occurs and the non-bound fraction is cleared from the blood through the kidneys. Patients with urinary incontinence are therefore advised to have their urine collected through a catheter, in order to avoid radioactive contamination. When the administered radiopharmaceutical is a gamma emitter, post-treatment scintigraphy will be possible, using the therapeutic dosage. This may be used for follow up and dosimetry purposes. Toxicity is mainly limited to myelo-suppression, and in particular thrombocytopenia. Depending on the radiopharmaceuticals’ energy and half-life, myelo-suppression is most profound four to eight weeks after initiation of treatment, followed by a recovery phase lasting

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for approximately the same period. Recovery however is dependant on the amount of radioactivity administered and the patients’ bone marrow reserve [39–41]. By calculating the percentage of the skeleton involved with metastases and taking into account the dosage and the patients’ bone marrow reserve, haematological toxicity can be predicted [42]. Contraindications for the use of radiopharmaceuticals for therapy of bone metastases are thrombocytopenia (< 100 × 109 /L), leucopenia (< 3 × 109 /L), spinal cord compression (acute external beam radiotherapy is indicated), acute renal insufficiency and pregnancy.

7.6.1 Characteristics of Radiopharmaceuticals Used for the Treatment of Bone Metastases The radiopharmaceuticals with a long half-life include the formerly used 32 Pphosphate. 32 P has a half-life of 14.3 days and emits beta-particles with a maximum energy of 1.71 MeV. Until the 1980s 32 P-phosphate was the most commonly used radiopharmaceutical for the palliation of painful osseous metastases [43–45]. However, because of its toxicity profile and better alternatives, it is not anymore used R for this purpose. 89 Sr-Chloride (Strontium-89 or Metastron ) is also a long-lived radiopharmaceutical which is widely used and approved by the FDA. 89 Sr has a half-life of 50.5 days. It decays to stable 89 Y (Yttrium-89), emitting predominantly high energy beta-particles (E max = 1.46 MeV) and a very small proportion of gamma rays (910 keV). Post-therapy scintigraphy is possible, because of ‘bremsstrahlung’, but qualitatively it is not as good as with 186 Re-HEDP (Rhenium186-Hydroxyethylenediphosphonic acid) or 153 Sm-EDTMP (Samarium-153R Ethylenediaminetetramethylenephosphonic acid or Quadramet ) [46]. The last 117m Sn(4+)-DTPA (Tin-117m-diethyleneradiopharmaceutical of this category is triaminepentaacetic acid). 117m Sn decays by isomeric transition with emission of dominant gamma-radiation of 156 keV energy. The gamma-radiation undergoes conversion, with the conversion electrons having the therapeutic potential. The energetic conversion electrons have a very short range in soft tissue of 0.2–0.3 mm [47, 48]. The other available bone radiopharmaceuticals are labelled with isotopes of relatively short half-life ranging from 0.7 to 6.7 days. 188 Re has the shortest half-life with 16.9 h or 0.7 days. It is inexpensively produced from a 188 W (Tungsten188)/188 Re generator, and a kit is available for easy radiolabelling of the bone seeking HEDP. This ‘on demand’ production is a major advantage over other radiopharmaceuticals. 188 Re has a high-energy beta-particle emission with a maximum energy of 2.1 MeV. Its ‘brother’ 186 Re-HEDP cannot be produced on site. It is commercially available and approved in some countries. It has a half-life of 3.7 days with maximum beta-particle energy of 1.07 MeV [49]. The only short-lived FDA approved radiopharmaceutical is 153 Sm-EDTMP. 153 Sm has a beta-particle emission of maximum 810 keV, a 103 keV gamma-radiation emission (28%), and a half-life of 46.8 h. Gamma-radiation permits post-treatment

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scintigraphy [50]. Besides 153 Sm the carrier EDTMP has also been labelled with 177 Lu. 177 Lu is produced by thermal neutron bombardment of a target prepared from natural Lu. It has a half-life of 6.71 days and decays by emission of beta radiation (E max = 497 keV) to stable 177 Hf. It also emits gamma photons of 113 keV (6.4%) and 208 keV (11%) which, like 153 Sm-EDTMP, are quite suitable for imaging in vivo distribution [51]. Last but not least we would like to mention the fairly new and unique radiopharmaceutical 223 Ra-Chloride (Radium-223-Chloride). This radiopharmaceutical emits alpha-particles with an energy ranging from 5.3 to 7.5 MeV and a half-life of 11.4 days. Because the range of alpha-particles in tissue is very low as compared to beta-particles, the so called collateral damage to the bone marrow is relatively low, while efficacy is high due to a high LET (linear energy transfer) radiation. They yield a massive deposition of energy per unit track length and induce predominantly non-repairable DNA double-strand breaks causing a high anti-tumor effect. First clinical experience with 223 Ra-Chloride has been quite encouraging [52, 53].

7.6.2 Biodistribution and Pharmacokinetics Bone metastases may be characterized as areas of increased bone metabolism due to the presence of malignant cells. The osteoblastic response increases the uptake of bone seeking radiopharmaceuticals. Because the used radionuclide is a calcium analogue, osteoblasts actively incorporate the radiopharmaceutical in the bone matrix (89 Sr-Chloride, 223 Ra-Chloride). These radionuclides are members of the IIA family of the periodic table and as divalent cations, are incorporated into hydroxyl-apatite. The phosphorus-compounds (HEDP, EDTMP, DTPA and Phosphate) bind to the hydroxyl-apatite component of the bone matrix. All radiopharmaceuticals show rapid and high uptake in the skeleton. This ranges from 80% for 117m Sn(4+)-DTPA, to 50% for 153 Sm-EDTMP, 177 Lu-EDTMP, 186 Re-HEDP and 188 Re-HEDP, and to 20% for 89 Sr-Chloride [53–56]. However, inter-patient variation is very high. In all cases extra-skeletal uptake activity is low and all the activity that is not taken up by the skeleton is rapidly excreted in urine. In most cases it is possible to acquire high quality images (with minimum soft tissue retention) only within a few hours after injection of the radiopharmaceutical. In clinical practice 89 Sr-Chloride, 153 Sm-EDTMP and 186 Re-HEDP are most widely used (Table 7.2), with the efficacy of treatment related to the uptake of radiopharmaceutcal around bone metastases. As already noted this can be usually predicted by a diagnostic scan using radiolabelled phosphonates. Table 7.2 Response rates in efficacy studies on single dose treatment Radiopharmaceutical

No. of studies

No. of patients

Response rate

153

13 21 13

9–118 5–60 26–527

61–95% 54–92% 37–96%

Sm-EDTMP 186 Re-HEDP 89 Sr-chloride

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7.7 Summary Different nuclear radiopharmaceuticals exist that are helpful for the diagnosis of bone metastases. The bone scintigraphy (imaging with 99m Tc-HDP or MDP) has been used for many years with good results. Its sensitivity remains until now superior to any other available imaging method. However, for certain cancers other SPET-radiopharmaceuticals can be used as well. PET radiopharmaceuticals have the advantage of quantification and are associated with an improved resolution. A bone specific PET radiopharmaceutical is 18 F-fluoride. The sensitivity seems to be equal to that of bone scanning, but larger patient studies have to confirm this. The palliation of metastatic bone pain is both effective and safe. Approximately 80% of the treated patients show a clinical response, with a consequent decrease in morbidity and an improvement in quality of life. In clinical practice it should be readily considered, especially in patients with widespread metastatic disease. Ongoing research aims for an optimized efficacy and individualized dosing schemes, to bring about an optimized response of pain, possibly also aiming to an improved survival. Finally, nuclear medicine has shown to have an important role for measuring and monitoring the response to treatments.

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35. Gayed I, Vu T, Johnson M, et al. (2003) Comparison of bone and 2-deoxy-2-(18F)fluoro-Dglucose positron emission tomography in the evaluation of bony metastases in lung cancer. Mol Imaging Biol 5:26–31 36. Lewington VJ (2002) A practical guide to targeted therapy for bone pain palliation. Nucl Med Commun 23:833–836 37. Saarto T, Janes R, Tenhunen M, et al. (2002) Palliative radiotherapy in the treatment of skeletal metastases. Eur J Pain 6:323–330 38. de Klerk JM, Zonnenberg BA, het Schip AD, et al. (1994) Dose escalation study of rhenium186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer. Eur J Nucl Med 21:1114–1120 39. de Klerk JM, van Dieren EB, het Schip AD, et al. (1996) Bone marrow absorbed dose of rhenium-186-HEDP and the relationship with decreased platelet counts. J Nucl Med 37:38–41 40. de Klerk JM, Zonnenberg BA, het Schip AD, et al. (1999) Can bone marrow scintigraphy predict platelet toxicity after treatment with 186Re-HEDP? Nucl Med Commun 20:833–836 41. de Klerk JM, het Schip AD, Zonnenberg BA, et al. (1994) Evaluation of thrombocytopenia in patients treated with rhenium-186-HEDP: guidelines for individual dosage recommendations. J Nucl Med 35:1423–1428 42. Cheung A, Driedger AA (1980) Evaluation of radioactive phosphorus in the palliation of metastatic bone lesions from carcinoma of the breast and prostate. Radiology 134:209–212 43. Shah Syed GM, Maken RN, Muzzaffar N, et al. (1999) Effective and economical option for pain palliation in prostate cancer with skeletal metastases: 32P therapy revisited. Nucl Med Commun 20:697–702 44. Silberstein EB (1993) The treatment of painful osseous metastases with phosphorus-32labeled phosphates. Semin Oncol 20:10–21 45. Cipriani C, Atzei G, Argiro G, et al. (1997) Gamma camera imaging of osseous metastatic lesions by strontium-89 bremsstrahlung. Eur J Nucl Med 24:1356–1361 46. Atkins HL, Mausner LF, Srivastava SC, et al. (1993) Biodistribution of Sn-117m(4+)DTPA for palliative therapy of painful osseous metastases. Radiology 186:279–283 47. Atkins HL, Mausner LF, Srivastava SC, et al. (1995) Tin-117m(4+)-DTPA for palliation of pain from osseous metastases: a pilot study. J Nucl Med 36:725–729 48. Liepe K, Hliscs R, Kropp J, et al. (2000) Rhenium-188-HEDP in the palliative treatment of bone metastases. Cancer Biother Radiopharm 15:261–265 49. Serafini AN (2000) Samarium Sm-153 lexidronam for the palliation of bone pain associated with metastases. Cancer 88:2934–2939 50. Ando A, Ando I, Tonami N, et al. (1998) 177Lu-EDTMP: a potential therapeutic bone agent. Nucl Med Commun 19:587–591 51. Nilsson S, Larsen RH, Fossa SD, et al. (2005) First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res 11:4451–4459 52. Nilsson S, Franzen L, Parker C, et al. (2007) Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 8:587–594 53. Blake GM, Zivanovic MA, McEwan AJ, et al. (1986) Sr-89 therapy: strontium kinetics in disseminated carcinoma of the prostate. Eur J Nucl Med 12:447–454 54. de Klerk JM, van Dijk A, het Schip AD, et al. (1992) Pharmacokinetics of rhenium-186 after administration of rhenium-186-HEDP to patients with bone metastases. J Nucl Med 33:646–651 55. Krishnamurthy GT, Swailem FM, Srivastava SC, et al. (1997) Tin-117m(4+)DTPA: pharmacokinetics and imaging characteristics in patients with metastatic bone pain. J Nucl Med 38:230–237 56. Singh A, Holmes RA, Farhangi M, et al. (1989) Human pharmacokinetics of samarium-153 EDTMP in metastatic cancer. J Nucl Med 30:1814–1818

Chapter 8

MAGNETIC RESONANCE IMAGING OF METASTATIC BONE DISEASE Ekaterini Solomou1 , Alexandra Kazantzi1 , Odysseas Romanos1 and Dimitrios Kardamakis2 1 Department of Clinical Radiology, Magnetic Resonance Unit, University Hospital of Patras, 26500 Patras, Greece, e-mail: [email protected] 2 Department of Radiation Oncology, University of Patras Medical School, Patras, Greece, e-mail: [email protected]

Abstract:

Early diagnosis of bone metastases is crucial in order to determine the prognosis and optimize therapy. Traditional methods, such as plain radiography or bone scintigraphy, lack either sensitivity or specificity. Computed tomography (CT) is quite sensitive, however, its ability to detect early deposits is limited. FDG PET – CT scan detects metastatic bone disease before occurrence of osteoblastic activity. Magnetic resonance imaging (MRI) has been shown to be the most sensitive imaging technique, with a sensitivity of up to 100% reported and its specificity was reported to reach 97%. MRI of bone metastases depends on the degree of bone resorption or deposition. The lesion pattern may be lytic, sclerotic or mixed. Adequate characterization of lesions depends on fat and water distribution in bone marrow, normal bone trabeculae, tissue vascularization, cell density and bone oedema. T1 – weighted spin – echo (SE), T2 – weighted turbo SE and STIR are the sequences most frequently used. Gadolinium enhancement demonstrates areas of greatest tumor activity. Diffusion-weighted imaging helps in the discrimination between benign and malignant vertebral body compression fractures. Wholebody MRI is a feasible alternative to bone scintigraphy in evaluating the entire skeleton. MRI is the modality of choice for the evaluation of bone metastases. It’s a non invasive technique, presenting great tissue contrast, without the use of ionizing radiation. MRI depicts metastases in an early stage and provides additional information about tumor extent. It helps in tumor screening and staging, as well as in the control of the disease progression and the post treatment evaluation.

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Key words: Magnetic resonance imaging · Metastases · Imaging · Bone marrow · Choice of sequence · Differential diagnosis

8.1 Introduction The skeletal system is the third commonest site for localization of metastatic cancer, after liver and lung [1]. Early diagnosis of bone metastases is crucial in order to determine prognosis and optimize treatment. Traditional methods, such as plain radiography or bone scintigraphy (BS) lack both in sensitivity and specificity. Radiography is limited by the fact that osteolytic changes are apparent several months after the onset of the disease, since 30–75% of the cancellous bone of a vertebral body or a long bone needs to be resorbed before the lesion can be detected on the X-ray. BS seems to be more sensitive in depicting skeletal lesions (reported sensitivity is 93%), but less capable for detecting lesions located in the bone marrow (reported sensitivity 80%) [2]. CT is sensitive in the detection of cortical or neurovascular involvement or soft tissue extension. However, its ability to detect early deposits in bone marrow is limited [3]. Almost 40 years ago, in 1971, Damadian observed that cancerous tissue has different magnetic resonance characteristics from those of normal tissues [4]. In 1977 the first in vivo images of human subjects were published [2], and since then the quality of the images obtained through MRI has improved significantly. MRI has shown to be the most sensitive imaging modality for the detection of bone metastases, allowing the direct visualization of bone marrow with a sensitivity of up to 100% [5–12]. It should be noted that the sensitivity of bone marrow scintigraphy is only 58%. MRI is superior to bone marrow scintigraphy also in terms of specificity (97 versus 85% respectively) [8]. Moreover, MRI techniques such a whole body MRI using T1-weighted and T2-weighted spin echo sequences in combination with STIR images, also have a have a higher sensitivity than BS (82 versus 71% respectively) [1]. Major advantages of MRI are that it is a non invasive technique and it does not involve ionizing radiation. Compressive myelopathy and spinal cord compression are emergencies that seek a prompt evaluation and treatment so that affected patients have a favorable therapeutic outcome [13]. In such cases, MRI should be the imaging modality of choice, since it has the ability to depict with high tissue resolution not only the vertebral bodies, but also the paraspinal soft tissues and intraspinal structures. In such patients the whole vertebral column should be studied since in 10% of cases multiple levels of cord compression exist. Other applications of MRI in metastatic bone disease include the following:

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Differential diagnosis between benign and malignant vertebral collapse [14]. Clarification of inconclusive findings of BS or radiography, as it can reveal additional information concerning tumor extent and vertebral morphology (Fig. 8.1) [8]. Depiction of metastases in an early stage, due to the high contrast between fat and metastatic deposits which have high water content [13].

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Through the evaluation of tumor extension into adjacent structures it provides valuable information about treatment decisions (as in the case of field shaping in radiotherapy for bone metastases) (Fig. 8.2). Monitoring of therapeutic response or disease progression.

Fig. 8.1 Metastatic lung cancer in thoracic spine. (A) High signal intensity in the bone marrow of thoracic vertebral bodies on STIR image. (B) Low signal on T1 SE. (C) T2 TSE shows low inhomogeneous signal on TH10 and high heterogeneous signal on TH11. At the level of TH10, spinal cord compression is obvious (arrow). (D) T1 FAT SAT with gadolinium depicts enhancement of the vertebral bodies as well as of the adjacent soft tissue masses, indicative of tumor spread

Fig. 8.2 Coronal (A) T1 (B) T1 FAT SAT + GD depicting focal metastatic lesion in the right femur. There is enhancement of the adjacent muscles after GD administration, indicating soft tissue infiltration

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There is a small proportion of patients who are unable to undergo MRI scanning due to claustrophobia, whereas for others it is medically contraindicated (patients with cardiac pacemakers, intracranial aneurysm clips or ferromagnetic fragments in or around the eye) [2]. Long acquisition times are often required in order to obtain optimal images. The use of some devices (such as moving table tops, table top extenders etc) and fast MR sequences have simplified the examination technique, without requiring patient repositioning, thus reducing examination time, especially in cases of the whole body imaging [15]. The use of MRI to screen the entire skeleton is not practical. Steinborn et al. and Eustace et al. have though shown that whole body MRI is a feasible alternative to 99m TC planar BS in the evaluation of the whole skeleton for metastases [16, 17]. Conclusively, MRI has been proven to be the investigation of choice for the imaging of bone metastases. It is extremely sensitive in differentiating benign and malignant vertebral collapse and detecting spinal cord compression, and very helpful in cases that radiographic or BS findings are inconclusive [6, 9, 18–21].

8.2 MRI Sequences in Use for the Detection of Bone Metastases Due to the continuous advents of MR technologies, spatial resolution and matrix sizes have improved image quality and have significantly reduced motion artefacts. With new coils and sequences the whole skeleton can be studied in 20 min, revealing more metastatic lesions as compared to BS [16]. Normal marrow contains both fat and water (yellow marrow 80% fat, and 15% water, and red marrow 40% fat and 40% water). The T1 and T2 characteristics of bone marrow differ according to the cellularity, water, protein and fat content. In an adult, fat is the major regulator of bone marrow signal in MRI images. Fat has a short T1 relaxation time, thus showing hyperintense (bright signal) on T1 weighted images. Consequently yellow bone marrow has high signal intensity on T1 weighed images, whereas red marrow has intermediate signal intensity [2]. In infiltrative disorders, as in the case of involvement of bones by tumor cells, fat disappears in a diffuse, disseminated or solitary pattern. Adequate detection and characterization of lesions depends on fat and water distribution in bone marrow, indirect visualization of normal bone trabeculae, indirect evaluation of bone edema and cell density, as well as tissue vascularization. Sequences displaying differences between fat and water signal are thus useful [2].

8.2.1 T1 Weighted Image (T1wi) Spin Echo T1 weighted spin echo (SE) images can accurately show differences in signal intensity between red and yellow bone marrow, reflecting differences in fat and water content. Yellow bone marrow (containing 80% fat) has a high signal on MR imaging, thus a region of low signal indicates the presence of a lesion. This is why this sequence is very useful and is usually the first to be used. In the case of hemopoietic

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Fig. 8.3 T1SE wi: Multiple areas of low signal indicate metastatic lesions from breast cancer. Normal bone marrow exhibits a high signal

red marrow which contains equally water and fat, the MRI signal is lower than fat, but higher than normal muscle tissue. In this case a marrow signal lower to muscle tissue and intervertebral discs in the spine is considered abnormal (Fig. 8.3).

8.2.2 T2 Weighted Image (T2wi) Turbo Spin Echo (TSE) T2 weighted TSE images show a decreased sensitivity for the differentiation between red and yellow marrow and consequently the sensitivity for the detection of bone marrow lesions is rather low. The sensitivity for bone marrow involvement is improved by applying long TR and TE times of heavily T2 weighted fast spin-echo, in addition to fat saturation (in such a case sensitivity is comparable to hat achieved through STIR imaging). Advantages of T2 TSE to STIR images are the significantly decreased imaging time and improved signal-to-noise ratio, whereas its drawbacks are the dependence on excellent magnetic field homogeneity for adequate fat suppression. High-field strength systems are required in contrast to STIR images, which can be obtained on low-or high field strength systems (Fig. 8.4).

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Fig. 8.4 Inhomogeneous low signal appearance of metastatic lesions on sagittal T2 wi TSE, with extension to the anterior epidural space at the level of mid thoracic spine

8.2.3 Fat Suppression Techniques This technique uses a 180◦ inversion pulse in order to cancel the fat signal. It is considered an excellent tool for the detection of bone marrow pathology. Short tau inversion recovery sequence (STIR) can be obtained on any MR unit; however, it is time consuming, restricted to a certain number of slices and has a low signalto-noise ratio. This can be overcome by using fast STIR sequences. Recent studies propose this sequence in the evaluation of metastases in patients where a whole body MRI is necessary. A limitation of STIR sequence is that it cancels every signal identical to fat, as in the cases of the presence of blood in haematomas or in contrast-enhanced tissue. Another limitation of this technique is its application in oncologic patients after treatment that results in bone marrow changes, such as edema, fibrosis, necrosis and hyperplasia of the red marrow. These alterations cannot be differentiated from active tumor [22]. High signal intensity indicates non suppression of fat, thus signaling the presence of a metastatic lesion (Fig. 8.5). Fat presaturation is also used to detect metastatic bone lesions. A saturation pulse with a narrow band at the exact fat frequency is used before the usual pulse. This sequence is not applicable for every MRI unit, because it is limited by local field

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Fig. 8.5 STIR imaging of pelvic bones shows multiple hyperintensities, due to orbital melanoma metastases

inhomogeneities, thus requiring a very homogeneous magnetic field. Conclusively the STIR technique can detect bone marrow lesions missed with blind biopsy or with other conventional imaging techniques. It may also be applied for the detection of skeletal and soft tissue disease in children [22].

8.2.4 Contrast Media Gadolinium (GD) increases the sensitivity and specificity of MR imaging. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) display no or limited increase in signal intensity on T1wi of normal bone marrow. The absence of uptake practically rules out tumor involvement. In contrast, various pathologies such as bone metastases show a strong signal increase. A pre-injection T1wi is mandatory, as the enhanced signal of the lesion can be equal to the signal of fatty marrow. Uptake is usually evaluated on T1wi SE sequences. T1wi with fat presaturation can also be used, making tissue enhancement more obvious. According to the literature, gadolinium enhanced MRI

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Fig. 8.6 Metastatic bone marrow lesions from lung cancer (A) T1 TSE and (B) T1 TSE + GD. Infiltration of sacral bone with inhomogeneous enhancement after gadolinium injection is depicted. The tumor extends anteriorly and posteriorly to S2 level

may also play a role in demonstrating areas of greatest tumor activity as a guide for needle biopsy (Fig. 8.6) [23]. Recently, gadolinium-based contrast agents have been linked to the development of a pathologic condition termed nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). This disease can occurred in patients with moderate to end-stage renal disease, after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. As of late December 2006, the FDA had received reports of 90 such cases of NSF/NFD. Characteristics include red or dark patches on the skin, burning, itching, swelling, hardening, and tightening of the skin, yellow spots on the whites of the eyes, joint stiffness with trouble moving or straightening the arms, hands, legs, or feet, pain deep in the hip bones or ribs, and muscle weakness. Thus contrast medium infusion policy should be conservative concerning patients with renal failure [24].

8.2.5 Bone Trabeculae Bone metastases can be also indirectly detected by MRI techniques. Trabecular bones yield no detectable signal due to the lack of mobile protons. However, they

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are responsible for magnetic field heterogeneities. They have minimal impact on SE sequences, as their effect is cancelled by the 180◦ pulse. In gradient-echo sequences field heterogeneity is not cancelled, so signal is present. If bone trabecula is destroyed, as in bone metastases, the signal will be higher as compared to the unaffected parts of bone. This is an indirect way to diagnose trabeculae lysis [25,26].

8.2.6 Diffusion-Weighted Imaging (Dwi) Dwi is an MRI technique that is sensitive to random water movements at spatial scales far below typical MRI voxel dimensions. It may be successfully applied in brain imaging and in diagnosing diseases that involve alterations in water mobility. Its capability of probing the microstructure of a biologic tissue at a sub-millimetre range is used to evaluate diffusion capacity. The latter is tissue specific and can be used for tissue characterization when quantitative diffusion measurements are available. Most of the pulse sequences developed for MRI can be adapted for Dwi: spin echo (SE), turbo spin echo (TSE), single-shot echo planar imaging (EPI), and steady-state free precession (SSFP) sequences. Physiological motion can frequently be affect by artifacts of Dwi sequences [27].

8.2.7 Chemical Shift Imaging In this sequence, the difference in resonance frequency between water and fat protons can be used. Normally the read-out gradient is centred on the echo, which

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Fig. 8.7 (A) STIR sequence, (B) T1 FAT SAT + GD, (C) gradient echo in phase, (D) out phase: TH6 vertebra shows normal signal on STIR sequence and T1 FAT SAT + GD (A,B) but chemical shift imaging is more sensitive in demonstrating metastatic pathology of TH6 vertebra (signal is not suppressed in out-phase sequence, as in normal bone marrow of the rest of the vertebrae) (C,D)

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appears symmetrically on the 90◦ pulse with respect to the 180◦ pulse. In this way, the signal produced is proportional to the sum of water and fat protons (in-phase image). By shifting the read-out window, it is possible to obtain images whose contrast is related to the difference between the quantities of water and fat protons (opposed-phase images) [28]. This type of sequence results in low signal intensity of intact red marrow and high signal intensity in pathologic cases. This phenomenon is applied in gradient-echo sequences, depending only on the echo time. When fat and water protons are in phase, their signals are added and when they are in opposed-phase, they are subtracted. When a bone metastasis is present, it replaces normal marrow by fatty marrow and no subtraction occurs. The difference from the signal produced by normal marrow, which always contains water and fat, will be emphasized on opposed-phase sequences (Fig. 8.7) [29].

8.3 Clinical Applications 8.3.1 Imaging Protocol A correct MR imaging algorithm in patients with bone metastases should include a T1 weighted spin-echo sequence in addition to either a T2 weighted turbo spin echo image or a short tau inversion recovery (STIR)/Fast STIR pulse sequence. Saggital images are mainly preferred for examination of the spine, whereas axial planes are useful, if compression of the spinal cord exists. Coronal sections are preferably used for the pelvis and upper femora (Fig. 8.8). T1 enhanced images should also be used, as well as T1-with fat presaturation. Coil selection and slice thickness is decided according to the anatomic region of interest [2].

Fig. 8.8 Metastatic lesions of the right iliac bone and the left femur on (A) T1SE wi, (B) STIR and (C) T1 FAT SAT plus gadolinium. Coronal planes are mandatory in cases of pelvic imaging

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8.3.2 Image Characteristics of Bone Metastases The image characteristics of bone metastases by using MRI depend on the degree of bone resorption or formation. Metastases usually initially infiltrate the medullary cavity and then the medullary bone, destroying at last the cortex [30]. On T1 weighted images focal or diffuse areas of low signal intensity are considered to be metastases, exhibiting replacement of the normal marrow by the tumor. T1 weighted images before and after contrast administration must be evaluated together. Metastatic lesions in fatty bone marrow that are hypointense on T1 images typically show contrast enhancement. On T2 sequences metastases have high, low or intermediate signal, depending on tumor morphology [13]. On STIR images hyperintense areas typically represent metastatic lesions (due to an increased content of water within tumor cells), which are easily detected because of the contrast which is created by the dark background of the suppressed signal intensity (Fig. 8.9) [31]. Osteoblastic metastases show a low signal on both T1 and T2 weighted images, whereas the signal on STIR images is versatile, ranging from no change in signal in sclerotic metastases, to elevation of signal in tumors with high cellular component (osteolytic lesions).

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Fig. 8.9 (A) T2-TSE image shows hyperintensity of C7 vertebral body (B) STIR technique detects multiple bone marrow lesions due to multiple myeloma, missed on T2TSE wi

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8.3.3 Differential Diagnosis from Benign Lesions Differential diagnosis of metastatic bone disease includes degenerative changes of vertebrae and specifically Type 1 Modic changes (low signal intensity on T1wi and high signal on T2wi). The pattern of this degenerative disease is found in only 4% of the general population, with Type 2 changes (high signal intensity on T1wi and iso/high on T2wi being the most frequent) in about 16% [32]. One should though stress that Type 2 changes do not pose problems for the differential diagnosis. Alterations in the adjacent intervertebral disk in conjunction with changes in the signal intensity of the bone marrow are considered to be benign in nature (Fig. 8.10) [32–37]. Concerning the vertebrae, criteria that should be taken into consideration for malignancy are: alterations of the signal extending into the pedicle, paraosseous tumor spread, as well as posterior vertebral body bulging [31]. The bull’s-eye or the halo sign is also useful for the differential diagnosis. If the above secondary criteria are absent, diagnosis may be difficult. Collapsed vertebral bodies may also cause difficulties in the differential diagnosis. Characteristics of benign disease are the presence of multiple fractures of non collapsed bodies without any specific differentiation of the signal intensity, ill-defined borders between normal and involved marrow, vertebral body fragmenta-

Fig. 8.10 Alterations of the bone marrow signal in the anterior part of vertebral endplates, adjacent to a degenerative disc (Type 2 Modic changes), on (A) T1 SE wi and (B) T2 TSE wi

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Fig. 8.11 Metastatic breast cancer: L2 vertebral body pathologic fracture demonstrates marrow replacement with low signal on T1 SE wi (A), intermediate on T2TSE wi (B), hyperintensity on STIR (C) and strong enhancement of L2 and prevertebral space on T1 FAT SAT + GD (D). In cases with no known primary malignancy, differential diagnosis should include acute fracture due to osteoporosis or injury. Diffusion weighted images would be helpful in discriminating among these entities

tion and disc rupture. Malignancy is suggested by the presence of multiple involvements of non collapsed vertebral bodies, by the spread to the posterior arch and by a convex posterior contour. [38]. Diffusion weighted images are helpful to distinguish a metastatic from an osteoporotic collapse, as the signal in metastasis is high, whereas it is lower than normal marrow in osteoporosis. Gradient echo sequences may also be used in the differential diagnosis. A high signal of the collapsed vertebral body is often seen in metastases, whereas a lower signal found in the non-collapsed body indicates a benign collapse. Neoplastic osteosclerotic lesions should also be differentiated from reactive sclerosis evident after fractures. The former may create diagnosis problems, since both osteoporotic and metastatic lesions decrease the bone marrow signal. Previous research has shown that acute compression fractures of vertebral bodies are depicted with abnormal signal intensity that is difficult to be differentiated from metastases (Fig. 8.11). In the cases that routine MR sequences are not helpful for the discrimination of acute benign from malignant vertebral body compression fractures, the use of diffusion weighted images in combination with contrast enhancement is mandatory [39, 40].

8.3.4 The Role of MRI Post Treatment MRI may also be useful post treatment to monitor the therapeutic outcome after radiation therapy or chemotherapy. On T1wi new lesions exhibit high signal in the

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irradiated marrow, whereas the signal does not change during chemotherapy [41]. The presence of low signal after irradiation or chemotherapy may be attributed to residual active tumor or fibrosis. Dynamic techniques are most appropriate to differentiate between the two entities. MRI can also be used in patients with metastatic disease after orthopaedic surgery (provided that metal hardware is MRI compatible) in order to depict recurrence or successful stabilisation.

8.4 MRI Compared to other Methods of Bone Imaging Plain radiographs have a low sensitivity for the detection of bone metastases which become apparent after loss of 50% of bone mineral content [42]. Since its introduction in the early ‘70s, BS with technetium-99m methylene diphosphonate has been the gold standard for bone metastases imaging. However BS yields a high percentage of false negative and false positive results, especially in cases of aggressive metastases, patients with degenerative lesions, fractures and osteoporosis [8]. According to the literature, the location of vertebral metastases is the most important factor for the difference in the detection rates between MRI and BS. The cause of positive findings on BS is the cortical involvement. Vertebral metastases in the early stages are small, located in the medullary cavity, without cortical involvement, so findings may be positive on MRI and negative on BS [43]. Large studies have shown the superiority of MRI imaging compared to BS and CT in respect to bone metastases detection. Daffner et al. in a series of 50 patients showed that MRI had no false positive or false negative results [6]. Avrahami et al. compared 40 patients with normal CT, plain radiographs and radionuclide bone scanning with MRI, reporting that MRI can detect minor lesions that were confirmed histologically [9]. The superiority of MRI over BS in terms of specificity was also proven by Frank et al. in a study involving 106 patients [12]. Similar results were obtained in the studies by Algra et al. and Gosfield et al. [13, 44]. Similarly, several studies have described the superiority of MRI over CT and BS for the detection of bone metastases [17]. There is an ongoing debate concerning the usefulness of MRI and BS in screening for metastatic disease in cancer patients. The sensitivity of MRI is high when extensive bone destruction is present and new bone formation is absent (resulting in negative BS). Also in cases of early bone involvement of the marrow by tumor cells, only MRI can depict the pathology. MRI can also reveal additional information about tumor extent, vertebral morphology and spinal cord compression. At present a major disadvantage of MRI is the relatively long acquisition time, which renders the visualisation of the entire skeleton a long-lasting procedure [8]. Development of fast imaging techniques such as echo planar imaging will probably override this obstacle. As mentioned above, Steinborn et al. [16] and Eustace et al. [45] have shown that whole-body MRI is a feasible alternative to 99m Tc planar bone scintiscanning in evaluating the entire skeleton for metastatic disease. Steinborn reported a sensitivity

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Table 8.1 Comparison among imaging modalities for the detection of skeletal metastases Examination

Sensitivity

Specificity

Accuracy

Plain radiograph MSCT Bone scintigraphy Bone marrow scintigraphy MRI Whole body MRI FDG-PET-CT

50% Comparable to BS 71–84% 58% 82–100% 82–96% 62–90%

– Comparable to BS 77–98% 85% 77–97% 76–100% 80%

– – 93% 62% 81% 91% 78%

Data based on references [1, 3, 5–12, 51–55].

of 91.4% for MRI and 84.8% for BS. Therefore, whole body MRI is emerging as an innovative tool for diagnosis of metastatic bone disease in the entire skeletal system, with the exception of rib metastases [16]. For the diagnosis of spinal cord compression, several studies showed that MRI is comparable with myelography and post-myelography CT. Sagittal T1 weighted images are usually required and sometimes axial T1, whereas T2 does not provide any further information. Gadolinium-enhanced T1 weighted images may depict obscure areas of cord compression in patients with extensive metastatic disease and a narrow spinal canal [46, 47]. Gadolinium-enhanced MR imaging is considered to be of equal diagnostic value to myelography in the diagnosis of leptomeningeal carcinomatosis. According to the literature MRI is the first choice examination for cord impingment evaluation, with myelography being the second choice when MRI does not reveal any pathology [23, 48, 49]. Finally, FDG PET-CT scan is a new imaging modality that also detects metastatic bone disease at an early stage, before the occurrence of osteoblastic activity. Schmidt et al. compared diagnostic accuracy of whole body MRI and FDG PET CT scan using parallel imaging (PAT), showing that both imaging modalities are robust for a systemic screening for metastatic bone disease. Through the same study it was though shown that PAT whole body MRI was slightly superior to PET-CT in diagnostic accuracy [50]. 18 F-FDG-PET and 18 F-fluoride-PET as well as PET-CT image fusion and the two in one PET/CT examinations appear to be slightly less sensitive to the whole body MRI in the detection of skeletal metastases. Extensive comparative studies of MRI with 18 F-FDG-PET and 18 F-fluoride-PET have not yet been carried out [51–55]. Table 8.1 compares the sensitivity, specificity and accuracy between the discussed imaging modalities [1, 3, 5–12, 51–55].

8.5 Summary Magnetic Resonance Imaging (MRI) is very sensitive in detecting bone metastases. The choice of sequences (Fat saturation, gradient echo, chemical shift imaging, diffusion weighted imaging and contrast media infusion), must be carefully se-

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lected in order to achieve an improved specificity. The depiction of bone metastases through MRI depends on the degree of bone resorption or deposition, which will also determine the type of the metastatic bone lesion (lytic, sclerotic or mixed). MRI has been gaining ground over other imaging modalities as the gold standard for the evaluation of patients with metastatic bone disease, being particularly useful for the early depiction of metastatic bone disease. Similarly, the value of MRI in cases with suspected spinal cord compression is unquestionable, and it is currently established as the first choice of radiologic evaluation. Its use is especially useful in detecting early metastatic bone involvement, spinal cord compression and for the differential diagnosis between benign or malignant vertebral collapse. Furthermore, it can be applied to cancer patients after radiotherapy or systemic treatments (chemotherapy or hormonal treatment), to monitor the therapeutic outcome or disease progression.

Abbreviations MRI CT T1wi SE T2wi TSE STIR GD Dwi EPI SSFP T1 FAT SAT T1 FAT SAT + GD T1 TSE + GD C TH L FDG PET PAT

Magnetic Resonance Imaging Computed Tomography T1 weighted image Spin Echo. T2 weighted image Turbo Spin Echo. Short tau inversion recovery sequence Gadolinium Diffusion-weighted imaging single-shot echo planar imaging steady-state free precession sequences. T1 fat saturation T1 fat saturation with gadolinium T1 turbo spin echo with gadolinium Cervical vertebra Thoracic vertebra Lumbar vertebra 2-[18 F] fluoro-2-deoxy-D-glucose Positron Emission Tomography Parallel imaging Strategies

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3. Ghanem N, Uhl M, Brink I, et al. (2005) Diagnostic value of MRI in comparison to scintigraphy, PET, MS-CT and PET/CT for the detection of metastases of bone. Eur J Radiol 55:41–55 4. Damadian R (1971) Tumor detection by nuclear magnetic resonance. Science 171:1151–1153 5. Vanel D (2003) MRI of bone metastases: the choice of the sequence. Cancer Imaging 4:30–35 6. Daffner RH, Lupetin AR, Dash N, et al. (1986) MRI in the detection of malignant infiltration of bone marrow. AJR Am J Roentgenol 146:353–358 7. Hanna SL, Fletcher BD, Fairclough DL, et al. (1991) Magnetic resonance imaging of disseminated bone marrow disease in patients treated for malignancy. Skelet Radiol 20:79–84 8. Ghanem N, Altehoefer C, H¨ogerle S, et al. (2002) Comparative diagnostic value and therapeutic relevance of magnetic resonance imaging and bone marrow scintigraphy in patients with metastatic solid tumors of the axial skeleton. Eur J Radiol 43:256–261 9. Avrahami E, Tadmor R, Dally O, et al. (1989) Early MR demonstration of spinal metastases in patients with normal radiographs and CT and radionuclide bone scans. J Comput Assist Tomogr 13:598–602 10. Delbeke D, Powers TA, and Sandler MP (1989) Correlative radionuclide and magnetic resonance imaging in evaluation of the spine. Clin Nucl Med 14:742–749 11. Kattapuram SV, Khurana JS, Scott JA, et al. (1990) Negative scintigraphy with positive magnetic resonance imaging in bone metastases. Skelet Radiol 19:113–116. 12. Frank JA, Ling A, Patronas NJ, et al. (1990) Detection of malignant bone tumors: MR imaging vs scintigraphy. AJR Am J Roentgenol 155:1043–1048. 13. Algra PR, Bloem JL, Tissing H, et al. (1991) Detection of vertebral metastases: comparison between MR imaging and bone scintigraphy. Radiographics 11:219–232 14. Yuh WT, Zachar CK, Barloon TJ, et al. (1989) Vertebral compression fractures: distinction between benign and malignant causes with MR imaging. Radiology 172:215–218 15. Nakanishi K, Kobayashi M, Takahashi S, et al. (2005) Whole body MRI for detecting metastatic bone tumor: comparison with bone scintigrams. Magn Reson Med Sci 4:11–17 16. Steinborn MM, Heuck AF, Tiling R, et al. (1999) Whole-body bone marrow MRI in patients with metastatic disease to the skeletal system. J Comput Assist Tomogr 23:123–129 17. Eustace S, Tello R, DeCarvalho V, et al. (1997) A comparison of whole-body turbo STIR MR imaging and planar 99mTc-methylene diphosphonate scintigraphy in the examination of patients with suspected skeletal metastases. AJR Am J Roentgenol 169:1655–1661 18. Albert K (2007) Evaluating bone metastases. Clin J Oncol Nurs 11:193–197 19. Nyman R, Rehn S, Glimelius B, et al. (1987) MRI in diffuse malignant bone marrow diseases. Acta Radiol 28:199–205 20. Colman LK, Porter BA, Redmond J III, et al. (1988) Early diagnosis of spinal metastases by CT and MR studies. J Comput Assist Tomogr 12:423–426 21. Mehta RC, Wilson MA, and Perlman SB (1989) False negative bone scan in extensive metastatic disease: CT and MRI findings. J Comput Assist Tomogr 13:717–719. 22. Kellenberger CJ, Epelman M, Miller SF, et al. (2004) Fast STIR Whole-Body MR Imaging in Children. RadioGraphics 24:1317–1330 23. Sze G (1988) Gadolinium DTPA in spinal disease. Radiol Clin North Am 26:1009–1024 24. Saifuddin A, Bann K, Ridgway JP, et al. (1994) Bone marrow blood supply in gadoliniumenhanced magnetic resonance imaging. Skeletal Radiol 23:455–457 25. Fransson A, Grampp S, and Imhof H (1999) Effects of trabecular bone on marrow relaxation in the tibia. Magn Reson Imaging 17:69–82 26. Sebag GH and Moore SG (1990) Effect of trabecular bone on the appearance of marrow in gradient-echo imaging of the appendicular skeleton. Radiology 174:855–859 27. Raya JG, Dietrich O, Reiser MF, et al. (2006) Methods and applications of diffusion imaging of vertebral bone marrow. J Magn Reson Imaging 24:1207–1220 28. Glover GH and Schneider E (1991) Three-point Dixon technique for true water/fat decomposition with B0 inhomogeneity correction. Magn Reson Med 18:371–383 29. Seiderer M, Staebler A, and Wagner H (1999) MRI of bone marrow: opposed-phase gradientecho sequences with long repetition time. Eur Radiol 9:652–661

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30. Peh WCG and Muttarak M (2003) Clinics in Diagnostic Imaging (82). Singapore Med J 44:101–105 31. Peh WCG and Muttarak M (2002) Bone metastases. eMedicine J 3(3) http://www.emedicine.com/radio/topic88.htm Cited 1 September 2008 32. Modic MT, Steinberg PM, Ross JS, et al. (1988) Degenerative disc disease: assessment of changes in vertebral body marrow with MR imaging. Radiology 166:193–199 33. Grenier N, Grossman RI, Schiebler ML, et al. (1987) Degenerative lumbar disc disease: pitfalls and usefulness of MR imaging in detection of the vacuum phenomenon. Radiology 164:861–865 34. Hajek PC, Baker LL, Goobar JE, et al. (1987) Focal fat deposition in axial bone marrow: MR characteristics. Radiology 162:245–249 35. Modic MT, Masaryk TJ, Ross JS, et al. (1988) Imaging of degenerative disc disease. Radiology 168:177–186 36. Sobel DF, Zyroff J, and Thorne RP (1987) Diskogenic vertebral sclerosis: MR imaging. J Comput Assist Tomogr 11:855–858 37. Hayes CW, Jensen ME, and Conway WF (1989) Non Neoplastic lesions of vertebral bodies: findings in magnetic resonance imaging. Radiographics 9:883–903 38. Cu´enod CA, Laredo JD, Chevret S, et al. (1996) Acute vertebral collapse due to osteoporosis or malignancy: appearance on unenhanced and gadolinium-enhanced MR images. Radiology 199:541–549 39. Frager D, Elkin C, Swerdlow M, et al. (1988) Subacute osteoporotic compression fracture: misleading magnetic resonance appearance. Skelet Radiol 17:123–126 40. Abanoz R, Hakyemez B, and Parlak M. (2003) Diffusion-weighted imaging of acute vertebral compression: differential diagnosis of benign versus malignant pathologic fractures. Tani Girisim Radyol 9:176–183 41. Holscher HC, van der Woude HJ, Hermans J, et al. (1994) Magnetic resonance relaxation times of normal tissue in the course of chemotherapy: a study in patients with bone sarcoma. Skeletal Radiol 23:181–185 42. Edelstyn GA, Gillespie PJ, and Grebbell FS (1967) The radiological demonstration of osseous metastases. Experimental observations. Clin Radiol 18:158–162 43. Taoka T, Mayr NA, Lee HJ, et al. (2001) Factors influencing visualization of vertebral metastases on MR imaging versus bone scintigraphy. AJR Am J Roentgenol 176:1525–1530 44. Gosfield E III, Alavi A, and Kneeland B (1993) Comparison of radionuclide bone scans and magnetic resonance imaging in detecting spinal metastases. J Nucl Med 34:2191–2198 45. Eustace SJ and Nelson E (2004) Whole body magnetic resonance imaging. BMJ 328:1387–1388 46. Williams MP, Cherryman GR, and Husband JE (1989) MRI in suspected metastatic spinal cord compression. Clin Radiol 40:286–290 47. Carmody RF, Yang PJ, Seeley GW, et al. (1989) Spinal cord compression due to metastatic disease: diagnosis with MR imaging versus myelography. Radiology 173:225–229 48. Godersky JC, Smoker WR, and Knutzon R (1987) Use of magnetic resonance imaging in the evaluation of metastatic spinal disease. Neurosurgery 21:676–680 49. Krol G, Sze G, Malkin M, et al. (1988) MR of cranial and spinal meningeal carcinomatosis: comparison with CT and myelopathy. AJNR 9:709–714 50. Schmidt GP, Schoenberg SO, Schmid R, et al. (2007) Screening for bone metastases: wholebody MRI using a 32-channel system versus dual-modality PET-CT. Eur Radiol 17:939–949 51. Galasko CSB (1977) The role of skeletal scintigraphy in detection of metastatic breast cancer. World J Surg 1:295–298 52. Haubold-Reuter BG, Duewell S, Schilcher BR, et al. (1993) The value of bone scintigraphy, bone marrow scintigraphy and fast spin-echo magnetic resonance imaging in staging of patients with malignant solid tumours: a prospective study. Eur J Nucl Med 20:1063–1069 53. Ghanem NA, Pache G, Lohrmann C, et al. (2007). MRI and (18)FDG-PET in the assessment of bone marrow infiltration of the spine in cancer patients. Eur Spine J 16:1907–1912

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54. Kumar J, Seith A, Kumar A, et al. (2008) Whole-body MR imaging with the use of parallel imaging for detection of skeletal metastases in pediatric patients with small-cell neoplasms: comparison with skeletal scintigraphy and FDG PET/CT. Pediatr Radiol 38:953–962 55. Schmidt GP, Kramer H, Reiser MF, et al. (2007) Whole-body magnetic resonance imaging and positron emission tomography-computed tomography in oncology. Top Magn Reson Imaging 18:193–202

Part III

Therapeutic Strategies

Chapter 9

RADIOTHERAPY AND BONE METASTASES Jan W.H. Leer1 and Yvette M. van der Linden2 1 Department of Radiotherapy, UMC St Radbound, Nijimegen, The Netherlands, e-mail: [email protected] 2 Radiotherapeutic Institute Friesland, Borniastraat 36, 8934 AD Leeuwarden, The Netherlands, e-mail: [email protected]

Abstract:

The optimal treatment of bone metastases in cancer patients is one of the major challenges in palliative medicine. Patients are confronted with complaints of bone metastases increasingly as life expectancy improves with more systemic therapies. Radiotherapy is an effective, often applied, palliative, non-invasive, local treatment modality for bone metastases. In this chapter the authors discuss the history of different fractionation schedules, the effectiveness of radiotherapy to treat pain, and it’s role in prevention of pathological fracturing by inducing remineralization. Also, the treatment of neurological deficits due to spinal cord or nerve compression will be discussed. Lastly, the issues on re-irradiation of bone metastases are mentioned.

Key words: Radiotherapy · Bone metastases · Uncomplicated bone pain · Pathological fracture · Remineralization · Neurological deficits · Reirradiation

9.1 Introduction Radiotherapy plays an important role in the treatment of cancer patients with complaints due to bone metastases. In the literature, there is abundant evidence of its effectiveness to treat bone pain [1–3], to induce remineralisation for strengthening of destabilized bone [4], and to treat neurological complaints due to nerve or spinal cord compression [5, 6]. A general rule in palliation is that any treatment should be short and effective for the remaining lifespan of the patient, preferably non-invasive, and should not cause severe and long lasting side effects. To improve and maintain the quality of D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 9,  C Springer Science+Business Media B.V. 2009

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life of the patients should be the aim of any palliative treatment. It is interesting to see that there is more difference in opinion on the optimal irradiation schedule for palliative treatments, than for curative treatments. Even today, although large studies and meta-analyses have indicated that a single fraction is the preferred treatment for bone metastases in most patients, a variety of used irradiation schedules exists. During ESTRO courses, participants from various countries are asked to prescribe a treatment schedule for a breast cancer patient with an osteolytic painful lesion in her column femoris. The patient was said to be treated by breast conserving treatment, 5 years before the appearance of this lesion for a pT1 No Mo breast cancer. In spite of the available literature, the answers show a great diversity in total dose and number of fractions from a single fraction of 8 Gy to 7 times 4 Gy or 10 times 3 Gy. One can wonder what the reasons for these differences are. A frequent answer is departmental policy. Also, the reimbursement system can be of influence as was suggested by Lievens et al., [7, 8]. But most likely it is based on the expectations doctors have of the effectiveness of certain schedules. In this chapter we try to find the evidence for a preferred radiotherapy schedule for each of the indications pain, remineralisation, and neurological complaints. In addition, we will focus on the combination of radiotherapy and surgery for selected indications, and on re-irradiation.

9.2 Radiotherapy for Pain Before we can discuss the effectiveness of a certain irradiation schedule for pain relief, we have to realize that until a couple of years ago there was no consensus how pain should be measured and how pain relief or progression of pain was defined. In a non-trial situation, pain generally is not measured in a systematic way with a validated pain instrument. Consequently, retrospective data are mostly useless. However, even in randomized trials different definitions of pain relief are used. For example, in the first analysis of the largest trial on bone metastases, the Dutch Bone Metastasis Study (DBMS) of 1999 on 8 Gy single fraction versus 24 Gy in 6 fractions in 1157 patients, a change in the use of analgesics was not taken into account. Also, effect of any retreatment was included in the comparison of the two treatment schedules [9]. In 2002, an international consensus agreement was published on endpoint definitions for future clinical trials in order to achieve more uniformity in bone metastases research [10]. They proposed clear definitions for partial and complete remissions as well as for progression of pain. Most importantly, the agreement stated that pain evaluation should be patient-based, should take into account changes in pain medication, and, effect of retreatment should be excluded from primary response evaluations. In the eighties and nineties of the last century, a number of clinical trials were performed, testing different schedules with multiple and single fractions [11–20]. The size of these trials was mostly small, and included patients with a variety in tumor types that were treated with various systemic treatments. Also, pain was often scored only by the doctor during a follow-up visit which makes interpretation

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of the data troublesome. As a consequence, the discussion on the optimal treatment schedule continued [21, 22], although a Cochrane analysis on 20 trials and 43 radiotherapy schedules by McQuay et al., with publications until 1998 favored single dose radiotherapy [23]. Since 1999, a few large well designed studies on fractionation in bone metastases were published [4, 9, 24] and their results included into the second Cochrane analysis by Sze et al., on 11 randomized studies in a total of 3435 patients [1]. Sze et al., concluded that single fraction radiotherapy was as effective as multiple fractions with pain control in 60–65% of the patients, and complete response in 33%. Three additional systematic reviews [3, 25, 26] and two recent randomized studies on 898 and 376 patients [27, 28] underline these firm conclusions. Responses occur after 3–4 weeks, and median duration of response is 11–24 weeks. A few issues on pain need further deepening; response in patients with different tumor types and different localizations, patients with a favorable prognosis, neuropathic pain, toxicity, and quality of life. 1. Response rates seem to be linked to prognosis and different tumor type. For example, in the DBMS on 1157 patients, patients with breast cancer had the best overall survival and also the best responses (Table 9.1) [29]. No differences are reported in response percentages between different localizations in the skeleton. For example, in the DBMS, 73% of 342 patients with spinal metastases without neurological complaints had a response regardless of radiotherapy schedule or radiotherapy technique (two opposed fields, versus single posterior field described at a certain dose depth) [30]. 2. With regard to patients with a more favorable prognosis, some participating institutes in the DBMS had an a priori belief that 1 × 8 Gy could not be effective enough for patients with a longer life expectancy. Therefore, 92 patients considered to have a favorable prognosis and a life expectancy of more than one year, were separately randomized. Although the number is small, there was no difference in effectiveness of the two schedules in this so called favorable group neither in the pain scores nor in the duration of relief and the progression rate [9]. It was interesting to see that only 53% of the patients who were judged to have life expectancy of more than one year indeed lived longer than one year. As is known form literature, physicians are not very good in predicting a life expectancy. Mostly, they overestimate the prognosis [31, 32]. An analysis of Table 9.1 Overall survival and response percentages to palliative radiotherapy in 1157 patients treated within the Dutch Bone Metastasis Study according to their primary tumor

Breast Prostate Lung Other

N

Median OS (in months)

95% CI

Response rates SF MF

P value

451 267 287 152

16.4 9.5 3.2 3.9

14.2–18.5 7.8–11.1 2.8–3.5 3.4–4.4

78% 77% 58% 63%

Ns Ns Ns Ns

80% 78% 62% 60%

OS = Overall survival, median in months; 95% CI = ninety-five percent confidence intervals; SF = single fraction of 8 Gy; MF = multiple fractions, 6 × 4 Gy.

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320 patients who did survive for more than one year after randomization in the DBMS showed response percentages of 87% after 8 Gy and 85% after 24 Gy, with no differences in time to and duration of response [33]. For all primary tumors, prognostic factors for survival were a good performance score, no visceral metastases, and non-opioid analgesics intake (all factors, MV P < 0.001). 3. In patients with specific neuropathic pain, a TROG study on 272 patients showed no significant differences between 8 Gy of 5 × 4 Gy, with responses in 53–61% of the patients [34]. 4. With respect to toxicity and quality of life, preliminary results from the DBMS and the RTOG study showed no major differences between a single fraction and multiple fractions [35, 36]. Detailed analyses are ongoing. To date, we can state that a single fraction of 8 Gy is as effective as multiple fractions for the treatment of painful bone metastases, and should be the golden standard.

