Gastrointestinal Oncology
Charles D. Blanke • Claus Rödel Mark S. Talamonti (Editors)
Gastrointestinal Oncology A Practical Guide
Editors Charles D. Blanke Division of Medical Oncology University of British Columbia West 10th Avenue 600 V5Z 4E6 Vancover, BC Canada
[email protected] Claus Rödel Department of Radiotherapy and Oncology Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7 60590 Frankfurt am Main Germany
[email protected]
Mark S. Talamonti Pritzker School of Medicine University of Chicago Chicago, IL USA and Department of Surgery NorthShore University Health System Northwestern University Evanston Northwestern Healthcare Ridge Avenue 2650 60201 Evanston, JL USA
[email protected]
ISBN 978-3-642-13305-3 e-ISBN 978-3-642-13306-0 DOI 10.1007/978-3-642-13306-0 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2010937908 © Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudioCalamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
Preface
Gastrointestinal oncology practitioners aim to establish effective prevention and treatment strategies for patients with malignancies involving the GI tract, ultimately leading to a reduction in morbidity and mortality from GI cancers. GI tumours arise from a number of distinct anatomic sites and may or may not share underlying biologic similarities; however, they differ in their required radiotherapeutic or surgical approaches for limited, curable disease, as well as their chemosensitivity and treatment patterns in the advanced or metastatic settings. The best therapeutic approach to these cancers is usually multidisciplinary, involving medical, surgical, and radiation oncologists, with strong input from pathologists, gastroenterologists, and specialists in diagnostic imaging. Making major strides in future GI cancer control will certainly involve both expert clinicians and researchers, specializing in areas including new drug development, clinical trial design, biostatistics, experimental and molecular therapeutics, and molecular pathology. This edition of Gastrointestinal Oncology: A Practical Guide features chapters devoted to each of the major GI anatomic sites, as well as sections on diagnostic imaging, interventional GI oncology, practical correlative science, and non-site specific tumours such as neuroendocrine cancers and gastrointestinal stromal tumours. The emphasis of this text is to furnish useful, evidence-based clinical advice, highlighting the multidisciplinary nature of GI oncology practice. This remains an incredibly exciting time in medicine. The knowledge leaps in molecular oncology in general and characterization and treatment of GI malignancies specifically have been prodigious. We hope you find the information in this text useful, guiding your everyday practice and stimulating thought regarding potential future advances. Vancouver, Canada Frankfurt, Germany Evanston, USA
Charles D. Blanke Claus Rödel Mark S. Talamonti
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Contents
1 Imaging in Gastrointestinal Cancer..................................................................... Minsig Choi and Anthony F. Shields
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2 Interventional Gastrointestinal Oncology........................................................... 21 Jennifer Chennat and Irving Waxman 3 Practical Gastrointestinal Oncology Correlative Science.................................. 43 Kay Washington and Christopher L. Corless 4 Esophageal Cancer................................................................................................ 67 Florian Lordick and Arnulf Hölscher 5 Gastric Cancer....................................................................................................... 101 John S. Macdonald, Scott Hundahl, Stephen R. Smalley, Denise O’Dea, and Edith P. Mitchell 6 Gastrointestinal Stromal Tumors......................................................................... 139 John R. Zalcberg, Desmond Yip, Christine Hemmings, Bruce Mann, and Charles D. Blanke 7 Multimodality Management of Localized and Borderline Resectable Pancreatic Adenocarcinoma.............................................................. 173 Michael B. Ujiki, William Small, Robert Marsh, and Mark S. Talamonti 8 Unresectable Pancreatic Cancer........................................................................... 205 Daniel Renouf, Laura A. Dawson, and Malcolm Moore 9 Liver Cancer........................................................................................................... 225 Joseph D. Thomas, George A. Poultsides, Timothy M. Pawlick, and Melanie B. Thomas 10 Carcinoma of the Biliary Tract............................................................................. 251 Sean P. Cleary, Jennifer Knox, and Laura Ann Dawson
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11 Neuroendocrine Cancers....................................................................................... 301 John A. Jakob, Carlo Mario Contreras, Eddie K. Abdalla, Alexandria Phan, and James C. Yao 12 Colon Cancer.......................................................................................................... 325 Sharlene Gill, Carl Brown, Robert Miller, and Oliver Bathe 13 Rectal Cancer......................................................................................................... 379 Claus Rödel, Dirk Arnold, and Torsten Liersch 14 Anal Cancer............................................................................................................ 423 Rob Glynne-Jones and Suzy Mawdsley Index ............................................................................................................................. 451
Imaging in Gastrointestinal Cancer
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Minsig Choi and Anthony F. Shields
1.1 Introduction Imaging has been an essential part of oncology since the discovery and use of X-rays by Roentgen. Gastrointestinal (GI) oncology has made extensive use of a number of imaging approaches which utilize X-rays, including plain films, contrast placed in the intestinal tract for barium swallows, upper gastrointestinal (UGI) series, barium enemas (BE), and in the last three decades, the extensive use of computed tomography (CT). A number of other techniques are now routinely employed including ultrasound (US), magnetic resonance imaging (MRI), and positron emission tomography (PET). Most imaging modalities provide adequate anatomic and structural images of cancer patients. Recent technological advances in functional imaging bring new insights to cancer staging and early monitoring of treatment response. This chapter concentrates on some of the new approaches to imaging and the application of older approaches where active research is being done in screening, diagnosis and staging, monitoring treatment, and surveillance in GI cancers. It also focuses on PET and PET-CT scans and novel ways of utilizing these methodologies to improve the clinical outcomes in GI cancer patients.
1.2 Screening Screening of GI cancers has most commonly been done using endoscopic procedures, since one can visualize the tumors, biopsy the lesions, and even remove small lesions at the same time. This approach has been the standard of practice in the upper GI tract in populations
M. Choi Karmanos Cancer Institute, Wayne State University School of Medicine A.F. Shields (*) Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, HW04HO, Detroit, MI 48201-2013, USA e-mail:
[email protected] C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_1, © Springer-Verlag Berlin Heidelberg 2011
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M. Choi and A.F. Shields
and patients with high risk of esophageal and stomach cancers. In the lower GI tract, colorectal cancer screening has employed a number of techniques including fecal blood testing, stool DNA analysis, colonoscopy, X-rays with BE, and more recently, CT colonography.
1.2.1 Colon Cancer Screening In recent years, colonoscopy has almost completely replaced BE for screening the entire colon, since colonoscopy has a higher sensitivity for cancer (95 and 82.9% in colonoscopy and BE, respectively) and more readily detects polyps (Rex et al. 1997; Rockey et al. 2004). Furthermore, an abnormal barium study generally requires a subsequent colonoscopy to obtain a biopsy or remove small polyps. The advent of CT colonography (also called virtual colonoscopy) may change the routine screening paradigm once again, but this remains an area of very active research. CT colonography allows one to obtain highresolution images of the colon that include the usual cross-sectional images and, in addition, one can obtain three-dimensional endoluminal views. A number of studies have analyzed the sensitivity and specificity of CT colonography and a meta-analysis of 24 studies with 4,181 patients, published between 1994 and 2003, found a sensitivity of 93% (95% confidence interval [CI]: 73%, 98%) and specificity of 97% (95% CI: 95%, 99%) for lesions >1 cm (Halligan et al. 2005). Another meta-analysis of 30 studies, published between 1997 and 2005, found that CT colonography had a sensitivity of 82% for polyps over 10 mm (95% CI: 76–88%) (Rosman and Korsten 2007). It should be noted that these meta-analyses included older studies and the methods used for CT colonography have been evolving over time with continuous software improvement. In fact, most of the studies in these meta-analyses primarily used 2D reconstruction for the initial evaluation. Furthermore, these studies took the optical colonoscopy as the “gold standard.” A study by Iannaccone et al. (2005) involved 88 patients who initially underwent CT colonography and standard colonoscopy on the same day, where the observers were unaware of the results of the other studies. The patients then underwent a repeat colonoscopy within two weeks by an endoscopist who had knowledge of the first examinations and this final evaluation served as the reference. On a per-polyp basis, for lesions ³6 mm, the sensitivities of CT colonography and colonoscopy were 86 and 84%, respectively. On a per-patient basis the sensitivities of CT colonography and colonoscopy were 84 and 90%, respectively. While lesions less than 6 mm were difficult to detect by CT colonography, for lesions ³6 mm the two approaches were comparable. CT colonography is now regularly reimbursed for patients who have incomplete colonoscopies in the United States. For routine screening, payment by Medicare was denied in 2009 because of concern that most of the comparative studies were conducted in patients under the age of 65. While the cost of CT colonography is less than a colonoscopy, the fact that an abnormal CT colonography study mandates colonoscopy lessens the advantage somewhat. In the study by Johnson et al., 17 and 12% of patients had lesions ³5 or ³ 6 mm, respectively, and would require colonoscopy depending on the chosen threshold. With the CT colonography threshold set at ³5 mm, the positive predictive value for the test
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was 0.45 for adenomas ³5 mm or cancer. Concerns about the radiation dose have also been raised, along with the cost and complications associated with the evaluation of extracolonic findings of unknown significance found on the CT scans. Overall 66% of the patients had extracolonic findings, but fortunately most were not thought to require further evaluation. The evaluation of extracolonic findings, which were needed in 16% of subjects in the study by Johnson et al. (2008), will lead to added costs and patient anxiety. One of the continuing issues is the need for complete bowel cleansing before CT colonography, as it is done before colonoscopy. To decrease the number of false positive CT colonography studies, patients are regularly given oral contrast after purging to help differentiate retained stool from polyps (Johnson et al. 2008). Similar approaches have been studied using minimal bowel preparation and combined fecal tagging. When compared to full preparation, these methods had sensitivities of 97 and 88%, respectively, for polyps ³6 mm (Nagata et al. 2009). Investigators are working on software filters to improve lesion detection and hence decrease the need for bowel cleansing (Oda et al. 2009). In summary, CT colonography is already finding routine use, but further testing and refinement are in order. New techniques may allow for limited bowel preparation, which is preferred by patients (Jensch et al. 2009).
1.2.2 Diagnosis and Staging CT has been the standard for the diagnosis and staging of GI cancers over the last 30 years. The CT scan has a sensitivity of 75–90%, and a specificity of 80–90% (McAndrew and Saba 1999; Pasanen et al. 1992), and can elucidate important abdominal structures. CT angiography can assess the relationship of the tumor to the neighboring major vessels. MRI adds little information after conventional CT scans except for the hepatobiliary system. Its use has been defined in the individual disease chapters and is excluded from this chapter.
1.2.3 PET Imaging: The Basics PET scans are a noninvasive imaging modality utilizing positron emitting radioisotopes to label molecules and create different images depending on the tissue concentrations. 18 F-Fluorodeoxyglucose (18F-FDG), an analog of glucose, is the most commonly used tracer and accumulates more specifically in metabolically active cells like cancer. It capitalizes on the distinctive feature of cancer, which has a higher glycolytic index known as the Warburg (1956) phenomenon. Aside from high glucose utilization, most cancer cells have a higher expression of the glucose transporter Glut-1 than normal cells (Aloj et al. 1999; Tohma et al. 2005). Inside the cell FDG is phosphorylated by hexokinase, but further glucose metabolism is prevented by the fluorine atom. Thus, FDG preferentially accumulates in the tumor cells as illustrated in Fig. 1.1. Detectors surrounding the patient during a PET scan capture the degree of tumoral 18F-FDG. Its avidity is expressed using a standardized uptake value
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Fig. 1.1 When glucose enters the cell, hexokinases phosphorylate glucose into glucose-6-phosphate. Glucose can undergo glycolysis producing CO2, water and energy. 18F-Fluorodeoxyglucose (18F-FDG) follows the same pathway as glucose, but, after phosphorylation, 18F-FDG is not further metabolized. Hence, FDG can preferentially accumulate in the tumor cells
(SUV). SUV is a semiquantitative measure of 18F-FDG uptake from PET images comparing it to the normal physiologic distribution. SUVs are dependent on several parameters: blood glucose level, tumor size, time after 18F-FDG injection, and spatial resolution of the images. Although kinetic parameters of 18F-FDG-PET can be expressed using Patlak and compartmental modeling, the need for prolonged imaging and the complexity of such modeling has limited most routine clinical studies to SUV quantitation to measure the activity of 18F-FDG in cancer (Gjedde and Diemer 1983; Patlak et al. 1983). 18 F-FDG became a useful radiotracer since it has a longer half-life of 110 min as compared to other radioisotopes. There are no pharmacologic adverse effects of the radiolabelled FDG since it uses an extremely low amount of tracer (less than a micromole). The high sensitivity and specificity of PET imaging makes it a useful tool in the diagnosis and staging of cancer patients (Bombardieri et al. 2001; Facey et al. 2007; Fletcher et al. 2008). Its reproducibility for quantitative metabolic measurements has been validated in malignant tumors using FDG-PET (Minn et al. 1995; Weber et al. 1999). PET is now approved for use in the United States for the initial staging of many cancers. Its use for restaging and assessment of treatment response has not been approved for reimbursement for GI cancers originating in the stomach, liver, pancreas, biliary tree, and small intestine, as well as neuroendocrine
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cancers (http://www.cancerpetregistry.org/indications_facilities.htm) (National Oncology PET Registry (NOPR) 2009; Avril et al. 2005; Avril and Weber 2005). Although the spatial resolution for PET scans continues to improve, current resolution is approximately 0.5 cm and low-contrast dose can limit the detection of lesions two to four times larger. Hence, the ability to detect subcentimeter lesions in oncology remains a challenge. Another limitation of PET is its lack of ability to distinguish infectious or inflammatory conditions from cancer. These acute conditions attract metabolically active granulocytes and monocytes that can lead to false positive findings, particularly after surgery and radiation therapy. Additionally, physiologic 18F-FDG uptake by normal tissues can lead to false positive findings. Brain and heart tissues in particular may have avid uptake (shortly after tracer injection) while moderate uptake may be seen in the liver, spleen, and GI tract. Finally, the FDG is excreted by the urinary system. Some other areas that can have increased physiologic uptake include muscles and brown fat and lymphatic tissues. The sensitivity of these areas may often be suboptimal when the patient has recently exercised stimulating muscles, or has had an infectious or inflammatory condition leading to activity in lymphatic tissues. The emergence of PET-CT has improved the confidence and accuracy of PET imaging because it can delineate clear anatomic relationships in areas with FDG activity. Increasingly, PET-CT is replacing dedicated PET devices in the United States and currently almost all of the new units being sold are combined PET-CT machines. Other advantages of PET-CT are its ability to perform both tests at a single convenient time point, and better-resolution images are provided as compared to fused images. Due to its recent emergence, clinical outcome using long-term survival data are not available for patients who were staged using PET-CT.
1.2.4 PET in Staging GI Cancers At this point, PET is only routinely done for staging prior to surgery in GI oncology patients with esophageal cancer. For other GI cancers, PET is regularly employed as a problem-solving tool to assist in staging when other clinical or imaging studies suggest that the patient may have more widespread disease. The role for PET scans in staging esophageal cancer is derived from multiple studies demonstrating changes in the clinical decision in patients planned for surgical intervention (Flamen et al. 2000; Kato et al. 2005; van Westreenen et al. 2004). As esophagectomy has an operative mortality of 4–10%, avoiding surgical intervention in patients with distant metastasis who will not benefit from surgery is paramount (Enzinger and Mayer 2003). However, PET scans are noted to be inferior to endoscopic ultrasound (EUS) in local and regional lymph node (LN) staging with a sensitivity of 51% and specificity of 84%. Sensitivity for PET in detecting distant metastasis is 67% and specificity of 97% (van Westreenen et al. 2004). PET is regularly used in conjunction with CT scans and endoscopic US for staging esophageal cancer. PET-CT has been shown to improve sensitivity, specificity, and accuracy in staging esophageal cancer patients. Recent data show a sensitivity of 93.9%, specificity of 92%, and accuracy of 92% in patients with locally advanced squamous esophageal cancer (Yuan et al. 2006). In most of the recent clinical studies, PET can detect unsuspected metastatic
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disease in 15–20% of patients, consequently changing the management approach to those patients (Flamen et al. 2000; Kato et al. 2005; van Westreenen et al. 2004). Staging of gastric carcinoma using PET is complicated by the high physiologic uptake of FDG in normal gastric mucosa. Sensitivity of primary tumors varies from 58 to 94% with specificity of 78–100% (Dassen et al. 2009). The wide ranges of sensitivity and specificity may be related to the location and tumor histology. Proximal gastric cancers behave like esophageal cancer and are easily detected with PET while tumors in the distal stomach have a low sensitivity. Tumor histology can also affect the PET sensitivity; tumors with diffuse subtype and mucinous adenocarcinoma have a low sensitivity due to the small concentration of active cancer cells compared to its background. Up to 30% of gastric cancers may not be assessed with PET (Ott et al. 2008; Stahl et al. 2003). Overall, locoregional staging using PET is poor with a sensitivity of 28% as compared to CT scan with a sensitivity of 68%, but with a higher specificity of 96% (Dassen et al. 2009). Limited studies done on PET for gastric cancer distant staging shows a sensitivity of 67–85% and specificity of 74–88% (Yoshioka et al. 2003). PET has a limited role in the initial staging of patients with colorectal cancer and currently is not routinely used if metastatic disease is not suspected based on CT or other studies. The benefit and risk ratio for surgical intervention in colorectal cancer is high and the morbidity is low. Additionally, precancerous adenomatous polyps also demonstrate higher FDG uptake and PET is not sensitive for locoregional staging. It is a useful test for patients with potentially resectable hepatic metastasis and in those with recurrent disease. PET can detect additional systemic metastasis and can be helpful in preventing futile laparotomies. Figure 1.2 illustrates
Fig. 1.2 Fused positron emission tomography/computed tomography (PET/CT) scans (a, c) and PET alone (b, d) of a patient with a lesion seen in the rectum (images c, d) and in the liver (images a, b). Because of an elevated creatinine the routine CT scan was done without contrast and did not show this liver lesion, although a larger lesion in the dome was visualized (not shown)
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a patient with recurrent rectal cancer with three liver lesions. The sensitivity of PET for hepatic lesions is 92% and specificity is high at 96% while CT has a sensitivity of 83% and specificity of 84% (Wiering et al. 2005). PET also has a sensitivity of 91% and specificity of 98% in detecting extrahepatic lesions as compared to 61 and 91% for CT. In a number of clinical studies, PET has been shown to alter therapeutic management in 20–32% of patients with potentially resectable metastatic disease. These changes include avoidance of surgery, initiation of palliative chemotherapy, or change in the extent of surgical interventions. PET is not helpful in detecting lesions less than 1 cm and in patients with peritoneal carcinomatosis. A recent randomized trial was done to compare the outcome in patients with potentially resectable liver metastases. Patients underwent routine staging with or without PET prior to planned surgery. Overall PET was found to decrease the number of futile surgeries by 38%. With routine CT evaluation of 75 patients who went to surgery, 34 (45%) were found to have unresectable disease or recurred within 6 months. When PET was included 21 of 75 (28%) patients had unnecessary surgery (Wiering et al. 2005; Ruers et al. 2009). Compared to the use of dedicated PET devices, data on the utilization of PET-CT are evolving; PET-CT in most clinical scenarios leads to a change in patient management in 11–21% (Lubezky et al. 2007; Rappeport et al. 2007; Selzner et al. 2004). In pancreatic cancer, even pancreaticoduodenectomy (Whipple procedure) cures only a tiny fraction of patients. This procedure has a high surgical and postoperative mortality of up to about 5%. Overall evidence shows that PET can be beneficial, mostly by avoiding futile surgeries. PET’s sensitivity is 91% and its specificity is 86% (BCBS 2000). PET is also a useful tool in the initial work-up of pancreatic masses of unknown origin (Heinrich et al. 2005; Sperti et al. 2007). Masses with increased FDG retention are more likely to be cancer, but inflammatory conditions can also be visualized with PET. On the other hand, PET can miss some mucinous tumors and those with extensive fibrosis. Table 1.1 summarizes the sensitivity and specificity of PET scan in staging for different GI cancers. In liver and hepatobiliary cancers, FDG-PET is not helpful in staging and surveillance. Hepatocellular cancer (HCC) shows poor uptake of FDG due to a high level of glucose6-phosphatase, which is responsible for dephosphorylating 18F-FDG (Garcea et al. 2009). Only 30–60% of primary HCC have avid FDG uptake (Okazumi et al. 1992). PET still Table 1.1 Sensitivity and specificity of positron emission tomography (PET) scan in gastrointestinal cancers Site Staging Sensitivity Specificity References Esophagus
Locoregional Distant
51% (34–69) 67% (58–76)
84% (76–91) 97% (90–100)
van Westreenen et al. (2004)
Stomach
Locoregional Distant
27.5% (18–46) 67–85%
96% (91–100) 74–88%
Dassen et al. (2009)
Liver
Whole body
61%
NA
Park et al. (2008)
Colorectum
Hepatic lesion Extrahepatic
88% (85–95) 92%
96% 95%
Wiering et al. (2005)
Colon
Whole body
85%
90%
Wiering et al. (2005)
Pancreas
Whole body
91%
86%
BCBS (2000)
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may be useful in patients at risk for HCCs who have a rising alpha-fetoprotein. In such patients liver scarring and regeneration may hide a growing tumor on routine CT and MRI. A positive PET scan may help direct biopsies, but a negative scan does not rule out cancer. A recent Korean study shows that FDG-PET has a sensitivity of 61%, which could be improved to 83% using dual tracer imaging using 11C-acetate (Park et al. 2008). However, performance of PET remained poor in small and well-differentiated tumors. Future studies with dual tracer imaging may prove to be valuable in PET for primary hepatobiliary tumors.
1.3 Monitoring Response to Treatment The recent advances in targeted therapy for cancer have led to individualized therapy for cancer patients based on molecular and other biomarkers. Monitoring such therapies itself may affect the clinical outcome. Normal CT and MRI scans measure anatomic changes to current treatment and such changes have been monitored through either the World Health Organization (WHO) classification or response evaluation criteria in solid tumors (RECIST) (Miller et al. 1981; Therasse et al. 2000). WHO classification defines tumor measurement by utilizing the product of two perpendicular diameters (bidimensional) as criteria for measurement. It groups response into four different categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Complete radiologic disappearance without any new lesions was considered CR. A 50% decrease in size is considered PR while a 30% increase in size was deemed progression of disease. Anything that does not meet the above criteria is considered SD (Miller et al. 1981). RECIST uses unidimensional measurement to simplify the monitoring and has been validated in recent clinical studies (Therasse et al. 2006). When multiple measurable tumors are noted, each measurement is added. Response is reported as PR if there is more than a 30% decrease in unidimensional diameter and PD if more than 20% growth is noted (Therasse et al. 2000). The RECIST working group reviewed 6,500 patients and more than 18,000 lesions to find out how the criteria affect patients and overall outcome. In 2009, the group came up with RECIST 1.1, decreasing the number of maximum target lesions from 10 to 5 (five to two per organ) and defined criteria for measuring LNs using the short axis. RECIST 1.1 also adds new lesions on FDG-PET as PD, incorporating new technology to the RECIST (Eisenhauer et al. 2009). Both WHO criteria and RECIST offer simple approaches to determine anatomic size and tumor changes during a therapeutic treatment as an indicator of response. Although RECIST has been validated to correlate with clinical outcome, these responses have been correlated to neither pathologic response nor survival outcome in certain GI cancers. In pancreatic cancer, for example, use of doublet therapy produces a higher response rate than does the use of gemcitabine alone, but no difference in overall survival is noted in multiple phase III trials (Oettle et al. 2005; Rocha Lima et al. 2004). Most trials in pancreatic cancer continue to use survival as the primary endpoint. Similarly, studies demonstrate that RECIST cannot accurately demonstrate clinical
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benefit in patients with GI stromal tumors (GIST) treated with imatinib (Benjamin et al. 2007; Choi et al. 2007). Cellular degradation and reconstruction of tumor tissue is the final step in treatment, making early monitoring difficult using anatomic images. The recent use of targeted therapies has led to other cutoffs to evaluating response, since tumor shrinkage may not be seen and disease stabilization is more common. Studies of drug development now include waterfall plots where the change in tumor size at a specified time or greatest change in size may be plotted (Arnold et al. 2008; Ratain et al. 2006). Instead of categorizing tumor response to arbitrary categories, waterfall plots measure change in tumor size as a continuous variable. Patients with limited tumor growth are considered to benefit from such a treatment even in the absence of major tumor shrinkage. Further improvements in both morphologic and functional imaging are clearly needed for better monitoring of patients with GI cancers. Early treatment monitoring is crucial to avoid toxicity and the costs associated with ineffective therapy. Furthermore, improved measurements may provide for the earlier use of alternate therapies to impact clinical outcome. PET data suggest the amount of FDG uptake in tumor cells is correlated with the number of viable cancer cells. Hence, decline in FDG-PET avidity is hypothesized to represent a decrease in the number of viable cancer cells, though it might also represent a transport phenomenon. This concept has been tested for PET in early assessment of cancer treatment in esophageal, breast, and head and neck cancers (Juweid and Cheson 2006). Wahl et al. recently reported new response criteria incorporating PET for monitoring cancer treatment, naming the system PET evaluation criteria in solid tumors (PERCIST) (Wahl et al. 2009). Actual usage of PERCIST will require validation studies in GI cancer and its treatments. If further studies could refine the use of PET in monitoring and correlate its results to clinical outcome, such progress will improve the current concept of individualizing therapy.
1.3.1 Use of FDG-PET in Monitoring Early Response to Treatment 1.3.1.1 Esophageal Cancer Recent clinical trials have shown that the use of neoadjuvant chemotherapy and chemoradiotherapy for locally advanced gastroesophageal cancer improves overall survival. Monitoring early response to therapy is important in this disease since patients responding to neoadjuvant therapy have better clinical outcomes than nonresponding patients. Weber et al. studied 37 patients with locally advanced gastroesophageal cancer who received neoadjuvant chemotherapy. FDG-PET was done at baseline and on day 14 of the first cycle of chemotherapy. The percentage change in SUV was more prognostic than the absolute value of SUV. Patients with more than a 35% decrease in SUV were considered PET responders while those who had less were considered nonresponders. The two-year survival and overall survival rates of PET responders were 49% and >48 months, respectively, as compared to 9% and 20 months, respectively, for nonresponders (p = 0.04).
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The same group assessed 44 patients with locally advanced gastric cancer. A similar outcome was noted; PET responders had survival of >48 months while nonresponders had 17 months (p = 0.001) (Weber et al. 2001). Nine patients did not have PET activity in the baseline and were excluded from further analysis. Wieder et al. evaluated 27 patients with neoadjuvant chemoradiotherapy and used 30% SUV changes as criteria for PET response. PET responders had median overall survival of >38 months as compared to 18 months for nonresponders (Wieder et al. 2004). Other similar studies assessing treatment response using PET for gastroesophageal cancer are listed in Table 1.2. A multi-institutional study testing the feasibility of PET-guided therapy in gastroesophageal cancer was conducted by Lordick et al. This study enrolled 110 patients with gastroesophageal cancer and the PET scan was done at 2 weeks after induction chemotherapy was used to identify patients with metabolic response. Metabolic responders were predefined as patients with SUV decrease of more than 35% from baseline. Patients who were metabolic responders continued to receive chemotherapy for 12 weeks while nonresponders discontinued chemotherapy and immediately had surgical resection. The median overall survival for metabolic responders was not reached, whereas median overall survival for nonresponders was 25.8 months (p = 0.015) (Lordick et al. 2007). The study also demonstrated a correlation of metabolic responders and pathologic response. Major histopathologic regression (Ia or Ib) was seen in 59% of patients who were metabolic responders but no histopathologic regression was seen in PET nonresponders. These findings may enable future clinical trials to utilize PET scans to tailor multimodality therapy for gastroesophageal cancers.
1.3.1.2 Colorectal Cancer There have been several small studies assessing PET in monitoring patients with colorectal cancers. Findlay et al. monitored 18 patients with colon cancer and liver metastasis who were treated with infusional 5FU and interferon. Although the tumor–liver ratio and SUV did not correlate with treatment response at 1–2 weeks, more than 15% decrease in tumor–liver ratio at 4–5 weeks was able to predict the ultimate response as measured by CT (done later in treatment) with a sensitivity of 100% and specificity of 90% (Findlay et al. 1996). No survival data were available for responders vs. nonresponders. Most of the other small studies investigated 20–30 patients who received chemoradiotherapy for rectal cancer and investigated different PET parameters and pathologic response. Guillem et al. reported a long-term outcome of 15 patients with locally advanced rectal cancer treated with 5FU-based chemoradiotherapy and usage of PET monitoring. An SUV change from baseline and at 5 weeks after chemoradiotherapy of less than 62.5% was predictive of disease recurrence (Guillem et al. 2004). Capirci et al. conducted the largest study, which investigated 81 patients with stage II and III rectal cancer who received neoadjuvant chemoradiotherapy. PET done at 1 month after completion of CRT had a sensitivity of 45% in detecting patients with complete pathologic response and specificity of 78% (Capirci et al. 2004). PET accuracy was only 56% and there were no survival data for comparison. Table 1.3 lists recent investigations using PET for response in colorectal cancer. Overall, utilization of PET for colorectal cancer treatment is still in the preliminary stage and further experimental trials are needed to further elucidate its usage.
37
36
17
27
35
110
Weber et al. (2001)
Flammen et al. (2000)
Downey et al. (2003)
Wieder et al. (2004)
Ott et al. (2003)
Lordick et al. (2007)
Chemotherapy
Chemotherapy
Neoadjuvant chemoradiotherapy
Chemoradiotherapy
Chemoradiotherapy
Chemotherapy
Table 1.2 Treatment response using FDG-PET for gastroesophageal cancer References Treatment n
35
35
30
52
80
35
Criterion (change in SUV) (%)
>48
>48
>38
22.5
16.3
>48
Responder (months)
25.8
17
18
6.7
6.4
20
Nonresponder (months)
0.015
0.001
0.011
0.001
0.02
0.04
p Value
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Table 1.3 Treatment response using FDG-PET for colorectal cancer References Treatment Criterion n
Comments
Amthauer et al. (2004)
20
Chemoradiotherapy with regional hyperthermia
36% reduction in SUV
Correlated with tumor response
Calvo et al. (2004)
25
CRT
SUV max change
SUV max correlated to survival at 3 years
Capirci et al. (2004)
81
CRT
Five point visual scale
Sensitivity = 45% Specificity = 79%
DimitrakopoulouStrauss et al. (2003)
28
FOLFOX chemotherapy
SUV not helpful
Fractal dimension of time activity with SUV was helpful
Guillem et al. (2004)
15
CRT
62.5% change in SUV
p = 0.08
Melton (2007)
21
Neoadjuvant treatment
75% reduction in SUV
Multiple parameters including CT volume changes
1.3.1.3 GI Stromal Tumors GISTs are mesenchymal neoplasms that generally express CD117, the product of the KIT proto-oncogenes. GISTs have high metabolic activity related to increased glycolysis and have been noted to have extremely high FDG-avidity. In patients treated with imatinib, PET can show changes as early as 24 h after the treatment (Abbeele 2001). Stroobants et al. studied 21 patients with sarcomas treated with imatinib and found that PET responders (SUV change >25%) after eight days of treatment had longer progression-free survival compared to nonresponders (92 vs. 12% at 1 year p = 0.001) (Stroobants et al. 2003). Antoch et al. studied 20 patients with advanced GIST and demonstrated that PET-CT correctly characterized the ultimate tumor response in 95% at 1 month as compared to 44% using CT scan (Antoch et al. 2004). In these limited studies, combining both morphologic and functional imaging provides additional information in patients with advanced GIST. For a variety of reasons, RECIST used in monitoring systemic treatment for GIST does not correlate well with clinical outcome. These include actual enlargement of tumors with successful therapy (related to cystic change) and subsequent long delays in achieving actual shrinkage. Choi et al. reviewed 40 patients with metastatic GISTs treated with imatinib and proposed newer criteria including both anatomic and tumor density criteria to improve the sensitivity of monitoring patients. The group demonstrated that a 10% decrease in unidimensional tumor size and 15% decrease in tumor density can better predict time to tumor progression than RECIST criteria (Choi et al. 2007). This was further validated by an additional 58 patients treated with imatinib in advanced GIST patients (Benjamin et al. 2007). Since newer CT criteria have similar findings compared with PET in advanced
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GIST patients, the relative merits of PET are unclear. But in patients with borderline resectable GIST and in patients with extensive tumor burden, early assessment of therapy with PET may provide an earlier opportunity to offer alternative therapy in these patients.