9.3 Prevention of a Fracture It is widely accepted that patients with an imminent fracture and a reasonable life expectancy and condition, should undergo prophylactic orthopedic surgery. However, prediction of a impending lesion is very difficult, and the predictive factors that are mostly used lead to a substantial surgical overtreatment. Both in painful and in non painful osteolytic metastases, prevention of a fracture could be another aim of the irradiation. A German study showed that remineralisation of osteolytic metastases was higher at three months after irradiation with 30 Gy than with 8 Gy, but no remarks on occurrence or actual prevention of fracturing were made [4]. In the Cochrane analyses by Sze, more fracturing was reported after 8 Gy than after multiple fractions, mostly based upon the Dutch publications [1, 9]. As patients with impending fractures were excluded from the Dutch trial, these results cannot unequivocally answer the question whether multiple fractions are better for the prevention of a fracture in large lesions. Although the number of fractures in the Dutch study was low (only 35 in 1157 patients), there were twice as many fractures after 8 Gy (4%) than after multiple fractions (2%) (P < 0.05). Most debilitating fractures occurred in 102 DBMS patients with femoral metastases, therefore, in a side study, all diagnostic pretreatment radiographs of these patients were collected and measured to identify lesional risk factors for fracturing and to evaluate the influence or the treatment schedule [37]. Fourteen fractures occurred during follow up, 10 after 8 Gy and only 4 after 24 Gy (P < 0.05). However, after correction for the a priori chance on a fracture as measured by the length of the cortical axial destruction, there was no difference between the two groups. Multiple fractions seemed to postpone the actual occurrence of a fracture (median time to fracture 7 weeks after 8 Gy and 20 weeks after 24 Gy). In a second paper on fracturing of the DBMS all known risk factors in the literature for impending fracturing were studied [38]. The simple and reliable measurement of the axial cortical de-

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struction had the best negative predictive value (97%). In the 102 DBMS patients with a femoral metastases, if the axial cortical destruction was equal or less than 3 cm, the chance that a fracture will occur during follow up was very small (3%). However, the positive predictive value of increased fracture risk if the axial cortical involvement is >3 cm was still too low (23%) and therefore, use of this criterion will lead to surgical overtreatment in about 75% of the patients [8, 9]. At present, a study runs in a few radiotherapy and orthopedic institutes in the Netherlands, in which the investigators focus on prediction of fracture risk based on CT scanning and finite element computer modeling.

9.4 Treatment of Spinal Cord Compression For a long time, radiotherapy has been the treatment of choice in the vast majority of patients with spinal cord compression (SCC), also in patients with a favorable prognosis. When it comes to invasive treatments, we have to realize that nowadays surgical techniques are more sophisticated as they were in previous times and that the hesitation for specialized surgeons to operate on patients with neurological deficits is reduced [39]. However, it remains a procedure with morbidity and a certain mortality rate. Therefore, it is necessary to select only those patients who could benefit from the combined approach. A recent publication indicated that in a selective group of patients with SCC from a single spinal metastasis and an expected good prognosis the outcome in terms of mobility was better when extensive surgery was given before radiotherapy [40]. However, this is only a small study on 101 patients, recruited in 10 years, without confirmation so far of its results by other randomized studies [41]. It has already been known for some years that patients, who are still ambulatory at presentation, have a higher chance on remaining ambulatory after irradiation than those who are already paraplegic or paralytic [42]. It is also known that tumor type has a predictive value for the neurological outcome of these patients. Furthermore, the speed of the onset of the spinal cord compression is of importance [43]. A slow (>14 days) development of neurological symptoms predicts a high chance on becoming ambulatory, whereas patients with a short neurological history hardly recover. Based on these data, one can question whether imminent SCC should remain a reason for emergency radiotherapy. Recently, Rades et al., published a scoring system to predict survival and neurological outcome based on retrospective data of 2096 irradiated patients [44]. Based on five variables patients were divided into five prognostic groups A to E with different outcomes with regard to overall survival and mobility. Patients with bad prognostic factors in groups A and B can best be treated with a single fraction of 8 Gy, and patients in group E with favorable prognostic factors and a radiosensitive tumor also with radiotherapy only. Two times 8 Gy seemed as effective as other schedules in this group. In groups C and D, radiotherapy only seemed not sufficient to improve mobility with regard to remaining life span. Perhaps, for patients in these groups, one could consider a combination of surgery and radiotherapy. Recently, the preliminary result of the prospective non-randomized SCORE-1 study on 231

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patients were published; on short course versus long course radiotherapy for SCC, in which no differences were noted for overall survival and ambulatory rates [45]. However, long course radiotherapy did lead to lesser in-field recurrences. Therefore, patients with an expected good prognosis might benefit from prolonged schedules. These findings still have to be confirmed in an ongoing randomized study by the same group. In a recent randomized study on 327 patients with an expected short survival (median survival 4 months) 2 × 8 Gy did not show any improvement of mobility when compared to 8 Gy [46].

9.5 Re-Irradiation In the Dutch study, as well as in others [1], the retreatment rate was higher in the single fraction group than in the multiple fractions groups, 24% as compared to 6% (P < 0.001). Although these re-treatments were given at the discretion of the treating physician, and therefore biased, some still believed that single fractions were less effective. However, when the DBMS data were reanalyzed with a focus on retreatment, it could be demonstrated that retreatment was given significantly earlier after the first treatment and at a significant lower pain score of the patients in the single fraction group as compared to the multiple fraction group, suggesting that the decision for retreatment was based on the lack of confidence of the physician in the effectiveness of the single fraction [29]. Also, the additive effect of the retreatment on the total response percentages was limited, response rates after 8 Gy raised from 71 to 75%, but remained 73% for the multiple fraction regimen. Another belief that exists on re-irradiation is that after a single fraction only multiple fractions should be given. Based on the data in the literature this may not be correct [29,47,48]. In the DBMS, there was no significant difference in primarily responding or non responding patients as in patients who showed initially progression of pain, whether a single fraction was followed by multiple fractions or vice versa. A single fraction followed by a second single fraction resulted in 74% chance on response and followed by multiple fractions in a 63% chance on response. It is important to realize that patients who did not respond on a first treatment had a 57–70% chance to respond on the second one irrespective of the schedule used. Similar observations were done in a recent study [49]. One has to keep in mind that all present data on re-irradiation are based on non-randomized analyses and relatively small numbers of patients. Therefore, a large international study is ongoing, in which in case of reirradiation patients are randomized between 1 × 8 Gy versus 5 × 4 Gy [50].

9.6 Summary What is the evidence for the role of radiotherapy for bone metastases? Several trials with together more than 4000 patients have shown that the response rate of painful bone metastases ranges between 60 and 80% with a complete

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remission rate of 15–30%. They also show that single fractions are equivalent to multiple fractions in terms of incidence of pain relief, duration of response and quality of life also for neuropathic pain. Corrected for the a priori chance on a fracture in femoral lesions, single fraction radiotherapy is also equally effective for pain, however, we need a better way to predict which lesion is at risk for a fracture. It seems that a more tailor made approach is possible for patients with spinal cord compression in which surgery might play a role. Whether this will improve the neurological outcome of these patients is not yet proven and should be subject of further studies. The issue of most optimal radiotherapy schedule for re-irradiation is still an open question and is investigated in an international randomized trial.

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15. Nielsen OS, Bentzen SM, Sandberg E, et al. (1998) Randomized trial of single dose versus fractionated palliative radiotherapy of bone metastases. Radiother Oncol 47:233–240 16. Niewald M, Tkocz HJ, Abel U, et al. (1996) Rapid course radiation therapy versus more standard treatment: a randomized trial for bone metastases. Int J Radiat Oncol Biol Phys 36:1085–1089 17. Okawa T, Kita M, Goto M, et al. (1988) Randomized prospective clinical study of small, large and twice-a-day fraction radiotherapy for painful bone metastases. Radiother Oncol 13:99–104 18. Price P, Hoskin PJ, Easton D, et al. (1986) Prospective randomised trial of single and multifraction radiotherapy schedules in the treatment of painful bony metastases. Radiother Oncol 6:247–255 19. Rasmusson B, Vejborg I, Jensen AB, et al. (1995) Irradiation of bone metastases in breast cancer patients: a randomized study with 1 year follow-up. Radiother Oncol 34:179–184 20. Tong D, Gillick L, Hendrickson FR (1982) The palliation of symptomatic osseous metastases: final results of the Study by the Radiation Therapy Oncology Group. Cancer 50:893–899 21. Ratanatharathorn V, Powers WE, Moss WT, et al. (1999) Bone metastasis: review and critical analysis of random allocation trials of local field treatment [see comments]. Int J Radiat Oncol Biol Phys 44:1–18 22. Blitzer PH (1985) Reanalysis of the RTOG study of the palliation of symptomatic osseous metastasis. Cancer 55:1468–1472 23. McQuay HJ, Collins SL, Carroll D, et al. (2000) Radiotherapy for the palliation of painful bone metastases. Cochrane Database of Systematic Reviews 1999, Issue 3. Art. No.: CD001793. DOI: 10.1002/14651858. CD001793 24. Bone Pain Trial Working Party (1999) 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Radiother Oncol 52:111–121 25. Falkmer U, Jarhult J, Wersall P (2003) A systematic overview of radiation therapy effects in skeletal metastases. Acta Oncol 42:620–633 26. Sze WM, Shelley MD, Held I, et al. (2003) Palliation of metastatic bone pain: single fraction versus mulifraction radiotherapy. A systematic review of randomised trials. Clin Oncol (R Coll Radiol) 15:345–352 27. Hartsell WF, Scott CB, Bruner DW (2005) Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97:798–804 28. Kaasaa S, Brenne E, Lundab JA (2006) Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy × 1) versus multiple fractions (3 Gy × 10) in the treatment of painful bone metastases. Radiother Oncol 79:278–284 29. van der Linden YM, Lok JJ, Steenland E, et al. (2004) Single fraction radiotherapy is efficacious: a further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment. Int J Radiat Oncol Biol Phys 59:528–537 30. van der Linden YM, Dijkstra PDS, Vonk EJA, et al. (2005) Prediction of survival in patients with metastases in the spinal column. Cancer 103:320–328 31. Chow E, Davis L, Panzarella T (2005) Accuracy of survival prediction by palliative radiation oncologists. Int J Radiat Oncol Biol Phys 61:870–873 32. Hartsell W, Desilvio M, Watkins Bruner D (2008) Can physicians accurately predict survival time in patients with metastatic cancer? Analysis of RTOG 97-14. Palliat Med 11:723–728 33. van der Linden YM, Steenland E, van Houwelingen H, et al. (2006) Patients with a favourable prognosis are equally palliated with single and multiple fraction radiotherapy: results on survival in the Dutch Bone Metastasis Study. Radiother Oncol 48:245–253 34. Roos DE, Turner SL, O’Brien PC, et al. (2005) Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol 75:54–63 35. van der Linden Y, Leer JWH, Warlam-Rodenhuis CC (2007) Quality of life in patients with painful bone metastases participating in a randomized trial: a mixed model analysis on endof-life issues. Int J Rad Onc Biol Phys 69:S31

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36. Bruner D, Winter K, Hartsell W (2004) Prospective health-related quality of life valuations (utilities) of 8 Gy in 1 fraction versus 30 Gy in 10 fractions for palliation of painful bone metastases: preliminary results of RTOG 97–14. Int J Rad Onc Biol Phys 60:S142 37. van der Linden YM, Kroon HM, Dijkstra PD, et al. (2003) Simple radiographic parameter predicts fracturing in metastatic femoral bone lesions: results from a randomized trial. Radiother Oncol 69:21–31 38. van der Linden YM, Dijkstra PD, Kroon HM, et al. (2004) Comparative analysis of risk factors for pathological fracture with femoral metastases. Results based on a randomised trial of radiotherapy. J Bone Joint Surg Br 86-B:566–573 39. Bartels RH, van der Linden YM, van der Graaf WT (2008) Spinal extradural metastasis: review of current treatment options. CA Cancer J Clin 58:245–259 40. Patchell R, Tibbs PA, Regine WF, et al. (2005) Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 366:643–648 41. van den Bent MJ (2005) Comment on: surgical resection improves outcome in metastastic epidrual spinal cord compression. Patchell et al. Lancet 366:643–648, Lancet 366:609–610 42. Rades D, Veninga T, Stalpers LJ, et al. (2006) Prognostic factors predicting functional outcomes, recurrence-free survival, and overall survival after radiotherapy for metastatic spinal cord compression in breast cancer patients. Int J Radiat Oncol Biol Phys 64:182–188 43. Rades D, Heidenreich F, Karstens JH (2002) Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 53:975–979 44. Rades D, Rudat V, Veninga T (2008) A score predicting posttreatment ambulatory status in patients irradiated for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 72:905–908 45. Rades D, Lange M, Veninga T, et al. (2008) Preliminary results of spinal cord compression recurrence evaluation (score-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression. Int J Rad Onc Biol Phys 73:228–234 46. Maranzano E, Trippa F, Casale M (2008) Single dose (8 Gy) versus short course (8 Gy × 2) radiotherapy in metastatic spinal cord compression: results of a phase III randomised multicentre trial. Radiother Oncol. 88:S139 47. Mithal NP, Needham PR, Hoskin PJ (1994) Retreatment with radiotherapy for painful bone metastases. Int J Radiat Oncol Biol Phys 29:1011–1014 48. Jeremic B, Shibamoto Y, Igrutinovic I (1999) Single 4 Gy re-irradiation for painful bone metastasis following single fraction radiotherapy. Radiother Oncol 52:123–127 49. van Helvoirt R, Bratelli K (2008) Both immediate and late retreatment with single fraction radiotherapy are effective in palliating patients with painful skeletal metastases: a prospective cohort analysis. Radiother Oncol 88:S51 50. Chow E, Hoskin PJ, Wu J, et al. (2006) A phase III international randomised trial comparing single with multiple fractions for re-irradiation of painful bone metastases: National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) SC 20. Clin Oncol 18:125–128

Chapter 10

BIPHOSPHONATES IN THE MANAGEMENT OF METASTATIC BONE DISEASE Fred Saad1 and Arif Hussain2 1 1560 Sherbrooke St east, Montreal, Quebec, H2L 4M1 Canada, e-mail: [email protected] 2 Medical Genito-Urinary Oncology, University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA, e-mail: [email protected]

Abstract:

Bone is the most common site for distant metastasis from solid tumors, and the interplay between cancer and bone increases osteoclastmediated bone resorption and can result in potentially devastating or life-limiting skeletal-related events (SREs) including pathologic fractures, bone pain requiring palliative radiotherapy, the need for orthopedic surgery, spinal cord compression, and hypercalcemia of malignancy (HCM). Therefore, bisphosphonates are emerging as an important component of care for patients with advanced malignancies involving bone. Bisphosphonates bind tightly to the bone surface. During bone resorption, these agents are ingested by osteoclasts, wherein they act as stable analogues of phosphorylated substrates, impeding further bone resorption or inducing apoptosis. Successive generations of bisphosphonates, each with increased antiresorptive activity, have been introduced into clinical practice. The most-recent generation bisphosphonate, zoledronic acid, has demonstrated the broadest clinical activity to date and is approved for the treatment of HCM and the prevention of SREs in patients with bone lesions from multiple myeloma or any solid tumor. In addition to the established benefits of bisphosphonates in the advanced cancer setting, emerging evidence suggests that these agents have antitumor effects and effectively prevent osteoporosis in patients receiving cytotoxic or hormonal therapy for early stage cancer.

Key words: Bisphosphonates · Bone metastases · Hypercalcemia of malignancy · Skeletal morbidity · Zoledronic acid D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 10,  C Springer Science+Business Media B.V. 2009

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10.1 Introduction Bone is the most common site for distant metastases from solid tumors [1, 2], and bone lesions are the most frequent cause of cancer-related pain in patients with advanced cancer [3, 4]. In addition to severe pain, the interactions between tumor and bone can manifest in other potentially debilitating skeletal complications including HCM, pathologic fracture, and spinal cord compression or vertebral collapse [5–7]. These events can significantly undermine quality of life for patients [8,9], and pathologic fractures have been correlated with significantly reduced survival [10]. Therefore, maintenance of bone health is emerging as an important component of care to preserve quality of life and functional independence for patients with advanced cancers [5, 8].

10.2 Mechanisms Underlying Bone Metastasis In addition to its structural role, bone is a vital framework that provides a compartment for hematopoiesis and a storage site for the body’s mineral reserves [1]. The human skeleton is a dynamic organ whose dry weight (excluding water and fat) composes approximately 10% of total body weight. Apart from the skin, the skeleton has the largest surface area of any organ. Bone contains an organic phase that is composed primarily of a matrix of type I collagen, wherein osteocytes and growth factors are embedded. The organic matrix of bone is mineralized by the addition of hydroxyapatite, which provides structural rigidity to the skeleton. The bone surface is the site of active remodeling processes by basic multicellular units (BMUs), which spatially couple the balanced activities of bone resorption (osteolysis) by osteoclasts and formation of new bone matrix (osteogenesis) by osteoblasts [1]. Osteoclasts originate from granulocyte-macrophage colony forming units and have receptors for calcitonin. Upon activation, osteoclasts secrete carbonic anhydrase, and the interface between the osteoclast and the bone surface is acidified by proton pumps. The acid results in dissolution of the mineral component of bone, followed by protease-mediated degradation of the organic matrix. Through this process, embedded growth factors are released from the bone matrix. These growth factors can then activate the second key component of the BMUs, the osteoblasts, to synthesize new bone matrix. Osteoblasts are of mesenchymal origin and have receptors for parathyroid hormone and 1,25 (OH)2 vitamin D. The coupling of osteoclasts and osteoblasts at the site of active bone remodeling and the balance between osteolysis and osteogenesis are normally tightly regulated; however, metastatic tumor cells can cause dysregulation of these processes (Fig. 10.1) [11]. In the “seed and soil” hypothesis, which was proposed by Sir Stephen Paget more than a century ago but remains a fundamental principle of cancer metastasis, the microenvironment of the bone serves as a fertile “soil” in which cancer cell “seeds” may grow [12, 13]. The unique properties of bone make the bone microenvironment especially conducive for the development of metastatic tumors. Sites of bone remodeling are highly vascularized, and cells are bathed in a rich

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Fig. 10.1 Pathophysiology of osteolytic and osteoblastic lesions. Bone remodeling is normally a tightly regulated process of balanced and spatially coupled osteolysis by osteoclasts and osteogenesis by osteoblasts. Tumor cells can produce a variety of factors that stimulate osteoclast-mediated osteolysis (1–2) or osteoblast-mediated osteogenesis (3). Osteolysis releases growth factors from the bone matrix that can stimulate tumor growth (4). Osteoblasts can also generate factors that affect tumor growth (5), although these pathways require further study and may differ depending on the associated primary cancer. PTHrP = Parathyroid hormone-related protein; IL = Interleukin; TGF-β = Transforming growth factor-beta; IGF = Insulin-like growth factor; FGF = Fibroblast growth factor. Adapted from Lipton [11]

milieu of bone marrow cell-derived and osteoblast-derived growth factors and cytokines [1,2,12–17]. The metastasis of cancer to bone involves a complex cascade of events that usurps the normal bone remodeling process to generate an environment even more conducive to tumor growth [1, 15, 16, 18]. Once circulating tumor cells arrest in the bone, they are stimulated by growth factors that are released into the bone microenvironment from the matrix by osteoclasts [2,16,19]. Many tumor cells secrete factors that increase osteoclast-mediated osteolysis, resulting in the release of various bone marrow-derived growth factors (e.g., transforming growth factorbeta [TGF-β], platelet-derived growth factor [PDGF], insulin-like growth factors [IGF], and bone morphogenetic proteins [BMPs]) that in turn stimulate the tumor cells [1, 2]. Thus, a vicious cycle is created in which the osteoclast plays a central role [19]. Some tumors (especially those of prostatic origin) secrete factors that stimulate osteoblasts, increasing their production of new bone matrix [20]. However, although the resulting osteoblastic lesions appear more dense on radiographs, the new bone tissue typically does not add to bone strength, and compensatory increases in osteolysis result in the release of growth factors and further undermine skeletal

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integrity [1]. Therefore, both osteolytic and osteoblastic lesions are associated with decreases in bone health. Because of the innate properties of some tissues, certain cancers appear to have a predilection for metastasis to bone. Growth factors that are released from the bone during osteolysis (such as TGF-β) can stimulate tumor cells to secrete parathyroid hormone-related protein (PTHrP), which in turn induces osteoblasts to increase secretion of the ligand (RANKL) for the receptor-activator of nuclear factor kappaB (RANK), resulting in osteoclast activation [21–24]. Other tumor-derived and/or host bone marrow cell-derived factors, such as interleukin (IL)-11, macrophage inflammatory protein 1-alpha (MIP-1α), IL-6, and tumor necrosis factor (TNF), can directly or indirectly (by modulating osteoblast function) enhance osteoclast activity [25–27].

10.2.1 Osteolytic Bone Lesions Osteolytic bone lesions result from the activation of osteoclasts and – in some cases – concurrent inhibition of osteoblasts, and appear as areas of increased bone translucency on radiographs. Key signal transduction intermediates for osteoclast activation include several members of the TNF-related family, such as RANK, RANKL, and osteoprotegerin (OPG) [18, 28–31]. Both RANKL and OPG are secreted by bone marrow stromal cells and osteoblasts. Secreted RANKL activates osteoclasts by binding to their RANK receptors. In contrast, OPG functions as a competitive inhibitor (decoy receptor) for RANKL, thus down-regulating osteoclast activity. Certain cancers, such as myeloma, express RANKL when they interact with bone marrow stromal cells [32], resulting in activation of osteoclasts and inhibition of osteoblasts [32]. Myeloma and some other cancers can activate bone resorption through the Wnt signal transduction pathway [12]. Wnt growth factors activate the pathway through the Wnt receptor and the low-density lipoprotein receptor-related protein (LRP) 5 or LRP6 co-receptors [33–35]. Myeloma cells can also secrete molecules such as dickkopf 1 (DKK1) that bind to the LRP5 co-receptor and inhibit Wnt signaling, thereby blocking osteoblast differentiation [36]. Thus, primary bone lesions from multiple myeloma (MM), which colonize the bone marrow, are typically highly osteolytic, and patients often also have generalized decreases in bone mass [37].

10.2.2 Osteoblastic Bone Lesions Osteoblastic bone lesions appear as regions of increased bone mineralization on radiographs. In contrast with the well-studied mechanisms responsible for generating osteolytic bone lesions, the enhanced osteoblast activity in bone metastases from solid tumors such as prostate cancer have not been as clearly defined. Several tumor-derived growth factors such as endothelin-1 (ET-1) and proteases such as

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urokinase-type plasminogen activator and prostate-specific antigen (PSA) have been shown to directly or indirectly stimulate osteoblasts [38–44]. Some human prostate cancer cell lines have also been found to express the osteoblast-specific transcription factor Runx2 (Cbfa1) [45]. Indeed, under appropriate conditions, prostate cancer cells in culture can also direct bone mineralization [46].

10.2.3 Malignant Osteolysis in Osteolytic and Osteoblastic Lesions For both osteolytic and osteoblastic bone lesions, excessive osteolysis undermines skeletal integrity [1, 16]. Even in patients with metastatic prostate cancer who have primarily osteoblastic bone lesions, rates of osteolysis are significantly elevated, consistent with prominent osteoclast activity [47–50]. When levels of bone collagen breakdown products were assessed in the urine of patients with malignant bone disease, moderately elevated levels were detected in patients with osteolytic bone lesions, but mean levels were approximately 3 to 4 times higher among patients with osteoblastic metastases [51, 52]. Therefore, although osteoblastic lesions appear as regions of increased mineralization on radiographs, increased osteogenesis is typically more than offset by the associated increases in osteolysis. Indeed, in both osteolytic and osteoblastic diseases, elevated rates of bone resorption (as reflected in urinary excretion of bone collagen breakdown products, as discussed later in this chapter) correlate with increased risks of skeletal morbidity and poor outcomes [53, 54].

10.3 Mechanisms of Biphosphonate Actions Bisphosphonates are small molecules that are deposited at sites of active bone remodeling, where they attach to the bone surface and are subsequently ingested by osteoclasts during osteolysis, resulting in inhibition of further osteoclast-mediated osteolysis and – for some agents – induction of osteoclast apoptosis. These agents are stable analogues of inorganic pyrophosphate (P O P) in which the central oxygen atom is replaced by a carbon atom, resulting in a P-C-P backbone. The P-C-P backbone is resistant to degradation by endogenous phosphatases, enabling bisphosphonates to function as inhibitors for enzymes with phosphorylated substrates [55, 56]. Two additional side chains (R1, R2) attach to the central carbon atom (Fig. 10.2) [57–59], resulting in a number of bisphosphonate derivatives with varying activities. In most bisphosphonates, a hydroxyl group (OH) is present in the R1 position (some exceptions include clodronate with chlorine [Cl] in the R1 position, and tiludronate with hydrogen [H] in the R1 position). Because of the phosphonic acid groups, bisphosphonates bind with high affinity to the calcium-containing hydroxyapatite in mineralized bone; this binding is especially strong when there is an OH group in the R1 position [59–61].

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Fig. 10.2 Chemical structures and antiresorptive activities of bisphosphonates registered for clinical use. Adapted from Russell et al. [57]. Relative activity information from Green et al. [58, 59]

The first generation of bisphosphonates were simple pyrophosphate analogues; however, the introduction of nitrogen-containing R2 groups allowed more specific targeting of farnesyl diphosphate (FPP) synthase, an essential enzyme in the mevalonate pathway [56]. This pathway is involved in the synthesis of sterols such as cholesterol and isoprenoids [56, 62]. The isoprenoids are necessary for the posttranslational modification (prenylation) of small G-proteins (such as members of the Ras family). Prenylation of the G-proteins is important for their function, including cell localization and integration of extracellular signals to downstream signaling pathways. When FPP synthase is inhibited, key signal transduction molecules such as Ras and Rho fail to become prenylated or geranylgeranylated, respectively, and therefore cannot effectively interact with cellular membranes (Fig. 10.3) [56, 63, 64]. Through their close interaction with the active site of FPP synthase, the nitrogen-containing bisphosphonates possess antiresorptive activity up to 10,000 times that of the earlier generation of agents (as determined by assays of relative inhibition of vitamin D-induced hypercalcemia in thyroparathyroidectomized rats, or inhibition of stimulator-induced calcium release from mouse calvaria in culture) [58]. The clinical usefulness of bisphosphonates lies in their ability to inhibit bone resorption, which underlies various pathologic conditions, ranging from osteoporosis and Paget’s disease to HCM and complications associated with cancer metastasis to bone. However, high doses of bisphosphonates can cause defects in bone mineralization. Because the newer, more potent bisphosphonates can effectively inhibit osteoclast-mediated bone resorption with lower doses, they are less likely to cause mineralization defects [65, 66].

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Fig. 10.3 Effects of Nitrogen-containing bisphosphonates on the mevalonate pathway. FPP = Farnesyl diphosphate; N-BPs = Nitrogen-containing bisphosphonates; FTIs = Farnesyltransferase inhibitors; GGTIs = Geranylgeranyltransferase inhibitors. Adapted from Yuasa et al. [63]

10.3.1 Effects Beyond Those on Osteoclast Function In addition to their effects on osteoclast-mediated osteolysis, recent in vitro and in vivo studies have demonstrated that bisphosphonates possess several other biologic activities that may be clinically beneficial, especially in the case of the newergeneration bisphosphonates. For example, the nitrogen-containing bisphosphonates have cytostatic (causing G1 - or S-phase arrest) and proapoptotic activities for several human cancer cell lines, including myeloma, breast, prostate, and others [67–70]. Moreover, the highly active nitrogen-containing bisphosphonate zoledronic acid has also shown synergistic antitumor and proapoptotic effects in combination with a broad range of cytotoxic chemotherapy agents including anthracyclines, platinum agents, and taxanes [68, 71–75]. Bisphosphonates can also inhibit several steps of the metastatic pathway [72], including adhesion of tumor cells to the bone matrix [63, 76, 77]. By chelating zinc, which is necessary for the activity

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of matrix metalloproteinases (MMPs), bisphosphonates can block the function of these enzymes and hence potentially inhibit extracellular matrix breakdown and tumor invasion [78]. Angiogenesis, an essential process for tumor growth, can also be affected by nitrogen-containing bisphosphonates. Zoledronic acid can inhibit endothelial cell proliferation and adhesion and angiogenesis [79], and early clinical testing has shown that treatment with zoledronic acid or pamidronate can lower serum levels of the proangiogenic cytokine vascular endothelial growth factor (VEGF) [80–82]. Finally, nitrogen-containing bisphosphonates have been shown to stimulate antitumor cytotoxic T cells (including the gamma-delta T cells, which recognize phosphor-antigens and have been shown to have anticancer effects in animal models) [83–89] and affect antigen-presenting cell function [90–92]. Although many of the effects of bisphosphonates on cells other than osteoclasts occur in the micromolar or millimolar range, such concentrations are potentially achievable locally in the bone microenvironment where bisphosphonates are preferentially concentrated [93]. However, the relative contribution of each of these additional mechanisms of action to the overall clinical benefits of bisphosphonates is currently unknown.

10.4 Clinical Uses of Biphosphonates Bisphosphonates are currently widely used not only in the oncology setting but also for the treatment of postmenopausal osteoporosis and diseases of bone metabolism (e.g., Paget’s disease). In the past decade, bisphosphonates have also become integral components of treatment regimens for patients with advanced cancers [5], and benefits are becoming apparent in earlier stages of the disease [94]. Bone metastases can have potentially debilitating or life-limiting complications, which are collectively referred to as SREs. These objectively measurable events include pathologic fractures, spinal cord compression, the need for surgery to stabilize bone, the need for radiation to palliate bone pain or prevent bone-related complications, and HCM [6, 95]. In prostate cancer, change in antineoplastic therapy primarily to treat bone pain is also considered an SRE [96]. These events occur in most patients with bone metastases during the course of their disease, regardless of the underlying cancer type, and patients may experience multiple SREs during their disease course (Fig. 10.4) [97]. In addition to the negative effects of SREs on patients’ quality of life [8], direct treatment costs for SREs can place a substantial burden on healthcare resources [98, 99]. Moreover, when indirect costs are included, such as those for supportive care during convalescence from SREs such as fractures and spinal cord compression, healthcare costs for patients with SREs are approximately double those for patients with advanced cancer who remain SRE-free [99, 100]. Therefore, cost savings from preventing SREs could potentially partially offset the costs for administering bone-targeted therapies in this setting [101].

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Fig. 10.4 Skeletal morbidity in patients with bone lesions from various cancers. (A) Proportion of patients with at least 1 skeletal-related event (SRE) for patients not receiving any bisphosphonate therapy in clinical trials of approximately 2 years’ duration, except for surgery to bone and spinal cord compression in multiple myeloma (∗ ), for which only 9-month data are available. Image is copyright Novartis, 2005. (B) Annual rate of SREs in patients not receiving bisphosphonate therapy in clinical trials of approximately 2 years’ duration. Adapted from Lipton [97]

10.4.1 Hypercalcemia of Malignancy Hypercalcemia of malignancy is a serious and potentially fatal complication in patients with advanced cancers [102]. Although this complication is relatively uncommon in patients with early-stage disease, it has been reported in up to 40% of patients with end-stage solid tumors, depending on the primary cancer type, and rates are even higher among patients with MM [103]. Hypercalcemia can be related to impaired renal function or paraneoplastic conditions, but, as with other SREs, osteoclast activation is a common underlying mechanism of HCM regardless of whether bone metastases are evident [102]. In the absence of clinical metastasis, HCM can occur because of the release of soluble factors (e.g., PTHrP, cytokines) into the circulation by cancer cells that activate osteoclasts. At the other end of the spectrum, enhanced osteoclast-mediated resorption because of local presence

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of tumor cells in the bone can lead to HCM [102]. Multiple myeloma is the most common hematologic malignancy associated with HCM, whereas breast and lung cancer account for a majority of the HCM cases in solid tumors [103]. Interestingly, although most patients with advanced prostate cancer have bone metastasis, hypercalcemia is rare in these men, possibly because of the predominantly osteoblastic character of prostate cancer bone metastases, which can result in sequestration of bone minerals [45, 104]. In addition to intravenous (IV) hydration, bisphosphonates have become a standard of care for managing HCM [105]. Although etidronate was the first bisphosphonate approved for the treatment of HCM, its use has largely been supplanted by that of the newer more active bisphosphonates. Studies comparing pamidronate to either etidronate or etidronate and clodronate demonstrated that IV pamidronate was more effective in lowering serum calcium levels than either of the first-generation compounds [106, 107]. This, coupled with the more convenient 1-day dosing schedule and lower rates of impaired bone mineralization with pamidronate versus etidronate and clodronate, established nitrogen-containing bisphosphonates as the standard bisphosphonate therapy for treating HCM [108, 109]. More recently, the newer-generation nitrogen-containing bisphosphonate zoledronic acid has demonstrated superiority over pamidronate in the treatment of HCM in two double-blind, double-dummy controlled trials [110]. Two hundred eighty-seven patients with HCM were randomized to one of three arms: zoledronic acid 4 mg or 8 mg via 5-min IV infusion or pamidronate 90 mg via 2-h IV infusion. By day 10, the proportions of patients achieving normalization of corrected serum calcium (CSC; the primary endpoint of the study) were 88.4% for zoledronic acid 4 mg (P = .002 versus pamidronate), 86.7% for zoledronic acid 8 mg (P = .015 versus pamidronate), and 69.7% for pamidronate 90 mg. A greater proportion of patients normalized CSC by day 4 in the 4-mg zoledronic acid arm than in the pamidronate arm (45% versus 33%; P = .005). The median duration of complete response was

Fig. 10.5 Time to relapse of hypercalcemia of malignancy among pamidronate- and zoledronic acid-treated patients. Reprinted from Major et al. (2001) Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled c 2001 American Society clinical trials. J Clin Oncol 19(2):558–567. Reprinted with permission  of Clinical Oncology, All rights reserved [110]

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32, 43, and 18 days for zoledronic acid 4 mg and 8 mg and pamidronate 90 mg, respectively (Fig. 10.5) [110]. Thus, with zoledronic acid more patients achieved normal CSC levels faster and for longer duration than with pamidronate. Based on these results, zoledronic acid was approved for HCM by the U.S. Food and Drug Administration (FDA) in 2001. Although the studies were done with zoledronic acid given at 4 or 8 mg over 5 min, current guidelines for HCM specify zoledronic acid 4 mg infused over 15 min. No specific minimal interval between repeat doses has been established, but, if necessary, doses can be repeated; it is generally recommended to wait a minimum of 7 days before administering a repeat dose. Since the regulatory approval of zoledronic acid, no other bisphosphonate has demonstrated superiority over pamidronate for the treatment of HCM [111].

10.4.2 Other Complications of Bone Metastasis Although the incidence of HCM is decreasing, other serious complications from tumor invasion to bone often occur. Indeed, bone metastases are the most frequent cause of severe cancer-related pain in the advanced disease setting [112]. Although there have been some variations in the primary and secondary endpoints used to assess the efficacy of bisphosphonates for treating malignant bone disease, in the more recently completed larger scale randomized trials the effect of bisphosphonates on the composite endpoint of SREs has been the primary criterion for evaluating their relative clinical effectiveness [95]. The SRE endpoint includes objectively measurable and clinically meaningful events including pathologic fracture, spinal cord compression, the need for orthopedic surgery or palliative radiotherapy to bone, and sometimes HCM (although an objective and skeletal-related complication of advanced cancer, HCM is typically not included as an SRE in trial primary endpoints because of regulatory restrictions on trial design). There are several parameters regarding using SREs as an endpoint in evaluating response. For instance, a conservative endpoint is the proportion of patients experiencing at least one SRE during the period of observation. Using this criterion, a patient experiencing two or more SREs during the observation period would count the same as a patient having only one SRE during the same period. On the other hand, the skeletal morbidity rate (SMR), defined as the number of SREs per patient per unit time, does not provide information regarding numbers of patients experiencing SRE, but rather indicates the number of SREs experienced by an individual patient over time. Another frequently used endpoint is the time to first occurrence of an SRE. In addition, statistical models such as that of Andersen and Gill evaluate not only the first event, but all non-censored events throughout the study and several chosen variables related to the event. This model can provide a composite view of the event patterns and the ongoing risk of events for patient treated on one arm of a trial relative to a control arm (hazard ratio [HR]) [95]. As an example, some of the bisphosphonate trials have incorporated the total number of SREs, time to first SRE, and interval between SREs into deriving HRs that describe the risk of developing a skeletal complication with respect to the bisphosphonate being tested.

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10.4.3 Complications in Different Cancer Types The most common hematologic malignancy associated with bone involvement is MM. Of the solid tumors, breast and prostate cancer patients account for approximately 80% of the malignant bone disease population, with other solid tumors making up the rest [6]. An overview of the role of bisphosphonates in these malignancies is presented below. 10.4.3.1 Multiple Myeloma Although early studies with oral etidronate demonstrated no meaningful benefits for patients with MM [113], early trials of oral clodronate suggested the potential for bisphosphonate benefits in this setting [114, 115]. In one trial, patients with newly diagnosed MM were randomized to oral clodronate 2,400 mg or placebo daily for 2 years, in addition to standard chemotherapy [114]. There was a significant reduction in the proportion of patients experiencing progression of bone lesions for clodronate versus placebo, although there was essentially no effect on other parameters such as incidence of fracture, HCM, or analgesic use. In a second randomized trial, newly diagnosed patients received clodronate 1,600 mg/day or placebo in addition to standard chemotherapy [115]. The incidence of pathologic fracture was lower for clodronate-treated patients versus placebo, but there were no significant differences in any other measured parameters. The more active nitrogen-containing bisphosphonates have demonstrated additional benefits for the prevention of SREs in patients with MM. In the first large randomized trial of IV pamidronate, 392 patients with Durie-Salmon stage III MM (at least one osteolytic bone lesion) were randomized to pamidronate (90 mg infused over 4 h every 4 weeks) or placebo [116]. Approximately two thirds of the patients were receiving first-line antimyeloma chemotherapy (stratum 1) and one third second-line therapy (stratum 2) at the time of enrollment. Results after 9 months and 21 months of treatment have been reported [116, 117]. The primary endpoint, mean number of SREs/year, was 1.1 in the pamidronate arm versus. 2.1 in the placebo arm at 9 months (P = .0006) [116] and 1.3 versus 2.2 at 21 months (P = .008) [117]. Although overall survival (OS) was not different between the two arms, OS for stratum 2 patients was 21 months in the pamidronate group compared with 14 months for placebo (P = .041), suggesting that pamidronate could have a survival benefit in a subgroup of MM patients. Based on the above data, IV pamidronate received approval by the FDA for use in patients with bone lesions from MM. Of note, pamidronate has not been tested directly against clodronate in myeloma patients. On the other hand, IV pamidronate has recently been compared with zoledronic acid in MM patients with osteolytic bone lesions in a randomized trial designed to determine whether efficacy was equivalent between these two drugs [118, 119]. At 12 months and 24 months of treatment, zoledronic acid 4 mg administered IV over 15 min decreased the proportion of patients experiencing an SRE and reduced the mean annual rate of SREs to the same extent as pamidronate 90 mg administered IV over 2 h [118, 119]. Both agents were generally well tolerated and had com-

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parable safety profiles. Furthermore, no differences between the two drugs were found in multiple event analyses of the ongoing risks of SREs [119]. Because these two agents appear to have similar efficacy for the prevention of SREs in patients with advanced MM, the shorter infusion time of zoledronic acid offers a potential advantage [120]. Guidelines for the use of bisphosphonates in this setting have been published (e.g., those of the American Society of Clinical Oncology and the National Comprehensive Cancer Network) [121–124]. 10.4.3.2 Breast Cancer Many trials with the first- and second-generation bisphosphonates have been reported in breast cancer. In this setting, the early-generation bisphosphonate clodronate has demonstrated clinical utility and received regulatory approval in the European Union but not the United States. In an early clinical trial, oral clodronate 1,600 mg/day significantly decreased the mean skeletal morbidity rate from 3.05 events/year to 2.19 events/year compared with placebo (P < .001) in patients with advanced breast cancer receiving systemic therapy (N = 173) [125]. Subsequent clinical trials in this setting have enrolled larger patient populations and evaluated treatment for a prolonged period of time. For example, two placebo-controlled trials of IV pamidronate (90 mg every 3 to 4 weeks for up to 2 years) have been conducted in women with metastatic breast cancer and at least one osteolytic bone lesion (N = 754). Women were undergoing concomitant chemotherapy in the first trial and concomitant endocrine therapy in the second trial [126, 127]. Results were consistent between these two studies [126–129]. The pooled data at 24 months revealed significant benefits for pamidronate versus placebo, including a lower proportion of women experiencing at least one SRE (excluding HCM; 51% versus 64%, respectively; P < .001), a lower rate of SREs (mean of 2.4 versus 3.7 SREs/year, respectively; P < .001), and longer median time to first SRE (12.7 versus 7 months, respectively; P < .001) [129]. These studies established pamidronate as a standard in patients with bone metastases from breast cancer [130]. During its clinical development, IV zoledronic acid (4 mg over 15 min) was compared with IV pamidronate (90 mg over 2 h) administered every 3 to 4 weeks in a trial designed to show non-inferiority of the new agent (zoledronic acid) to the former standard of care (pamidronate) in women with stage IV breast cancer and at least one skeletal lesion [118, 119]. In both arms, women also received standard systemic therapy for breast cancer. Results have been reported at 12 and 24 months of treatment [118, 119]. At 12 months, zoledronic acid was found to be equivalent to pamidronate in percentage of patients with at least one SRE, median time to first SRE, mean SMR, and relative reductions in pain and analgesic use [118]. Interestingly, in the subgroup of women treated with hormone therapy, zoledronic acid produced a striking reduction in the mean annual incidence of radiation to bone compared with pamidronate (0.33 versus 0.58 events/year, respectively; P = .015). The 24-month trial results demonstrated that zoledronic acid not only maintained its equivalence to pamidronate, but that it significantly reduced the ongoing risk of SREs by 20% versus pamidronate in patients with breast cancer (P = .025) [119].

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Fig. 10.6 Relative risk reductions for skeletal-related events versus placebo for bisphosphonates in phase III clinical trials [125,126,128,131,132,136–138]. SRE = Skeletal-related event. Adapted from Pavlakis et al. [135]

Benefits were especially profound among patients within the hormone-therapy stratum, in whom zoledronic acid decreased the ongoing risk of SREs by 30% relative to pamidronate (P = .0009) [119]. In a subsequent placebo-controlled trial of zoledronic acid in patients with bone metastases from breast cancer, which was required for registration of this agent in Japan, 4 mg zoledronic acid not only significantly reduced the rate and risk of SREs, but also significantly reduced pain levels throughout the course of the trial (P < .05 for all) [131]. Intravenous and oral ibandronate have been investigated in placebo-controlled trials in patients with bone metastases from breast cancer [132–134]. In a 2-year trial in patients with bone metastases from breast cancer (N = 466), ibandronate (6 mg via 1- to 2-h infusion every 3 to 4 weeks) significantly reduced the proportion of 12-week periods affected by SREs compared with placebo (1.19 versus 1.48, respectively; P = .004) and significantly reduced the mean annual rate of SREs compared with placebo (2.65 versus 3.64 SREs/year, respectively; P = .032) [132]. However, IV ibandronate did not significantly reduce the proportion of patients who experienced an on-study SRE compared with placebo. Oral ibandronate demonstrated some benefits in reducing the risk of SREs, but these only achieved statistical significance when clinical trial data from two separate trials were pooled together [133]. A large Cochrane Database Systems analysis was performed on the overall benefits of bisphosphonate therapy in patients with bone metastases from breast cancer [135]. This analysis confirmed the beneficial effects of bisphosphonates as a class in patients with advanced breast cancer (Fig. 10.6) [125, 126, 128, 131, 132, 135–138] and revealed that, of all bisphosphonates tested, zoledronic acid has demonstrated the largest reduction in risk of SREs versus placebo in this setting [135].

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Table 10.1 Efficacy of bisphosphonates in randomized, placebo-controlled trials in patients with bone metastases secondary to prostate cancer Study

Patients, N Drug

Smith [139]

57

Etidronate

Elomaa et al. [140]

75

Clodronate

Kylmala et al. [141]

57

Clodronate

Strang et al. [142]

55

Clodronate

Dearnaley et al. [143]

311

Clodronate

Ernst et al. [144]

208

Clodronate

Small et al. [145]

236

Saad et al. [96, 146]

643

Dose

Efficacy results

7.5 mg/kg (IV, days 1–3), then 400 mg/day (oral) 3,200 mg/day (1st month), then 1,600 mg/day (oral) 300 mg/day (IV, days 1–5), then 1,600 mg/day (oral) 300 mg/day (IV, days 1–3), then 3,200 mg/day (oral) 2,080 mg/day (oral)

No significant benefits

1,500 mg (IV q 3 weeks) Pamidronate 90 mg (IV q 3 weeks) Zoledronic acid

4 mg (IV q 3 weeks)

↓ Pain and analgesic use (1st month only); ↓ Serum calcium levels ↓ Pain by 10% (not significant)

No significant benefits

↑Bone progression-free (P = .066) and overall survival (P = .082) ↓Worsening of WHO PS (P = .008) ↓ Pain (not significant) No significant benefits in pain or proportion of patients with SREs ↓ Proportion of patients with ≥ 1 SRE (P = .028) ↑ Time to 1st SRE (P = .009) ↓ Rate of skeletal morbidity (P = .005)

IV = Intravenous; WHO PS = World Health Organization performance status; q = Every; SRE = Skeletal-related event. Adapted from Saad [147].

10.4.3.3 Prostate Cancer Early studies of bisphosphonates in patients with bone metastases from prostate cancer suggested that these agents could have palliative effects, but it was not until the introduction of zoledronic acid that any bisphosphonate demonstrated statistically significant long-term reductions in SRE risks compared with placebo in this setting (Table 10.1) [96, 139–147]. The majority of these studies enrolled patients with hormone-refractory prostate cancer. However, other studies have suggested that treatment is beneficial for patients with bone metastases regardless of the hormone sensitivity of the tumors. For example, a recent study in 311 men with metastatic hormone-sensitive metastatic prostate cancer randomized to oral clo-

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dronate versus placebo for 3 years revealed a notable improvement in symptomatic bone progression-free survival in the clodronate group, although benefits did not achieve statistical significance compared with placebo [143]. Subgroup analyses suggested that patients who initiated bisphosphonate therapy at an earlier stage of metastatic disease were more likely to experience treatment benefits. In contrast with the inconsistent benefits of clodronate in this setting, zoledronic acid (4 mg by 15-min infusion every 3 weeks) significantly reduced the proportion of patients with an on-study SRE by a relative 22% (38% versus 49% for placebo; P = .028), delayed the median time to first SRE by more than 5 months (488 versus 321 days for placebo; P = .009), and reduced the ongoing risk of SREs by 36% (as assessed in the Andersen-Gill model; P = .002) compared with placebo in a 2-year randomized placebo-controlled trial [96, 146]. Zoledronic acid is the first and only bisphosphonate to receive worldwide regulatory approval for the treatment of men with bone metastases from prostate cancer. In the United States, bone lesions must have progressed despite hormonal therapy (e.g., patients must have hormone-resistant prostate cancer before zoledronic acid is indicated). However, the underlying pathophysiology of bone metastases is similar in both hormone-sensitive and hormone-refractory prostate cancers, and there is no evidence that the hormone sensitivity of the cancer would affect the efficacy of zoledronic acid [148]. Indeed, in the clinical trial of zoledronic acid in patients with breast cancer, benefits were especially profound in the stratum of patients undergoing hormonal therapy [119]. Currently, an ongoing multi-center double-blind placebo-controlled clinical trial, CALGB protocol 90202, is evaluating zoledronic acid 4 mg IV every 4 weeks in hormone-sensitive prostate cancer patients with bone metastasis who have started androgen ablation therapy within 6 months of trial entry. This trial, which allows for cross-over from the placebo arm to the zoledronic acid arm at the time of developing hormone resistance while on androgen ablation, will help define the role of bisphosphonate therapy across the spectrum of hormone sensitive prostate cancer with metastasis to bone. 10.4.3.4 Other Solid Tumors To date, zoledronic acid is the only bisphosphonate that has demonstrated efficacy in preventing SREs in patients with bone metastasis from a variety of solid tumors other than breast cancer and prostate cancer in a randomized placebo-controlled trial (Table 10.2) [149–157]. In this trial, which enrolled a total of 773 patients with bone metastases from non small-cell lung cancer or other solid tumors, patients were treated with zoledronic acid or placebo every 3 weeks for 9 months in the core portion of the trial, with an additional 12-month extension phase. Approximately 50% of the enrolled patients had non-small cell lung cancer, and the majority had already experienced SREs prior to study enrollment. The median survival of the enrolled group was 6 months, reflecting the advanced stages of cancer in the trial. In the core (9-month) analyses [149,150], zoledronic acid 4 mg reduced the proportion of patients with at least one SRE (excluding HCM) compared with the placebo group (38% versus 44%, respectively; P = .127), but the between-group difference did not

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Table 10.2 Efficacy of bisphosphonates in clinical trials in patients with bone metastases secondary to solid tumors other than breast or prostate Study

Design

Patients, N

Drug

Efficacy results

Rosen et al. [149, 150]

RCT (versus placebo)

773

Zoledronic acid

Piga et al. [151]

RCT (versus placebo)

66

Oral clodronate

Heras et al. [152]

RCT (versus placebo)

150 (colorectal cancer)

Ibandronate

Kiagia et al. [153]

Open-label single-arm

32

Ibandronate

Kritikos et al. [154]

Controlled

13

Ibandronate

12

Pamidronate

20 (lung cancer)

Pamidronate

For 4 mg vs placebo: ↓ in % of patients with ≥ 1 SRE (−HCM; P = .127, +HCM, P = .039); ↑ median time to first SRE (P = .009) and time to first pathologic fracture (P = .020); ↓ risk of SREs in multivariate analysis For 1,600 mg/day vs placebo: No SRE data; trends for less deterioration in KPS and pain; ↓ in need for analgesics (P = .042) ↓ in % of patients with ≥ 1 SRE (P = .029); ↑ median time to first SRE (P = .009); ↓ risk of SREs in multivariate analysis (P = .003) For 4 mg vs baseline: No SRE data; 75% pts had ↓ or stable analgesic use; ↓ serum calcium (P = .03) and alkaline phosphatase (P = NS) For ibandronate vs pamidronate: No SRE data; ↓ analgesic usage and serum calcium (P ≤ .05) For 30–60 mg vs baseline: No SRE data; 60% of patients had ↓ pain

Rankovic and Mrdja [155]

Open-label single-arm

RCT = Randomized, controlled, double-blind trial; SRE = Skeletal-related event; HCM = Hypercalcemia of malignancy; KPS = Karnofsky Performance status; NS = Not significant.

reach statistical significance unless HCM was included as an SRE in the analysis (38% versus 47%, respectively; P = .039). Zoledronic acid also extended the median time to first SRE (excluding HCM) by 2 months compared with placebo (P = .023). Benefits remained significant at the 21-month analysis; however, because of the poor prognosis of this population, very few patients survived for the duration of the study [150]. Except for lung cancer, the most common tumor type in this study was renal cell carcinoma (RCC; representing approximately 10% of the population of enrolled patients), and exploratory analyses of this subset revealed significant benefits despite the low statistical power (N = 74) [158]. Zoledronic acid 4 mg

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significantly prolonged the median time to first SRE versus placebo (not reached at 9 months versus 72 days for placebo; P = .006) [158, 159]. Furthermore, the time to first pathologic fracture was 168 days for the placebo arm and was not yet reached at 9 months for zoledronic acid 4 mg (P = .003) [158,159]. These data suggest that zoledronic acid may be particularly beneficial in RCC patients with bone metastases.

10.5 Safety and Tolerability of Bisphosphonates The adverse-event profile of bisphosphonates varies depending on route of administration. Oral bisphosphonates are associated with gastrointestinal toxicity [160,161]. Because of the potential for gastrointestinal intolerance, strict dosing guidelines have been developed that require patients to stand or sit in an upright position after administering each dose. To aid in absorption of oral bisphosphonates, these agents must be taken after fasting and only with water [161]. These requirements may limit the utility of oral bisphosphonates in cancer patients, especially in elderly patients who might have difficulties in swallowing medications, fasting, or remaining upright for prolonged periods of time. All IV bisphosphonates are associated with dose- and infusion rate-dependent effects on renal function [162]; however, because of rapid clearance from the circulation after IV infusion by uptake in the bone and excretion by the kidneys, exposure to other tissues is limited, which minimizes potential systemic toxicity. The bulk of excretion by the kidneys occurs within 24 h of drug administration. Both glomerular and tubular mechanisms may be involved in excretion of bisphosphonates by the kidneys. Therefore, serum creatinine should be monitored prior to administering each dose of IV bisphosphonates, and prescribing information should be consulted for adjusted dosing based on creatinine clearance rates. Flu-like symptoms (including fever, chills, arthralgias, myalgias) are relatively common in patients after the initial dose, but tend to subside with the second and subsequent administrations. The levels of certain cytokines such as TNF-α and IL-6 (but not IL-1) can increase in the serum of patients within 24–72 h of IV administration [163]. The significance of this in the context of the acute-phase reaction is not clear, however, as there may be no correlation between serum cytokine levels and the acute symptoms [163]. The possibility of metabolic abnormalities, particularly with hypocalcemia and hypophosphatemia, also exists with bisphosphonate use. To minimize the risk of hypocalcemia in the recently conducted large-scale zoledronic acid trials for bone metastasis, both calcium and vitamin D supplements were used. Recently, there have been reports of osteonecrosis of the jaw among cancer patients receiving complex treatment regimens including bisphosphonates for the advanced cancer [164]. This condition, defined as exposed bone within the oral cavity that does not heal within 6 weeks of appropriate dental care and that occurs in the absence of osteoradionecrosis or metastatic disease in the jaw, is described in detail in Chapter 12

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10.6 Initiation of Therapy and Duration of Treatment Currently, with the exception of the prostate cancer indication for zoledronic acid in the United States (which states that the prostate cancer must have progressed despite hormonal therapy), the approved bisphosphonates are indicated for administration to patients with diagnosed bone lesions. For patients with cancer-related bone metastases, currently there is no evidence to suggest that physicians should wait until after the onset of symptoms to initiate bisphosphonate therapy. Indeed, there are several reasons why early treatment may be optimal. Exploratory analyses of the phase III trials of zoledronic acid revealed that although zoledronic acid was beneficial in all patient subsets, the reduction in the rate of SREs versus placebo was most profound among patients who initiated treatment before onset of bone pain compared with patients who were not treated with zoledronic acid until after painful bone lesions developed [148, 165, 166]. Moreover, because bisphosphonates have been shown to delay the onset of SREs, early treatment could preserve patients’ functional independence throughout their disease course. Indeed, patients who have already experienced an SRE have a higher risk of experiencing subsequent SREs. Moreover, some SREs have been associated with significant decreases in survival. For example, in an exploratory analysis of pathologic fractures and survival among the 3,049 patients who enrolled in the large phase III trials of zoledronic acid for malignant bone disease [96, 119, 146, 149, 150, 167, 168], pathologic fractures were associated with significantly increased risks of death for all cancer types evaluated except for lung cancer, in which high fracture rates and poor survival limited the statistical power of the analyses [10]. Therefore, preventing or delaying the onset of pathologic fractures could potentially provide survival benefits for these patients. The duration of bisphosphonate therapy for skeletal metastasis has not been clearly defined, although once initiated, patients are generally maintained on it throughout the course of their disease [5]. Experience suggests that bisphosphonates can be administered safely over a relatively long term (for at least 2 years). However, a theoretical concern is that because bisphosphonates become incorporated into bone with very slow turnover, continued accumulation with prolonged use could make the bone brittle and compromise its ability to sustain/respond to stress and strain [169]. However, the effects of nitrogen-containing bisphosphonates on bone mineralization and repair in patients with advanced cancer are unknown. Indeed, in some patient subsets, zoledronic acid (compared with placebo) has been shown to improve the response rate of bone metastases during treatment [158, 159].

10.7 Exploratory Analyses of Bone Markers During bone remodeling, fragments of bone collagen or procollagen and enzymes are released into the serum (Fig. 10.7) [170]. These biochemical markers of bone resorption and bone formation can be measured in the serum or urine of patients and

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Fig. 10.7 Biochemical markers of bone remodeling. BALP = Bone-specific alkaline phosphatase; TRAcP = Tartrate-resistant acid phosphatase; MMPs = Matrix metalloproteinases. Adapted from Fohr et al. [170]

can provide important insight not only into the ongoing interactions between tumor and bone [171, 172], but also into the patient’s prognosis [53, 54, 173–175]. The phase III clinical trials of zoledronic acid for the prevention of SREs in patients with malignant bone disease included substudies in which bone marker levels were assessed throughout the trials. Correlative analyses between baseline and on-study levels of the osteolysis marker N-telopeptide of type I collagen (NTX) and the osteogenesis marker bone-specific alkaline phosphatase (BALP) revealed that elevated NTX levels were associated with significantly increased risks of SREs and death compared with patients with normal NTX. This correlation was found for all tumor types during treatment with bisphosphonates or in the absence of bone-targeted therapy [53, 54]. Recent measurements appeared to have better prognostic potential compared with baseline measurements. Correlations between clinical outcomes and elevated BALP were similar but less consistent [53, 54]. Further analyses of these databases have yielded important insight into the benefits of antiresorptive therapies in patients with malignant bone disease. In the subset of patients who were evaluated for urinary NTX levels at baseline and after 3 months on study, approximately half had baseline NTX levels higher than the upper limit of normal (≥64 nmol/mmol creatinine; Fig. 10.8) [174]. Within 3 months, the majority of patients (≥70%) treated with zoledronic acid in each study had achieved normal NTX levels (NTX <64 nmol/mmol creatinine; Fig. 10.9) [174], and almost all patients with normal baseline NTX maintained normal NTX levels during treatment [174]. In contrast, most patients treated with placebo did not have decreases in their NTX levels on study. Interestingly, transition to normal NTX levels during treatment was associated with significantly improved survival compared with persistently elevated NTX (Fig. 10.10) [174]. The differences in survival between

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Fig. 10.8 NTX levels are often elevated in cancer patients with bone lesions. HRPC = Hormone-resistant prostate cancer; NSCLC/OST = Non-small cell lung cancer or other solid tumors. Data from Lipton et al. [174]

patients with elevated NTX at both baseline and 3 months and patients with elevated NTX that normalized during zoledronic acid treatment ranged from approximately 6 months to more than 1 year, depending on the tumor type. Moreover, a recent pooled analysis of all placebo-controlled phase III trials of zoledronic acid in patients with bone metastases revealed that zoledronic acid significantly improved OS by 17% compared with placebo in patients with NTX ≥ 64 nmol/mmol creatinine at baseline [176]. Among patients with especially elevated baseline NTX (≥ 100 nmol/mmol creatinine), zoledronic acid produced a 26% decrease in the risk of death (P = .006). These analyses suggest that malignant bone disease can have a

Fig. 10.9 Zoledronic acid effectively normalizes NTX levels within 3 months in the majority of treated patients. NTX = N-telopeptide of type I collagen; E→N = Patients whose NTX levels normalized at 3 months from elevated baseline levels; E→E = Patients whose NTX levels remained elevated at 3 months; HRPC = Hormone-resistant prostate cancer; NSCLC/OST = Non-small cell lung cancer or other solid tumors. Data from Lipton et al. [174]

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Fig. 10.10 Normalization of NTX within the first 3 months of zoledronic acid therapy is associated with significantly improved survival versus persistently elevated NTX. NSCLC/OST = Non-small cell lung cancer or other solid tumors; HRPC = Hormone-resistant prostate cancer; E→N = Patients whose NTX levels normalized at 3 months from elevated baseline levels; E→E = Patients whose NTX levels remained elevated at 3 months. Adapted from Lipton et al. [174]

substantial effect on a patient’s overall prognosis. Whether the basis of this benefit is through reduction in tumor burden in bone or through the prevention of potentially debilitating or life-limiting SREs is unknown.

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10.8 Biphosphonates and Other Issues in Cancer Patients Two emerging issues in the context of cancer and bisphosphonates are preventing bone metastasis in patients at high risk and minimizing the risk of osteoporosis from anticancer therapies. Several recent reviews on bisphosphonates have highlighted these clinically important issues [177–180].

10.8.1 Prevention of Bone Metastases There is a solid preclinical rationale that bisphosphonates have activities that could delay or prevent the development of bone metastases if they are administered in the early cancer setting [78, 79, 181–185]. Clinical trials of the relatively weak firstgeneration bisphosphonate clodronate suggested that these effects may translate into clinical benefits. In one of these studies, 1,000 women with operable breast cancer receiving standard adjuvant therapy received clodronate 1,600 mg/day or placebo for 2 years [186]. At a median follow-up of 5 years, there were no statistical differences in the incidence of skeletal or extraskeletal metastasis, although OS favored the clodronate arm (P = .047). A smaller randomized trial (N = 302) in a more selected population of women with T1-4 N0-2 breast cancer and tumor cells in the bone marrow (as determined by immunohistochemistry) but without overt skeletal metastasis has also been reported [187]. After initial local therapy (mastectomy or breast-conserving surgery with radiation) women received appropriate adjuvant therapy with or without 2 years of clodronate 1,600 mg/day [187]. Approximately 50% of the enrolled women had no axillary node involvement. At a median followup of 3 years, the incidence of distant metastasis was 50% lower in the clodronate group compared with the nonclodronate group, with a significant decrease in both skeletal and extraskeletal lesions. Furthermore, OS favored the clodronate group (P = .001) [187]. In an updated follow-up of the trial, although the difference in visceral metastasis was no longer statistically significant between the two groups, lower incidence of bone metastasis and increased OS were maintained in the clodronate group [188]. In contrast to this study, another trial of similar size (N = 299) in women with node-positive breast cancer receiving adjuvant therapy with or without clodronate 1,600 mg/day for 3 years showed no OS benefit for clodronate [189]. Similar rates of skeletal metastasis were found between the clodronate and control groups. However, the incidence of extraskeletal metastasis was significantly higher in patients who received clodronate, who also had poorer OS. With the contradictory outcomes of these trials, the role of clodronate in the adjuvant setting in high-risk breast cancer remains unresolved, and hopefully will be clarified with an ongoing, much larger trial, sponsored by the National Surgical Adjuvant Breast and Bowel Project (NSABP), in this patient population. Recent clinical trials of the more active, newer-generation bisphosphonate zoledronic acid have investigated potential synergies between this agent and adjuvant therapies for breast cancer. Potential synergy between zoledronic acid and the aromatase inhibitor (AI) letrozole is being investigated in 3 trials with parallel

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design, the Zometa/Femara Adjuvant Synergy Trials (Z-FAST, ZO-FAST, E-ZOFAST). These trials enrolled more than 2,600 postmenopausal patients with hormone-responsive, estrogen-receptor–positive and/or progesterone-receptor–positive, stage I to IIIa breast cancer [190]. Patients were randomized to letrozole for 5 years plus either immediate treatment with zoledronic acid (4 mg every 6 months; upfront arm) or zoledronic acid initiated only when indicated by predetermined bone health parameters (delayed arm). Integrated analyses from these trials show that the median time to disease recurrence was somewhat longer and that disease recurrence rates at 12 months were significantly reduced in the upfront versus delayed zoledronic acid arms (0.84% versus 1.9%, respectively; P = .04) [191]. Moreover, a pooled 24-month study revealed a significant improvement in disease-free survival (DFS) for the upfront versus the delayed zoledronic acid treatment arms (47% reduction in risk of a disease recurrence or death for upfront versus delayed in a stratified multivariate analysis; P = .0183) [192]. The Austrian Breast and Colorectal Cancer Study Group Trial 12 (ABCSG12) is a large adjuvant therapy trial evaluating the efficacy of ovarian suppression plus anastrozole (ANA) or tamoxifen (TAM), alone or in combination with twice-yearly zoledronic acid, in premenopausal women with early-stage hormoneresponsive breast cancer [193]. In this large, randomized, controlled study of an AI and zoledronic acid as adjuvant therapy in premenopausal women, DFS was the primary endpoint; relapse-free survival (RFS) and OS were secondary endpoints. After surgery, patients were randomized to goserelin plus one of four treatment arms: TAM or ANA alone, or TAM or ANA in combination with zoledronic acid (4 mg every 6 months). With a median follow-up of 48 months, therapy was well tolerated overall, although the rate of uterine polyps was significantly higher for TAM versus ANA. No significant difference was observed in DFS between TAM and ANA (HR = 1.10; 95% confidence interval (CI) = 0.79, 1.54; P = .59). However, addition of zoledronic acid significantly reduced the risk of DFS events by 36% (HR = 0.64; 95% CI = 0.46, 0.91; P = .01) and RFS events by 35% (HR = 0.65; 95% CI = 0.46, 0.92; P = .015) compared with endocrine therapy alone. Moreover, there was a trend toward a 40% improvement in OS for zoledronic acid compared with endocrine therapy alone (HR = 0.60; 95% CI = 0.32, 1.11; P = .10) [194]. Rates of contralateral breast cancer, locoregional recurrence, and distant recurrence (including skeletal metastases) were each numerically lower with zoledronic acid versus no zoldedronic acid. Adverse events among the four groups were generally mild to moderate and were consistent with those previously reported during adjuvant endocrine therapy [195]. There were no confirmed cases of renal toxicity or osteonecrosis of the jaw associated with zoledronic acid treatment. Results from these trials suggest that the addition of zoledronic acid (4 mg every 6 months) to adjuvant endocrine therapy has benefits that extend beyond the prevention of AI-associated bone loss. These clinical results suggest that the antitumor activity of zoledronic acid observed in preclinical studies can translate into significant clinical benefits. Other ongoing trials of bisphosphonates in the adjuvant therapy (e.g., SWOG-0307, NSABP B-34, AZURE, SUCCESS, NATAN, AZAC, ZEUS, RADAR, STAMPEDE, and Study 2419) will enroll a total of more than 20,000

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patients. Long-term follow-up of these trials and other ongoing studies will provide further insight into the activity of bisphosphonates in the early cancer setting. The role of zoledronic acid in treatment of early cancers is expected to evolve.

10.8.2 Osteoporosis in Cancer Bone loss is being recognized as an increasingly important problem in patients with cancer, especially in breast and prostate cancers. In the early cancer settings, both of these malignancies are often treated with hormone-deprivation therapies, and elevated risks of fractures have been reported [177, 180]. Because cancer is more prevalent among the elderly and because advanced age is associated with decreases in bone mineral density (BMD), patients may be at high risk for osteoporotic fractures even before they receive anticancer therapies [23]. In premenopausal women with breast cancer, purposeful suppression of ovarian function as part of endocrine therapy or ovarian ablation as a result of systemic chemotherapy can lead to decreased BMD and increased risk of osteoporosis. Tamoxifen can also decrease BMD in premenopausal women (in postmenopausal women tamoxifen can actually increase BMD). In postmenopausal women, agerelated osteopenia and osteoporosis can be aggravated by the use of AIs that further decrease residual estrogen levels. Oral clodronate and risedronate have been shown to decrease the chemotherapy-induced loss in BMD in women with breast cancer [196, 197]. Several doses and schedules of zoledronic acid have been evaluated in a study of postmenopausal women with low BMD [198]. Even with once-a-year dosing, zoledronic acid (4 mg IV) was found to increase BMD to levels seen with daily oral bisphosphonate therapy. In the early breast cancer setting, zoledronic acid (4 mg every 6 months) has demonstrated significant efficacy for preventing bone loss during AI- and tamoxifen-based therapies in Z-FAST, ZO-FAST, and ABCSG12 [193, 199]. These studies enrolled more than 3,000 women and compose the largest dataset to date for evaluating the effects of bisphosphonates on BMD in patients with early breast cancer. In these studies, zoledronic acid was generally well tolerated, and potential benefits beyond the preservation of bone health were identified, as described previously. Significant BMD losses occur in men with prostate cancer undergoing androgendeprivation therapy. Although oral alendronate has shown efficacy in treating men with osteoporosis from a variety of causes, there are limited prospective data on its efficacy in preventing bone loss in men with prostate cancer [200]. However, initial results from a randomized, double-blind, crossover trial of oral alendronate in men undergoing androgen deprivation (N = 112) showed that early treatment with alendronate could actually increase BMD in this setting [201]. However, further studies of alendronate are needed to confirm these results. The effects of IV pamidronate have been determined in men with prostate cancer and established bone metastasis, as well as in men with locally advanced/recurrent prostate cancer but without bone metastasis [202, 203]. In the former trial, men had to be receiving androgen deprivation for at least 6 months before trial entry, whereas in the latter study men were

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assigned prospectively to androgen deprivation with or without pamidronate. In the former trial BMD increased when patients received pamidronate, and decreased with placebo [202]. The latter trial demonstrated that pamidronate initiated at the time of instituting androgen deprivation and administered periodically thereafter (every 3 months) can prevent androgen-deprivation-induced osteoporosis [203]. In a more recent trial in men with M0 prostate cancer starting androgen-deprivation therapy, zoledronic acid (4 mg IV every 3 months for 1 year) was compared with placebo [204]. The primary endpoint of the trial was percentage change in BMD from baseline to end of study at 1 year. This study demonstrated that zoledronic acid actually increased BMD during androgen ablation. Although pamidronate and zoledronic acid have not been compared directly, data from the last trial would suggest that zoledronic acid is more effective in that it not only prevents bone loss but also increases BMD in the setting of concurrent androgen ablation.

10.9 Summary The role for bisphosphonates in the treatment of patients with advanced cancers is expanding. Bisphosphonates are part of the standard therapies used to treat HCM. In patients with bone lesions from solid tumors and MM, bisphosphonates have become an important adjunct to systemic anticancer therapies to reduce the risk of painful and potentially debilitating SREs. Further optimization of bisphosphonate use and prediction of treatment outcome, based on their effects on bone resorption and bone formation markers, is promising but will require additional studies. As more data are obtained from ongoing and future studies in earlier cancer settings, such as adjuvant therapy to prevent bone metastasis and supportive therapy to improve BMD and protect against iatrogenically-induced osteoporosis, the role of bisphosphonates will continue to evolve. R Acknowledgments We thank Catherine Browning, PhD, ProEd Communications, Inc. , for her medical editorial assistance with this manuscript.

Abbreviations ABCSG-12 AI ANA BALP BMD BMPs BMUs

Austrian Breast and Colorectal Cancer Study Group Trial 12 Aromatase inhibitor Anastrozole Bone-specific alkaline phosphatase Bone mineral density Bone morphogenetic proteins Basic multicellular units

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CSC DFS DKK-1 ET-1 FDA FGF FPP FTIs GGTIs HCM HR HRPC IGF IL IV KPS LRP MIP-1α MM MMPs N-BPs NS NSCLC/OST NTX OPG OS PDGF PTHrP PSA RANK RANKL RCC RCT RFS SMR SREs TAM TGF-β TNF TRAcP VEGF WHO PS Z-FAST, ZO-FAST, E-ZO-FAST

Corrected serum calcium Disease-free survival dickkopf 1 Endothelin-1 U.S. Food and Drug Administration Fibroblast growth factor Farnesyl diphosphate Farnesyltransferase inhibitors Geranylgeranyltransferase inhibitors Hypercalcemia of malignancy Hazard ratio Hormone-resistant prostate cancer Insulin-like growth factor Interleukin Intravenous Karnofsky performance status Lipoprotein receptor-related protein Macrophage inflammatory protein 1-alpha Multiple myeloma Matrix metalloproteinases Nitrogen-containing bisphosphonates Not significant Non-small cell lung cancer or other solid tumors N-telopeptide of type I collagen Osteoprotegerin Overall survival Platelet-derived growth factor Parathyroid hormone-related protein Prostate-specific antigen Receptor activator of nuclear factor kappaB RANK ligand Renal cell carcinoma Randomized, controlled, double-blind trial Relapse-free survival Skeletal morbidity rate Skeletal-related events Tamoxifen Transforming growth factor-beta Tumor necrosis factor Tartrate-resistant acid phosphatase Vascular endothelial growth factor World Health Organization performance status Zometa/Femara Adjuvant Synergy Trials

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Chapter 11

COMBINED RADIOTHERAPY AND BISPHOSPHONATES: STATE OF ART Vassilios Vassiliou and Dimitrios Kardamakis Department of Radiation Oncology, University of Patras Medical School, 26500 Patras, Greece, e-mail: [email protected]

Abstract:

In the event of malignancy bone metastases are common and are inevitably accompanied with potentially serious complications that may deteriorate the clinical and performance status (PS) of patients, or even threaten life. Both radiotherapy (RT) and bisphosphonates (BPs) have an established and important role in the management of metastatic bone disease when applied as monotherapies. Their concomitant use may though result in a synergistic or additive effect that may bring about an improved therapeutic outcome as evidenced through radiologic (objective) and clinical (objective) evaluations. The current chapter describes in detail the potential interactions between BPs and RT and presents the results of both clinical and animal studies implementing their concurrent use. Through clinical studies a considerable reduction of the mean patient pain scores was noted, accompanied by a marked limitation of the opioid analgesic need. Similarly, a significant improvement of the patient’s quality of life (QOL) and PS scores was noted. The worth noticing clinical response was associated with an enhanced reossification of metastatic bone lesions. This may be responsible for the marked improvement of the clinical status of patients, since it has been shown that bone density has a strong, negative and statistically significant correlation with pain (the main factor affecting negatively both the PS and QOL of evaluated patients). The results of animal studies involving tumor induced osteolysis reinforce our hypothesis about the synergistic activity between BPs and RT, since their concurrent application was shown to bring about a significant increase of bone density and an improved bone stability, biomechanical strength and micro-architecture.

Key words: Bisphosphonates · Radiotherapy · Bone metastases · Bone density · Pain · Clodronate · Ibandronate · Pamidronate · Zoledronic acid · Etidronate D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 11,  C Springer Science+Business Media B.V. 2009

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11.1 Introduction In the event of malignancy the skeleton is among the most favored sites for metastases [1], being the third commonest metastatic site after liver and lungs [2]. The development of metastatic bone lesions is a potentially catastrophic complication since they may bring about severe complications including pain, pathological fractures, spinal cord or nerve root compression, impaired mobility and hypercalcaemia [2–5]. Such complications may deteriorate both the QOL and clinical status of affected patients [6, 7] and may even reduce the expected survival [8]. The mechanisms and pathophysiology of bone metastases is complex, involving numerous processes both at the primary and metastatic site. These processes include detachment of tumor cells from the primary malignancy, circulation in the bloodstream and migration, arrest at a distant (metastatic) site, invasion of the neighboring normal tissues, proliferation and formation of blood supply through the process of neo-angiogenesis [9]. Several factors favor the high frequency of skeletal metastases, including the high and slow blood flow in the bone marrow compartment [10], the adhesive molecules of tumor cells that promote tumor cell binding to stromal cells and bone matrix [11] and the fertile soil of the osteomedullary compartment that enhances tumor cell homing [12]. The overall management of metastatic bone disease should be multidisciplinary and include treatment modalities such as analgesic medications, RT, BPs and radioisotopes. Both RT and BPs have an established role in the management of metastatic bone lesions and have demonstrated their effectiveness through numerous clinical trials. Recent clinical studies have though shown that apart from being effective when applied as sole treatment modalities, their concomitant use may bring about an improved therapeutic outcome. The possible interactions between RT and BPs include normal tissue tolerance, spatial cooperation and additive or super-additive effects. The latter brings about a synergistic activity and an enhanced reossification at sites of metastatic bone lesions that may be responsible for the worth noticing clinical response observed in patients managed by combined RT and BPs. Notably it was recently shown that the correlation between pain and bone density is strong, negative and statistically significant [7]. The results of published trials investigating the effectiveness of the concomitant use of RT and BPs are promising, since a significant clinical and radiological response was recorded. More specifically, a considerable decrease in the mean pain scores of patients was observed, as well as a worth noticing improvement in the mean scores of QOL and PS. The significant clinical response was accompanied by a considerable increase in bone density in regions of bone metastases and pain relief was accompanied by a marked reduction in analgesic opioid consumption. Even though promising and encouraging, the results of such clinical trials should be corroborated by larger, randomized studies.

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11.2 Radiotherapy as a Sole Treatment Modality RT is an established treatment modality for the management of bone metastases since many decades [13], achieving a significant pain response and reduction in complication rates [14, 15]. The above can be accomplished by both single fraction (SF) and multi fraction (MF) RT, with overall pain response rates (sum of partial and complete pain responses) reaching 58 and 59% respectively [14]. Additionally complete pain response (pain score of zero) rates after SF and MF RT were reported to be 23 and 24% respectively [14]. Wide-field external RT may be successfully applied for the palliation of patients with widespread metastatic skeletal disease. In such cases whole- or hemi-body RT offers significant symptomatic relief in up to 91% of treated patients, with 45% reporting a complete pain response [16]. A potential alternative to wide-field RT is the management of patients with radioactive isotopes. Two of the most commonly used radionuclides in Europe and USA are strontium-89 and samarium-153, bringing about considerable pain relief. The overall pain response rates of radionuclide therapy have been reported to range between 40 and 95% [17]. Even though it is well known that RT can achieve significant pain responses, the exact mechanism of action by which this is brought about is uncertain. RT has shown to cause a high level of tumor cell kill even in tumors that are relatively radioresistant [18], causing a shrinkage of the metastatic tumor mass. This effect by itself does not though explain the early pain responses that are observed in up to 25% of patients within the 48 h after whole-body RT [19]. The tumor shrinkage may though indirectly reduce the osteoclastic activity at metastatic bone sites by decreasing the osteoclastic mediator release, allowing osteoblasts to repair and reossify metastatic skeletal lesions [6, 20]. Moreover, it has been found that RT causes a considerable suppression of urinary bone resorption markers, the level of suppression correlating with the response to treatment [21,22]. This finding may implicate that the analgesic effect of RT is brought about via the inhibition of osteoclastic activity at metastatic bone lesions and it could be an important link for the possible synergistic activity between RT and BPs.

11.3 Biphosphonate use in Patients with Metastatic Bone Disease The use of BPs in oncologic patients has increased considerably in recent years, becoming an integral part of the overall therapeutic management of patients with metastatic bone disease [23–26]. Apart from being effective in deceasing bone pain scores [27–29], BPs have also shown to significantly reduce the risk of potential skeletal related events (SREs) such as pathologic fractures, radiation or surgery to bone, spinal cord compression and hypercalcaemia [27, 30–35]. Furthermore, the

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application of BPs in patients with bone metastases has resulted in an improvement or maintenance of QOL [28, 36, 37]. BPs have a great variability both in their chemical structure and their physicochemical and biological properties [38]. They are compounds that are similar to pyrophosphates (ppi) which have a P-O-P structure. The general BP structure includes a central carbon atom in the place of oxygen, a replacement that enables the accommodation of two side chains (R1 and R2). These side chains are responsible for both the binding ability of BPs and their anti-resoptive activity [35]. BPs are classified into 3 generations, with clodronate and etidronate being first generation compounds. These compounds have a weak anti-resoptive activity which is a result of the simple substituents of the central carbon atom [39]. Second generation BPs such as pamidronate and ibandronate contain a primary nitrogen atom in their R2 chain, rendering them more potent than the non-nitrogen containing first generation BPs. The third generations BPs are the most potent BP compounds and typical examples of this generation are zoledronic acid (containing a tertiary amine within a ring structure) and risedronate (containing a nitrogen atom in a pyridyl ring). The potency among the three generations of BPs differs significantly, with the relative potency of clodronate to ibandronic acid and zoledronic acid being 1:857:16,700 [40]. BPs have a marked affinity for mineralized bone matrix, binding avidly to it and selectively concentrating on bone resorption surfaces where there is an increased bone mineral exposure [41]. The concentration of BPs at sites of active resoptive activity was reported to be in the range of 0.1–1 mM [42]. BPs are internalized by osteoclasts by active endocytosis [43], causing a reduction in both their activity and viability. After being internalized, non-nitrogen containing BPs are metabolized into cytotoxic analogues of ATP, ultimately reducing osteoclastic viability through apoptosis [44]. Nitrogen-containing BPs inhibit the mevalonate pathway through the farnesyl diphosphate and geranyl diphosphate synthases [45]. This inhibition leads to the loss of prenylated proteins that are essential for the post-translation lipid modification (prenylation) of small guanine triphosphates such as Ras, Rho and Rac [46]. Prenylated proteins are responsible for the regulation of many key osteoclast cell functions, including cellular morphology, membrane ruffling, endosomal function, integrin-induced intracellular signaling and the ATPase function. The loss of these proteins and the deregulations of the aforementioned cellular functions, ultimately bring about cellular death via apoptosis [35]. It may be though worth to note that it has been reported that the marked reduction in the resoptive activity of osteoclasts is caused predominantly through an early and strong functional inhibition rather than a decrease in their viability [47].

11.4 Interactions between Radiotherapy and Biphosphonates The interactions between systemic anti-cancer agents such as BPs or chemotherapy and local treatments such as RT, are summarized into four different mechanisms. These include (1) additive and (2) super-additive effects, (3) spatial cooperation and (4) changes in the tolerance of normal tissues [19, 48].

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11.4.1 Additive and Super-additive Interactions and Synergistic Activity The viscous cycle involved in osteolytic metastases involves (1) the release of several osteolytic mediators from tumor cells, (2) an enhanced osteoclastic activity that causes extensive bone resorption, (3) the release of growth factors during the process of bone destruction and (4) tumor cell growth that further induces bone destruction through lysis [1, 49]. As already discussed, local external RT achieves a high tumor cell kill in metastatic bone lesions, indirectly decreasing osteoclastic activity by causing a drastic reduction in the release of osteoclastic mediators. On the contrary, BPs exert a direct and selective action on osteoclasts, that also inhibits osteoclastic activity. Their common action on osteoclasts interrupts the vicious cycle of lytic metastases described above, bringing about a positive-synergistic activity within metastatic bone lesions. This enables osteoblasts to achieve an enhanced reossification and remodeling of the destructed bone [3, 6, 20]. As it will be discussed in detail in the “results” section, the enhanced reossification in metastatic bone lesions may be responsible for the significant and worth noticing clinical response reported in studies that investigated the effectiveness of the concomitant use of RT and BPs in patients with metastatic bone disease. Interestingly, it was recently reported that pain in areas of bone metastases has a negative, strong and statistically significant association with bone density [7]. Additionally, the biochemical changes of metastatic bone lesions that result from the reduced osteoclastic activity, may bring about an additive or super-additive effect that may also contribute to the significant pain response [3, 6, 20]. Neither RT nor BPs are completely effective when used as sole treatment modalities [20]. This is concluded from the routine clinical practice as well as published clinical studies in which it is readily seen that patients with bone metastases managed with BPs are referred for radiotherapy as a result of persisting or relapsing pain, whilst others who were initially treated with RT, benefit from the subsequent application of BPs. It has been estimated that 30–40% of breast cancer patients with bone metastases and 15–20% of patients with multiple myeloma managed with BPs, will also undergo RT either due to persisting bone pain or impending pathological fracture [20]. As seen from a different scope, the use of RT in patients with bone metastases managed with BPs is decreased as a result of the reduction in the frequency of potential SREs. It can therefore be concluded that RT and BPs may complement each other, achieving an improved therapeutic outcome when applied concurrently.

11.4.2 Spatial Cooperation In spatial cooperation, local treatments such as RT and/or surgery are used to deal with the primary tumor, and systemic treatment modalities such as chemotherapy and/or hormonal therapy are applied to manage microscopic or asymptomatic disease that is found outside the radiation treatment field. The same concept also

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applies for metastatic bone lesions, since RT can effectively manage locally symptomatic bone lesions, whereas the concomitant use of BPs will improve the therapeutic response in the metastatic bone lesion under irradiation, but at the same time it will manage metastatic bone lesions located elsewhere, by impending their progression and enhancing reossification [20, 50]. BPs may also bring about a pain reduction in skeletal regions not submitted to radiotherapy and their use is especially useful in patients with multiple metastatic bone lesions.

11.5 Normal Tissue Protection and Tolerance One of the major concerns for the concomitant application of two different treatment modalities is the toxicity to normal tissues, with the ideal case being that toxicities do not overlap i.e., the application of a systemic treatment does not decrease the normal tissue tolerance to RT and vice versa. The prescribed RT doses for the treatment of metastatic bone lesions are in general well below the radiation tolerance levels of normal tissues [20]. There are though two exceptions that need to be noted, the first being upper hemibody RT that is used in patients with wide spread multiple bone metastases. In such a case, lung toxicity is a major concern. The second case that should be discussed is the irradiation of large parts of the skeleton (wide field irradiation), that may result in a marked bone marrow suppression [20]. BPs do not in any way interfere with lung or bone marrow function, since their activity is selective and brings about a decrease in osteoclastic activity. The concurrent administration of RT and BPs should be therefore be considered safe and well tolerated, as has been already reported in published studies that evaluated the effectiveness of their concomitant use [3,6,51–55]. The only adverse events or toxicities recorded in the above studies were side-effects associated with the intravenous BP treatment and included a flu-like syndrome, pyrexia, myalgias, arthralgias and diffuse bone pain.

11.6 Clinical Studies Evaluating the Therapeutic Outcome of Patients Managed by Combined RT and BPs Up to date, a total of 7 studies that investigate the effectiveness of the concomitant application of RT and BPs have been published in the scientific literature and will be presented below. Additionally, the results of the combined application of RT and BPs in induced osteolysis animal models will also be discussed, since they support our hypothesis for the synergistic activity between RT and BPs. The first trial that will be presented is a phase II, randomized study, involving a total of 52 patients with lytic bone metastases from various primary malignancies. All patients were submitted to MF RT in the region of the painful bone lesion (36–40 Gy) and also received concomitantly intravenous infusions of ibandronate (4 mg). The administration of ibandronate was either performed as a single dose (group A) or as separate 1 mg doses over a period of four weeks (group B). This

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was subsequently followed by monthly intravenous infusions of 3 mg ibandronate. In spite of the fact that ibandronate dosing was suboptimal, a significant reduction in the patient pain scores was recorded, accompanied by a considerable decrease in the need of analgesics. More specifically, the median pain score that was evaluated through the visual analogue scale (VAS, 0 = no pain; 10 = worst possible pain), was reduced from 8 to 1 point, eight weeks post the onset of the combined treatment. At the same time point the reduction in the median WHO analgesic intake scale score (AIS, 0 = no analgesics; 1 = NSAIDs; 2 = weak opioids; 3 = morphine) was from 3 to 1 points. Furthermore, a complete recalcification in regions of bone metastases was noted in 16/52 patients (31%) and a partial recalcification was recorded in 24/52 (46%) of cases. No significant differences were recorded between the two evaluated groups in terms of pain response or analgesic scores, or recalcification rates and no side effects were observed. The authors concluded that the concomitant application of RT and ibandronate brought about a fast and substantial pain relief which was maintained in the long-term [51]. Kouloulias V and colleagues have published 3 different clinical studies that investigated the therapeutic outcome of patients with lytic bone metastases from various primary tumors, managed with the combined use of RT and monthly intravenous infusions of pamidronate [52–54]. The first study published by the above author involved 18 women with breast cancer and metastatic bone disease, managed with RT and monthly intravenous infusions of 180 mg pamidronate. The first BP infusion was administered concomitantly with MF RT, with the total irradiation dose reaching 30 Gy (in 10 fractions). Changes in bone density of treated bone metastases were followed by analyzing the mean value and energy of gray-level histograms of plain radiographs (MVGLH and EGLH). At the time point of 6 months post the onset of the combined treatment, the radiological evaluation revealed a reduction in the mean EGLH by 11.1% and an increase in the MVGLH by 11.6% (as compared to the baseline evaluation) (p < 0.05). The level of reossification correlated highly with pain response, since the mean bone pain score (BPS) that was calculated by multiplying bone pain severity (0–3) with pain frequency (0–3), was found to decrease by a total of 6.3 points. A statistically significant improvement in the mean PS of patients (evaluated by the ECOG scale) was also noted. The only toxicities that were recorded during the study were BP-treatment related and included a flu-like syndrome in 7 patients and myalgias or arthralgias in a total of 5 patients [52]. The second study by Kouloulias et al. evaluated the radiologic and clinical response in 42 patients with osteolytic metastases from various primary tumors. Patients were separated into 3 different treatment groups, with all undergoing RT. In group A pamidronate dose was increased stepwise from 90 to 180 mg (group A, n = 11), group B patients received monthly intravenous infusions of 180 mg pamidronate (group B, n = 15) and group C patients were treated by RT alone (group C, n = 16). The total dose of RT was 30 Gy, administered in 10 fractions and for groups A and B the first intravenous pamidronate infusion was performed concurrently with RT. During the study all patients were submitted to both radiological and clinical evaluations. These were carried out at baseline and at several time points after the onset of the combined treatment, including 6 months. The radiological

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evaluation of patients at the time point of 6 months revealed statistically significant differences from baseline in MVGLH and EGLH values for all groups. Interestingly, the recalcification was significantly higher in group B patients versus group A (p < 0.05), while in group C it was inferior to that achieved in either group A or B. The clinical evaluation was carried out by the assessment of BPS, AIS and PS (ECOG scale). At the time point of 6 months for all the 3 groups and for all the aforementioned clinical assessments, statistically significant improvements were recorded as compared to baseline (p < 0.05). In more detail, baseline BPS was found to decrease by 6.3, 6.7 and 5.2 points for groups A, B and C respectively. The corresponding improvement in the mean PS scores was by 2.6, 2.7 and 2.2 points respectively. During the study 2 patients of group A and 5 of group B developed a flu like syndrome. Myalgias or arthralgias were also reported by 4 patients of group A and 6 of group B. Through the above study it was demonstrated that both the radiologic response (re-ossification) and pain response achieved by the combined treatment, were superior to that brought about when RT was used as a sole treatment modality [53]. In the last study by the same author 33 breast cancer patients with metastatic bone lesions were managed by combined fractionated RT (30 Gy in 10 fractions) and monthly intravenous infusions of 180 mg pamidronate. The clinical response was evaluated through the BPS and PS (ECOG), but also by following changes in the QOL of patients evaluated by using the EORTC-Core Quality of life questionnaire (QLQ-C30, 0–100). The radiological response was evaluated by monitoring the changes in the MVGLH and EGLH and by using the international Union Against Cancer (UICC) criteria. According to these criteria a complete radiological response is considered to be a complete recalcification, with a disappearance of measurable lesions. As compared to the evaluation at the onset of therapy, at 6 months of treatment the mean BPS of patients was decreased by 5.8 points and the mean PS score was found to improve by 2.4 points (for both p < 0.001). QOL was also found to improve significantly, since at the same evaluation time point the average score of global QOL scale was shown to increase from 11.9 to 83.3 points (p < 0.001). Similarly, the mean score of the physical functioning scale was also found to improve by a total of 55.9 points (p < 0.001). The considerable improvement in the clinical status of patients that may be characterized as worth-noticing was accompanied by a marked increase in the level of recalcification, with 88% of patients achieving a complete and 12% a partial radiological response (UICC criteria). The analysis of digitalized radiographs showed that MVGLH increased by 9.5% and EGLH decreased by 10.8%. During the treatment period, a flu-like syndrome that was a result of the BP treatment occurred in 13/33 patients. Additionally, a total of 27 patients complained of arthralgias or diffuse myalgias. Through this trial it was shown that the concurrent administration of RT and pamidronate was well tolerated and brought about a high therapeutic response [54]. Two of the most recently published clinical trials that studied the therapeutic response of patients with bone metastases managed with the concurrent application of RT and BPs, were conducted by Vassiliou et al. [3, 6]. In both trials enrolled patients had bone metastases from a variety of primary solid tumors. All patients received fractionated external beam RT up to a total dose of 30–40 Gy over 3–4.5

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weeks and 10 monthly intravenous infusions of 6 mg ibandronate. The therapeutic response was evaluated by implementing both clinical (subjective) and radiological (objective) assessments carried out at the onset of the combined therapy (baseline) and at 3, 6 and 10 months thereafter. The clinical evaluation was performed by using the VAS (0–10), the Karnofsky performance status index (KPS, 0–100) and the EORTC QOL questionnaire (QLQ-C30) (physical functioning scale, 0–100). At all evaluation time points a detailed record of the analgesic consumption for pain management was kept and opioid analgesic requirement was converted into daily oral morphine equivalents (mg). Pain response was assessed by using the following criteria: (1) a complete pain response was defined as a pain score of zero at the irradiated anatomical site without concomitant increase in opioid analgesic consumption (stable or reduced opioid use), (2) a partial response corresponded to either a pain score reduction of ≥1 point at the treatment site without any increase in opioid analgesic need, or a ≥25% reduction in opioid analgesic intake with unchanged pain score, (3) pain progression was defined as either a pain score increase ≥1 point, or ≥25% increase in opioid use and (4) stable pain defined as unchanged pain score and analgesic consumption. Radiological assessments were performed by using computed tomography (CT), carried out at the same evaluation time points as clinical assessments. All irradiated anatomical areas with known metastatic bone lesions were scanned with a slice thickness of 3 mm, while using a bone algorithm. Bone metastases were subsequently delineated by expert radiologists, with the bone density of each lesion measured in Hounsfield Units (HU). Any treatment related adverse events were recorded and graded by using the WHO criteria. The first study by Vassiliou and coworkers included a total of 45 patients [3]. At the time point of 3 months post the onset of the combined treatment the mean pain score of patients was found to decrease from 6.3 to 0.8 points (p < 0.001), with 68.9% of patients reporting a complete pain response and 31.1% a partial pain response. Notably, the overall pain response (sum of the percentage of patients experiencing a complete and partial pain response) was 100%. At the evaluation time point of 10 months the patient mean pain score was further reduced to 0.5 points, with 80.8% of patients reporting a complete pain response and 11.5% a partial pain response. In parallel to the significant pain responses, both the percentage and the daily opioid consumption in oral morphine equivalents were markedly reduced. This was a clear indication that the recorded pain response was not in any case a result of a better analgesic management. Significant improvements were also noted for both KPS and QOL at all of the assessment time points. Analytically, the mean score for KPS increased from 64 points at the baseline to 83.4 at 3 months and to 87.3 points at 10 months (for all changes p < 0.001). QOL was also found to improve considerably, with the mean score increasing from 40.9 at baseline, to 82.2 at 3 months and to 88.5 points at study end (all p < 0.001). The excellent clinical response was accompanied by a significant radiological response, with the radiological assessments revealing an enhanced reossification in the anatomical regions of bone metastases. As compared to baseline, bone density was shown to increase by 20% at 3 months and by 73% 10 months post the onset of the combined therapy. Figure 11.1 presents transverse CT images before (pre) and 10 months after (post) the onset of treatment, depicting evidence of re-ossification [3].

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Fig. 11.1 CT images before (pre) and 10 months after the onset of the combined treatment (post), presenting evidence of reossification (a) in a patient with a lytic metastatic lesion an upper left upper rib from lung carcinoma; (b) in a patient with renal carcinoma and an osteolysis in the left iliac bone; (c) renal carcinoma patient with a lytic metastatic bone lesion in the right iliac bone. This figure is reprinted from the Int J Radiat Oncol Biol Phys 67(1):264–272, Figure 6, copyright 2007, with kind permission of Elsevier Inc.

It should be pointed out that during the study period no re-treatments (reirradiation) due to pain relapse or impending pathologic fracture were recorded and only minor BP-related adverse events were observed. The fact that no retreatments were carried out during the study period may be of high therapeutic

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importance, since the re-treatment rates after fractionated or single fraction RT were reported to be 8 and 20% respectively [14]. The Spearman rank order correlation coefficient (Rs ) was used to evaluate the correlation between the clinical and radiological parameters assessed in the study. Interestingly it was found that baseline bone pain was the main factor that affected negatively KPS (Rs =−0.38) and QOL (Rs =−0.78) of evaluated patients. Similarly, the correlation between bone density and pain was shown to be strong, negative and statistically significant (Rs = −0.43) [3]. The latter may have both clinical and therapeutic implications, since the excellent pain response observed in the study, as well as the accompanied considerable improvements in QOL and KPS, could be a result of the significant increase of bone density in the metastatic bone lesions under treatment. The negative and strong correlation between pain and bone density (Rs = − 0.57) was also reported in a study by the same author and colleagues that evaluated the correlation between the different types of bone metastases and the clinical status of patients [7]. Combined RT and ibandronate were also used to manage 52 patients with different types of metastatic bone lesions (lytic, mixed or sclerotic) [6]. Apart from the assessment of the effectiveness of the combined treatment, the study investigated any possible differences in the level of clinical and radiologic response between patients with the three different types of bone metastases. CT was both used to monitor changes in bone density and to group patients according to the type of the bone metastasis that was to be irradiated. As compared the initial evaluation at baseline, statistically significant improvements were noted at all of the assessment time points, for all the patient groups, in both clinical parameters such as pain, QOL (physical functioning scale) and KPS and radiological parameters such as bone density (all p < 0.001). The average pain score of the lytic group was found to decrease from 8.1 at the initial assessment, to 1.5 points at the time point of 3 months. The corresponding reductions in the mean pain scores for patients with mixed and sclerotic metastases were from 6.2 to 0.5 and from 4.4 to 0.3 points respectively. Notably, at the same evaluation time point, the percentage of patients reporting a complete pain response for the lytic, mixed and sclerotic groups was 40.9, 75 and 78.5% respectively. At study end (10 months of follow up) the mean pain scores for the 3 groups of patients were further reduced (Fig. 11.2). The percentage of patients with a complete pain response at study end was 64.3% for the lytic, 83.3% for the mixed and 90% for the sclerotic group. As in the previous study, in parallel to the significant pain responses, the percentage and opioid intake measured in oral morphine equivalents was markedly reduced for all groups during the study period. To note that from 6 months onwards, only the patients with osteolytic metastases consumed such analgesics. Worth noticing improvements were also noted for all groups in QOL (physical functioning), since at the evaluation time point of 3 months the mean score of QOL for the lytic group was reported to increase from 29.7 to 73.7 points, for the patients of the mixed group from 40.6 to 83.7 points and for the patients with sclerotic metastases from 52.5 to 81.4 points (Fig. 11.2). The KPS of patients was also considerably improved, since at 3 months post the onset of the combined therapy the mean KPS score of the lytic group was found to increase from

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Fig. 11.2 Graphical representation of the variation of the mean scores of pain, QOL, KPS and bone density for the 3 groups during the study period. This figure is reprinted from Clin. Experimental Metastasis Journal, 24:169–178, Figure 1, copyright 2007, with kind permission of Springer Science + Business Media B.V

60.9 to 81.3 points, for the mixed group from 64.4 to 84.4 points and for the sclerotic group from 69.3 to 83.6 points (Fig. 11.2) [6]. The radiological evaluation carried out by CT revealed that at 10 months post the onset of treatment bone density was almost tripled for the lytic group and almost doubled for patients of the mixed group (Fig. 11.2). As also reported in the previous study, the re-treatment rate was zero. Figure 11.2 depicts the variation of the mean scores of pain, QOL, KPS and bone density for patients of the three groups during the study. Regarding adverse events recorded during the 10-month study period,

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4 patients complained about grade II pyrexia and 3 for diffuse grade II bone pain [4]. The above study did not only show that the concomitant application of BPs and RT is effective and safe in managing patients with different types of metastatic bone lesions, but it also revealed that the degree of clinical and radiologic response differs between patients with different types of bone metastases. In spite of the fact that statistically significant improvements were recorded for all groups of patients and the therapeutic outcome at study end was comparable between groups, patients with lytic bone metastases had the highest overall clinical and radiological response (as compared to baseline), despite the fact that for this group the mean values of all evaluated parameters were the worst of the 3 groups at all assessment time points (apart from pain at 10 months) (Fig. 11.2). Furthermore, the percentage of patients with lytic bone lesions experiencing a complete pain response was the least of the 3 groups throughout the 10-month study period [6]. The most recently published clinical study that investigated the effectiveness of the combination of RT and zoledronic acid, is the study by Maˇnas A and co-workers. In this study 118 patients suffering from bone metastases from a variety of primary neoplasms were either managed with 6 or 8 Gy SF RT and monthly intravenous infusions of 4 mg zoledronic acid. All patients underwent clinical evaluations in order to monitor changes in pain (VAS), functional status and QOL. The time to the onset of skeletal events was also recorded. The authors reported that the mean time to skeletal events was significantly greater in the group managed with 8 Gy (p = 0.021). Similarly in the same group of patients an improvement in functional status was noted. Pain responses and improvement in QOL were comparable among the two groups [56].

11.7 Concomitant Application of BPs and RT in Animal Models of Tumor Induced Osteolysis The concurrent application of BPs and RT was also studied in animal models in which lytic bone lesions were induced after intraosseous injections of tumor cells. Krembien et al. investigated the combined effect of BPs and RT on the level of remineralisation and restabilization of lytic bone lesions in male Wistar rats. Walker carcinosarcoma 256B cells were injected into both proximal tibia metaphyses on day one of the study. All rats were irradiated with a single dose of 17 Gy on day 7 and sacrificed on day 49. Group 1 served as the control group and received only irradiation, whereas groups 2 and 3 were additionally treated with BPs (clodronate; daily intraperitoneal injection dose of 20 mg/kg). The administration of BPs in group 2 rats was carried out before radiation treatment on days 3–6, a schedule that was referred to as early BP treatment. In group 3 BPs were administered concurrently with RT on days 7–10 (simultaneous BP treatment). Apart from bone density, the end points of the study included microstructural parameters of bone (all evaluated on day 49). X-ray absorptiometry was used to measure bone density and histomorphometry was performed to investigate microstructural parameters [57].

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The analysis of results revealed that post irradiation bone density was significantly higher among animals managed with the early BP treatment, as compared to the control group and the group that was treated with the simultaneous schedule (p = 0.001). Similarly, through the histomorphometric analysis of bone, it was found that the microstructural parameters (bone area, trabecular number and separation), were better-preserved in the early treatment group. The authors concluded that early application of BP in combination with RT leads to an improved remineralisation and restabilization of osteolytic metastatic lesions [57]. In the second animal model of tumor induced bone lysis that will be discussed, the effect of RT administered concomitantly with zoledronic acid was evaluated. In this study breast cancer cells were injected into the right femur of 30 female nude mice. The animals were separated in three different treatment groups: no treatment, irradiation with 20 Gy and 20 Gy plus zoledronic acid. Animals were irradiated 3 weeks post tumor cell injection and the zoledronic acid infusions were administered once a week for a total of 6 weeks. Progression of tumor induced osteolysis was monitored through lateral radiographs and bone densitometry was performed by using dual-energy X-ray absorptiometry. Furthermore, total bone analysis was carried out by using a micro-CT scanner and mechanical testing was performed by whole-limb torsional testing. Mice were euthanized at nine weeks or earlier in the case of lameness or pathology [58]. Mice that received the combined treatment had a higher bone density, bone volume and mechanical strength as compared to mice that were only irradiated (p < 0.05). Similarly through the statistical analysis it was revealed that the femora of mice managed with the concomitant treatment did not significantly differ in bone density and strength from normal bones. Additionally the micro-CT reconstructions showed that the combined treatment resulted in an improved microarchitecture (as compared to the 20 Gy group). This finding may have an important clinical implication since the restoration of normal bone qualities after combined treatment decreases the risk of complications such as pathologic fractures. The authors reported that the application of RT together with zoledronic acid restored the normal qualities of bone with respect to density, mechanical strength and microarchitecture [58]. In both of the above studies it was readily seen that the concomitant application of RT and BPs results in an increased level of re-ossification that is accompanied by an improved bone stability [57], mechanical strength [58] and improved microarchitecture [57, 58]. The above results reinforce our hypothesis concerning the synergistic activity between RT and BPs at sites bone metastases that brings about an enhanced reossification [3, 6, 59].

11.8 Conclusions and Future Perspectives It is well known that RT and BPs play a key role in the overall management of patients with metastatic bone lesions, achieving a reduction of the risk of skeletal complications and bringing about a significant analgesic effect that improves the physical status of affected patients. Even though it has been shown that the analgesic

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effect of RT in patients with bone metastases from solid is double to that achieved by the use of BPs [20], neither of them has a complete efficacy when applied as a sole treatment modality. Furthermore, as described earlier, through spatial cooperation and synergistic-additive or super-additive effects, one may complement the other achieving an improved therapeutic response. As seen from the aforementioned clinical studies, the additive-synergistic activity between RT and BPs brings about an enhanced reossification in areas of bone metastases. This was a common outcome of all of the presented studies that assessed the effectiveness of RT combined with BPs and in every one of them the high re-ossification level was accompanied by a marked pain relief and significant improvements in KPS and QOL. Notably, the clinical and radiological responses that were reported in the studies implementing the combined treatment appear to be superior to those achieved by either treatment when used as a monotherapy. Interestingly, the combined treatment proved to be superior to RT alone in terms of increase in bone density and microarchitecture in both of the discussed studies involving animal models of tumor induced osteolysis [57, 58]. Even though the results of the studies that investigated the effectiveness of the combined application of BPs and RT are to our opinion both promising and encouraging and offer a new therapeutic perspective for the overall management of patients with metastatic bone lesions, they should be corroborated by larger randomized clinical studies. Similarly, it would also be very useful to investigate further the interactions between RT and BPs and determine the most effective treatment scheme in regards to RT fractionation and BP dosing and sequencing.

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V. Vassiliou and D. Kardamakis monitoring of recalcification using assessment of grey-level histogram in plain radiographs. Int J Radiat Oncol. Biol Phys 57:143–157 Vassiliou V, Vomvas D, Christopoulos C, et al. (2006) Combined radiotherapy-chemotherapy: lessons from the management of bone metastases or inoperable lung carcinoma. Rev Clin Pharmacol Pharmacokinet Int Ed 20:120–121 Maˇnas A, Casas F, Ciria JP, et al. (2008) Randomized study of single dose (8 Gy vs 6 Gy) of analgesic radiotherapy plus zoledronic acid in patients with bone metastases Clin Transl Oncol 10:281–287 Krempien R, Huber PE, Harms W, et al. (2003) Combination of early bisphosphonate administration and irradiation leads to improved remineralisation and restabilization of osteolytic metastases in animal tumor model. Cancer 98:1318–1324 Arrington SA, Darmon TA, Mann KA, et al. (2008) Concurrent administration of zoledronic acid and irradiation leads to improved bone density, biochemical strength, and microarchitecture in a mouse model of tumor-induced osteolysis. J Surg Oncol 97:284–290 Vassiliou V, Kalogeropoulou C, Kardamakis D (2008) Clinical and radiologic response in patients with bone metastases managed with combined radiotherapy and bisphosphonates. J Surg Oncol 98:567–568

Chapter 12

BIPHOSPHONATES IN THE TREATMENT OF BONE METASTASES – OSTEONECROSIS OF THE JAW Cesar Augusto Migliorati NSU College of Dental Medicine, 3200 S. University Drive, Fort Lauderdale, Florida 33328, USA, e-mail: [email protected]

Abstract:

Bisphosphonates changed the way cancer patients with bone cancer and cancer metastatic to bone are treated. They promote considerable improvement in patient’s quality of life, reduce pain and decrease the risk of skeletal adverse events like pathological fractures. However, for some patients, these improvements come with a high price when they develop bisphosphonate adverse events. One serious adverse event that has been recently described is osteonecrosis of the jawbones (BON). This complication may affect up to 10% of those patients taking an intravenous formulation of bisphosphonates, more commonly pamidronate and zoledronic acid. Risk factors, diagnostic procedures, patient management and prevention will be the main focus of the discussion. In addition, we will review what is known about the pathobiology of this oral cavity complication of bisphosphonate therapy and will identify areas for future research.

Key words: Bisphosphonates · Osteonecrosis · Osteonecrosis of the jaws · Cancer therapy · Metastasis · Bone necrosis

12.1 Introduction BON is a recently described long-term oral complication of supportive therapy of cancer [1]. Cases of untreatable osteonecrosis of the mandible and maxilla have been diagnosed not only in patients with cancer metastatic to bone but also in osteoporosis patients who were being treated with a bisphosphonate [2–5]. Most of the cases reported affect patients taking the i.v. formulations (pamidronate and zoledronic D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 12,  C Springer Science+Business Media B.V. 2009

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acid) [3]. However, a smaller number of patients taking the oral bisphosphonates (alendronate, risedronate, and ibandronate) have also been diagnosed with this oral complication [6].

12.2 Definition and Clinical Findings Bisphosphonate osteonecrosis (BON) is defined as the unexpected appearance of necrotic bone in the oral cavity in a patient taking a bisphosphonate and who has not received radiation therapy to the head and neck (Fig. 12.1). The exposed bone is persistent for at least 6–8 weeks after proper care is delivered [7, 8]. The necrotic area can be identified after a dental procedure (i.e., dental extraction) or be spontaneous and found during routine clinical examination. About 70% of the patients complain of severe pain and 30% are asymptomatic. In the early stages, BON can appear as an infected area that may resemble a routine endodontic or periodontal problem [1]. In all situations, treatment of BON has been unsuccessful [9, 10]. Newer approaches like local bone debridment, local resection, the use of lasers, and the use of hyperbaric oxygen therapy may prove beneficial but need larger case series and studies for confirmation of efficacy [11–19]. The process may progress to neighboring areas, leading to tooth loss and, in more severe cases, large resections of jawbones [5,7]. BON can result in loss of function and, in more advanced cases, a pathological fracture can occur, requiring hospitalization and extensive antibacterial therapy and surgical reduction or resection of the fractured area [3–5]. Fig. 12.1 Breast cancer patient treated with zoledronic acid for bone metastasis. Note large area of exposed necrotic bone on the left mandible

12.3 Radiographic Findings Radiographic findings of BON can only be seen in well-established clinical cases. There are currently no radiographic tests that could help the clinician to detect early bony changes indicative of BON. Imaging changes can usually be seen when cases are already advanced and clinical exposed bone can be observed. Panoramic

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Fig. 12.2 Periapical radiograph of the mandibular molar region of a breast cancer patient treated with aredia and zoledronic acid. Observe areas of sclerosis around the roots of tooth # 19 (molar). The extraction site of tooth # 18 shows lack of healing and early changes of necrosis

radiograph are recommended for routine dental evaluation of patients at risk or with BON [9,10]. However, a recent study suggested that computerized tomography (CT) provided better assessment of osseous findings that the panoramic radiograph [20]. In a previous study, a comparison between imaging techniques evaluated for the diagnosis of BON demonstrated that technetium-99m-methylene diphosphonate (99 Tcm -DMP) presented superior results when compared with CT and magnetic resonance imaging (MRI) [21]. The role of routine periapical radiographs in the early diagnosis of BON has not yet been established. However, it has been observed that patients with BON present with radiographic sclerosis or thickening of the lamina dura (Fig. 12.2) that some believe could be an early indication of changes in bone remodeling at the area of osteonecrosis [9].