1.4 Surveillance 1.4.1 Surveillance After Potentially Curative Resection The role of surveillance studies in patients with resected cancer is to detect early recurrences of the original disease, which may be curatively resected, to detect systemic recurrence, which may benefit from drug therapy while metastatic burden is still relatively small, and to detect new primary cancers, which are amenable to curative resection. These simple goals must be kept in mind when choosing the best evaluation scheme for following such patients, particularly for said middle group. Few data exist to demonstrate that the early detection of asymptomatic, advanced cancer leads to significant improvement in survival, in GI or other solid malignancies. However, passive monitoring, especially without radiographic surveillance, is often difficult to explain to patients. Colorectal cancer surveillance has been found to be useful in some studies because patients may develop metastatic disease, particularly to the liver or lungs, which is amenable to resection for cure. Local recurrence in the bowel or second cancers in the colon may also be detected and these can also be removed with curative intent. Standard guidelines now indicate that CT evaluation of the chest and abdomen be done yearly for the first 3 years after resection (Desch et al. 2005). This guideline is based on three separate metaanalyses, which demonstrated that CT surveillance produced a 20–33% decrease in death rates (Figueredo et al. 2003; Jeffery et al. 2002; Renehan et al. 2002). A study by Chau et al. (2004) demonstrated that CT scans complemented testing for carcinoembryonic antigen (CEA). While the optimal scheme for surveillance continues to evolve, physicians are generally adopting a reasonable scheme to detect treatable, recurrent disease. Future studies may also examine the use of PET combined with routine CT in the surveillance of patients with resected colorectal cancer. One small study randomized 130 patients to routine imaging, which included US every 3 months, chest X-ray every 6 months and abdominal CT at 9 and 15 months. To this series of tests, the investigators added PET (not PET/CT) at 9 and 15 months after resection (Sobhani et al. 2008). Patients in the PET group had recurrence detected earlier (12.1 ± 3.6 months) than in the control group (15.4 ± 4.9 months) (p = 0.01). The patients with recurrence in the PET group underwent surgery with curative intent in 10 of 23 cases while only 2 of 21 had such surgery after routine evaluation (p < 0.01). Further study of this approach is warranted. The role of imaging in the routine surveillance after resection of esophageal, gastric, biliary, and pancreatic cancers is not well defined since there is lack of objective data. For gastric cancer, the National Comprehensive Cancer Network (NCCN) guidelines only suggest imaging when clinically indicated. On the other hand, the NCCN guidelines suggest
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Fig. 1.3 CT scan of a patient with recently diagnosed large gastric gastrointestinal stromal tumors (GIST) and liver metastases (a). The patient underwent resection of the stomach lesion due to bleeding and was then started on imatinib. A repeat CT scan about 11 months later (b) shows that the largest lesion has remained stable in size, but decreased in density and other low-density lesions have become apparent elsewhere in the liver consistent with a response to treatment
that pancreatic cancer patients, after potentially curative resections, may have CT scans every 3–6 months for 2 years and then annually. Given the low likelihood that any detectable disease would be amenable to surgery with curative intent, this approach is expected to produce little clinical benefit. Patients with extensive disease metastases not eligible for curative approaches, no longer need to have other follow-up tests. For example, patients with extensive liver metastases may continue to have regular CT scans and CEA levels drawn to monitor treatment response, but tests directed at finding new primary cancers, such as colonoscopies, are no longer necessary. Similarly, patients with other life-limiting diseases, be they cardiac dysfunction, severe chronic obstructive lung disease, dementia, or another metastatic cancer will not benefit from surveillance for their cancers and do not require extensive testing with imaging or serum markers (Fig. 1.3).
1.5 Summary Routine and innovative imaging approaches are used for screening, diagnosis and staging, monitoring treatment, and surveillance in GI cancers. While screening endoscopy has been the standard for diagnosing most GI tumors, noninvasive CT colonography has evolved and is beginning to find routine use in practice. The sensitivity and specificity of CT colonography are 93% (73–98%) and 97% (95–99%), respectively, for lesions >1 cm. The main limitation for CT colonography is that an abnormal CT colonography study mandates colonoscopy. Further testing in the elderly group and refinement in technology would make CT colonography more useful in general practice.
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For diagnosis and staging, the CT scan has been the backbone of imaging over the last 30 years. Functional imaging modalities, such as PET scans, are now employed as an added tool to assist in the diagnosis and staging of GI cancers. PET helps detect more widespread disease so futile surgical interventions can be avoided. In most of the recent clinical studies, PET can detect unsuspected metastatic disease in 15–20% of esophageal cancer patients, consequently changing the management approach to those patients. These changes include avoidance of surgery or initiation of palliative chemotherapy. Similar findings were noted for some studies of colorectal and pancreatic cancers. With these data, PET has been adopted for routine staging for esophageal cancers and data are evolving in other GI cancers. Clinical trials data using functional imaging for early treatment monitoring for GI cancers are limited. The best data are in esophageal cancer, where a multi-institutional study showed that PET done at 2 weeks after induction chemotherapy could be used to identify patients with metabolic response. The PET responders had improvement in overall survival and pathologic response at the time of surgery. Another area of utility for early treatment monitoring could be in patients with borderline resectable GIST with extensive tumor burden. PET may provide an earlier opportunity to offer alternative therapy in these patients. Future clinical trials using functional imaging may enable clinicians to provide rapid adjustments to therapy for each patient. The role of surveillance in patients with resected cancer is to detect early recurrence, which is amenable to curative resections. In three separate meta-analyses, CT surveillance for colorectal cancer patients produced a 20–33% improvement in overall survival. CT scans complement testing with CEA. Hence, for high-risk patients with stage II and III colorectal cancer who underwent surgical resection, an annual CT, along with regular serum CEA and colonoscopy is recommended. PET CT may be more useful in this setting; however, data are evolving and further studies using PET CT in surveillance are warranted. Ultimately, the proper application of all available imaging technology will render improved clinical outcomes in GI cancer patients.
References van den Abbeele AD for the GIST Collaborative PET Study Group (Dana-Farber Cancer Institute, OHSU, Helsinki University Central Hospital, Turku University Central Hospital, Novartis Oncology (2001) F18-FDG-PET provides early evidence of biological response to STI571 in patients with malignant gastrointestinal stromal tumors (GIST). Proc Am Soc Clin Oncol 20:362 Aloj L, Caraco C, Jagoda E, Eckelman WC, Neumann RD (1999) Glut-1 and hexokinase expression: relationship with 2-fluoro-2-deoxy-D-glucose uptake in A431 and T47D cells in culture. Cancer Res 59:4709–4714 Amthauer H, Denecke T, Rau B, Hildebrandt B, Hunerbein M, Ruf J, Schneider U, Gutberlet M, Schlag PM, Felix R, Wust P (2004) Response prediction by FDG-PET after neoadjuvant radiochemotherapy and combined regional hyperthermia of rectal cancer: correlation with endorectal ultrasound and histopathology. Eur J Nucl Med Mol Imaging 31:811–819
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Antoch G, Kanja J, Bauer S, Kuehl H, Renzing-Koehler K, Schuette J, Bockisch A, Debatin JF, Freudenberg LS (2004) Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 45: 357–365 Arnold D, Hinke A, Reinacher-Schick AC, Schmiegel W, Graeven U, Kubicka S, Weikersthal LF, Moosmann N, Schmoll H, Heinenam V (2008) Waterfall plot analysis of XELOX or XELIRI with cetuximab or bevacizumab in patients with advanced colorectal cancer (ACRC): combined analysis of two randomized first-line phase II trials of the AIO CRC study group. 2008 ASCO annual meeting. J Clin Oncol 26: (May 20 suppl; abstr 4067) Avril NE, Weber WA (2005) Monitoring response to treatment in patients utilizing PET. Radiol Clin North Am 43:189–204 Avril N, Sassen S, Schmalfeldt B, Naehrig J, Rutke S, Weber WA, Werner M, Graeff H, Schwaiger M, Kuhn W (2005) Prediction of response to neoadjuvant chemotherapy by sequential F-18fluorodeoxyglucose positron emission tomography in patients with advanced-stage ovarian cancer. J Clin Oncol 23:7445–7453 Benjamin RS, Choi H, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, Charnsangavej C (2007) We should desist using RECIST, at least in GIST. J Clin Oncol 25:1760–1764 Blue Cross Blue Shield (2000) FDG PET Positron Emission Tomography in Pancreas [Brochure]. Chicago Bombardieri E, Aliberti G, de Graaf C, Pauwels E, Crippa F (2001) Positron emission tomography (PET) and other nuclear medicine modalities in staging gastrointestinal cancer. Semin Surg Oncol 20:134–146 Calvo FA, Domper M, Matute R, Martinez-Lazaro R, Arranz JA, Desco M, Alvarez E, Carreras JL (2004) 18F-FDG positron emission tomography staging and restaging in rectal cancer treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 58:528–535 Capirci C, Rubello D, Chierichetti F, Crepaldi G, Carpi A, Nicolini A, Mandoliti G, Polico C (2004) Restaging after neoadjuvant chemoradiotherapy for rectal adenocarcinoma: role of F18FDG PET. Biomed Pharmacother 58:451–457 Chau I, Allen MJ, Cunningham D, Norman AR, Brown G, Ford HE, Tebbutt N, Tait D, Hill M, Ross PJ, Oates J (2004) The value of routine serum carcino-embryonic antigen measurement and computed tomography in the surveillance of patients after adjuvant chemotherapy for colorectal cancer. J Clin Oncol 22:1420–1429 Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, Benjamin RS (2007) Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 25:1753–1759 Dassen AE, Lips DJ, Hoekstra CJ, Pruijt JF, Bosscha K (2009) FDG-PET has no definite role in preoperative imaging in gastric cancer. Eur J Surg Oncol 35:449–455 Desch CE, Benson AB III, Somerfield MR, Flynn PJ, Krause C, Loprinzi CL, Minsky BD, Pfister DG, Virgo KS, Petrelli NJ (2005) Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 23:8512–8519 Dimitrakopoulou-Strauss A, Strauss LG, Rudi J (2003) PET-FDG as predictor of therapy response in patients with colorectal carcinoma. Q J Nucl Med 47:8–13 Downey RJ, Akhurst T, Ilson D, Ginsberg R, Bains MS, Gonen M, Koong H, Gollub M, Minsky BD, Zakowski M, Turnbull A, Larson SM, Rusch V (2003) Whole body 18FDG-PET and the response of esophageal cancer to induction therapy: results of a prospective trial. J Clin Oncol 21:428–432 Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
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17
Enzinger PC, Mayer RJ (2003) Esophageal cancer. N Engl J Med 349:2241–2252 Facey K, Bradbury I, Laking G, Payne E (2007) Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers. Health Technol Assess 11:iii–iv, xi-267 Figueredo A, Rumble RB, Maroun J, Earle CC, Cummings B, McLeod R, Zuraw L, Zwaal C (2003) Follow-up of patients with curatively resected colorectal cancer: a practice guideline. BMC Cancer 3:26 Findlay M, Young H, Cunningham D, Iveson A, Cronin B, Hickish T, Pratt B, Husband J, Flower M, Ott R (1996) Noninvasive monitoring of tumor metabolism using fluorodeoxyglucose and positron emission tomography in colorectal cancer liver metastases: correlation with tumor response to fluorouracil. J Clin Oncol 14:700–708 Flamen P, Lerut A, Van Cutsem E, De Wever W, Peeters M, Stroobants S, Dupont P, Bormans G, Hiele M, De Leyn P, Van Raemdonck D, Coosemans W, Ectors N, Haustermans K, Mortelmans L (2000) Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma [in process citation]. J Clin Oncol 18:3202–3210 Fletcher JW, Djulbegovic B, Soares HP, Siegel BA, Lowe VJ, Lyman GH, Coleman RE, Wahl R, Paschold JC, Avril N, Einhorn LH, Suh WW, Samson D, Delbeke D, Gorman M, Shields AF (2008) Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med 49:480–508 Garcea G, Ong SL, Maddern GJ (2009) The current role of PET-CT in the characterization of hepatobiliary malignancies. HPB (Oxford) 11:4–17 Gjedde A, Diemer NH (1983) Autoradiographic determination of regional brain glucose content. J Cereb Blood Flow Metab 3:303–310 Guillem JG, Moore HG, Akhurst T, Klimstra DS, Ruo L, Mazumdar M, Minsky BD, Saltz L, Wong WD, Larson S (2004) Sequential preoperative fluorodeoxyglucose-positron emission tomography assessment of response to preoperative chemoradiation: a means for determining longterm outcomes of rectal cancer. J Am Coll Surg 199:1–7 Halligan S, Altman DG, Taylor SA, Mallett S, Deeks JJ, Bartram CI, Atkin W (2005) CT colonography in the detection of colorectal polyps and cancer: systematic review, meta-analysis, and proposed minimum data set for study level reporting. Radiology 237:893–904 Heinrich S, Goerres GW, Schafer M, Sagmeister M, Bauerfeind P, Pestalozzi BC, Hany TF, von Schulthess GK, Clavien PA (2005) Positron emission tomography/computed tomography influences on the management of resectable pancreatic cancer and its cost-effectiveness. Ann Surg 242:235–243 Iannaccone R, Catalano C, Mangiapane F, Murakami T, Lamazza A, Fiori E, Schillaci A, Marin D, Nofroni I, Hori M, Passariello R (2005) Colorectal polyps: detection with low-dose multidetector row helical CT colonography versus two sequential colonoscopies. Radiology 237:927–937 Jeffery GM, Hickey BE, Hider P (2002) Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev CD002200 Jensch S, Bipat S, Peringa J, de Vries AH, Heutinck A, Dekker E, Baak LC, Montauban van Swijndregt AD, Stoker J (2010) CT colonography with limited bowel preparation: prospective assessment of patient experience and preference in comparison to optical colonoscopy with cathartic bowel preparation. Eur Radiol 20;146–56 Johnson CD, Chen MH, Toledano AY, Heiken JP, Dachman A, Kuo MD, Menias CO, Siewert B, Cheema JI, Obregon RG, Fidler JL, Zimmerman P, Horton KM, Coakley K, Iyer RB, Hara AK, Halvorsen RA Jr, Casola G, Yee J, Herman BA, Burgart LJ, Limburg PJ (2008) Accuracy of CT colonography for detection of large adenomas and cancers. N Engl J Med 359:1207–1217 Juweid ME, Cheson BD (2006) Positron-emission tomography and assessment of cancer therapy. N Engl J Med 354:496–507 Kato H, Miyazaki T, Nakajima M, Takita J, Kimura H, Faried A, Sohda M, Fukai Y, Masuda N, Fukuchi M, Manda R, Ojima H, Tsukada K, Kuwano H, Oriuchi N, Endo K (2005) The incremental effect of positron emission tomography on diagnostic accuracy in the initial staging of esophageal carcinoma. Cancer 103:148–156
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Lordick F, Ott K, Krause BJ, Weber WA, Becker K, Stein HJ, Lorenzen S, Schuster T, Wieder H, Herrmann K, Bredenkamp R, Hofler H, Fink U, Peschel C, Schwaiger M, Siewert JR (2007) PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol 8:797–805 Lubezky N, Metser U, Geva R, Nakache R, Shmueli E, Klausner JM, Even-Sapir E, Figer A, BenHaim M (2007) The role and limitations of 18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan and computerized tomography (CT) in restaging patients with hepatic colorectal metastases following neoadjuvant chemotherapy: comparison with operative and pathological findings. J Gastrointest Surg 11:472–478 McAndrew MR, Saba AK (1999) Efficacy of routine preoperative computed tomography scans in colon cancer. Am Surg 65:205–208 Melton GB, Lavely WC, Jacene HA, Schulick RD, Choti MA, Wahl RL, Gearhart SL (2007) Efficacy of preoperative combined 18-fluorodeoxyglucose positron emission tomography and computed tomography for assessing primary rectal cancer response to neoadjuvant therapy. J Gastrointest Surg 11:961–969; discussion 969 Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214 Minn H, Zasadny KR, Quint LE, Wahl RL (1995) Lung cancer: reproducibility of quantitative measurements for evaluating 2-[F-18]-fluoro-2-deoxy-D-glucose uptake at PET. Radiology 196:167–173 Nagata K, Okawa T, Honma A, Endo S, Kudo SE, Yoshida H (2009) Full-laxative versus minimum-laxative fecal-tagging CT colonography using 64-detector row CT: prospective blinded comparison of diagnostic performance, tagging quality, and patient acceptance. Acad Radiol 16:780–789 National Oncology PET Registry (NOPR) (2009) Cancers and indications eligible for entry in the NOPR. http://www.cancerpetregistryorg. Accessed 10 Aug 2009 Oda M, Kitasaka T, Mori K, Suenaga Y, Takayama T, Takabatake H, Mori M, Natori H, Nawano S (2009) Digital bowel cleansing free colonic polyp detection method for fecal tagging CT colonography. Acad Radiol 16:486–494 Oettle H, Richards D, Ramanathan RK, van Laethem JL, Peeters M, Fuchs M, Zimmermann A, John W, Von Hoff D, Arning M, Kindler HL (2005) A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 16:1639–1645 Okazumi S, Isono K, Enomoto K, Kikuchi T, Ozaki M, Yamamoto H, Hayashi H, Asano T, Ryu M (1992) Evaluation of liver tumors using fluorine-18-fluorodeoxyglucose PET: characterization of tumor and assessment of effect of treatment. J Nucl Med 33:333–339 Ott K, Fink U, Becker K, Stahl A, Dittler HJ, Busch R, Stein H, Lordick F, Link T, Schwaiger M, Siewert JR, Weber WA (2003) Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: results of a prospective trial. J Clin Oncol 21:4604–4610 Ott K, Herrmann K, Krause BJ, Lordick F (2008) The value of PET imaging in patients with localized gastroesophageal cancer. Gastrointest Cancer Res 2:287–294 Park JW, Kim JH, Kim SK, Kang KW, Park KW, Choi JI, Lee WJ, Kim CM, Nam BH (2008) A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma. J Nucl Med 49:1912–1921 Pasanen PA, Eskelinen M, Partanen K, Pikkarainen P, Penttila I, Alhava E (1992) A prospective study of the value of imaging, serum markers and their combination in the diagnosis of pancreatic carcinoma in symptomatic patients. Anticancer Res 12:2309–2314 Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3:1–7 Rappeport ED, Loft A, Berthelsen AK, von der Recke P, Larsen PN, Mogensen AM, Wettergren A, Rasmussen A, Hillingsoe J, Kirkegaard P, Thomsen C (2007) Contrast-enhanced FDG-PET/
1 Imaging in Gastrointestinal Cancer
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CT vs. SPIO-enhanced MRI vs. FDG-PET vs. CT in patients with liver metastases from colorectal cancer: a prospective study with intraoperative confirmation. Acta Radiol 48:369–378 Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, Gore M, Desai AA, Patnaik A, Xiong HQ, Rowinsky E, Abbruzzese JL, Xia C, Simantov R, Schwartz B, O’Dwyer PJ (2006) Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505–2512 Renehan AG, Egger M, Saunders MP, O’Dwyer ST (2002) Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials. BMJ 324:813 Rex DK, Rahmani EY, Haseman JH, Lemmel GT, Kaster S, Buckley JS (1997) Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice. Gastroenterology 112:17–23 Rocha Lima CM, Green MR, Rotche R, Miller WH Jr, Jeffrey GM, Cisar LA, Morganti A, Orlando N, Gruia G, Miller LL (2004) Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22:3776–3783 Rockey DC, Koch J, Yee J, McQuaid KR, Halvorsen RA (2004) Prospective comparison of aircontrast barium enema and colonoscopy in patients with fecal occult blood: a pilot study. Gastrointest Endosc 60:953–958 Rosman AS, Korsten MA (2007) Meta-analysis comparing CT colonography, air contrast barium enema, and colonoscopy. Am J Med 120(203–210):e204 Ruers TJ, Wiering B, van der Sijp JR, Roumen RM, de Jong KP, Comans EF, Pruim J, Dekker HM, Krabbe PF, Oyen WJ (2009) Improved selection of patients for hepatic surgery of colorectal liver metastases with 18F-FDG PET: a randomized study. J Nucl Med 50:1036–1041 Selzner M, Hany TF, Wildbrett P, McCormack L, Kadry Z, Clavien PA (2004) Does the novel PET/CT imaging modality impact on the treatment of patients with metastatic colorectal cancer of the liver? Ann Surg 240:1027–1034; discussion 1026–1035 Sobhani I, Tiret E, Lebtahi R, Aparicio T, Itti E, Montravers F, Vaylet C, Rougier P, Andre T, Gornet JM, Cherqui D, Delbaldo C, Panis Y, Talbot JN, Meignan M, Le Guludec D (2008) Early detection of recurrence by (18)FDG-PET in the follow-up of patients with colorectal cancer. Br J Cancer 98:875–880 Sperti C, Bissoli S, Pasquali C, Frison L, Liessi G, Chierichetti F, Pedrazzoli S (2007) 18-Fluorodeoxyglucose positron emission tomography enhances computed tomography diagnosis of malignant intraductal papillary mucinous neoplasms of the pancreas. Ann Surg 246:932–937; discussion 937–939 Stahl A, Ott K, Weber WA, Becker K, Link T, Siewert JR, Schwaiger M, Fink U (2003) FDG PET imaging of locally advanced gastric carcinomas: correlation with endoscopic and histopathological findings. Eur J Nucl Med Mol Imaging 30:288–295 Stroobants S, Goeminne J, Seegers M, Dimitrijevic S, Dupont P, Nuyts J, Martens M, van den Borne B, Cole P, Sciot R, Dumez H, Silberman S, Mortelmans L, van Oosterom A (2003) 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer 39:2012–2020 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216 Therasse P, Eisenhauer EA, Buyse M (2006) Update in methodology and conduct of cancer clinical trials. Eur J Cancer 42:1322–1330 Tohma T, Okazumi S, Makino H, Cho A, Mochiduki R, Shuto K, Kudo H, Matsubara K, Gunji H,
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Ochiai T (2005) Relationship between glucose transporter, hexokinase and FDG-PET in esophageal cancer. Hepatogastroenterology 52:486–490 van Westreenen HL, Westerterp M, Bossuyt PM, Pruim J, Sloof GW, van Lanschot JJ, Groen H, Plukker JT (2004) Systematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer. J Clin Oncol 22:3805–3812 Wahl RL, Jacene H, Kasamon Y, Lodge MA (2009) From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 50(Suppl 1):122S–150S Warburg O (1956) On the origin of cancer cells. Science 123:309–314 Weber WA, Ziegler SI, Thodtmann R, Hanauske AR, Schwaiger M (1999) Reproducibility of metabolic measurements in malignant tumors using FDG PET. J Nucl Med 40:1771–1777 Weber WA, Ott K, Becker K, Dittler HJ, Helmberger H, Avril NE, Meisetschlager G, Busch R, Siewert JR, Schwaiger M, Fink U (2001) Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 19:3058–3065 Wieder HA, Brucher BL, Zimmermann F, Becker K, Lordick F, Beer A, Schwaiger M, Fink U, Siewert JR, Stein HJ, Weber WA (2004) Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 22:900–908 Wiering B, Krabbe PF, Jager GJ, Oyen WJ, Ruers TJ (2005) The impact of fluor-18-deoxyglucosepositron emission tomography in the management of colorectal liver metastases. Cancer 104:2658–2670 Yoshioka T, Yamaguchi K, Kubota K, Saginoya T, Yamazaki T, Ido T, Yamaura G, Takahashi H, Fukuda H, Kanamaru R (2003) Evaluation of 18F-FDG PET in patients with advanced, metastatic, or recurrent gastric cancer. J Nucl Med 44:690–699 Yuan S, Yu Y, Chao KS, Fu Z, Yin Y, Liu T, Chen S, Yang X, Yang G, Guo H, Yu J (2006) Additional value of PET/CT over PET in assessment of locoregional lymph nodes in thoracic esophageal squamous cell cancer. J Nucl Med 47:1255–1259
Interventional Gastrointestinal Oncology
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Jennifer Chennat and Irving Waxman
2.1 Endoscopic Mucosal Resection Endoscopic mucosal resection (EMR), initially developed in Japan to treat early gastric cancer, has evolved into a minimally invasive alternative treatment approach for early cancers throughout the upper and lower gastrointestinal tract. This endoscopic technique involves removal of affected mucosal tissue, in most cases with the use of preresection saline injection lifting of the target lesion to separate it from the submucosal layer. The lesion is most often removed with an endoscopic snare that applies electrocautery. The advantage of EMR is the added information provided by deeper en-bloc resection specimens for histological analysis. The standard treatment of Barrett’s esophagus (BE) with high-grade dysplasia (HGD) has been esophagectomy, due to the previously estimated 40% pooled risk of harboring occult invasive adenocarcinoma (Ferguson and Naunheim 1997; Pellegrini and Pohl 2000). However, more recent analysis of the literature points toward a much lower rate of invasive cancer at 12% (Konda et al. 2008). Intramucosal cancer (IMC) in the setting of BE has also traditionally been treated by esophagectomy, despite a relatively low incidence of lymph node metastasis of less than 1%, associated with noninvasive, T1a disease (Buskens et al. 2004; Pech et al. 2008; Stein et al. 2005). The use of EMR to treat focal areas of BE with HGD/IMC has been reported in several prior studies. However, focal resection solely of neoplastic areas has been associated with a high rate of synchronous and recurrent lesions noted by various groups, ranging from 14 to 47%, and increasing with longer observation times (Ell et al. 2000; Nijhawan and Wang 2000; May et al. 2002a, b; Pech et al. 2003; Larghi et al. 2005; Mino-Kenudson et al. 2005). With these issues in mind, circumferential endoscopic resection of BE has been utilized with promising results by
J. Chennat Assistant Professor of Medicine, The Center for Endoscopic Research & Therapeutics (CERT), Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, 5758 S. Maryland Avenue, MC 9028, Chicago, IL 60637, USA e-mail:
[email protected] I. Waxman () Center for Endoscopic Research and Therapeutics (CERT), University of Chicago Medical Center, 5758 S. Maryland Avenue, MC 9028, Chicago, IL 60637, USA e-mail:
[email protected] C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_2, © Springer-Verlag Berlin Heidelberg 2011
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select groups with the curative intention to eradicate all Barrett’s epithelium thereby reducing or eliminating metachronous lesion development (Peters et al. 2006; Seewald et al. 2003; Giovannini et al. 2004; Larghi et al. 2007). EMR is the only endoscopic modality which serves the dual function of curative potential and provision of more accurate histological staging. In our institution, EMR resulted in a 45% rate of upstaging or downstaging of final BE neoplasia histology when comparing pre-EMR biopsies with resection specimens (Chennat et al. 2009) (Figs. 2.1 and 2.2). With respect to esophageal squamous cell carcinoma (SCC), EMR has been shown to have similar rates of survival in patients with m3 or sm1 disease as compared to those who underwent surgery (Kodama and Kakegawa 1998). Thus, EMR may be an acceptable alternative particularly in patients at higher surgical risk (Shimizu et al. 2002). Follow-up intervals for surveillance after esophageal EMR have not been clearly defined to date, and should be performed in a protocol fashion. The absolute indications for gastric EMR include well or moderately differentiated mucosal adenocarcinoma without ulceration or with an ulcer scar smaller than 2 cm for
Fig. 2.1 Long segment Barrett’s esophagus with high-grade dysplasia
Fig. 2.2 Postendoscopic mucosal resection (EMR) of long segment Barrett’s esophagus with high-grade dysplasia
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superficially elevated lesions. These lesions have a negligible risk of lymph node metastasis. Poorly differentiated or signet ring cell morphology are contraindications to EMR regardless of lesion size (Larghi and Waxman 2007). EMR has also been applied to early neoplastic gastric lesions, with acceptable long-term outcomes, demonstrating a 1.9% recurrence rate in a pooled series analysis of documented complete resections (Kojima et al. 1998). However, the recurrence rate has been noted to be 18% in another series when incomplete resection occurred (Ono et al. 2001). The use of EMR for neoplastic duodenal lesions has been reported with less frequency in the literature. Outcomes of larger series have demonstrated complete resection without major complications in the setting of duodenal nonampullary adenomas with HGD or carcinoma (Ahmad et al. 2002; Oka et al. 2003) (Figs. 2.3 and 2.4). The data on endoscopic removal of ampullary early neoplastic adenomatous lesions generally recommend the assessment of these lesions with endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography to exclude invasive or biliary/pancreatic ductal involvement (Binmoeller et al. 1993). Long-term success rates of EMR of these lesions have been documented in the range of 70–80%, but careful endoscopic surveillance is still mandated for follow-up (Catalano et al. 2004). Colonic polypoid and nonpolypoid lesions with evidence of HGD or intramucosal carcinoma have been shown by various studies to be successfully treated by EMR technique, with recurrence rates ranging from zero to 15% (Caputi Iambrenghi et al. 2009; Kudo 1993;
Fig. 2.3 Duodenal adenoma
Fig. 2.4 Postendoscopic mucosal resection of duodenal adenoma
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Fig. 2.5 Tubulo-villous adenoma in the rectum
Fig. 2.6 Postendoscopic mucosal resection of tubulo-villous adenoma in the rectum
Kudo et al. 2000) (Figs. 2.5 and 2.6). Lateral spreading tumors of the colorectum, which have different clinicopathologic features, have also been successfully addressed by EMR techniques (Hurlstone et al. 2004; Tanaka et al. 2001). Procedure-related complications such as bleeding and even perforation in certain cases can be successfully managed endoscopically (Raju 2009).
2.2 Endoscopic Submucosal Dissection Due to concern about incomplete lesion resection via EMR, endoscopic submucosal dissection (ESD) has been developed and utilized particularly by the Japanese for more complete and extensive endoscopic resections (Figs. 2.7–2.10). Although the risk of perforation is higher with ESD vs. EMR, the safety profile and efficacy of ESD in patients with advanced age or poor performance status has been published (Hirasaki et al. 2005). ESD also has been utilized successfully in scenarios where prior EMR has been incomplete, leaving residual neoplasia in place. However, the use of ESD in locations where prior EMR has been attempted can be technically more challenging and less feasible due to tissue fibrosis formation (Yokoi et al. 2006).
2 Interventional Gastrointestinal Oncology Fig. 2.7 Intramucosal gastric cancer (T1) involving the pylorus
Fig. 2.8 Marking of desired endoscopic resection margins
Fig. 2.9 Postendoscopic submucosal dissection (ESD) with pylorus preservation
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Fig. 2.10 Surveillance endoscopy 3 months after ESD with expectant scar and no residual cancer seen
2.3 Endoscopic Ultrasound EUS and EUS-guided fine-needle aspiration (EUS-FNA) have together evolved into useful diagnostic and therapeutic modalities. Clinical management has been significantly affected by the addition of FNA technique to this procedure. The overall complication rate from EUS-FNA is less than 1% (Dye and Waxman 2002). The accuracy and direct clinical impact of EUS-FNA is largely related to the availability of on-site cytopathology services. The clinical impact of on-site cytopathology in the evaluation of EUS-FNA for suspected malignancy cases has been previously studied by our center. A confirmatory diagnosis of positive or negative malignancy status was made more frequently if on-site cytopathology interpretation was present, decreasing the likelihood of an inadequate specimen or need for repeat procedure. Resources for on-site cytopathology evaluation should be allocated by all EUS centers (Klapman et al. 2003).
2.3.1 Pancreatic Adenocarcinoma The role of EUS-FNA has become increasingly prominent in the diagnosis and treatment management of pancreatic adenocarcinoma (Figs. 2.11 and 2.12). Larger series have found that pancreatic adenocarcinoma EUS accuracy ranges from 78 to 94% for T stage disease and from 64 to 82% for N stage disease (Varadarajulu and Eloubeidi 2005). Chang et al. found that for pancreatic lesions, EUS-FNA had a sensitivity of 92%, specificity of 100%, and diagnostic accuracy of 95% for pancreatic lesions and 83, 100, and 88% for lymph nodes, respectively. Thus, with this level of accuracy, EUS-FNA peripancreatic N staging has had a direct impact on the reduction of unwarranted surgical procedures for these cancer patients, whom some authorities deem incurable by surgical resection (Chang et al. 1997). EUS-FNA confers an added advantage over computed tomography (CT)-guided FNA of pancreatic lesions regarding two aspects. Through its direct ultrasound visualization,
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Fig. 2.11 Pancreatic head mass measuring 5.1 cm visualized on endoscopic ultrasound (EUS) imaging
Fig. 2.12 EUS-guided fine needle aspiration (FNA) of pancreatic mass
EUS-FNA can safely target pancreatic lesions that are in close proximity to surrounding vascular structures. EUS also characterizes lesions considered too small to be detected by CT or magnetic resonance imaging (MRI) (Fig. 2.1). EUS-FNA offers a valuable role as a salvage diagnostic modality when CT-guided percutaneous FNA or endoscopic retrograde cholagiopancreatography (ERCP) cytology brushing samples are negative, but a strong clinical suspicion of pancreatic cancer persists (Fig. 2.2) (Gress et al. 2001).
2.3.2 Pancreatic Cystic Lesions Pancreatic mucinous cystic neoplasms have malignant potential, and therefore require a differing management algorithm, often involving surgical resection. EUS-FNA derived
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cytologic specimens in combination with cystic fluid tumor markers such as CEA (carcinoembryonic antigen) level help identify these lesions (Figs. 2.13 and 2.14). In a study which compared EUS-FNA diagnoses with final surgical pathology, FNA made an accurate diagnosis in 10/11 cases of pancreatic cystic lesions, with sensitivity and specificity for detection of malignancy of 100 and 89%, respectively, while the accuracy for identification of mucinous cystic neoplasms was 100% (Moparty et al. 2007). EUS-FNA cystic CEA levels have been purported to be the most accurate (79%) diagnostic method for mucinous cystic lesions of the pancreas (Brugge et al. 2004). A multivariate analysis study found that the strongest predictor of mucinous neoplasia is the presence of identifiable mucin, followed by a CEA level greater than 300 ng/mL. Presence of extracellular mucin in cystic fluid. The determination of cystic fluid extracellular mucin presence has also been recommended in the work-up of mucinous lesions (Shami et al. 2007). Despite the ongoing controversies surrounding which type of marker is the optimal cystic diagnostic sample, EUS-FNA still serves an integral role in obtaining pancreatic cystic fluid for analysis.
Fig. 2.13 Intraductal papillary mucinous neoplasm (IPMN) seen on EUS
Fig. 2.14 Characteristic major papilla endoscopic “fish eye” appearance in the setting of IPMN
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2.3.3 Hepatobiliary Neoplasms Recent studies have shown that EUS-FNA may have an adjunctive diagnostic role in the work up of hepatobiliary cancers. In one study, 27 of 28 total patients had nondiagnostic or equivocal sampling of their biliary lesions via ERCP, percutaneous transhepatic cholangiogram (PTC), and/or CT-guided biopsy. EUS-FNA demonstrated a positive impact on management in 84% of total patients, by avoiding surgery for tissue diagnosis in patients with inoperable disease, facilitating surgery in patients with unidentifiable cancer by other modalities, and avoiding surgery in benign disease (Eloubeidi et al. 2004). In addition, EUS-FNA has an ancillary role in establishing M-stage disease in hepatic metastasis states. When a lesion, particularly in the left hepatic lobe, is not amenable to CT-guided or percutaneous biopsy, it oftentimes can been accessed transgastrically (Nguyen et al. 1999).
2.3.4 Submucosal Gastrointestinal Lesions The ability of EUS to differentiate the five-layer gastrointestinal wall anatomy is the fundamentally unique aspect of this modality (Figs. 2.15 and 2.16). With the availability of miniprobe EUS, lesions in the right colon can be assessed also via a standard colonoscope. The accuracy rate for EUS-FNA of submucosal lesions is high (80%), and thus, potentially affects clinical decision making (Arantes et al. 2004). Distinguishing true leiomyomas from gastrointestinal stromal tumors (GISTs) has significant implications, as the two neoplasms have different prognoses and treatment options. Immunohistochemical findings that define these lesions can be derived readily from cell block material obtained by EUSguided FNA (Stelow et al. 2003).
Fig. 2.15 Gastric gastrointestinal stromal tumor (GIST) seen in fundus on endoscopy exam
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Fig. 2.16 Gastric GIST with characteristic submucosal splitting seen on EUS exam
2.3.5 Gastric Cancer EUS has an overall 80% accuracy for T staging and 70% for N staging, and has been found to be superior to CT (Xi et al. 2003; Javaid et al. 2004). The major impact EUS-FNA has on gastric cancer management comes from the novel technique of endoscopic ultrasound guided paracentesis (EUS-P) of ascites to determine M staging. One study found that aspiration through EUS-FNA of a mean volume of 6.8 mL of ascites has a sensitivity, specificity, positive predictive value, and negative predictive value of 94, 100, 100, and 89%, respectively, for diagnosing malignant ascites. Accordingly, the finding of malignant ascites has significant impact on patient management, rendering a poorer prognosis (Kaushik et al. 2006).
2.3.6 Esophageal Neoplasms As a complementary exam, EUS is used in conjunction with CT and positron emission tomography (PET) scanning in the staging of esophageal carcinoma. EUS vs. EUS-FNA for lymph node staging has been shown to have a sensitivity of 63 vs. 93% (p = 0.01), specificity 81 vs. 100% (not significant), and accuracy 70 vs. 93% (p = 0.02), respectively (Vazquez-Sequeiros et al. 2001). Celiac lymph node M1a disease confirmation via EUSFNA has been found to be superior to CT scanning. As celiac lymph node involvement carries a poorer prognosis, and is usually treated with nonsurgical methods, this determination is critical (Parmar et al. 2002). In cases of early-stage esophageal neoplastic disease, where minimally invasive procedures such as EMR can be considered for potentially curative treatment, EUS-FNA
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has impacted management. Detecting unsuspected malignant lymphadenopathy via conventional endosonography and EUS-FNA dramatically changed the course of management in 20% of patients referred to our center for endoscopic therapy of BE with high-grade dysplasia or intramucosal carcinoma. Based on these results, we believe that conventional endosonography and EUS with FNA when nodal disease is suspected should be performed routinely in all patients referred for endoscopic therapy in this setting (Shami et al. 2006). Subcarinal and supracarinal lymph node metastases proves critical in selection of transthoracic or transhiatal esophagectomy surgical strategy for distal esophageal carcinomas. In patients with a resectable distal esophageal carcinoma and subcarinal and/or supracarinal lymph nodes visualized on preoperative EUS, Fockens et al. prospectively studied the impact of EUS-FNA on surgical decision making. If EUS-FNA sampling of lymph nodes was positive for malignancy, then transthoracic resection was offered. Patients without demonstrated lymph node metastases were offered a transhiatal resection. Out of the 48 patients included in the study, lymph node metastases were found in 23% with EUSFNA. Out of the 13 patients who had lymph nodes which were suspicious for malignancy on EUS, 31% had their diagnosis status changed to nonmalignant nodes with FNA confirmation. Conversely, EUS-FNA proved lymph node malignancy presence in 9% of 35 patients who had nonsuspicious-appearing nodes on EUS. Therefore, EUS-FNA has considerable impact on clinical decision management in distal esophageal carcinoma cases when transhiatal resection was presumptively planned (Marsman et al. 2006).
2.3.7 Colorectal Carcinoma Recently, locoregional stage-focused colorectal cancer therapy has been given higher emphasis. EUS-FNA colorectal cancer N-staging, especially nonjuxtatumoral lymph nodes, has been shown to have clinical impact on decision making. This technique also aids in detecting disease recurrence (Shami et al. 2004). In the setting of re-staging after chemoradiation therapy, EUS has virtually no role, due to posttreatment induced local inflammation. However, when recurrence is not present intralumenally, and is suspected in the face of rising CEA levels, EUS-FNA can be helpful (Dye and Waxman 2002).
2.3.8 Lung Malignancy The posterior mediastinum can be accessed for FNA through the esophageal wall, for staging of lung cancer. Sensitivity, specificity, and accuracy for EUS-FNA in mediastinal analysis have been reported as 91, 100, and 93%, respectively. Certain experts advocate EUS-FNA as the initial diagnostic procedure for suspected lung cancer with enlarged mediastinal lymphadenopathy, to possible reduce the number of surgical staging procedures (Annema et al. 2005; Micames et al. 2007).
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2.3.9 Therapeutic Applications of EUS-FNA The following section will highlight EUS-FNA-based interventional applications with specific targeted therapies.
2.3.9.1 Celiac Plexus Blockade Refractory pain management via celiac plexus neurolysis (CPN) through EUS guidance for inoperable pancreatic cancer has become an increasingly utilized modality. EUS utilizes an anterior approach to the celiac axis, so that the risk of resultant paraplegia is theoretically negligible, while posterior percutaneous approach confers a 1% risk (Raj and Chen 2006). In a large prospective study, 78% of patients had lower pain score at 2 weeks after EUS-CPN, with a sustained response of up to 24 weeks, independent of narcotic usage or adjuvant therapy (Gunaratnam et al. 2001).
2.3.9.2 EUS-Guided Pancreatico-Biliary Access/Drainage When achieving selective ductal drainage through standard ERCP is unsuccessful, EUSguided pancreatic or biliary access of the desired duct has been effectively performed as an alternative to surgery or percutaneous drainage (Figs. 2.17 and 2.18). EUS-FNA puncture is performed into an obstructed and dilated biliary or main pancreatic duct. After fluoroscopic guidewire access is established via the FNA needle, a transenteric fistula is created, through which stent placement in the desired duct can be performed, either directly or via a rendezvous ERCP. At qualified high-volume EUS/ERCP centers, this technique can
Fig. 2.17 EUS-guided pancreatic ductal access with contrast injection under fluoroscopy
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Fig. 2.18 Pancreatic stent placed after EUS-guided pancreatic ductal access for rendezvous procedure
serve as an alternative salvage approach to difficult pancreatico-biliary access cases, with acceptable success and complication rates (Shami and Kahaleh 2007).
2.3.9.3 EUS-Guided Fine Needle Injection A concept known as EUS-guided fine-needle injection (EUS-FNI) has evolved from using EUS-FNA as a portal to introduce various agents with therapeutic capabilities. Chang et al. have reported on injection of allogeneic mixed lymphocytic culture into unresectable pancreatic tumors. However, the study was terminated early when survival was determined to be less favorable in the lymphocytic culture recipients compared with the patient group receiving gemcitabine (Chang et al. 2000). Feasible injection of a replication-deficient adenovector into unresectable pancreatic tumors, with well-tolerated and fair responses has also been reported by the same investigator (Raju 2009).
2.4 Endoscopic Management of Malignant Gastrointestinal Obstruction 2.4.1 Malignant Esophageal Obstruction The palliation of malignant esophageal obstruction has been enhanced by the development of self-expanding metallic covered or uncovered stents (SEMS) (Figs. 2.19 and 2.20). These devices offer relief from dysphagia, poor nutrition, and weight loss. A host of alternate nonstent therapies have been utilized such as argon plasma coagulation, photodynamic therapy, laser, brachytherapy, local injection of alcohol, and antineoplastic drugs. However, they have lost popularity due to lack of efficacy or expense, precluding logistical
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Fig. 2.19 Nonoperable malignant esophageal stenotic obstruction
Fig. 2.20 Postesophageal stent prosthesis placement for relief of dysphagia
usage. The use of chemoradiation adjunctively with stent placement can be a strategy for malignant dysphagia relief, though the acute local inflammation from the chemoradiation can make tissue more friable and irritated temporarily (Fleischer and Sivak 1985; Christiaens et al. 2008; Okunaka et al. 1990; Homs et al. 2005; Wadleigh et al. 2006; Burris et al. 1998). It has been shown that covered metal stents help prevent tumor in growth without substantially raising migration rates, when compared to uncovered ones (Vakil et al. 2001). However, stent migration still presents itself as a significant complication particularly in distal esophageal obstructions (Verschuur et al. 2008). The use of SEMS as sole therapy for patients with inoperable disease who have not already received, or are unfit for, chemoradiotherapy has been studied. Thousand stents were placed in 951 patients. Long-term follow-up was obtained for 35% with a median survival of 250 days (IQR 130–431, 95% CI 217–301). Mean dysphagia scores improved from 3.3 (SD 0.6) pre-SEMS to 1.0 (SD 1.3) for 78 patients still alive and 1.8 (SD 1.2) at
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time of death of 165 patients. SEMS-related mortality was 0.3%, demonstrating that SEMS can effectively palliate inoperable esophageal cancer (White et al. 2009).
2.4.2 Malignant Gastro-Duodenal Obstruction Endoscopic palliation of gastro-duodenal malignant obstruction can help obviate the need for otherwise invasive surgery in patients with limited life expectancy with unresectable cancer. In a study where 81 stents were inserted into 75 patients, the technical and clinical success rates were 98 and 87%, respectively. The median stent patency was 55 days (95% CI 40–70 days). The median survival was 79 days (95% CI 58–123 days). Stent occlusion caused by tumor ingrowth or overgrowth occurred in 31%. Use of covered stents (odds ratio 0.29, 95% CI 0.11–0.76; p = 0.01) and chemotherapy after stent placement (odds ratio 0.34, 95% CI 0.13– 0.91; p = 0.03) were significant prognostic factors for ongoing stent patency after a multivariate analysis. This study found that endoscopic stenting is a safe and effective palliation treatment for malignant gastric outlet obstruction and a covered stent and chemotherapy are significant prognostic factors for stent patency (Cho et al. 2009). Successful stent placement in otherwise endoscopically inaccessible regions of the small bowel has been described for malignant obstruction using double-balloon-enteroscopy-assisted techniques (Ross et al. 2006).
2.4.3 Malignant Colorectal Obstruction Colorectal obstruction expandable metallic stent placements for either palliation or preoperatively as a bridge to surgery have become mainstays of therapy (Figs. 2.21–2.23). Studies have shown that for acute colonic obstruction, outcomes of SEMS placement are more favorable to surgery with the respect of overall medical cost and mortality. Risks of stent placement include tumor ingrowth, migration, and tenesmus/pain if stent placement is close to the anal verge (Dekovich 2009; Siddiqui et al. 2007).
Fig. 2.21 Malignant obstruction at the ileocecal valve with guidewire for future stent placement
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Fig. 2.22 Endoscopic view after ileocolonic stent placement across malignant stenosis
Fig. 2.23 Fluoroscopic view after ileocolonic stent placement across malignant stenosis
2.4.4 Malignant Biliary Obstruction Malignant biliary obstructions often result from intrinsic biliary tract cancers or extrinsic compression from pancreatic tumors or surrounding lymphadenopathy. The onset of jaundice portends greater morbidity and mortality in these patient populations, who also may be immunosuppressed by adjuvant or palliative chemotherapy. In cases of operable disease, ERCP plastic biliary stenting will provide temporary therapeutic relief of jaundice prior to surgery. The plastic stent variety has a three-month patency as advocated by industry, and will require repeat future stent exchanges. In an effort to reduce the need for repeat procedures, and enhance longer stent patency, SEMS have been developed for the biliary tract for inoperable cases. Cross-sectional imaging (preferably magnetic resonance cholangiopancreatography [MRCP]) is often utilized preprocedurally to determine the appropriateness of endoscopic stent therapy and to guide stent placement. Hilar cholangiocarcinomas particularly benefit from the preprocedure “mapping” provided by 3-D reconstructive MRCP imaging, so as to avoid “blind” contrast injection into otherwise undrainable hepatic systems.
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Fig. 2.24 24 Hilar malignant biliary obstruction cholangiogram via endoscopic retrograde cholangio-pancreatography (ERCP)
Fig. 2.25 Postbilateral self-expanding metal stent placement across malignant hilar biliary obstruction
Self-expanding metal stents are preferred over plastic stents for their cost effectiveness if patient survival is estimated to be greater than 6 months. Photodynamic therapy is a treatment option for local but inoperable cholangiocarcinoma which is capable of prolonging survival (Stern and Sturgess 2008) (Figs. 2.24 and 2.25).
2.5 Conclusion The field of interventional gastrointestinal endoscopy is transforming into a robust specialty that can offer a wide array of minimally invasive nonsurgical alternatives for diagnostic and therapeutic objectives in gastrointestinal oncology patients. The outcomes of these techniques are often favorable to surgical approaches. Development of improved endoscopic imaging and ancillary devices will enhance the field’s progress and further enable physicians to accomplish previously incomprehensible techniques for hopefully better quality of patient care.
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References Ahmad NA, Kochman ML, Long WB et al (2002) Efficacy, safety, and clinical outcomes of endoscopic mucosal resection: a study of 101 cases. Gastrointest Endosc 55:390–396 Annema JT, Versteegh MI, Veselic M et al (2005) Endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of lung cancer and its impact on surgical staging. J Clin Oncol 23:8357–8361 Arantes V, Logrono R, Faruqi S et al (2004) Endoscopic sonographically guided fine-needle aspiration yield in submucosal tumors of the gastrointestinal tract. J Ultrasound Med 23:1141–1150 Binmoeller KF, Boaventura S, Ramsperger K et al (1993) Endoscopic snare excision of benign adenomas of the papilla of Vater. Gastrointest Endosc 39:127–131 Brugge WR, Lewandrowski K, Lee-Lewandrowski E et al (2004) Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 126:1330–1336 Burris HA III, Vogel CL, Castro D et al (1998) Intratumoral cisplatin/epinephrine-injectable gel as a palliative treatment for accessible solid tumors: a multicenter pilot study. Otolaryngol Head Neck Surg 118:496–503 Buskens CJ, Westerterp M, Lagarde SM et al (2004) Prediction of appropriateness of local endoscopic treatment for high-grade dysplasia and early adenocarcinoma by EUS and histopathologic features. Gastrointest Endosc 60:703–710 Caputi Iambrenghi O, Ugenti I, Martines G et al (2009) Endoscopic management of large colorectal polyps. Int J Colorectal Dis 24(7):749–753 Catalano MF, Linder JD, Chak A et al (2004) Endoscopic management of adenoma of the major duodenal papilla. Gastrointest Endosc 59:225–232 Chang KJ, Nguyen P, Erickson RA et al (1997) The clinical utility of endoscopic ultrasoundguided fine-needle aspiration in the diagnosis and staging of pancreatic carcinoma. Gastrointest Endosc 45:387–393 Chang KJ, Nguyen PT, Thompson JA et al (2000) Phase I clinical trial of allogeneic mixed lymphocyte culture (cytoimplant) delivered by endoscopic ultrasound-guided fine-needle injection in patients with advanced pancreatic carcinoma. Cancer 88:1325–1335 Chennat J, Konda VJ, Ross AS et al (2009) Complete Barrett’s eradication endoscopic mucosal resection: an effective treatment modality for high-grade dysplasia and intramucosal carcinoma – an American single-center experience. Am J Gastroenterol 104:2684 Cho YK, Kim SW, Hur WH, et al (2009) Clinical outcomes of self-expandable metal stent and prognostic factors for stent patency in gastric outlet obstruction caused by gastric cancer. Dig Dis Sci. 2010 ;55(3):668–74 Christiaens P, Decock S, Buchel O et al (2008) Endoscopic trimming of metallic stents with the use of argon plasma. Gastrointest Endosc 67:369–371 Dekovich AA (2009) Endoscopic treatment of colonic obstruction. Curr Opin Gastroenterol 25:50–54 Dye CE, Waxman I (2002) Endoscopic ultrasound. Gastroenterol Clin North Am 31:863–879 Ell C, May A, Gossner L et al (2000) Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett’s esophagus. Gastroenterology 118:670–677 Eloubeidi MA, Chen VK, Jhala NC et al (2004) Endoscopic ultrasound-guided fine needle aspiration biopsy of suspected cholangiocarcinoma. Clin Gastroenterol Hepatol 2:209–213 Ferguson MK, Naunheim KS (1997) Resection for Barrett’s mucosa with high-grade dysplasia: implications for prophylactic photodynamic therapy. J Thorac Cardiovasc Surg 114:824–829 Fleischer D, Sivak MV Jr (1985) Endoscopic Nd:YAG laser therapy as palliation for esophagogastric cancer. Parameters affecting initial outcome. Gastroenterology 89:827–831 Giovannini M, Bories E, Pesenti C et al (2004) Circumferential endoscopic mucosal resection in Barrett’s esophagus with high-grade intraepithelial neoplasia or mucosal cancer. Preliminary results in 21 patients. Endoscopy 36:782–787
2 Interventional Gastrointestinal Oncology
39
Gress F, Gottlieb K, Sherman S et al (2001) Endoscopic ultrasonography-guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann Intern Med 134:459–464 Gunaratnam NT, Sarma AV, Norton ID et al (2001) A prospective study of EUS-guided celiac plexus neurolysis for pancreatic cancer pain. Gastrointest Endosc 54:316–324 Hirasaki S, Tanimizu M, Nasu J et al (2005) Treatment of elderly patients with early gastric cancer by endoscopic submucosal dissection using an insulated-tip diathermic knife. Intern Med 44: 1033–1038 Homs MY, Eijkenboom WM, Siersema PD (2005) Single-dose brachytherapy for the palliative treatment of esophageal cancer. Endoscopy 37:1143–1148 Hurlstone DP, Sanders DS, Cross SS et al (2004) Colonoscopic resection of lateral spreading tumours: a prospective analysis of endoscopic mucosal resection. Gut 53:1334–1339 Javaid G, Shah OJ, Dar MA et al (2004) Role of endoscopic ultrasonography in preoperative staging of gastric carcinoma. ANZ J Surg 74:108–111 Kaushik N, Khalid A, Brody D et al (2006) EUS-guided paracentesis for the diagnosis of malignant ascites. Gastrointest Endosc 64:908–913 Klapman JB, Logrono R, Dye CE et al (2003) Clinical impact of on-site cytopathology interpretation on endoscopic ultrasound-guided fine needle aspiration. Am J Gastroenterol 98:1289–1294 Kodama M, Kakegawa T (1998) Treatment of superficial cancer of the esophagus: a summary of responses to a questionnaire on superficial cancer of the esophagus in Japan. Surgery 123: 432–439 Kojima T, Parra-Blanco A, Takahashi H, et al (1998) Outcome of endoscopic mucosal resection for early gastric cancer: review of the Japanese literature. Gastrointest Endosc 48:550–554; discussion 554–555 Konda VJ, Ross AS, Ferguson MK et al (2008) Is the risk of concomitant invasive esophageal cancer in high-grade dysplasia in Barrett’s esophagus overestimated? Clin Gastroenterol Hepatol 6:159–164 Kudo S (1993) Endoscopic mucosal resection of flat and depressed types of early colorectal cancer. Endoscopy 25:455–461 Kudo S, Kashida H, Tamura T et al (2000) Colonoscopic diagnosis and management of nonpolypoid early colorectal cancer. World J Surg 24:1081–1090 Larghi A, Waxman I (2007) State of the art on endoscopic mucosal resection and endoscopic submucosal dissection. Gastrointest Endosc Clin N Am 17:441–469, v Larghi A, Lightdale CJ, Memeo L et al (2005) EUS followed by EMR for staging of high-grade dysplasia and early cancer in Barrett’s esophagus. Gastrointest Endosc 62:16–23 Larghi A, Lightdale CJ, Ross AS et al (2007) Long-term follow-up of complete Barrett’s eradication endoscopic mucosal resection (CBE-EMR) for the treatment of high grade dysplasia and intramucosal carcinoma. Endoscopy 39:1086–1091 Marsman WA, Brink MA, Bergman JJ et al (2006) Potential impact of EUS-FNA staging of proximal lymph nodes in patients with distal esophageal carcinoma. Endoscopy 38:825–829 May A, Gossner L, Pech O et al (2002a) Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett’s oesophagus: acute-phase and intermediate results of a new treatment approach. Eur J Gastroenterol Hepatol 14:1085–1091 May A, Gossner L, Pech O et al (2002b) Intraepithelial high-grade neoplasia and early adenocarcinoma in short-segment Barrett’s esophagus (SSBE): curative treatment using local endoscopic treatment techniques. Endoscopy 34:604–610 Micames CG, McCrory DC, Pavey DA et al (2007) Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: a systematic review and metaanalysis. Chest 131:539–548 Mino-Kenudson M, Brugge WR, Puricelli WP et al (2005) Management of superficial Barrett’s epithelium-related neoplasms by endoscopic mucosal resection: clinicopathologic analysis of 27 cases. Am J Surg Pathol 29:680–686
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Moparty B, Logrono R, Nealon WH et al (2007) The role of endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration in distinguishing pancreatic cystic lesions. Diagn Cytopathol 35:18–25 Nguyen P, Feng JC, Chang KJ (1999) Endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (FNA) of liver lesions. Gastrointest Endosc 50:357–361 Nijhawan PK, Wang KK (2000) Endoscopic mucosal resection for lesions with endoscopic features suggestive of malignancy and high-grade dysplasia within Barrett’s esophagus. Gastrointest Endosc 52:328–332 Oka S, Tanaka S, Nagata S et al (2003) Clinicopathologic features and endoscopic resection of early primary nonampullary duodenal carcinoma. J Clin Gastroenterol 37:381–386 Okunaka T, Kato H, Conaka C et al (1990) Photodynamic therapy of esophageal carcinoma. Surg Endosc 4:150–153 Ono H, Kondo H, Gotoda T et al (2001) Endoscopic mucosal resection for treatment of early gastric cancer. Gut 48:225–229 Parmar KS, Zwischenberger JB, Reeves AL, et al (2002) Clinical impact of endoscopic ultrasound-guided fine needle aspiration of celiac axis lymph nodes (M1a disease) in esophageal cancer. Ann Thorac Surg 73:916–920; discussion 920–921 Pech O, May A, Gossner L et al (2003) Barrett’s esophagus: endoscopic resection. Gastrointest Endosc Clin N Am 13:505–512 Pech O, Behrens A, May A et al (2008) Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s oesophagus. Gut 57:1200–1206 Pellegrini CA, Pohl D (2000) High-grade dysplasia in Barrett’s esophagus: surveillance or operation? J Gastrointest Surg 4:131–134 Peters FP, Kara MA, Rosmolen WD et al (2006) Stepwise radical endoscopic resection is effective for complete removal of Barrett’s esophagus with early neoplasia: a prospective study. Am J Gastroenterol 101:1449–1457 Raj M, Chen RY (2006) Interventional applications of endoscopic ultrasound. J Gastroenterol Hepatol 21:348–357 Raju GS (2009) Endoscopic closure of gastrointestinal leaks. Am J Gastroenterol 104:1315–1320 Ross AS, Semrad C, Waxman I et al (2006) Enteral stent placement by double balloon enteroscopy for palliation of malignant small bowel obstruction. Gastrointest Endosc 64:835–837 Seewald S, Akaraviputh T, Seitz U et al (2003) Circumferential EMR and complete removal of Barrett’s epithelium: a new approach to management of Barrett’s esophagus containing highgrade intraepithelial neoplasia and intramucosal carcinoma. Gastrointest Endosc 57:854–859 Shami VM, Kahaleh M (2007) Endoscopic ultrasonography (EUS)-guided access and therapy of pancreatico-biliary disorders: EUS-guided cholangio and pancreatic drainage. Gastrointest Endosc Clin N Am 17:581–593, vii–viii Shami VM, Parmar KS, Waxman I (2004) Clinical impact of endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration in the management of rectal carcinoma. Dis Colon Rectum 47:59–65 Shami VM, Villaverde A, Stearns L et al (2006) Clinical impact of conventional endosonography and endoscopic ultrasound-guided fine-needle aspiration in the assessment of patients with Barrett’s esophagus and high-grade dysplasia or intramucosal carcinoma who have been referred for endoscopic ablation therapy. Endoscopy 38:157–161 Shami VM, Sundaram V, Stelow EB et al (2007) The level of carcinoembryonic antigen and the presence of mucin as predictors of cystic pancreatic mucinous neoplasia. Pancreas 34: 466–469 Shimizu Y, Tsukagoshi H, Fujita M et al (2002) Long-term outcome after endoscopic mucosal resection in patients with esophageal squamous cell carcinoma invading the muscularis mucosae or deeper. Gastrointest Endosc 56:387–390
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Siddiqui A, Khandelwal N, Anthony T et al (2007) Colonic stent versus surgery for the management of acute malignant colonic obstruction: a decision analysis. Aliment Pharmacol Ther 26:1379–1386 Stein HJ, Feith M, Bruecher BL, et al (2005) Early esophageal cancer: pattern of lymphatic spread and prognostic factors for long-term survival after surgical resection. Ann Surg 2005;242:566– 573; discussion 573–575 Stelow EB, Stanley MW, Mallery S et al (2003) Endoscopic ultrasound-guided fine-needle aspiration findings of gastrointestinal leiomyomas and gastrointestinal stromal tumors. Am J Clin Pathol 119:703–708 Stern N, Sturgess R (2008) Endoscopic therapy in the management of malignant biliary obstruction. Eur J Surg Oncol 34:313–317 Tanaka S, Haruma K, Oka S et al (2001) Clinicopathologic features and endoscopic treatment of superficially spreading colorectal neoplasms larger than 20 mm. Gastrointest Endosc 54:62–66 Vakil N, Morris AI, Marcon N et al (2001) A prospective, randomized, controlled trial of covered expandable metal stents in the palliation of malignant esophageal obstruction at the gastroesophageal junction. Am J Gastroenterol 96:1791–1796 Varadarajulu S, Eloubeidi MA (2005) The role of endoscopic ultrasonography in the evaluation of pancreatico-biliary cancer. Gastrointest Endosc Clin N Am 15:497–511, viii–ix Vazquez-Sequeiros E, Norton ID, Clain JE et al (2001) Impact of EUS-guided fine-needle aspiration on lymph node staging in patients with esophageal carcinoma. Gastrointest Endosc 53:751–757 Verschuur EM, Repici A, Kuipers EJ et al (2008) New design esophageal stents for the palliation of dysphagia from esophageal or gastric cardia cancer: a randomized trial. Am J Gastroenterol 103:304–312 Wadleigh RG, Abbasi S, Korman L (2006) Palliative ethanol injections of unresectable advanced esophageal carcinoma combined with chemoradiation. Am J Med Sci 331:110–112 White RE, Parker RK, Fitzwater JW et al (2009) Stents as sole therapy for oesophageal cancer: a prospective analysis of outcomes after placement. Lancet Oncol 10:240–246 Xi WD, Zhao C, Ren GS (2003) Endoscopic ultrasonography in preoperative staging of gastric cancer: determination of tumor invasion depth, nodal involvement and surgical resectability. World J Gastroenterol 9:254–257 Yokoi C, Gotoda T, Hamanaka H et al (2006) Endoscopic submucosal dissection allows curative resection of locally recurrent early gastric cancer after prior endoscopic mucosal resection. Gastrointest Endosc 64:212–218
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Kay Washington and Christopher L. Corless
3.1 The Molecular Bases of Gastrointestinal Cancer Gastrointestinal (GI) cancers, like other human malignancies, are characterized by the accumulation of a variety of genetic alterations, including mutations that lead to inactivation of tumor suppressor genes or activation of oncogenes. These genetic and epigenetic changes can be used to classify tumors on the molecular level, and form the basis for development of new prognostic and predictive markers. While a number of molecular prognostic factors in GI cancers have been recognized or postulated (Table 3.1), few have been validated in large data sets to date and their utilization is not yet considered a standard of care. The essential prognostic factors for carcinomas across all GI sites remain the anatomic stage as classified, using TNM categories, lymphovascular invasion, and achievement of margin-negative surgical resection in potentially curable neoplasms. However, with the development of therapies targeted to specific molecular pathways involved in tumorigenesis, characterization of molecular alterations in individual GI malignancies has become important for prediction of response to therapy and thus may be used in some situations to guide selection of treatment options. Currently, the two most prominent examples are colorectal carcinoma and gastrointestinal stromal tumors (GISTs), for which molecular testing for prediction of response to therapy has become widely applied in certain clinical settings, such as KRAS mutational testing prior to treatment with cetuximab in high stage colorectal carcinoma.