12.4 Osteonecrosis and the Cancer Patients with Bone Metastasis In recent years, bisphosphonates became the mainstay in the management of skeletal complications of cancer. Drugs like clodronate, pamidronate, zoledronic acid and ibandronate can effectively prevent bone complications in cancer patients with metastatic bone disease [22–25]. However, bisphosphonates can also cause a number of adverse effects, including BON [26]. Therefore, the ideal therapy should aim to achieve a balance between the palliative action of bisphosphonates and tolerability and maintenance of the patient’s quality of life. Woo and colleagues [6] showed that the prevalence of BON in cancer patients receiving bisphosphonates intravenous therapy is 6–10%. The prevalence of BON in the osteopenia/osteoporosis is much smaller. However, the risk factors that put only certain individuals at risk for BON have not been determined. Most of the studies investigating the incidence of BON in populations have produced data from retrospective reviews and only a few have been prospective. A summary of the most significant studies can be seen in Table 12.1. As it can be observed, there seems to be a higher incidence of cases when patients are followed prospectively. This fact could

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C.A. Migliorati Table 12.1 Incidence of BON in cancer patients in retrospective and prospective studies

Author

Retrospective prospective

Incidence

Malignant disease

Durie et al. [52]

Retrospective Survey

75/1203 (6.2%) confirmed cases only

Multiple Myeloma Breast Ca

Mavrokokki et al. [53]

Retrospective in most States Prospective in South Australia (showed higher frequency)

Malignancy

Badros et al. [54]

Retrospective

No extractions: 1 in 87 to 114 pts (0.88–1.15%) Extractions: 1 in 11 to 15 pts (6.67–9.1%) 3% (in house patients only)

Wang et al. [55]

Retrospective

3.8% MM 2.5% B 2.9% P

Multiple Myeloma Breast Prostate

Hoff et al. [56]

Retrospective

2.4% MM 1.2% B

Multiple Myeloma Breast

Bamias et al. [57]

Prospective

6.7% Overall 9.9% MM 2.9% B 6.5% P

Multiple Myeloma Breast Prostate

Boonyapakorn et al. [58]

Prospective

22%

Multiple Myeloma Breast

Walter et al. [59]

Prospective

18.6%

Prostate

Multiple Myeloma

be explained by a more stringent follow-up that includes a complete oral cavity evaluation and also the participation of well-trained dental professionals. Therefore, it is advisable that future trials evaluating the incidence/prevalence of BON in cancer patients receiving any form of medication that suppresses bone remodelling, should include prospective oral evaluations done by well-trained dental professionals.

12.5 Pathobiology One unique feature of BON is that this complication of bisphosphonate therapy has only been described in the jawbones (mandible and maxilla) [6]. Amongst all cases reported in the literature so far, there is only one report of a patient who developed BON in the oral cavity and later developed osteonecrosis of the auditory canal [27]. It is intriguing however, that in the orthopedic field bisphosphonates are used to prevent and treat osteonecrosis of the femoral head and no cases of osteonecrosis have been seen [28–30]. Nevertheless, the efficacy of this form of therapy for the

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treatment of osteonecrosis needs further investigation [31]. Thus, if bisphosphonates behave in different fashion in various body sites, it is possible that site-specific pathobiologic mechanisms may be responsible for this difference in the biological behavior of BON. There is as yet no scientific explanation for the mechanisms that lead to the formation of BON. Bisphosphonates are potent inhibitors of osteoclastic bone resorption [32]. With one of the arms of bone remodeling suppressed by the medication, it is plausible to think that bone turnover is altered [33]. Bone Multicellular Units (BMUs) are small complex units of bone composed of cells (osteoclasts and osteoblasts), blood vessels, and loose connective tissue. BMUs are activated every time microfractures or damage to the skeleton from daily activity occurs. For instance, in the jawbones, microfractures and bone damage result from mastication, speech, swallowing and parafunctional habits like clenching and malocclusion. The bone remodeling process is orchestrated by osteoblasts that secrete calciotropic hormones and cytokines attracting osteoclasts to the area that needs remodeling. Osteoclasts express receptors called receptor activator for nuclear factor κB (RANK). The binding of cytokine RANK-Ligand (RANKL) from osteoblasts activates osteoclasts into final differentiation promoting resorption of the damaged bone and the formation of new bone. The process is balanced by the endogenous osteoprotegerin that inhibits RANKL when bone resorption is completed, placing the system in a resting phase. In a patient taking a bisphosphonate, the inhibitory effect bisphosphonates on osteoclasts prevents resorption of damaged bone. Therefore, “old bone” is preserved and new bone is deposited over damaged bone. It has been proposed that the lack of resorption of bone microfractures and microdamage of the skeleton pave the way for osteonecrosis to develop [34, 35]. Recent publications have suggested that in addition to bone remodeling suppression, there may be soft tissue toxicity at the area where osteonecrosis develops. Moreira et al. [36] demonstrated that alendronate is toxic to the subcutaneous tissue in rats, inducing inflammation, micro-abscess formation and necrosis. Reid et al. [37] suggested that with prolonged use, bisphosphonates accumulate in the alveolar bone in the jaws. When there is surgical manipulation of the area (i.e., dental extraction), there is local release of medication incorporated in bone. This causes toxicity to the overlying epithelium inhibiting healing. Recent in vitro work [38] demonstrated that pamidronate inhibits keratinocytes in culture and that the dose of medication is an important determinant of cell inhibition. In another study [39] it was demonstrated that beagle dogs treated for 3 years with alendronate, develop bone matrix necrosis in the non-alveolar portion of the jaws. Based on the information available one could speculate that during bisphosphonate intake, bioavailable drug is highly incorporated in the jawbones. The constant intake of medication provides additional drug at the local sites due to high vascularization in the jaws. Daily activity of mandibular movements and mastication promote bone microfractures and damage. This probably releases at this site additional bisphosphonate that was incorporated or at the surface of bone. Matrix osteonecrosis occur spontaneously due to the inhibition o bone remodeling and lack of removal of old bone. This process might cause increased discomfort leading the patient to seek

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dental care. Bone matrix necrosis cannot be diagnosed by clinical or radiographic examination. Routine dental care with periodontal and endodontic therapy does not resolve symptoms and probably facilitate the release of loads of bisphosphonates further increasing the inhibition of bone turnover. Available bisphosphonates can also initiate toxic damage over keratinocytes. The area might become exposed to the oral environment and is immediately infected by oral flora. Without resolution of symptoms, the tooth is extracted, initiating a much larger process of tissue healing that cannot be completed facilitating the clinical characterization of osteonecrosis. If this mechanism is correct, the process of osteonecrosis probably starts prior to tooth extraction or surgical manipulation of the area. The entire process can be further complicated by the type of disease (tumor vs. osteoporosis) the type of bisphosphonates being taken by the patient (i.v. v.s oral), the dose and time on therapy, other systemic diseases (diabetes) and immunosuppression (corticosteroids use), individual susceptibility to the medication, and excessive bone turnover inhibition [40, 41] that may occur in susceptible patients, perpetuating the clinical osteonecrosis.

12.6 Patient Management It is recommended that a trained dental professional do the management of patients with BON. This professional must have knowledge about the oral complication. In order to properly manage a patient, the dental professional must understand about bisphosphonates and their mechanism of action, as well as the possibility that these drugs may remain in the skeleton for many years [35,42]. Current recommendations for patient management are readily available [7–10, 43, 44] and include:

r r

A dental evaluation of patients prior to intravenous (IV) administration of bisphosphonates. This evaluation aims the prevention of oral complications of bisphosphonate therapy and should focus on the elimination of all potential oral sites of infection. The initial evaluation and treatment should achieve as best as possible a state of good oral and dental health so that during the active phase of bisphosphonate therapy only maintenance hygiene appointments will be necessary (every 3–6 months). Procedures of the initial evaluation should include:

1. A comprehensive extra oral and intraoral examination and radiographs (periapical and panoramic whenever possible). 2. Periodontal treatment (routine scaling and root planing) as needed. 3. Extraction of teeth with negative prognosis with respect to periodontal condition or restorative needs. 4. Caries control. Elective and/or complex dental treatment should be delayed depending on the urgency of the medical treatment. 5. Oral hygiene instructions and prescription of good home oral hygiene practices should be given. Patients should be placed on periodic follow-up.

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Once a patient begins bisphosphonate therapy, dental care should be provided as needed. There are no prospective scientific studies to support specific recommendations on whether or not providing dental treatment for patients taking a bisphosphonate drug places any risk for the development of BON [9, 10]. Our clinical experience indicates that: 1. Routine restorative care may be provided. 2. Scaling and prophylaxis should be done as atraumatically as possible with gentle soft tissue management. 3. Dental extractions have to be avoided if possible. When dental extraction is necessary, we believe that the extraction of the infected tooth is more important than to leave the source of infection untreated. The use of either penicillin V-K or clindamycin for a few weeks may help to reduce the incidence of local complication. In cases of persistent infection, metronidazole can be added to this regimen. However, if root canal therapy is possible it should take preference over extraction. 4. Other dental procedures that do not require bone manipulation may be done without the risk of complication. When BON is diagnosed, the focus of the dental treatment should be on elimination of infection, frequent superficial debridment of the necrotic bone with the objective of maintaining bone surface smooth and free of sharp areas, and immaculate control of oral hygiene [9, 10]. Active infection must be controlled to deter the progress of BON. When purulent secretion is present it should be cultured for microorganism identification and selection of specific antibiotic therapy [9]. Although penicillin is the first choice antibiotic in dentistry, amoxicillin and/or clindamycin may provide better bone penetration and wider spectrum of coverage. Metronidazole can be added in case of resistance to therapy [9]. Chlorhexidine mouth rinse used 3–4 times a day is also recommended to reduce bacterial load and colonization. In some severe cases, hospitalization and IV antibiotic therapy are necessary [9, 43]. All this treatment should be coordinated between the oncology team and the dental team. More invasive treatment modalities have been recently published. More aggressive cases or refractory BON can be treated with marginal bone resection and the use of platelet-rich plasma or autologous platelet-derived growth factors [14,17,45]. A case report shows a patient with BON second to an oral bisphosphonate who was treated with local measures that included necrotic bone debridment, chlorexidine rinses, systemic antibiotics and low-dose parathyroid hormone [18]. Although the use of hyperbaric oxygen therapy (HBO) has been discouraged when early cases of BON were reported to the literature [3, 5, 9], recent case series have suggested that HBO associated to local measures and systemic antibiotics might be useful in the treatment of BON [16,46]. The use of Nd:YAG laser technology associated with other clinical measures has been also suggested by European groups as an alternative for the management of BON [12, 15].

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The majority of cases of BON reported so far have been associated with invasive dental procedures like dental extractions. Some have proposed the use of serum CTX, a C-Terminal telepeptide of collagen marker of bone resorption activity in serum, as a clinical tool to assess the risk of BON in patients taking oral bisphosphonates, and who need invasive dental procedures [47]. However, because of the low number of patients tested and the fact that the study was not controlled, it is to premature to use this test in the clinical decision making process, when managing patients taking bisphosphonates. Medical oncologists may face a decision about discontinuation of bisphosphonate therapy when a patient develops BON. There is no current scientific evidence to support discontinuation of bisphosphonate therapy in order to promote healing of necrotic osseous tissues in the oral cavity. On the other hand, severe consequences can result from discontinuation of therapy [48]. Thus, this decision must be made based on risks and benefits of discontinuation. Clinical experience suggests that discontinuation of therapy may be beneficial for the healing of the necrotic area in cases where long-term follow up is possible. Bisphosphonates incorporate into the bone matrix and may remain active for years [35,41], Therefore, stopping bisphosphonate

(A)

(B)

(C)

(D)

Fig. 12.3 Breast cancer patient treated with zoledronic acid for several years. ( a) Observe tooth # 19 (first molar left mandible) presenting with gingival recession, exposed alveolar bone, and purulent secretion. ( b) Periapical radiograph of tooth # 19 showing clear evidence of osteonecrosis involving both roots. Bone is radiolucent and the bone trabeculate is very loose. ( c) Follow up examination one month post extraction of tooth #19. The necrotic area around the tooth was treated for about two years with local therapy and occasional administration of systemic antibiotics. Note complete healing of the area. (d) Periapical radiograph showing the osseous healing at the area where tooth # 19 and the osteonecrosis process used to be

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for a few months may have little effect on the bisphosphonate that has already been incorporated into bone. However, in our experience, after several months without bisphosphonate therapy and maintenance of the necrotic area as infection-free as possible, we have observed that some patients sequester the necrotic bone and reepithelialization of the area occurs (Fig. 12.3). Prospective studies will, with time, bring the answers that our patients and we are looking for. Therefore, our current recommendation is to continue the therapy if the use of bisphosphonate is important for the control of the metastatic disease or hypercalcemia. If the bisphosphonate is only being used prophylatically it could be discontinued until disease re-activation is diagnosed.

12.7 Future Research and Conclusions The use of bisphosphonates has changed the way patients with hypercalcemia of malignancy and cancer metastatic to bone are managed. New evidence is now suggesting a role of bisphosphonates in the treatment of solid tumors. Therefore, the use of this medication is going to increase. Although the benefits of bisphosphonate therapy are well recognized there are side effects associated with it. It is clear that BON is one of the complications of bisphosphonate therapy. The risk for developing BON is higher with the use of i.v. bisphosphonates. New protocols for the longterm use of bisphosphonates, dose schedule and the use of different formulations of high and low potency have to be evaluated in order to determine potential benefits and less adverse events. It was recently demonstrated [49] that one i.v. infusion of 5 mg zoledronic acid is enough to decrease the cases of fracture in post-menopausal women for a whole year. The investigation of similar effects in cancer patients would be desirable [50]. BON presents difficult management issues and its prevention would be of benefit. Future well-controlled randomized studies addressing the usefulness of serum CTX test can provide much needed information to help prevent BON. Maintenance of oral hygiene has been advocated since the first cases of BON were reported. In a recent publication [51] a group from Italy demonstrated that the institution of preventative dental measures prior to the initiation of bisphosphonate therapy can decrease the incidence of BON in patients with cancer. It is important to keep in mind that BON affects only a small group of patients and the risk factors involved in this mechanism have yet to be established. It is possible that genetic polymorphisms could play a role in making a group of individuals more susceptible to the antiresorptive action of the bisphosphonates but this remains to be proven.

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46. Shimura K, Shimazaki C, Taniguchi K, et al. (2006) Hyperbaric oxygen in addition to antibiotic therapy is effective for bisphosphonate-induced osteonecrosis of the jaw in a patient with multiple myeloma. Int J Hematol 84:343–345 47. Marx RE, Cillo JE Jr, Ulloa JJ (2007) Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum ctx testing, prevention, and treatment. J Oral Maxillofac Surg 65:2397–2410 48. Gallego L, Junquera L (2008) Consequence of therapy discontinuation in bisphosphonateassociated osteonecrosis of the jaws. Br J Oral Maxillofac Surg accessed online on January 12, 2009 49. Black DM, Delmas PD, Eastell R, et al. (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822 50. Greenspan SL, Brufsky A, Lembersky BC, et al. (2008) Risedronate prevents bone loss in breast cancer survivors: a 2-year, randomized, double-blind, placebo-controlled clinical trial. J Clin Oncol 26:2644–2652 51. Ripamonti CI, Maniezzo M, Campa T, et al. (2008) Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol accessed online on January 12, 2009 52. Durie BG, Katz M, Crowley J (2005) Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 353:99–102; discussion 99–102 53. Mavrokokki T, Cheng A, Stein B, et al. (2007) Nature and frequency of bisphosphonateassociated osteonecrosis of the jaws in australia. J Oral Maxillofac Surg 65:415–423 54. Badros A, Weikel D, Salama A, et al. (2006) Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24:945–952 55. Wang EP, Kaban LB, Strewler GJ, et al. (2007) Incidence of osteonecrosis of the jaw in patients with multiple myeloma and breast or prostate cancer on intravenous bisphosphonate therapy. J Oral Maxillofac Surg 65:1328–1331 56. Hoff AO, Toth BB, Altundag K, et al. (2008) Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23:826–836 57. Bamias A, Kastritis E, Bamia C, et al. (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580–8587 58. Boonyapakorn T, Schirmer I, Reichart PA, et al. (2008) Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 44:857–869 59. Walter C, Al-Nawas B, Grotz KA, et al. (2008) Prevalence and risk factors of bisphosphonateassociated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate. Eur Urol 54:1066–1072

Chapter 13

SURGICAL MANAGEMENT OF BONE METASTASES Markku Nousiainen, Cari M. Whyne, Albert J.M. Yee, Joel Finkelstein and Michael Ford Department of Surgery, University of Toronto, Orthopaedic Surgeon, Holland Ortopaedic and Arthritic Centre, Sunnybrook Health Sciences Centre, 621-43 Wellesley St. East, Toronto, Ontario, Canada M4Y 1H1, e-mail: [email protected]

Abstract:

Orthopaedic and spinal surgery can provide significant palliation to patients with symptoms arising for bony metastatic involvement in addition to patients that are at risk for skeletally related events (SREs). This chapter will review the role of surgery in the management of bone metastases and discuss factors that need to be considered prior to surgery. The treatment of pathologic fractures and the evaluation of pre-critical bony lesions will be presented. An overview of assessing the need for potential surgical intervention(s) by different criteria and reported scoring systems will be reviewed as well as a synopsis of the surgical treatment and management for appendicular, pelvic, and vertebral metastasis. Novel approaches to more accurately guide fracture risk prediction radiologically will be presented and the role of emergent surgery discussed.

Key words: Bone metastases · Surgery · Skeletal related events · Fracture

13.1 Introduction and the Role of Surgery in the Management of Bone Metastases Orthopaedic and spinal surgery can provide significant palliation to patients with symptoms arising for bony metastatic involvement in addition to patients that are at risk for SREs. The decision and timing when to proceed with surgical intervention falls in the realm of the art behind medicine and involves decision making that relies on the strength of physician–patient relations and informed consent. The realistic goals of what surgery can afford needs to be aligned with patient goals with an D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 13,  C Springer Science+Business Media B.V. 2009

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understanding of the palliative goal of surgery. Surgery is sometimes considered synonymous with “hope” and dependent on the patient, appropriate education regarding the reasons to consider surgery warrant clarity. In general, the role(s) of surgery in the management of bone metastases is to: 1. Relieve pain that is refractory to conventional medical and radiotherapies in the treatment symptomatic bone metastases 2. Stabilize metastatically involved bone that is a significant risk for pathologic fracture 3. Stabilize pathologic fractures with bony pain 4. Decompress the spinal canal of neurocompressive tumor pathology that may pose risk for neurologic deterioration Knowing when to and when not to perform surgery is paramount in clinical decision making. Whilst there will are some clinical and radiographic guidelines that may help in this process, the authors of the chapter wish to stress the importance of physician–patient discussion as this is what really will guide the success of our medical and surgical therapies. It is ultimately patient satisfaction with the process and hopefully the improvement in pain and quality of life that translate successful palliation. Metastatic cancer is the most common malignant disease of bone. In the United States alone, approximately 1.2 million new cases of cancer are diagnosed. Of these, up to 50% have the potential to spread to bone, with prostate, lung, and breast cancer being responsible for more than 80% of cases of metastatic bone disease [1]. Bone metastases often produce significant pain and disability early in the course of disease as a result of pathologic fractures, anemia, and hypercalcemia [2]. Seventy percent of the bone metastases occur in the axial skeleton and 10% in the appendicular skeleton with preference towards the proximal ends of long bones [3]. Approximately 1% of bone metastases fracture. The risk of fracture is dependent on anatomical location, geographic size of the lesion, and tumor invasiveness [3, 4]. Forty percent of pathological fractures occur within the proximal femur and it is estimated that approximately 10% of bone metastases require surgical intervention [5]. Breast carcinoma is the most common cause of pathologic fracture, followed by kidney, lung, and thyroid carcinoma, and lymphoma [6]. It is important to remember that pathologic fractures may occur either due to either osteolytic, mixed, or osteoblastic lesions; in all instances, the structural integrity of the lesion is less than that of normal bone [6]. For most patients, a pathological fracture heralds the end-stage of their disease. Half will die within 6 months of surgery for pathological fracture or paraplegia and only a few will survive for several years [4]. The treatment of bone metastases involves a multidisciplinary approach. Avoiding the potential complications related to bone metastases is the rationale that often prompts an orthopedic assessment. Assessments are broadly characterized into four groups: impending fractures, pathological fractures, spinal instability and spinal cord/cauda equina compression. Pain is the most common presentation of a patient with of a skeletal metastasis, two thirds of which will have a radiographically detectable lesion [7].

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The primary goals of surgery are to: a. b. c. d. e.

Preserve/restore skeletal integrity, Preserve/restore function, Eliminate/prevent neurological compromise, Minimize hospitalization/rehabilitation, and Improve quality of life.

The decision-making process is based on a risk benefit analysis of the magnitude of the surgery planned to the physiological capacity/life expectancy of the patient to survive a sufficient time postoperatively to benefit from better pain control, regain function and a better quality of life. As such, the ultimate goal of orthopaedic intervention is to provide therapies that improve patient palliation at acceptable risk. A minimum life expectancy of 6 weeks is advocated prior to considering orthopedic surgical interventions. Life expectancy is dependent on the cancer primary, the burden of bone metastases, the anatomical location of the metastases, and the presence or absence of a pathological fracture [4, 8–10]. Harrington demonstrated that the life expectancy following a pathological fracture was dependant on the primary tumor [11, 12]. The mean survival after a pathological fracture was 29 months in patients with prostate cancer, 22 months in patients with a breast primary, and 12 and 4 months for patients with kidney and lung cancer, respectively. Ultimately, these are a high-risk group of patients to treat and mortality rates are high. Mortality is reported to be 15% at 4–6 weeks and 50% at 6 months following surgery [11,12]. In line with translational research methods, we have identified predictors of outcome from a population based study using Cox multivariate regression to model survival and perioperative complications as a function of cancer type, age, gender, and preoperative neurological status. This study identified significant risk factors that were associated with poor survival and outcome. Primary cancers of the lung, melanoma, and upper gastrointestinal tract had the poorest survivorship. Increasing age and primary lung cancer were significant risk factors for death within thirty days of surgery. Lung primary cancer had a 2.65 relative risk of mortality within 30 days [13]. A pre-operative neurological deficit was an independent determinant of worse prognosis when confounding factors were taken into account. Patients with preoperative neurological deficits were 19% more likely to die compared to those without deficits. Furthermore, patients with preoperative neurological deficits were 71% more likely to get a post-operative infection [13].

13.2 Preoperative Medical Factors Inclusion of medical factors in the decision making process is paramount. Embarking on a surgical procedure is a risk/benefit analysis that should be inclusive of best evidence. Very rarely is surgery for metastatic disease curative. Given the palliative

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Table 13.1 American Society of Anesthesiologists Classification∗ ASA Class

Class Definition

Rate of PPCs of Class,%

I II III

A normally healthy patient 1.2 A patient with mild systemic disease 5.4 A patient with systemic disease that is not 11.4 incapacitating IV A patient with an incapacitating systemic 10.9 disease that is a constant threat to life V A moribund patient who is not expected to NA survive for 24 hours with or without operation ∗ Information is from reference 9. ASA = American Society of Anesthesiologists; NA = not applicable; PPC = postoperative pulmonary complication.

nature of the surgery, the threshold for risk should be high. The patient and family who have been told that they have six to 12 months to live should not suddenly discover that it has been shortened to a day or two. Currently the standard for preoperative medical assessment of all patients is the American Society of Anaesthesiologists (ASA) rating system (Table 13.1). Given the demographics of the typical patient population with metastases, medical comorbidities are not uncommon. The ASA score has to be weighed against the magnitude of the surgical stressor. Rarely are we able to dramatically reduce the ASA rating. It is incumbent upon us to reduce the surgical time, blood loss and the extent of secondary trauma to the patient. Management of the patient with metastatic disease is dependent upon a multidisciplinary approach. A myocardial infarction two weeks prior to presentation is not factored into some of the other prognostic tools that we use (Tokuhashi score, Karnofsky performance score) [14]. Input from our Medicine and Anaesthesia colleagues is as important as the advice that we get from our referring oncologists.

13.2.1 What You Need To Tell Them Duration and estimated blood loss are the two most important parameters. The maximum duration and maximum estimated blood loss are the numbers that should be disclosed. All too often, the “hoped for”, “optimal”, or “average” numbers are given resulting in a potential shortfall of preparedness.

13.2.2 What We Need From Them Mortality rates are procedure dependent. What we need is a threshold that we can approach with respect to mortality rates and this will dictate whether we are going to do a minimally invasive procedure or a more aggressive en bloc resection.

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13.3 Assessing the Need of Surgical Interventions by Different Criteria and Scoring Systems There have been numerous systems developed that may guide clinical decision making regarding orthopaedic or spinal surgery for symptomatic bony metastases. Much of the historic literature in appendicular skeletal metastases has focused on twodimension radiographic analysis. Often, surgical residents are taught that if there is greater than 50% cortical involvement, or greater than 2.5 cm diameter of the cross-sectional area of a weight bearing long bone, such lesions should undergo prophylactic surgical stabilization to deal with the issue of an impending pathologic fracture. With modern generation CT and MRI imaging, 3-dimensional renderings of pathologic bony lesions have provided much more detail regarding bony architecture and have the potential to more accurately gauge the risk for pathologic fracture when compared to two orthogonal views on routine plain radiography. This is of particular interest in the spine where vertebral involvement involves a complex of anterior, middle, and posterior vertebral column involvement with inherent issues of neural tissue passage in the spinal canal. The ability to predict a pathologic burst fracture of the spine is more important to the preservation of normal spinal cord function that the potential for a wedge-compression pathologic fracture. Plain radiographs of the spine and bone show only very advanced bony destruction and longitudinal assessments by CT or MR imaging is more routinely practiced in guiding patient care. Translational research opportunities coupling modern imaging with more accurate prediction models of fracture risk is an area that is attaining increasing interest and shows promise in transforming clinical practice and care by providing more accurate assessments of pathologic fracture risk versus conventional clinical assessments based on plain radiographic imaging and surgeon based assessments of “low, medium, high” risk. Fidler et al. found that the incidence of long bone fractures was related to the cortical involvement based on plain radiographs [14]. When 25–50% of the cortex was involved the fracture incidence was 3.7%, this rose to 61 and 79%, respectively, when 50–75% and 75% of the cortex was involved [14]. Similarly, Mencke proposed prophylactic internal fixation if the ratio of the width of the metastasis to the diameter of the bone exceeds 0.60 or there was ≥13 mm of axial cortical destruction of the femoral neck or ≥30 mm cortical destruction of the femoral shaft or ≥50% cortical destruction [15]. Mirrel devised a clinical scoring system grading the site, the pain, the type of lesion and the amount of cortex affected on a 12-point scale. He proposed any score below 7 should be treated by irradiation and any score above 7 should be prophylactically nailed [16, 17]. However, Damran et al. has shown this score to have a high false negative rate with a specificity of 35% but a sensitivity of 95% [18]. The management of impending fractures should never be based on radiographic appearances alone. Only those that are symptomatic should be considered for surgical intervention. In some recent scoring systems, clinical and radiographic parameters have been coupled together to provide a “risk” assessment that potentially guides therapeutic intervention. There have been more recent RCT’s that evaluate the potential for

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surgery to facilitate patient palliation when compared to conventional non-surgical routes. In the study by Patchell et al., the ability to surgery and radiation to more effectively palliate single level spinal pathology when compared to radiotherapy alone has been demonstrated [19]. However, the clinical presentation is often of multi-level spinal or bony disease and the right therapy in this patient population remains to be conclusively determined. The more patient and radiographic variables the more complex the decision making process and as such a greater difficulty exists in designing and conducting a sufficiently powered RCT. Similar scoring systems to predict the probability of developing a pathological fracture exist for spinal metastasis. Tokuhashi et al. devised a system to help predict the prognosis of metastatic spine tumors [20]. It was based on the general condition of the patient, the number of extraspinal bone metastasis, the number of metastasis in the vertebral body, presence of visceral metastasis, the primary cancer and the degree of spinal cord spinal palsy. He recommended complete excision of the tumor with curettage, decompression and stabilization for a lesion with a good prognosis (above 9) and stabilization with no or partial resection of the tumor in cases with a poor prognosis (below 5). This scoring system has been validated and revised to provide guidance on the best surgical approach [21–26]. Taneichi tried to predict which spinal metastasis represented impending fractures [27]. He suggested the area of the vertebra involved that led to impending fractures differed at different levels of the spinal column. In the thoracic spine 50–60% of the vertebral body only or 25–30% involvement with costovertebral joint destruction led to a pathological fracture. In the thoracolumbar and lumbar spine it was 35–40% of the vertebral body or 20–25% with pedicle involvement [27]. This scoring system has never been validated.

13.4 Fracture Risk Assessment As described above, initial attempts at developing guidelines for prophylactic stabilization in the management of metastatic bone defects utilized retrospective reviews of radiographs and clinical data. This approach which identifies factors unique to patients who sustain fractures has not been able to successfully generate comprehensive guidelines for bone metastases [28]. For example, previous retrospective clinical record and radiographic examination studies determined that fracture risk in metastatically involved femurs could not be established by measurements from standard radiographs alone [29]. Radiographically lesions are often immeasurable as no clean boundaries exist. Large errors occur when measuring simple defects from plain radiographs; errors have been found up to 100% in measuring diaphyseal defects [30]. High percentages of lesions (16–29%) are also missed using radiographs alone [31]. Even in long bones, existing clinical guidelines that use some measure of defect geometry to assess fracture risk allow for probabilities of clinical errors as much as 42% [28], visual analysis of CT and plain radiographs have not been successful in estimating strength reductions or load bearing capacity in metastatically involved bones.

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One hundred thoracic and lumbar vertebra containing lytic metastatic lesions were radiographically studied by Taneichi et al. in an attempt to establish criteria for impending collapse [27]. Increased tumour size and pedicle destruction were found to elevated fracture risk using a multivariate regression model. While clinical studies have been unable to provide definitive guidelines for intervention, they have demonstrated that preoperative condition clearly influences the outcome of treatment. Early treatment is advantageous in the prevention of more serious irreversible clinical manifestations [32]. However quantitative analyses utilizing CT data and composite beam theory have been applied to predict fracture risk of metastatically involved vertebrae [33]. This technique is based upon the theory that flexion, extension and lateral bending loads are important in fracture risk assessment. As such, both axial and bending rigidities are calculated using intensity based quantification of bone density on 2D axial vertebral cross sections to quantify fracture risk. This approach incorporates a strain based failure criteria in which specimens with higher rigidities were hypothesized to fail at higher loads, with minimum values used to predict the site and load at which vertebral failure will occur. Such image based analyses using composite beam theory and qCT derived structural properties have been successful in predicting fracture prospectively in cadaveric vertebral, femoral and bone core studies (with simulated and actual lesions) and in retrospective evaluation of clinical imaging [33–37]. This criterion was developed based on focal lytic lesions, but as it makes no assumption regarding the nature of the tumour it can be applied to assess a wide array of metastatic disease and primary tumours in the skeleton [33–37]. However, this method does not differentiate in the prediction of fracture type (burst or compression). Difficulty in using this technique clinically may also arise due to uncertainties of applied loading, which determines the relative importance of bending and axial rigidity. To date, application of CT based structural rigidity analyses have been shown to be highly sensitive but only moderately specific to vertebral fracture with very successful clinical application to juvenile chondrosarcomas in the femur [35, 36]. Using an experimentally validated three-dimensional poroelastic finite element model, a set of biomechanically based guideline equations were developed to specifically assess the risk of burst fracture in the metastatically involved spine [38]. The behaviours of vertebrae with lytic metastases were quantified through parametric analyses and a formula was defined to relate patient-specific variables to burst fracture risk. Normalized vertebral bulge (radial displacement of the vertebral body) and normalized vertebral axial displacement were utilized as measures of the risk of initiation of burst fracture and analyzed with respect to factors representing load-exposure (load, loading rate) and load-bearing capacity (tumour size, trabecular bone density, disc quality, and pedicle involvement). The equation-based guidelines reflected the risk and mechanism of burst fracture in the metastatically involved vertebral model. The validity of these guideline equations was demonstrated though a CT based retrospective study of 92 thoracic and lumbar vertebrae with lytic metastases [39]. The biomechanically based vertebral bulge guideline equation predicted vertebral stability and gave a clear threshold value specific for burst fracture risk While, vertebral axial displacement and tumour size alone also showed strong

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predictive ability, they did not provide definite thresholds for burst fracture. The excellent sensitivity and specificity of this biomechanically based guideline equation in application to retrospective clinical data has prompted ongoing prospective study of this method [39]. However, these guidelines have not been conducted to accommodate the consideration of mixed osteolytic/osteoblastic lesions. Accurate vertebral segmentation is required to effectively quantify the impact of metastatic tumour involvement on fracture risk in the spine. Manual segmentation involves extensive and time-consuming user interaction, thus automation of vertebral segmentation for quantification purposes is highly attractive. A semiautomated method to accurately segment tumour-bearing vertebrae has been developed using demons deformable image registration and level set methods [40]. By maintaining morphology of an atlas, the demons-level set composite algorithm can accurately differentiate between trans-cortical tumours and surrounding soft tissue, successfully segmenting the vertebral body and trabecular centrum of healthy and metastatically involved vertebrae. Histogram based methods have been implemented to quantify lytic and blastic tumour involvement using these segmentations [41]. It was found that a patient-specific healthy vertebral body histogram is able to characterize healthy trabecular bone throughout an individual’s thoracolumbar spine with a Gaussian distribution (Fig. 13.1). This allowed determination of patient-specific intensity thresholds for lytic and blastic tumour. Using these

a

b

c

d 800

Count

Total lytic blastic

400

0 4

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484

604

Bone Density (HU)

Fig. 13.1 CT based image segmentation of (A) lytic and (B) blastic tissue, (C) reconstruction and (D) histogram based analysis for a small tumor in a lateral T7 vertebral body

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optimized thresholds to segment tumour tissue within vertebrae, allows quantitative characterization of tumour volumes, disease severity, and temporal progression/treatment effect. Automated segmentation and quantitative analytical methods have great potential in extending the clinical and research capacity of CT, MRI and other image-based evaluations of the stability of the metastatic spine.

13.5 Surgical Treatment of Appendicular and Pelvic Metastases The four main goals in managing patients with a pathologic fracture include: (1) pain relief; (2) preservation or restoration of function; (3) skeletal stabilization; and (4) local tumor control [6]. While most patients with a pathologic bony lesion without a fracture can be managed by systemic and radiation therapy alone, the majority of pathologic fractures are best treated with surgery [6]. Despite the fact that some fractures have the ability to heal on their own, the length of time required for healing is inappropriate for patients with a limited life expectancy. In addition, the time to achieve bony union is increased secondary to the negative local biologic effect of the metastasis [6]. Thus, the indications for surgery include: (1) a life expectancy of ≥1 month for fractures of the weight-bearing dome of the acetabulum and a life expectancy of greater than three months for a fracture outside the weightbearing dome of the acetabulum; (2) medical condition amenable to undergoing surgery; (3) remaining bone adequate to support the proposed surgical construct; and (4) ability for surgery to provide patient mobilization and facilitation of general care [5]. Before embarking upon surgery, a firm diagnosis of the metastatic lesion must be made. The diagnosis is made with a thorough history and physical examination, plain radiographs of the entire bone, bone scan, and blood and urine investigations. If the diagnosis is unclear, obtaining a CT or MRI can help differentiate between the etiologies of pathologic fracture and delineate the soft tissue component of the lesion [6]. If the diagnosis is still not identified, then a fine-needle or open incisional biopsy is indicated. The most effective surgical means to relieve pain and restore function is with internal fixation or prosthetic replacement. The goals of these procedures are to convert open-segment defects into closed defects, restore bone strength to withstand physiological loads, and allow for immediate weight bearing [6]. This focus is different from the management of non-neoplastic fractures, whose goal is to promote fracture healing. As such, techniques such as prosthetic replacement or stabilization with polymethylmethacrylate (PMMA) are used in metastatic situations. The general rule is to treat a bone only once. Resection of the tumor deposit is an important part of the management of pathologic fractures. Intralesional curettage is the predominant technique used in most cases. This provides local tumor control, helps prevent local progression, allows for better assessment of remaining bone, permits PMMA to be used to fill the defect more effectively, thus providing improved stability to the fixation construct, and

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allows surgical adjuvants such as postoperative radiotherapy to have increased rates of success [6]. Closed fracture fixation techniques are indicated only in situations where the fracture is anticipated to heal with stabilization and adjuvant therapy alone or the fixation itself will outlast the patient’s projected survival [6]. Although uncommon, the indications for extralesional excision include the involvement of expendable bone with tumors (i.e., fibula, iliac wing, ribs, clavicle, scapula), epiphyseal fractures, a solitary metastasis when there has been a long interval between treatment of the primary tumor and development of the metastasis, or when the patient has a long projected survival, as with renal or thyroid carcinoma [4, 42]. Surgical adjuvants include angiography, cryosurgery, chemotherapy, and radiotherapy. Angiography should be used preoperatively to embolize hypervascular tumors such as renal and thyroid carcinomas, so as to minimize intraoperative bleeding. Residual local tumor can be treated with systemic chemotherapy, if sensitive. Postoperative radiation remains the principal surgical adjuvant for the vast majority of cases. It is delivered to the whole surgical field and extends the full length of the bone so as to suppress tumor growth and maintain structural integrity to the remaining bone to avoid a future pathologic fracture [6]. It is important to note that if radiation is used in the management of a lesion without surgical stabilization, there is an increased risk of pathologic fracture in the peri-radiation period [6]. The induced hyperemic response at the periphery of the tumor weakens the adjacent bone and increases the risk of spontaneous fracture. The bone should be protected until its structural integrity has been restored through healing. Fractures involving the three different regions of bones, epiphysis, metaphysis, and diaphysis, are managed with different forms of fixation. Epiphyseal fractures are best treated with resection and endoprosthetic implantation. Long-stemmed prostheses are used so as to prevent future pathologic fractures from occurring at distal sites secondary to disease progression or adjuvant radiotherapy. This tactic provides immediate bony stability and enables full weight bearing, rapidly restoring patient function [6]. In the proximal femur, hemiarthroplasty is indicated if there is no degenerative change or the hip and no evidence of metastatic disease in the acetabulum [4]. A total hip arthroplasty is performed if there is acetabular destruction [4]. Because humeral head fractures are associated with extensive destruction of the rotator cuff soft tissues or associated tuberosities, the aim of surgical management with hemiarthroplasty is to regain shoulder stability and pain relief; restoration of rotator cuff function is not a primary objective [11]. Metaphyseal fractures can be managed in a variety of ways. Load-sharing devices, such as intramedullary nails, are the implants of choice in the majority of metaphyseal fractures. Because they can span the entire bone, reduced rates of fixation failure and future fracture proximal or distal to the implant are seen. Reaming is advisable since a nail of wider diameter may provide better stability, less pain, and may reduce the risk of implant breakage or nonunion. Nevertheless, nails can fail if the fracture does not heal. Thus, intramedullary nails are contraindicated in situations where metaphyseal fragments cannot be adequately stabilized with the proposed construct, where it is assumed that stabilized bone will not heal, and when densely sclerotic lesions are present (making nailing difficult) [6]. In these instances,

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implantation of a prosthetic replacement or fixation with plates and screws and PMMA insertion is indicated. Prosthetic replacement can be challenging as adequate attachment of associated apophyseal areas, such as the greater and lesser trochanter of the femur or the greater and lesser tuberosity of the humerus, may be difficult due to tumor involvement. Diaphyseal fractures are ideally managed tumor curettage, bone cementing, and insertion of an intramedullary device. If proximal and distal interlocking screws cannot provide adequate stability, or if the intramedullary canal is too small to accept a nail (as may occur in the case of certain humeral shaft fractures), plate fixation and cementing may be considered [11]. If a diaphyseal lesion is associated with an epiphyseal or metaphyseal lesion, a cemented long-stemmed prosthesis is used. The most common long bone to sustain a pathologic fracture is the femur. The majority of fractures in the femur involve the proximal portion; 50% of these are in the femoral neck, 30% are in the subtrochanteric region, and 15% are in the intertrochanteric region [5]. The ideal management of femoral neck fractures involves either hemi- or total hip arthroplasty. Inter- or sub-trochanteric fractures are best managed by intramedullary nailing with a reconstruction nail (which permits screw fixation into the femoral head and neck) [5]. In lesions where extensive osteolysis is encountered and irradiation is planned in the postoperative course of treatment, augmentation with PMMA may be necessary [11]. In lesions that have been irradiated prior to the fracture and there is no plan for postoperative irradiation, primary bone grafting can be considered [11]. Other treatment options, such as external fixation, cast/brace immobilization, and amputation, may also be used to manage certain pathologic fractures. External fixation and cast/brace immobilization are indicated when (1) extensive disease precludes effective internal fixation; (2) the patient is pre-terminal and adequate pain relief can be managed with surgery; or (3) infection, sepsis, or the patient’s medical status prohibits surgery. Amputations are effective in managing (1) extremity lesions that can or should not be reconstructed; (2) ulcerated or infected lesions; (3) cases with intractable pain; and/or (4) cases where rehabilitation after reconstructive surgery is too time consuming, such as with the foot. See Table 13.2 for a summary of methods of treatment for metastatic lesions to bones of the upper and lower extremities. The indications for surgical treatment of impending fractures remain controversial. Although multiple authors such as Harrington, Mirels, and Healey have provided criteria predictive of pathologic fracture, these are neither highly sensitive nor specific (see Table 13.3 for a summary of Mirels’ scoring system). Nevertheless, operating on impending fractures is indicated if the surgery will minimize pain or when the treatment for the impending fracture is significantly safer or more effective than surgery that would be performed once the bone has fractured completely. Patient outcomes are improved when prophylactic surgical intervention is chosen instead of managing a fracture once it occurs; shorter hospitalization, earlier home discharge, earlier return to premorbid function, improved survival, and fewer hardware complications are enjoyed [43].

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Table 13.2 Summary of surgical options for management of metastatic lesions to appendicular bone Bone-Location

Surgical Management

clavicle scapula glenoid proximal humerus – epiphysis proximal humerus – proximal third

rare rare resection/reconstruction long-stemmed hemiarthroplasty long-stemmed hemiarthroplasty or allograft/hemiarthroplasty composite reconstruction locked intramedullary nailing or internal fixation with PMMA (if extensive bone loss after curettage) or intercalary spacer (if large segmental defect, failed fixation) bicondylar plate fixation or endoprosthetic reconstruction or flexible intramedullary nails (if lesion above epicondyles) internal fixation with PMMA or flexible rods intralesional surgery with curettage and PMMA or amputation (if distal and extensive) internal fixation with PMMA or distal femoral replacement internal fixation with PMMA or proximal tibial replacement locked intramedullary nailing or internal fixation with PMMA (if extensive bone loss after curettage) internal fixation with PMMA intralesional surgery with curettage and PMMA or amputation (if distal and extensive)

humerus – diaphysis

distal humerus

forearm hand supracondylar femur proximal tibia tibia – diaphysis tibia – distal foot

Table 13.3 Predicting the risk of pathologic fracture. Prophylactic fixation is recommended with a score of at least 9 points. Adapted from Mirels [16] Feature – size site pain radiographic image

Points 1 <1/3 upper extremity mild blastic

2 1/3–2/3 lower extremity moderate mixed

3 >2/3 pertrochanteric femur mechanical lytic

13.5.1 Pelvis and Acetabulum Improvements in systemic oncological treatment have led to prolonged survival of patients and an increase in the number of patients with destructive lesions of the pelvis. Diffuse involvement of the pelvis, particularly the periacetabular area, is of significant concern, as it can lead to mechanical instability that may cause severe pain and functional disability [44, 45]. 13.5.1.1 Non-Surgical Treatment Pathologic pelvic fractures outside the area of the acetabulum rarely require surgical stabilization and reconstruction [45]. In consultation with medical and radiation

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oncologists, analgesics, bisphosphonates, radiation, hormone, and chemotherapy should be considered if bone destruction is limited and the patient has not received prior treatment [45]. Lesions not involving the weight-bearing area of the acetabulum can be treated with modification of weight-bearing and external beam radiation [45]. Structurally significant lesions of the ischium, pubis, or sacroiliac area are rare and are usually managed effectively with radiation alone. Avulsion fractures of the anterior superior and inferior spines, iliac crest, and superior and inferior rami are common and are treated non-operatively [46,47]. In addition, patients with extensive bony lesions, advanced disease, or poor functional status may not benefit from surgical intervention. If the tumor is responsive to non-surgical treatment (i.e., early myeloma or lymphoma), extensive bone destruction may be surgically managed during or after medical and radiation treatment [46]. 13.5.1.2 Surgical Treatment Despite the successes of non-operative care, bony destruction or disabling symptoms may continue. Surgical management is considered if (1) acute symptoms do note abate after a period of protected weight-bearing, use of analgesics, and antineoplastic treatment; (2) restoration of satisfactory function with control of pain is not achieved within one to three months following radiation therapy; (3) a pathologic fracture develops in the acetabulum or ipsilateral femur; or (4) there is an impending fracture of the ipsilateral femur [45,48]. Although the surgical management of a patient with periacetabular metastasis can be a major surgical procedure with a significant risk of complications, surgery has become more successful with the evolution of joint replacement procedures and prosthetic components. Several studies have shown that surgery provides pain relief, improves function, and maintains and restores mobility to those with periacetabular metastases [49–51]. Proper pre-operative planning includes obtaining appropriate diagnostic imaging studies to accurately assess the location of the tumor. This requires a combination of plain radiographs (Judet views determine the extent of columnar involvement) and computed tomography (CT). CT is especially useful in determining the integrity of the medial wall, acetabular dome, and any associated soft tissue component of the tumor. Classification of acetabular defects is based on the location of the fracture, the extent of osteolysis associated with the tumor or irradiation, and surgical issues relating to achieving stable implant fixation [45]. Harrington’s classic classification system describes the extent of acetabular involvement with particular attention to which areas of the acetabular walls are deficient (see Table 13.4) [11]. Levy et al. described a similar classification system and suggested that as most lesions involve mixed segments, acetabular destruction should be classified as minor, major, and massive [52]. As with the appendicular skeleton, cases involving metastatic renal and thyroid carcinoma and multiple myeloma require preoperative angiography and embolization in order to minimize intraoperative blood loss and allow for a more controlled reconstruction. Preoperative angiography and embolization should also be

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Table 13.4 Harrington classification of acetabular defects from metastatic disease. Adapted from Harrington KD (1981) The management of acetabular insufficiency secondary to metastatic malignant disease. J Bone Joint Surg 63(A):653–664. [53]. Class

Features

1 2 3 4

minor defect: superior & medial walls intact; lateral cortices intact major defect: deficient medial wall massive defect: deficient lateral cortices & superior dome resection required for cure

considered in other tumors when extensive osteolysis exists without a clearly defined margin or when there is evidence of an extra-cortical soft tissue mass [53]. When a sharp, sclerotic tumor margin is apparent on plain radiographs, the metastatic lesion is likely to be slowly progressive and not as vascular [53]. The choice of reconstruction is based upon the existing structural damage to the acetabulum and by following the aforementioned general principles of the surgical treatment of metastatic bone disease, which include gross tumor removal, filling the bone defect, and bypassing the defect with a prosthetic component [6, 45]. According to Harrington’s classification, patients with Class I deficiency (lateral cortices and lateral and medial walls intact) can be treated with routine total hip arthroplasty with cementing of both the acetabular and femoral component. Mesh may be used to support the medial wall of the acetabulum and to prevent migration of PMMA into the pelvis. Long-stemmed femoral components are used to stabilize the femur because of the possibility of additional metastatic foci in the proximal two-thirds of the femur. Cementing of the acetabulum and femur is necessary as conventional total hip arthroplasty fails due to insufficient surrounding bone, leading to loosening and migration [11]. Patients with Class II lesions (medial wall deficient) typically present with protrusion of the femoral head through the medial acetabular wall (secondary to the tumor or post-irradiation osteonecrosis). Surgical management of this situation involves the use of special acetabular cups to transfer weight-bearing stresses across the deficient medial wall to the anterior and posterior columns. In cases where the columns are intact at the level of the acetabulum, bypass of the defect using a roof ring is indicated. In situations where the columns are deficient or there is evident or potential pelvic instability, an anti-protrusio, or reconstruction cage, is used. After tumor excision, the resultant bone deficiency is cemented (or bone grafted if the patient has a good prognosis) [45]. The roof ring or anti-protrusio cage is then firmly placed onto the intact rims prior to having a cemented polyethylene cup inserted into it. Screws affixing the ring or cage to bone/cement provide additional stability. A long-stemmed, cemented femoral component is implanted as with a Class I deficiency. Class III lesions (medial, lateral, and superior walls deficient) are the most challenging lesions to manage. As there is no intact bone on which to lie the anti-protrusio cage and the bony deficiency cannot be successfully supplemented by using PMMA alone or by placing the acetabular cup in a more proximal position, a more elaborate reconstruction is indicated. This involves placing several large

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Steinmann pins across the deficient area from the iliac wing into the low anterior or posterior column. Cement is injected into the deficient areas of bone, around the Steinmann pins, which behave as reinforcement bars. An anti-protrusio cage is placed upon this construct and a polyethylene cup is cemented into place. Mesh along the medial wall prevents extravasation of PMMA into the pelvis. Management of Class IV lesions (resection required for cure) is rare. Most lesions requiring this treatment involve solitary metastatic hypernephromas, unifocal lymphomas, or thyroid carcinomas that continue to be symptomatic despite prior radio- and chemotherapy. The principles of reconstruction apply the same techniques as with Class III lesions. Adequate resection of tumor should not be compromised in an effort to make pelvic reconstruction easier; it may be necessary to perform an internal hemipelvectomy alone [11]. In cases that require either partial or near-complete hemipelvectomy for tumor control, several reconstructive options exist. These include the use of hemipelvic allograft, autograft (if tumor lysis has not weakened the bone to the point that it can no longer support weight, it is possible to autoclave the bony segment and use it to reconstruct the pelvic ring) [11], or custom-made pelvic endoprostheses in association with total hip arthroplasty [54]. Alternatively, a saddle prosthesis can be implanted [55]. All options provide adequate functional outcomes despite the major surgery required. Surgical approaches for metastatic reconstruction involve either a KocherLangenbeck or lateral transgluteal hip approach. The lateral one or two windows of the ilioinguinal approach are used in addition when tumor within the acetabular dome requires further exposure and Steinmann pins need to be inserted into the ilium/anterior column. After tumor removal, bleeding is controlled with sponges soaked in adrenaline and thrombin. In situations where bleeding occurs despite previous embolization, rapid curettage followed by packing with Gelfoam or polymethylmethacrylate (PMMA) should minimize blood loss [45]. Review of the outcomes of patients that undergo acetabular and femoral reconstruction indicates that the majority experience a marked improvement in pain and ability to ambulate. Although the risk of incurring a surgical complication can be significant (including perioperative death, dislocation, infection, nerve palsy, deep venous thrombosis, and reconstruction failure), these procedures do provide an improvement in the quality of life in patients who have a poor long-term survival secondary to their disease [6, 48, 50, 51, 53, 56]. 13.5.1.3 Minimally Invasive Techniques Innovative minimally invasive techniques such as percutaneous radiofrequency ablation, osteoplasty, and cryosurgery are evolving. The main advantage these techniques have over surgery is that they are less morbid – surgical exposure, blood loss, and surgical time are minimized. Radiofrequency ablation is useful as it can be performed with regional anesthesia, can treat patients not considered suitable for surgery, and is effective in treating painful metastases after radiation therapy. Cryosurgery, using liquid nitrogen

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to induce tissue necrosis, provides excellent local control in numerous benignaggressive and malignant bone tumors with minimal bone and functional loss [57]. Liquid nitrogen is used with caution, as the morbidity of skin necrosis, infection, temporary neuropraxia, fracture, and damage to underlying cartilage does exist [57]. Percutaneous osteoplasty, involving the injection of PMMA, calcium sulfate copolymers, or polymer resins with ceramic particles has been found to be effective in providing pain relief and filling in and stabilizing bony defects [45]. The main indications for acetabuloplasty include pain, impending fractures, and the need for bone reinforcement. Contraindications include articular cortical destruction of the acetabular roof more than 5 mm in diameter and soft tissue involvement more than three times the area of bone destruction [58]. To avoid local progression, radiotherapy is recommended after the procedure [45]. Complications from osteoplasty include intraarticular and soft tissue PMMA leakage, fever, renal insufficiency, thrombophlebitis, hypotension, pulmonary embolism, and cardiac arrest [45].

13.6 Surgical Intervention for Vertebral Metastases Harrington demonstrated that there is some utility in the surgical management of spinal metastases [59]. This has been confirmed with subsequent papers [60]. The addition of radiotherapy is adjunctive [20]. We have tools at our disposal to correct virtually any spinal problem that we encounter. We need to apply these tools responsibly. I have seen many x-rays presented at meetings of impressive constructs. Never leaving the hospital and missing your granddaughter’s birthday, however, is not a good outcome. Specific preoperative questions need to be answered. 1. What is the patient’s current functional status? 2. Can I safely improve that status? 3. How much of an impact will my treatment have on this patient’s remaining quality/quantity of life? 4. Can we achieve our goals minimally invasively? 5. If more extensive surgery is required, what can we do to minimize the surgical “footprint”?

13.6.1 The Cervical Spine Rarely is the cervical spine amenable to a minimally invasive solution. Anterior column involvement is the norm. Craniocervical lesions left untreated are potentially catastrophic. Impending collapse/instability are typically managed with posterior occipitocervical stabilization techniques. Modern day constructs allow for safe and reliable reestablishment of biomechanical stability (Fig. 13.2). That being said, occipital plates coupled to C1 lateral mass screws or C1–C2 transarticular screws and

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Fig. 13.2 Occiput-C3 stabilization in a patient with metastatic destruction of the left O-Cl complex

caudal lateral mass screws are typically augmented by older techniques. “One shot” surgery is the goal here. Adjunctive interspinous cables and PMMA are used to achieve that aim. Subaxial lesions usually require an anterior approach (Fig. 13.3). Post-corpectomy reconstruction is rife with anterior column support options. Historically PMMA with K-wires showed utility and occasionally but not always failed before the patient died. Preformed PMMA cylinders held in place with kick out plates cranially and caudally are an economically viable and biomechanically sound favourite. PMMA is allowed to polymerize in the appropriate size syringe/section of chest tube. Plastic is removed and the strut is appropriately cut and shaped to size. Using a section of chest tube allows for a lordotic strut. Allograft is reserved for potential 5–10 year survivors, ie. non-Hodgkin’s lymphoma. Autograft is not a good choice for a lethal condition. Cages are convenient but costly.

13.6.2 Cervicothoracic Junction This region of the spine is perhaps the most difficult and demanding surgical challenge. Pedicle screws in the lower cervical spine are required given deficient lateral

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Fig. 13.3 C2-C7 circumferential stabilization with allograft fibular struts in a 40 y.o. male with Non-Hodgkins lymphoma

mass anatomy. Differences in screw and rod sizes between the cervical and thoracic regions require rod couples that can be easy to assemble or incredibly difficult, depending on design and local anatomy. A sternal split to access the anterior column is not a good option in palliative spine surgery. Invariably anterior column support is lacking, resulting in huge biomechanical demands on a posterior tension side construct. Multilevel fixation is the key. Cement augmentation of the caudal thoracic screws should be seriously considered. Bone mineral densities of less than .6–.8 gm/cm2 are a very strong indication for PMMA in the screw holes. Liberal use of interspinous cables connected to the construct aids in load sharing.