K. Washington (*) Department of Pathology, Vanderbilt University Medical Center, C-3321 MCN, Nashville, TN 37232, USA e-mail:
[email protected] C.L. Corless Department of Pathology, Oregon Health & Science University and Knight Cancer Institute, Portland, OR, USA C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_3, © Springer-Verlag Berlin Heidelberg 2011
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Table 3.1 Potential molecular markers for colorectal carcinoma Category Marker Application/comments Microsatellite instability
RT-PCR, IHC
Testing for hereditary non-polyposis colon cancer (HNPCC); prognostic marker; possibly predictive for response to 5-FU based therapies
Allelic imbalances/ LOH
18q
Prognostic marker; unclear if predictive
Chromosomal instability
DNA ploidy
Prognostic marker
Methylation
Genome-wide or specific
Defines CIMP+ subset of colorectal cancers
Oncogene expression
Ras, myc
No clinical application as biomarker at present in GI cancers
Loss of tumor suppressor gene
Bcl-2, p21, p27, p53
No clinical application as biomarker at present in GI cancers
Proliferation/apoptosis
Bcl-2, bax, ki67
No clinical application as biomarker at present in GI cancers
Angiogenesis
VEGF
No clinical application as biomarker at present in GI cancers
Inflammation
Cox-2
No clinical application as biomarker at present in GI cancers
Cell adhesion
Ecad, b-catenin, CD44
No clinical application at present in GI cancers
Predictive markers
EGFR, TS, VEGF, KRAS mutation
KRAS mutation predicts lack of response to cetuximab and is recommended prior to treatment with anti-EGFR antibody therapy TS may have utility as predictive marker but is not recommended for clinical use at present time EGFR testing is not recommended at present
3.2 Molecular Pathways of Colorectal Carcinoma In terms of molecular profiling, colorectal carcinoma is arguably the most extensively characterized human malignancy, for a number of reasons: high prevalence, accessibility of precursor lesions (adenomas) for study, and recognition of well-defined familial syndromes (familial adenomatous polyposis coli and Lynch syndrome) that led to break-through observations identifying causative molecular factors. Two major pathways of carcinogenesis
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for colorectal carcinomas are recognized: chromosomal instability and microsatellite instability (MSI). Chromosomal instability, present in roughly 85% of colorectal carcinomas, is characterized by accumulation of genomic abnormalities such as widespread chromosomal gains and losses and translocations, and aneuploidy. MSI accounts for 10–15% of colorectal carcinomas and is characterized by genome-wide alterations in the size of repetitive DNA sequences known as microsatellites. This variability in microsatellite sequences is a consequence of defective DNA mismatch repair and may be due to germline mutation in a gene involved in the mismatch repair mechanism, or epigenetic mechanisms such as gene hypermethylation in sporadic cases. A third mechanism of tumorigenesis in colorectal carcinomas, referred to as CpG island methylator phenotype or CIMP+, has been recently described; in these colorectal tumors, epigenetic changes due to widespread DNA methylation, particularly that of CpG islands in the promoter regions of genes, leads to inactivation of tumor suppressor genes. CIMP-high tumors have been described as demonstrating a distinct clinicopathologic profile, such as association with proximal tumor location, high grade histology, high levels of MSI, high BRAF mutation rate, and low TP53 mutation rate (Samowitz et al. 2005; Weisenberger et al. 2006; Shen et al. 2007).
3.2.1 Chromosomal Instability Pathway Colorectal carcinomas characterized by chromosomal instability are usually characterized by mutations in APC, the tumor suppressor gene mutated in individuals with familial adenomatous polyposis coli. In sporadic colorectal cancers, the APC mutation is somatic, occurring very early in the adenoma-carcinoma sequence, and the chromosomal instability observed in very small early adenomas and dysplastic aberrant crypt foci is likely related to defective chromosome segregation association with APC inactivation. In FAP, affected individuals inherit one mutant copy of APC that is functionally inactive, or the mutation arises as a spontaneous germline mutation in approximately 25% of affected individuals (Bisgaard et al. 1994). Clinical consequences of chromosomal inactivation include worsening prognosis with increasing number of allelic changes (Kern et al. 1989), which may be reflected in aneuploidy (Sinicrope et al. 2006). These tumors often show p53 mutations associated with loss of 17p, which occurs at the transition from non-invasive adenoma to the appearance of carcinoma. KRAS mutation, another early event in colorectal carcinogenesis, occurs later, as evidenced by its presence in only 20% of adenomas with APC mutation (Tsao and Shibata 1994). Regulation of b-catenin by APC appears to be the key to its tumor suppressor activity.
3.2.2 Microsatellite Instability Pathway Defects in the DNA mismatch system lead to colorectal carcinoma in two settings: Lynch syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC), and in sporadic carcinomas. Lynch syndrome, accounting for 1–4% of colorectal carcinoma, is an autosomal dominant disorder caused by mutation in one of several genes involved in mismatch repair,
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such as MLH1, MSH2, MSH6, and PMS2. Defects in the functioning of the mismatch repair system lead to DNA replication errors in simple short tandem DNA repeat sequences of one to six bases, called microsatellites, which are scattered throughout the genome. MSI is a change in length of microsatellites due to insertion or deletion of repeating units during DNA replication, secondary to failure of the DNA replication system to correct these errors. Genetic instability occurs in the repetitive sequences of microsatellites because the replication machinery slips more frequently on repetitive sequences than on non-repetitive sequences. High levels of MSI in sporadic colorectal carcinomas are due to somatic hypermethylation of the MLH1 promoter, leading to inactivation of the MLH1 gene and loss of expression of the gene product. MSI in colon cancer was discovered in 1993, and was recognized as the genetic basis for the pathogenesis of many cases of HNPCC. In mismatch repair-deficient cells, genes that contain microsatellites in the coding region are more prone to frameshift mutations. One example is frameshift mutations in TGFbRII, found in colorectal but not endometrial cancer. Two of the DNA mismatch repair genes, MSH3 and MSH6, themselves contain coding microsatellites that can be mutated in MSI-H cancers and are thus mutational targets. The original Bethesda guidelines for the identification of individuals with HNPCC proposed a panel of five markers (BAT25, BAT26, D2S123, D5S346, D17S250) (Boland et al. 1998) for detection of MSI. If two or more microsatellite sequences are mutated the tumor is considered to show high levels of MSI (MSI-H); if only one is mutated, then the tumor is classified as showing low levels of MSI (MSI-L) and additional testing with other microsatellite sequences is recommended for definitive classification. Tumors showing no microsatellite mutations are considered microsatellite stable (MSS). Because mononucleotide markers are more sensitive than di- or trinucleotide microsatellites, the revised Bethesda guidelines following a 2002 NCI workshop recommended that a secondary panel of mononucleotide markers such as BAT-40 be used to exclude MSI-L cases in which only the dinucleotide repeats are mutated (Umar et al. 2004). Revised guidelines are effective in identifying MLH1/MSH2 mutation carriers with a sensitivity of ~82% and specificity of ~98%. In general, 50% or more of the microsatellites will have mutations in the tumor cells.
3.2.2.1 Specific Genetic Alterations in the MIS Pathway Inactivation of the TGFb signaling pathway is common in MSI-H carcinomas, with 90% of such tumors showing mutation of the TGFbRII gene and the remaining 10% showing mutations within IGFIIR. Other mutations include BAX, mutated in ~50% of MSI-H cancers, and activating mutations in b-catenin, found in ~25% of MSI-H cancers (MirabelliPrimdahl et al. 1999). APC mutation is rare in MSI-H cancers.
3.2.2.2 Practical Applications of MSI Testing Detection of defects in mismatch repair in colorectal carcinomas is important for detection of Lynch syndrome, and examination of the tissue for defective DNA mismatch repair is
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recommended if any of the criteria in the revised Bethesda guidelines (Umar et al. 2004) are met. These guidelines recommend testing for MSI in the following situations:
• Colorectal carcinoma in a patient younger than 50 years of age • Synchronous or metachronous colorectal or other HNPCC-related tumors, such as
endometrial, small bowel, gastric, ovarian, pancreatic, biliary, ureteral or renal pelvis carcinomas, brain tumors, sebaceous gland adenomas, and keratoacanthomas, in a patient of any age • Colorectal carcinoma with histologic features associated with MSI-H status (medullary, mucinous or signet ring cell differentiation, presence of numerous tumor infiltrating lymphocytes, or presence of Crohn’s disease-like peritumoral lymphocytic reaction) (Alexander et al. 2001; Greenson et al. 2003), in a patient less than 60 years of age • Colorectal carcinoma in one or more first-degree relatives with an HNPCC-associated tumor, with one of the cancers being diagnosed under age 50 years • Colorectal cancer in two or more first-or second-degree relatives with HNPCC-related tumors, regardless of age Pre-symptomatic detection of carriers could lead to increased surveillance and potentially reduce morbidity and mortality from colorectal carcinomas and other cancers in these patients. The specificity of MSI testing can be increased by using primarily on at risk populations such as colorectal cancer patients under the age of 50 or patients with a strong family history of HNPCC associated tumors (e.g., colorectal, endometrial, gastric, or upper urinary tract urothelial carcinoma) (Umar et al. 2004). MSI in colorectal carcinomas has been associated with a more favorable prognosis in many (Halling et al. 1999; Benatti et al. 2005; French et al. 2008) but not all (Kim et al. 2007; Lamberti et al. 2007) retrospective case studies and a population based study (Samowitz et al. 2001) compared to tumors with intact mismatch repair, and a recent pooled analysis of randomized clinical trials (Sargent et al. 2008) showed a 49% reduction in disease-free survival in patients not receiving chemotherapy who had MSS tumors, compared to those with MSI-H colorectal carcinomas. Factors that may account for these reported differences in prognostic impact (reviewed in Sinicrope and Sargent 2009) include insufficient sample size, given that MSI-H tumors represent roughly 15% of colorectal carcinomas, and the relatively modest magnitude of the effect of MSI status on outcome. In addition, emerging data suggest that high levels of MSI may serve as a predictor of response to 5-FU based chemotherapy (Ribic et al. 2003; Sargent et al. 2008; Jover et al. 2009), in that MSI-H tumors show relative resistance to these regimens. Although MSI testing for prognostic and predictive purposes is not clearly established and has not yet been accepted as standard of care, use of MSI testing to influence treatment decisions for stage II colon cancer patients is therefore advocated by some investigators (Sinicrope and Sargent 2009). PCR-based techniques for MSI testing can be used to screen at risk colorectal cancer patients for possible HNPCC cost-effectively; immunohistochemistry for detection of loss of expression of gene products associated with mismatch repair may also be used to determine tumor mismatch repair status. Because patients with an MSI-H phenotype may have a heritable germline mutation in one of several DNA MMR genes, appropriate genetic counseling prior to testing is indicated. Follow-up germline testing for HNPCC after
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determination of MSI-status may help in making a definitive diagnosis of the disorder and aid in the pre-symptomatic detection of carriers in at risk individuals. PCR-based MSI testing is generally performed with at least five microsatellite markers, generally mononucleotide or dinucleotide repeat markers. Because dinucleotide repeats may have lower sensitivity and specificity for identifying MSI-H tumors, currently used panels often include more mononucleotides and fewer dinucleotides. Many laboratories now use a commercially available kit for MSI testing that utilizes five mononucleotide markers. Both PCR-based MSI testing (Fig. 3.1) and immunohistochemistry for mismatch repair proteins (Fig. 3.2) use formalin-fixed, paraffin-embedded tissue sections, which are usually readily available from routinely processed tissue submitted for examination through
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190
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130
150
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6300 4200 2100 0 90 6300 4200 2100 0
Fig. 3.1 Polymerase chain reaction-based testing for microsatellite instability (MSI) shows variation in size of microsatellites in the colorectal carcinoma (bottom) compared to normal colonic mucosa (top) in a case showing high levels of MSI. Figure courtesy of Dr. Cindy Vnencak-Jones, Vanderbilt University Medical Center
Fig. 3.2 Immunohis tochemistry for MSH2 shows retention of nuclear expression in normal colonic crypts and loss of expression in the adenocarcinoma (arrows) in this case of colorectal carcinoma arising in a Lynch syndrome patient
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the pathology laboratory. The detection of MSI in a tumor by microsatellite analysis requires that the DNA used for the analysis be extracted from a portion of the tumor that contains approximately ³40% tumor cells and is thus dependent upon tumor cellularity. If the results of DNA MMR IHC and MSI testing are discordant, (e.g., MSI-H phenotype with normal IHC or abnormal IHC with MSS phenotype) then the laboratory should make sure that the same sample was used for MSI and IHC testing and that there was no sample mix-up. Examination of expression of MLH1, MSH2, MSH6, and PMS2 is the most common IHC testing method used for suspected MSI-H cases; antibodies to these mismatch repair proteins are commercially available. Any positive reaction in the nuclei of tumor cells is considered as intact expression (normal), and it is common for intact staining to be somewhat patchy. Intact expression of all four proteins indicates that mismatch repair enzymes tested are intact but does not entirely exclude Lynch syndrome, as approximately 5% of families may have a missense mutation (especially in MLH1) that can lead to a nonfunctional protein with retained antigenicity. Rarely, defects in lesser-known mismatch repair enzymes may also lead to a similar result. Loss of expression of MLH1 may be due to Lynch Syndrome or methylation of the promoter region (as occurs in sporadic MSI colorectal carcinoma). Genetic testing is ultimately required for this distinction, although a specific BRAF mutation is present in many sporadic cases, but not familial cancers. Loss of MSH2 expression essentially always implies Lynch syndrome. PMS2 loss is often associated with loss of MLH1 and is only independently meaningful if MLH1 is intact. MSH6 is similarly related to MSH2. Analysis for somatic mutations in the V600E hot spot in BRAF may be indicated for tumors that show high levels of MSI, as this mutation has been found in sporadic MSI-H tumors but not in HNPCC-associated cancers (Domingo et al. 2005). Use of BRAF mutational analysis as a step before germline genetic testing in patients with MSI-H tumors may be a cost-effective means of identifying patients with sporadic tumors for whom further testing is not indicated (Bessa et al. 2008).
3.3 Molecular Alterations in GI Cancers with Current Clinical Applications 3.3.1 KRAS KRAS, a small G-protein that functions as a signal transducer and integrator downstream of the epidermal growth factor receptor (EGFR), is a key component in the EGFR signaling cascade. Activating mutations in KRAS serve to isolate this signaling pathway from the effects of EGFR and render EGFR inhibition ineffective. In sporadic colorectal carcinomas, activating KRAS mutations involving codons 12, 13, or 61 have been detected in roughly 40–50% of tumors (Vogelstein et al. 1988; Karapetis et al. 2008); the mutation is usually a
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missense mutation involving codon 12. Interestingly, KRAS mutation is associated with exophytic tumors, and is not found in flat adenomas or flat carcinomas (Yashiro et al. 2001). Cetuximab, a monoclonal antibody therapy directed against the extracellular domain of EGFR, was originally approved only for patients whose colorectal carcinomas expressed EGFR. However, it was observed that some patients with EGFR-negative tumors received therapeutic benefit from anti-EGFR treatment, and recent advances have shown that only tumors with wild-type KRAS show significant response to these agents. Accumulating data from both randomized and non-randomized studies (Lievre et al. 2006; Amado et al. 2008; Bokemeyer et al. 2008; Karapetis et al. 2008; Van Cutsem et al. 2009b), reviewed by Jimeno et al. (2009), suggest that colorectal cancer patients whose tumors show KRAS mutations should not receive EGFR-targeting monoclonal antibody therapy. These findings may partially explain the lack of correlation of immunohistochemical evidence of EGFR expression in tumors with efficacy of anti-EGFR therapies. While the predictive value of KRAS mutations regarding monoclonal antibody-based antiEGFR therapy is now well established, the prognostic value of KRAS mutation independent of treatment remains controversial. A large series of over 3,400 colorectal cancers patients found that only the glycine to valine mutation on colon 12, found in 8.6% of all cases, had a significant impact on disease free survival and overall survival (Andreyev et al. 2001). This mutation appeared to have a more significant negative impact on patients with Stage III disease, compared to those with Stage II tumors. However, several retrospective subset analyses from large randomized studies have failed to confirm this finding, including studies in which no difference relative to KRAS mutational status was observed in among patients treated with best supportive care (Ince et al. 2005; Amado et al. 2008; Karapetis et al. 2008).
3.3.1.1 Practical Applications of KRAS Mutational Analysis While clinical guidelines for KRAS mutational analysis in colorectal cancer are evolving, current provisional recommendations from the American Society for Clinical Oncology are that all patients with stage IV colorectal carcinoma, who are candidates for anti-EGFR antibody therapy, should have their tumors tested for KRAS mutations (http://www.asco. org/portal/site/ASCO/). Anti-EGFR antibody therapy is not recommended for patients whose tumors show mutation in KRAS codons 12 or 13. Testing for KRAS mutational status is generally initiated by the treating physician in most medical centers, although some institutions have implemented reflex testing for stage III or stage IV colorectal cancers. Polymerase chain reaction-based methods remain the cornerstone for KRAS mutational analysis; several commercial kits based upon allele-specific assays are available but none has been approved to date by the Federal Drug Administration. Refinements in DNA extraction techniques from formalin-fixed paraffin-embedded tissue blocks have increased sensitivity of DNA testing and eliminated the need for fresh or frozen tissue samples. Careful selection of the tumor block by the pathologist is necessary to minimize dilution of tumor DNA by contaminating normal cells such as fibroblasts, endothelial cells, and inflammatory cells; a target of at least 70% tumor cells is recommended. The most appropriate tissue for analysis appears to be the primary tumor, although testing of metastases
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is acceptable if the primary tumor is not available. Insufficient data exist to support recommendation of dual testing of primary and metastatic tumor (Conlin et al. 2005).
3.3.2 Allelic Imbalance in 18q Allelic loss of chromosome 18q is common in colorectal carcinomas, and is reported in 50% to almost 75% of tumors (Jen et al. 1994; Watanabe et al. 2001). Chromosome 18q21 contains several genes implicated in colorectal carcinogenesis, including DCC (deleted in colon cancer gene), as well as SMAD4 and SMAD2, involved in transforming growth factor signaling, although it remains unclear which genes on chromosome 18q play the most important roles in colorectal carcinoma tumorigenesis. While the preponderance of published studies support allelic imbalance in 18q as a poor prognostic marker, not all studies have been able to confirm this finding (Choi et al. 2002; Popat and Houlston 2005; Popat et al. 2007). Overall, Stage II colorectal carcinomas with 18q allelic imbalance appear to behave as poorly as average stage III carcinoma. Whether 18q allelic imbalance is a predictive factor for response to chemotherapy is unknown. For these reasons, current testing guidelines recommend that testing for 18q status in colorectal cancer be performed only in the clinical trial setting (Locker et al. 2006; Duffy et al. 2007).
3.3.3 Other Molecular Abnormalities Loss of p53 is a late event in colorectal carcinomas, occurring in about 50–75% of cancers (Vogelstein et al. 1988, 1989). Mutational status of TP53 has not been shown to have major prognostic or predictive value, however, and clinical testing is not recommended for GI carcinomas (Locker et al. 2006; Duffy et al. 2007). High tumor levels of thymidylate synthase (TS), the major target for 5-FU based therapies, have been associated with more advanced disease and poor response to adjuvant therapy in some but not all retrospective studies (Lenz et al. 1998; Paradiso et al. 2000; Allegra et al. 2002; Johnston et al. 2003). However, no standardized assay is available, and controversy exists regarding the best testing method and determination of a threshold value for resistance to 5-FU based therapy (Popat et al. 2004).
3.4 Molecular Testing in Other GI Cancers For GI cancers other than colorectal carcinoma and GI stromal tumors, tissue-based testing for potentially prognostic or predictive biomarkers is not currently recommended as standard of care. However, recent data from the ToGA trial demonstrate improved survival in locally advanced, recurrent, or metastatic gastroesophageal and gastric adenocarcinomas in patients whose tumors were positive for human epidermal growth factor receptor 2 (HER2) and were
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treated with trastuzumab added to standard chemotherapy (Van Cutsem et al. 2009a). These results suggest that testing gastric cancers for over-expression of HER2, as currently performed for breast cancers, should be considered, especially for patients with metastatic disease. For small bowel carcinomas, testing for defects in mismatch repair is important for detection of Lynch syndrome. Examination of the tissue for defective DNA mismatch repair should be considered in small intestinal carcinomas regardless of patient age (Umar et al. 2004), if other predisposing conditions such as familial adenomatous polyposis coli are absent. In addition, emerging data suggest that the frequency of MSI (18%) in small intestinal carcinomas is roughly equal to that of colon cancer (Planck et al. 2003) and may be associated with better survival (Brueckl et al. 2004). However, this latter indication for testing is not clearly established and has not been accepted as standard of care.
3.5 Summary of Recommendations for Molecular Testing in GI Carcinomas For colorectal carcinoma, testing for MSI and BRAF V600E mutational status is currently recommended for detection of Lynch syndrome and should be considered for stage II cancers in which microsatellite status would influence choice of therapy. Given the association between Lynch syndrome and small bowel adenocarcinomas, testing of these tumors for microsatellite status is also recommended. KRAS mutational analysis is indicated for colorectal cancers before treatment with anti-EGFR antibody therapy. Given results of the recent Phase III clinical trial in advanced gastric cancer, testing for overexpression of HER2 in these tumors should be performed if treatment with trastuzumab is a therapeutic option.
3.6 Gastrointestinal Stromal Tumor (GIST) GISTs are the most common mesenchymal neoplasms of the GI tract. GISTs may arise anywhere in the GI tract, but they most commonly occur in the stomach (50%), followed by the small bowel (25%) and colon/rectum (10%) (Brainard and Goldblum 1997; Tworek et al. 1997, 1999a, b; DeMatteo et al. 2000; Miettinen et al. 2000a, b, 2003, 2005b, 2006b). GISTs can also develop within the mesentery, omentum, retroperitoneum, and pelvis (Miettinen et al. 1999; Reith et al. 2000).
3.6.1 Pathology GISTs have a wide range of histologic appearances, from spindle cell to epithelioid, and immunohistochemistry is strongly recommended to verify the diagnosis (Kindblom et al. 1998; Sarlomo-Rikala et al. 1998; Fletcher et al. 2002). The tumors usually express
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KIT/CD117 (95%), DOG1 (98%), and CD34 (60–70%), and may show varying degrees of staining for smooth muscle actin (30–40%), S100 (5%), desmin (1–2%), and keratin (1–2%) (Kindblom et al. 1998; Sarlomo-Rikala et al. 1998; Fletcher et al. 2002). Approximately 5% of GISTs are KIT-negative and a subset of these cases may benefit from KIT-targeted therapy (Fletcher et al. 2002). Therefore, it is recommended that KITnegative GISTs be reviewed by a reference pathologist. GISTs range in size from small nodules less than 1 cm in diameter to large masses upwards of 35 cm (median 5 cm) (Demetri et al. 2004). GISTs share a number of electron microscopic and immunophenotypic features with the interstitial cells of Cajal (ICC) (Ramon y Cajal 1893; Thuneberg 1982; Sanders 1996; Kindblom et al. 1998; Kluppel et al. 1998). ICC are innervated cells associated with Auerbach’s plexus that have autonomous pacemaker function and coordinate peristalsis throughout the GI tract. It is widely hypothesized that GISTs either arise from ICC or share a common stem cell with them.
3.7 Oncogenic Kinase Mutations in GISTs Approximately 75–80% of GISTs have oncogenic mutations in the KIT gene (Hirota et al. 1998; Rubin et al. 2001; Heinrich et al. 2003a; Wardelmann et al. 2003). Most involve the juxtamembrane domain (exon 11) and consist of in-frame deletions or insertions, missense mutations, or combinations thereof. Mutations also occur in the extracellular domains of KIT (exons 8 and 9), as well as in the kinase I and II domains (exons 13 and 17) (Fig. 3.3). Among the 20–25% of GISTs that lack KIT gene mutations, approximately one third (8% of all GISTs) have mutations in a homologous receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA) (Heinrich et al. 2003b; Hirota et al. 2003). Sites of
KIT and PDGFRA Mutations in GISTs Genotyping of 1581 Cases Wild-type (18.6%) KIT
PDGFRA
Exon 8 (1 case) Exon 9 (9.9%)
Fig. 3.3 KIT and plateletderived growth factor receptor alpha (PDGFRA) mutations in gastrointestinal (GI) stromal tumors
Exon 11(60%)
Exon 12 (1.2%)
Exon 13 (2%)
Exon 14 (0.5%)
Exon 17 (1.3%)
Exon 18 (6.4%) CL Corless & MC Heinrich, unpublished
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mutations in this kinase parallel those in KIT (Fig. 3.3). KIT and PDGFRA mutations are mutually exclusive. Altogether, 85–90% of GISTs have a mutation in one or the other of these kinase genes (Fig. 3.3). Binding of KIT ligand (stem cell factor) results in dimerization of two KIT receptors, activation of their respective kinase domains, and phosphorylation of a variety of signaling substrates known to promote cell growth and survival (Blume-Jensen et al. 1991). The most common mutations affect the juxtamembrane region of KIT (exon 11), which, based on structural studies, normally serves to inhibit KIT dimerization in the absence of KIT ligand (Mol et al. 2004). Disruption of this domain promotes spontaneous kinase activation (Fig. 3.3) (Kitayama et al. 1995; Ma et al. 1999; Chan et al. 2003). Mutations in the kinase II domain, which are the most common type of mutation in PDGFRA, alter the socalled “activation loop,” which conformationally regulates the ATP-binding pocket. Through these and probably other mechanisms, mutations of KIT and PDGFRA promote continuous oncogenic signaling in GISTs. The importance of kinase mutations in GISTs is supported by a number of observations. KIT mutations are common in small (£1 cm), incidentally discovered GISTs, indicating that they occur very early in development (Corless et al. 2002; Agaimy et al. 2007). GIST extracts contain activated (phosphorylated) KIT or PDGFRA. Inhibition of KIT by kinase inhibitors blocks the growth of GIST cell lines (Tuveson et al. 2001; Nakatani et al. 2005; Heinrich et al. 2006; Tarn et al. 2006). Similarly, introduction of KIT shRNA into these cell lines also inhibits their growth (Heinrich et al. 2006). Expression of mutant KIT in transgenic “knock-in” mice results in KIT-positive spindle cell tumors that morphologically resemble GIST (Sommer et al. 2003; Rubin et al. 2005). Finally, GIST tumors that initially respond to the KIT/PDGFRA inhibitor imatinib mesylate (Gleevec/Glivec, Novartis) often become secondarily resistant through the acquisition of new mutations in KIT or PDGFRA that interfere with drug binding, which indicates a continued dependence on signaling from these kinases (Chen et al. 2004; Antonescu et al. 2005; Debiec-Rychter et al. 2005; Heinrich et al. 2006).
3.8 Molecular Classification of GISTs Subclassification of GISTs according to their kinase mutation status has both biological and clinical implications (Table 3.2). Whereas KIT exon 9-mutant GISTs arise almost exclusively in the small intestine and colon, GISTs with a PDGFRA D842V substitution (the single most common PDGFRA mutation), are limited to the stomach and omentum. In addition, GISTs with KIT exon 9 mutations are often high-risk or overtly malignant, suggesting an inherently more aggressive biology (Lasota et al. 1999; Sakurai et al. 2001; Corless et al. 2004). In contrast, PDGFRA-mutant tumors may be less aggressive overall than KIT-mutant GISTs (Lasota et al. 2004). GISTs with juxtamembrane mutations of KIT or PDGFRA, as well as “wild-type” GISTs, occur at all locations in the GI tract. As detailed below, the molecular subtypes of GIST differ greatly in their response to treatment with kinase inhibitors.
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3 Practical Gastrointestinal Oncology Correlative Science Table 3.2 Molecular classification of gastrointestinal stromal tumors (GISTs) Objective Genotype Approximate Familial In vitro frequency (%) examples sensitivity responsesa to imatinib (CR + PR by RECIST) KIT mutation Exon 8 Exon 9 Exon 11 Exon 13
80 <1 10 67 1
None None 10 Kindreds 2 Kindreds
Yes Yes Yes Yes
Exon 17
1
2 Kindreds
Yes
PDGFRA mutation Exon 12
5–8 1
2 Kindreds
Yes
Exon 14 Exon 18
<1 5
None None
Yes D842V is resistant
NR 34–40% 65–67% (Responses reported) (Responses reported)
(Responses reported) NR (Responses reported)
Progressive diseasea
NR 17% 3% – –
– NR Yes – D842V
Most others are sensitive Wild-type
12–15
23–40%
19%
NR no cases reported a Data combined from EORTC-AustralAsian phase III trial and North American SWOG phase III trial (Sinicrope et al. 2006)
3.8.1 GIST Variants Familial GIST is related to heritable mutations in KIT or PDGFRA (Hirota et al. 2000, 2002; Isozaki et al. 2000; Beghini et al. 2001; Maeyama et al. 2001; Chompret et al. 2004; Carballo et al. 2005; Hartmann et al. 2005; Ince et al. 2005; Kim et al. 2005; O’Riain et al. 2005; Lasota and Miettinen 2006). In kindred with such mutations, affected members develop multiple GISTs of the stomach and small bowel as early as age 18; diffuse ICC hyperplasia is often evident in the adjacent gut wall. Additional findings may include pigmented macules involving the skin of the perineum, axilla, hands and face, as well as evidence of skin mastocytosis (urticaria pigmentosa). Testing for germline KIT and PDGFRA mutations is clinically available and should be sought in the context of appropriate genetic counseling. Pediatric GIST are rare but have been divided into two subgroups: those with tumors that harbor a KIT or PDGFRA mutation similar to adult GISTs, and those with non-mutant tumors. Interestingly, the latter group dominates, being comprised almost exclusively of females presenting with gastric GIST by 20 years of age (Miettinen et al. 2005a; Prakash et al. 2005).
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Many of these cases overlap with Carney triad, a non-hereditary syndrome in which patients develop gastric GIST, paraganglioma and/or pulmonary chondroma (Carney 1999). GISTs in Type I Neurofibromatosis (NF1, von Recklinghausen’s neurofibromatosis) arise primarily in the small intestine. Approximately 7% of NF1 patients, will develop one or more GISTs, which tend to follow an indolent course (Zoller et al. 1997). The tumors are strongly KIT-positive by immunohistochemistry, yet they are generally negative for KIT mutations (Kinoshita et al. 2004; Andersson et al. 2005; Takazawa et al. 2005; Yantiss et al. 2005; Miettinen et al. 2006a).