13.6.3 Thoracic Spine An anterior approach is useful for lesions from T4 caudally. A thoracotomy, however, is a morbid approach and rarely used for palliative surgery at our institution. A posterior vertebrectomy allows for multiple points of cranial and caudal pedicle screw fixation (Fig. 13.4) [61]. A PMMA strut anteriorly, with or without sacrifice of an intercostal nerve for access, restores excellent stability when compressed after

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Fig. 13.4 Circumferential cord compression managed with sub-total posterior vertebrectomy and PMMA reconstruction

insertion. A preformed PMMA strut using a 20 cc syringe filled with cement and the plastic cut away after polymerization is a favoured technique. A finger packed “glob” of cement works well too. Compression post-insertion is required to establish stability and minimize any potential for migration. A laminectomy alone is rarely indicated, given its known ineffectiveness, well documented in the literature [62].

13.6.4 Lumbar Spine The posterior approach is again favoured here. Similar to the thoracic spine, a posterior vertebrectomy and PMMA strut is commonly used. If the extent of collapse has been dramatic, a shortening procedure is another alternative. Care must be taken to ensure an adequate decompression cranial and caudal to the lesion to accommodate dural buckling. Anterior surgery via a transperitoneal or retroperitoneal approach is, again, not without significant potential for morbidity. The number of fixation points is reduced and this increases the probability of construct failure.

13.6.5 Minimally Invasive Techniques Wherever possible cement augmentation using percutaneous vertebroplasty (PV) or Kyphoplasty [Kyphon-Medtronic TM] is performed [63]. In cases of metastatic epidural spinal cord compression (MESCC) these procedures are coupled with a

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Fig. 13.5 Decompression and Kyphoplasty post embolization for renal metastasis. Note visible embolization coil. There was immediate resolution of the presenting axial pain and rediculomyelopathy. Hospital length of stay was 2 days

posterolateral decompression (Fig. 13.5). Leakage rates are reduced with the Kyphoplasty technique and favoured when there is a posterior vertebral wall deficiency [64]. Thoracoscopic and laparoscopic techniques are gaining acceptance but are not widely used. There are obvious advantages to a more minimal approach to spinal surgical palliation. The small surgical footprint leads to shortened resolution times. The surgery to radiation interval is measured in days with markedly reduced potential for postirradiation wound complications. The same cannot be said for larger procedures although focused beam technology is reducing that known complication. Ideally, with improved predictive ability and vigilant surveillance, catastrophic deformity, collapse and serious neurological compromise will be outdated. A more minimally invasive approach allows for a more widespread use in a prophylactic fashion. Being paralyzed prior to one’s impending death can and should be preventable.

13.7 Emergency Surgery This is often required for symptomatic pathologic fractures that profoundly impacts ambulatory capacity. As such, pathologic fractures in weight bearing long bones and pathologic burst fractures in the spine with progressive spinal cord compression and neurologic impairment often warrants surgical consultation. Pathological fractures

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in upper extremity long bones may be of lesser importance as it pertains to ambulatory capacity unless in the presence of multiple bony disease with existing impairment to lower extremity function. The role of spinal surgery for metastatic spinal cord compression warrants discussion. Surgery is often indicated for one of two goals: to stabilize the spine and to decompress the neural elements. Extensive bony metastatic involvement of the spine, particularly at a level with both significant anterior and posterior involvement can result in spinal instability with micromotion that causes recalcitrant axial based pain that often can render a patient non-ambulatory due to axial pain. This may occur in the absence of significant spinal canal compromise or neurologic symptoms/signs. With the advent of minimally invasive surgical strategies such as PV and kyphoplasty, the ability to relieve pain axially can be significant. Another consideration is the neural elements. The presence or absence of neurologic impairment and the rate of neurologic deterioration appear important prognostic factors in considering potential success of decompressive surgery in reversing neurologic impairment that has occurred. When neurologic deterioration is rapid or when significant neurologic impairment has existed beyond 48 h, the ability of surgery to reverse (improve) the condition is guarded and better arguments of surgery in affording stability need to be considered in the context of patient symptoms. In the long bone, the surgical treatment of a pathologic fracture is typically similar to those that have not fractured although the technical aspects of surgery may be somewhat more involved and the factor of patient morbidity with fracture warrants consideration. Areas that should be watched closely and intervened upon early are bony lesions involving the weight bearing long bones, in particular the femoral neck and subtrochanteric regions. The decision for emergency surgery also warrants consideration of patient clinical condition. The ability to tolerate a general anaesthetic (lung and cardiac function), the ability to withstand the usual stresses of surgery in the context of post surgical infection (acceptable neutrophil count in patients who have had recent chemotherapy), and overall patient conditioning (Karnofsky performance status) are all issues that warrant pre-surgical assessment. The risk of surgery must be outweighed by the potential benefits dependant on the patient. As such, even in the context of a patient presenting with pathologic fracture or progressive spinal cord compression, surgical consideration of anaesthetic risks and perioperative morbidity/mortality needs to be weighed in the context of the individual patient. With appropriate patient counselling, surgical treatment of patients with symptomatic bony metastatic involvement is unarguably one of the more rewarding cases that has the ability to significantly improve patient quality of life in their time remaining [59].

References 1. Janjan N (2001) Bone metastases: approaches to management. Semin Oncol 28:28–34 2. Swanson KC, Pritchard DJ, Sim FH (2000) Surgical treatment of metastatic disease of the femur. J Am Acad Orthop Surg 8:56–65 3. Hage WD, Aboulafia AJ, Aboulafia DM (2000) Incidence, location, and diagnostic evaluation of metastatic bone disease. Orthop Clin North Am 31:515–528, vii

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4. Bauer HC (2005) Controversies in the surgical management of skeletal metastases. J Bone Joint Surg Br 87:608–617 5. Sim FH (1992) Metastatic bone disease of the pelvis and femur. Instr Course Lect 41:317–327 6. Healey JH, Brown HK (2000) Complications of bone metastases: surgical management. Cancer 88:2940–2951 7. Galasko CS (1972) Skeletal metastases and mammary cancer. Ann R Coll Surg Engl 50:3–28 8. Bauer HC, Wedin R (1995) Survival after surgery for spinal and extremity metastases. Prognostication in 241 patients. Acta Orthop Scand 66:143–146 9. Hansen BH, Keller J, Laitinen M, et al. (2004) The Scandinavian Sarcoma Group skeletal metastasis register. Survival after surgery for bone metastases in the pelvis and extremities. Acta Orthop Scand Suppl 75:11–15 10. Katagiri H, Takahashi M, Wakai K, et al. (2005) Prognostic factors and a scoring system for patients with skeletal metastasis. J Bone Joint Surg Br 87:698–703 11. Harrington KD (1997) Orthopedic surgical management of skeletal complications of malignancy. Cancer 80:1614–1627 12. Harrington KD (1986) Impending pathologic fractures from metastatic malignancy: evaluation and management. Instr Course Lect 35:357–381 13. Finkelstein JA, Zaveri G, Wai E, et al. (2003) A population-based study of surgery for spinal metastases. Survival rates and complications. J Bone Joint Surg Br 85:1045–1050 14. Fidler M (1981) Incidence of fracture through metastases in long bones. Acta Orthop Scand 52:623–627 15. Menck H, Schulze S, Larsen E (1988) Metastasis size in pathologic femoral fractures. Acta Orthop Scand, 1988. 59:151–154 16. Mirels H (1989) Metastatic disease in long bones: a proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res 249:256–264 17. Mirels H (1989) Metastatic disease in long bones: a proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res 415:S4–S13 18. Damron TA, Morgan H, Prakash D, et al. (2003) Critical evaluation of Mirels’ rating system for impending pathologic fractures. Clin Orthop Relat Res 415:S201–S207 19. Patchell RA, Tibbs PA, Regine WF, et al. (2005) Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 366:643–648 20. Tokuhashi Y, Matsuzaki H, Toriyama S, et al. (1990) Scoring system for the preoperative evaluation of metastatic spine tumor prognosis. Spine 15:1110–1113 21. Tokuhashi Y, Matsuzaki H, Oda H, et al. (2005) A revised scoring system for preoperative evaluation of metastatic spine tumor prognosis. Spine 30:2186–2191 22. Enkaoua EA, Doursonnian L, Chatellier G, et al. (1997) Vertebral metastases: a critical appreciation of the preoperative prognostic Tokuhashi score in a series of 71 cases. Spine 22:2293–2298 23. Huch K, Cakir B, Ulmar B, et al. (2005) Prognosis, surgical therapy and progression in cervical and upper-thoracic tumor osteolysis. Z Orthop Ihre Grenzgeb 143:213–218 24. Ulmar B, Huch K, Naumann U, et al. (2007) Evaluation of the Tokuhashi prognosis score and its modifications in 217 patients with vertebral metastases. Eur J Surg Oncol 33:914–919 25. Ulmar B (2007) Prognosis scores of Tokuhashi and Tomita for patients with spinal metastases of renal cancer. Ann Surg Oncol 14:998–1004 26. Ulmar B, Richter M, Cakir B, et al. (2005) The Tokuhashi score: significant predictive value for the life expectancy of patients with breast cancer with spinal metastases. Spine 30:2222–2226 27. Taneichi H, Kaneda K, Takeda N, et al. (1997) Risk factors and probability of vertebral body collapse in metastases of the thoracic and lumbar spine. Spine 22:239–245 28. Hipp JA, Springfield DS, Hayes WC (1995) Predicting pathologic fracture risk in the management of metastatic bone defects. Clin Orthop Relat Res 312:120–135

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29. Keene JS, Sellinger DS, McBeath AA, et al. (1986) Metastatic breast cancer in the femur. a search for the lesion at risk of fracture. Clin Orthop Relat Res 203:282–288 30. Hipp JA, Katz G, Hayes WC (1991) Local demineralization as a model for bone strength reductions in lytic transcortical metastatic lesions. Invest Radiol 26:934–938 31. Haller J, Andre MP, Resnick D, et al. (1990) Detection of thoracolumbar vertebral body destruction with lateral spine radiography. Part II: clinical investigation with computed tomography. Invest Radiol 25:523–532 32. Constans JP, de Divitiis E, Donzelli R, et al. (1983) Spinal metastases with neurological manifestations. Review of 600 cases. J Neurosurg 59:111–118 33. Whealan KM, Kwak SD, Tedrow JR, et al. (2000) Noninvasive imaging predicts failure load of the spine with simulated osteolytic defects. J Bone Joint Surg Am 82:1240–1251 34. Hong J, Cabe GD, Tedrow JR, et al. (2004) Failure of trabecular bone with simulated lytic defects can be predicted non-invasively by structural analysis. J Orthop Res 22:479–486 35. Snyder BD, Hanser-Kara DA, Hipp JA, et al. (2006) Predicting fracture through benign skeletal lesions with quantitative computed tomography. J Bone Joint Surg Am 88:55–70 36. Windhagen HJ, Hipp JA, Silva MJ, et al. (1997) Predicting failure of thoracic vertebrae with simulated and actual metastatic defects. Clin Orthop Relat Res 344:313–319 37. Windhagen H, Hipp JA, Hayes WC (2000) Postfracture instability of vertebrae with simulated defects can be predicted from computed tomography data. Spine 25:1775–1781 38. Whyne CM, Hu SS, Lotz JC (2003) Biomechanically derived guideline equations for burst fracture risk prediction in the metastatically involved spine. J Spinal Disord Tech 16:180–185 39. Roth SE, Mousavi P, Finkelstein J, et al. (2004) Metastatic burst fracture risk prediction using biomechanically based equations. Clin Orthop Relat Res 419:83–90 40. Hardisty M, Gordon L, Aqarwal P, et al. (2007) Quantitative characterization of metastatic disease in the spine. Part I. Semiautomated segmentation using atlas-based deformable registration and the level set method. Med Phys 34:3127–3134 41. Whyne C, Hardisty M, Wu F, et al. (2007) Quantitative characterization of metastatic disease in the spine. Part II. Histogram-based analyses. Med Phys 34:3279–3285 42. Althausen P, Althausen A, Jennings LC, et al. (1997) Prognostic factors and surgical treatment of osseous metastases secondary to renal cell carcinoma. Cancer 80:1103–1109 43. Katzer A, Meenen NM, Grabbe F, et al. (2002) Surgery of skeletal metastases. Arch Orthop Trauma Surg 122:251–258 44. Jacofsky DJ, Haidukewych GJ (2004) Management of pathologic fractures of the proximal femur: state of the art. J Orthop Trauma 18:459–469 45. Papagelopoulos PJ, Savvidou OD, Galanis EC, et al. (2006) Advances and challenges in diagnosis and management of skeletal metastases. Orthopedics 29:609–620; quiz 621–622 46. Wunder JS, Ferguson PC, Griffin AM, et al. (2003) Acetabular metastases: planning for reconstruction and review of results. Clin Orthop Relat Res 415:S187–197 47. Weber KL, Gebhardt MC (2003) What’s new in musculoskeletal oncology. J Bone Joint Surg Am 85-A:761–767 48. Marco RA, Sheth DS, Boland PJ, et al. (2000) Functional and oncological outcome of acetabular reconstruction for the treatment of metastatic disease. J Bone Joint Surg Am 82: 642–651 49. Aboulafia AJ, Buch R, Mathews J, et al. (1995) Reconstruction using the saddle prosthesis following excision of primary and metastatic periacetabular tumors. Clin Orthop Relat Res 314:203–213 50. Allan DG, Bell RS, Davis A, et al. (1995) Complex acetabular reconstruction for metastatic tumor. J Arthroplasty 10:301–306 51. Stark A, Bauer HC (1996) Reconstruction in metastatic destruction of the acetabulum. Support rings and arthroplasty in 12 patients. Acta Orthop Scand 67:435–438 52. Levy RN, Sherry HS, Siffert RS (1982) Surgical management of metastatic disease of bone at the hip. Clin Orthop Relat Res 169:62–69

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53. Harrington KD (1981) The management of acetabular insufficiency secondary to metastatic malignant disease. J Bone Joint Surg Am 63:653–664 54. Abudu A, Grimer RJ, Cannon SR, et al. (1997) Reconstruction of the hemipelvis after the excision of malignant tumours. Complications and functional outcome of prostheses. J Bone Joint Surg Br 79:773–779 55. Renard AJ, Veth RP, Schreuder HW, et al. (2000) The saddle prosthesis in pelvic primary and secondary musculoskeletal tumors: functional results at several postoperative intervals. Arch Orthop Trauma Surg 120:188–194 56. Nilsson J, Gustafson P, Fornander P, et al. (2000) The Harrington reconstruction for advanced periacetabular metastatic destruction: good outcome in 32 patients. Acta Orthop Scand 71:591–596 57. Schreuder HW, Keijser LC, Veth RP (1999) Beneficial effects of cryosurgical treatment in benign and low-grade-malignant bone tumors in 120 patients. Ned Tijdschr Geneeskd 143:2275–2281 58. Cotten A, Deprez X, Migaud H, et al. (1995) Malignant acetabular osteolyses: percutaneous injection of acrylic bone cement. Radiology 197:307–310 59. Wai EK, Finkelstein JA, Tangente RP, et al. (2003) Quality of life in surgical treatment of metastatic spine disease. Spine 28:508–512

Chapter 14

THE ROLE OF CHEMOTHERAPY IN THE TREATMENT OF BONE METASTASES Thomas Makatsoris and Haralabos P. Kalofonos Division of Oncology, University of Patras Medical School, 26504 Patras, Greece, e-mail: [email protected]

Abstract:

In the event of malignancy the skeleton is one of the most commonly affected organs. Metastatic bone disease is associated with significant morbidity and severe complications and has become an increasingly important quality of life issue. The four main treatment modalities that are currently used for the management of bone metastases are medical treatment (including chemotherapy, bisphosphonates, and hormone therapy), radiotherapy, radiopharmaceuticals and surgery. In most cases the above treatments are either used sequentially or concomitantly, depending on the extent and location of metastases, associated symptoms, performance status and prognosis of patients. Combination chemotherapy has shown to be an effective treatment for the overall management of patients with bone metastases, especially for patients with metastatic breast, prostate and small cell lung cancer. The therapeutic outcome and response rates are though limited in chemotherapy-resistant tumors such as non small cell lung cancer and melanoma.

Key words: Chemotherapy · bone Metastases · Breast cancer · Prostate cancer · Lung cancer

14.1 Introduction The development of metastatic bone disease is a source of significant morbidity in cancer patients and bone metastases have become an increasingly important quality-of-life issue. The skeleton is an organ which is most commonly affected by metastatic cancer [1]. Breast and prostate carcinomas have a marked predilection to metastasize to bone, having an incidence of 65–75% and 68% respectively. In addition, lung, thyroid, and renal carcinoma metastasize to bone in approximately D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 14,  C Springer Science+Business Media B.V. 2009

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30–40% of cases [2,3]. Bone metastases are somewhat less frequent in gastrointestinal tract tumors. Survival after metastasis to bone varies greatly, depending on tumor type and sites of involvement. The mean survival ranges from 3 months in patients with lung carcinoma to 19 months in those with thyroid and breast carcinoma [4]. The mean survival for patients with skeletal-only metastases is 12 months, as compared to 3 months in patients with both pulmonary and bone metastasis. The decline in mortality rates observed over the last few years translates into more patients living with metastatic bone disease and the challenge for the oncologist is to improve the quality of life of such patients. The treatment of metastatic disease requires a broad approach that addresses systemic and focal disease. Pain relief is one of the major goals, as well as the prevention of possible fractures and improvement of mobility and ambulation. The complex nature of metastatic disease requires the combined efforts of a team of medical, surgical, radiation, and orthopedic oncologists. Systemic disease necessitates a combination of chemotherapy, hormonal therapy, immunotherapy, and bisphosphonate therapy. Focal complications are best addressed with surgery or radiotherapy, or both.

14.2 Treatment of Bone Metastases Currently, four main modalities exist for the treatment of metastatic bone disease: medical treatment, radiation therapy, radiopharmaceuticals and surgery. In the majority of the patients, these treatments are combined, depending on the severity of symptoms, location of bone metastases, performance status and life expectancy of the patient. The role of surgery for the treatment of skeletal metastases is generally palliative and is aimed in improving the quality of life by relieving pain, preserving skeletal function, shortening hospitalization time, and facilitating patient care. The choice of surgical procedure depends on the location, number and size of metastases, as well as on the histological type of the primary tumor. Radiation therapy provides excellent palliation for localized metastatic bone pain and is also effective in preventing or treating pathologic fractures and spinal cord compression. Radiopharmaceuticals may be used for the palliation of metastatic bone pain as an alternative or adjunct to external beam radiation therapy. Advantages over conventional radiotherapy include the ability to treat multiple diffuse sites with mild bone marrow depression, intravenous administration, and fewer adverse effects. Commonly used radiopharmaceuticals include strontium chloride-89, sodium phosphate-32 and samarium-153 lexidronam.

14.2.1 Medical Therapy Medical management targets mainly systemic disease. Based on the histology of primary cancer, therapy may include chemotherapeutic agents, bisphosphonates, hormone therapy, immune therapy, and stem cell or bone marrow transplantation.

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In deciding whether to use systemic therapy – chemotherapy, hormonal therapy, or immunotherapy, for the treatment of metastatic bone disease, the oncologist should first know the histologic type of tumor. Furthermore, the involved bones must be stable with no risk of pathologic fracture. Tumors considered to be sensitive to chemotherapeutic agents are small cell lung cancer, testicular carcinoma, all small round blue cell tumors, Hodgkin’s and nonHodgkin’s lymphomas [5]. A second group of tumors that is moderately sensitive to systemic treatments includes breast carcinoma and ovarian carcinoma. This latter group responds slower and to a less degree to systemic therapy.

14.2.2 Breast Cancer The incidence of skeletal metastases in patients with breast cancer varies from 49 to 84% [6]. Approximately 15% of these patients present with viscera-dominant disease and bone involvement. Thirty percent or more will have bone dominant metastases [7]. The survival of patients with breast cancer and bone metastases is influenced mainly by the subsequent development of metastases at extra-skeletal sites. In a single-centre review of 367 patients with bone metastases, patients with additional organ involvement had a median survival of 1.6 years, versus 2.1 years for those with disease remaining clinically confined to the skeleton (p < 0.001) [8]. Patients with only bone metastatic disease are more likely at the time of diagnosis to be elderly, post-menopausal with lobular carcinoma, who present initially with N0 or N1 disease and are less likely to have poorly differentiated ductal (grade III) carcinomas. The natural history of bone metastases from breast carcinoma can be studied in the subgroup of patients who present with bone only involvement. This group seems to have a favorable prognosis compared to patients with metastases in other sites, with their primary breast tumor commonly being estrogen receptor-positive [9]. Almost 85% of these patients respond to endocrine treatment. Combination chemotherapy has also been reported to be an effective treatment in this subgroup, but it is associated with a greater incidence of adverse effects. Early chemotherapy studies did not include a validated instrument for the assessment of pain relief and quality of life was and final conclusions for the management of patients with metastatic bone disease will be reached when the results from contemporary studies will be available. Furthermore the longer period of disease control after treatment reported for these patients may reflect a biologically more favorable subset of disease rather than responsiveness to systemic treatment. The concomitant presence of metastatic disease in other sites, i.e., lung, liver and central nervous system, often determines the nature of the primary treatment selected for the management of patients with metastatic breast cancer. Women with bone predominately lytic metastases should be treated with bisphosphonates in combination with calcium citrate and vitamin D if the expected survival is 3 months or longer. Additionally bisphosphonates can be safely administered concomitantly

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with chemotherapy or endocrine therapy [10, 11]. Women considered to be appropriate candidates for initial endocrine therapy for recurrent or metastatic disease include those whose tumors are estrogen receptor- and/or progesterone receptorpositive, those with bone or soft tissue disease only, and those with limited, asymptomatic visceral disease. In postmenopausal women with previous antiestrogen therapy and who are within 1 year of antiestrogen exposure, current evidence supports the use of a selective aromatase inhibitor as the preferred first-line therapy for their recurrent disease [12]. For postmenopausal women who are antiestrogen naive or those managed with antiestrogen therapy at least 1 year before, the aromatase inhibitors appear to have a superior outcome compared with tamoxifen, although the differences are modest [13]. In premenopausal women without previous exposure to an antiestrogen, initial treatment with an antiestrogen with or without a LHRH antagonist is preferred. Breast carcinoma is generally considered to be a reasonably chemosensitive malignancy. However, only few publications provide details regarding response by anatomic site. The response of metastatic bone lesions to a variety of single chemotherapy agents is generally reported to be in the range of 18–42% [7]. Cyclophosphamide has shown response rates in osseous disease ranging from 23 to 31% and 5-FU from 18 to 37% [14]. Adriamycin has been reported to produce a partial response rate in 19% in patients with osseous lesions who have been treated previously [15]. Response rates of bone metastases to the more recently available taxanes (paclitaxel and docetaxel), range from 30 to 67% [16,17]. Early reports suggest that vinorelbine may have a somewhat less activity against bone metastases as compared with the significant effect of the taxanes on soft tissue and visceral lesions. However, this observation may relate to patient selection and a relative paucity of reports [18]. An international randomized clinical trial, in which enrolled patients suffering from lytic bone metastases were managed with chemotherapy ± pamidronate, provided the opportunity to examine the efficacy of modern chemotherapy schedules for the management of metastatic bone disease. Patients were randomized either to receive placebo or were treated with a variety of chemotherapy regimens. The agents used included 5-FU (66%), cyclophosphamide (51%), doxorubicin (38%), methotrexate (38%), mitoxantrone (24%), and vinblastine (28%), applied either alone or in different combinations. Among the 195 randomized patients, 117 (60%) had only bone metastases. Overall no complete responses were reported, 18% of patients noted a partial response, and 32% were assessed as “no change”. The skeletal morbidity rate (number of complications/year) at 24 months was 2.5 and 65% of these patients developed skeletal complications with a median onset of 7.0 months from the initiation of chemotherapy [19]. The response rates of bone metastases to commonly used combination chemotherapy regimens reported in the literature range from 56 to 87% [7]. Most studies are far away from ideal in their design, so the readers cannot derive definite conclusions regarding the efficacy of chemotherapy on bone metastases. Furthermore only a minority of such studies were designed with a primary end point the response of

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bone metastases to chemotherapy. In addition, almost all of these studies include patients with metastases other than bone. The report by Scheid et al. from the M.D. Anderson Cancer Center provides a unique opportunity to assess the activity of a specific and commonly employed regimen, such as 5-FU, doxorubicin, and cyclophosphamide (FAC) in a group of breast carcinoma patients with bone-only metastases [20]. The investigators reported a 7% complete response rate, a 52% partial response rate, and a 32% disease stabilization in a total of 195 patients. In this series, the majority of patients appeared to have had a significant benefit from the treatment with chemotherapy. The responses were quite durable, with a median time to tumor progression of 14 months. The median survival of the entire group was 35 months when measured from the time of diagnosis of bone metastases and 28 months when measured from the start of FAC chemotherapy [20].

14.2.3 Prostate Cancer The growth of prostate cancer is highly dependent on circulating androgens and in particular testosterone. The standard treatment for metastatic prostate cancer is hormone ablation therapy either by surgical castration (orchidectomy) or medical castration with luteinising hormone-releasing antagonists (LHRH) with or without anti-androgens. Androgen ablation therapy induces palliation of symptoms in many patients; however, over time the majority of them become refractory to hormone therapy, with less than 50% surviving at 5 years. In the past, chemotherapy for hormone resistant prostate cancer (HRPC) has had a modest impact on the treatment of this disease. In one study by Tannock et al., the combination of mitoxantrone with prednisone was reported to induce a palliative response in 29% of patients with symptomatic disease, compared to a 12% response in patients receiving prednisone alone [21]. Quality of life also improved in the combination arm. In another trial, mitoxantrone combined with hydrocortisone was shown to induce a delay in disease progression and an improvement in the quality of life [22]; however, in both trials chemotherapy did not result in an improvement of overall survival. Recently, docetaxel-based regimens have been shown to confer a survival benefit in two phase III studies involving patients with HRPC (TAX 327 and Southwest Oncology Group [SWOG] 9916) [23, 24]. TAX 327 was a three arm study that compared two different schedules of docetaxel with the standard three weekly mitoxantrone regimen (12 mg/m2 ). One group was randomised to receive weekly docetaxel (30 mg/m2 ) for 5 weeks out of 6 and the other group received docetaxel (75 mg/m2 ) every 3 weeks. The planned treatment duration was 30 weeks. Patients in all three groups received prednisone (5 mg) twice daily; in addition, patients in the docetaxel group received premedication with dexamethasone. The primary endpoint was overall survival. Secondary end-points were pain response, PSA response and quality of life. A total of 1006 patients were randomised, with baseline characteristics being well balanced among the three treatment groups. There was a significantly longer survival time with three weekly docetaxel than with mitoxantrone

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(hazard ratio 0.76; p = 0.0009), but not with weekly docetaxel compared to mitoxantrone. The median survival was 18.9 months in the three weekly docetaxel arm, 17.4 months in the weekly docetaxel group and 16.5 months in the mitoxantrone arm. Pain reduction was most pronounced in patients who received docetaxel every 3 weeks (35% compared with 31% on weekly docetaxel and 22% on mitoxantrone) and tumor response was 12% versus 8% versus 7% respectively [23]. The Southwest Oncology Group (SWOG) 9916 trial compared docetaxel plus estramustine to mitoxantrone plus prednisolone in 674 patients with advanced HRPC. Eighteen per cent of patients had a rising PSA as the only manifestation of progressive disease. Patients randomised to docetaxel arm received docetaxel (60 mg/m2 ), estramustine (280 mg three times a day for 5 days) and premedication with dexamethasone, on a three weekly cycle. Patients randomised to mitoxantrone arm received mitoxantrone three times weekly (12 mg/m2 ) plus 5 mg prednisone twice a day. Both overall survival and time to progression were significantly improved in the docetaxel arm. The median survival in the docetaxel arm was 17.5 months compared to 15.6 months in the mitoxantrone arm (p = 0.02). PSA response was higher in the docetaxel group, with pain relief being similar in both arms [24]. Thus, the above studies have put docetaxel-based regimens to be regarded as the standard of care for patients with metastatic HRPC. However, the value of adding estramustine to docetaxel remains to be determined. Consequently based on the phase III trial results, 3-weekly docetaxel and prednisone is the preferred first-line chemotherapy treatment. Alternative regimens include every 3-week docetaxel and estramustine, weekly docetaxel and prednisone and every 3-week mitoxantrone and prednisone. Mitoxantrone with prednisone have shown to provide a palliative benefit in castrated patients with painful bony metastases from recurrent prostate cancer. However their efficacy as a second line therapy after docetaxel has not been determined yet. In a different study vinorelbine has also shown a considerable palliative benefit in patients with metastatic HRPC with disease progression after hormonal therapy. In this study, patients were randomised to receive either intravenous vinorelbine and hydrocortisone or hydrocortisone alone until disease progression. The authors reported that patients managed with vinorelbine plus hydrocortisone had a significantly higher benefit than those receiving hydrocortisone alone, when a decrease in pain intensity, analgesic consumption and performance status were used as end points [25]. The traditional option of the concurrent application of glucocorticoids and external-beam radiation for symptomatic bone metastases remains a treatment of choice for patients with focal pain or impending pathologic fractures. The use of radiopharmaceuticals with either strontium-89 or samarium-153 occasionally benefits patients with widespread painful skeletal metastases non responsive to palliative chemotherapy or systemic analgesia. The risk of causing bone marrow suppression, which might influence the ability to provide additional systemic chemotherapy, should be considered before radionuclide therapy is initiated [26]. Other chemotherapy drugs that are under study include satraplatin, which is a third-generation orally bioavailable platinum compound with structural similarities

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to cisplatin [27] and ixabepilone, an epothilone that belongs to a new class of anticancer agents with a mechanism of action similar to the taxanes [28]. In an attempt to improve the results obtained with docetaxel-based chemotherapy in HRPC, taxanes have been combined with novel targeted agents. Atrasentan is an endothelin-A receptor (ETAR) antagonist. Endothelin-1 (ET-1) has been implicated in the progression of prostate cancer and the development of bone metastases. A meta-analysis that included 1002 patients treated with atrasentan or placebo in phase II or III trials, demonstrated that atrasentan therapy resulted in a significantly longer time to progression, time to bone pain and time to biochemical progression than placebo [29]. Angiogenesis appears to play an important role in the growth and spread of prostate cancer [30]. Plasma VEGF level at diagnosis predicts clinical and biochemical progression and in HRPC this factor may be related to survival [31]. These data provide a rationale for evaluating angiogenesis inhibitors, such as bevacizumab, in combination with docetaxel in HRPC patients. The Cancer and Leukaemia Group B (CALGB) performed a phase II study (CALGB 90006) which involved 75 chemotherapy-naive men with progressive HRPC, managed with docetaxel, estramustine and bevacizumab [32]. A PSA response rate of 81% (61/75) was observed. The median time to progression was 9.7 months and overall survival was 21 months. These results compare favorably with historical controls including the TAX 327 and SWOG 9916 data.

14.2.4 Lung Cancer Approximately 30 to 40% of patients with advanced non-small cell lung cancer (NSCLC) develop bone metastases [33]. However, only 2.3% of lung cancer patients present with bone metastases as a first manifestation of the disease [34]. Such bone metastases are usually lytic in type, and are distributed mainly in the spine, pelvis, ribs and extremities. The occurrence of bone metastases in patients with NSCLC is generally regarded as a sign of poor prognosis. The current recommendations indicate that any newly diagnosed NSCLC patient with abnormal clinical findings should be evaluated with the most appropriate investigation for the exclusion of skeletal disease. Up to 40% of patients with small cell carcinoma (SCLC) may have a positive bone scan at diagnosis, and bone metastases are frequently detected in asymptomatic patients. The importance of evaluating these patients for bone metastases lies in the early detection of metastatic sites in weight-bearing bones that are at risk for fracture, and lesions in the vertebrae which can result in spinal cord compression. Asymptomatic patients with bone metastases are ideal candidates for initial systemic chemotherapy. These patients have been included in clinical trials investigating systemic chemotherapy. However, only limited information is available on the efficacy of chemotherapy on bone metastases, mainly because it is difficult to assess response to treatment in bone, and due to the fact that bone metastases are defined as non-target lesions in the Response Evaluation Criteria in Solid Tumors [35]. There

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are currently no reports on the objective response of bone metastases to chemotherapy in patients with NSCLC, but pain relief has been observed in a percentage of 30–61% of NSCLC patients receiving cisplatin-based chemotherapy, gemcitabine or gefitinib [36–38]. Many drugs are active against stage IV NSCLC. Patients with stage IV disease with a good performance status benefit from chemotherapy and more specifically by administrating a platinum-based regimens [39, 40]. Additionally, taxanes (paclitaxel, docetaxel), vinorelbine, the camptothecin analogs (irinotecan, topotecan), and gemcitabine have been studied in these patients. Chemotherapy combinations using these drugs produce a 1-year survival rate of 30–40% and are superior to single agents. Such regimens include carboplatin/paclitaxel, cisplatin/paclitaxel, cisplatin/vinorelbine, gemcitabine/cisplatin, and docetaxel/cisplatin. In recent years, specific targeted therapies have been developed for the treatment of advanced NSCLC. For recurrent and metastatic disease, first-line therapy with bevacizumab in combination with chemotherapy has been used for patients with a performance status of 0–2 who meet the eligibility criteria (non-squamous cell histology, no history of hemoptysis, no CNS metastases, and no ongoing therapeutic anticoagulation) [41]. Erlotinib, which is a small molecule that inhibits the epidermal growth factor receptor (EGFR), is recommended as a second- or third-line therapy for progressive disease [42]. In small-cell lung cancer, 50–80% of patients with bony symptoms may show pain relief after receiving combination chemotherapy. Unfortunately, the survival of these patients is usually too short for the evaluation of radiologic response (reossification).

14.3 Summary Bone metastases are a major source of morbidity in patients with metastatic cancer and have huge implications for resource utilization. Unfortunately, for many patients with skeletal metastases there is little in the way of effective systemic antitumor treatment; palliation of symptoms is best achieved with local treatments such as radiotherapy, surgery, and analgesia. Chemotherapy is an effective and important component of the comprehensive management of patients with metastatic cancer. It provides a mode of therapy for all of the manifestations of disseminated cancer, including bone metastases. Combination chemotherapy brings about significant benefits in patients with metastatic bone disease secondary to carcinomas of the breast, prostate and small cell lung cancer. Chemotherapy is though of only limited and temporary benefit in relatively chemotherapy-resistant solid tumors, such as non-small cell lung cancer or melanoma. Patients with skeletal metastases from these tumors derive most benefit from local palliative radiotherapy. The problems of response assessment often lead to underreporting of true response rates. Both clinical and objective radiologic criteria should evaluate the therapeutic outcome of patients with metastatic bone disease managed with systemic

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treatments. Furthermore, biochemical markers of bone metabolism are under investigation and it seems that they will be helpful in assessing the response to treatment. Finally, advances in the understanding of the biology of bone metastases will hopefully lead to the development of new treatment modalities that will target their formation and progression.

References 1. Coleman RE (1997) Skeletal complications of malignancy. Cancer 80:1588–94. 2. Plunkett T, Rubens R. (1999) The biology and management of bone metastases. Crit Rev Oncol Hematol 31:89–96. 3. Galasko C. (1986) Skeletal metastases. Clin Orthop Relat Res 210:18–30. 4. Finkelstein J, Zaveri G, Wai E, et al. (2003) A population-based study of surgery for spinal metastases: survival rates and complications. J Bone Joint Surg Br 85:1045–50. 5. Savage P, Ward W. (2000) Medical management of metastatic skeletal disease. Orthop Clin North Am 31:545–55. 6. Bhardwaj S, Holland JF. (1982) Chemotherapy of metastatic cancer in bone. Clin Orthop Relat Res 169:28–37. 7. Harvey HA. (1997) Issues concerning the role of chemotherapy and hormonal therapy of bone metastases from breast carcinoma. Cancer 80:1646–51. 8. Coleman RE, SmithP, Rubens RD. (1998) Clinical course and prognostic factors following recurrence from breast cancer. Br J Cancer 77:336–40. 9. Sherry MM, Greco FA, Johnson DH, et al. (1986) Metastatic breast cancer confined to the skeletal system. An indolent disease. Am J Med 81:381–6. 10. Hillner BE, Ingle JN, Chlebowski RT, et al. (2003) American Society of Clinical Oncology 2003. Update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042–57. 11. Rosen LS, Gordon DH, Dugan Jr. W, et al. (2004) Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100:36–43. 12. Buzdar A, Douma J, Davidson N, et al. (2001) Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19:3357–66. 13. Mouridsen H, Gershanovich M, Sun Y, et al. (2001) Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19:2596–606. 14. Cadman E, and Bertino JR (1976) Chemotherapy of skeletal metastases. Int J Radiat Oncol Biol Phys 1:1211–5. 15. Gottleib, JA, Rivkin SE, Spigel SC, et al. (1974) Superiority of adriamycin over oral nitrosoureas in patients with advanced breast cancer. Cancer 33:519–26. 16. Ravdin PM, Burris HA 3rd, Cook G, et al. (1995) Phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. J Clin Oncol 13:2879–85. 17. Abrams JS, Vena DA, Baltz J, et al. (1995) Paclitaxel activity in heavily pretreated breast cancer: a National Cancer Institute Treatment Referral Center trial. J Clin Oncol 13: 2056–65. 18. Degardin M, Bonneterre J, Hecquet B, et al. (1994) Vinorelbine (navelbine) as a salvage treatment for advanced breast cancer. Ann Oncol 5:423–6. 19. Hortobagyi GN, Theriault RL, Porter L, et al. (1996) Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 335:1785–91.

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20. Scheid V, Buzdar AU, Smith TL, et al. (1986) Clinical course of breast cancer patients with osseous metastasis treated with combination chemotherapy. Cancer 58:2589–93. 21. Tannock IF, Osoba D, Stockler MR, et al. (1996) Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 14:1756–64. 22. Kantoff PW, Halabi S, Conaway M, et al. (1999) Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 17:2506–13. 23. Tannock IF, de Wit R, Berry WR, et al. (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–12. 24. Petrylak DP, Tangen CM, Hussain MH, et al. (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513–20. 25. Abratt RP, Brune D, Dimopoulos MA et al. (2004) Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer. Ann Oncol 15:1613–21. 26. Ben-Josef E, Porter AT. (1997) Radioisotopes in the treatment of bone metastases. Ann Med 29:31–5. 27. Petrylak DP, Witjes F, Ferrero J, et al. (2007) A Phase III, Randomized, Double-blind Trial of Satraplatin and Prednisone versus Placebo and Prednisone for Patients with Hormone Refractory Prostate Cancer (HRPC). Orlando: Prostate Cancer Symposium. 28. Rosenberg JE, Weinberg VK, Kelly WK, et al. (2007) Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients: randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Cancer 110:556–63. 29. Vogelzang NJ, Schulman CC, Dearnaley DP, et al. (2005) Meta-analysis of clinical trials of atrasentan 10 mg in metastatic hormone-refractory prostate cancer. J Clin Oncol 23:Abstract 4563. 30. Weidner N, Carroll PR, Flax J, et al. (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401–9. 31. George DJ, Halabi S, Shepard TF, et al. (2001) Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res 7:1932–6. 32. Picus J, Halabi S, Rini B, et al. (2003) The use of bevacizumab (B) with docetaxel (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): initial results of CALGB 90006. Proc Am Soc Clin Oncol 22:Abstr act1578. 33. Quint LE, Tummala S, Bressin LJ, et al. (1996) Distribution of distant metastases from newly diagnosed non-small cell lung cancer. Ann Thorac Surg 62:246–50. 34. Kagohashi K, Satoh H, Ishikawa H, et al. (2003) Bone metastasis as the first manifestation of lung cancer. Int J Clin Pract 57:184–6. 35. Kimura M, Tominaga T. (2002) Outstanding problems with response evaluation criteria in solid tumors (RECIST) in breast cancer. Breast Cancer 9:153–9. 36. Vansteenkiste J, Vandebroek J, Nackaerts K, et al. (2003) Influence of cisplatin use, age, performance status and duration of chemotherapy on symptom control in advanced non-small cell lung cancer: detailed symptom analysis of a randomised study comparing cisplatin-vindesine to gemcitabine. Lung Cancer 40:191–9. 37. Ellis PA, Smith IE, Hardy JR, et al. (1995) Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 71:366–70. 38. Zhang XT, Li LY, Wang SL, et al. (2005) Improvements in quality of life and disease-related symptoms in patients with advanced non-small cell lung cancer treated with gefitinib. Chin Med J (Engl) 118:1661–4. 39. Souquet PJ, Chauvin F, Boissel JP, et al. (1993) Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 342:19–21.

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40. Sekine I, Sumi M, Saijo N. (2008) Local control of regional and metastatic lesions and indication for systemic chemotherapy in patients with non-small cell lung cancer. Oncologist 13:21–7. 41. Sandler A, Gray R, Perry MC, et al. (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–50. 42. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–32.

Chapter 15

HORMONOTHERAPY OF BONE METASTASES Konstantinos Kamposioras1 and Evangelos Briasoulis2 1 University General Hospital “Athens,” Greece, e-mail: [email protected] 2 Ioannina University Medical School, University Campus, S. Niarchou Av 1, 45110 Ioannina, Greece, e-mail: [email protected]; [email protected]

Abstract:

Hormone-dependent tumors have a proclivity to metastasize to bone where they form two distinct types of bone lesions, which depend on whether osteoclastic (breast and thyroid cancer) or osteoblastic (prostate cancer) activity prevails. Regardless the types of bone lesion, these cancers usually behave indolently and share in common a significant sensitivity to surgical or medical hormone depleting therapies. Such therapeutic strategies are castration interventions and administration of selective inhibitors of hormone biosynthesis (aromatase inhibitors for breast cancer) or hormone receptors (tamoxifen for breast and anti-androgens for prostate cancer). Hormonotherapy of hormonesensitive bone metastases is typically shown effective over protracted periods of time and it usually outperforms chemotherapy in benefiting these patients. Therefore hormonotherapy should be considered as an upfront treatment option for patients with such cancers. Cancer research is currently investigating the molecular mechanisms, which underlie the apparent close ties of hormonal driven cancers and the microenvironment of bone. Improvements in the biological understanding are hoped to boost clinical research into developing most optimal hormonal management of hormone sensitive bone metastases.

Key words: Prostate cancer · Breast cancer · Bone metastases · Hormonotherapy · Therapeutic castration

15.1 Introduction Hormone-dependent tumors have a proclivity to metastasize to bone. Those tumors are the estrogen-receptor positive breast and the prostate cancer which constitute major causes of cancer related deaths worldwide and also the differentiD. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 15,  C Springer Science+Business Media B.V. 2009

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300 Fig. 15.1 A clip of S. Paget’s seminal article of the “seed and soil” theory [8]

K. Kamposioras and E. Briasoulis THE

DISTRIBUTION OF SECONDARY GROWTHS IN CANCER OF THE BREAST. BY STEPHEN PAGET, F.R.C.S., ASSISTANT SURGEON TO THE WEST LONDON HOSPITAL AND THE METROPOLITAN HOSPITAL

AN attempt is made in this paper to consider “metastasis” in malignant disease, and to show that the distribution of the secondary growths is not a matter of chance.

ated cancer of thyroid [1–6]. The osseous tropism of breast cancer was initially recognized late in the 19th century when the surgeon Stephen Paget having autopsied 735 fatal cases of breast cancer, argued in his seminal article published in 1889 in the Lancet (Fig. 15.1) that “in a cancer of the breast the bones suffer in a special way, which cannot be explained by any theory of embolism alone . . . the same thing is seen much more clearly in those cases of cancer of the thyroid body where secondary deposition occurs in the bones with astonishing frequency”. In attempt to explain his observations Paget introduced the “seed and soil” theory quoting an earlier “organ predisposition” idea of Austrian doctor Ernst Fuchs which he had proposed by studying metastatic spread of choroid melanomas [7, 8]. Many investigators have attempted throughout the years to decode the molecular mechanisms which underlie the apparent close ties of hormonal driven cancers and the microenvironment of bone. Yet, we still lack molecular biochemical data sufficient to formulate a clear “seed” and “soil” understanding of this biological phenomenon [9–11]. However, from a clinical stand point, most oncologists feel more at-ease when confront patients with bone metastases of hormone-dependent tumors than others with visceral metastases from several solid tumors, because in the first case metastases can be controlled over prolonged time with simple, subtoxic hormonal medications [12–14].

15.2 Types of Bone Metastases Tumors can cause two distinct, although overlapping types of skeletal lesions when they metastasize to bone. Both types of bone lesions are consequences of disturbance of the normal continuous remodelling of bone which depends on whether osteoclastic or osteoblastic activity prevails [15–19]. Breast and thyroid cancers produce predominately osteolytic type of bone metastases while prostate cancer is typically associated with the development of osteoblastic metastases [6, 20–24]. However, osteoblastic metastases may also occur infrequently in breast cancer and osteolytic in prostate cancer, while approximately 15% have mixed type osseous metastases [25–28].

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15.3 Occurrence of Breast and Prostate Bone Metastases It is estimated that approximately 50–70% of women with advanced breast cancer have skeletal metastases [29]. In illustrating figures, in the year 2008, 40,000 women are expected to die of metastatic breast cancer in the United States. Since two-thirds of with patients with metastatic breast cancer have bone metastases and also two-thirds of breast cancers express estrogen receptors we can estimate that approximately 20,000 of breast cancer patients may develop hormone sensitive bone metastases each year in the US [2, 30–32]. With regard to prostate cancer, approximately 30% have bone metastases already at the time of diagnosis and near all 28,000 patients who are estimated to die of prostate cancer in the year 2008 in the US, will die with bone metastases [31, 33].

15.4 Hormonotherapy 15.4.1 Rationale Metastatic in bone hormone-receptor positive breast cancer and also prostate cancer, although incurable, they usually respond well to hormonal therapies and run indolently with reported median survival of treated patients 4–6 years [34–37]. Moreover it is acknowledged that hormonotherapy strategies outperform chemotherapy in benefiting patients with bone metastases [12, 38–40].

15.4.2 Assessing Response to Therapy: Limitations Reported results of several clinical trials which evaluated in the past the antitumor activity of therapies against bone metastases, should be considered with some sceptism because of methodological issues in this clinical setting [39, 41, 42]. In such studies, the evaluation the response of bone metastases to treatment has typically relied on subjective endpoints such as pain relief and quality of life and on evaluable although not measurable data such as recalcification of previously lytic lesions or reduction of “hot spots” on scintigraphy [39]. Difficulties in response assessment of bone metastases pertain mostly to the breast cancer. Reports from phase II and phase III trials of endocrine therapy have repeatedly provided estimates of the activity of endocrine therapies of osseous metastases in breast carcinoma, but unfortunately, they commonly failed to report the response duration in bone or the survival in patients with bone dominant metastases [43]. This problem has found a solution in the case of prostate cancer with the wide adoption of the PSA response evaluation criteria proposed by Bubley et al., in 1999 [44].

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15.5 Breast Cancer 15.5.1 Early Studies Endocrine therapy was first introduced into the clinics as a therapeutic option for metastatic breast cancer when Sir Beatson reported in 1896 that oophorectomy could induce tumor regression in breast cancer patients [45]. Oophorectomy was understood to work therapeutically in these cases through reduction of oestrogen levels. Later on, in the middle of the 20th century clinical investigators undertook the first systemic approaches to study and compare surgical and pharmaceutical endocrine therapy and first results appeared promising. In surgical approaches, Pearson & Ray reported a 28% response rate in 53 patients and Fracchia et al., 33% in 141 breast cancer patients, all with bone metastases, who were treated with hypophysectomy [46, 47]. Moreover, Fracchia et al., describing the results of adrenalectomy as a therapeutic intervention in patients with advanced breast cancer reported an interersting 36% response rate in a cohort of 500 of whom 329 patients had bone metastases [48]. When the first therapeutic compounds emerged into clinics, they were first compared with established at that time surgical endocrine interventions. Nemoto et al., reported that 5 out of 12 breast cancer patients with bone metastases responded to tamoxifen (42%) compared with 7 out of 11 who responsed to adrenalectomy (64%) [49]. Moreover Santen et al., in another clinical trial in which 96 postmenopausal women with metastatic breast carcinoma were randomized to receive surgical adrenalectomy or medical therapy with an adrenal inhibitor, aminoglutethimide (AG), plus replacement hydrocortisone, they found that 17 of 34 breast patients with bone metastases responded to aminoglutethimide compared with 8 out of 22 to adrenalectomy [50]. Two randomised studies that compared oestrogens and androgens appear to be also of historical interest. Kennedy reported 3 out of 12 bone responses to diethylstilboestrol compared with 2 out of 15 to testosterone [51], and Goldenberg et al. reported that 2 out of 8 breast cancer patients with bone metastases responded to diethylstilboestrol compared with 4 out of 10 who responded to fluoxymesterone [52]. It should be mentioned that because the assessment of expression of hormonal receptors was very limited before the eighties, the results of trials conducted before 1980 were rarely analyzed by considering the expression of estrogen receptors in tumor cells [53–55].

15.5.2 Initial Hormonotherapy Today, it is advised that hormonotherapy of breast cancer bone metastases should solely be considered for women with oestrogen-receptor–positive tumors [56]. Tamoxifen, a Selective Estrogen Receptor Modulator (SERM) which blocks the binding of estrogen to its receptor by competitive antagonism, has been the first and continues to be the recommended hormonal therapy for postmenopausal women

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with metastatic ER-positive tumors [57]. However, although this drug has been used for more than 30 years, there have not been specific data on skeletal response rates [58]. Noteworthy, in one of the first studies Lerner et al., reported that 7 of 18 patients with bone metastases responded to tamoxifen. The investigators of that study drew attention to an observed correlation between response and positive oestrogen-receptor assay and acknowledged a value in this test as a means to select patients for tamoxifen treatment [59]. Second to tamoxifen, progestins and inhibitors of the aromatization of androgens were also proven active against metastatic breast cancer, but a series of relatively small trials failed to demonstrate significant differences in favour of any agent when used as initial hormonal therapy, especially for patients with bone metastases [60– 63]. Characteristically, Hortobagyi et al., reported 9 responses among in a cohort of 18 patients with bone metastases who were treated with medroxyprogesterone acetate, van Veelen et al., reported a 40% response rate for medroxyprogesterone acetate (MPA) and 23% for tamoxifen in 25 and 31 patients respectively, and Muss et al., reported a 33% response rate to oral high dose MPA compared with a 13% response rate for tamoxifen in breast cancer patients with bone metastases [64–66]. Aromatase inhibitors (AIs) are a class of drugs which block aromatase the enzyme that catalyzes the last steps of estrogen biosynthesis, by increasing the aromaticity of androgens through successive hydroxylations of the A ring [67]. These drugs have a potency to suppress effectively peripheral aromatase activity and the biosynthesis of residual estrogens from extra-ovarian produced androgenic substrates in postmenopausal women [68–70]. Today, a third generation of aromatase inhibitors/inactivators (AI) are pushing aside tamoxifen as first line treatment in postmenopausal women with metastatic ER-positive breast cancer [71]. The superiority of AIs over tamoxifen as first line hormonotherapy in postmenopausal patients was clearly evidenced in a large study (907 women, median follow-up 18 months), in which letrozole resulted in more tumor regressions and was associated with a longer time to disease progression than tamoxifen (9.4 versus 6.0 months; P = 0.0001) [72]. The observed benefit was statistically significant irrespectively of previous adjuvant use of tamoxifen and the site of disease [73]. Nonetheless the first evidence of clinical value of third-generation aromatase inhibitors become known when a series of trials demonstrated that AI given as second-line therapy after tamoxifen surpassed in efficacy megestrol acetate, even though responses of bone metastases were not shown significantly different [74, 75]. Lately, a meta-analysis which considered 25 randomized trials with 8504 patients mostly with hormonereceptor–positive tumors showed that third generation aromatase inhibitors and inactivators were superior to tamoxifen and progestins as first-line treatment for advanced disease [76].

15.5.3 Hormonotherapy of Relapsed Bone Metastases The options for second line hormonotherapy may vary broadly, depending on the choice and effectiveness of first line therapy.

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Progestins have been used for years as second-line therapeutic option, considered by many as standard therapy in patients who had relapsed to tamoxifen [77]. However data on bone metastases are sparse and inconsistent with considerable variation of response rates reported in clinical studies which reached a 21% in early eighties. Smith et al., for example reported 40 responses in a cohort of 192 breast cancer patients with bone metastases [78, 79]. The first generation inhibitor of the aromatization of adrenal androgens aminoglutethimide has been studied in patients with metastatic breast cancer who had relapsed after a first line endocrine therapy, usually tamoxifen, but not specifically in regard to bone metastases [80]. Interestingly, in two randomised studies the response rates were in favour of aminoglutethimide when it was compared with tamoxifen. Lipton et al., found a trend towards better activity of aminoglutethimide in women with bone metastases [9 of 27 CR plus PR (33%)] when compared with tamoxifen [4 of 27 (15%)] [81]. Similarly Smith et al., reported that aminoglutethimide achieved better response rates in bone metastases (35%) than tamoxifen (17%) [82]. More recently, new generation aromatase inhibitors were compared with megestrol acetate in randomized trials as second-line hormonal therapy in patients with metastatic breast carcinoma refractory to tamoxifen. Buzdar et al. reported separate trials which compared anastrozole and fadrozole against megestrol acetate (MGA) but both failed to show any superiority for the aromatase inhibitors with respect to the response rate of bone metastases [74,83]. However, in the Thurlimann et al., study a substantial higher rate of progression in bones in the formestane (5l/68) than in the MGA arm (25/53) was observed [72]. A third line hormonotherapy option has recently become available for metastatic in bone breast cancer. This is fulvestrant, a new type of estrogen receptor antagonist which downregulates the ER and is devoid of agonist actions [84]. Fulvestrant has been shown active in patients with metastatic ER+ tumors having received prior hormonotherapy with AI and also tamoxifen [85]. Moreover it has been found equally active and well-tolerated with nonsteroidal aromatase inhibitor examestane in a randomized trial of 693 postmenopausal women with HR+ advanced/metastatic breast cancer progressing or recurring after nonsteroidal AI. Interestingly 563 patients with bone metastases were included in that trial [86].