3.9 Kinase Genotype and Treatment with Imatinib Mesylate Metastatic GIST typically presents with tumors isolated to the peritoneal cavity and/or the liver. Historically, the median survival of patients with advanced GIST was only 18–24 months, because these tumors respond poorly to conventional cytotoxic chemotherapy agents and probably radiation therapy (Shiu et al. 1982; Ng et al. 1992a, b; DeMatteo et al. 2000; Demetri et al. 2006). Imatinib mesylate is a small molecule tyrosine kinase inhibitor with activity against KIT, PDGFRA, PDGFRB, ABL and BCR-ABL (Buchdunger et al. 2000). It mimics ATP structurally and binds competitively to the ATP binding sites of its target kinases thereby shutting down signaling activity. A number of phase I/II and III clinical trials have demonstrated the efficacy of imatinib in the treatment of metastatic GIST (Heinrich et al. 2003b, 2008; Debiec-Rychter et al. 2004, 2006). Disease control is observed in 70–85% of patients and the median progression free survival is in the range of 20–24 months. Imatinib is approved by the U.S. FDA for the treatment of unresectable and metastatic GIST. Two randomized, multi-center phase III trials were conducted in Europe/AustralAsia and North America to compare the relative efficacy of 400 mg vs. 800 mg of imatinib (DebiecRychter et al. 2006; Heinrich et al. 2008) (additional details available in Chap. 6). These trials served to establish two important differences between the various genotypic subtypes of GIST. First, progression free and overall survivals were significantly better for patients with KIT exon 11-mutant GIST as compared those with exon 9-mutant tumors, tumors lacking a KIT or PDGFRA mutation (wild-type tumors), and tumors with a PDGFRA D842V mutation (which is inherently imatinib resistant). Second, the progression free survival of patients with exon 9-mutant tumors was better on the 800 mg arm as compared with the 400 mg arm in the Europe/AustralAsia study. This trend was also seen in the North American trial (Heinrich et al. 2008). In contrast, exon 11-mutant and WT tumors responded equally well to 400 and 800 mg of imatinib (Debiec-Rychter et al. 2006; Heinrich et al. 2008).
3.9.1 Adjuvant Imatinib and Kinase Genotype A large randomized trial of 12 months of adjuvant imatinib vs. placebo for fully resected GISTs 3 cm or larger showed a clear benefit of drug treatment in regard to progression free
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survival, leading to FDA approval of adjuvant therapy (Dematteo et al. 2009). Correlative genotyping studies conducted in this trial will be completed in 2009–2010.
3.10 Imatinib Resistance Although imatinib has dramatically improved the quality of life and survival of patients with advanced GIST, the majority of patients are not cured (Benjamin et al. 2003; Heinrich et al. 2003a; Verweij et al. 2004). Resistance to the drug can be divided into two categories. A minority of patients (10–15%) have tumors that do not respond to treatment within the first 6 months of treatment. KIT exon 9-mutant and wild-type tumors are over-represented in this group (Heinrich et al. 2003a; Debiec-Rychter et al. 2004). However, most patients develop one or more sites of disease progression after more than 6 months of clinical response. Such secondary resistance is almost invariably related to the acquisition (or selection) of new kinase mutations in KIT (or PDGFRA) that interfere with imatinib activity (Fletcher et al. 2003; Chen et al. 2004; Tamborini et al. 2004; Antonescu et al. 2005; Debiec-Rychter et al. 2005; Heinrich et al. 2006). In all likelihood, the emergence of these secondary mutations is due to a population of GIST cells for which imatinib is cytostatic rather than cytocidal. As with other cancers, medical cure of GIST may require eradication of the transformed stem cells that give rise to the tumor.
3.10.1 Sunitinib Sunitinib (Sutent, Pfizer) is FDA-approved for the treatment of patients with imatinib-resistant GIST. In addition to targeting KIT, sunitinib has antiangiogenic effects through inhibition of vascular endothelial growth factor receptor. In the pivotal, double-blind, placebo-controlled phase III trial of this drug, the median time to progression was 6.3 months vs. 1.5 months on placebo (Demetri et al. 2006). Interestingly, analysis of a phase I/II trial revealed that patients with KIT exon 9-mutant GIST, or wild-type GIST, had better and more durable responses to sunitinib than those with KIT exon 11-mutant tumors (Maki et al. 2005). This is probably because exon 11-mutant tumors have a higher frequency of secondary resistance mutations, many of which confer cross-resistance to sunitinib. Screening for secondary resistance mutations to predict the benefit of sunitinib therapy has been proposed, but there is remarkable inter- and intra-tumoral heterogeneity of these mutations, making it impractical to assess disease status on the basis of limited biopsy material.
3.10.2 Other Tyrosine Kinase Inhibitors Other kinase inhibitors being tested for the treatment of imatinib-resistant GIST include dasatinib (Sprycel, Bristol Myers Squibb), sorafenib (Nexavar, Bayer) and nilotinib
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(Tasigna, Novartis). There are as yet no data on whether kinase genotyping will have a role in predicting benefit from these drugs in either the pre- or post-imatinib setting.
3.11 Recommendations for GIST Genotyping Based on the data from the phase III trials, kinase genotyping is recommended by the NCCN for all newly diagnosed high-risk and malignant GISTs (Demetri et al. 2007). Mutation status can be used to predict the likelihood of benefit from imatinib therapy and to determine the optimal dose for treatment. At a minimum, gastric tumors should be screened for KIT exon 11 mutations, which predict for the best overall imatinib response and survival. Small and perhaps large intestinal GISTs should be screened for mutations in KIT exons 11 and 9, as the latter appear to respond better to higher dose imatinib (800 mg/ day). For tumors lacking an exon 11 or 9 mutation, additional screening to rule out mutations in KIT (exons 13 and 17) and PDGFRA (exons 12, 14 and 18) is necessary to establish a WT genotype, which is associated with a significantly shorter PFS on imatinib. This additional screening can identify PDGFRA mutations that are responsive to imatinib as opposed to the inherently resistant substitution D842V. GIST genotyping is sometimes used in the setting of disease progression on imatinib to help determine whether dose escalation should be pursued or a switch should be made to sunitinib or another kinase inhibitor. Patients with KIT exon 9-mutant GIST may benefit from a higher dose of imatinib, while those with exon 11-mutant or WT GISTs are more likely to respond to another inhibitor. As discussed above, screening for specific imatinib-resistant mutations in progressing patients is not recommended due to the remarkable heterogeneity of such mutations between individual tumor nodules.
3.12 Summary This chapter has discussed current recommendations for molecular testing of GI carcinomas and stromal tumors, emphasizing selection of tests that impact clinical decisionmaking. However, as we move into the era of individualized medicine, recommendations and practice patterns are rapidly changing as tumor molecular characteristics predictive of response to available therapies are identified. For instance, KRAS mutational status as a predictor of response to monoclonal antibody-based anti-EGFR therapy has emerged as new and powerful tool in selection of therapy in advanced colorectal cancer. Correlative science from retrospective studies and from prospective clinical trials will remain critically important in further advances in tailoring treatment options for the individual patient.
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References Agaimy A, Wunsch PH, Hofstaedter F, Blaszyk H, Rummele P, Gaumann A et al (2007) Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol 31:113–120 Alexander J, Watanabe T, Wu T-T, Rashid A, Li S, Hamilton SR (2001) Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 158:527–535 Allegra CJ, Parr AL, Wold LE, Mahoney MR, Sargent DJ, Johnston P et al (2002) Investigation of the prognostic and predictive value of thymidylate synthase, p53, and Ki-67 in patients with locally advanced colon cancer. J Clin Oncol 20:1735–1743 Amado RG, Wolf M, Peters M, Van CE, Siena S, Freeman DJ et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634 Andersson J, Sihto H, Meis-Kindblom JM, Joensuu H, Nupponen N, Kindblom LG (2005) NF1associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics. Am J Surg Pathol 29:1170–1176 Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ et al (2001) Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer 85:692–696 Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B et al (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11:4182–4190 Beghini A, Tibiletti MG, Roversi G, Chiaravalli AM, Serio G, Capella C et al (2001) Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer 92:657–662 Benatti P, Gafa R, Barana D, Marino M, Scarselli A, Pedroni M et al (2005) Microsatellite instability and colorectal cancer prognosis [see comment] [erratum appears in Clin Cancer Res 2006 Jun 15;12(12):3868–3869]. Clin Cancer Res 11:8332–8340 Benjamin RS, Rankin C, Fletcher C, Blanke C, Von Mehren M, Maki R et al; for the Sarcoma Intergroup (2003) Phase III dose-randomized study of imatinib mesylate (ST1571) for GIST: Intergroup S0033 early results. Proc Am Soc Clin Oncol 22:814 Bessa X, Balleste B, Andreu M, Castells A, Bellosillo B, Balaguer F et al (2008) A prospective, multicenter, population-based study of BRAF mutational analysis for Lynch syndrome screening. Clin Gastroenterol Hepatol 6:206–214 Bisgaard ML, Fenger K, Bulow S, Niebuhr E, Mohr J, Bisgaard ML et al (1994) Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat 3:121–125 Blume-Jensen P, Claesson-Welsh L, Siegbahn A, Zsebo KM, Westermark B, Heldin CH (1991) Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis. EMBO J 10:4121–4128 Bokemeyer C, Bondarenko I, Hartmann JT, De Braud FG, Volovat C, Nippgen J et al (2008) KRAS status and efficiency of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. J Clin Oncol 26:178s Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW et al (1998) A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257 Brainard JA, Goldblum JR (1997) Stromal tumors of the jejunum and ileum: a clinicopathologic study of 39 cases. Am J Surg Pathol 21:407–416 Brueckl WM, Heinze E, Milsmann C, Wein A, Koebnick C, Jung A et al (2004) Prognostic significance of microsatellite instability in curatively resected adenocarcinoma of the small intestine. Cancer Lett 203:181–190
60
K. Washington and C.L. Corless
Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ et al (2000) Abl proteintyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295:139–145 Carballo M, Roig I, Aguilar F, Pol MA, Gamundi MJ, Hernan I et al (2005) Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation. Am J Med Genet A 132:361–364 Carney JA (1999) Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc 74:543–552 Chan PM, Ilangumaran S, La Rose J, Chakrabartty A, Rottapel R (2003) Autoinhibition of the kit receptor tyrosine kinase by the cytosolic juxtamembrane region. Mol Cell Biol 23: 3067–3078 Chen LL, Trent JC, Wu EF, Fuller GN, Ramdas L, Zhang W et al (2004) A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 64:5913–5919 Choi SW, Lee KJ, Bae YA, Min KO, Kwon MS, Kim KM et al (2002) Genetic classification of colorectal cancer based on chromosomal loss and microsatellite instability predicts survival. Clin Cancer Res 8:2311–2322 Chompret A, Kannengiesser C, Barrois M, Terrier P, Dahan P, Tursz T et al (2004) PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 126:318–321 Conlin A, Smith G, Carey FA, Wolf CR, Steele RJC (2005) The prognostic significance of K-ras, p53, and APC mutations in colorectal carcinoma. Gut 54:1283–1286 Corless CL, McGreevey L, Haley A, Town A, Heinrich MC (2002) KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 160:1567–1572 Corless CL, Fletcher JA, Heinrich MC (2004) Biology of gastrointestinal stromal tumors. J Clin Oncol 22:3813–3825 Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M et al (2004) Use of c-KIT/ PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 40:689–695 Debiec-Rychter M, Cools J, Dumez H, Sciot R, Stul M, Mentens N et al (2005) Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 128:270–279 Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT et al (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093–1103 DeMatteo RP, Lewis JJ, Leung D, Mundan SS, Woodruff JM, Brennan MF (2000) Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 231:51–58 Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD et al (2009) Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373:1097–1104 Demetri GD BR, Blanke CD et al (2004) NCCN task force report: optimal management of patient with gastrointestinal stromal tumor (GIST) – expansion and update of NCCN clinical practice guidelines. J Natl Compr Canc Netw 2(suppl 1):S1–S26 Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J et al (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368:1329–1338
3 Practical Gastrointestinal Oncology Correlative Science
61
Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H et al (2007) NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST) – update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5(suppl 2):S1–S29; quiz S30 Domingo E, Niessen RC, Oliveira C, Alhopuro P, Moutinho C, Espin E et al (2005) BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Oncogene 24:3995–3998 Duffy MJ, Van Dalen A, Haglund C, Hansson L, Holinski-Feder E, Klapdor R et al (2007) Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur J Cancer 43:1348–1360 Fletcher JA, Corless C, Dimitrijevic S, von Mehren M, Eisenberg B, Joensuu H et al; for the GIST Working Group (2003) Mechanisms of resistance to imatinib mesylate (IM) in advanced gastrointestinal stromal tumor (GIST). Proc Am Soc Clin Oncol 22:815 Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ et al (2002) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33:459–465 French AJ, Sargent DJ, Burgart LJ, Foster NR, Kabat BF, Goldberg R et al (2008) Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res 14:3408–3415 Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Trougouboff P, Tomsho LD et al (2003) Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol 27:563–570 Halling KC, French AJ, McDonnell SK, Burgart LJ, Schaid DJ, Peterson BJ et al (1999) Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers [see comment]. J Natl Cancer Inst 91:1295–1303 Hartmann K, Wardelmann E, Ma Y, Merkelbach-Bruse S, Preussner LM, Woolery C et al (2005) Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology 129:1042–1046 Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H et al (2003a) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349 Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N et al (2003b) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710 Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ et al (2006) Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24:4764–4774 Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD et al (2008) Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 26:5360–5367 Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S et al (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580 Hirota S, Okazaki T, Kitamura Y, O’Brien P, Kapusta L, Dardick I (2000) Cause of familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germline mutation of the c-kit gene. Am J Surg Pathol 24:326–327 Hirota S, Nishida T, Isozaki K, Taniguchi M, Nishikawa K, Ohashi A et al (2002) Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene. Gastroenterology 122:1493–1499 Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y et al (2003) Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology 125:660–667
62
K. Washington and C.L. Corless
Ince WL, Jubb AM, Holden SN, Holmgren EB, Tobin P, Sridhar M et al (2005) Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 97:981–989 Isozaki K, Terris B, Belghiti J, Schiffmann S, Hirota S, Vanderwinden JM (2000) Germlineactivating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. Am J Pathol 157:1581–1585 Jen J, Kim H, Piantadosi S, Liu ZF, Levitt RC, Sistonen P et al (1994) Allelic loss of chromosome 18q and prognosis in colorectal cancer [see comment]. N Engl J Med 331:213–221 Jimeno A, Messersmith WA, Hirsch FR, Franklin WA, Eckhardt SG (2009) KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. J Clin Oncol 27:1130–1136 Johnston PG, Benson AB III, Catalano P, Rao MS, O’Dwyer PJ, Allegra CJ et al (2003) Thymidylate synthase protein expression in primary colorectal cancer: lack of correlation with outcome and response to fluorouracil in metastatic disease sites. J Clin Oncol 21:815–819 Jover R, Zapater P, Castells A, Llor X, Andreu M, Cubiella J et al (2009) The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status [see comment]. Eur J Cancer 45:365–373 Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer [see comment]. N Engl J Med 359:1757–1765 Kern SE, Fearon ER, Tersmette KW, Enterline JP, Leppert M, Nakamura Y et al (1989) Clinical and pathological associations with allelic loss in colorectal carcinoma [corrected] [erratum appears in JAMA 1989 Oct 13;262(14):1952]. JAMA 261:3099–3103 Kim HJ, Lim SJ, Park K, Yuh YJ, Jang SJ, Choi J (2005) Multiple gastrointestinal stromal tumors with a germline c-kit mutation. Pathol Int 55:655–659 Kim GP, Colangelo LH, Wieand HS, Paik S, Kirsch IR, Wolmark N et al (2007) Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study [see comment]. J Clin Oncol 25:767–772 Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM (1998) Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 152:1259–1269 Kinoshita K, Hirota S, Isozaki K, Ohashi A, Nishida T, Kitamura Y et al (2004) Absence of c-kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patients. J Pathol 202:80–85 Kitayama H, Kanakura Y, Furitsu T, Tsujimura T, Oritani K, Ikeda H et al (1995) Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. Blood 85:790–798 Kluppel M, Huizinga JD, Malysz J, Bernstein A (1998) Developmental origin and Kit-dependent development of the interstitial cells of cajal in the mammalian small intestine. Dev Dyn 211:60–71 Lamberti C, Lundin S, Bogdanow M, Pagenstecher C, Friedrichs N, Buttner R et al (2007) Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer. Int J Colorectal Dis 22:145–152 Lasota J, Miettinen M (2006) A new familial GIST identified. Am J Surg Pathol 30:1342 Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M (1999) Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol 154:53–60 Lasota J, Dansonka-Mieszkowska A, Sobin LH, Miettinen M (2004) A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential. Lab Invest 84:874–883
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Lenz HJ, Hayashi K, Salonga D, Danenberg KD, Danenberg PV, Metzger R et al (1998) p53 Point mutations and thymidylate synthase messenger RNA levels in disseminated colorectal cancer: an analysis of response and survival. Clin Cancer Res 4:1243–1250 Lievre A, Bachet J-B, Le Corre D, Boige V, Landi B, Emile J-F et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66: 3992–3995 Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS et al (2006) ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer [see comment]. J Clin Oncol 24:5313–5327 Ma Y, Cunningham M, Wang X, Ghosh I, Regan L, Longley B (1999) Inhibition of spontaneous receptor phosphorylation by residues in putative alpha-helix in the KIT intracellular juxtamembrane region. J Biol Chem 274:13399–13402 Maeyama H, Hidaka E, Ota H, Minami S, Kajiyama M, Kuraishi A et al (2001) Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene. Gastroenterology 120:210–215 Maki R, Fletcher JA, Heinrich M et al (2005) Results from a continuation trial of SU11248 in patient (pts) with imatinib (IM)-resistant gastrointestinal stromal tumor (GIST). Proc Am Soc Clin Oncol 24:Abstract 9011 Miettinen M, Monihan JM, Sarlomo-Rikala M, Kovatich AJ, Carr NJ, Emory TS et al (1999) Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases. Am J Surg Pathol 23:1109–1118 Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J (2000a) Esophageal stromal tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas. Am J Surg Pathol 24:211–222 Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J (2000b) Gastrointestinal stromal tumors and leiomyosarcomas in the colon: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases. Am J Surg Pathol 24:1339–1352 Miettinen M, Kopczynski J, Makhlouf HR, Sarlomo-Rikala M, Gyorffy H, Burke A et al (2003) Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. Am J Surg Pathol 27:625–641 Miettinen M, Lasota J, Sobin LH (2005a) Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol 29: 1373–1381 Miettinen M, Sobin LH, Lasota J (2005b) Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with longterm follow-up. Am J Surg Pathol 29:52–68 Miettinen M, Fetsch JF, Sobin LH, Lasota J (2006a) Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 30:90–96 Miettinen M, Makhlouf H, Sobin LH, Lasota J (2006b) Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol 30:477–489 Mirabelli-Primdahl L, Gryfe R, Kim H, Millar A, Luceri C, Dale D et al (1999) Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer Res 59:3346–3351 Mol CD, Dougan DR, Schneider TR, Skene RJ, Kraus ML, Scheibe DN et al (2004) Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem 279:31655–31663
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Nakatani H, Kobayashi M, Jin T, Taguchi T, Sugimoto T, Nakano T et al (2005) STI571 (Glivec) inhibits the interaction between c-KIT and heat shock protein 90 of the gastrointestinal stromal tumor cell line, GIST-T1. Cancer Sci 96:116–119 Ng EH, Pollock RE, Munsell MF, Atkinson EN, Romsdahl MM (1992a) Prognostic factors influencing survival in gastrointestinal leiomyosarcomas. Implications for surgical management and staging. Ann Surg 215:68–77 Ng EH, Pollock RE, Romsdahl MM (1992b) Prognostic implications of patterns of failure for gastrointestinal leiomyosarcomas. Cancer 69:1334–1341 O’Riain C, Corless CL, Heinrich MC, Keegan D, Vioreanu M, Maguire D et al (2005) Gastrointestinal stromal tumors: insights from a new familial GIST kindred with unusual genetic and pathologic features. Am J Surg Pathol 29:1680–1683 Paradiso A, Simone G, Petroni S, Leone B, Vallejo C, Lacava J et al (2000) Thymidilate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients. Br J Cancer 82:560–567 Planck M, Ericson K, Piotrowska Z, Halvarsson B, Rambech E, Nilbert M (2003) Microsatellite instability and expression of MLH1 and MSH2 in carcinomas of the small intestine [see comment]. Cancer 97:1551–1557 Popat S, Houlston RS (2005) A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status, and colorectal cancer prognosis. Eur J Cancer 41: 2060–2070 Popat S, Matakidou A, Houlston RS (2004) Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 22:529–536 Popat S, Zhao D, Chen Z, Pan H, Shao Y, Chandler I et al (2007) Relationship between chromosome 18q status and colorectal cancer prognosis: a prospective, blinded analysis of 280 patients [erratum appears in Anticancer Res 2007 Mar-Apr;27(2):1231]. Anticancer Res 27:627–633 Prakash S, Sarran L, Socci N, DeMatteo RP, Eisenstat J, Greco AM et al (2005) Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol 27:179–187 Ramon y Cajal S (1893) Sur les ganglions et plexus nerveux de l’intestin. Comp Rend Soc Biol Paris 45:217–223 Reith JD, Goldblum JR, Lyles RH, Weiss SW (2000) Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol 13:577–585 Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257 Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R et al (2001) KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61:8118–8121 Rubin BP, Antonescu CR, Scott-Browne JP, Comstock ML, Gu Y, Tanas MR et al (2005) A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E. Cancer Res 65:6631–6639 Sakurai S, Oguni S, Hironaka M, Fukayama M, Morinaga S, Saito K (2001) Mutations in c-kit gene exons 9 and 13 in gastrointestinal stromal tumors among Japanese. Jpn J Cancer Res 92:494–498 Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M et al (2001) Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level [see comment]. Cancer Epidemiol Biomarkers Prev 10:917–923 Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA et al (2005) Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer [see comment]. Gastroenterology 129:837–845 Sanders KM (1996) A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract. Gastroenterology 111:492–515
3 Practical Gastrointestinal Oncology Correlative Science
65
Sargent DJ, Marsoni S, Thibodeau SN, Labianca R, Hamilton SR, Torri V et al (2008) Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and stage III colon cancer (CC): a pooled molecular reanalysis of randomized chemotherapy trials. J Clin Oncol 26(suppl 15):Abstract #4008 Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M (1998) CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol 11:728–734 Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y et al (2007) Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A 104:18654–18659 Shiu MH, Farr GH, Papachristou DN, Hajdu SI (1982) Myosarcomas of the stomach: natural history, prognostic factors and management. Cancer 49:177–187 Sinicrope FA, Sargent DJ (2009) Clinical implications of microsatellite instability in sporadic colon cancers. Curr Opin Oncol 21:369–373 Sinicrope FA, Rego RL, Halling KC, Foster N, Sargent DJ, La Plant B et al (2006) Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology 131:729–737 Sommer G, Agosti V, Ehlers I et al (2003) Gastrointestinal stromal tumors in a mouse model by targeted mutations of the Kit receptor tyrosine kinase. Proc Natl Acad Sci U S A 100:6706–6711 Takazawa Y, Sakurai S, Sakuma Y, Ikeda T, Yamaguchi J, Hashizume Y et al (2005) Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen’s disease). Am J Surg Pathol 29:755–763 Tamborini E, Bonadiman L, Greco A, Albertini V, Negri T, Gronchi A et al (2004) A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 127:294–299 Tarn C, Skorobogatko YV, Taguchi T, Eisenberg B, von Mehren M, Godwin AK (2006) Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms. Cancer Res 66:5477–5486 Thuneberg L (1982) Interstitial cells of Cajal: intestinal pacemaker cells? Adv Anat Embryol Cell Biol 71:1–130 Tsao J-I, Shibata D (1994) Further evidence that one of the earliest alterations in colorectal carcinogenesis involves APC. Am J Pathol 145:531–534 Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD et al (2001) STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 20:5054–5058 Tworek JA, Appelman HD, Singleton TP, Greenson JK (1997) Stromal tumors of the jejunum and ileum. Mod Pathol 10:200–209 Tworek JA, Goldblum JR, Weiss SW, Greenson JK, Appelman HD (1999a) Stromal tumors of the abdominal colon: a clinicopathologic study of 20 cases. Am J Surg Pathol 23:937–945 Tworek JA, Goldblum JR, Weiss SW, Greenson JK, Appelman HD (1999b) Stromal tumors of the anorectum: a clinicopathologic study of 22 cases. Am J Surg Pathol 23:946–954 Umar A, Boland R, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J et al (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268 Van Cutsem E, Kang Y, Chung H, Shen L, Sawaki A, Lordick F et al (2009a) Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy (CT) in firstline human epidermal grown factor receptor 2 (HER2)-positive advanced gastric cancer. J Clin Oncol 27:Abstract LBA4509 Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A et al (2009b) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417
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Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY et al (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364:1127–1134 Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532 Vogelstein B, Fearon ER, Kern SE, Hamilton SR, Preisinger AC, Nakamura Y et al (1989) Allelotype of colorectal carcinomas. Science 244:207–211 Wardelmann E, Losen I, Hans V, Neidt I, Speidel N, Bierhoff E et al (2003) Deletion of Trp-557 and Lys-558 in the juxtamembrane domain of the c-kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors. Int J Cancer 106:887–895 Watanabe T, Tsung-Teh W, Catalano PJ, Ueki T, Satriano R, Haller DG et al (2001) Molecular predictors of survival after adjuvant therapy for colon cancer. N Engl J Med 344:1196–1206 Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA et al (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer [see comment]. Nat Genet 38:787–793 Yantiss RK, Rosenberg AE, Sarran L, Besmer P, Antonescu CR (2005) Multiple gastrointestinal stromal tumors in type I neurofibromatosis: a pathologic and molecular study. Mod Pathol 18:475–484 Yashiro M, Carethers JM, Laghi L, Saito K, Slezak P, Jaramillo E et al (2001) Genetic pathways in the evolution of morphologically distinct colorectal neoplasms. Cancer Res 61:2676–2683 Zoller ME, Rembeck B, Oden A, Samuelsson M, Angervall L (1997) Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer 79:2125–2131
Esophageal Cancer
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Florian Lordick and Arnulf Hölscher
4.1 Epidemiology In contrast to gastric cancer incidence, which is decreasing worldwide, the incidence and prevalence of esophageal carcinoma is rising at an alarming rate worldwide (Pohl 2005). This rise is due primarily to an increase in the rate of adenocarcinoma of the distal esophagus (Kamangar et al. 2006). At many institutions in the world, adenocarcinomas of the esophagus now outnumber squamous cell esophageal cancers. Because of marked differences in the pathogenesis, tumor location, tumor biology, and characteristics of the affected patients (Table 4.1), squamous cell carcinoma and adenocarcinoma of the esophagus should be treated as separate entities to a certain extent. This differentiation is frequently not made when treatment results for esophageal cancer are reported. Esophageal cancer is the ninth most common cancer in the world. Esophageal cancer is a disease of mid to late adulthood (60–70 years). There is a marked variation in its incidence according to sex, geographical area, and racial and economical background. The annual age-adjusted incidence rate among males varies from less than 5 cases per 100,000 population among whites in the United States to 18.7–26.5 per 100,000 cases in some regions of France, with up to 100 cases per 100,000 in Linxian (China) or the Caspian region of Iran. In most countries, esophageal cancer is two to four times more frequent in men than in women. In China and Iran, this cancer is almost as frequent in women as in men. Esophageal squamous cell carcinoma occurs five times more often among blacks than whites; this excess is greater at younger ages. Esophageal cancer is one of the most common malignancies among black men younger than 55. In China, the country with the
F. Lordick (*) Third Medical Department, Klinikum Braunschweig, Hannover Medical School, Celler Straße 38, 38104 Braunschweig, Germany e-mail:
[email protected] A. Hölscher Department of Surgery and Centre of Integrated Oncology (CIO), University of Cologne, Cologne, Germany C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_4, © Springer-Verlag Berlin Heidelberg 2011
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Table 4.1 Comparison of patient characteristics for those with squamous cell esophageal cancer and adenocarcinoma of the distal esophagus Adenocarcinoma of Squamous cell p Value the distal esophagus esophageal carcinoma Median age
53.4 years
62.6 years
<0.001
Male-to-female ratio
7:1
8:1
NS
Profession (prevalence) Academic White collar Blue collar
20.8% 27.2% 52.2%
52.9% 27.7% 20.2%
<0.001
Alcohol abuse (prevalence)
69.7%
42.3%
<0.001
Smoking (prevalence)
69.3%
51.9%
<0.05
Malnutrition (prevalence)
24.1%
1.9%
<0.001
Pulmonary function (mean FEV1,% of normal)
82.5%
93.7%
<0.05
Cardiovascular risk factors (prevalence)
19.5%
34.8%
<0.01
Impaired liver function (prevalence)
35.3%
24.9%
<0.05
FEV1 forced expiratory volume in 1 s; NS not significant Data are for patients treated at the Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 1982–2000
highest mortality rate due to this disease, incidence rates have been decreasing since the 1970s, probably as a consequence of a diet with higher contents of foods rich in proteins, carotene, vitamins C and E, and riboflavin. At the same time, more cases of squamous cell carcinoma are due to an increase in the consumption of tobacco and alcohol, reflecting the economic changes in these areas.
4.2 Etiologic Factors 4.2.1 Squamous Cell Cancer Both alcohol consumption and smoking increase risk, typically in a synergistic manner. In a study made on a French population, among heavy smokers and heavy drinkers
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the relative incidence risk was >100-fold. Risk is five times higher among cigarette smokers than nonsmokers. The risk depends mainly on the duration of consumption: a moderate intake during a long period carries a higher risk than a high intake during a shorter period (Launoy et al. 1997). Among drinkers of alcohol, the risk appeared increased and related to the amount consumed (20–50-fold), with former and current consumption having similar effects. A very low risk is associated with a low alcohol intake. Smoking and drinking are independent risk factors. Racial differences may account for the excessive risk of esophageal cancer in black men. In countries with the highest esophageal cancer rates (some parts of China, Iran, South Africa), micronutrient deficiencies (beta-carotene, several B vitamins, vitamin C, magnesium, zinc, and certain minerals) prevail. Some dietary habits have been associated with increased risk: pickled vegetables and other foods that may become moldy or fermented, very hot drinks and foods, diets rich in cereals but with low intake of fruit and vegetables. Randomized trials investigating the effects of supplementation with vitamins and minerals on esophageal cancer risk have recently been reported from China where, after 5 years of supplementation, death rates from cancer were significantly lower (by 13%) among those who received the combination of beta-carotene, vitamin E, and selenium. Another effect of the supplements was a greater proportion of dysplasia regression (Qiao et al. 2009). From these results, it appears likely that improved nutrition may help lower the incidence of esophageal cancer among individuals at high risk. Other factors that may play a minor role are occupational exposures to asbestos, vulcanization combustion products, and several types of metal dust (chromium, nickel, beryllium). Ionizing radiations may also increase the risk. Several reports have described the occurrence of esophageal carcinoma after thoracic radiation. Radiation therapy for breast cancer may increase the risk for developing esophageal squamous cell carcinoma 10 or more years after radiation therapy (Ahsan 1998). Genetic predisposition to the malignancy is uncommon (Dhillon et al. 2001). Ninety-five percent of patients with congenital palmar and plantar keratosis (tylosis) develop an esophageal cancer before the age of 65 (Moodley et al. 2007). Predisposing conditions to esophageal carcinoma are chronic inflammation, achalasia, caustic injury, and Plummer-Vinson syndrome (Kamangar et al. 2009). Predisposing agents act as inducers of dysplasia which is recognized as a preneoplastic situation. Human papillomavirus (HPV) infection, notably HPV types 16 and 18, may play an important role in the pathogenesis of squamous cell carcinoma in high-incidence areas, including China and South Africa. HPV infection occurs infrequently in association with squamous cell carcinoma in patients from low-risks areas (He et al. 1997; Rugge et al. 1997; Turner et al. 1997). An elevated risk of esophageal carcinomas following tobacco-related malignancies has been reported (Kesting et al. 2009; Yokoyama et al. 2008).
4.2.2 Adenocarcinoma The increase in esophageal and esophagogastric junction adenocarcinomas is not yet completely understood. Adenocarcinoma preferentially develops in metaplastic epithelium of
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the distal esophagus which occurs as a sequela of chronic gastroesophageal reflux disease (Lagergren et al. 1999). Obesity is a predisposition that facilitates gastroesophageal reflux disease and has been identified to be associated with esophageal adenocarcinoma. Consumption of lower esophageal sphincter relaxing drugs has been identified as another risk factor while the presence of Helicobacter pylori infection as well as high fruit and vegetable intake have been associated with a protective effect (Lagergren 2005). These risk factors seem to have differential effects in the male and female populations (Löfdahl et al. 2008). Eighty-five percent of patients presenting with adenocarcinoma of the distal esophagus have a history of reflux symptoms (Leers et al. 2005; Witzig et al. 2006). According to the person who first described this transformation in 1953, this metaplasia is called Barrett’s epithelium (Thompson et al. 1983). The tumor that develops in this epithelium is called Barrett’s carcinoma. An esophageal columnar metaplasia can be found in more than 90% of patients with adenocarcinoma of the esophagus. Persons with Barrett’s esophagus have a 125-fold lifetime risk to develop an adenocarcinoma of the esophagus. Predisposing lesions are low-grade and high-grade intraepithelial dysplasias which are triggered by a variety of genetic mutations and epigenetic events (Hao et al. 2006; Tischoff and Tannapfel 2008; Wiech et al. 2009). The risk for developing cancer is significantly higher for a long- vs. a short-segment esophagus but even in short-segment metaplasia (<3 cm of length), the risk for developing cancer seems to be elevated at least in some studies (Rudolph et al. 2000; Thomas et al. 2007). Several chemopreventive strategies for populations at risk have been postulated, among which low-dose intake of aspirin is probably the most promising one (Neumann et al. 2009). The Aspect trial is currently recruiting patients; first interim results are awaited in 2011 (Das et al. 2009).
4.3 Classification and Pathology 4.3.1 Squamous Cell Carcinoma Squamous cell carcinoma has been the most common histotype among esophageal malignancies. Macroscopically it can be classified into vegetating, infiltrating, and ulcerated tumors. Most of them appear histologically as well-differentiated neoplasms. Poorly differentiated cancers may be composed of polyhedral cells, sometimes simulating a glandular-like epithelium. In other cases, either “small cells” or giant cells may be present in poorly differentiated squamous cancers. In advanced cancers, histology frequently demonstrates areas of necrosis. Tumor grading does not seem to be a significant prognostic parameter. Verrucous carcinoma is a rare variant of well-differentiated squamous cancers. Spindle cell carcinoma is a variant of poorly differentiated squamous cancers; it may be mistaken for a sarcoma or carcinosarcoma. Basaloid squamous cell carcinoma is a recently recognized variant of poorly differentiated squamous cancers; after surgery the prognosis is similar to that of patients with typical squamous cell carcinoma.
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4.3.2 Adenocarcinoma Adenocarcinoma is now the most common histotype of esophageal cancers in most regions with a more Western-type lifestyle. It is formed by a glandular epithelium, with papillary and/or tubular structure. Most esophageal adenocarcinomas originate from areas of Barrett’s epithelium, or glandular metaplasia of the esophageal mucosa. Adenocarcinoma has a site predilection for the distal third of the esophagus. Macroscopic characteristics of these tumors are similar to those of squamous cancers. Other sites of origin of adenocarcinomas are islands of heterotopic gastric mucosa or cardiac glands and esophageal glands in the submucosa.
4.3.3 Precancerous Lesions Dysplasia is an epithelial precancerous lesion. Histologically it is characterized by nuclear enlargement and hyperchromaticity with increased mitotic activity. Dysplasia in the esophagus can be either squamous or glandular. Squamous cell dysplasia is found preceding or combining with squamous carcinoma. Glandular dysplasia is associated with adenocarcinoma complicating Barrett’s esophagus; dysplasia develops more frequently in the intestinal than in the gastric type of mucosa. Increasing grades of dysplasia, from mild to severe, appear to be associated with increasing risk of cancer. In China, when dysplasia was histologically evaluated, the cumulative incidence of squamous cell carcinoma is reported to be 30% for moderate dysplasia and 65% for severe dysplasia or carcinoma in situ in a 3.5-year observation period (Lightdale 1996). High-grade dysplasia is described as carcinoma in situ. Natural history of high-grade glandular dysplasia is not well defined, since high-grade dysplasia can remain stable without progressing, or it can even disappear. High-grade dysplasia in Barrett’s esophagus may be associated with invasive cancer in one third of patients (Spechler 1994).
4.3.4 Differential Pathologic Diagnosis Experienced pathologists may differ in the interpretation of microscopic specimens: an 87% interobserver agreement was found in distinguishing intra-mucosal carcinoma and high-grade dysplasia from lesser degrees of dysplasia or no dysplasia. Pathologists who are less regularly confronted with the assessment of esophageal dysplasia may have difficulties in making this differentiation. If an esophageal resection for a high-grade dysplasia is planned, it is recommended that a second experienced pathologist confirms the diagnosis.
4.3.5 Specific Histotypes Rare histotypes are found in only 4% of esophageal malignancies.
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Other epithelial cancers are adenosquamous carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, small cell carcinoma, undifferentiated carcinoma, and pseudosarcomatous carcinoma. Non-epithelial cancers are leiomyosarcoma and Kaposi sarcoma. Miscellaneous tumors are carcinosarcoma, malignant melanoma, carcinoid, and malignant lymphoma.
4.3.6 Lymphatic Spread Lymphatic spread depends on the location of the primary tumor and does primarily concern the locoregional lymph nodes. Correspondingly, squamous cell cancer often causes lymph node metastases of the mediastinum while adenocarcinoma more often metastasizes to the paracardiac and perigastric regions along the lower curvature. Nevertheless, especially in advanced stages, both subtypes also often metastasize from the upper parts of the mediastinum down to the pericoeliac region. The rate of lymph node metastases correlates with the T stage and is relevant for therapy planning and for the assessment of the prognosis. Regarding early detection of esophageal cancer and the potential of endoscopic therapy in early stages, the rate and dissemination of lymph node metastases in early stages is of particular interest (Bollschweiler et al. 2006; Liu et al. 2005; Westerterp et al. 2005). A differentiation between mucosal and submucosal cancer and the corresponding thirds according to the Japanese classification (sm-1, sm-2, sm-3) has gained importance. When compared according to these stages, there seem to be no major differences in the rates of affected lymph nodes between adenocarcinoma and squamous cell cancer. The critical step for lymph node spread is the infiltration of the submucosal layer. sm-1 cancers can cause lymph node metastases in up to 10–20% while sm-3 cancers may cause lymph node metastases in up to 50–60% (Hölscher and Vallböhmer 2007). Reports about a significantly more frequent prevalence of lymph node metastases in squamous cell carcinoma compared with adenocarcinoma in T1 stages can be explained by a significantly more frequent infiltration of the submucosal layers (particularly sm-3) of squamous cell cancers in these series (Bollschweiler et al. 2006). Stage-adapted comparisons between T2 and higher-staged tumors also reveal no significant differences between the squamous cell and adenocarcinoma subtypes.
4.3.7 Distant Metastases Distant metastases are most frequently localized in the liver, in the peritoneum, and in the lung. Distant lymph node metastases are associated with a poor prognosis similar to that of hematogenous distant metastases but involvement of coeliac lymph nodes (formerly classified M1a) is in the range of involvement of other locoregional lymph node groups (Hofstetter et al. 2007).
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4.3.8 Anatomic Classification Of therapeutic relevance is also the topographic relationship of the esophagus to the tracheo-bronchial system. As a result of their proximity in the upper mediastinum and cervical region the risk of infiltration of the trachea or bronchi by wall-penetrating esophageal tumors is high. This is not the case in the lower mediastinum. Consequently, esophageal cancers are often classified as tumors of the upper, the middle, and the lower mediastinum. Another important classification is Siewert’s classification concerning tumors located at the gastroesophageal junction (Fig. 4.1) (Siewert and Stein 1998). Type I adenocarcinoma of the esophagogastric junction are primarily cancers occurring in Barrett’s esophagus. Those cancers are surgically treated by esophagectomy while for type II and type III cancers many centers prefer extended gastrectomy according to Siewert’s recommendations. Currently, the TNM classification has been renewed. Tables 4.2 and 4.3 give an overview of the latest version of the TNM classification and staging system of the International Union of Cancer Classification (Sobin et al. 2009).
4.4 Symptoms The major symptom leading to diagnosis of esophageal cancer is dysphagia. Less frequently, patients complain about odynophagia, which means pain on swallowing food and fluids (Leers et al. 2005; Witzig et al. 2006). In most patients, dysphagia is a symptom occurring in advanced disease. Other symptoms associated with more advanced tumors are hematemesis, hoarseness which is due to recurrent nerve paralysis, respiratory symptoms Anatomic Cardia
Type I Type II Type III
Fig. 4.1 Adenocarcinoma of the esophagogastric junction (AEG type I–III) according to Siewert’s classification
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Table 4.2 TNM stages of esophageal cancer according to the UICC TNM classification system, 7th edn (Sobin et al. 2009) Tis
Carcinoma in situ /high-grade dysplasia
T1
Lamina propria or submucosa
T1a
Lamina propria or muscularis mucosae
T1b
Submucosa
T2
Muscularis propria
T3
Adventitia
T4
Adjacent structures
T4a
Pleura, pericardium, diaphragm, or adjacent peritoneum
T4b
Other adjacent structures, e.g., aorta, vertebral body, trachea
N0
No regional lymph node metastasis
N1
1–2 regional lymph nodes
N2
3–6
N3
>6 (N1 was site dependent)
M
Distant metastasis
M1
Distant metastasis (M1a,b were site dependent)
Table 4.3 Anatomical stage groups of esophageal cancer according to the UICC TNM classification system, 7th edn (Sobin et al. 2009) Stage IA
T1
N0
M0
Stage IB
T2
N0
M0
Stage IIA
T3
N0
M0
Stage IIB
T1, T2
N1
M0
Stage IIIA
T4a T3 T1, T2
N0 N1 N2
M0 M0 M0
Stage IIIB
T3
N2
M0
Stage IIIC
T4a T4b Any T
N1, N2 Any N N3
M0 M0 M0
Stage IV
Any T
Any N
M1
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due to esophago-tracheal fistula, weight loss, and swelling of cervical lymph nodes. A history of heartburn is typical for many patients with Barrett’s cancer. According to a recent study, the delay between onset of alarming symptoms and diagnosis was 2.2 months (Witzig et al. 2006). In the Western world, early cancers are mainly diagnosed on the basis of surveillance endoscopies in case of Barrett’s esophagus or when upper gastrointestinal endoscopy is performed for the clarification of nonspecific abdominal symptoms.
4.5 Clinical Diagnostics An effective diagnostic workflow is subdivided into the primary diagnosis and staging (Table 4.4). The crucial investigation for the primary diagnosis is upper gastrointestinal tract endoscopy with biopsy. This investigation is necessary to prove malignancy and to allocate the malignancy to one of the histologic subtypes. At the same time, endoscopy will provide information about the location and local extent of the tumor. An accurate staging is necessary for all treatment decisions. The exclusion or proof of distant metastases is of paramount interest, as in case of distant metastases the goals of treatment are palliative. The most important investigation for the exclusion of distant metastases is computed tomography (CAT scan) of the neck, thorax and abdomen. Magnetic resonance tomography does not augment the accuracy of diagnosis and is not a routine procedure in the diagnostic workflow of esophageal cancer. Sonography of the abdomen is a useful and sensitive investigation, especially for the detection of liver metastases, but it cannot replace computed tomography. According to the current literature, the diagnostic Table 4.4 Clinical diagnostics in esophageal cancer Diagnostics Aim (a) Primary diagnostics Endoscopy + biopsy Endosonography Multisclice CT of the neck + thorax + abdomen 3D reconstruction of CT images
Histologic verification, localization Depth of infiltration, uT-category (uN with less accuracy) Distant metastases, infiltration of adjacent organs, pleural effusion, ascites Localization of the primary tumor with regard to the tracheobronchial system
(b) Supplementary diagnostics depending on results from (a) Bronchoscopy + Biopsie Infiltration of the trachea or the main bronchi Laparoscopy + biopsy + laparoscopic Peritoneal carcinomatosis and liver metastases ultrasound Thoracoscopy Pleural carcinomatosis, lung metastases PET Distant metastases
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benefit of whole-body positron emission tomography (PET) is limited after state-of-the-art staging, and so broad implementation in daily clinical practice is questionable. However, before indicating neoadjuvant therapy and esophagectomy in locally advanced tumors, PET should be performed to increase the sensitivity for exclusion of distant metastases (van Westreenen et al. 2007). Bone scans are not part of routine staging procedure and should be limited to patients with specific bone-associated symptoms or findings. In case of ascites, laparoscopy should be performed to exclude peritoneal carcinomatosis. Following the exclusion of distant metastases, sophisticated staging of the primary tumor is of interest as clinical treatment is based on the categorization of the primary tumor (Fig. 4.2). Locoregional staging is most reliably performed by means of endoscopic ultrasound (Hardwick and Williams 2002; Kelly et al. 2001). Its average accuracy for T staging is 84% (range 60–90%) and for nodal staging 77% (range 50–90%) (Rösch 1995). If the tumor cannot be passed endoscopically and accordingly cannot be investigated with endoscopic ultrasound, a T3 or T4 category must be assumed. In proximal and mid-esophageal tumors, tracheobronchoscopy, with multiple biopsies and brush and washing cytology examinations, is recommended to rule out tumor infiltration, indicating that the tumor is not resectable and (possibly) indicating an enhanced risk of esophagotracheal fistula after radiation therapy (Riedel et al. 1998, 2001). With regard to patient perception of clinical diagnostics, significant but small differences were observed in patient burden for imaging tests to evaluate esophageal cancer. The perceived burden of PET was lower than that of endoscopic ultrasound, but higher than the burden of computed tomography. However, absolute values were low for all tests and therefore patient burden will not be a key feature for the construction of an optimal staging algorithm for esophageal cancer EC (Westerterp et al. 2008).
4.6 Preoperative Risk Assessment Abdominothoracic esophagectomy implies a significant risk of postoperative morbidity and mortality. This may even be higher after neoadjuvant chemoradiation. Many of the patients presenting with esophageal cancer have concomitant diseases associated with alcohol or tobacco consumption in squamous cell cancer and with obesity and other cardiovascular risk factors in adenocarcinoma. The preoperative assessment of risk factors is of paramount interest. Several scores have been developed (Bartels et al. 1998, 2000; Bollschweiler et al. 2000; Steyerberg et al. 2006). An evaluation of pulmonary, cardiac, renal, hepatic, and endocrine functions is essential for the exclusion of excessive perioperative risks. Patients with a high-risk score have been recommended to be excluded from esophagectomy and to be offered alternative treatment options (Bartels et al. 2000) (Fig. 4.2). Cirrhosis of the liver, current alcohol misuse, and irreversible severe pulmonary impairment are regarded as absolute contraindications against esophagectomy. Cardiac risk, especially coronary heart disease must be carefully evaluated and treated by coronary angioplasty if indicated. All this must be done before any neoadjuvant treatment is started.
Any TN M1b
uT3/T4-Nx M0/M1a
uT1sm/2-Nx M0/M1a
uT1m – Nx M0
ECOG-PS < 2
ECOG-PS > 2
nicht resektabel
resectable
Chemotherapy
Best supportive Care
RCTx
Fig. 4.2 Therapy of esophageal cancer according to staging
Resection
Preoperative therapy (CTx or RCTx)
RCTx
Abdomino-thoracic esophagectomy
Rtx bei T1sm
EMR
Esophagectomy or limited esophagectomy (Merendino)
EMR
RCTx
Normal surgical risk
High surgical risk
High surgical risk
Normal surgical risk
High surgical risk
Normal surgical risk
Primary treatment
CTx: chemotherapy; ECOG-PS: performance status according to Eastern Cooperativ Group; EMR: Endoscopic mucosal resection; RTx: radtiation; RCTx: radichemoradiation
In resectable tumors surgical risk assessment including • ECG • echocardiography • stress test • coronary angiography if indicated • spirometry • renal, hepatic and endocrine function
PET-CT before neoadjuvant therapy
Computed tomography neck, thorax, abdomen
Endosonography
Abdominal sonography
Biopsy/ Histology
Endoscopy
Clinical Diagnostics
Postop. RTx may be considered in R1 resected patients
No routine adjuvant treatment indicated
Adjuvant therapy
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4.7 Indications and Selection of Treatment Modalities The goals of curative treatment of esophageal cancer are the radical resection with a low risk of perioperative mortality and the minimization of a recurrence risk. The algorithm is individualized and is mainly based on the preoperative TNM classification of the tumor and the individual oncological and medical risk profile (Fig. 4.2).
• Endoscopic mucosal resection (EMR) has its proven indications and is an important therapeutic approach in T1 mucosal cancer (Pech and Ell 2009a).
• Radical transthoracic esophagectomy is the operation of choice, having shown a prog-
nostic advantage over subradical transhiatal esophagectomy in a prospective randomized controlled trial in the Netherlands (Hulscher et al. 2002). • A resection of the distal esophagus and reconstruction, according to Merendino, with limited lymphadenectomy is indicated in adenocarcinoma of the distal esophagus, limited to the mucosal layer (Stein et al. 2007). • Radical resection after neoadjuvant therapy is warranted in locally advanced stages. There are positive results from meta-analyses for neoadjuvant chemotherapy in locally advanced adenocarcinoma and for neoadjuvant chemoradiation in squamous cell cancer and adenocarcinoma (Gebski et al. 2007). • Definitive chemoradiation may replace surgical resection in patients with co-morbidities or in patients who are not willing to take the risks of radical esophagectomy; but local tumor control is significantly better with resection and survival has a strong trend to favor surgery (Stahl et al. 2005).
4.8 Endoscopic Therapy Centers now have an experience of more than 10 years with EMR in early esophageal cancer (Ell et al. 2000). Criteria for an EMR with curative intention are as follows:
• Infiltration restricted to the mucosal layer (T1a) • Tumor diameter £2 cm • No ulcerative tumor • Histopathologic grading G1 or G2 • No lymphatic and no vascular invasion (L0, V0) The most commonly used techniques for endoscopic therapy are EMR and endoscopic submucosal dissection (ESD) (Inoue et al. 2010). While smaller lesions with a diameter up to 1 cm can be removed by EMR, bigger lesions traditionally required a “piecemeal resection” which made the histopathological
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assessment of resection margins difficult, if not impossible. With current ESD techniques, lesions of >1 cm can also be resected “en bloc.” There are more data for endoscopic resection in early Barrett’s cancer than in T1 squamous cell cancer. Compared to surgery, there are significantly less R0 resections with endoscopic resection (74.5% vs. 100%) (Vieth et al. 2004). However, the clinical success rate seems to be very high according to the results of Ell and co-workers. In experienced centers, the five-year survival rate after endoscopic mucosa resection for early Barrett’s cancer is equivalent to that after surgical resection (Pech and Ell 2009b). A major debate is around the question as to how the remaining Barrett’s epithelium after endoscopic resection of the neoplasia should be treated. There are competing approaches, e.g., surveillance, photodynamic therapy, radiofrequency ablation, and resection. Prospective comparative trials are missing thus far. EMR has also been performed for early squamous cell cancer. Most results come from Japanese centers (Higuchi et al. 2009), but there is also some experience in Western centers. According to current results, early squamous cell cancers of the esophagus can also be treated endoscopically. The recurrence rate is about 26%, especially in cancers with multifocal characteristics; but in case of local recurrence, salvage procedures can be performed successfully (Pech et al. 2007).
4.9 Surgical Therapy The goal of oncological surgery in esophageal cancer is a radical (R0) resection together with an adequate lymphadenectomy.
4.9.1 Procedures
• Transthoracic en-bloc esophagectomy with radical mediastinal lymphadenectomy and
abdominal lymphadenectomy (so-called two-field lymphadenectomy) followed by reconstruction with high intrathoracic or cervical anastomosis after gastric pull-up or colon interposition. This procedure can be extended by a three-field lymphadenectomy (Hölscher et al. 2003; Hölscher and Vallböhmer 2007) (Fig. 4.3). • Transhiatal/cervical (synonym: transmediastinal) esophagectomy with lymphadenectomy of the lower mediastinum and abdominal lymphadenectomy followed by reconstruction with cervical anastomosis of a gastric pull-up or colon interposition • Distal esophagectomy with lymphadenectomy of the lower mediastinum and partial abdominal lymphadenectomy and reconstruction by jejunal interposition (Merendino procedure) (Gutschow et al. 2004; Stein et al. 2007) (Fig. 4.4). • Resection of the cervical esophagus with regional lymphadenectomy and reconstruction by a free jejunal interposition with microvascular anastomosis (Ott et al. 2009b) (Fig. 4.5).
80 Fig. 4.3 Transthoracic en-bloc esophagectomy with radical mediastinal lymphadenectomy and abdominal lymphadenectomy
Fig. 4.4 Limited cardia resection with jejunal interposition
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Fig. 4.5 Resection of the cervical esophagus with regional lymphadenectomy and reconstruction by a free jejunal interposition with microvascular anastomosis
The procedure of choice for ³T1b tumors in squamous cell cancer of the distal esophagus as well as for Barrett’s cancer is a transthoracic en-bloc esophagectomy with a twofield lymphadenectomy and a high intrathoracic anastomosis. In a randomized controlled trial there was no significant overall survival benefit for this approach. However, compared with limited transhiatal resection, extended transthoracic esophagectomy for type I esophageal adenocarcinoma showed an ongoing trend toward better five-year survival. Moreover, patients with a limited number of positive lymph nodes in the resection specimen seem to benefit from an extended transthoracic esophagectomy (Hulscher 2002; Omloo et al. 2007). Apart from the results of the randomized controlled trial, the rationale for this choice is as follows: In all esophageal cancers of category T1sm or higher, the rate of lymph node metastases is at least 30% or more. Affected lymph nodes can be localized in the mediastinum or in the locoregional abdominal lymph nodes. According to the current literature (Stein et al. 2005; Feith et al. 2003), there seems to be a preferred lymphatic drainage according to the location of the primary tumor but bidirectional lymphatic spread is also possible. A clear preoperative distinction between affected and non-affected lymph nodes
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is not possible. Sentinel-node techniques are currently not sufficiently established outside clinical trials, although results from experienced centers are interesting (Burian et al. 2004; Grotenhuis et al. 2009; Natsugoe et al. 2009; Piert et al. 2007; Takeuchi et al. 2009). In limited transhiatal/cervical procedures the lymph nodes of the middle and upper mediastinum cannot be completely resected which limits the radicality of this surgical approach. Due to these considerations, limited transhiatal/cervical resection is no more the procedure of choice but can be used as an alternative approach in patients with limited pulmonary function for avoiding thoracotomy and unilateral pulmonary ventilation in selected patients with distal adenocarcinoma of the esophagus. Another attempt to limit the surgical trauma and to reduce postoperative complications that are associated with laparotomy is laparoscopic ischemic conditioning of the stomach for esophageal replacement (Hölscher et al. 2007). Most esophageal cancers are located in the distal and middle third of the esophagus and can be resected with safe margins by transthoracic esophagectomy and intrathoracic transection allowing for a high intrathoracic anastomosis. Preparation of the cervical esophagus can thereby be avoided which limits the morbidity of the procedure. Only in carcinomas located above the tracheal bifurcation, a cervical transection and cervical anastomosis should be performed in order to ensure a sufficient radicality. The high intrathoracic anastomosis has a similar mortality but a lower insufficiency rate compared to cervical esophagogastrostomy and leads to a good swallowing function. Leakage, strictures, and subsequent stenosis are more frequently found with cervical anastomosis (Hölscher et al. 2003; Ott et al. 2009a). With a limited distal esophagectomy and reconstruction according to Merendino the extent of lymphadenectomy is even more limited (Gutschow et al. 2004; Stein et al. 2007). The lymph nodes of the middle and upper third of the mediastinum are left behind and a lymphadenectomy of the lesser gastric curvature is limited at least when the vagal nerve is not resected. Consequently, this procedure should be limited to patients without suspicion of extended lymphatic spread, especially mucosal cancers in Barrett’s esophagus and is an alternative to endoscopic resection. Merendino’s procedure cannot be recommended for T1sm (submucosal) cancer, because the risk for lymphatic spread is 30% in this patient population (Bollschweiler et al. 2006; Liu et al. 2005). Merendino’s procedure can also not be recommended in very long Barrett’s metaplasia segments, because then neoplastic lesions would be left behind which limits the curative intention of this approach (Westerterp et al. 2005). For squamous cell cancer of the cervical esophagus, a limited cervical resection via a cervical and sternal approach and reconstruction with a free jejunal interposition can be performed. In the largest prospective series with this approach, the complete R0 resection rate was 72.5%. Median overall survival was 34.3 months; one-, three- and five-year survival rates were 83.8, 47.0, and 47.0%, respectively. Despite high complication and reoperation rates, the mortality rate was low, even after preoperative chemoradiation. But randomized comparisons with definitive chemoradiation are lacking thus far (Ott et al. 2009b).
4.9.2 Perioperative Morbidity and Mortality Diagnostic and therapy of postoperative complications are listed in Table 4.5.
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4 Esophageal Cancer Table 4.5 Diagnostic and therapy of postoperative complications following esophagectomy Complication Diagnostic Therapy Recurrent nerve palsy
Clinical, bronchoscopy
Respiratory support, tracheotomy, logopedics
Tracheobronchial lesions
Bronchoscopy
Spontaneous ventilation, tracheotomy, stent
Anastomotic leakage
Contrast enhanced X-ray endoscopy
Thoracic: Stent, re-thoracotomy Cervical: Wound incision, drainage
Necrosis of the interposition
Endoscopy
Resection of the interposition
Interposition retention/pylorospasm
Endoscopy Contrast enhanced X-ray
Dilatation Erythromycin
Anastomotic stenosis
Contrast enhanced X-ray endoscopy
Dilatation
Chylothorax
Pleurocentesis
Conservative, ligature
The most frequent general complications following esophagectomy comprise bronchopneumonia, delirium tremens in alcoholics, and cardiac dysrhythmia, especially atrial fibrillation, which all have to be treated accordingly, usually in intensive care units. It has always to be kept in mind that general symptoms can be associated with or superimposed to surgical complications (Stippel et al. 2005). For reaching good results in esophageal surgery, all procedures must be highly standardized. Not only the surgeons but also the whole team including anesthetists, intensive care physicians, radiologists, pathologists etc., must be trained. The postoperative mortality is clearly reduced in centers with a high case load (Birkmeyer et al. 2002; Hölscher et al. 2004). According to the German literature analysis, 20 esophagectomies per year are necessary in order to achieve a hospital mortality rate of <5%. Also long-term outcome seems to be better in high-volume centers (Birkmeyer et al. 2007).
4.9.3 Long-Term Surgical Outcome The crucial prognostic factor in esophageal surgery is a resection with tumor-free margins (R0) (Hölscher et al. 1995; Roder et al. 1994). Survival analysis demonstrates that almost all patients with macroscopic tumor residuals or with microscopically involved margins die within two years, while in patients with tumor-free margins the five-year survival rate is 40%. Due to a variety of reasons the survival rate of patients with squamous cell cancer of the esophagus is lower than for patients with adenocarcinoma (Siewert et al. 2001). Best surgical results are achieved with radical transthoracic esophagectomy (Hulscher et al. 2002; Omloo et al. 2007). T category and N category are both very strong and independent prognostic factors. The outcome of patients presenting with N1 disease depends on the ratio of invaded vs. resected
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lymph nodes. The smaller this ratio is kept, the better the prognosis (Hölscher et al. 1995; Roder et al. 1994). Improvements in prognosis can be achieved with preoperative therapy. Response to preoperative treatment has been shown to be an independent prognostic factor (Brücher et al. 2006; Brücher et al. 2009; Javeri et al. 2008; Schneider et al. 2005; Siewert et al. 2001). Concerning quality of life, even after 3 years, patients who underwent esophagectomy suffered persistent problems with physical function and specific symptoms. These findings may be used to inform patients of the long-term consequences of surgery (Lagergren et al. 2007a).
4.10 Perioperative Treatment Despite the optimization of surgical treatment as delineated above, long-term outcome in locally advanced stages is still poor with surgical therapy alone. This is why neoadjuvant and adjuvant therapies have been tested in randomized controlled trials. Adjuvant treatment following esophagectomy is difficult to deliver due to the relatively high complication rate, morbidity, weight loss, and digestive disorders associated with esophagectomy. Current retrospective data suggest that postoperative radiation therapy may be beneficial in selected cases (Schreiber et al. 2010). However, controlled randomized trials could not establish a role for adjuvant radiation therapy in resected esophageal cancer. The same is true for postoperative chemotherapy, for which randomized controlled trials could show only moderate benefit in subgroups of patients (Ando et al. 1997, 2003). After these unsatisfying results regarding the role of any postoperative treatment, the research focus was directed to neoadjuvant preoperative treatment which theoretically may have several advantages. Neoadjuvant therapy may shrink the tumor and thus enable R0 resection in cases with marginally resectable tumors. It also may improve the systemic relapse rate by eliminating hematogenous metastases early in the course of treatment. Finally, it allows for response monitoring “in vivo” by conventional and investigational imaging technologies (Lordick et al. 2004; Lordick 2009).
4.10.1 Neoadjuvant Radiation Neoadjuvant radiation without chemotherapy has been investigated in five fully published randomized controlled trials. Clinical response to neoadjuvant radiation was reported in about two thirds of patients. But a significant survival advantage was reported in only one study (Nygaard et al. 1992). Two studies reported a worse outcome with neoadjuvant radiation. In a recent meta-analysis including 1,147 patients from five randomized controlled trials, the investigators conclude that neoadjuvant radiation leads to a relative risk reduction for the endpoint death with a hazard ratio (HR) of 0.89, 95% confidence interval (CI) 0.78–1.01. The survival difference is 3% after 2 years and 4% after 5 years. This is not statistically significant (p = 0.062) (Arnott et al. 2005). Preoperative radiation alone is therefore not indicated for esophageal cancer.
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4.10.2 Neoadjuvant Chemotherapy Nine randomized controlled trials have been performed investigating the role of preoperative chemotherapy. Seven studies enrolled patients with squamous cell cancer only; two studies allowed for the inclusion of squamous cell and adenocarcinoma (Allum et al. 2009; Kelsen et al. 1998; Medical Research Council 2002). Only the newest study organized by the United Kingdom Medical Research Council could demonstrate a small, although significant survival advantage for patients receiving neoadjuvant chemotherapy (Allum et al. 2009). In contrast to other randomized studies, the proportion of patients with adenocarcinoma of the esophagus in the British study was >60%. In the subgroup analysis of patients with adenocarcinoma a significant survival advantage was found. Several older meta-analyses could demonstrate improved R0 resection rates but only marginally improved survival rates for patients treated with neoadjuvant chemotherapy in resectable esophageal cancer. Of note, most patients who were analyzed had squamous cell cancers (Urschel et al. 2002; Malthaner and Fenlon 2003). There is no significant increase in the postoperative complication rate or mortality rate following neoadjuvant chemotherapy. However, severe (grade 3) and life-threatening (grade 4) toxicities are observed in 32 patients treated neoadjuvantly with cisplatin and 5-fluorouracil and a death rate of 1.6–2.1% has been reported (Urschel et al. 2002; Malthaner and Fenlon 2003). A recently published meta-analysis of over 1,724 patients enrolled in 11 randomized controlled trials showed a significant survival advantage for patients treated with neoadjuvant chemotherapy with a relative risk reduction of 10% and a two-year survival difference of 7%. This meta-analysis presented subgroup analyses according to the histopathologic subtype. While the difference was nonstatistically significant for squamous cell cancer (HR 0.87; 95% KI 0.75–1.03, p = 0.12), the difference was statistically significant for adenocarcinoma of the esophagus (HR 0.78; 95% KI 0.64–0.95, p = 0.014) (Gebski et al. 2007). In summary, it has been shown that neoadjuvant chemotherapy improves the prognosis of patients with locally advanced adenocarcinoma of the esophagus without increasing the postoperative mortality rate.