15.5.4 Hormonotherapy for Bone Confined Metastatic Breast Cancer Bone-confined metastatic breast cancer has been recognized as a distinct clinical entity. We have shown that if metastatic disease remains confined to bone for a minimum of 24 months it will probably follow indolent clinical course for which it is prudent to use gentle therapeutic approaches and mostly remain adherent to hormonotherapy [34]. In this clinical setting we demonstrated that 80% of patients responded to first line hormonal therapy with tamoxifen and a 44% responded also to second line hormonotherapy [any of medroxyprogesterone, aromatase inhibitors and triptorelin, a gonadotropin releasing hormone agonist]. Approximately

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Fig. 15.2 Survival of patients with bone-confined metastatic breast carcinoma (n 104) after the diagnosis of skeletal metastases. M1 (dashed line):patients with bony metastases present at the time of diagnosis; M0 (solid line): patients with bony metastases that occurred during follow-up [34]

two thirds in this cohort patients had also received systemic bisphosphonates [34]. Similar data of hormonal efficacy in this clinical setting had also been reported by Sherry et al. In their study a 87% of treated patients responded to the first hormonal therapy with a median duration of response 10 months, 76% responded to a second line treatment with median duration of response 12 months, and another 60% responded also to the third line hormonal therapy [37]. The indolent course of this metastatic in bone disease taken together with the prolonged life expectancy in these patients allows clinicians to utilize multiple lines of hormonotherapy in combination with bisphosphonates before considering a shift to chemotherapy in the interest of protecting the quality of life of patients. (Figs. 15.2 and 15.3)

Fig. 15.3 Suggested hormonotherapy algorithm for premenopausal and postmenopausal patients with bone-only breast cancer metastases. Bisphosphonates apply to both clinical settings

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15.5.5 Hormonotherapy Combinations A number of investigators have shown that the addition of corticosteroids can increase the antitumor effects of endocrine therapies against metastatic breast cancer. Characteristically Rubens et al., reported a higher overall response rate, response duration, and survival when prednisolone was added to ovarian irradiation or tamoxifen in the treatment of 194 women with advanced breast carcinoma [87]. Apart from the combination with corticosteroids all other possible combinations of hormonal therapies failed to improve the treatment outcome over single agent therapies [88–91]. For instance, Mouridsen et al. showed that the addition of MPA did not improve antitumor activity of tamoxifen in terms of response rate at different sites of metastases, including bone [92]. It is certain that endocrine therapy with either aromatase inhibitors or selective estrogen-receptor modulators will finally lead to endocrine resistance and disease progression in all thus treated patients. Today clinical and translational research focuses on the development of optimal combinations between aromatase inhibitors and inhibitors of the human epidermal and insulin-like growth-factor receptor pathways which are upregulated in hormone-resistant breast cancers. Preliminary data from phase II studies of such combination therapies are encouraging [93]. The combination of hormonotherapy with bisphosphonates is currently recognized as a valid therapeutic option which was recently introduced in the therapy of breast cancer bone metastases [94]. Following the demonstration of significant reductions in pain and skeletal morbidity compared with placebo with zoledronic acid breast cancer patients with bone metastases is advisable to receive bisphosphonates in combination with anticancer treatment [95, 96]. The clinical significance of this therapeutic practice had initially reveal in a randomized trial in which 371 breast carcinoma patients with osteolytic bone metastases on endocrine therapy were given either pamidronate 90 mg as a 2-h infusion monthly for 2 years or a placebo infusion. That study demonstrated that the addition of bisphosphonates to endocrine therapy produced a sustained reduction in skeletal complications [97]. An additional benefit effect of bisphosphonates is that can offset the induced by the aromatase inhibitors bone loss [98, 99].

15.6 Prostate Cancer Prostate cancer is the second most frequently diagnosed cancer and the third most common cause of cancer related deaths among men in the western-type economically developed world with medical and social consequences comparable to those of breast cancer in women [100]. Key features of this cancer are its hormone-dependency and typical association with bone metastases [101]. Prostate cancer is unique among solid tumors in that it threats patients’ survival and quality of life through bone rather than visceral metastatic involvement. Nearly all treatments of metastatic prostate cancer are directed towards osseous metastatic disease with the aim to prevent their

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complications or palliate bone symptoms [102–104]. Untreated patients confront an array of potential sequelae that include bone pain, fractures, hematologic consequences of packed marrow, and neurologic impairment resulting from cranial metastases or cord compression [105,106]. However, in prostate cancer patients with bone metastases, hormonotherapy has the potency to effectively palliate symptoms and even provide survival benefits [5, 107].

15.6.1 Initial Hormonotherapy Prostate cancer progression is driven by functional androgen receptor signaling. Therefore treatment of metastatic disease has logically been focused on androgen deprivation since Huggins and Hodges published their Noble Prize-winning paper 60 years ago in which they demonstrated the high sensitivity of prostate cancer to androgens. Ever since, hormonotherapy remains the mainstay of systemic therapy of metastatic prostate cancer despite transient duration of responses [108, 109]. The target for endocrine treatment of prostate cancer is to deprive cancer cells of androgens. As shown by Kyprianou at al., apoptotic regression of androgen-dependent prostate cancer cells can be induced by any procedure that reduces intracellular concentration of dihydrotestosterone by 80% or more [110]. From a clinical point, it should be noted that it is not imperative to start hormonotherapy immediately upon diagnosis of bone metastases in all patients with prostate cancer. The American Society of Clinical Oncology (ASCO) suggests that hormonotherapy for metastatic in bone prostate cancer can be delayed in low risk patients until the development of symptoms because in a number of old patients the disease may follow a very indolent course [103].

15.6.2 Castration Castration, the time-honoured frontline treatment for metastatic prostate cancer, is a clinical condition defined by testosterone levels below 50 ng/mL in men. This threshold level has recently redefined to <20 ng/mL [111]. The first methods of therapeutic castrating interventions were bilateral orchiectomy which was permanent and pharmaceutical with diethylstilbestrol which was reversible. Estrogens were thought to suppress Luteinising Hormone [LH] from the anterior pituitary and lower the production of testosterone by the Leydig cells. However, estrogens are no longer considered as a valid therapeutic option in metastatic prostate cancer because of significant thromboembolic and cardiovascular toxicity [108, 112, 113]. ASCO at present recommends bilateral orchiectomy as an acceptable first-line therapy, although it seems that a majority of men would rather opt the potentially reversible medical castration with Luteinizing Hormone–Releasing Hormone (LHRH, also called gonadotropin-releasing hormone), GnRH agonists [103, 114–117]. Currently potent LHRH agonists with a hundred -fold greater receptor affinity and reduced susceptibility to enzymatic degradation compared with the naturally

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occurring LHRH, have revolutionised the treatment of patients with advanced prostate carcinoma. These drugs are administered by injection at intervals of 1–3 months. Current studies demonstrate that only about 5% of patients treated with LHRH agonists fail to achieve suppression of testosterone below the level 50 ng/mL [118]. However medical doctors must be aware that LHRH agonists can induce initially a tumour flare effect by inducing a transient increase in LH production and thereof increase of testosterone levels in plasma which usually lasts 1–2 weeks [119]. Therefore patients who commence on LHRH therapy should be warned for the possibility of transiently increased bone pains. Moreover increased medical vigilance is required in patients at risk of metastatic compression of the spinal cord or ureteric obstruction [120]. In such cases either surgical castration should be considered as the treatment of choice or patients should be offered introduction therapy with an antiandrogen for a minimum of 5 days prior to injection of the LHRH agonist with the aim to prevent the flare effects of transient increase of LH and testosterone [121]. LHRH antagonists which lack the undesirable flare effects are now being developed as a next generation castration medicines for prostate cancer [122]. These drugs have now entered clinical investigation [123]. There are several LHRH agonists available for clinical use today, including goserelin, leuprorelin, buserelin and tritorelin, but they have not been tested against each other in randomised controlled trials in the setting of metastatic bone prostate cancer [124, 125].

15.6.3 Antiandrogens Antiandrogens, or androgen antagonists, are pharmaceutical compounds which are capable to inhibit the biologic effects of endogenous circulating androgens by competing with them and preventing acquisition of a transcriptionally active conformation of the androgen receptors [126, 127]. It is recommended that non-steroidal monotherapy can be considered as alternative to castration for the therapy of metastatic prostate cancer, especially in patients who are willing to retain sexual interest and function [103, 128]. Among antiandrogen drugs, the most comprehensively studied one which in addition achieved median survival of treated patients similar to that of castration, is bicalutamide [129, 130]. Steroidal antiandrogens, of which cyproterone acetate is the main representative, have been abandoned as a therapeutic option in metastatic prostate cancer due to toxicity concerns [103, 131].

15.6.4 Combined Androgen Blockade Surgical of medical castration has been used for years as a standalone androgendeprivation therapy for metastatic prostate cancer [132, 133]. However, in early 1980s it was found that approximately 50% of androgens remain in the prostatic tissue following medical or surgical castration, and that adrenal dehydroepiandrosterone [DHEA] plays a major role of as a source of the androgens synthesized

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locally in the prostate and other peripheral target tissues [134, 135]. Based on these observations, the combined androgen blockade (CAB) therapeutic strategy was developed whereby the androgens of both testicular and adrenal origins were blocked simultaneously at start of treatment with the combination of either orchiectomy or an LHRH agonist and a pure antiandrogen [135, 136]. Recently, a randomized clinical trial and an individual patient data meta-analysis demonstrated that non-steroid antiandrogens can improve survival when added to medical or surgical castration, but with a cost of poorer quality of life. The above data, despite some limitations, provide a Level I evidence in support that combined androgen blockade should be considered as upfront hormonal therapy for patients with prostate cancer bone metastases [137–140].

15.6.5 Intermittent Androgen Blockade The therapeutic concept of intermittent therapeutic blockade of androgen (IAB) is principally based on experimental studies showing that continuous exposure to reduced androgens can promote prostate tumorigenesis by promoting selection of molecular events which can lead to more aggressive, hormone-refractory tumors. Moreover IAB, aims also to ameliorate negative treatment effects on the quality of life of patients [141]. However this therapeutic strategy, although it has been proven feasible, it is considered experimental because the available data are so far inconclusive to support clinical recommendations [142, 143]. Definite answers are expected to show up from currently running phase III randomized clinical trials which compare intermittent versus continuous combined ADT. Until then the use of intermittent androgen blockade should be considered only in the context of clinical trials [103].

15.6.6 Second Line Hormonotherapy Endocrine therapy of metastatic in bone prostate cancer is by definition palliative and not curative. Even though androgen-deprivation treatment can prolong median survival in prostate cancer patients with bone metastases and benefit a 10% of them with a 10 years symptomless period, the great majority will eventually experience disease recurrence [144]. Progression to androgen-independent status is expected after a median time of 18 months from hormone deprivation [145–147]. However, available research data indicate that relapsed prostate cancers remain potentially sensitive to intracellular androgens and meaningful responses can further be achieved with novel therapeutic approaches [148–150]. Recent advances in the understanding of the biology of prostate cancer have opened new insights into the issue of resistance-associated mechanisms of castrationrecurrent prostate cancer. First, it has been found that the levels of tissue androgens remain capable of activating the androgen receptors which may additionally upregulate to hyperactive status in hormone-refractory phenotype [151–156]. Secondly,

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adrenal glands secrete hundredfold higher than testosterone levels of the inactive precursor steroids DHEA, its sulfate DHEAS and also androstenedione (4-dione), which are converted into potent androgens in peripheral tissues, including the prostate [157]. Finally, it has been shown that the active androgens made locally in the prostate can exert their action by interacting with the androgen receptor in the same cells where their synthesis takes place without being released the active androgen in the circulation (intracrine function). It is suggested that novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment are required to achieve optimal clinical efficacy in the therapy of metastatic prostate cancer [158–161].

15.6.7 Hormonotherapy Combinations Similarly to bone metastases of breast cancer, glucocorticoids appear to be the best drug-partners to androgen-deprivation hormonal therapy in prostate cancer [162]. Glucocorticoids have been proven active as single agents and also capable to suppress androgen-independent prostate cancer growth possibly through inhibition of tumor-associated angiogenesis by decreasing VEGF and IL-8 production directly through glucocorticoid receptors [162, 163]. However, the use of bisphosphonates in the treatment of metastatic prostate cancer remains questionable. Hormonotherapy of metastatic prostate cancer is known to induce bone loss which ranges from 0.6 to 9.6% in 1 year after the initiation of androgen depletion therapy [164]. Moreover experiments in mouse models point out that increased bone resorption due to androgen deprivation may facilitate the development and progression of bone metastases [165]. Despite of that, we still lack consensus on the routine use of bisphosphonates in these patients, although it has been shown that these drugs can prevent therapy-related bone loss in hypogonadal men with prostate cancer [166–168]. However, although not officially recommended, bisphosphonates might be individually considered for the treatment of refractory bone pain and the prevention of skeletal events [169, 170]. Recent data support that zoledronic acid administered annually can effectively prevent bone loss in hypogonadal men with metastatic prostate cancer [171].

15.7 Differentiated Thyroid Cancer Differentiated Thyroid Cancer (DTC), the most common malignancy of the endocrine system, besides its carcinogenesis initiation factors, is highly dependable on the pituitary thyroid-stimulating hormone for its increase and prosgression [172]. The incidence rate of CTC has been continuously increasing over the last two decades, yet it remains relatively uncommon and highly treatable [173, 174]. Among the differentiated histotypes, it is follicular carcinoma which shows a tendency to develop remote metastases in lung and bone, hitherto at low

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rates [175, 176]. Moreover a small proportion of DTC patients are diagnosed on the basis of the detection of bone metastases [177]. The tendency of DTC to form bone metastases and its increasing incidence has lately renewed the interest in diagnosing and investigating the physiology of bone metastases from thyroid cancer [178–180]. TSH (thyroid-stimulating hormone)-suppressive hormonal therapy with thyroxin constitutes a life-long therapeutic strategy in the case of differentiated thyroid cancers because of the known endocrine dependency of these tumors [181, 182]. Thyroxine starts following postoperative radioactive iodine ablation as a replacement therapy with the aim to suppress TSH which is considered an important growth factor for TDC [183–186]. Current data show that treatment of bone metastases from TDC is usually not curative but palliative. [175, 187] Bone metastases that demonstrate uptake of I131 must be treated with recombinant human TSH (rhTSH) aided therapeutic radioiodide [188–190] while TSH ablative hormonotherapy by thyroxine should be considered in cases not sensitive to I131 [191]. In this contest, medical doctors must be aware that patients with massive bone metastases of follicular thyroid carcinoma and treated with thyroxine are at risk of thyrotoxicosis which can be caused by hyperconversion of administered thyroxine to T3 in the tumor tissue [192].

15.8 Concluding Remarks Hormone-dependent tumors primarily the estrogen-receptor positive breast and the prostate cancer that make a major cancer burden worldwide, and also thyroid cancer, have a well recognized tendency to metastasize to bone. When metastasize in bone, these tumors produce two distinct, although somehow overlapping types of skeletal lesions which are understood as consequences of disturbance of the normal continuous remodelling of bone. The type of bone lesions depends on whether osteoclastic or osteoblastic activity prevails. Breast and thyroid cancers produce predominately osteolytic type of bone metastases while prostate cancer is typically associated with the development of osteoblastic metastases. Clinical experience with hormonotherapy of bone metastases is well established despite inherent difficulties in assessing objective response of bone metastases. In general, oncologists feel comfortable when they confront patients with bone metastases of hormone-dependent tumors because these tumors can be controlled over prolonged periods of time with simple, subtoxic hormonal manipulations/medications. Moreover, it is widely acknowledged that hormonotherapy strategies outperform chemotherapy in benefiting patients with bone metastases. Cancer research is currently oriented to decode the molecular mechanisms which underlie the apparent close ties of hormonal driven cancers and the microenvironment of bone. Improvements in the biological understanding and gene profiling are hoped to boost clinical research into developing optimal hormonal management of hormone sensitive bone metastases.

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Chapter 16

RADIONUCLIDE THERAPY Giovanni Storto IBB; CNR, via Pansini 5, 80131 Napoli, Italy, e-mail: [email protected]

Abstract:

Most patients with advanced cancer develop metastatic bone disease; this untreatable evolution of the disease weights heavily on cancerrelated mortality and morbidity. Although bone metastases are often clinically silent, some conditions may support bone pain. Therapeutic strategies for pain palliation could include treatments directed at the source of the pain as well as may focus on comprehensive care of patient. Among the different, mostly palliative, therapies used to treat bone metastases, bone-targeted approaches using bisphosphonates, radiopharmaceuticals, or endothelin receptor antagonists currently hold great promise in terms of efficacy and tolerability. The use of boneseeking radiopharmaceuticals for pain palliation continues to represent an irreplaceable tool in critical pain conditions. The systemic radionuclide therapy has gained full consideration, with its efficacy being widely accepted. It offers the prospective of pain relief with negligible side effects. Recently, it has been also implemented in combination with other therapeutic modalities. Future considerations for systemic metabolic radiotherapy include its use at an earlier stage in high-risk patients who are likely to develop bone metastases. In addition, this therapy could be implemented in asymptomatic patients with positive bone scans.

Key words: Bone pain palliation · Pain management · Radionuclide therapy · Combined therapy

16.1 Introduction Most patients with advanced cancer complain with bone metastasis [1–4]; this untreatable evolution of the disease weights heavily on cancer-related mortality and morbidity. Therapeutic strategies to prevent the advancement of the disease and its complications are being persistently investigated [5–7]. Although bone metastases D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 16,  C Springer Science+Business Media B.V. 2009

321

322

G. Storto Table 16.1 Therapeutic management in bone pain syndromes due to metastases

Analgesics

Pharmaceuticals

Non-steroidal Chemotherapy anti-inflammatory drugs (NSAIDs) Non narcotic

Hormones

Narcotic

Bisphosphonates

Radiation

Interventional procedures

Anesthesia

Single and multiple external beam radiation therapy (EBRT) Radiopharmaceutical therapy Wide-field (EBRT)

Local surgery

Local anesthesia

Radiofrequency ablation (RF) Others (acupuncture)

Peptide compounds Unsealed sources Steroids CNS drugs (psychomimetics)

are often clinically silent, some conditions may support bone pain [8, 9]. In fact, when bone metastases occur, osteolytic activity increases. This leads to osteopenia and increased risk of developing fractures. The calcium released from the bone matrix during this process can lead to a severe metabolic condition, the hypercalcemia of malignancy. Moreover, bone pain might also represent a primitive, discrete symptom as a part of the metastatic disease, reducing the performance status and decreasing the quality of life. In addition, bone pain may constitute a particularly invalidating condition. Therapeutic strategies for pain palliation could include treatments directed at the source of the pain as well as may focus on comprehensive care of patient [2]. The different approaches to deal with pain symptoms related to cancer are displayed in Table 16.1. Among the different, mostly palliative, therapies used to treat bone metastases, bone-targeted approaches using bisphosphonates, radiopharmaceuticals, or endothelin receptor antagonists currently hold great promise in terms of efficacy and tolerability [10–15]. The use of bone-seeking radiopharmaceuticals for pain palliation was adopted almost 50 years ago and actually continues to represent an irreplaceable tool in critical pain conditions [16].

16.2 The Role of Radionuclides in the Management of Metastatic Bone Disease As an alternative, sometime complementary, therapeutic approach to painful bone metastases, the systemic radionuclide therapy has gained full consideration, with its efficacy being widely accepted [17–21]. It offers the prospective of pain relief with negligible side effects. At present, radionuclides such as Strontium-89 (Sr-89), Samarium-153 (Sm-153) and Rhenium-186 (Re-186) are recommended for periodic use in cancer patients presenting multiple uncontrolled painful sites of bone metastases in which the use of multiple or single fields of external beam radiation is not possible. They represent an attractive therapeutic modality for patients

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with metastatic bone cancer, as therapy is delivered directly to the main reservoir of disease [22]. However, no trial of any bone-seeking radiopharmaceutical alone has resulted in a significant overall survival benefit or to consistently deliver radiation to realize substantial cell kills. The first radioactive isotope artificially produced was P-30 in 1933 [23], Sr-89 was first reported in 1937 even if the bone-seeking features of strontium were advocated in 1874 [24]. Later, P-32 and Sr-89 were consequentially used in clinical studies for the bone pain palliation from metastatic cancer as well as in multiple myeloma and leukemic diseases [25]. The dosimetric advantages of different radionuclides have been widely supported so far [26]. The underlying opinion sustaining the role of bone-seeking radiopharmaceuticals in the management of metastatic bone disease is that the absorbed dose to metastatic sites would offer a suitable therapeutic gain when compared with the absorbed dose to normal tissues, such as bone marrow. It is well-known that the absorbed dose to metastatic bone is functionally related to the energy delivered within the tumor which reflects the radiopharmaceutical concentration at the tumor site, the tumor residence time and beta particle energy. Several radiopharmaceuticals have been used for palliating pain due to bone metastases (Table 16.2). These agents are mainly administered intravenously targeting the metastatic painful sites via accretion to the reactive bone, determining high target/background ratio and sparing normal bone. As reported above, the therapeutic features of radionuclides used in bone pain palliation are related to the energy of emitted particles, such as beta and Auger electrons, which determines the range of tissue penetration. The osteoblastic lesions represent the main target of i.v. administered bone-seeking agents. However, they reach mixed and osteolytic lesions as well, being the latter usually surrounded with metabolic active bone. Systemic radioisotope therapy has been recognized to be effective in alleviating pain, improving quality of life and reducing the need of supportive analgesic therapies. More than 50% of treated patients have shown pain relief which is achieved within one to four weeks depending on the radiopharmaceutical. Typically, the painrelief effect last several months and repeated administrations may be given in case of refractory or relapsed syndromes when bone marrow has recovered. Systemic therapy with radionuclides may be implemented alone, when pain symptoms have taken Table 16.2 Radiopharmaceuticals used in bone pain palliation Radio-compounds Half-life (days) β-energy, MeV (maximum) Sr-89 chloride Sm-153 EDTMP Re-186 HEDP Re-188 HEDP P-32 compounds Sn-117m DTPA

50.5 1.93 3.7 0.7 14.3 14

Maximum range in tissues (mm)

1.46 6.7 0.81 3.4 1.07 4.7 2.12 11.0 1.71 8 Conversion electrons 0.25

γ-energy, keV (%) – 103 (28) 137 (9) 155 (15) – 158 (86)

EDTMP: ethylenediaminetetramethylenephosphonate; HEDP: hydroxyethylidine diphosphonate; DTPA: diethylenetriaminepentacetic acid.

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Fig. 16.1 Patient with low-grade pain syndrome due to bone metastases from prostate cancer. 2516 MBq of Sm-153 EDTMP was administered early, on a PET-F-18 Fluoride result-basis, as well. Note differences between conventional bone scans (Tc-99m MDP, Sm-153 EDTMP) and PET-F-18 Fluoride, all performed within three weeks

place but also in the course of a comprehensive therapeutic approach by merging potentialities of others analgesic or curative treatments such as chemotherapy, bisphosphonates, radiation and surgery [27–29]. Moreover, no therapeutic constrains hamper the use of radionuclides in metastatic bone lesions early, before pain syndrome would has effect. It could be postulated that the earlier the treatment the better the outcome. In this context, for example, our group is implementing the use of other diagnostic modalities such as F-18 fluoride PET-TC, routinely, in order to obtain earlier a more complete assessment of bone metastatic involvement (Fig. 16.1). Future considerations for systemic metabolic radiotherapy include its use at an earlier stage in high-risk patients who are likely to develop bone metastases. In addition, this therapy could be implemented in asymptomatic patients with positive bone scans.

16.3 Indications, Contraindications and Special Precautions Bone pain palliation by radionuclides is properly indicated in patients presenting advanced metastatic cancer who need to control their pain syndrome and aim to improve their quality of life. Within a comprehensive multidisciplinary approach the role of nuclear medicine therapeutic procedures appears to be crucial, in particular if, level of pain, number of painful sites, likely of survival and quality of life have been correctly considered on a patient basis. Most of patients with metastatic cancer

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Table 16.3 Indications for commonly used bone-seeking radiopharmaceuticals in patients with bone metastases from cancer Indications Sr-89 chloride Prostate, breast and lung cancer

r r

Sm-153 EDTMP Prostate, breast, lung cancer and osteosarcoma Cancer with several painful bone metastases Positive bone scintigraphy

Re-186 HEDP Prostate and breast

Re-188 HEDP Prostate, breast and lung cancer

Bone pain characteristics

r r r r r

Pain requiring heavy analgesia Multiple sites of pain Multiple wondering pain Multiple site of pain requiring external radiation in most painful site Pain relapsed within a previously irradiated metastatic site

Perspectives

r r r r r

Adjuvant or combined with other therapeutic modalities Limited number of painful bone metastases Single site of pain Multiple sites involved on bone scan but pain-free or not requiring analgesia regularly Earlier stage in high-risk patients likely to develop bone metastases

to bone and positive phosphonate bone scan have been shown to be successfully treated by radioisotopes. Patients with multiple sites of pain, pain requiring heavy analgesia, multiple wondering pain and pain relapsed within a previously irradiated site are candidate to radionuclide therapy. Moreover, clinical trials support the use of bone-seeking radioisotopes in patients with a limited number of painful sites [30], less widespread disease as well as adjuvant to radiotherapy [31]. Finally, some studies have advocated the use of unsealed sources in patients with single site of pain and pain not requiring analgesia [28, 30–33]. Although the evidence of a clinical benefit in these situations has to be fully demonstrated, we agree with authors who verified in such conditions a delay in pain progression and the reduction of additional therapeutic interventions. Furthermore, we support the idea of those authors who prospectly sponsored the use of bone-seeking radionuclides in patients with multiple sites involved on bone scan but pain free or presenting pain not requiring analgesics regularly [34] (Table 16.3). Once radionuclides have administered a delay in the start of response has to be expected. During this period a pain flare phenomenon may occur but it is transient and resolves spontaneously within 1–2 weeks. Life expectancy of 2–3 months from the time of injection should be considered as relative contraindication. Platelet count lower than 100,000/mm3 constitutes a contraindication to treat patients with bone-seeking radionuclides whereas a count lower than 60,000/mm3 should be considered the level contraindicating the therapy absolutely. Moreover, white cells count <2,500/mm3 or the evidence of global and rapid reduction of blood counts contraindicates the therapy. Radionuclide therapy should be reconsidered after

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Table 16.4 Contraindications for commonly used bone-seeking radiopharmaceuticals in patients with bone metastases from cancer Contraindications

r r r r r r r r r

Platelet count lower than 100.000/mm3 White cells count <2.500/mm3 Evidence of global and rapid reduction of blood counts Radiotherapic or surgical stabilization in patients with spinal cord compression Actual or imminent cord compression or pathologic fracture Recent myelosuppressive chemotherapy Disseminated intravascular coagulopathy (DIC; for Sr-89) Karnofsky performance status <40 Life expectancy <12 weeks

radiotherapic or surgical stabilization in patients with spinal cord compression or in those presenting actual or impending pathologic fractures. To avoid an additive, myelotoxic effect, therapy with isotopes should not be administered prior to myelosuppressive chemotherapy. It has been shown that high grade thrombocytopenia may occur in patients with disseminated intravascular coagulopathy [35, 36] which has been reported as complication of advanced cancer [37]. Thus, in these patients a careful monitoring of platelet counts is mandatory (Table 16.4). Efficacy of re-treatments in the course of relapsed pain or disease progression is similar to that of initial therapy. The additive toxicity seems to be not significant. Among the bone-seeking radionuclides, Sr-89, Sm-153 and Re-186 have been widely accepted in clinical practice and they represent the object of the largest part of literature.

16.3.1 Strontium (Sr-89) Strontium-89 has a physical half-life of 50.5 days and decays by beta emission with an energy of 1.46 MeV, it is used as chloride salt and chemically mimes the calcium. Sr-89 is biodistributed to sites where normally calcium is metabolized to form new bone. Thus, 70% is retained in bone, the remaining amount is excreted in the urine and gastrointestinal tract. In normal bone the biologic half-life seems to be among 14 days whereas that of bone reacting to metastases is approximately 50 days. As a result, the tumor concentration of Sr-89 might be up to 5–10 times that in normal bone. Response to Sr-89 is most effective in patient with limited bony involvement, in patients presenting higher performance status (more than 75%) and those having osteoblastic lesions [33]. Delay in the beginning of response was reported between 4 days and 28 days with a response duration of up to 15 months. It seems to be effective in pain palliation when repeated activities are administered in patients who have responded to the initial administration [38]. Sr-89 is contraindicated in patients with impending spinal cord compression or pathologic fractures. It appears, throughout

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several trials [39–41], that a Sr-89 mean administered activity of 2.1 MBq/kg represents the most cost-effective amount to be considered in order to obtain significant pain relief.

16.3.2 Samarium (Sm-153) Samarium-153 is reactor-produced by neutron bombardment of enriched Sm-152 oxide. It is complexed with the chelator of ethylenediaminetetramethylenephosphonate (EDTMP), is delivered as Sm-153 lexidronam and has a physical halflife of 46.3 h. Sm-153 decays emitting both beta- and gamma rays. The maximum beta-particle energies are 0.81 MeV (20%), 0.71 MeV (50%) and 0.64 MeV (30%) whereas the gamma photon energy is 103 keV (29%). Chelation of Sm-153 with EDTMP constitutes a complex that selectively accumulates in skeleton in association with hydroxyapatite mainly in areas of accelerated turnover [42]. It is cleared rapidly from the blood with an half-life of about 5 min. Sm-153 is mainly eliminated in the urine within about 6 h. Bone metastases contains about five times more Sm-153 than normal bone. Sm-153 was approved in the USA and Europe for the palliative therapy of pain from prostate, breast and lung cancer that had spread to the bone as well as in osteosarcoma. Interestingly, Sm-153 has been used successfully in benign diseases [43] such as rheumatoid arthritis, Paget’s disease and ankylosing spondylitis. Pain relief is typically reported within 5–10 days and may last up to 4 months. Re-treatment has been described as feasible, safe and efficacious [44] also in order to improve the duration of pain response [45]. Contraindications are similar to those recommended for Sr-89. Evaluating a large number of clinical studies, it appears that the most cost-effective activity to be administered is 37 MBq/kg [46].

16.3.3 Rhenium (Re-186) Although Rhenium-186 has been evaluated in several trials its use has to be considered still investigational and not for routine treatment. However, data from literature [47, 48] suggest that Re-186 is an active and safe agent in bone pain palliation being its haematological toxicity mild and reversible. Re-186 is complexed with 1-1 hydroethylidene diphosphate (Re-186-HEDP) has an half-life of 3.7 days and decay emitting a beta particle with a 1.07 MeV energy as well as a gamma emission of 137 keV. It is cleared from the blood with a half-life of 41 h and about 70% of the administered activity is excreted in the urine during 24 h. Re-186 HEDP bonds to hydroxyapatite crystals reaching high concentrations in reactive bone to metastases. Most of clinical trials reported an overall response rate of up to 80% using Re-186, it was implemented in patients with hormone-refractory prostate cancer and with breast cancer and efficacy compared with that of placebo being it significantly higher. Delay in pain relief is usually of 1–3 weeks with a duration of 5–12 months. A mean activity of 19 MBq/kg is recommended. Re-186 HEDP is at least

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as effective in breast cancer patients with painful bone metastases as in patients with metastatic prostate cancer. It is to be preferred to radiopharmaceuticals with a long physical half-life in those patients who tend to have more extensive haematological toxicity since they have been pretreated with bone marrow suppressive chemotherapy [49].

16.3.4 Other Bone-Seeking Radionuclides P-32 decays by beta emission with a half-life of 14.3 days. The beta particle maximum energy is 1.71 MeV. P-32 has been administered as HEDP and pyrophosphate [50] as well as orthophosphate and polimetaphosphate. Phosphorus is bound to the hydroxyapatite matrix in the bone as phosphate and in the soft tissues and bone marrow as well. By virtue of the particular biodistribution of P-32, bone marrow appears to receive higher dose as compared to that delivered at bone metastatic sites. Re-188 HEDP has been implemented in palliative management of bone pain. It is easily produced from a tungsten-188/Re-188 generator. Its effective half-life in bone is about 16 h. Recently several data concerning the efficacy of Re-188 as boneseeking radionuclide have been reported [51–54]. The overall response rate reported was up to 80% and pain relief seems to occur 1–8 weeks after administration lasting up to 3 months. A reversible fall in platelet and leucocyte counts has been reported. In patients with prostate and breast cancer preliminary studies have demonstrated the efficacy of Sn-117m in palliating bone pain [55]. It emits conversion electrons of a limited range (about 0.25 mm) and a gamma photon of 158.6 keV, has a physical half-life of 14 days and is supplied as Sn-117m diethylenetriaminepentacetic acid (DTPA). The overall response rate was 75% with minimal myelotoxic effects.

16.4 Clinical Trials Studies reporting on the use of bone-seeking radionuclides for the management of metastatic bone cancer enclose pain as the main outcome measure. Unfortunately, it was assessed by various methods [20, 21, 38, 56–59], which complicate the analysis of data. The objective assessment of bone pain could also be difficult lacking appropriate quality of life measurement techniques. Most studies used scoring systems according to different criteria, which make unfeasible and conflicting the ultimate judgment on results. In general, complete responses to Sr-89 ranged from 8 to 77% and the proportion of patients who did not respond ranged from 14 to 52%. Fortyfour percent of patients reported some degree of response [60]. Studies undertaken for the evaluation of therapeutic effects of Sm-153 demonstrated some degree of pain palliation in 30–85% of patients [61, 62]. However, it has been shown that all radionuclides used in clinical practice gave comparable response rates. Up to 70–90% of patients were considered responders with 20–30% of them reporting a complete response.

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Among the numerous studies carried out from his group, Robinson et al. [63] reported an overall response rate of 81 with 15% of patients achieving complete response and no significant toxicity. A previous study from the same group [59] enrolled patients who received one or more doses of Sr-89. A mean activity of 1.48 MBq/kg was administered as first treatment whereas for each subsequent therapy were given 1.11 MBq/kg. Best results were obtained almost three weeks after the therapy in patients presenting prostate carcinoma (80% response) and breast cancer (89%). Several more trials outlined the efficacy of Sr-89 [20, 30, 33, 38, 39, 56, 57, 59, 64–71]; in particular Fuster et al. [70] reported a palliative response in 92% of patients and Sciuto et al. [64] in 84% of patients with breast cancer. Moreover, large series have sustained the effectiveness of Sr-89 in patients with breast and prostate cancer with about 30% of responders who became pain free. Buchali et al. [69] studied 98 patients with painful bone metastases from prostate cancer. Most of them received 37 MBq of Sr-89 and the response rate was 86%. Concerning the administered activity, no advantage was found using higher doses within the range of 1.5–3.0 MBq/kg as demonstrated by Laing et al. [41] in a multicenter study. Response rate was 75 and 22% of patients became pain free by 12 weeks. Pain relief started between 10 and 20 day after Sr-89 administration but maximum relief was registered normally at 6 weeks, at that time a nadir in platelet counts was recorded. Relief was preserved for 4–15 months with a mean of 6 months. Some authors [72] compared the effects of 150 MBq of Sr-89 with unlabeled strontium chloride in a randomized placebo-controlled study. Twenty-six patients were evaluated and 8 of 13 who were given radionuclide therapy presented complete or partial response. A dose escalation study was carried out by Haesner et al. [73] in patients with prostate cancer. Patients received 3 injections of Sr-89, ranging from 0 (placebo) to 150 MBq, among those receiving the radionuclide, 59% had partial or complete response whereas 34% responded in the placebo group. In order to consolidate the response or retreat relapsed or refractory bone pain, patients may receive repeated doses once they have shown at least some response to the first administration. Kasalicky et al. [38] studied patients who received from 2 to 5 injections of Sr-89. The degree of palliation was slightly better as compared to that following the first injection and the duration of response increased after each subsequent administration. Response length was about 5 months after 5 injections at the cost of only mild myelosuppression. Toxicity was reported as low also in the study of Pons et al. [21] who treated patients with prostate and breast cancer with 150 MBq of Sr-89 reporting a complete or partial response in 89% of them and no response in the remaining. Responses tend to be lower with greater toxicity in the course of advanced disease [18–21, 74]. Other authors [58, 75] evaluated the efficacy of Sr-89 in patients with end-stage disease indicating overall response rates up to 67% at 11 weeks. A number of patients experienced severe thrombocytopenia and bleeding at the time of death few weeks after the injection and another group had only a 23-weeks median survival. A painful flare response has been reported in 10–20% of patients receiving Sr-89 but it was transient. In general, the clinical practice suggests that Sr-89 is not indicated

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in end-stage disease, in patients with life expectancy <3 months and in those presenting DIC [58]. The efficacy and risk of side effects of radionuclide treatment in patients with painful osseous metastases has been recently re-evaluated by Zorga P et al. [76] who, on a patient-based assessment, confirmed that palliative strontium89 treatment is effective with very mild haematoxicity. Phase III, randomized trials that assessed the efficacy and safety of Sr-89 as adjuvant to local or hemibody EBRT represented the most important studies on this radionuclide. However, concerning the therapy with bone-seeking radiopharmaceuticals, the still open question is whether chemotherapeutics and sensitizers can improve the efficacy of treatment. McEwan et al. [77] demonstrated that in patients previously treated with wide-field irradiation and with local-field irradiation who additionally received 1.5 MBq/kg of Sr-89 the response rates were 83 and 71%, respectively, without significant toxicity. Moreover, a randomized phase III study by Porter et al. [31] focused on the management of endocrine-resistant prostate cancer in a trans-Canadian trial. In this study patients were randomized to receive either EBRT alone or combined treatment (EBRT plus Sr-89). They provided additional information on the role of high activities of Sr-89 (400 MBq) as adjuvant therapy. The time of symptom relief was longer in the group receiving combined EBRT and Sr-89 therapy, with a delayed need for additional EBRT to new sites of bone pain in this group. Although the authors suggested a tumoricidal effect highlighted by the reduction in serum tumor markers (prostate-specific antigen [PSA] and prostatic acid phosphatase), a consistent number of complications was observed. WBC and platelet counts fell to a greater degree and remained depressed longer. On the other hand, some authors [78] suggested that Sr-89, adjuvant to ERBT, does not reduce the number of patients with subjective progression at 3 months. Recently, Ron et al. [79] studied the correlation between the efficacy of local external beam radiotherapy and the efficacy of strontium-89 in the palliation of osteoblastic metastatic bone pain indicating that response to external radiotherapy could be considered as a marker of Sr-89 efficacy in the same patient. Mertens et al. [80] used low-dose cisplatin infusion as a radiosensitizer in patients with prostate cancer treated with Sr-89. The overall pain response was similar to that reported in the literature but, the quality of response appeared enhanced. Median survival was 8 months without significant additional toxicity. Sciuto et al. [81] validated the idea of the enhancement of response by radiosensitizers and later confirmed their data [28]. They compared the responses in patients treated with 148 MBq of Sr-89 and patients receiving the same dose of Sr-89 and low-dose of carboplatin. Response of patients receiving carboplatin was superior to those receiving Sr-89 alone. Tu et al. [82] reported a randomized phase II trial in patients with prostate cancer metastatic to bone. Patients were randomized to receive doxorubicine or doxorubicine and Sr-89. The group treated combining the therapies showed a longer survival (27.7 versus 16.8 months). Preliminary data suggest that Sr-89 combined with estramustine and vinblastine is effective in controlling pain, reducing tumor burden and in reducing requirements for radiotherapy [83]. A dose escalation study carried out by Resche et al. [84] constituted a crucial contribution to the implementation of Sm-153 EDTMP as bone-seeking

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radiopharmaceutical to treat bone pain. Patients were treated with either 18.5 MBq/kg or 37 MBq/kg of Sm-153 and pain responses evaluated on a patient-rated basis by a Visual Analogue Scale (VAS) as well as a Physician’s Global Assessment (PGA). Both dose levels were useful in alleviating pain, but the degree of improvement was greater in the group of patients receiving the higher dose, at each week after initiation of therapy. A statistically significant decrease occurred, from baseline, at weeks 3 and 4 (P < 0.005). None of the changes, in the lower dose group, was statistically significant. A further ascending-dose study had been performed by Collins et al. [34]. Patients were treated with activities ranged from 37 MBq/kg to 111 MBq/kg. Relief of bone pain was observed at all dose levels but not in all patients. The proportion of patients who experienced partial or complete relief of pain was between 70 and 80%. In general, palliation was observed at 1 weeks after Sm-153 administration and was dose-independent. The magnitude of the fall in platelets and white cells counts was dose dependent, the nadir value was reached at 4 and 2 weeks, respectively. Later, Serafini et al. [85, 86] conducted a double-blind placebo controlled trial comparing placebo with 18.5 and 37 MBq/kg of Sm-153. Both doses were more effective than placebo; the efficacy variables included a VAS, a PGA, and daily opioid analgesic use. VAS score decreased greater in the higher dose group whereas remained essentially unchanged from baseline in the placebo group. In the higher dose group, the change in the area under the pain curve VAS was significantly different from that of the placebo group in each of the first 4 weeks (P < 0.034). After the administration of 37 MBq/kg a relatively rapid onset of pain relief (during the first week) was reported allowing an early reduction in the use of opioid analgesics. In addition, the effects were durable as most of patients presented some pain relief 16 weeks after the administration. Hematological toxicity was limited. A similar placebo-controlled study was reported by Sartor et al. [87] who randomized patients with hormone-refractory prostate cancer to receive placebo or 37 MBq/kg of Sm-153. Scores of efficacy-variables such as VAS and the use of opioid analgesics decreased significantly over time in the group treated with the radioisotope. The nadir of platelet and white cells counts was reported at a median of 4 weeks and recovered after 5–8 weeks. Patients with relapsed pain syndrome may be safely retreated with Sm-153EDTMP lacking the evidence of additional toxicity. Some authors [44] reported on patients with hormone-refractory prostate cancer who received multiple administrations of radiopharmaceutical. The median interval between doses was 133 days (range, 55–595 days), with doses ranging between 2 and 11 per patient. The mean administered dose was 2,997 ± 629 MBq. Grade 3 or grade 4 toxicity of white cells and platelets was unusual (<10% of doses). Similarly to Sr-89, Samarium-153 has been combined with chemotherapy as adjuvant. Turner et al. [88] reported preliminarily, on 15 patients treated using Sm-153-EDTMP (740 MBq) combined with intravenous bolus of doxorubicin or mitomycin or with a 3-day bolus of fluoracil. A complete pain response was observed in 4 patients (25%) and a partial response was noted in 8 (50%), for an overall response rate of 75%. Maini et al. [46] have recently reviewed on the role of Sm-153 in bone pain palliation stating that the mean

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pain palliation rate, after a single treatment in breast cancer, is about 80%; toxicity is generally mild and transitory. Recently, the efficacy and toxicity of the commonly used radiopharmaceuticals has been comprehensively assessed by Liepe et al. [89]. Seventy-seven percent of patients reported pain relief after treatment with 188Re-HEDP, 67% after treatment with 186Re-HEDP, and 72% after Sr-89. The maximum nadir of platelet and leukocyte counts was observed between the second and fifth week later for all radionuclides and was reversible within 12 weeks. There were no significant differences in bone marrow toxicity.

16.5 Radionuclide Therapy and/or External Radiotherapy: A Still Open Question Bone pain may beneficiate from all forms of radiation therapy. All modalities offer comparable response rates being them of about 70–90%. Moreover, complete responses are observed in 20–30% of responders. The advantage of external beam techniques is that of more rapid palliation whereas that of systemic radionuclide therapy is a more persistent response, particularly when compared with hemibody radiotherapy. Unsealed source therapy offers the possibility to treat multiple painful sites as well as the chance to retreat patients with subsequent administrations. In general, pain from osteoblastic metastases can significantly be improved by both external radiotherapy and Sr-89, whereas lytic metastases are only responsive to external irradiation. Toxicity is mild and re-treatment is usually possible with radionuclides. Moreover, external beam radiotherapy has to be considered when a spinal cord or nerve root compression is demonstrated, or when osteolytic metastases, with danger of fracture, are visualized. External radiotherapy has been used for many years to treat bone pain. Both local-field and wide-field procedures may provoke haematological and gastrointestinal effects. In this context, Sr-89 has gained clinical importance as less toxic and effective alternative in bone pain palliation. In a consistent number of patients Quilty et al. [30] compared the effects of Sr-89 (200 MBq) with either local field (148 patients) or wide field (157 patients) external beam radiotherapy. Patients were first stratified according to appropriateness for local or hemibody radiotherapy then randomly allocated to that form of treatment or to receive Sr-89. Pain syndromes and toxicity were monitored after 4, 8 and 12 weeks. There was no significant difference in median survival. All treatments provided effective pain relief lasting up to 3 months. In particular, response rates were 63.6% after hemibody radiotherapy versus 66.1% after strontium-89, and 61% after local radiotherapy versus 65.9% in the comparable Sr-89 group. Fewer patients complained with new pain sites after strontium-89 than after local or hemibody radiotherapy. In the local radiotherapy group radiation to a new site was required by 12 patients whereas it was necessary in only 2 patients who received the strontium-89. Platelets and leukocytes fell by an average of 30–40% after Sr-89 without significant sequelae.

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A retrospective study [64] compared the results of treatment using hemibody irradiation (HBI) with those of isotope therapy using the Sr-89, in prostate cancer. Pain control assessed at 3 months was similar for HBI and Sr-89 matched-cases, with 63 and 52% showing some benefit, respectively. The authors concluded that response is most likely with either approach when patients have a good performance status and a limited extent of disease. Efficacy of Sr-89 was also compared with palliative local-field radiotherapy in patients with hormone-refractory prostate cancer [90]. There was no difference in progression-free survival or time to progression. Subjective response was seen in 34.7% of patients treated with Sr-89 and in 33.3% in those who received external radiotherapy. There was no difference in treatment toxicity between the two groups. Considering the global therapeutic approach to the palliation of bone metastases, Chow et al. [91] have interestingly reviewed the current pattern of practice of radiation oncologists in Canada, on a case/questionnairesbasis. For the cases with a single painful bone metastasis, over 98% would prescribe radiotherapy. The most common dose fractionation was 20 Gy in 5 fractions. For the cases with diffuse symptomatic bone metastases, half body irradiation (HBI) and radionuclides were recommended more frequently in prostate cancer than in breast cancer. Strontium was the most commonly recommended radionuclide. In conclusion, radiotherapy, either in the form of targeted external beam radiotherapy or systemic administration of radionuclides should be considered a welltolerated and highly effective treatment for the palliation of symptomatic bone metastases, both this procedures entailing similar subjective response rates.

16.6 Combination of Radionuclides with Biphosphonates The main, future challenge will be to develop strategies able to enhance the effectiveness of radionuclide therapy either alone or in combination with other currently accepted forms of pain palliation (Table 16.5). There has been substantial discussion as to whether there might be advantage in combining bisphosphonates with Table 16.5 Review of radiopharmaceuticals used as adjuvant or combined to other therapeutic modalities in metastatic bone cancer Reference

Year

Radionuclide

Adjuvant/combined

[77] [80] [88] [31] [81] [82] [83] [101] [78] [79] [29] [102]

1990 1992 1992 1993 1996 2001 2002 2002 2003 2004 2006 2008

Sr-89 Sr-89 Sm-153 Sr-89 Sr-89 Sr-89 Sr-89 Sr-89 Sr-89 Sr-89 Sr-89 Sm-153

Local or hemibody EBRT Cisplatin Doxirubicine, mytomicin, fluoracil EBRT Carboplatin Doxirubicine Estramustine, vinblastine Bisphosphonates; olpadronate EBRT Local EBRT Bisphosphonates; zoledronic acid Bisphosphonates; zoledronic acid

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bone-seeking radiopharmaceuticals. In fact, it was speculated about the interference between the different therapies [11–14]. The potential of both agents to beneficially alter the course of metastatic process is fascinating [92]. Indeed, combined treatments with radiopharmaceuticals and bisphosphonates or chemotherapy would be implemented also in order to spare the toxicity of chemotherapy or the cost of long-term therapies. Bisphosphonates have become the treatment of choice for tumor-induced hypercalcaemia and recently they have been used alone or in combination with cytotoxic agents in the palliative treatment of patients with bone metastases. Thus, they seem to represent an ideal compound to be merged in a multi-drug therapeutic approach. New bisphosphonates that are a hundred times more powerful with respect to clodronate and pamidronate are currently investigated [93]. Among these, zoledronic acid is the first bisphosphonate shown to relay a remarkable clinical benefit in the therapy of osteoblastic bone metastases [94–96]. It is a newer nitrogen-containing bisphosphonate that was demonstrated to be as effective as pamidronate in reducing skeletal complications [97] but was superior in the treatment of hypercalcemia [98]. Sr-89, a calcium-analogue, represents a suitable therapeutic modality for patients with metastatic bone cancer, in particular in those having painful bone metastases from prostate and breast cancer [74, 99]. Both the latter approaches to painful bone metastases, bisphosphonates, and radionuclides, have been commonly used independently [18–20, 100], or sometimes in combination with other therapeutic modalities [30, 31, 82, 84] but rarely or never in combination to each other [92, 101]. Generally, Sm-153-lexidronam and other bisphosphonates compete for the same binding sites on the hydroxyapatite crystal and should not be administered on the same day but, this contention needs to be confirmed on a clinical basis. On this context, Lam et al. [102] have recently reported on the combined use of Sm-153 and zoledronic acid in prostate cancer patients. They investigated the possible drug interactions as both agents accumulate in areas with increased osteoblastic activity. The effect of zoledronic acid on global bone uptake of (153)Sm-EDTMP was calculated indirectly by the cumulative activity excreted in the urine. Authors concluded that Zoledronic acid treatment does not influence (153)Sm-EDTMP skeletal uptake and that combined treatment is feasible and safe. Previous trials reported a significant decrease in spinal cord compression in a group of patients receiving Sr-89 and olpadronate when compared with a control group [101]. The benefits of Sr-89 and the bisphosphonate appeared to be synergistic. Recently, our group [29] has compared the efficacy of a combined therapeutic modality using zoledronic acid and Sr-89 with that of the same agents used alone in patients with bone metastatic cancer. In patients with painful bone metastases from prostate or breast cancer the combined therapy with Sr-89-chloride and zoledronic acid is significantly more effective in treating pain and improving the overall performance status than Sr-89-chloride and zoledronic acid used separately. In our setting, reduction in pain was associated with improvement in all dimensions of quality of life, and in the scale for overall well-being. From a conceptual point of view, we have speculated that strontium could effectively improve its tumor residence time in bone metastases metabolic environment considering that the greater the bone remodeling

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due to bisphosphonates, the greater the uptake and retention of Ca-equivalents. The hypothesis could be sustained by the slightly worst hematological toxicity profile observed in the group receiving combined therapy. It accounts for an enhanced radionuclide intake and, accordingly, greater bone marrow suppression. Further data are needed to confirm these initial impressions. Future trials are important to support combined treatments because of the potential impact on patient management.

16.7 Toxicity Depending on the physical characteristics of the specific radionuclide, they work out a different effect and toxicity profile. In most cases bone marrow toxicity is the major concern. However, it appears limited and reversible making repetitive treatments relatively safe. The toxic effects associated with Sr-89 seem to be mild and reversible. About 15% of patients have a transient pain flare response occurring approximately in the first 10 days. However, haematologic toxic effects are the most common side effects with a median decrease of 27% in white cell counts which occurs in 12–80% of patients. Platelet counts usually fall by an average of 29% in 29–80% of patients at fifth week, whereas red cells counts reduce rarely. Generally blood counts recover without the need of supportive interventions. This mild myelotoxicity usually occurs when an averaged dose of 20–24 Gy is delivered to the tumor [103–105]. Leong et al. [106] reported about the use of Sr-89 in the case of disseminated intravascular coagulation (DIC) whereas others demonstrated the successful use of Sm-153-lexidronam for controlling the DIC [107]. Approximately 10% of patients exhibited a painful flare response within 48 h after receiving Sm-153-EDTMP. Sm-153-lexidronam has been associated with only a mild and transient myelosuppression. White cell and platelet counts are reduced by 40–50% from baseline, with the nadirs occurring at a median of 4 week and recovery after approximately 5–8 week. Less than 10% of patients exhibited grade 3 or 4 myelotoxicity. Olea et al. [108] briefly reported on the results of the International Atomic Energy Association Multicenter Study on the efficacy and toxicity of Sm-153- EDTMP in the palliative treatment of painful skeletal metastasis. Patient exhibited mild to moderate myelotoxicity, which recovered completely. Sm153-lexidronam is contraindicated in patients who are allergic to phosphates. Up to 36% of patients recorded a fall in platelet count and 29% neutropenia after Re186 [47, 48, 109–111], both reversible. Other adverse events are generally attributed to the patients’ principal disease and rarely related to the intravenous administration of radionuclides.

16.8 Economics The actual economic context require that a treatment should be cost effective, easy to transport, uncomplicated to administer and should not create radiation protection issues. All these topics contribute to the global cost of systemic radionuclide therapy

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each of them with a different but definite weight. In general, the accurate assessment of these costs is complicate. However, it should be pointed out that the cost of other pain-relief modalities such as EBRT depends, for example, on the number of fractions required. Moreover, the cost of hemibody radiotherapy can be higher because of the additional supportive therapies required and subsequent hospitalizations due to toxicity, if any. Macklis et al. [112] estimated the average monthly costs for palliative radiotherapy which ranged between $850 and $4,000 depending on the treatment duration. Radiopharmaceuticals offer the advantage of wide applicability. This therapeutic modality can be implemented also in peripheral institutions with well-trained personnel and not only in major medical hospitals. Bone-seeking radionuclides may be easily administered without the need for expensive injection devices. Moreover, it has been proven that unsealed source therapy improves the quality of life and diminishes the need of analgesics and complementary radiotherapies of cancer patients with bone pain. Intuitively, using these agents, the overall long-term cost of bone pain palliation will be reduced. Several studies have assessed the cost-effectiveness of systemic radionuclide therapy. Malmberg et al. [113] demonstrated that Sr-89 therapy in addition to EBRT was advantageous to the patient and reduced the pain management costs. McEwan et al. [114] demonstrated the cost effectiveness of this form of therapy. The cost required for the treatment of patient receiving Sr-89 was lower than that of the group receiving placebo. The use of radiopharmaceuticals in the therapeutic algorithm of bone pain accounts for a reduction of the overall cost.

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Part IV

Assessment of Therapeutic Response

Chapter 17

ASSESSMENT OF THERAPEUTIC RESPONSE Orit Freedman1 , Mark Clemons2 , Vassilios Vassiliou3 , Dimitrios Kardamakis3 , Christine Simmons4 , Mateya Trinkaus4 and Edward Chow5 1 University of Toronto, Toronto, Ontario, Canada, e-mail: [email protected] 2 Department of Medical Oncology, Princess Margaret Hospital (5-205), 610 University Avenue Toronto, Ontario, Canada M5G 2M9, e-mail: [email protected] 3 Department of Radiation Oncology, University of Patras Medical School, Patras, Greece, e-mail: [email protected] 4 Department of Medical Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada, e-mail: [email protected] 5 Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada, e-mail: [email protected]

Abstract:

Bone is the most common site of metastasis in cancer patients. Bone metastases are associated with increased morbidity as reflected through pain, reduced quality of life and so called skeletal related events (SREs) as well as worsening patient mortality reflected through decreased survival. This chapter will review the most up-to-date knowledge regarding the assessment of therapeutic response in patients with bone metastases. This includes clinical evaluation, pain and quality of life parameters, biochemical methods of monitoring and radiological measurement of response. Finally, limitations of clinical trial design will be discussed, and future options for trial design are presented.

Key words: Clinical assessment · Therapeutic response · Skeletal related events · Risk factors · Tumour markers · Radiological assessment

17.1 Introduction Bone is the most common site of metastasis in cancer patients, and may complicate a wide range of malignancies including carcinomas of the breast, prostate, thyroid, kidney, bronchus, and multiple myeloma. Bone metastases are associated with increased morbidity as reflected through pain, reduced quality of life and so called D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 17,  C Springer Science+Business Media B.V. 2009

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SREs. The treatment of metastatic bone disease is complex and unfortunately palliative. This chapter will review the assessment of therapeutic response in patients with bone metastases including evaluation of clinical response, biochemical methods, and radiological measurement. Finally, limitations of clinical trial design will be discussed.

17.2 Clinical Assessment Measures Bone metastases can cause significant morbidity, including pain, impaired mobility, pathologic fracture, spinal cord or nerve root compression, hypercalcemia, and bone marrow infiltration.

17.2.1 Pain Bone pain is a common complication of bony metastatic disease, and indeed bone metastases are the most common cause of cancer-related pain [1, 2]. The mechanisms by which bony metastases cause pain are poorly understood, and are the subject of multiple trials. These mechanisms likely include local production of growth factors and cytokines (either tumour-induced or tumour-produced), tumour induced osteolysis, stimulation of ion channels, and direct nerve infiltration [3]. Incredibly, approximately two thirds of bone metastatic sites in patients are painless, highlighting the importance of uncovering the pathophysiologic mechanisms of pain [4].