4.10.3 Neoadjuvant Chemoradiation Neoadjuvant chemoradiation has been the most frequently studied neoadjuvant treatment modality for locally advanced esophageal cancer within the last years. Most studies included patients regardless of the histopathologic subtype of their cancer. One study included patients with adenocarcinoma only (Walsh et al. 1996); three other studies included a majority of patients with adenocarcinoma (Urba et al. 2001; Burmeister 2005; Tepper et al. 2008). Meta-analyses come to the result that neoadjuvant chemoradiation leads to a significantly improved survival rate and an improved locoregional tumor control rate (Fiorica et al. 2004; Gebski et al. 2007; Greer et al. 2005; Urschel and Vasan 2003). But postoperative mortality was also found to be increased after neoadjuvant chemoradiation. This effect
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was less marked when studies using single doses of >2 Gy were excluded from the metaanalysis (Fiorica et al. 2004). The deleterious effects of neoadjuvant chemoradiation are not sufficiently understood thus far. Neoadjuvant chemoradiation with higher doses leads to an impaired alveolar diffusion capacity and therefore to impaired pulmonary gas exchange. In patients undergoing previous chemoradiation, there is an increased rate of postoperative respiratory complications (Abou-Jawde et al. 2005). With regard to cellular immunity, neoadjuvant chemoradiation seems to suppress T-lymphocytes which leads to an increased risk of encountering postoperative septic complications (Heidecke et al. 2002). A significant decline in the postoperative complication rate and mortality rate following neoadjuvant chemoradiation was achieved with the introduction of a two-stage operation which means that reconstruction of the intestinal passage is done >7 days after esophagectomy (Stein et al. 2001). In the most recent meta-analysis (Gebski et al. 2007), 1,209 patients who were enrolled in ten randomized studies were analyzed. The HR for survival after neoadjuvant chemoradiation vs. surgery alone was 0.81 (95% CI 0.70–0.93; p = 0.002) corresponding to a difference in the two-year-survival rate of 13%. This was in the same range for adenocarcinoma and for squamous cell cancer of the esophagus. A small randomized trial that was finished prematurely due to low accrual randomized patients to receiving an unusual preoperative chemotherapy regimen (18 weeks of cisplatin/5-fluorouracil) vs. an investigational chemoradiation regimen (12 weeks of cisplatin/5-fluorouracil followed by cisplatin/etoposide plus radiation, dose 30 Gy) (Stahl et al. 2009). Due to the exploratory character of this study comparing two experimental arms and the limited number of enrolled patients, no major conclusions can be drawn. The study showed a similar R0 resection rate in both arms. The study also showed a trend toward an improved survival rate in the chemoradiation arm with an HR of 0.67 (95% CI 0.41–1.07) and a trend toward an increased postoperative mortality rate (10.2% after chemoradiation vs. 3.8% after chemotherapy alone). In summary, the survival rates are significantly better after neoadjuvant chemoradiation, even though postoperative mortality may be increased in comparison to surgery alone. This is true for adenocarcinoma and for squamous cell carcinoma of the esophagus, albeit for adenocarcinoma the benefit seems to be in the same range as for chemotherapy without radiation. Patients with clinically staged uT3/T4 tumors and/or with lymph node involvement (stages II and III) are candidates for neoadjuvant treatment (Fig. 4.2).
4.10.4 Quality of Life Esophagectomy has a negative influence on health-related quality of life (HRQL) during the first postoperative year. A recent study examined HRQL during preoperative chemotherapy/chemoradiotherapy treatment and compared postoperative recovery of HRQL in patients undergoing combined treatment with patients undergoing surgery alone. Deterioration in most aspects of HRQL occurred during preoperative chemotherapy.
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Patients proceeding to concomitant radiotherapy further deteriorated with specific problems with reflux symptoms and role function (difference between means >15, p < 0.01). After neoadjuvant treatment, but before surgery, HRQL returned to baseline levels. Six weeks after surgery, patients reported marked reductions in physical, role, and social function (difference between means >30, p < 0.01) and increase in fatigue, nausea and emesis, pain, dyspnea, appetite loss, and coughing (difference between means >15, p < 0.01). Recovery of HRQL was not hampered by preoperative treatment, and fewer problems with postoperative nausea, emesis, and dysphagia were reported by patients who had undergone neoadjuvant treatment compared with patients who had undergone surgery alone. In conclusion, preoperative chemotherapy or chemoradiotherapy had a negative impact on HRQL that was restored in patients proceeding to surgery. Recovery of HRQL after esophagectomy was not impaired by neoadjuvant treatment. These results supported the use of neoadjuvant treatment before surgery (Blazeby et al. 2004). A new quality of life questionnaire has been developed by the European Organization of Research and Treatment of Cancer. The QLQ-OG25 is recommended to supplement the EORTC QLQ-C30 when assessing HRQL in patients with esophageal, junctional or gastric cancer (Lagergren et al. 2007b).
4.10.5 Treatment Protocols 4.10.5.1 Chemotherapy In the largest trial showing a significant survival advantage for neoadjuvant chemotherapy, patients received two preoperative cycles of cisplatin 80 mg/m2 on day 1 (over 4 h, as usually given in the United Kingdom, 1 h in many other countries) plus 5-fluorouracil 1,000 mg/m2/day on days 1–4 (24-h-infusion), to be repeated after 3 weeks (Allum et al. 2009; Medical Research Council 2002).
4.10.5.2 Chemoradiation In view of the many and heterogenous schedules that have been investigated and the conflicting results that exist, it is not possible to identify an optimal neoadjuvant chemoradiation regimen. Outside clinical trials, radiation should be conventionally fractionated. Single doses should not exceed 2 Gy. Limited experience exists with hyperfractionated or accelerated protocols which should not be used outside of clinical trials. Doses that have been investigated in randomized trials were between 20 and 45 Gy with a trend to higher response rates with higher doses but also more pulmonary toxicity. A total dose of 45 Gy with single doses of 1.8 Gy has been established as standard of care in many experienced institutions.
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Cisplatin and continuous infusions with 5-fluorouracil are usually given as concomitant chemotherapy. To avoid the typical toxicities associated with cisplatin, oxaliplatin was tested with reasonable results in phase II, but randomized studies are lacking (Khushalani et al. 2002; Lorenzen et al. 2008). Therefore, oxaliplatin may serve as a substitute for cisplatin in patients presenting with contraindications against cisplatin infusions. Esophagitis is the dose limiting toxicity of mediastinal radiotherapy. 5-Fluorouracil may augment this specific adverse effect. Therefore, 5-fluorouracil-free regimens have been developed. The combinations of cisplatin plus paclitaxel or cisplatin plus docetaxel or cisplatin plus irinotecan have yielded interesting results (Brenner et al. 2004; Ilson et al. 2003; Ruhstaller et al. 2009). But the superiority of these newer regimes vs. cisplatin plus 5-fluorouracil has not been proven in a randomized controlled trial. The interval between the end of concomitant chemoradiation and surgery should usually be 4–6 weeks. This standard which is based on expert knowledge and some theoretical considerations has never been tested in a clinical trial. While recovery from acute skin and mucosal toxicities usually takes place within the first 6 weeks following chemoradiation, it is also known that within this time frame there is the greatest risk for developing radiation induced pneumonitis (Mehta 2005). In our own experience, a time interval of 4–8 weeks between the end of radiation and surgery has proved to be of value.
4.10.6 Response Evaluation and Response Prediction A couple of recent trials investigated the significance of response during and after neoadjuvant therapy. Histopathologic remission has been shown to be an important prognostic factor (Berger et al. 2005; Brücher et al. 2006; Rohatgi et al. 2005; Schneider et al. 2005; Swisher et al. 2005). Histological type of esophageal cancer might affect response to neoadjuvant chemoradiation and subsequent prognosis (Bollschweiler et al. 2009). Response evaluation by established clinical methods like endoscopy, re-biopsy, and endoscopic ultrasound does not accurately predict histopathologic response. Post-treatment endoscopic biopsy is a poor predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer and the American Joint Committee on Cancer staging system does not accurately predict survival in patients receiving multimodality therapy for esophageal adenocarcinoma (Rizk et al. 2007). Often, conventional clinical assessment cannot distinguish between tumor and fibrous tissue or post-radiation edema. Of note, post-treatment endoscopic biopsy is a poor predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer (Sarkaria et al. 2009). Supplementary information is provided by Fluordeoxyglucosepositron emission tomography (FDG-PET). FDG-PET is a preferred method in clinical studies to assess post-therapeutic response and to predict survival (Swisher et al. 2004; Flamen et al. 2002; Downey et al. 2003; Wieder et al. 2004, 2007). However, FDG-PET is not able to predict histopathologic complete response (Vallböhmer et al. 2009). Therefore minimal residual disease cannot be excluded by post-therapeutic FDG-PET and therefore this assessment should not be used outside of clinical trials to exclude patients from surgery or to delay surgery.
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Meanwhile, it has become clear that patients who do not respond to neoadjuvant treatment have a very poor prognosis that is even worse than the prognosis for patients who do not receive neoadjuvant chemotherapy or neoadjuvant chemoradiation (Kelsen et al. 2007; Bollschweiler et al. 2009). These patients are probably no good candidates for neoadjuvant treatment. FDG-PET signals have been used to identify patients who do not respond to neoadjuvant treatment and should be offered alternative treatment options. Higher glucose uptake – as measured by FDG-PET – seems to correlate with a better chance for responding to neoadjuvant therapy (Javeri et al. 2009; Lordick et al. 2007; Rizk et al. 2009). Data for early response evaluation by monitoring tumor glucose uptake during neoadjuvant chemotherapy by FDG-PET are particularly interesting and promising. An insufficient decrease of the FDG uptake after only 14 days of neoadjuvant chemotherapy indicates patients who have a very poor chance of responding to further chemotherapy (Ott et al. 2006; Weber et al. 2001). An interventional study showed that early response monitoring by FDG-PET can be integrated into a clinical treatment algorithm and can help to guide neoadjuvant treatment (Lordick et al. 2007).
4.11 Definitive Chemoradiotherapy 4.11.1 Randomized Studies In randomized studies, primary simultaneous chemoradiation has proved to be superior compared with conventionally fractionated radiotherapy with regard to local tumor control, relapse-free survival, and overall survival. One-year survival is improved by about 9% and two-year survival by about 8% (Herskovic et al. 1992; Kleinberg et al. 2007). It is crucial that chemotherapy and radiotherapy are given simultaneously. To clarify the optimal dose of radiotherapy given in combination with cisplatin and 5-fluorouracil, a randomized trial compared 50.4 with 64.8 Gy (Minsky et al. 2002). The higher radiation dose failed to show superiority with regard to local tumor control, relapse-free survival, and overall survival. In contrast, acute side effects and therapy-associated deaths were increased. Therefore, the regimen as published by the Radiation Therapy Oncology Group (RTOG 85–06) with a radiation dose of 50.4 Gy (conventional fractionation of 1.8–2.0 Gy/day) with concomitant cisplatin (75 mg/m² day 1) and 5-fluorouracil (1,000 mg/m² days 1–4, repeated week 5) has remained a standard of care. Radiation split-course regimes are less effective in achieving local tumor control and should not be used (Crehange et al. 2007). Only when there are absolute contraindications against chemotherapy or when the treatment goal is clearly palliative, patients should be treated with radiotherapy alone.
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4.11.2 Chemoradiation vs. Surgery Recent randomized studies compared definitive chemoradiation with neoadjuvant chemoradiation followed by esophagectomy in locally advanced esophageal cancer. Of note, no such comparison is available for adenocarcinoma of the esophagus (Lordick et al. 2006). Briefly, these studies could not show a statistically significant survival advantage for surgical resection vs. definitive chemoradiation in locally advanced squamous cell carcinoma of the esophagus. However, in the German multicenter study, a difference in threeyear survival of 7% favoring resection was seen. But as the endpoint of this study was planned to show non-inferiority of chemoradiation, this difference failed to be statistically significant (Stahl et al. 2005). Local tumor control was significantly better after surgery. Subgroup analyses suggest a benefit of surgery especially for those patients who do not respond to neoadjuvant chemoradiation. Of note, in both large European randomized trials, the postoperative mortality rate was >10% (Stahl et al. 2005; Bedenne et al. 2007). Surgery and continuation of chemoradiation had the same impact on quality of life in patients with locally advanced, resectable esophageal cancer although a significantly greater decrease in quality of life was observed in the postoperative period (Bonnetain et al. 2006). In conclusion, resection should be offered to all fit patients presenting with locally advanced esophageal squamous cell cancer who are willing to undergo surgery and who are able to understand the advantages and limitations and risks of a surgical procedure. In patients with increased surgical risks and in patients who are not consenting to a surgical resection, definitive chemoradiation is an alternative which leads to comparable survival results. It should be emphasized that only few data exist for the definitive chemoradiation of esophageal adenocarcinoma. In this respect, surgery remains the unchallenged standard of care for R0 resectable localized esophageal adenocarcinoma.
4.12 Treatment of Metastatic Disease 4.12.1 Chemotherapy Distant metastases are found in approximately 50% of patients newly diagnosed with esophageal cancer. Additionally, in about 50% of patients with resected esophageal cancer distant metastases occur as metachronous lesions. The indication for palliative chemotherapy is based on individual factors and preferences and on the patients’ motivation. Randomized studies comparing best supportive care with or without chemotherapy have not been performed in esophageal cancer. In a recently published analysis of a large database of patients treated in randomized trials coordinated by the Royal Marsden Hospital, no significant differences were demonstrated on multivariate analyses in overall survival, response rate, and toxic effects among patients with
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Cisplatin 30 mg/m2 weekly 4/6 weeks Irinotecan 65 mg/m2 weekly 4/6 weeks Ilson et al. (1999)
Cisplatin 80 mg/m2 d1 Vinorelbine 25 mg/m2 d1, 8, qd22 (Conroy et al. 2002) SCC
SCC/AC
SCC
34% (95% CI: 23–46%)
57% (95% CI: 41–73%)
35% (95% CI: 20–54%)
Response rate
3.6 months (PFS)
27 weeks (TTP)
TTP/PFS
6.8 months
4.2 months
40 weeks
Duration of response
AC adenocarcinoma; CI confidence interval; PFS progression-free survival; SCC squamous cell cancer; TTP time to progression
44
Cisplatin 100 mg/m2 d1 5-FU 1,000 mg/m2 d1–5, qd22 Bleiberg et al. (1997)
Table 4.6 Phase II studies for the treatment of advanced esophageal cancer Histology n
6.8 months
14.6 months
33 weeks
Median survival
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Table 4.7 Chemotherapy regimens for the treatment of advanced esophageal cancer
a
First-line therapy
Cisplatin/5-FU (modified Bleiberg et al. 1997) Cisplatin/Vinorelbin (Conroy et al. 2002)
Cisplatin 80 mg/m2 day 1 5-FU 1,000 mg/m2 days 1–4, repeated day 22 Cisplatin 80 mg/m2 day 1 Vinorelbin 25 mg/m2 days 1 + 8, repeated day 22
Second-line therapya
Capecitabine/Docetaxel (Lorenzen et al. 2005)
Capecitabine 1,000 mg/m2 days 1–14 Docetaxel 75 mg/m2 day 1, repeated day 22
May also be used in first line, when there are contraindications against the use of cisplatin
advanced esophageal, esophagogastric junction, and gastric adenocarcinoma (Chau et al. 2009). Therefore, patients with metastatic adenocarcinoma of the esophagus should be treated with the same chemotherapy regimen as patients with advanced gastric adenocarcinoma. Whether this is also true for new biologically targeted drugs remains to be shown. Combination chemotherapy consisting of cisplatin plus 5-fluorouracil or another combination partner has achieved 25–50% tumor remissions (mostly partial responses) (Table 4.6). In more recent studies, chemotherapeutic drugs of the newer generation were investigated. For patients with progression after platin-based first-line chemotherapy, no standards are available thus far. The combination of docetaxel every 3 weeks and the oral fluoropyrimidine capecitabine yielded interesting response rate and may be considered after failure of platin-containing chemotherapy (Lorenzen et al. 2005). Interesting chemotherapy regimens for the treatment of advanced esophageal cancer are found in Table 4.7. The current clinical research is focused on the characterization of new therapeutic targets and evaluation of biologically targeted drugs. The epidermal growth factor receptor (EGFR) family seems to be of particular interest for testing new treatments in esophageal cancer. First clinical studies investigating the value of anti-EGFR-directed therapy have been published (Dragovich et al. 2004; Lorenzen et al. 2009). Other targets may also play a role in the near future.
4.12.2 Local Treatment Treatment of tumor stenosis which is often found associated with advanced tumor stages is primarily endoscopic. Endoscopic dilation of the esophagus can lead to immediate patency and relief of symptoms. As these effects usually are of short duration, dilatation often is stabilized by the insertion of a stent, by thermic (radiofrequency) ablation, or by insertion of a percutaneous endoscopic gastrostomy (PEG). Exophytic tumors can be effectively treated with Nd-YAG laser or with an argon plasma beamer. These methods are technically limited in long-segment tumor stenosis; moreover,
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palliative effects are usually of short duration because tumor regrowth may lead to recurrent stenosis after 4–6 weeks. Radiotherapy does also effectively provide relief from symptoms caused by tumor stenosis. Stents that are inserted before the start of radiation should be extractable in case of tumor remission. Esophagotracheal or esophagobronchial fistula constitute a contraindication against endoscopic laser or beamer therapy. In this situation, covered stents should be inserted. It should be kept in mind that besides some early complications of stenting, especially pain in 40% of patients, late complications may occur in about a third of endoscopically stented patients. These are stent migration or dislocation or restenosis in the stent by tumor growth. This may necessitate further treatment like the insertion of another stent or thermic ablation within the stent.
References Abou-Jawde JM, Mekhail T, Adelstein DJ et al (2005) Impact of induction concurrent chemoradiotherapy on pulmonary function and postoperative acute respiratory complications in esophageal cancer. Chest 128:250–256 Ahsan H, Neugut AI (1998) Radiation therapy for breast cancer and increased risk for esophageal carcinoma. Ann Intern Med 128(2):114 Allum WH, Stenning SP, Bancewicz J et al (2009) Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol 27:5062–5067 Ando N, Iizuka T, Kakegawa T et al (1997) A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study. J Thorac Cardiovasc Surg 114:205–259 Ando N, Iizuka T, Ide H et al (2003) Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study – JCOG9204. J Clin Oncol 21:4592–4596 Arnott SJ, Duncan W, Gignoux M et al (2005) Preoperative radiotherapy for esophageal carcinoma. Cochrane Database Syst Rev:CD001799 Bartels H, Stein HJ, Siewert JR (1998) Preoperative risk analysis and postoperative mortality of oesophagectomy for resectable oesophageal cancer. Br J Surg 85:840–844 Bartels H, Stein HJ, Siewert JR (2000) Risk analysis in esophageal surgery. Recent Results Cancer Res 155:89–96 Bedenne L, Michel P, Bouché O et al (2007) Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 25: 1160–1168 Berger AC, Farma J, Scott WJ, Freedman G et al (2005) Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol 23:4330–4337 Birkmeyer JD, Siewers AE, Finlayson EV et al (2002) Hospital volume and surgical mortality in the United States. N Engl J Med 346:1128–1137 Birkmeyer JD, Sun Y, Wong SL et al (2007) Hospital volume and late survival after cancer surgery. Ann Surg 245:777–783 Blazeby JM, Sanford E, Falk SJ et al (2004) Health-related quality of life during neoadjuvant treatment and surgery for localized esophageal carcinoma. Cancer 103:1791–1798
94
F. Lordick and A. Hölscher
Bleiberg H, Conroy T, Paillot B et al (1997) Randomized phase II study of cisplatin and 5-fluorouracil (5-FU) versus cisplatin alone in advanced oesophageal cancer. Eur J Cancer 33:1216–1220 Bollschweiler E, Schröder W, Hölscher AH et al (2000) Preoperative risk analysis in patients with adenocarcinoma or squamous cell carcinoma of the oesophagus. Br J Surg 87:1106–1110 Bollschweiler E, Baldus SE, Schröder W et al (2006) High rate of lymph node metastasis in submucosal esophageal squamous-cell carcinomas and adenocarcinomas. Endoscopy 38: 144–151 Bollschweiler E, Metzger R, Drebber U et al (2009) Histological type of esophageal cancer might affect response to neo-adjuvant radiochemotherapy and subsequent prognosis. Ann Oncol 20: 231–238 Bonnetain F, Bouché O, Michel P et al (2006) A comparative longitudinal quality of life study using the Spitzer quality of life index in a randomized multicenter phase III trial (FFCD 9102): chemoradiation followed by surgery compared with chemoradiation alone in locally advanced squamous resectable thoracic esophageal cancer. Ann Oncol 17:827–834 Brenner B, Ilson DH, Minsky BD et al (2004) Phase I trial of combined-modality therapy for localized esophageal cancer: escalating doses of continuos-infusion paclitaxel with cisplatin and concurrent radiation therapy. J Clin Oncol 22:45–52 Brücher BL, Becker K, Lordick F et al (2006) The clinical impact of histopathologic response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer 106:2119–2127 Brücher BL, Swisher SG, Königsrainer A et al (2009) Response to preoperative therapy in upper gastrointestinal cancers. Ann Surg Oncol 16:878–886 Burian M, Stein HJ, Sendler A et al (2004) Sentinel lymph node mapping in gastric and esophageal carcinomas. Chirurg 75:756–760 Burmeister B, Smithers M, Gebski V et al (2005) A randomised phase III study comparing surgery alone with chemoradiation therapy followed by surgery for resectable carcinoma of the oesophagus: an intergroup study of the Trans-Tasman Radiation Oncology Group (TROG) and the Australasian Gastro-Intestinal Trials Group (AGITG). Lancet Oncol 6:659–668 Chau I, Norman AR, Cunningham D et al (2009) The impact of primary tumour origins in patients with advanced oesophageal, oesophago-gastric junction and gastric adenocarcinoma – individual patient data from 1775 patients in four randomised controlled trials. Ann Oncol 20:885–891 Conroy T, Etienne PL, Adenis A et al (2002) Vinorelbine and cisplatin in metastatic squamous cell carcinoma of the oesophagus: response, toxicity, quality of life and survival. Ann Oncol 13:721–729 Crehange G, Maingon P, Peignaux K et al (2007) Phase III trial of protracted compared with splitcourse chemoradiation for esophageal carcinoma: Federation Francophone de Cancerologie Digestive 9102. J Clin Oncol 25:4895–4901 Das D, Chilton AP, Jankowski JA (2009) Chemoprevention of oesophageal cancer and the AspECT trial. Recent Results Cancer Res 181:161–169 Dhillon PK, Farrow DC, Vaughan TL et al (2001) Family history of cancer and risk of esophageal and gastric cancers in the United States. Int J Cancer 93:148–152 Downey RJ, Akhurst T, Ilson D, Ginsberg R et al (2003) Whole body 18FDG-PET and the response of esophageal cancer to induction therapy: results of a prospective trial. J Clin Oncol 21:428–432 Dragovich T, McCoy S, Fenoglio-Preiser CM et al (2004) Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol 24:4922–4927 Ell C, May A, Gossner L et al (2000) Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett’s esophagus. Gastroenterology 118:670–677 Feith M, Stein HJ, Siewert JR (2003) Pattern of lymphatic spread of Barrett’s cancer. World J Surg 27:1052–1057
4 Esophageal Cancer
95
Fiorica F, Di Bona D, Schepis F et al (2004) Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis. Gut 53:925–930 Flamen P, Van Cutsem E, Lerut A, Cambier JP et al (2002) Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer. Ann Oncol 13:361–381 Gebski V, Burmeister B, Smithers BM et al (2007) Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol 8:226–234 Greer SE, Goodney PP, Sutton JE et al (2005) Neoadjuvant chemoradiation for esophageal carcinoma: a meta-analysis. Surgery 137:172–179 Grotenhuis BA, Wijnhoven BP, van Marion R et al (2009) The sentinel node concept in adenocarcinomas of the distal esophagus and gastroesophageal junction. J Thorac Cardiovasc Surg 138:608–612 Gutschow C, Schröder W, Wolfgarten E et al (2004) Operation nach Merendino mit Vaguserhaltung beim Frühkarzinom des gastroösophagealen Übergangs. Zentralbl Chir 129:276–281 Hao Y, Triadafilopoulos G, Sahbaie P et al (2006) Gene expression profiling reveals stromal genes expressed in common between Barrett’s esophagus and adenocarcinoma. Gastroenterology 131:925–933 Hardwick RH, Williams GT (2002) Staging of oesophageal adenocarcinoma. Br J Surg 89:1076–1077 He D, Zhang DK, Lam KY et al (1997) Prevalence of HPV infection in esophageal squamous cell carcinoma in Chinese patients and its relationship to the p53 gene mutation. Int J Cancer 72:959–964 Heidecke CD, Weighardt H, Feith M et al (2002) Neoadjuvant treatment of the esophageal cancer: immunosuppression following combined radiochemotherapy. Surgery 132:495–501 Herskovic A, Martz K, al-Sarraf M et al (1992) Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992(326):1593–1598 Higuchi K, Koizumi W, Tanabe S et al (2009) Current management of esophageal squamous-cell carcinoma in Japan and other countries. Gastrointest Cancer Res 3:153–161 Hofstetter W, Correa AM, Bekele N et al (2007) Proposed modification of nodal status in AJCC esophageal cancer staging system. Ann Thorac Surg 84:365–373 Hölscher AH, Vallböhmer D (2007) Surgical treatment of esophageal tumors including local ablation. Zentralbl Chir 132:18–36 Hölscher AH, Bollschweiler E, Bumm R et al (1995) Prognostic factors of resected adenocarcinoma of the esophagus. Surgery 118:845–855 Hölscher AH, Schröder W, Bollschweiler E et al (2003) Wie sicher ist die hoch intrathorakale Ösophagogastrostomie? Chirurg 74:726–733 Hölscher AH, Metzger R, Brabender J et al (2004) High-volume centers – effect of case load on outcome in cancer surgery. Onkologie 27:412–416 Hölscher AH, Schneider PM, Gutschow C et al (2007) Laparoscopic ischemic conditioning of the stomach for esophageal replacement. Am Surg 245:241–246 Hulscher JBF, Van Sandick JW, De Beure AGEM et al (2002) Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347:1662–1669 Ilson DH, Saltz L, Enzinger P et al (1999) Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 10:3270–3275 Ilson DH, Bains M, Kelsen DP et al (2003) Phase I trial of escalating-dose irinotecan given weekly with cisplatin and concurrent radiotherapy in locally advanced esophageal cancer. J Clin Oncol 21:2962–2969 Inoue H, Minami H, Kaga M et al (2010) Endoscopic mucosal resection and endoscopic submucosal dissection for esophageal dysplasia and carcinoma. Gastrointest Endosc Clin N Am 20:25–34
96
F. Lordick and A. Hölscher
Javeri H, Arora R, Correa AM et al (2008) Influence of induction chemotherapy and class of cytotoxics on pathologic response and survival after preoperative chemoradiation in patients with carcinoma of the esophagus. Cancer 113:1302–1308 Javeri H, Xiao L, Rohren E et al (2009) The higher the decrease in the standardized uptake value of positron emission tomography after chemoradiation the better the survival of patients with gastroesophageal adenocarcinoma. Cancer 115:5184–5192 Kamangar F, Dores GM, Anderson WF (2006) Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24:2137–2150 Kamangar F, Chow WH, Abnet CC et al (2009) Environmental causes of esophageal cancer. Gastroenterol Clin North Am 38:27–57 Kelly S, Harris KM, Berry E et al (2001) A systematic review of the staging performance of endoscopic ultrasound on gastro-oesophageal carcinoma. Gut 49:534–539 Kelsen DP, Ginsberg R, Pajak TF et al (1998) Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339:1979–1984 Kelsen DP, Winter KA, Gunderson LL et al (2007) Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol 25:3719–3725 Kesting MR, Schurr C, Robitzky L et al (2009) Results of esophagogastroduodenoscopy in patients with oral squamous cell carcinoma – value of endoscopic screening: 10-year experience. J Oral Maxillofac Surg 67:1649–1655 Khushalani NI, Leichman CG, Proulx G et al (2002) Oxaliplatin in combination with protractedinfusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer. J Clin Oncol 20:2844–2850 Kleinberg L, Gibson MK, Forastiere AA (2007) Chemoradiotherapy for localized esophageal cancer: regimen selection and molecular mechanisms of radiosensitization. Nat Clin Pract Oncol 4:282–294 Lagergren J (2005) Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk? Gut 54(suppl 1):i1–i5 Lagergren JL, Bergstrom R, Lindgren A et al (1999) Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340:825–831 Lagergren P, Avery KN, Hughes R et al (2007a) Health-related quality of life among patients cured by surgery for esophageal cancer. Cancer 110(3):686–693 Lagergren P, Fayers P, Conroy T et al (2007b) Clinical and psychometric validation of a questionnaire module, the EORTC QLQ-OG25, to assess health-related quality of life in patients with cancer of the oesophagus, the oesophago-gastric junction and the stomach. Eur J Cancer 43(14):2066–2073 Launoy G, Milan CH, Faivre J et al (1997) Alcohol, tobacco and oesophageal cancer: effects of the duration of consumption, mean intake and current and former consumption. Br J Cancer 75:1389–1396 Leers JM, Bollschweiler E, Hölscher AH (2005) Refluxanamnese von Patienten mit Adenokarzinom der Speiseröhre. Z Gastroenterol 43:275–280 Lightdale CJ (1996) Diagnosis of esophagogastric tumors. Endoscopy 28:22–26 Liu L, Hofstetter WL, Rashid A et al (2005) Significance of the depth of tumor invasion and lymph node metastasis in superficially invasive esophageal adenocarcinoma. Am J Surg Pathol 29:1079–1085 Löfdahl HE, Lu Y, Lagergren J (2008) Sex-specific risk factor profile in oesophageal adenocarcinoma. Br J Cancer 99:1506–1510 Lordick F (2009) Principles of neoadjuvant therapy. Chirurg 80:1000–1005 Lordick F, Stein HJ, Peschel C et al (2004) Neoadjuvant therapy for oesophagogastric cancer. Br J Surg 91:540–551 Lordick F, Ebert M, Stein HJ (2006) Current treatment approach to locally advanced esophageal cancer: is resection mandatory? Future Oncol 2:717–721
4 Esophageal Cancer
97
Lordick F, Ott K, Krause BJ et al (2007) Use of PET to assess early metabolic response and to guide treatment of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol 8:797–805 Lorenzen S, Duyster J, Lersch C et al (2005) Capecitabine plus docetaxel every three weeks in first- and second-line metastatic oesophageal cancer: final results of a phase II trial. Br J Cancer 92:2129–2133 Lorenzen S, Brücher B, Zimmermann F et al (2008) Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial. Br J Cancer 99:1020–1026 Lorenzen S, Schuster T, Porschen R et al (2009) Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 20:1667–1673 Malthaner R, Fenlon D (2003) Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev 4:CD001556 Medical Research Council Oesophageal Cancer Working Party (2002) Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomized controlled trial. Lancet 359:1727–1733 Mehta V (2005) Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: pulmonary function, prediction, and prevention. Int J Radiat Oncol Biol Phys 63:5–24 Minsky B, Pajak TF, Ginsberg RJ et al (2002) INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 20:1151–1153 Moodley R, Reddi A, Chetty R et al (2007) Abnormalities of chromosome 17 in oesophageal cancer. J Clin Pathol 60:990–994 Natsugoe S, Kaminosono H, Arigami T et al (2009) Upper G.I. cancer: the esophagus and stomach. III. The current status and overview on sentinel node navigation surgery of esophageal cancer. Gan To Kagaku Ryoho 36:1442–1446 Neumann H, Mönkemüller K, Vieth M et al (2009) Chemoprevention of adenocarcinoma associated with Barrett’s esophagus: potential options. Dig Dis 27:18–23 Nygaard K, Hagen S, Hansen HS et al (1992) Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 16:1104–1109 Omloo JM, Lagarde SM, Hulscher JB et al (2007) Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clinical trial. Ann Surg 246:992–1000 Ott K, Weber WA, Lordick F et al (2006) Metabolic imaging predicts response, survival and recurrence in adenocarcinomas of the esophagogastric junction (AEG) in a prospective trial. J Clin Oncol 24:4692–4698 Ott K, Bader FG, Lordick F et al (2009a) Surgical factors influence the outcome after Ivor-Lewis esophagectomy with intrathoracic anastomosis for adenocarcinoma of the esophagogastric junction: a consecutive series of 240 patients at an experienced center. Ann Surg Oncol 16:1017–1025 Ott K, Lordick F, Molls M et al (2009b) Limited resection and free jejunal graft interposition for squamous cell carcinoma of the cervical oesophagus. Br J Surg 96:258–266 Pech O, Ell C (2009a) Endoscopic therapy of Barrett’s esophagus. Curr Opin Gastroenterol 25:405–411 Pech O, Ell C (2009b) Editorial: resecting or burning: what should we do with the remaining Barrett’s epithelium after successful ER of neoplasia? Am J Gastroenterol 104:2693–2694 Pech O, May A, Gossner L et al (2007) Curative endoscopic therapy in patients with early esophageal squamous-cell carcinoma or high-grade intraepithelial neoplasia. Endoscopy 39:30–35