17.2.2 Pathologic Fractures Destruction of bone by metastatic disease causes microfractures, with the ensuing instability leading to pathologic fractures of the bone. While fractures most commonly occur in ribs and vertebrae, fractures of long bones can produce considerable disability too. A number of radiological features may predict imminent fracture including large lesions, predominant osteolytic component, and erosion of the cortex [5]. These features may be used to intervene proactively using surgical and/or radiation techniques in patients at high risk of long bone fracture.

17.2.3 Compression of the Spinal Cord Suspected spinal cord compression is a medical emergency, requiring urgent evaluation and treatment. The most common symptom of spinal cord compression is pain, often localized to the area of the tumour and may worsen with activities that increase intradural pressure. Pain may be worse at night with a radicular component.

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Late symptoms include neurological impairment such as sensory changes, weakness, paralysis, urinary retention, incontinence and impotence. At this stage these symptoms are often irreversible despite treatment, stressing the importance of early detection and management.

17.2.4 Hypercalcemia Prior to the widespread use of bisphosphonate therapy (BP) in patients with breast cancer and bony metastases, hypercalcemia occurred in approximately 30% of cases, usually in the late stages of disease [6]. Symptoms of hypercalcemia are often systemic and nonspecific including fatigue, anorexia, constipation, and abdominal pain. Left untreated, hypercalcemia can cause progressive renal and neurological impairment, with death ultimately resulting from renal failure and cardiac arrhythmias. Nowadays the occurrence of hypercalcemia is usually in patients already established on bisphosphonate therapy and is often a pre-terminal event.

17.3 Assessment of Skeletal-Related Events Randomized trials comparing BPs with either placebo or no treatment in secondary prophylaxis (i.e., patients with breast cancer and established bone metastases) have shown that once bone metastases are present, BP treatment in addition to chemotherapy or hormonal therapy can significantly reduce the frequency of and delay the onset of SREs [7]. The majority of trials have used a composite end point defined as an SRE, which generally includes the most common clinical complications of bone metastases encompassing radiation for bony pain, surgery/radiotherapy to bone, pathologic fracture, spinal cord compression, and hypercalcemia. Using this composite end point, treatment effect can be analyzed in a number of different fashions. A first event descriptor, or time to first SRE provides an objective and readily assessable estimate of treatment effect, and is the preferred end point according to the U.S. Food and Drug Administration since it accounts for the patients’ time on the study [8]. This endpoint however only captures data of the first event, and ignores what occurs afterwards to any individual patient. Skeletal morbidity rates (SMRs) or skeletal morbidity period rates (SMPRs) assess the number of events that occur during a designated period of time. These can therefore account for the occurrence of multiple events in single patients, but statistically assume that these events occur at a constant rate. This analysis may not reflect clinical experience, in that there is often clustering of skeletal events. Analyses assuming a linear event rate may therefore overestimate the differences between study groups and consequently overestimate study effect [9]. Regression analyses (such as Poisson analysis) are able to account for inter and intra-patient variation in event rates, however Poisson analyses do not account for variability in event rate [10]. Andersen-Gill multiple event analysis calculates a hazard ratio that indicates the extent to which one treatment

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is beneficial over another using multiple-event analyses. In order to account for and attempt to reflect the complexity of clinical experience, other statistical models have been developed as well [11].

17.4 Clinical Risk Factors for Skeletal-Related Events Currently a one-size fits all approach is used to guide bisphosphonate therapy globally – patients commence 3–4 weekly intravenous therapy from the time of diagnosis of metastatic breast cancer until death. There are, however, many patients who will not have an SRE even if they do not receive a bisphosphonate. Conversely, the absolute benefit in reducing and delaying SREs with bisphosphonates is only around 13–20%; it is clear therefore that many patients remain at significant risk of further events despite BP use. These patients may benefit from use of a more potent bisphosphonate (such as zoledronic acid), or may benefit from prophylactic surgical intervention. In one study, 87 charts from two Canadian institutions from 1999 to 2005 were reviewed and examined retrospectively for possible clinical risk factors for skeletal related events (M. Clemons, personal communication). On Cox regression, baseline history of osteoporosis was predictive of SRE development (HR = 4.2; p = 0.025). In patients with and without osteoporosis, median time to SRE was 305 and 866 days respectively (p < 0.001). This demonstrates the importance of baseline bone density in assessing patient risks for SREs.

17.5 Measurement of Pain and Quality of Life 17.5.1 Evaluation of Bone Pain The goal of palliative treatment is to prolong quality of life and hopefully also the quantity of life. Given the paramount importance of pain and quality of life assessment, it is important to examine the evaluation measures that have been utilized. Early trials did not make a formal assessment of bone pain because of the inadequacy of pain assessment methodology for patients with bone metastases. Instead, it was indirectly assessed by estimating the radiation requirement for pain, and radiation therapy was undertaken as clinically required [12]. The requirement for radiotherapy to the bone is considered an SRE in the composite end points of bisphosphonate trials. This requirement represents a significant part of the SRE end point. Therefore, in a roundabout way, SRE outcomes in these trials do incorporate some measure of pain relief. However, there is a need for a more direct assessment of metastatic bone pain relief. Randomized, placebo-controlled studies of pamidronate used a scoring system that measured both the severity (graded 0–3) and frequency (graded 0–3) of pain [13, 14]. The final bone pain score was equal to the product of the two individual scores. A score of 0 indicated no pain, while a score of 9 indicated severe, constant pain. Analgesic use was also estimated using a composite score. A final score was

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obtained by multiplying a score for the type of medication by a score for the frequency at which it was administered. Phase III trials of i.v. and oral ibandronate used a simple, five-point scale – 0 (no pain), 1 (mild pain), 2 (moderate pain), 3 (severe pain), and 4 (intolerable pain) – that patients were asked to complete every 3–4 weeks, during each study visit, to evaluate bone pain over the previous week [15–19]. Analgesic use was scored on a seven-point scale: 0 (none), 1 (mild analgesia; e.g., paracetamol or nonsteroidal anti-inflammatory drugs [NSAIDs]), 2 (mild analgesia and NSAIDs), 3 (moderate analgesia; e.g., codeine), 4 (opiates, morphine equivalent of <40 mg daily), 5 (opiates, = 40 mg but <100 mg morphine equivalent daily), and 6 (= 100 mg morphine equivalent daily). The Brief Pain Inventory comprises a composite of four pain scores (worst, least, and average pain over the last week and current pain) and is validated for cancer pain rather than metastatic bone pain [20]. This was used in the placebo-controlled trial of zoledronic acid and a randomized comparative study of zoledronic acid versus pamidronate [21]. A five-point scale was used to measure analgesic use, ranging from 0 (no analgesic use) to 4 (strong narcotics). A range of other scales for both bone pain and analgesic use has been used by other studies. These include a visual analogue scale [22], variants of pain-point scales [23], and analgesic use on a four- or five-point scale [22, 24]. While all these instruments represent an improvement in pain relief by a decrease in pain score, scale variations make it difficult for clinicians to estimate if the effect on pain relief differs among drugs.

17.5.2 Quality of Life (QoL) Measures QoL measurements are subjective, multidimensional constructs reflecting functional status, psychosocial well-being, health perceptions, and disease- and treatmentrelated symptoms from the patient’s perspective. They incorporate expectation, satisfaction, a value system, and many other aspects of a patient’s life. In general, QoL has been poorly estimated in bisphosphonate studies. Pamidronate studies have used the Spitzer QoL instrument [25], which is intended to be completed by a health care professional and consists of only five items; activity, daily living, health, support, and outlook. This instrument was designed to assess the relative benefits and risks of various treatments for serious illness and of supportive programs, such as palliative care or hospice care. It is not suitable for measuring the QoL in ostensibly healthy people. Studies of clodronate [24] and ibandronate [18,19] used the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) [26]. This instrument is composed of modules that assess QoL for specific cancers in clinical trials. The current instrument consists of 30 items with five functional scales: physical function, role function, cognitive function, emotional function, and social function. Recently the bone metastases module (BM22) has been developed in conjunction with EORTC for future clinical trials in bone metastases (EORTC QLQ website).

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However, neither the Spitzer nor the European instrument addresses in depth the QoL issues related to the complications of bone metastases, such as mobility, functional impairment, and the side effects of bony progression, (such as pathological fractures, hypercalcemia, and spinal cord compression). There is an urgent need to develop a QoL instrument specific to bone metastases that addresses these issues. Two such scores for quality of life measurement are currently being formulated, the FACT-BP (functional assessment of chronic illness therapy-bone pain) and the FACT-BTCSQ (functional assessment of chronic illness therapy – bone treatment convenience and satisfaction questionnaire) [27].

17.6 Use of Markers of Bone Resorption to Guide Treatment 17.6.1 Tumour Markers Tumour markers are metabolic byproducts released by the tumour into circulation. A tumour marker is most helpful when serum concentrations are closely associated with the extent of disease being monitored. Several candidate markers have been assessed in breast cancer, but none to date have been widely recommended for routine clinical use [28]. Markers including CA15-3 and carcinoembronic antigen (CEA) have been demonstrated to correlate with mortality, and in one study, the combination of three markers (CA 15-3, CEA and ESR) predicted subsequent disease progression [29]. These markers correlate with progression in general, but do not distinguish progression in a particular organ site, such as in the bone.

17.6.2 Bone Markers Clinical benefit from BPs seems to be related to the effective suppression of accelerated bone resorption. The aim of BP treatment in advanced cancer should be to normalize bone resorption. A tailored approach with the use of biochemical markers to monitor the degree of bone resorption to guide BP therapy may be a more appropriate, safer, and cost-effective approach than the currently licensed and recommended fixed 3- to 4-week schedule of i.v. treatment. Bone resorption in bone metastasis can be assessed by the measurement of specific biochemical markers that are derived from the breakdown of type I collagen, the main protein in bone. While many markers of bone formation and resorption have been studied (Table 17.1), the most widely used markers are two markers, urinary N-terminal cross-linked type I collagen telopeptide (uNTx) and C-terminal cross-linked type I telopeptide (CTX). Studies have shown that a single dose of either pamidronate or zoledronic acid given to patients with bone metastasis will drop uNTx levels by an average of 44– 70% [30]. Zoledronic acid has been shown to be more effective than pamidronate at suppressing initially high uNTx levels. Moreover, NTX levels among patients with metastatic bone disease strongly correlated with the number of skeletal-related events and/or death [30–32]. Subsequently, these data have been confirmed by evaluation of a large data set from patients with bone metastases (n 3,000) included in

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Table 17.1 Markers of bone formation and resorption Markers of bone formation

Markers of bone resorption

Bone-specific alkaline phosphatase Osteocalcin N-terminal propeptide of procollagen type I C-terminal propeptide of procollagen type I Urinary calcium excretion Urinary hydroxyproline Pyridinoline Deoxypyridinoline N-terminal cross-linked type I collagen telopeptide C-terminal cross-linked type I collagen telopeptide

the phase 3 development program of zoledronic acid [33–35]. Overall, elevated NTx levels predict subsequent SREs while normalization of NTx rates is associated with reduction in SREs. Early small studies suggested a link between bone resorption markers and pain. In the pooled analysis of a phase III trials of ibandronate, significant reduction in NTx were accompanied by a significant lowering of bone pain scores and less of an increase in analgesic use at 96 weeks as compared to placebo [36, 37]. Among a cohort of breast cancer patients with progressive bone metastases being treated with a second generation BP, Clemons et al. demonstrated an improvement in pain scores and a significant fall in uNTX levels after switching to zoledronic acid. Importantly, the fall in uNTX levels was a useful predictor for palliative pain response to zoledronic acid [36]. Ideally, non-invasive measurements of bone markers could guide BP treatment, including optimal doses and frequency of administration choice of BP agent and potential indications for switching or stopping a particular BP. This hypothesis is being tested in a large National Cancer Research Institute supported phase 3 clinical trial in the United Kingdom (BISMARK, EudraCT no. 2005-001376-12). In this trial 1,400 patients with breast cancer – associated bone metastases are being treated with zoledronic acid, either on a regular schedule of 4 mg iv. every 3–4 weeks, or as indicated by NTx levels. Under the marker-directed schedule, patients receive zoledronic acid 4 mg iv. q 3–4 weeks (NTx level > 100 nmol/mmol creatinine), every 8–9 weeks (NTx level 50–100 nmol/mmol creatinine) or every 15–16 weeks (NTxlevel < 50 nmol/mmol creatinine). The primary endpoint is development of a SRE. Secondary endpoints include QoL, pain, analgesic use, health economics, change in systemic therapy, and survival [35].

17.6.3 Other New Biochemical Markers Research over the past 5 years has identified other promising markers for assessment of metastatic bone disease. Tartrateresistant acid phosphatase isoform 5b is a lyososomal enzyme secreted specifically by activated osteoclasts [38]. Serum concentrations of this enzyme are increased in patients with breast cancer who have metastatic bone disease, and the concentrations decrease on administration of bisphosphonates [38,39]. A study of 28 patients with breast cancer and bone metastases

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showed that concentrations of tartrate-resistant acid phosphatase isoform 5b decreased by 39% 1 week after infusion of 60 mg pamidronate in patients who showed a response; concentrations decreased by only 18% in patients who did not respond (p = 0·01) [40]. Therefore, further work with this marker is clearly warranted. Bone sialoprotein is synthesized mainly by osteoblasts and deposited in the bone matrix where it binds integrins. Tumour cells that metastasize to bone also secrete this protein ectopically, especially cells from breast tissue and prostate tissue. [41]. Serum concentrations of bone sialoprotein are increased in patients with metastatic bone disease [42] and this compound might therefore have potential role as a prognostic marker. [43] However, few data are available on changes in concentrations of bone sialoprotein during antineoplastic therapy. Seibel and co-workers [44] reported that serum concentrations decreased by 60% within 4 days of treatment with intravenous bisphosphonate in 15 patients with bone metastases from breast cancer. Further assessment of this marker has been hindered by lack of an available immunoassay. The receptor activator of nuclear factor κB ligand (RANKL)-osteoprotegerin system also has a potential role in the clinical assessment of bone metastases. Both factors are produced mainly by osteoblasts, and RANKL acts directly on its receptor, RANK, to activate osteoclasts and induce differentiation of osteoclast precursors. Osteoprotegrin is a soluble decoy receptor for RANKL and thus inhibits osteoclastogenesis [45]. Analysis of the ratio of serum osteoprotegrin to RANKL might be useful for assessment of bone metastases and response to therapy. However, initial investigations in patients with cancer have not consistently shown that the ratio is increased. Lipton and colleagues [46] did not associate osteoprotegrin concentration with bone metastases in a series of advanced solid tumours, although concentrations were significantly higher in patients with hepatic metastases and soft-tissue metastases. Subsequent studies, although retrospective, have shown that increased concentrations of osteoprotegrin have greater diagnostic accuracy than do those of Cterminal product in the diagnosis of bone metastases in prostate cancer, although RANKL concentrations did not change compared with controls [47]. Interestingly, bisphosphonates are associated with an increase in osteoprotegrin concentrations in cultured primary human osteoblasts [48], suggesting a new mechanism of action. Furthermore, a recombinant osteoprotegrin peptide has entered clinical trials as an antiresorptive agent [49]. However, no studies have yet investigated how serum concentrations of RANKL and osteoprotegrin are affected by bisphosphonates or antineoplastic therapy.

17.7 Use of Radiological Methods for the Assessment of Therapeutic Response Radiological imaging methods are not only effective in the detection and assessment of the extent of bone metastases, but offer an objective and useful means for the evaluation and monitoring of therapeutic response. Several imaging modalities

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have been employed for assessing the therapeutic outcome, including plain and digitalized radiographs, bone scintigraphy, dual energy X-ray absorptiometry (DEXA), computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET). Some of these methods are limited by diagnostic drawbacks that will be discussed, so that misinterpretations and false therapeutic decisions are avoided.

17.7.1 Plain and Digitalised Radiographs The criteria of the International Union against Cancer (UICC), state that a positive response to treatment is evidenced radiographically through the recalcification of lytic lesions [50]. During the process of healing, osteolytic metastatic lesions may regain their normal radiographic appearance or become sclerotic. Healing is brought about centripetally and the affected area ultimately becomes sclerotic [51]. Progressive disease is indicated by additional lysis or development of new metastatic lesions of any type (lytic, mixed, and sclerotic) or the loss of the sclerotic response that was initially recorded [51]. The use of serial radiographs for monitoring the therapeutic response may be problematic, since more than 50% of trabecular bone should be destroyed so that a bone metastasis is detected [52]. Furthermore, changes in bone density in regions of bone metastases may take months to be detected [28] and new sclerotic lesions resulting from disease progression may be differentiated from those caused by healing with difficulty [51]. Last but not least, the measurement of bone density changes by employing plain radiographs is limited by the fact that they can be used only for bones that are not situated between complicated layers of moving organs, such as the thorax and abdomen [53]. Plain and digitalized radiographs have been employed in several studies for the evaluation of therapeutic response. In the study by Heller M and coworkers, 58 patients with bone metastases from breast cancer undergoing antineoplastic treatment, were radiographically monitored for 7.2 years. Indicators of disease regression were reported to be recalcification or re-ossification of primary osteolytic lesions (46.8%), the depiction of marginal sclerosis around lytic defects (15.9%) and lack of progression for a period of 9–12 months (11.6%). In patients with osteosclerotic lesions, regression was evidenced as decreased sclerosis. Recurrence or progression of disease were reported in cases of detection of new metastases (36.6%), progression of osteolysis (26.6%) and increased sclerosis (7.3%) [54]. In a different study involving 274 breast cancer patients with metastatic bone disease, radiographic monitoring was carried out to follow the therapeutic outcome over a period of 10 years. Signs of regression were reported to be recalcification of osteolytic lesions, the formation of marginal sclerosis around the defect and the lack of progression over a period of 12 months. The corresponding percentages were 11.6, 13.6 and 10.5% respectively. Reduction of sclerosis or structural loosening was also considered as an indicator of regression in patients with osteoblastic lesions (2.5%). The manifestation of new

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metastases and/or increase in lesion size, as well as the depiction of lysis in primary sclerotic or mixed metastases, were considered as recurrence or progression of disease and were recorded in 56.9 and 2.5% of patients respectively [55]. The duration of response in lytic bone lesions was found to be less favorable and complex treatments such as the combination of chemotherapy or hormonal therapy and irradiation resulted in a favorable objective response [55]. Digitalized radiographs have been also used to asses the response to treatment in patients with metastatic bone disease from various primary tumors. Patients were managed with the application of concurrent radiotherapy and pamidronate [56–58]. Image analysis was based on measuring first order statistics of the gray-level histogram in terms of the mean value (MVGLH) and energy (EGLH). The application of digitalized radiographs to follow changes in bone density in regions of bone metastases was reported to be feasible and cost effective [8], and decalcification was detected earlier than in the case of conventional radiographs [59]. Figure 17.1 presents the reossification achieved at 6 and 24 months post the onset of the combined treatment in a patient with a lytic metastasis in the femur.

17.7.2 Bone Scintigraphy Serial bone scintigraphy has also been employed in the evaluation of therapeutic response in patients with metastatic bone disease [60]. Even though bone scintigraphy is more sensitive than conventional radiography, it lacks in specificity and anatomical detail [28]. What is actually visualized through this imaging modality is not the tumor itself, but the radioactivity that accumulates in areas of hyperemia or new bone formation. Successful treatment is demonstrated by a decreased avidity for the bone-seeking radionuclide, irrespective of the type of bone metastases [61]. A positive response to treatment may be also associated with an initial flare within 4–12 weeks from the onset of treatment that may be the result of the healing process [51, 62–64]. The flare brings about a worsening of the bone scan and may result in premature discontinuation of potentially beneficial treatments [63] since it can not be distinguished from scintigraphic appearance of disease progression [65]. Interpretation of bone scans should be therefore carried out with caution for the first 6 months post the onset of treatment and tentative response criteria incorporating bone scintigraphy, clinical and radiological assessments should be used to avoid false diagnosis [64, 66]. Progressive disease is indicated by the formation of new foci, increased uptake and enlargement of existing lesions. In cases that disease is rapidly progressive, new bone is hardly formed and diminished uptake may be depicted [51]. Post radiotherapy 3 phases of scintigraphic appearance have been described. Initially there is a hyperemic phase which is accompanied by an increased radionuclide uptake and lasts for a few days. This is followed by an increased uptake that is associated with reossification and lasts for a few months (this phase is dependent on the radiotherapy fractionation scheme that is applied). The last phase is characterized by a reduction in the isotopic uptake, a result of the decreased new bone formation and vascularity. This phase lasts for years and the uptake ultimately returns to normal [61].

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0.15 P(I) 0.1

EGLH = 0.113 MVGLG = 163.23

0.05 0 150 155 160 165 170 175 180

0.2 0.15 P(I)

6-MONTHSPOST BASELINE EGLH = 0.101 MVGLG = 181.07

0.1 0.05 0 160 165 170 175 180 185 190

0.2 0.15 P(I)

24-MONTHSPOST BASELINE EGLH = 0.065 MVGLG = 234.15

0.1 0.05 0 210 215 220 225 230 235 240

Fig. 17.1 Plain radiographs presenting a lytic metastasis in the femur at baseline and at 6 and 24 months post the onset of therapy. The corresponding assessments of grey-level histograms in terms of MVGLH and EGLH are presented on the right of each image. By using the UICC criteria a complete response was recorded at the time point of 24 months (restoration of normal calcification, no new lesions). This figure is reprinted from Kouloulias et al. [58], Fig. 2, copyright 2003, with kind permission of Elsevier Inc.

The use of serial bone scanning in assessing therapeutic response in patients with metastatic bone lesions was evaluated in several clinical trials. Citrin DL et al. used serial bone scintigraphy and radiography to follow the therapeutic outcome of 34 women with metastatic breast cancer managed with systemic treatment [67]. The authors reported that bone scanning was more accurate and sensitive than radiographs in assessing the status of metastatic bone disease and that bone scintigraphy findings correlated well with the response of soft tissue and visceral disease [67]. Similarly, in a different clinical trial, 51 breast cancer patients with bone metastases undergoing treatment with bisphosphonates were monitored by the use of whole-body scintigraphy. Bone scintigraphy was performed prior to

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the onset of therapy with zoledronic acid and at least 6 months thereafter to avoid the flare effect. At baseline 41 (80.4%) patients were found to have multiple (over 3) metastases, 9 (17.6%) had a single metastatic lesion (up to 3) and one (1.9%) suffered from a solitary bone metastasis. Post treatment 4 (8%) patients showed a complete therapeutic response (no bone lesions were visualized), 21 (41%) had a partial response (decrease in the number and intensity of lesions), 16 patients (31%) had stable disease (no change in scintigraphic appearance) and 10 (20%) were found to have disease progression [68]. Finally, serial bone scintigraphy was used together with clinical, biochemical and radiographic evaluations to follow the therapeutic response of 50 breast cancer patients with bone metastases managed with combination chemotherapy. Response to therapy in metastatic sites other than bone correlated well with radiographic improvement of metastatic bone lesions (91%), but less well with scintigraphic changes (57%). A concordance between clinical and radiographic findings was also shown, suggesting progression of metastatic disease in 81% of patients and between scintigraphic and clinical findings in 72% of them. The changes in the levels of carcinoembrionic antigen (CEA) closely reflected the alterations in clinical and radiographic evaluations. The authors concluded that the combination of scintigraphy, radiography and clinical evaluation with CEA measurements resulted in a highly selective and accurate method to evaluate response to treatment [69]. Bone scintigraphy was also successfully used for the determination of the extent of metastatic bone disease, that has shown to correlate with disease prognosis [70, 71] and proved to be a useful indicator of response to treatment [67, 71]. The prognostic significance of the extent of skeletal involvement was evaluated in a clinical trial involving 191 patients with metastatic androgen-independent prostatic cancer. The extent of metastatic bone disease was assessed by using a bone scan index (BSI). In this system each bone is evaluated individually and assigned a numeric score. The score represents the product of the percentage of the involved bone with tumor, times the known weight of the bone that is derived from the reference man. Through the study it was shown that the extent of metastatic bone disease correlated well with prognosis, since patients with BSI values <1.4%, 1.4% to 5.1% and >5.1% had a median survival of 18.3, 15.5 and 8.1 months respectively [70]. In a different study also involving patients with advanced prostatic cancer undergoing hormonal treatment, bone metastases were quantitatively evaluated by serial bone scans using computer-assisted image analysis. Both the extent of disease (EOD) and percentage of positive areas on the bone scans (%PABS) were quantified and patients were followed for a mean of 33 months. Serial values of EOD and %PABS were found to decrease during treatment in 11 patients with partial response and in 12 with progressive disease who had no bone metastasis progression. In the remaining 19 patients, progression of metastatic bone disease was evident since EOD grades and %PABS were found to increase. It was also found that survival curves showed that %PABS was a useful prognostic indicator, since patients with a > 25% decline post therapy survived longer than those with a smaller percentage reduction in %PABS [71].

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17.7.3 Dual-Energy X-Ray Absorptiometry Dual-energy absorptiometry (DEXA) is an established diagnostic method for the measurement of bone mineral density (BMD) and follow up of patients with osteoporosis, entailing minimal radiation exposure [52]. DEXA has also been used to asses and monitor the therapeutic response in patients with metastatic bone lesions managed with systemic treatments. In a study by Berrutti and coworkers, 14 patients with bone metastases from various primary tumors underwent repeated DEXA scans prior and after treatment. Nine patients with osteolytic lesions were managed with chemotherapy and bisphosphonates. Out of these patients BMD was found to increase in 4, decreased in another 4 and remained stable in one. BMD changes were found to parallel the variations in biochemical markers and symptomatology. Five patients with osteosclerotic lesions from prostatic carcinoma were managed with hormonal therapy and chemotherapy. BMD was unchanged in one patient, but was found to increase in 4. Increased BMD was associated with pain improvement and decreased PSA levels in two patients and with a worsening of pain and increased PSA levels in the remaining two [72]. DEXA was also employed to monitor treatment-related BMD alterations in another study involving 6 prostate cancer patients with bone metastases in lumbar vertebrae. BMD was shown to increase over 12 months in 3 patients who had biochemical progression, whereas in patients who responded to therapy BMD was found to decrease (as compared to the baseline assessment) [73]. The response to systemic therapy was also monitored by DEXA in 9 patients with lytic metastatic bone lesions from breast cancer. Apart from DEXA, patients were evaluated with radiographs, computed tomography (CT), and bone scintigraphy at baseline and at 2 and 6 months thereafter. For patients responding to therapy, the median percentage change in BMD was 10.7, 5.0 and 16.7% at 0–2, 2–6 and 0–6 months respectively. Statistically significant BMD changes were recorded at 0–2 and 0–6 months. The percentage changes in BMD of skeletal lesions at 0–2 and 2–6 months correlated well with the changes on skeletal radiographs (Spearman rank order correlation coefficient [Rs] = 0.51, p = 0.011) and CT (Rs = 0.41, p = 0.05), but less so with the bone scan results (Rs = 0.293, p = 0.19) [74]. In spite of the interesting results of the above studies, larger trials are needed to corroborate the results and establish the effectiveness of DEXA for assessing the therapeutic response of patients with metastatic bone disease.

17.7.4 Computed Tomography Computed tomography (CT) provides skeletal images of high spatial resolution and is thought to be highly sensitive and specific for detecting metastatic bone lesions [75]. It has also proved to be extremely useful in the evaluation and confirmation of equivocal skeletal lesions, as in the case of patients with increased uptake on skeletal scintigraphy and normal bone radiographs, or in cases of solitary lesions depicted through bone scanning [51, 76].

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Among the first researchers who employed CT for the assessment of the therapeutic outcome of patients with metastatic bone lesions were Reinbold WD and coworkers. In their clinical trial, 19 patients with osteolytic vertebral metastases who underwent fractionated radiotherapy (total dose 40 Gy) were monitored by the use of quantitative CT. The bone density of metastatic bone lesions was measured at the onset of therapy and 3 months after the completion of treatment. Immediately after radiotherapy a decrease of bone density by 24.7% was noted, followed by a significant increase by 60.6% at the time point of 3 months. The increase in bone density was accompanied by a significant analgesic effect, since in 13 out of 19 patients a complete pain response was achieved [77]. In a different feasibility study by Chow E et al., CT was used to measure the bone density changes in 25 patients who were managed with either single (8 Gy) or multifraction (20 Gy in 5 fractions or 30 Gy in 10 fractions) radiotherapy. CT scans were performed at irradiated sites prior to treatment and 3 months after the delivery of radiotherapy. The median percentage change at 3 months following single fraction radiotherapy was 128, whereas after 20 Gy in 5 fractions and 30 Gy in 10 fractions the corresponding increments were 141 and 145 respectively [78]. The remineralisation effect accomplished in the region of bone metastases post radiotherapy was shown by the application of quantitative CT in other studies as well [79–81]. Bone density alterations in patients with bone metastases from solid tumors managed with combined radiotherapy and bisphosphonates were also followed by the use of CT in two recent studies [82,83]. In the first trial, 45 patients received external beam radiotherapy in combination with 10 monthly cycles of 6 mg intravenous ibandronate [82]. All patients taking part in the study underwent clinical and radiologic evaluations prior to treatment and at 3, 6 and 10 months post the onset of treatment. Two radiologists contoured bone metastases (at irradiated sites) in the most representative CT slices (3–5 mm thickness) and CT images with the delineated bone lesions were compared between the evaluation time points. Bone density (measured in Hounsfield units, HU) was found increase by 20% at the time point of 3 months, 46% at 6 months and 73% at 10 months. The significant increase in bone density was accompanied by a worth noticing clinical response since at 10 months 80.8% of patients reported a complete pain response [82]. In the second study CT was not only used to monitor reossification of patients managed with radiotherapy in conjunction with bisphosphonates, but also to classify and group patients according to the type of bone metastasis: lytic, mixed or sclerotic [83]. Interestingly, the level of reossification and clinical response differed between the 3 groups, with the lytic group exhibiting the highest radiological response as compared to baseline. At 10 months of follow up, bone density was almost tripled for the lytic group and almost doubled for the mixed group. The increase in bone density for the sclerotic group at the same time point was by 138 HU. The authors reported that CT proved to be a practical, efficient and useful method for both the classification of bone metastases and evaluation of therapeutic response [83]. Figure 17.2 presents typical examples of CT images depicting the recalcification achieved in three different patients with lytic (Fig. 17.2a), mixed (Fig. 17.2b) and sclerotic (Fig. 17.2c) metastatic bone lesions.

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Fig. 17.2 Computed tomography images prior (pre) and 10 months after (post) the onset of the combined therapy depicting evidence in of recalcification: (a) lytic bone lesion in the right acetabulum of a renal cancer patient, (b) mixed-type bone metastasis in a cervical vertebra of a breast cancer patient, (c) sclerotic bone metastasis in a thoracic vertebra of a breast cancer patient. This figure is reprinted from Vassiliou et al. [83], Fig. 3, copyright 2007, with kind permission of Springer Science + Business Media B. V.

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One may support that CT can not be routinely used to assess the therapeutic response due to the total accumulated radiation. This may be partially true if we consider that nowadays cancer patients undergo routine CT scanning (thorax, pelvis, abdomen) for staging and follow up in many oncological centers [84, 85]. It may be also worth to note that CT of thorax, abdomen and pelvis identify the vast majority of bone metastases, since the thoraco-lumbar spine, pelvis, proximal femora and proximal humeri are the commonest sites of metastatic bone disease [82, 85, 86].

17.7.5 Magnetic Resonance Imaging Magnetic resonance imaging (MRI) is the radiological investigation of choice for the detection of bone marrow metastases and early cancellous involvement by tumor [87]. It was reported that both CT and MRI are more sensitive than radiographs in detecting minor bone density alterations [75]. The value of MRI in the assessment of therapeutic response in patients with bone metastases was investigated in only a few studies that are discussed below. Ciray I and coworkers used MRI for the evaluation of early response of breast cancer bone metastases to chemotherapy [87]. The total number of patients recruited in the study was 18 and MRI scans were performed prior to treatment and after a median of 6 courses of chemotherapy. Therapeutic response was evaluated by investigating changes in tumor size (assessed quantitatively by measuring all focal changes of bone metastases) and by following changes in the pattern and signal intensity. T1-weighted and long TE IR-TSE sequences were used for the evaluation of all patients. Both MRI sequences were equally effective in evaluating patients with progressive (n = 2) or stable disease (n = 4). Long TE IR-TSE was more accurate than T1-weighted images in demonstrating partial response, since the corresponding percentage of such patients was 58 and 17% respectively [88]. T1-weighted MRI was also used to asses the therapeutic outcome of 41 patients with breast cancer and vertebral metastases [89]. MRI images prior and post treatment were evaluated and changes in number, size and signal intensity (SI) were recorded during 68 intervals (mean length 6.9 months). For each interval between MR imaging, an objective assessment of overall response to treatment (regression, no change, progression) was performed by using standard assessment criteria. Post therapy the number of metastatic lesions was unchanged in 53% of cases and increased in the remaining 47%. Similarly, the size of metastatic bone lesions was found to increase in 43% of cases, remained stable in 54% and decreased in 3%. Changes in SI occurred in about one one-third of cases and the most commonly observed change was the one from low homogenous SI to low heterogenous SI. However, no correlation between SI changes and response to therapy was reported. The authors concluded that T1weighted MRI response based on size and number changes predicted accurately progression of disease (79% of cases) and stable disease (75% of cases), but could not predict regression of disease [89]. The evaluation of response of bone metastases in 18 patients with breast cancer was assessed by MRI and conventional methods such as plain radiographs, bone

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scintigraphy, pain and analgesic scale and serum CA 15-3, in a study by Saip P et al. MRI was performed by using T1-weighted sequences and the volume of the bone lesions and tissue component were measured. A patient was considered to be a complete or partial responder if a complete or partial response were observed in any of the conventional methods applied in the study. Treatment response was found to be more concordant between plain radiographs and MRI findings (91%) and the rate of concordance for all conventional methods and MRI was 61%. Apart from providing useful clinical information, MRI proved to be helpful for the assessment of patients with conflicting evaluation results [90]. Prostate cancer patients with metastatic bone disease undergoing chemotherapy were evaluated by axial-skeleton MRI (AS-MRI) to quantify bone metastases and measure tumor response. A total of 20 patients underwent AS-MRI prior to treatment and 6 months after completion of chemotherapy, employing both T1 and T2weighted sequences [91]. Therapeutic response was assessed by using the RECIST criteria [92]. AS-MRI allowed an accurate estimation of complete response (n = 2), partial response (n = 2), stable disease (n = 5) and tumor progression (n = 11) [44]. In a different study involving patients with bone metastases from a variety of solid tumors, the therapeutic outcome was monitored by both CT and MRI. A total of 7 patients underwent evaluation with MRI by obtaining images in both axial and sagital planes. T1TSE sequence with and without gadolinium (paramagnetic contrast agent, Gd) enhancement was used to evaluate patients prior to therapy (combined radiotherapy and bisphosphonates) and 3 months thereafter. At the evaluation time point of 3 months, signal intensities of metastatic lesions with and without Gd enhancement were significantly lower than the corresponding baseline values (p <0.001), (Table 17.2). At baseline enhancement with Gd resulted in a 57% increase of signal intensity, whereas at 3 months the enhancement was limited to 15% (Table 17.2). Figures 17.3 and 17.4 depict the signal intensity changes after Gd enhancement at baseline and at 3 months post the onset of therapy in a patient with bone metastases from lung cancer. MRI (diffusion-weighted) was also used to asses the therapeutic response of 24 patients with metastatic disease of the spine from a variety of primary solid tumors, managed with external beam radiotherapy [93]. For comparison purposes MRI was performed at different time points from the completion of therapy. More specifically nine patients underwent MRI at 1 month, seven patients at 2 months and Table 17.2 MRI evaluations of bone metastatic lesions at baseline and after 3 months of treatment in T1 TSE images. This table is reprinted from Int J Radiat Oncol Biol Phys 67(1):264–272, Table 5, copyright 2007, with kind permission of Elsevier Inc. Mean signal intensity, arbitrary units Enhancement −Gd +Gd

Baseline 413.6 649.3

3 months 332.6∗ 382.2∗

Abbreviations: MRI = Magnetic Resonance imaging; T1TSE = T1-weighted turbo spin echo; Gd = Gadolinium paramagnetic contrast agent. ∗ p < 0.01 compared with baseline value, paired t-test.

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Fig. 17.3 Sagital plane images with T1TSE sequences presenting a metastatic bone lesion in the 8th thoracic vertebra prior to therapy in a patient with lung cancer. Before the enhancement with Gadolinium paramagnetic contrast agent (a) a low signal was seen. On the contrary after Gd enhancement (b) a considerable increase in signal intensity was depicted

Fig. 17.4 MRI images in sagital plane (T1 TSE sequences) of the same patient, 3 months post the onset of the combined treatment. (a) A low signal was depicted prior to Gd enhancement. (b) Post Gd enhancement and as compared to Fig. 3b, the increase in signal intensity was significantly reduced

three patients at 6 months post treatment. Prior to therapy the signal intensity of metastatic lesions was found to be hyper-intense to normal vertebral bodies. In the 23 patients with clinical improvement post treatment, the metastatic lesions were found to be hypo-intense relative to normal vertebral bodies. In one patient with no clinical response, a hyper-intense bone marrow was depicted on MRI and after bone scintigraphy an increased uptake was revealed. The authors reported that diffusion weighted MRI was successful in assessing the therapeutic outcome and that a positive response is associated with a decreased signal intensity of the vertebral bone marrow at the follow up evaluations [93]. Even though MRI is an effective, rapid, reliable [94] and safe (in terms of radioprotection) method to asses the therapeutic response of patients with bone metastases, further studies should be performed in order to set criteria for response to

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therapy and establish the most suitable imaging parameters. Drawbacks for routine response assessments are the high cost, availability and the duration of examination.

17.7.6 Positron Emission Tomography Positron emission tomography (PET) has become widely available and plays an important role for staging of patients at diagnosis [28] and follow up. It has also been successfully applied for monitoring the response of breast cancer patients to neoadjuvant chemotherapy [95]. Interestingly, through several studies it was shown that [18 F] fluorodeoxyglucose PET (FDG PET) has a greater specificity and sensitivity than conventional bone scintigraphy with technitium-99 (99 TC) in detecting bone metastases from tumor types such as breast, lung and renal-cell carcinoma [96–99]. It should though be noted that FDG PET has a lower sensitivity for the detection of osteoblastic than for osteolytic lesions, as a result of the lower metabolic activity of blastic bone metastases [100]. This fact may limit the application of PET in the assessment of sclerotic bone lesions from prostate [101] or other primary tumors giving rise to osteosclerotic metastatic lesions. In a retrospective study by Stafford SE et al., FDG PET was applied to monitor the response of bone dominant breast cancer to therapy. Twenty-four women managed with bisphosphonates and other antineoplastic therapies underwent whole body FDG PET at several time points during the course of therapy. The quantitative interpretation of FDG PET scans involved the measurement of the change in the standard uptake value (SUV) of the most active metastases at a follow up of 4.9 months. The changes in FDG SUV post treatment correlated strongly with both the clinical assessment results and with the levels of the tumor marker CA 27. These preliminary results showed that serial whole-body FDG-PET could be very helpful in the quantitative evaluation of therapeutic response of breast cancer patients [102]. FDG PET was also used to define planning target volume (PTV) and follow response to therapy in three patients who underwent hypo-fractionated stereotactic radiosurgery due to recurrent spinal metastases. All patients had received previous conventional external radiotherapy after treatment with metallic spinal fixation. Prior to stereotactic radiosurgery, CT-based planning was performed, corrected by the FDG PET hyper-uptake area. The response to treatment was monitored by FDG PET at one and 6 months after completion of stereotactic radiosurgery. The evaluation of response to therapy by using FDG PET was carried out by measuring the changes in the SUV of successive PET scans. Furthermore the relative SUV alterations from pretreatment values were evaluated by calculating the reduction index (RI). This index represented the ratio of SUV change to pretreatment SUV. One month post therapy RI ranged from 0.007 to 0.7, however at 6 months SUV correlated with the clinical outcome of patients. From the 3 patients taking part in the study, one showed marginal failure and in the other two the tumor was locally controlled (RI values were 0.65 and 0.87 respectively). The authors concluded that PET was successfully used to determine define PTV in patients with recurrent spinal metastases hidden under metallic artifacts and proved to be a valuable imaging

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Fig. 17.5 FDG PET in a woman with advanced breast carcinoma and multiple bone and liver metastases managed with two cycles of docetaxel and one cycle of vinorelbine. (A) Scan images prior to treatment. (B) Post therapy a substantially decreased metabolic activity is depicted in all metastatic lesions, indicating a response to treatment. This figure is reprinted from Clamp et al. [28], Fig. 2, copyright 2004, with kind permission of Elsevier Inc.

modality to follow the therapeutic outcome. Additionally, the mass responses measured as SUV changes correlated well with the clinical outcome [103]. Figure 17.5 presents coronal and saggital FDG PET images prior and post chemotherapy, in a woman with hepatic and skeletal metastases from breast carcinoma. The decreased metabolic activity in all lesions post treatment indicates a response to treatment. As in the case of bone scintigraphy, a potential drawback of FDG PET for assessing response to treatment, is the early flare in tracer uptake following hormonal therapy [104]. Furthermore, PET is nowadays an expensive technique and is only available in a few specialist centers [28].

17.8 Limitations of Current Clinical Trials Assessment of therapeutic response must be specific, clinically relevant, and timely in order to rapidly evaluate new drugs and approaches to treatment. Treatment with modern-day bisphosphonate therapy has significantly reduced SREs, such that trials

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with SREs as the sole endpoints require larger sample sizes and are therefore increasingly expensive and time-consuming. Pain and Quality of life measures are of paramount importance, but trials would benefit from standardized, bone-specific measurement scores that would be widely implemented in order to be able to compare results between trials. Biochemical assessment of response using urinary N-telopeptide is a highly attractive option, since, while not perfect it represents a non-invasive, early, and relatively inexpensive measurement of response. However further studies exploring the correlation between uNTx and pain and QOL measures are required, as well as studies demonstrating the usefulness of uNTx over time during treatment with bisphosphonates (i.e., does uNTx invariably increase prior to an SRE?). uNTx is not accurate in patients with inadequate creatinine clearance, and may not be as relevant in assessment of new therapeutic interventions that have mechanisms of action that differ from bisphosphonates. There is a clear need for studies that use bone specific biomarkers to tailor treatment with bisphosphonate or antineoplastic therapy in general. Whether these studies should aim for normalization of markers, a specific decrease in marker concentration (e.g., 50%), or should merely target stabilization of concentrations is not yet clear, especially in advanced breast cancer where clinical benefit from endocrine therapy is seen equally with disease stabilization and with response when assessed by conventional criteria. The multicentre BISMARK (bisphosphonate therapy directed by bone-resorption markers) trial is taking the first step towards addressing this issue. The question of changing the strategy of clinical management in patients when an increase in marker concentrations suggests progressive metastatic bone disease also needs to be addressed. Discontinuation of bisphosphonates at the time of increase would reduce hospital visits for intravenous infusions in patients who are unlikely to gain further benefit, thus having a positive effect on quality of life and lowering costs [105]. Other options might be to reassess antineoplastic therapies or change the type or route of bisphosphonate administration, which would be especially informative because most clinicians tend to continue patients on the same bisphosphonate [106]. In summary, new radiological techniques and the use of bone-resorption biomarkers hold promise for assessing response to BPs in metastatic bone disease. Future research needs to define whether the use of these imaging techniques and markers will have a positive effect on guiding appropriate use of BPs and prognosticating disease outcome.

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Chapter 18

OUTCOME MEASURES IN BONE METASTASES CLINICAL TRIALS Amanda Hird1 and Edward Chow2 1 Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre University of Toronto, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5 e-mail: [email protected] 2 Department of Radiation Oncology, Sunnybrook Health Science Centre, University of Toronto, Toronto, ON, Canada e-mail:[email protected]

Abstract:

Bone metastases are the most common manifestation of metastatic disease in advanced cancers. Management of bone metastases is increasingly multidisciplinary in nature and as a result, we have witnessed an increased survival of this population. Therefore, there is an increased need to accurately monitor the benefits and side effects of these treatments. This chapter will outline the trials and tribulations that have been encountered leading to the development of standardized outcome assessment tools for use in bone metastases clinical trials. The evaluation of pain response in previous clinical trials and the subsequent establishment of the International Bone Metastases Consensus Working Party endpoints we be explored. This chapter will also discuss various pain assessment tools, when response should be evaluated, and the value of subjective analyses of what constitutes a meaningful pain response for patients. The development of a comprehensive, universal bone metastases-specific quality of life (QOL) questionnaire will be examined, outlining the differences in perspectives of what patients and health care professionals believe to be most relevant issues for patients with bone metastases.

Key words: Bone metastases · Pain · Response · Endpoints · Quality of life

18.1 Introduction Bone metastases are the most common manifestation of metastatic disease in advanced cancers, particularly in breast, prostate, and lung carcinomas [1]. Treatment of bone metastases involves localized therapies, such as external beam radiotherapy, D. Kardamakis et al. (eds.), Bone Metastases, Cancer Metastasis – Biology and Treatment 12, DOI 10.1007/978-1-4020-9819-2 18,  C Springer Science+Business Media B.V. 2009

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as well as systemic interventions, including chemotherapy, hormonal therapy, and bisphosphonates among others. Management of bone metastases is increasingly multidisciplinary in nature. With advances in effective systemic treatment and supportive care, survival of patients with bone metastases has improved substantially. Certain subsets of patients with bone metastases (e.g., breast and prostate cancer with predominately bone or bone-only metastases) have life expectancies that range from 2 to 5 years [2]. Successful management of bone metastases during these years is essential for reducing the skeletal complications and for maximizing patient QOL. There have been clinical trials in various disciplines addressing the optimal management of bone metastases. As the survival of bone metastases patients increases, there is an increased need to accurately monitor the benefits and side effects of their treatments. Clinical trials have routinely included survival and tumour control as the primary endpoints. As most treatments aim at relieving symptoms, palliative endpoints such as pain score, analgesic consumption, skeletal related events, and QOL warrant inclusion as routine trial endpoints [3]. This chapter will discuss the traditional bone metastases radiation clinical trial endpoints, as well as new developments aimed to facilitate comparison of response rates between trials. Quality of life assessment within this population will also be explored in depth.

18.2 Evaluation of Pain Response in Bone Metastases Clinical Trials 18.2.1 The Results of Previous Studies In the past two decades, numerous randomized control trials have investigated the effectiveness of single versus multiple fraction radiotherapy for the alleviation of metastatic bone pain [4]. Three well-conducted meta-analyses compiling single fraction versus multiple fraction radiotherapy have agreed that for the purpose of pain relief, there is no significant difference between the fractionation schedules [4–6]. A significantly higher re-treatment rate for both intention-treat and evaluable patients was evident in patients treated with a single fraction [4]. Despite the evidence, the optimal fractionation regimen remains controversial and varies between countries. Surveys on patterns of practice demonstrate reluctance among radiation oncologists worldwide to adopt single fractionation as standard practice [7–20]. This debate is largely caused by differences in conclusions based on the endpoints used. Response to radiotherapy is mainly a function of endpoint – different trial conclusions are reflected in the use of inconsistent endpoint definitions [21]. In their randomized dose fractionation trial, the Radiation Therapy Oncology Group study (RTOG 7402) initially concluded that low-dose, short-course schedules were as effective as high-dose protracted programs [22]. However, a subsequent

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analysis using combined pain and analgesic scores, with or without re-treatment, suggested improved complete response with protracted fractionation schedules [23]. Similarly, a randomized Canadian trial compared the efficacy of a single 8–20 Gy in five daily fractions in the treatment of bone metastases. Pain relief was defined as a reduction in the pain score at the treated site with reduced analgesics or a pain score of zero at the treated site without an increase in analgesics. Pain relief was significantly higher for patients treated with multiple fractions. However, when response was defined as pain relief alone regardless of analgesic consumption, the two regimens gave the same response rates [24]. The type of pain scale employed, inclusion of QOL as an endpoint, and the duration of follow-up also influence observed treatment response. The Danish bone pain trial reported pain relief of 62% at 4-weeks in the single fraction arm when assessed with the categorical scale (improvement of at least one category on the five-point categorical scale). However, response dropped to 49% when defined as 50% reduction in pain on the visual analogue scale. Complete response changed from 15% at 4-weeks to 25% at any time during the entire follow-up period of 20 weeks. If the criteria for complete repose included no use of morphine, it became 12%. This number was further decreased to only 4% if the global QOL score that recorded complete well being was also included [25]. This diversity in endpoint definitions emphasizes that complete and partial response as reported by one study cannot be directly compared with another. In addition to defining response, there exists an innate difficulty of measuring a response when radiotherapy is given as a local treatment, while cancer pain can come from multiple sites, which are often also palliated by other systemic agents, including a variety of analgesics, chemotherapy, hormonal therapy, and, more recently, bisphosphonates. Other confounding issues include the role of analgesic consumption in assessing treatment response, definition of partial response and the interpretation of re-treatment. It is clear that future trials in palliative radiotherapy evaluating clinical outcomes must not only account for patient-related eligibility criteria, radiotherapy techniques and assessment tools, but will also need to address possible treatment effects from an increasingly complex multi-disciplinary management of this group of patients [21].

18.2.2 International Consensus on Palliative Radiotherapy Endpoints In order to promote consistency in future clinical trial design for palliating bone metastases, an International Bone Metastases Consensus Working Party on endpoint measurements was established in April 2000 in conjunction with the American Society for Therapeutic Radiology and Oncology (ASTRO), the European Society for Therapeutic Radiology and Oncology (ESTRO), and the Canadian Association of Radiation Oncology (CARO). The working party aimed to reach a consensus on a set of commonly accepted endpoint measurements for future radiotherapy trials involving external beam radiotherapy. Consensus was reached on the following [26].

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18.2.2.1 Eligibility Criteria for Future Trials It was recommended that for studies involving more than one tumour site, stratification should be made by tumour type involved. Patients should have measurable pain, for example: a minimum pain score of 2 out of 10, at the time of entry. Since performance status has been shown to correlate with the duration of survival [27,28], performance status should be an eligibility criterion for studies designed to assess pain relief for a duration of more than 3 months. Because the physician’s prediction of life expectancy is often inaccurate [29, 30], minimum life expectancy has limited reliability as an entry criterion [26].

18.2.2.2 Pain and Analgesic Assessments A patient-assessed assessment with an ordinal pain scale of 0–10 was recommended. The measured pain should relate to the worst and average pain for the previous three days at the treated site(s). The use of a body diagram to define the painful site(s) is encouraged at clinic visits and in mailed questionnaires [26]. All narcotic analgesics, including regular and breakthrough doses, should be converted into a daily oral morphine equivalent for analgesic scoring [31]. Adjuvant analgesics should also be recorded [26].

18.2.2.3 Follow-Up and Timing of Assessments The baseline pre-treatment assessment is essential and should be undertaken as close to the time of treatment delivery as possible. Follow-up can be any combination of clinic visits, mailed questionnaires and telephone interviews. The minimum followup agreed upon was at 2-weeks, 1-month, and then monthly until 6 months after delivery of radiation treatment. Longer follow-up was encouraged for patients with prolonged survival [26].

18.2.2.4 Endpoints Response rates should be determined at 1-, 2- and 3-months following radiotherapy. Complete response is defined as a pain score of zero at the treated site with no concomitant increase in analgesic intake (stable or reducing analgesics in daily oral morphine equivalents). Partial response is defined as any of the following [26]:

r r

pain reduction of two or more at the treated site on a 0–10 scale without analgesic increase; analgesic reduction of 25% or more from baseline without an increase in pain.

Pain progression is defined as an increase in the pain score of two or more points above baseline at the treated site with stable analgesic use, or an increase of 25% or more in daily oral morphine equivalent compared with baseline with the pain score stable or one point above baseline [26].

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Reporting response rates at fixed time-points (i.e., at 1-, 2-, and 3-months) may result in lower observed rates compared to reporting response occurring at any time during follow-up, as illustrated in the Danish study [25]; however, responses occurring beyond 3-months may reflect secondary interventions, such as re-irradiation, new systemic therapy, or more aggressive pain management [26]. It was pointed out that the actuarial rate of response assumes that non-evaluable patients that are lost due to death or illness will have the same probability of demonstrating the desired response. That assumption may overestimate the true response rate. The crude response rate represents a more conservative method of estimating true response; hence it should be reported as well. A measure of “sustained response” would be dependent of the survival duration of study patients and the frequency of the followup assessments [26]. As discussed, the response rate to radiotherapy is a function of endpoint [26]. This was further illustrated in a study comparing response rates employing the International Bone Metastases Consensus endpoints versus the traditional response endpoints [32]. The former takes into account both pain scores and analgesia, and as a result, complete and partial response are reduced when compared to the traditional pain only endpoints [26]. Nevertheless, the International Bone Metastases Consensus endpoints more accurately reflect the efficacy of palliative radiotherapy in relieving metastatic bone pain since significant increases in pain medications are not misconstrued as radiotherapy response. Due to this decrease in response rates to radiotherapy, extra caution during sample size calculations is advised [32].

18.2.3 Pain Assessment Tools Valid pain assessment tools are required to adequately evaluate pain intensity and the effectiveness of the pain management plan, including pain response following a given intervention [33]. Commonly used scales to assess this construct include visual analogue scales (VAS), verbal descriptor scales (VDS), or numeric rating scales (NRS). The VAS is a 10 cm line with ends of “no pain” and “pain as bad as it could be”, on which patients can mark their pain intensity; the VDS contains a list of adjectives that describe levels of pain (i.e., no pain, mild, moderate, or severe pain); and the NRS allows patients to describe the intensity of pain in numbers. For example, NRS may use an 11-point scale where zero indicates no pain and 10 represents worst possible pain. Numerical scales are also frequently used for measuring changes in pain over time and correlating pain intensity with other important outcomes, such as QOL or functional interference. NRS are utilized in the International Bone Metastases Consensus Working Party endpoints for evaluation of pain response following radiotherapy for bone metastases [26]. The Brief Pain Inventory (BPI) is one of the most commonly employed NRS used to measure pain intensity and functional interference in cancer-related research [34]. Developed by Cleeland and Ryan [35], this validated patient-based assessment tool evaluates pain on three dimensions: worst pain, average pain, and current pain. In addition, seven indicators of function interference are explored: general activity,

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normal work, walking ability, mood, sleep, relationships with others, and enjoyment of life [35]. Analgesic consumption over the preceding 24-hour period is also recorded. Multiple studies have shown the intensity of the worst pain rating correlates most substantially to functional interference [34–40]. As such, it has been recommended that a patient’s worst pain score should be used in the assessment of overall radiotherapy response [34]. Utilizing the BPI in the palliative cancer population has also revealed varying levels of correspondence of the three dimensions of pain (mild, moderate, or severe) with functional interference [34]. To date, a number of studies have attempted to establish cutpoints for mild, moderate and severe pain on a numeric scale. Such investigations are important for several reasons, as outlined by Anderson [41]. Most patients prefer to describe their pain severity using verbal rating scales such as mild, moderate or severe when communicating with healthcare providers [42]. However, some current clinical practice guidelines for cancer pain, such as the World Health Organization analgesic ladder [43], are based on the assessment of pain using categorical scales (i.e., mild, moderate or severe), while others, such as the American Pain Society Cancer Pain Guidelines [44] and the National Comprehensive Cancer Centre Network guidelines [45], are based on both categorical and numerical pain scales. A lack of consensus as to what these pain categories mean numerically may result in difficulty for clinicians to interpret and follow treatment guidelines. The categorization of pain into three grades help clinical research studies to summarize the prevalence of different levels of pain intensity within a population (for example, the number of patients experiencing an increase of pain from mild to moderate). To compare results across studies, consistent definitions of mild, moderate and severe pain are required [46]. In 1995, Serlin et al. [40] began an investigation of grading mild, moderate and severe pain on a numeric scale using a novel multivariate statistical approach. Using the BPI responses of over 1,800 patients with cancer-related pain from four countries, it was found that the optimal upper cutpoint for mild and moderate pain was four and six, respectively. A non-linear relation between pain severity and functional interference was also observed. Subsequent studies with other populations and origin of pain using the same method were conducted. However, pain severity cutpoints were inconsistent across studies, where the upper boundary for mild and moderate pain varied between three to five, and six to eight, respectively [46]. A similar study replicated the methodology employed by Serlin et al. [40]. Results confirmed a non-linear relationship between cancer pain severity and functional interference in 199 bone metastases patients treated with palliative radiotherapy [46]. The optimal cut points for mild and moderate pain were four and six (mild = 1–4, moderate = 5–6, and severe = 7–10) [46], verifying Serlin et al.’s findings. The classification of discrete pain categories is valuable for clinical evaluation, research and public policy. More research, however, is needed to determine if the three categories of pain are adequate; to determine the minimal clinically meaningful reduction in pain measured categorically; and lastly, if this reduction is the same as that for pain measured numerically [46].

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18.2.4 When Should We Define Response? Although it was recommended by the International Bone Consensus Working Party to assess pain response at 1-, 2-, and 3-months following radiotherapy [26], validation of this recommendation was required. A recent study by Li et al. concluded that 2-months after radiotherapy is the most appropriate time point to measure response rates for the following reasons: (i) the maximum pain relief for some patients may take more than 4 weeks to achieve; and (ii) attrition poses a major problem when response rates are measured at a later date [47]. In addition, response occurring beyond 3-months may reflect secondary interventions, such as re-irradiation, new systemic therapy, or more aggressive pain management [26]. Therefore, a 2-month interval from treatment to evaluation of response may be ideal.

18.2.5 What Constitutes a Meaningful Change in Pain Score? Benefits of palliative radiotherapy for bone metastases are assessed by the change in pain intensity often measured by pain scores. Previous studies have shown that clinicians and family members tend to overestimate the benefits of treatment interventions [48–55]. Patient self-assessment should therefore be the preferred measure of benefit or success of the treatment. Patients are often not informed of what pain score they provided at baseline when they are asked to score their current pain during a follow-up assessment. Some patients inform their pain is better when compared with the baseline pain but the current pain score is increasing when compared with that at the baseline. The reverse also happens. It is therefore important to determine a meaningful improvement or decline in scores to assess the benefits of the treatment such as palliative radiotherapy. In a 2005 study, patients were asked their pain score and pain perception over a period of 11 days (for patients who received a single treatment) to 22–24 days (for patients who received 10 daily treatments) [56]. Seven hundred and ninety seven pain scorings from 88 patients were collected. Patients perceived an improvement in their pain status when their self-reported pain score decreased by at least two points on a scale of 0–10 [56]. A subsequent study was launched to validate the 2005 finding (Chow et al., 2008, Validation of meaningful change in pain scores in the treatment of bone metastases, personal communication and submitted for publication). A total of 1,431 pain scorings were obtained. A pain score decrease of 2–10 points at follow-up was consistently reported by patients as an improvement when compared to the baseline pain. However, when the change in pain score decreased by only one point, only 39% of patients reported the pain as the same and 41% of patients reported the pain as better when compared with baseline (Chow et al., 2008, Validation of meaningful change in pain scores in the treatment of bone metastases, personal communication and submitted for publication). Through the results of these two

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studies, it appears that patients perceived the current pain to be less than the baseline pain when they reported a decline of their pain score of two or more. Recent bone metastases randomized trials [57, 58] and the International Bone Metastases Consensus endpoints [26] defined partial response as a reduction of pain score by two or more points on a pain scale of 0–10. This definition appears to be supported.

18.2.6 Patient Perspective of Minimal Meaningful Pain Relief Traditional clinical trial endpoints have been solely defined by investigators with no contribution from patients as to what constitutes a meaningful partial response to treatment. This coincides with the endpoint definitions suggested by the International Bone Metastases Consensus Working Party [26]. Partial responses have been arbitrarily defined independently of the severity of the bone pain before radiotherapy. The perception of the treatment benefit varies among individuals. It also depends on the health status of the individual and is subject to change with time and experience [59]. Studies are required to investigate the magnitude of the minimal significant pain reduction from the patient perspective. Investigators would then be able to incorporate patient derived definition of partial response in future trials. This is important as many patients receiving palliative radiotherapy will not achieve a complete response [60]. Our group explored the minimum reduction in pain level with no change in analgesic consumption that an individual patient would expect by 2 months in order to justify the proposed course of palliative radiotherapy – a patient derived definition of partial response. Study patients were asked to rate their current level of pain at the time of interview (on a scale of 0–10, 0 = no pain, 10 = worst pain ever). Subsequently, patients were asked to quantify the minimum level of pain reduction (by 2 months) that they think would justify their palliative radiotherapy [60]. Patients with higher pain score required a greater magnitude of minimum pain reduction. A reduction of six and seven were expected in patients with pain scores of nine and 10 respectively, whereas a reduction of one and two were expected in patients with pain scores of three and four, respectively. When expressed as a ratio for this magnitude compared with the baseline pain score, it appeared that patients expected a reduction of 50–70% in their baseline pain following radiation treatment [60]. From these results, it would be reasonable to consider a pain score reduction of two thirds from the baseline as the partial response. Farrar et al. recommended using a benchmark of 33% total pain relief as a clinically meaningful response [61]. We have made significant progress in employing patient based assessment of pain-related symptoms. Nevertheless, it is high time to incorporate patient expectation in our future definition of a treatment response [60]. Moreover, patients’ subjective evaluation of QOL requires further exploration.

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18.3 Assessing Quality of Life in Patients with Bone Metastases Previous clinical trials on bone metastases have largely focused on the objective endpoints such as analgesic consumption, hypercalcaemia, pathological fractures, spinal cord compression, and use of surgery and radiation [3]. The World Health Organization describes health as “not merely the absence of disease or infirmity, but a state of physical, mental and social well-being” [62]. In palliative trials, as well as symptom control, QOL is a major endpoint. Quality of life measurement is a subjective, multidimensional construct reflecting functional status, psychosocial well-being, health perceptions, disease- and treatment-related symptoms from the patient’s perspective. It incorporates expectation, satisfaction, value system and the many aspects of a patient’s life [63]. Since palliative interventions unlikely lead to survival prolongation and significant tumor regression, QOL is a more meaningful endpoint when compared with the traditional endpoints such as survival times and local control. Quality of life issues are an important consideration for patients when making decision for the treatment of bone metastases. More interventional studies now aim towards enhancing patients’ QOL, often by reducing the toxicity. Regulatory bodies are giving increasing importance to QOL studies as an independent endpoint in determining the cost-effectiveness of competing therapies. With advancement in systemic treatment of advanced cancer with osseous metastases (i.e., radiopharmaceuticals, bisphosphonates, chemotherapies, orthopedic interventions, and additional systemic treatments), there is more need than ever for the development of a QOL assessment tool specific to bone metastases patients in order for a comprehensive assessment of the benefits and side effects of these specific interventions [3]. However, robustly developed bone metastases specific QOL instruments are lacking. Traditionally, patients with bone metastases in clinical trials have completed general QOL assessment tools. These instruments are generic for malignancy and not designed with the intent to cover the key QOL issues relevant to cancer patients with bone metastases. Patients uniformly expressed that these instruments were not relevant for their situations as they did not thoroughly address the QOL issues related to the disease and the complications of bone metastases such as hypercalcaemia, pathological fractures, spinal cord compression, mobility and functional impairment of the diseased bone, nor the side effects of medical treatments. There is general agreement that the patient is the most appropriate source of information regarding his/her QOL [51]. Only the patients can report their subjective experiences and priorities. Unfortunately, at present, there is a gap between theory and practice of QOL assessment in the clinical setting. It has been reported that 85% of physicians feel patients are the best judge of their own QOL [64], yet definitions and measures of QOL are usually based, to a great extent, on the researchers’ and clinicians’ perception of what QOL issues are most relevant to their patients [65]. Many studies have shown that the agreement between patient and physician responses is poor and physician assessments are not appropriate as substitutes for self-assessment in palliative care. Furthermore, in a survey by Bezjak et al., 78%

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of responding physicians acknowledged that when physicians and patients discuss QOL issues they may not be talking about they same thing [64]. Patients with bone metastases experience their own distinct symptoms and emotional issues when facing advanced cancer and its treatment. While pain is the most common symptom associated with this diagnosis, it is not clear exactly which pain characteristics or psychological issues influence QOL most profoundly [66]. Understanding the patient’s perspective and how it compares to that of the health care professional (HCP) will help us to recognize the differences and develop management strategies better addressed to individual patient needs. In a study by Detmar et al, almost all patients expressed a willingness to initiate and discuss the physical aspects of his or her disease [67]. On the other hand, 25% of patients felt it was only appropriate to discuss emotional functioning at the initiative of their physician. An even greater reluctance was observed concerning the issues of social functioning and family life, with 28–36% of patients waiting for the doctor to first raise the topic and another 20% preferring not to hold a discussion on the issues at all. This suggests that patients may be uncertain about which issues are appropriate to discuss with their physician [67]. Physical issues such as symptoms from the disease or treatment may be thought of as the primary responsibility of the physician, while the psychosocial problems, including “worry” issues, seem to fall into a more private domain and patients may be uncomfortable bringing them up with HCPs. Several physicians echo this position on the discussion of psychological issues. It was reported that physicians felt that discussion of the physical aspects of their patient’s health was primarily their responsibility, while a number indicated that the discussion of psychosocial health problems should be shared with other health care providers [67]. In the case of emotional and social functioning, all physicians indicated that they generally defer the initiation of the topics to their patients [67]. Consequentially, this miscommunication may hinder the discussion of psychosocial issues, which can lead to inaccurate diagnoses and inadequate treatment [47] as physicians tend to overlook problems/symptoms that are not obvious or mentioned explicitly by the patient [68].

18.3.1 Quality of Life Assessment in Bone Metastases Clinical Trials Quality of life as an outcome measure is increasingly being incorporated into trials in the palliative care setting [69]. Five trials of localized palliative radiotherapy for bony metastases have examined this endpoint [25, 58, 69–71]. In a randomized trial comparing two fractionation schedules (10 Gy in a single fraction versus 22.5 Gy in five fractions) in 280 patients, Gaze et al. [70] assessed QOL and emotional status, and found no differences in these measures when comparing single to extended fractionation. The physicians in the study completed the Spitzer QOL index [72] according to the verbal description most closely reflecting the patient’s status. The Spitzer index contains five items relating to activity,

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daily living, health, support and outlook, each rated from zero to two. The patients completed a Hospital Anxiety and Depression (HAD) questionnaire to assess clinically significant levels of anxiety and depression. Assessment occurred at baseline, at one-week, three-four weeks after completion of radiotherapy and then at two monthly intervals. Of 216 patients assessed post treatment, the QOL and HAD scores were available for 209 and 200 respectively. The study by Gaze et al. found no association between initial QOL parameters and the likelihood of achieving pain control. The prevalence of both anxiety and depression, as per the HAD scale, was reduced following treatment. The median HAD score was reduced from six pre-treatment to five after irradiation. The prevalence of definite (HAD score ≥ 11) and borderline (HAD score 7–10) anxiety and depression at baseline were 49 and 39%. After treatment they had reduced to 35 and 32%, respectively. The QOL as assessed by the Spitzer Index improved from a median pre-treatment score of six (range 0–10) to a median of seven (range 1–10) post radiotherapy. There was no difference in changes in HAD or QOL according to fractionation schedule. It must be noted that the physicians assessed QOL in this study, hence the possibility of over-estimation of post-treatment Spitzer scores. Nevertheless, there was a trend of improvement of patient self-rated anxiety and depression [70]. Nielsen examined global QOL using VAS (visual analogue scale) in a trial of a single 8 versus 20 Gy in 4 fractions [25]. Two hundred and forty-one patients were enrolled in this trial. The patients completed the pain and global QOL evaluation forms on the first day of radiation treatment and then at clinic visits 4-, 8-, 12- and 20-weeks after treatment. With the exception of the initial and final visits, two clinic visits could be replaced by correspondence. The authors reported that there was no difference in the relative change in QOL at any stage between the two treatment arms. At 4-weeks, approximately 34, 20, and 11% of patients in each arm achieved increases of greater than or equal to 25, 50, and 75% respectively in their VAS QOL when compared to their pre-treatment status. However, the proportion of patients achieving complete well being was only 7% in each arm [25]. In the largest reported randomized prospective trial for the palliation of bone metastases (1,157 patients evaluated) comparing two fractionation schemes, QOL assessment was one of several endpoints [58]. Steenland and colleagues used an extensive questionnaire comprising the Rotterdam Symptom Checklist [73] and the EORTC QLQ-C30 [74]. In addition, overall QOL was also measured using five EuroQOL questions on mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The questionnaire (containing almost 60 questions) was filled out by the patients at baseline, then weekly for 3 months, and monthly for up to 2 years. The analysis of repeated measures showed that no statistically significant differences in overall QOL were observed between the two fractionation schedules. Further details of the more specific domains of QOL, the assessment of the various QOL instruments and the impact of local radiotherapy on QOL in this study are yet to be published [58]. A single arm trial by Fossa [71, 75] specifically examined the endpoint of QOL after palliative radiotherapy for men with hormone refractory prostate cancer. In this

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trial, 31 patients were treated with the radioisotope 89 Sr (strontium) and 106 received external beam radiotherapy. Of the latter group, 24 patients with poor performance status were treated with single fraction hemi-body irradiation (HBI), the remainder with fractionated treatments to localized fields. Only 19 of 31 men treated with strontium and 54 of the 106 men receiving external beam radiotherapy completed the 3-month questionnaire. The 73 patients who completed the questionnaire reported slight pain relief, with mean score decreasing from 51 to 44. This is perhaps not surprising given that only one patient in the strontium arm and eight patients in the external beam radiotherapy arm had less than six hot spots on bone scan. In fact, two thirds of the study population had 20 or more hot spots. Three-months after radiotherapy, 20 of 57 evaluable patients had reduced their analgesic intake, 17 reported no change in dose and 20 had increased their analgesic requirement. The global QOL was virtually unchanged, with a mean of 54 pre-treatment and of 52 at 3-months. Given the advanced disease in this study population, there were likely other sites of pain outside the irradiated fields. This may explain the lack of impact on QOL in this study. A study by our group [69] was in keeping with the findings in Gaze and Nielsen studies [25,70]. Other than global and index pain, there were statistically significant improvement in patient anxiety and sense of well being with palliative radiotherapy. There was slight worsening of fatigue scores immediately after the delivery of radiotherapy in the entire cohort. Measures may be employed to overcome this transient period of worsening fatigue. Further studies are required to correlate the clinical significance with the statistical significance of the ESAS symptoms [69]. Most treatment interventions have associated side effects. It is vitally important to document if the interventions have an impact on QOL while attempting to palliate specific symptoms. Though external beam radiotherapy is a local treatment, studies have shown it can improve patient QOL as well [69].

18.3.2 Differences in Perspectives: Patients and Health Care Professionals The use of diverse QOL questionnaires in bone metastases trials indicates that there is a strong need for a comprehensive QOL assessment tool developed directly with bone metastases patients and their treating HCPs. In conjunction with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Group, the Bone Metastases Module (EORTC QLQ-BM22) was developed to supplement the EORTC QLQ-C30 (C30) [74]. In the initial phase of development, it was evident that the patient and HCP data presented a difference in perspective with respect to the most important issues for cancer patients with bone metastases [76]. Preliminary interviews with patients and HCPs generated a list of 61 items relevant to patients with bone metastases (Table 18.1). This list was formatted into a questionnaire and distributed to a new cohort of bone metastases patients and HCPs. A total of 413 patients (174 male and 239 female) and 152 HCPs were interviewed

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across the five cancer centres in Canada, Australia, and Germany. The patient population was from a variety of backgrounds, primary cancer sites, and receiving a variety of local and systemic treatments. The 152 HCPs interviewed were from a variety of disciplines, namely radiation oncology, medical oncology, and nursing. Palliative care physicians, social workers, surgeons, a radiation therapist, a pharmacist and a psychosocial-spiritual worker were also interviewed [76]. The extent to which patients experienced each of the 61-issues during the course of his or her illness was compared to how relevant HCPs felt each item was to bone metastases patients in terms of QOL scores [(1) “not at all” to (4) “very much”]. Patients and HCPs had significantly different mean scores for all of the 61 items Table 18.1 List of 61 quality of life issues rated for relevancy by bone metastases patients and health care professionals Symptom 1 2 3 4 5 6 7 8 9 10 11 12 13

Long-term (or chronic) pain Short-term (or acute), severe pain Pain at rest (i.e., when sitting) Pain with activity (i.e., when walking) Pain aggravation with movement or weight-bearing Uncontrolled, unmanageable pain Pain at night preventing sleep Aches and stiffness Lack of energy Numbness Tingling Burning sensation Postural problems

Function 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Limited movement due to pain Difficulty planning activities outside the home Difficulty travelling outside the home (i.e., using public transportation, driving, sitting in a car) Difficulty in carrying out meaningful activity (including employment) Able to perform self-care Able to return to work promptly Difficulty carrying out usual daily tasks (i.e., grocery shopping, work outside the home, housework) Difficulty bending Difficulty lifting Difficulty standing up Difficulty climbing stairs Difficulty sitting Difficulty lying in bed Difficulty lying flat Ability to have sex

Side effect from treatment of bone metastases 29 Drowsiness 30 Confusion 31 Dizziness

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Table 18.1 (continued) Psychosocial 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58

Able to perform role functioning (including domestic and family roles) Feeling socially isolated Strengthened relationships with family/friends Have a clear, alert mind Feel in control, positive, and confident Hope to live as long as possible Reluctance to pain medication Fear of addiction to pain medication Anxiety Frustration Mood changes Emotional stress of diagnosis of advanced, incurable cancer Increased focus on spiritual issues Loss of interest in activities you normally enjoy Loess of interest in sex Worry about pain Worry about suffering Worry about loss of mobility compromising independence Worry about becoming dependent on others Worry about current health status Worry about the future Worry about becoming bed-bound Worry about disease progression, deterioration in condition, and future complications Worry about running out of medical treatments Worry about hospitalization Worry about ending days in a hospital or nursing home Worry about death

Treatment expectation 59 Hope for sustained pain relief (reduce pain for as long as possible) 60 Hope treatment will reduce pain as much as possible Other issue 61 Financial burden due to the illness Issues in italics are in the EORTC QLQ-C30

(p < 0.0055) except for the item “feel in control, positive and confident” where the mean scores were 3.07 and 3.10 respectively (p = 0.2215). In addition, the mean scores reported by HCPs were almost always higher than that of patients [76]. Both patients and HCPs were asked to list five to ten issues that affected bone metastases patients most profoundly (Table 18.2). Patients and HCPs agreed that four items affected bone metastases patients profoundly: “long-term (chronic) pain”, “difficulty carrying out usual daily tasks”, “able to perform self-care” and “able to perform role functioning”. However, the difference in ranking between the two groups was substantial with respect to the somatic and psychosocial issues. Patients focused more on psychosocial items (4 of 10 items) and included three “worry” issues within their top 10 (“worry about becoming dependent on others”, “worry about loss of mobility compromising independence” and “worry about disease

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Table 18.2 Patient and health care professional top ten relevant issues to assess quality of life in bone metastases patients Rank Issue

% Patients Issue

1 2

41.4 39.7

Able to perform self-care 62.1 Uncontrolled unmanageable 61.0 pain not relieved by pain killers

38.7

Long-term (or chronic) pain

54.2

37.3

52.4

32.9

Short-term (or acute) severe pain Pain at night preventing sleep

50.0

32.6 32.1

Limited movement due to pain Pain at rest (when sitting)

46.9 45.1

32.0

Pain with activity (when walking)

41.0

24.3

Able to perform role 39.3 functioning (including domestic and family roles) Difficulty carrying out usual 35.9 daily tasks (grocery shopping work outside the home housework)

3 7 5

6 7

8

9

10

Long-term (or chronic) pain Difficulty carrying out usual daily tasks (grocery shopping work outside the home housework) Worry about becoming dependent on others Worry about loss of mobility compromising independence Worry about disease progression deterioration in condition and future complications Able to perform self-care Difficulty in carrying out meaningful activity (including employment) Able to perform role functioning (including domestic and family roles) Financial burden due to the illness

Hope treatment will reduce pain as 23.6 much as possible

% HCP

Boldface represents items that patients and HCPs agree should be included in the top ten.

progression, deterioration in condition and future complications”). These issues ranked 20th, 22nd, and 16th respectively by HCPs. Instead, HCPs focused more on items respective to symptoms (seven of 10 items) with an emphasis on issues relating to pain (seven of 10 items). Overall, somatic issues received much lower rankings from patients than from HCPs [76]. In this study, HCPs tended to focus on issues relating to cancer pain when rating items for the module [76]. Cancer pain is a significant problem in the bone metastases population [1] and many of the HCPs interviewed are involved in its treatment. Unrelieved cancer pain can have a negative impact on patient QOL [77–83], but it is not necessarily the sole or the most significant influencer. Rustøen et al. found that pain characteristics only had a small impact on QOL, explaining just 8.6% of the variance of QOL scores [66]. When physical and social functioning were added to the analysis the explained variance increased to 28.4%; however, depression seemed to have the most significant impact with an increase of 14–42.4% explained variance [66]. Therefore, pain is a problem for patients with bone metastases but there are additional and more important issues to patients in terms of influencing QOL. In the care of bone metastases patients, HCPs are frequently involved in the management of cancer pain, which could explain why they felt it was such a significant problem.

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However, in terms of QOL, HCPs need to realize that psychosocial issues tend to have a larger impact [76]. Patients are best able to define and measure their own QOL because it is such a subjective experience [51]. What one patient regards as a severe problem may be considered only minimal to another patient [68]. It is generally accepted that the patient’s perspective is the gold standard for the measurement of QOL and as a result, they should be the primary source regarding what issues are included in a QOL assessment tool [65]. The relevance of each domain may vary according to stage of illness, treatment, age and cultural background [65], which makes it important that a wide range of patients are interviewed in the development of the instrument. If we are able to understand the patient’s perspective of their illness, we can develop management strategies appropriate to their individual needs [76]. Health care professionals provide a more objective evaluation of the patients’ problems and symptoms [68]. They tend to outline what is typical in any given situation [84]. Some feel that HCP assessments are more meaningful for determining clinical significance because patient improvements are evaluated on clinical parameters [85]. The HCPs’ perspective is also important in the development of QOL instruments as they are responsible for the administration and incorporation of the tools into their everyday practice. In 1996, merely 7% of HCPs formally collected and used QOL information [86]. The following year, Bezjak et al. reported that although 74% of physicians felt QOL research data should be incorporated into clinical practice, 48% believed existing QOL instruments do not give clinically relevant results [64]. Many feel that current QOL instruments are too complicated, time consuming or costly to incorporate into clinical practice [87]. Patterns of practice studies have shown physicians’ reluctance to incorporate findings of randomized clinical trials [88, 89], so it is unlikely HCPs will accept an instrument they feel is inadequate. Therefore, it is important that HCPs contribute to the questionnaire development in terms of its content and structure. Further investigation regarding the specific comments or complaints HCPs have with current QOL instruments is needed [76]. Quality of life research has proven that it is necessary and can be applied to the clinical setting. Results of QOL assessments have provided significant contributions to the approval of new chemotherapeutic agents and supportive care measures [90, 91]. The next step is moving it into the “patient’s realm” [84] so that they can use this information to lead a healthier and more meaningful life. One suggestion is to have physicians sit down with patients and go through their QOL scores to identify the changes since their last visit. Although this may be time-consuming, it would facilitate discussion [92] and help physicians understand the patient’s total environment so that they could better manage their treatment. In a study by Detmar et al., physicians who had access to patient QOL scores identified a greater percentage of patients with moderate-to-serve health problems than those that did not [92]. It is important to help the patient interpret the data and suggest how they can employ this information into their daily life, just as we do with their disease and treatment information [76].

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It is clear that patients and HCPs have different opinions on what the most important issues in QOL are for patients with bone metastases. It is important that HCPs recognize these differences in their clinical practice to better improve their understanding of the patient’s situation and diagnostic capabilities. Although it may not be possible to alleviate patient worries and concerns in a population where the disease is essentially incurable, a simple discussion of these issues is very important to patients. It was suggested that ongoing developments of QOL instruments should aim at identifying issues that most affect patients’ QOL experience and providing an objective assessment tool for HCPs to adopt into their everyday practice. Only through this, they say, can we hope to improve the chances that physician and patients will use the QOL information generated effectively [76].

18.4 The Development of the Bone Metastases Module For more than two decades, the EORTC has cultivated a modular approach to the evaluation of QOL in cancer patients in clinical trials. This advancement in QOL assessment began with the development of the EORTC QLQ-C30 (C30) general questionnaire [74] and has since led to the development of several validated modules for specific cancer diagnoses. More recently, the EORTC QLQ-C15-PAL was developed from the C30 to accommodate palliative cancer patients – those with a low performance status and for whom a 30-item questionnaire would prove quite tiresome and challenging [93]. The information collected in the patient and HCP interviews outlined in the pervious section served as a valid foundation for the Bone Metastases Module, EORTC QLQ-BM22 (BM22). In collaboration with the EORTC, the BM22 was developed to address this immediate need for a comprehensive QOL assessment tool for use in clinical trials and routine clinical assessment of bone metastases patients. The module development process is highly specific and regulated by the EORTC Quality of Life Group. This process consists of four phases: Phase I: Generation of relevant QOL issues; Phase II: Operationalization; Phase III: Pretesting of the provisional module; and Phase IV: Large scale international field testing of the module [94].

18.4.1 Early Development Preliminary open-ended interviews with HCPs and bone metastases patients were conducted. Any issues relating to QOL of patients with any stage of bone metastases were recorded. As mentioned previously, HCPs from a variety of disciplines (i.e., radiation oncology, medical oncology, palliative care services, orthopaedic surgery, nursing, radiation therapy, pharmacy, and psychosocial-spiritual care) were consulted for the initial list of items. Likewise, patients with bone metastases from a wide spectrum of disease states and treatment clinics (i.e., receiving chemotherapy,

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radiation, orthopaedic services, pain management, and supportive care) were interviewed. This list of 61 relevant items was formatted into a questionnaire and administered at five centres: Odette Cancer Centre (OCC), Toronto, Ontario, Canada; Princess Margaret Hospital (PMH), Toronto, Ontario, Canada; Tom Baker Cancer Centre (TBCC), Calgary, Alberta, Canada; Liverpool Hospital, Liverpool, New South Wales, Australia; and Charit´e Hospital (Universit¨atsmedizin Berlin), Berlin, Germany. In total, 413 patients (174 male and 239 female) and 152 HCPs were interviewed across the five centres. Both populations were heterogeneous in nature in order to accurately assess which issues were most relevant across a variety of bone metastases treatments and prognoses. The list was operationalized into 22 questions and formatted in accordance with EORTC templates: questions arranged for “during the past week;” phrased in the “have you had” format and measured on a 4-point scale from (1) “not at all” to (4) “very much”.

18.4.2 Pretesting the Module The original English version of the BM22 was translated, using a rigorous translation process based on iterative forward–backward procedures into a multitude of languages, including Chinese, Danish, Dutch, French, German, Greek, Italian, Japanese, Norwegian, Spanish (European and South American), Swedish, and Turkish. The BM22 was pre-tested on 170 patients from nine countries. Participating countries included Argentina, Australia, China (Hong Kong), Canada, Germany, Greece, the Netherlands, Spain and the United Kingdom. The majority of patients (68%) were non-English speaking. Overall, there were 83 men (49%) and 87 women (51%). The median age was 60 years (range 29–92). Median time from primary cancer diagnosis to diagnosis of bone metastases was 1 year (range: 0–21). Patients interviewed were from a variety of ages and primary cancer sites that were undergoing various therapies. The BM22 was well received in all nine countries. Patients found the questionnaire easy to complete and relevant to their condition (Table 18.3).

18.4.3 Features of the BM22 As mentioned previously, pain is the most common symptom associated with bone metastases – severe pain can present in 50–75% of all bone metastases patients. Not only is pain the most prevalent symptom associated with osseous metastasis, but also the most debilitating. During interviews with HCPs, it was uniformly expressed that pain is a significant issue that must be addressed in the final questionnaire. The treatment objective in managing bone metastases is to either minimize pain or prevent it altogether. Thus, if the BM22 is to be used as a QOL questionnaire in a

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Table 18.3 Issues Included in the Bone Metastases Quality of Life Questionnaire (EORTC QLQBM22) Location of pain (1) back (2) leg(s) or hip(s) (3) arm(s) or shoulder(s) (4) chest or ribs (5) buttocks Pain characteristics (6) constant pain (7) intermittent pain (8) pain not relieved by medications Functional interference (9) pain while lying down (10) pain while sitting (11) pain when trying to stand up (12) pain while walking (13) pain with activities such as bending or climbing stairs (14) pain with strenuous activity (15) pain interfered with your sleeping (16) modify your daily activities Psychosocial aspects (17) felt isolated from those close to you (18) worried about loss of mobility (19) worried about becoming dependent on others (20) worried about your health in the future (21) felt hopeful your pain will get better (22) felt positive about your health

clinical setting, it is necessary to include pain items in order to accurately assess patient response to treatment. For example, a patient who presents with inability to walk due to pain may experience a significant pain reduction following radiotherapy or hormone therapy. As a result, ambulation may be possible once more. The assessment of characteristics of the pain (i.e., items 6–8 & 15) and the gradient that assesses pain during various movements (i.e., items 9–14) will enable clinicians to assess changes in functional status over time. Bone metastases frequently affect more than one region of the bone. Successful localized treatment to one specific bony metastatic site may “unmask” pain in other metastatic bone regions. Therefore, questions that specify the exact location of pain (i.e., items 1–5) will enable clinicians to differentiate pain scores in multiple metastatic sites and accurately assess if a treatment has had a local or systemic impact. Although the BM22 consists of many pain-related items, which were expressed as relevant to include in the module based on the responses of HCPs in preliminary interviews, the BM22 also includes the most significant psychosocial QOL aspects as indicated by the patients themselves. A separate psychosocial scale (items 17–22) addresses feelings of isolation, as well as concerns about loss of mobility,

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dependency, and future health. As modeled in the C30 general questionnaire, the BM22 concludes with two positively-framed items: feeling of hope that pain will improve and feeling positive overall about one’s health. The BM22 encompasses a variety of symptom, functional, and psychosocial domains expressed by both patients and HCPs to be the relevant to patients with bone metastases. The BM22 has been approved for use in international clinical trials as well as in routine clinical assessment of QOL in bone metastases patients receiving a variety of treatments. Finalization of the module will occur following Phase IV large-scale international field testing.

18.5 Closing Remarks This chapter has outlined the trials and tribulations that have been encountered leading to the development of standardize outcome assessment tools for use in bone metastases clinical trials – from establishing meaningful pain response endpoints to balancing what patients and HCPs believe to be most relevant QOL issues relevant to bone metastases patients and harmonization of these items into a comprehensive QOL questionnaire. Widespread use of the International Bone Metastases Consensus endpoints and the EORTC QLQ-BM22 for assessment of pain response and QOL will facilitate inter-study comparisons and reveal optimal systemic and localized bone metastasesspecific treatments, tailored to the needs of the patient. We encourage investigators to use patient-based assessment of pain scores, analgesic consumption, health related QOL, as well as any other study specific endpoint evaluation tools in future bone metastases clinical trials.

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Index

A Acetabulum, 271, 272, 274–276, 359 Adrenalectomy, 302 Adriamycin, 290 Advanced metastatic cancer, 324 Analgesia, 292, 294, 325, 349, 375 Androgen blockade, 79 combined, 308–309 intermittent, 309 Angiogenesis, 40, 42, 43, 51–68, 139, 202, 234, 293, 310 metastasis, 51–68 Angiogenic factors, 51, 52, 53, 55, 58 Angiography, 272, 275–276 Anorexia, 87, 347 Antiandrogens, 308–309 Antiangiogenic therapy, 52, 65 Apoptosis, 10, 14, 15, 18, 19, 26, 58, 59, 62, 63, 65, 66, 68, 195, 199, 236 Aromatase inhibitors, 290, 299, 303, 304, 306 B Benign lesions, 174 Bicalutamide, 308 Biodistribution, 140, 158, 328 Biphosphonates, 52, 66, 68, 195–220, 235, 236, 251–259, 333–335 BM22, 349, 382, 387–390 Bone anatomy, 3–27, 138 biomarkers, 93–111 density, 60, 81–83, 123, 128, 132, 233, 234, 237, 239, 241, 243–247, 269, 270, 348, 353, 354, 358, 360 destruction, 3, 31, 33, 34, 37, 39, 40, 41, 44, 45, 64, 67, 83, 95, 100, 106, 119, 120, 121, 123, 125, 128, 130, 139, 176, 237, 275, 278 functions, 3, 21, 23

markers, 93–95, 101–106, 108, 110, 213, 350, 351 marrow, 4, 7, 8, 11, 12, 14, 16–18, 21, 22, 31, 33–38, 40, 43, 59–60, 62, 64, 65, 66, 77, 79, 80, 84, 120, 151, 154, 157, 163–171, 173–175, 177, 197–198, 217, 234, 238, 288, 292, 323, 328, 332, 335, 346, 360, 362 metastasis, 3, 16, 23, 31–46, 51–68, 77–85, 93, 94, 96, 110, 119, 120, 131, 151, 156, 172, 186–187, 195, 196–198, 204, 205, 210, 212, 217, 219, 220, 243, 252, 253–254, 268, 288, 321, 333, 350, 353, 356, 358, 359 epidemiology, 137–140 surgery, 80, 84, 263–267, 271, 278, 287, 288, 294, 324, 379 Multicellular units (BMUs), 196, 255 necrosis, 251 non-cellular matrix, 15–16 pain palliation, 66, 333, 381 uncomplicated, 185 physiology, 21, 62, 137, 138 scan, 33, 57, 79, 102, 140, 143, 144, 146, 148, 149, 154, 155, 271, 293, 321, 324, 355–357, 382 scintigraphy, 84, 119, 120, 128, 142, 144, 150, 154, 155 C Calcium, 12, 14, 16, 21, 23–26, 35, 37, 51, 57, 58, 79, 86, 87, 95, 97, 98, 102, 138, 158, 199, 211, 212, 278, 289, 326, 334, 351 Camera, 137, 140–142, 148 Cancellous bone, 3–5, 7, 8, 15, 20–22, 94, 128, 164

395

396 Cancer breast, 31–33, 38, 39, 41, 42, 44, 45, 57–61, 63, 64, 65, 78, 80, 82, 84–86, 105–107, 109, 127, 130, 140, 149, 150, 155, 167, 175, 186, 187, 207, 208, 210, 217–219, 237, 239, 240, 246, 252, 253, 258, 264, 287, 289, 299–306, 310, 327–329, 332–334, 347, 348, 350–353, 355–357, 359, 360, 363, 365 lung, 32, 52, 78, 99, 100, 104–106, 122, 126, 137, 138, 140, 149, 155, 165, 170, 204, 210, 211, 213–216, 265, 287, 289, 293, 294, 325, 327, 361, 362 melanoma, 16, 32, 42, 67, 139, 140, 149, 169, 265, 287, 294, 300 prostate, 16, 31–33, 36, 38, 44, 45, 59, 62–64, 67, 78, 79, 86, 96, 100–102, 104–107, 109, 126, 140, 144, 151–154, 198, 199, 202, 204, 206, 209–210, 213, 214–216, 219, 220, 265, 287, 291–293, 299–301, 306–311, 324, 327–331, 333, 334, 352, 361, 372, 381 renal, 32, 67, 101, 359 thyroid, 140, 145, 299, 300, 310, 311 differential, 145, 310–311 upper gastrointestinal tract, 265 Castration, 291, 299, 307–309 Chemotherapy, 37, 54, 58, 63, 65, 103, 131, 175–176, 178, 201, 206, 207, 236, 237, 272, 275, 277, 283, 287–295, 299, 301, 305, 311, 322, 324, 326, 328, 331, 334, 347, 354, 356, 357, 360, 361, 363, 364, 372, 373, 387 Clinical assessment, 240, 241, 267, 345, 346, 352, 363, 387, 390 Clinical features, 77–89 Clinical trials, 44, 45, 66, 88, 101, 186, 203, 204, 207, 208, 210, 211, 213, 217, 234, 240, 293, 301, 309, 325, 327, 328, 349, 352, 355, 364, 371–390 Clodronate, 67, 107, 199, 204, 206, 207, 209, 211, 217, 219, 233, 236, 245, 253, 334, 349 Cochrane database, 187, 188, 208 Collagen, 4–7, 9, 10, 14–16, 18, 25, 42, 93, 95–99, 102, 138, 196, 199, 213, 215, 258, 350, 351 Combined therapy, 241, 243, 321, 334, 335, 359 Compact bone, 3, 5–7, 15, 21, 22

Index Complications, 61, 66, 77, 80, 84, 86, 93, 103–106, 110, 120, 196, 200, 202, 205, 233, 234, 246, 253, 256, 259, 264, 265, 273, 275, 278, 282, 287, 288, 290, 306, 307, 321, 330, 334, 347, 350, 372, 379, 384, 385 Computer-aided detection (CAD), 119, 132, 132 Computer tomography (CT), 119, 120, 122–125, 127–134, 141, 143–146, 148, 154, 155, 163, 164, 176, 177, 189, 241–244, 246, 253, 267–271, 275, 353, 357, 358, 360, 361, 363 multi-detector (MDCT), 120, 129, 134 multislice, 119 Contrast media, 169–170 Cost, 33, 110, 120, 154, 202, 309, 327, 329, 334–336, 350, 354, 363, 379 Cryosurgery, 272, 277 Cyclophosphamide, 290, 291 Cytokines, 5, 11, 16, 22, 34–38, 56, 57, 63, 64, 95, 138, 197, 203, 212, 255, 346 D Differential diagnosis, 127, 143, 150, 164, 174, 175, 178 Dose, 66, 105, 107, 108, 109, 110, 145, 158, 186, 187, 205, 209, 212, 238, 239, 240, 245, 255, 256, 257, 259, 303, 323, 328, 329–331, 333, 335, 350, 358, 372, 382, Dual-energy X-ray absorptiometry (DEXA), 246, 357 E Economics, 335, 351 Emergency surgery, 282, 283 Enchondral ossification, 3, 4, 17–19 Endothelin-1 factor (ET-1), 198, 221, 293 Endpoints, 106, 1, 205, 218, 301, 351, 365, 371–375, 378–381, 390 Estrogen, 14, 219, 302, 303 receptor, 64, 78, 79, 218, 289, 290, 299, 301–304, 306, 311 Etidronate, 204, 206, 209, 233, 236 F 18F-deoxyglucose (FDG), 143, 149–156, 163, 177, 363, 364 Fatigue, 23, 77, 87–89, 347, 382 Fibroblast growth factor (FGF), 19, 23, 35, 38, 43, 51, 57, 58, 60, 61, 197 Fluoracil (5-FU), 290, 291, 331, 333 Fluoxymesterone, 302

Index Fracture, 5, 15, 32, 33, 80, 83–85, 93, 103, 106, 120, 123, 124, 175, 185, 188, 189, 191, 205, 206, 212, 213, 237, 252, 259, 263, 267–275, 278, 283, 293, 326, 332, 346, 347 impending, 188, 264, 267, 268, 273, 275, 278 long bone, 267, 346 pathological, 77, 80, 103, 185, 234, 237, 251, 252, 264–265, 268, 271–275, 282, 350 risk assessment, 267, 268–269 Function, 3–27, 36, 41, 42, 56, 68, 79, 85–87, 85–87, 95, 198–203, 212, 219, 236, 238, 252, 265, 267, 271–273, 275, 283, 288, 308, 310, 349, 372, 375, 383 G Gadolinium (Gd), 163, 165, 169–172, 175, 177, 361, 362 Gamma camera, 140–142, 148 H Heparenase, 59, 60 Hormone dependency, 306 Hormonotherapy, 299–311 combinations, 306, 310 second line, 303, 304, 309 Hounsfield Units (HU), 81, 82, 129, 241, 358 Hydroxyapatite, 13, 16, 143, 148, 196, 327, 328, 334 Hypercalcemia, 33, 77, 80, 86–87, 120, 195, 200, 203–204, 211, 259, 264, 322, 334, 346, 347, 350 Hypoxia, 53, 59 I Ibandronate, 105–107, 133, 208, 211, 233, 236, 238, 239, 241, 243, 252, 253, 349, 351, 358 Image, 120, 122, 128–130, 132, 133, 140, 142, 144–147, 156, 158, 164–167, 172, 173, 175, 177, 241, 242, 269–271, 274, 354, 356–364 Imaging, 84, 94, 103, 110, 120–122, 128, 131, 137, 138, 140, 142, 143, 146–155, 158, 163, 164, 166, 167, 169, 171, 172, 176–178, 252, 253, 269, 275, 352, 354, 360–363, 365 Insulin-like growth factor (IGF), 9, 23, 24, 35, 52, 57, 62, 64, 197 Integrin, 12, 13, 15, 24, 36, 40, 58, 65–68, 100, 236

397 Interactions, additive, 237 Interactions, super-additive, 237 Interleukin (IL), 197 Interleukin-3 (IL-3), 40 Interleukin-6 (IL-6), 35, 38, 40, 41, 43, 52, 64, 67, 212 Interleukin-11 (IL-11), 42, 57–58, 61 Intramembranous ossification, 3, 4, 20 Iodine, 123, 145, 311 Isotope, 140, 142, 156, 235, 323, 333 K Karnofsky performance status (KPS), 81, 88, 89, 211, 241, 243, 244, 247, 266, 283, 326 L Life expectancy, 185, 187, 265, 271, 288, 305, 326, 330, 374 Luteinizing Hormone-Releasing Hormone (LHRH), 290, 291, 307–309 M Magnetic resonance imaging (MRI), 84, 120, 163–178, 253, 353, 360, 361 diffusion-weighted imaging (Dwi), 163, 171, 175, 178 fat suppression techniques, 167, 168 weighted image, 166, 167 Malaise, 87 Malignancy, 25, 77, 80, 86, 123, 174, 175, 195, 203–205, 211, 233, 234, 254, 259, 287, 290, 310, 322, 379 Malignant, 3, 15, 25, 36, 37, 55, 56, 62, 63, 85, 103, 120, 123, 125, 131, 144, 149–151, 154, 158, 163, 164, 166, 175, 178, 199, 205, 213–215, 254, 264, 276, 278 Mechanotransduction, 3, 23, 24 Metastatic disease, 78, 80, 121, 125, 127, 130, 132, 133, 144, 153, 155, 159, 176, 177, 210, 212, 259, 265, 266, 269, 272, 276, 288–290, 294, 304, 306, 307, 322, 346, 356, 361, 371 Mineral homeostasis, 3, 10, 21, 23, 25 MIP-1alpha (α) factor, 38–40, 198 Module, 349, 382, 385, 387–390 Morbidity, 33, 77, 79, 80, 83, 88, 105, 139, 159, 189, 195, 199, 203, 205, 207, 209, 278, 281, 283, 287, 290, 294, 306, 321, 345–347 Multidisciplinary approach, 264, 266, 324 Multi-fraction radiotherapy, 235

398 Multiple myeloma, 31, 32, 62, 64, 66, 79, 86, 87, 99–101, 103, 105, 139, 140, 144, 173, 195, 198, 202, 203, 204, 206, 220, 237, 254, 275, 323, 345 N Natural history, 77–89, 289 Necrosis, 7, 11, 19, 37, 39, 41, 80, 132, 168, 198, 251, 253, 255, 278 Needle biopsy, 131, 170 Nephrogenic systemic fibrosis (NSF) or Nephrogenic fibrosing dermopathy (NFD), 170 Neurological deficits, 185, 189, 265 Normal tissue, 146, 164, 234, 236, 238, 323 Nuclear medicine, 137–159, 324 O Octreotide, 146 Opioids, 81, 82, 89, 188, 233, 234, 239, 241, 243, 331 Oral morphine equivalent, 81, 88, 89, 241, 243, 374 Ossification enchondral, 3, 4, 17–19 intramembranous, 3, 4, 20 Osteoblast, 3–12, 14–18, 20–27, 31, 34–38, 40–45, 51, 53, 57, 59, 62, 67, 94–97, 138, 139, 143, 158, 196–198, 235, 237, 255, 352, 353 Osteocalcin, 9, 10, 15, 24, 95, 97, 102, 105, 351 Osteoclast, 3, 8, 11–14, 18, 22, 25, 31, 34, 39, 51, 57, 60, 63, 66–68, 98, 99, 107–109, 195–200, 203, 236, 352 Osteocyte, 3, 6–11, 20, 138, 196 Osteolysis, 10, 42, 68, 131, 196, 197, 199, 201, 214, 233, 238, 242, 245–247, 273, 275, 276, 346, 353 Osteonecrosis, 251, 253–256, 258, 276 biphosphonate (BON), 251–254, 256, 257, 259 of the jaw, 212, 218, 251 Osteoporosis, 13–15, 22, 26, 38, 39, 83, 94, 99–101, 132, 175, 176, 195, 200, 202, 217, 219, 220, 251, 253, 256, 348, 357 Osteotropism, 57–59, 78, 79, 120, 139 P Paget’s disease, 7, 14, 66, 96, 99, 123, 144, 200, 202, 327 Pain, 33, 44, 77, 80–85, 87–89, 93, 100, 103, 106–109, 122, 124, 131, 154, 159,

Index 170, 185–188, 190, 191, 195, 202, 205, 207–209, 211, 213, 233–235, 237–245, 247, 251, 252, 264, 265, 267, 271–275, 277, 278, 282, 283, 288, 289, 291–294, 301, 306, 307, 310, 321–326, 345–349, 351, 357, 358, 361, 365, 371–378, 380–385, 388–390 management, 241, 321, 336, 375, 377, 388 Palliation, 65, 131, 134, 137, 156, 157, 159, 185, 235, 263–265, 268, 282, 288, 291, 294, 321–324, 326–333, 336, 381 Palliative, 88, 107, 108, 156, 185, 187, 195, 205, 209, 253, 264, 265, 280, 288, 291, 292, 294, 309, 311, 321, 322, 327–330, 333–336, 346, 348, 349, 351, 372, 373, 375–383, 387 Pamidronate, 66, 100, 103, 106, 107, 132, 202, 204–207, 209, 211, 219, 220, 233, 236, 239, 240, 251, 253, 255, 290, 306, 334, 348–351, 354 Paraplegia, 264 Parathyroid hormone (PTH), 9, 11, 12, 17, 19, 23, 25, 26, 38, 39, 41, 78, 86, 97, 138, 144, 153, 196, 197, 257 Pathogenesis of bone metastasis, 31, 64 Patient, 26, 31–33, 37–46, 57, 58, 61, 64–67, 77–89, 93, 94, 96–100, 119–126, 129–132, 134, 139, 142, 144–152, 154–156, 158, 159, 164–166, 168, 170, 172, 176–178, 185–191, 195, 196, 198, 199, 202–210, 233–247, 251–259, 263–279, 283, 287–294, 299–311, 321–336, 345–365, 371–390 Pelvis, 4, 17, 120, 123, 128, 129, 153, 155, 172, 274, 276, 277, 293, 360 Performance status, 66, 77–80, 82, 83, 85, 209, 211, 233, 241, 244, 283, 287, 288, 292, 294, 322, 326, 333, 334, 374, 382, 387 Pharmacokinetics, 158 Phosphorus, 25, 138, 158, 328 Platelet-derived growth factor (PDGF), 35, 38, 42, 43, 51, 57, 58, 63, 67, 197, 257 Positron emission tomography (PET), 120, 129, 130, 141, 142, 147–151, 154–156, 177, 324, 363, 364 /CT, 120, 130, 141, 148, 177 radiopharmaceuticals, 147, 154, 158, 159 scan (PET scan), 140, 143, 151, 154, 363

Index Prevention, 51–68, 84, 110, 185, 188, 195, 206, 214, 216, 217, 218, 251, 256, 259, 269, 288, 310 Prognosis, 40, 60, 61, 64, 77–89, 163, 164, 187, 189, 190, 211, 214, 216, 256, 265, 268, 276, 287, 289, 293, 356 Prostate-specific antigen (PSA), 68, 79, 144, 153, 154, 199, 291–293, 301, 330, 357 Q Quality of life (QoL), 66, 77, 80–82, 84, 88, 103, 120, 159, 185, 187, 188, 191, 196, 202, 233–235, 240, 241, 243–245, 247, 251, 253, 264, 265, 277, 283, 287–289, 291, 301, 305, 306, 309, 322–324, 328, 334, 336, 345, 348, 349, 350, 364, 365, 371–373, 375, 378–383, 385–390 R Radiation therapy, 131, 175, 252, 271, 275, 277, 288, 322, 332, 348, 387 Radiofrequency ablation, 277, 322 Radiograph, plain, 119–134, 163, 164, 176, 177, 239, 267, 268, 271, 275, 276, 353, 354, 360 Radiological assessment, 129, 241, 345, 354 Radionuclides, 107, 138, 156, 158, 235, 322–326, 328, 332–336 Radionuclide therapy, 108, 235, 292, 321–336 Radiopharmaceutical, 137, 138, 140, 143, 145–147, 149, 152, 154, 156–159, 287, 288, 292, 321–323, 326, 328, 330–334, 336, 379 Radiotherapy, 54, 65, 85, 88, 89, 93, 103, 107–109, 127, 132–134, 156, 165, 178, 185–191, 195, 205, 233–247, 268, 272, 278, 287, 288, 294, 321, 324, 325, 330, 332, 333, 336, 347, 348, 354, 358, 361, 363, 371–378, 380–382, 389 RANKL, 11, 12, 25, 35, 37–41, 43, 45, 100, 198, 255, 352 RANK receptor, 25, 38, 198 Reimbursement, 186 Re-irradiation, 185, 186, 190, 191 Remineralisation, 185, 186, 188, 245, 246, 358 Remodelling, 3, 10, 11, 14, 15, 21–23, 31, 33, 37, 41, 45, 51, 57, 58, 62, 93, 94, 102, 108, 123, 138, 139, 196, 197, 199, 213, 214, 237, 253–255, 300, 311, 334

399 Resolution spatial, 128, 129, 166, 357 temporal, 120 Response, 4, 10, 16, 17, 19, 23–25, 33, 51–54, 61–63, 79, 85, 88, 93, 94, 96–98, 102, 105, 107–109, 119, 131, 132, 134, 138, 139, 147, 150, 155, 156, 158, 159, 165, 186, 187, 190, 191, 204, 205, 213, 233–235, 237–241, 243, 245, 247, 272, 287, 290–295, 301–306, 311, 325–333, 335, 345–365, 371–378, 389, 390 Risk benefit analysis, 265 factors, 44, 83–85, 188, 251, 253, 259, 265, 345, 348 fracture assessment, 268–271 S Samarium, 140, 157, 235, 288, 292, 322, 327, 331 Seed and soil hypothesis, 35, 51, 56, 196, 300 Single fraction radiotherapy, 187, 191, 358 Skeletal morbidity, 195, 199, 203, 205, 207, 209, 290, 306, 347 Skeletal related events (SREs), 45, 66, 80, 103–107, 195, 202, 203, 205–211, 213–215, 220, 235, 237, 263, 345, 347, 348, 351, 364, 372 Skull, 4, 17, 20, 21, 83, 121, 125, 127, 140, 146, 153, 155 Spatial cooperation, 234, 236, 237, 247 SPECT, 130 Spinal cord compression, 33, 77, 80, 84, 85, 120, 130, 156, 164–166, 176–178, 185, 189, 191, 195, 196, 202, 203, 205, 235, 281–283, 288, 293, 326, 334, 347, 350, 379 Spine, 84, 120, 123–126, 128–130, 132, 134, 165, 167, 168, 172, 267–271, 275, 278–283, 293, 360, 361 Strontium, 157, 235, 288, 292, 322, 323, 326, 329, 330, 332–334, 382 Surgery, 80, 84, 85, 176, 186, 188, 189, 191, 195, 202, 203, 205, 217, 218, 235, 237, 263–268, 271, 273–275, 277–283, 287, 288, 294, 322, 324, 347, 379, 387 Surgery, emergency, 282–283 Survival, 12, 32–35, 37, 38, 41, 43–45, 51, 52, 54, 57–59, 62, 65, 67, 77–79, 84, 85, 87, 96, 100, 101, 103–106, 139, 140, 159, 187–190, 196, 206, 209, 210, 213, 214, 216, 218, 234, 265,

400 272–274, 277, 288, 289, 291–294, 301, 305–309, 323, 324, 329, 330, 332, 333, 345, 351, 356, 371, 372, 374, 375, 379 Symptom clusters, 77, 88–89 Synergistic activity, 233–235, 237, 238, 246, 247 T Tamoxifen, 218, 219, 290, 299, 302–304, 306 Taxanes, 201, 290, 293, 294 Technetium, 140, 176, 253 Therapeutic response, 107, 165, 238, 240, 241, 247, 345–365 Tolerance, 234, 236, 238 Toxicity, 61, 156, 157, 187, 188, 212, 218, 238, 255, 307, 308, 326–336, 379 Transforming growth factor (TGF), 19, 23, 35, 38, 39, 41–44, 45, 51, 53, 55, 57, 60, 61, 64, 86, 197 Translational research, 265, 267, 306 Treatment, 26, 33, 51, 60, 62–67, 77, 79, 80, 84, 85, 87–89, 94, 97, 103, 105, 107–110, 119, 131–134, 145, 147, 151, 156–159, 163, 164, 168, 175, 178, 185, 186, 188–190, 195, 202, 204–205, 212–215, 218–220, 234–247, 251–259, 263, 264, 269, 271, 273–278, 283, 287–295, 299, 301, 303, 305–311, 321, 322, 324,

Index 326, 327, 329, 330, 332–336, 345–358, 360–365, 371–374, 376–390 response, 133, 361, 373, 378 Tropism, 57, 300 Tumor markers, 77–79, 330, 345, 350, 363 Tumor necrosis factor (TNF), 11, 37–39, 41, 80, 198, 212 V Vascular Endothelial Growth Factor (VEGF), 19, 35, 40, 43, 51–53, 55, 59, 61–68, 202, 293, 310 Vascularization, 4, 16, 163, 166, 255 Vitamin D, 9, 11, 12, 25–27, 38, 196, 200, 212, 289 W Wolff’s law, 8, 10 X X-ray, 5, 85, 94, 120–123, 126, 128, 143, 164, 245, 246, 278, 353 Z Zoledronic acid, 39, 66, 104–107, 110, 195, 201, 204–213, 215–220, 233, 236, 245, 246, 251–253, 258, 259, 306, 310, 333, 334, 348–351, 356