98
F. Lordick and A. Hölscher
Piert M, Burian M, Meisetschläger G et al (2007) Positron detection for the intraoperative localisation of cancer deposits. Eur J Nucl Med Mol Imaging 34:1534–1544 Pohl H, Welch HG (2005) The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 19(97):142–146 Qiao YL, Dawsey SM, Kamangar F et al (2009) Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. J Natl Cancer Inst 101:507–518 Riedel M, Hauck RW, Stein HJ et al (1998) Preoperative bronchoscopic assessment of airway invasion by esophageal cancer: a prospective study. Chest 113:687–695 Riedel M, Stein HJ, Mounyam L et al (2001) Extensive sampling improves preoperative bronchcoscopic assessment of airway invasion by supracarinal esophageal cancer. Chest 119: 1652–1660 Rizk NP, Venkatraman E, Bains MS et al; American Joint Committee on Cancer (2007) American Joint Committee on Cancer staging system does not accurately predict survival in patients receiving multimodality therapy for esophageal adenocarcinoma. J Clin Oncol 25:507–512 Rizk NP, Tang L, Adusumilli PS et al (2009) Predictive value of initial PET-SUVmax in patients with locally advanced esophageal and gastroesophageal junction adenocarcinoma. J Thorac Oncol 4:875–879 Roder JD, Busch R, Stein HJ et al (1994) Ratio of invaded to removed lymph nodes as a predictor of survival in squamous cell carcinoma of the oesophagus. Br J Surg 81:410–413 Rohatgi P, Swisher SG, Correa AM et al (2005) Characterization of pathologic complete response after preoperative chemoradiotherapy in carcinoma of the esophagus and outcome after pathologic complete response. Cancer 104:2365–2372 Rösch T (1995) Endosonographic staging of esophageal cancer: a review of literature results. Gastrointest Endosc Clin N Am 5:537–547 Rudolph RE, Vaughan TL, Storer BE et al (2000) Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus. Ann Intern Med 132:612–620 Rugge M, Bovo D, Busatto G et al (1997) p53 Alterations but no human papillomavirus infection in preinvasive and advanced squamous esophageal cancer in Italy. Cancer Epidemiol Biomarkers Prev 6:171–176 Ruhstaller T, Widmer L, Schuller JC et al (2009) Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02). Ann Oncol 20:1522–1528 Sarkaria IS, Rizk NP, Bains MS et al (2009) Post-treatment endoscopic biopsy is a poor-predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer. Ann Surg 249:764–767 Schneider PM, Baldus SE, Metzger R et al (2005) Histomorphologic tumor regression and lymph node metastases determeine prognosis following neoadjuvant radiochemotherapy for esophageal cancer. Implications for response classification. Ann Surg 242:684–692 Schreiber D, Rineer J, Vongtama D et al (2010) Impact of postoperative radiation after esophagectomy for esophageal cancer. J Thorac Oncol 5(2):244–250 Siewert JR, Stein HJ (1998) Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 85:1457–1459 Siewert JR, Stein HJ, Feith M et al (2001) Histologic tumor type is an independent prognostic parameter in esophageal cancer: lessons from more than 1,000 consecutive resections at a single center in the Western world. Ann Surg 234:360–367 Sobin LH, Gospodarowicz Mk, Wittekind C (eds) (2009) TNM classification of malignant tumours, 7th edn. Wiley VCH, Weinheim Spechler S (1994) Barrett’s esophagus. Semin Oncol 21:431–437 Stahl M, Stuschke M, Lehmann N et al (2005) Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 23: 2310–2317
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Stahl M, Walz MK, Stuschke M et al (2009) Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 27:851–856 Stein HJ, Bartels H, Siewert JR (2001) Esophageal cancer: indications for two-stage procedures. Chirurg 72:881–886 Stein HJ, Feith M, Bruecher BL et al (2005) Early esophageal cancer: pattern of lymphatic spread and prognostic factors for long-term survival after surgical resection. Ann Surg 242:566–573 Stein HJ, Hutter J, Feith M et al (2007) Limited surgical resection and jejunal interposition for early adenocarcinoma of the distal esophagus. Semin Thorac Cardiovasc Surg 19:72–78 Steyerberg EW, Neville BA, Koppert LB et al (2006) Surgical mortality in patients with esophageal cancer: development and validation of a simple risk score. J Clin Oncol 24: 4277–4284 Stippel DL, Taylan C, Schroder W et al (2005) Supraventricular tachyarrhythmia as early indicator of a complicated course after esophagectomy. Dis Esophagus 18:267–273 Swisher SG, Maish M, Erasmus JJ et al (2004) Utility of PET, CT, and EUS to identify pathologic responders in esophageal cancer. Ann Thorac Surg 78:1152–1157 Swisher SG, Hofstetter W, Wu TT et al (2005) Proposed revision of the esophageal cancer staging system to accommodate pathologic response following preoperative chemoradiation (CRT). Ann Surg 241:810–820 Takeuchi H, Fujii H, Ando N et al (2009) Validation study of radio-guided sentinel lymph node navigation in esophageal cancer. Ann Surg 249:757–763 Tepper J, Krasna MJ, Niedzwiecki D et al (2008) Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 26:1086–1092 Thomas T, Abrams KR, De Caestecker JS et al (2007) Meta analysis: cancer risk in Barrett’s oesophagus. Aliment Pharmacol Ther 26:1465–1477 Thompson JJ, Zinsser KR, Enterline HT (1983) Barrett’s metaplasia and adenocarcinoma of the esophagus and gastroesophageal junction. Hum Pathol 14:42–61 Tischoff I, Tannapfel A (2008) Barrett’s esophagus: can biomarkers predict progression to malignancy? Expert Rev Gastroenterol Hepatol 2:653–663 Turner JR, Shen LH, Crum CP et al (1997) Low prevalence of human papillomavirus infection in esophageal squamous cell carcinomas from North America: analysis by a highly sensitive and specific polymerase chain reaction-based approach. Hum Pathol 28:174–178 Urba SG, Orringer MB, Turrisi A et al (2001) Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 19:305–313 Urschel JD, Vasan H (2003) A meta-analysis of randomised controlled trials that compared neoadjuvant chemoradiation and surgery alone for resectable esophageal cancer. Am J Surg 185:538–543 Urschel JD, Vasan H, Blewett CJ (2002) A meta-analysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer. Am J Surg 183:274–279 Vallböhmer D, Hölscher AH, Dietlein M et al (2009) [18F]-Fluorodeoxyglucose-positron emission tomography for the assessment of histopathologic response and prognosis after completion of neoadjuvant chemoradiation in esophageal cancer. Ann Surg 250:888–894 van Westreenen HL, Westerterp M, Sloof GW et al (2007) Limited additional value of positron emission tomography in staging oesophageal cancer. Br J Surg 94:1515–1520 Vieth M, Ell C, Gossner L, May A et al (2004) Histological analysis of endoscopic resection specimens from 326 patients with Barrett’s esophagus and early neoplasia. Endoscopy 36:776–781 Walsh T, Noonan N, Hollywood D et al (1996) A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462–467 Weber WA, Ott K, Becker K et al (2001) Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 19:3058–3065
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Westerterp M, Koppert LB, Buskens CJ et al (2005) Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction. Virchows Arch 446:497–504 Westerterp M, van Westreenen HL, Deutekom M et al (2008) Patients’ perception of diagnostic tests in the preoperative assessment of esophageal cancer. Patient Prefer Adherence 2:157–162 Wiech T, Nikolopoulos E, Weis R et al (2009) Genome-wide analysis of genetic alterations in Barrett’s adenocarcinoma using single nucleotide polymorphism arrays. Lab Invest 89: 385–397 Wieder H, Brucher BL, Zimmermann F et al (2004) Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 22:900–908 Wieder HA, Ott K, Lordick F et al (2007) Prediction of tumor response by FDG-PET: comparison of the accuracy of single and sequential studies in patients with adenocarcinomas of the esophagogastric junction. Eur J Nucl Med 34:1925–1932 Witzig R, Schönberger B, Fink U et al (2006) Delays in diagnosis and therapy of gastric cancer and esophageal adenocarcinoma. Endoscopy 38:1122–1126 Yokoyama A, Omori T, Yokoyama T et al (2008) Risk of metachronous squamous cell carcinoma in the upper aerodigestive tract of Japanese alcoholic men with esophageal squamous cell carcinoma: a long-term endoscopic follow-up study. Cancer Sci 99:1164–1171
Gastric Cancer
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John S. Macdonald, Scott Hundahl, Stephen R. Smalley, Denise O’Dea, and Edith P. Mitchell
5.1 Epidemiology Gastric cancer represents a challenging health problem around the world. It is the fourth most common cancer behind lung, breast, and colon and rectum cancers. An analysis of the worldwide incidence and mortality from gastric cancer had estimated that 691,432 new cases among men and 375,111 cases among women would occur in 2007 (Garcia et al. 2007). It was also estimated that approximately 800,000 patients would die of this disease annually (Garcia et al. 2007). In the United States, it was estimated that 21,000 new cases of gastric cancer would occur in 2010, with 10,570 deaths expected (Jemal et al. 2010). There are significant geographic variations in the incidence of gastric cancer. Nearly 70% of new cases of gastric cancer occur in developing countries (Garcia et al. 2007). An estimated 42% of all cases occur in China alone. This disease is far more common in geographic areas such as East Asia, Eastern Europe, Costa Rica, and parts of Central and South America than it is in the United States or Western Europe (Parkin et al. 2005). In most countries, the incidence and death rates for men are twice as high as those for women. In high-incidence countries (Jemal et al. 2010; Parkin et al. 2005), the intestinal form of
J.S. Macdonald () Aptium Oncology Inc, 8201 Beverly Boulevard, Los Angeles, CA 90048, USA e-mail:
[email protected] S. Hundahl VA Northern California Health Care System, Mather, CA 95655, USA and U.C. Davis, Sacramento, CA 95817, USA S.R. Smalley Olathe Regional Oncology Center, Olathe, KS, USA D. O’Dea Mount Sinai Medical Center New York, New York, USA E.P. Mitchell Thomas Jefferson University, Philadelphia, PA, USA C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_5, © Springer-Verlag Berlin Heidelberg 2011
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gastric cancer associated with intestinal metaplasia and Helicobacter pylori (H. pylori) mediated gastritis is significantly more common than the diffuse form. Japan is the only country demonstrating a moderately good survival rate for patients diagnosed with stomach cancer. This finding is likely due to earlier diagnosis secondary to mass screening, including the use of newer endoscopic techniques such as photofluoroscopy (Parkin et al. 2005). Most patients with gastric cancer in the U.S. are symptomatic at the time of diagnosis and have locally advanced or metastatic disease. In North America, survival is improving secondary to greater numbers of endoscopic examinations for various upper abdominal symptoms, leading to earlier diagnosis of cancer. A small percentage of gastric cancers are hereditary, but the vast majority of cases are related to environmental, socioeconomic, and dietary risk factors. A steady decline in gastric cancer rates in developed countries has been observed over the past 50 years with rates dropping by more than 80% (Garcia et al. 2007). The decline may be due to improvements in food storage and preservation as well as lifestyle changes. Increased availability of fresh fruits and vegetables and the decreased use of salted and preserved foods have also contributed to the decline (Garcia et al. 2007). Changes in the prevalence of H. pylori may also play a role, with H. pylori infection becoming less prevalent in relatively wealthy western countries. Decrease in H. pylori infection is due to better sanitation, increased use of antibiotics, and increased screening in developed countries.
5.2 Etiology The great majority of malignant tumors of the stomach are adenocarcinomas (Macdonald et al. 1992). The histology of gastric adenocarcinoma falls into two broad subtypes: the intestinal and diffuse types. The intestinal type is the form of gastric cancer seen in countries with high incidence rates, and it is also referred to as the endemic form of stomach cancer. The intestinal type arises in the antrum or antral-corpus junction. The histologic type varies with tumor location in the stomach. Diffuse-type cancers involve the corpus, and intestinaltype cancers may be seen in the gastroesophageal junction (Hundahl et al. 2006). In high-incidence countries, the most common gastric cancers are the intestinal-antral types, which are usually associated with pre-existing intestinal metaplasia, atrophic gastritis, and chronic H. pylori infections. The remaining types of gastric cancers in highincidence countries are diffuse-type tumors. Diffuse-type gastric cancers may also be associated with the presence of H. pylori but generally do not develop on the background of intestinal metaplasia. In high-incidence countries, these diffuse-type cancers occur in geographic locations where a high prevalence of H. pylori exists. The relationship of H. pylori infection to the etiology of diffuse-type cancers is not as clear as the bacteria’s role in intestinal-type cancers. Diffuse-type cancers are more common in younger patients and may be associated with brisk mucosal inflammatory infiltrates that may in some cases, be related to H. pylori infection (Hundahl et al. 2006). Intestinal-type cancers of the proximal stomach and gastroesophageal junction are less common in high-incidence countries. These are usually associated with gastro esophageal reflux disease (GERD). These GERD-associated tumors occur most commonly
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in middle-aged white men, and, although the distal esophagus is most commonly involved, the cardioesophageal junction also frequently exhibits tumors. It becomes difficult to determine whether these cancers are gastroesophageal junction stomach tumors or distal esophageal malignancies. The tumors associated with GERD also appear to be more common in obese men who drink alcohol and smoke cigarettes. It is considered possible that all three factors (drinking, smoking, and obesity) decrease the tone of the gastroesophageal sphincter mechanism and thus favor GERD (Parkin et al. 2005; Macdonald et al. 1992; van den Brandt and Goldbohm 2006). Gastric malignancies other than adenocarcinomas account for <10% of gastric cancers (Berlin and Washington 2006). These tumors of the stomach include undifferentiated gastric carcinomas with lymphoid stroma, hepatoid carcinomas, adenoacanthomas, adenosquamous and squamous cell carcinoma, parietal cell carcinoma, oncocytic gastric carcinoma, carcinoid tumors, and gastrointestinal stromal tumors (GIST) (Berlin and Washington 2006). GIST tumors are discussed elsewhere in this book. Choriocarcinomas, teratomas, and yolk sac tumors all occur as primary gastric tumors; although these germ cell neoplasms are very uncommon, the stomach is the most common site of nongonadal, nongestational germ cell tumors (Berlin and Washington 2006). Lymphoma occurs in the gastrointestinal (GI) tract, and the stomach is the most common site for GI lymphomas. Most gastric lymphomas are of the non-Hodgkin’s type, with the majority classified as B-cell lymphomas (Berlin and Washington 2006). Mucosa-associated lymphatic tissue (MALToma) neoplasms are low-grade neoplastic processes associated with H. pylori colonization and occur in the stomach. These neoplastic B-cell proliferations appear to initially develop as polyclonal proliferations, which may be successfully treated with antibiotic therapy directed at eradication of H. pylori before the MALToma has evolved to a monoclonal, truly malignant neoplasm (Berlin and Washington 2006; Wotherspoon et al. 1993; Manson 2006).
5.3 Environmental Risks and Prevention A number of epidemiologic studies have examined various factors associated with the development of gastric cancer. Low socioeconomic class and low education level have been associated with a higher incidence of gastric cancer. A higher incidence has also been seen in those who work in coal, nickel, and asbestos mining and in the processing of timber and rubber (Wu-Williams et al. 1990). Blood group A, gastric ulcer, ionizing radiation, and previous gastric resection are also associated risk factors (Hundahl et al. 2006). Diet also plays a role in the development of gastric cancer. Diets with a high intake of smoked and cured meats, as well as diets with a high intake of salt or salt-preserved foods, have been associated with gastric cancer (van den Brandt and Goldbohm 2006). Diets deficient in raw vegetables and fruits, vitamin C, and antioxidants also are associated with gastric cancer. Obesity has been linked to approximately 25–40% of gastric cancers (NCCN). Smoking and alcohol consumption have been associated with gastroesophageal junction tumors. Dietary and lifestyle changes may play a modest role in the prevention of gastric cancer (van den Brandt and Goldbohm 2006).
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Evidence linking H. pylori infection to gastric cancer was considered sufficient for the International Agency for Research on Cancer to classify it as carcinogenic in humans (Parkin et al. 2005). The role of H. pylori infection in carcinogenesis is probably indirect, with the bacteria serving as a factor in causing gastritis. This chronic gastritis may lead to dysplasia and eventually carcinoma. The infection is acquired in childhood, and prevalence is related to socioeconomic status. The primary prevention strategy for reducing the risk of gastric cancer includes reducing the prevalence of H. pylori infection by improving hygienic conditions and increasing the use of antibiotics to eradicate H. pylori in cases harboring the bacteria.
5.3.1 Genetic Risk Approximately 1–3% of gastric cancers are associated with an inherited gastric cancer syndrome (NCCN guidelines). The lifetime risk for diffuse gastric cancer in individuals with the gene mutation is approximately 67% for men and 83% for women. Hereditary diffuse gastric cancer (HDGC) is strongly associated with an autosomal dominant susceptibility to develop diffuse gastric cancers. These diffuse cancers are poorly differentiated adenocarcinomas that infiltrate the stomach wall, causing thickening of the wall without forming a distinct mass (Kaurah and Huntsman 2004). Most cases of HDGC occur before the age of 40, with an average onset age of 38 years. Germline mutations in the E-cadherin gene, CDH1, have been identified in families with HDGC. The CHD1 gene is the only gene known to be associated with HDGC (Kaurah and Huntsman 2004). In 1999, the International Gastric Cancer Linkage Consortium defined HDGC as the presence of two or more documented cases of diffuse gastric cancer in first- or seconddegree relatives, with at least one case diagnosed before age 50 or three or more documented cases of diffuse gastric cancer in first- or second-degree relatives, regardless of age of onset (Kaurah and Huntsman 2004). Genetic testing was recommended for individuals falling into these categories. In 2004, the criteria for consideration of genetic testing were revised. The six criteria for consideration of CDH1 molecular genetic testing are outlined in Table 5.1. Due to the broad nature of the recommendations, it may not be practical for use in regions of high gastric cancer incidence, such as Japan (Kaurah and Huntsman 2004). Other cancers reported in family members of patients with HDGC are lobular breast cancer and colorectal cancer. Patients with these neoplasms in HDGC families have not, at this point, been recommended as candidates for genetic testing (Kaurah and Huntsman 2004). Management options for carriers of CDH1 germline mutations include prophylactic gastrectomy or intensive surveillance for early detection and treatment of gastric cancer (Blair et al. 2006). Current methods of surveillance use chromogastroscopy. The use of newer sophisticated endoscopic techniques (Berlin and Washington 2006), such as spectroscopy and autofluorescence, have not been studied in HDGC. Small studies of prophylactic gastrectomy have shown that they can be performed safely and prevent cancers in carriers of CDH1 germ-line mutations (Newman and Mulholland 2006). Prophylactic gastrectomy and surveillance remain controversial and require further study to fully understand the risks and benefits of these approaches.
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Table 5.1 Criteria for consideration of CDH1 Molecular genetic testing Two or more cases of gastric cancer in a family, with at least one diffuse gastric cancer diagnosed before age 50 years Three or more cases of gastric cancer in a family, diagnosed at any age, with at least one documented case of diffuse gastric cancer An individual diagnosed with diffuse gastric cancer before 45 years of age An individual diagnosed with both diffuse gastric cancer and lobular breast cancer (no other criteria met) One family member diagnosed with diffuse gastric cancer and another family member diagnosed with lobular breast cancer (no other criteria met) One family member diagnosed with diffuse gastric cancer and another family member diagnosed with signet ring colon cancer (no other criteria met)
5.4 Diagnosis and Workup Early diagnosis of gastric cancer often is not possible because patients are asymptomatic during the initial stages of gastric cancer. The symptoms of stomach cancer frequently are vague and nonspecific. They include complaints such as weight loss, epigastric discomfort, nausea, vomiting, fatigue, anorexia, and early satiety. Dysphagia is common in patients with GE junction/distal esophageal cancers and early satiety is seen in patients with more distal cancers. In low-incidence countries, upper GI symptoms or positive fecal occult blood testing may trigger endoscopic investigation. In Japan, mass screening with upper GI contrast studies and endoscopy has proven successful in obtaining early diagnosis (Hundahl et al. 2006). Mass screening is expensive and not practical in other high-risk countries without the resources to support the technology and logistics involved. Although the double barium upper GI series may still be helpful in defining a gastric abnormality, the most common diagnostic test used at initial evaluation is upper endoscopy. While barium studies may identify gastric lesions, negative studies may be seen in a substantial minority of cases (Dooley, 1984). However in the infiltrative submucosal form of typically poorly differentiated gastric cancers, endoscopy can be negative because of lack of mucosal abnormalities. In such cases demonstrating the linitis plastica variant of stomach cancer, an area of the stomach without peristalsis on the barium study may be a strong indication that cancer is present. Endoscopy can be helpful in providing information about tumor location, distance from the esophagogastric junction, and extent of mucosal involvement. Biopsies for tissue diagnosis can be performed during this test. Endoscopic ultrasound examination is useful to evaluate depth of tumor, penetration of the wall, and assessment of gross lymph node enlargement. This is a reliable way of assessing patients preoperatively (Hundahl et al. 2006). Diagnostic/therapeutic laparoscopy is useful in identifying cases with disseminated and/or technically unresectable disease and, therefore, may spare patients full
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laparotomy. The extent of disease at laparotomy usually is greater than predicted preoperatively. Computed tomography (CT) scanning provides additional information for staging purposes before laparotomy and assists in decision making regarding curative vs. palliative resections. CT scanning is helpful in detecting distant metastatic disease, extraregional adenopathy, and signs of locally advanced disease (Hundahl et al. 2006). Positron-emission tomography (PET) scanning is being used in patients receiving preoperative neoadjuvant therapy to indicate the possibility of disseminated cancers before curative resection is attempted. PET scanning is also being used to detect recurrent disease and distant organ metastases. However, PET scanning has not proved as useful in gastric cancers as in other tumors. Primary tumor uptake is only seen in approximately 75% of cases. Neither mucuscontaining tumors nor diffuse-type tumors, particularly poorly differentiated scirrhous tumors, image well in PET scans (Hundahl et al. 2006). PET scanning, however, may be a useful means to assess the benefit of chemoradiation therapy in the management of welldifferentiated adenocarcinomas of the esophagus. Currently, no reliable serum tumor markers exist in gastric cancer. CEA and CA19-9 have been noted to be elevated in approximately 40–50% of patients with disseminated disease (Macdonald et al. 1992). Comprehensive physical examination is imperative in the workup of gastric cancer. Common physical findings in surgically incurable patients include palpable lymph node metastases in the left supraclavicular area (Virchow node) or left axilla (Irish node). Periumbilical nodules (Sister Joseph nodes) represent peritoneal dissemination of tumor. Hepatomegaly or ascites may be present. Epigastric mass or pelvic masses due to Krukenberg tumor (ovarian metastases) or pelvic peritoneal drop metastases (Blumer shelf) may be detected on physical examination, and a careful pelvic/rectal examination should be part of the initial evaluation of all gastric cancer cases.
5.5 Staging There are two major classification systems currently in use for gastric carcinoma. The Japanese classification system is based on the location of positive lymph nodes. The other staging system was developed jointly by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) and is used in countries in the western hemisphere (Sayegh et al. 2004a). This system is based on tumor/node/metastasis classification (Table 5.2).
5.6 Surgical Treatment In contrast to other parts of the GI tract, the stomach’s relationships to adjacent key structures and the highly complicated lymphatic network, combined with the risk associated with various surgical treatment options, have rendered description of a truly optimal oncologic
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Table 5.2 American Joint Committee on Cancer (AJCC) staging Primary tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria T1: Tumor invades lamina propria or submucosa T2: Tumor invades the muscularis propria or the subserosa T2a: Tumor invades muscularis propria T2b: Tumor invades subserosa T3: Tumor penetrates the serosa (visceral peritoneum) without invading adjacent structures T4: Tumor invades adjacent structures Regional lymph nodes (N) NX: Regional lymph node(s) cannot be assessed N0: No regional lymph node metastasis* N1: Metastasis in 1–6 regional lymph nodes N2: Metastasis in 7–15 regional lymph nodes N3: Metastasis in more than 15 regional lymph nodes Distant metastasis (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis Stage groupings Stage 0 Tis, N0, M0 Stage IA T1, N0, M0 Stage IB T1, N1, M0 T2a, N0, M0 T2b, N0, M0 Stage II T1, N2, M0 T2a, N1, M0 T2b, N1, M0 T3, N0, M0 Stage IIIA T2a, N2, M0 T2b, N2, M0 T3, N1, M0 T4, N0, M0 Stage IIIB T3, N2, M0 Stage IV T4, N1, M0 T4, N2, M0 T4, N3, M0 (continued)
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Table 5.2 (continued)
T1, N3, M0 T2, N3, M0 T3, N3, M0 Any T, any N, M1
*At least 15 lymph nodes must be examined and free of tumor for a case to be considered N0
approach elusive. The topic of optimal gastric cancer surgery has remained controversial for over 70 years. Fortunately, results from prospective, randomized surgical trials conducted over the past two decades have pointed to some clear answers. Today, the historical “onesize-fits-all” approach has been largely abandoned in favor of customized surgery appropriate to both the extent and location of the cancer, and the condition of the patient.
5.6.1 Extent of Organ Resection (Subtotal vs. Total Gastrectomy and Margins) Several prospective randomized clinical trials address the potential value of routine total gastrectomy vs. subtotal gastrectomy for distal cancers, which can be potentially cleared by either procedure (Gouzi et al. 1989; Bozzetti et al. 1997, 1999; Robertson et al. 1994). The trials consistently fail to show any survival advantage for routine total gastrectomy, and, indeed, a Hong Kong Trial (Robertson et al. 1994) that included the addition of an extended node dissection to the total gastrectomy arm showed worse survival when routine total gastrectomy was selected. A trend to higher 30-day mortality with total gastrectomy (up to 3% with total gastrectomy) was also documented. Intraoperative frozen section analysis of organ margins fails to solve the issue of margin adequacy. Most have confronted a situation in which a “frozen-section-negative” margin proves involved on permanent section. Further guidance concerning margin adequacy can be gleaned from series addressing rates of margin positivity and distance between edge of resection and tumor. In a series by Bozetti and colleagues, with 285 proximal margins assessed, the positive margin rate was 5% if the margin was 3–5.9 cm and 0% if the margin was 6 cm or greater. Subset analysis revealed that if a tumor had not invaded deeper than the muscularis propria, a margin of 3 cm was also safe (Bozzetti et al. 1982). United States experts generally agree with this advice, and, paralleling Japanese recommendations (Japanese Gastric Cancer Association 1998), note that a margin of 3 cm for an intestinal-type cancer with a well- circumscribed edge (i.e., Borrmann I or II), and not invading the serosa, is quite safe.
5.6.2 Endoscopic Mucosal Resection (EMR) For selected superficial or noninvasive “early gastric cancer” (i.e., Tis or T-1 tumor), EMR has emerged as a reasonable option (Ono et al. 2001; Pathirana and Poston 2001;
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Sano et al. 2000; Sasako 1997; Hiki 1996; Kobayashi et al. 2003). In the classic technique of EMR, a submucosal injection of saline floats the area of tumor-bearing mucosa off the underlying muscularis propria and the lesion is resected with a special cautery snare with hooks to preserve specimen orientation for margin analysis. The procedure can be technically challenging, but innovations such as the use of incision endo-forceps (Yamamoto et al. 2001), aspiration mucosectomy (Yoshikane et al. 2001), a stabilizing distal magnetic anchor (Kobayashi et al. 2004), and double endoscope resection techniques (Kuwano et al. 2004) can facilitate it. Laparoscopic resection is another option, but the potential risk of intra-abdominal seeding and/or port site tumor implantation in node-negative T-1 tumors otherwise suitable for EMR, make EMR the appropriate choice for such lesions (Kobayashi et al. 2003). Selection of cases suitable for EMR hinges on the absence of disease in the regional lymphatics. A combined series of 5,265 surgically treated T-1 cases from the National Cancer Center Hospital and the Cancer Institute Hospital in Tokyo offers unsurpassed guidance (Gotoda et al. 2000). For intramucosal tumors, none of the 1,230 well-differentiated cancers of less than 30-mm diameter, regardless of ulceration findings, were associated with metastases (95% confidence interval (CI), 0–0.3%). Regardless of tumor size, none of 929 cancers without ulceration were associated with nodal metastases (95% CI, 0–0.4%). For submucosal cancers, there was a significant correlation between tumor size larger than 30 mm and lymphatic-vascular involvement with an increased risk of nodal involvement. None of the 145 well-differentiated adenocarcinomas of less than 30-mm diameter without lymphatic or venous permeation were associated with nodal involvement, provided that the lesion had invaded less than 500 mm into the submucosa (95% CI, 0–2.5%) (Gotoda et al. 2000). In an 11-year, 445-case series by Ono and colleagues (2001) from the National Cancer Center Hospital in Tokyo, there were no gastric cancer-related deaths during a median follow-up period of 38 months (3–120 months). Although bleeding and perforation occurred in 5%, there were no treatment-related deaths (Japanese Gastric Cancer Association 1998). For selected superficial T-1 cancers, EMR performed by experienced personnel can generate superb results and can certainly be recommended, especially since local recurrences can be addressed with salvage gastrectomy.
5.6.3 Lymphadenectomy and “D-Level” Trials Lymphadenectomy for gastric cancer is mandatory for tumors not fitting EMR criteria. The extent of lymphadenectomy in gastric cancer has been historically defined according to (several variations of) Japanese-defined nodal treatment. Such definitions reflect mandates contained in various editions of Japanese standardized treatment/staging rules, dating from 1963 to the present (Sayegh et al. 2004b; Kajitani 1981; Japanese Classification of Gastric Carcinoma 1995; Degiuli et al. 1998). The Japanese treatment and classification system has, since its inception, included numeric designations for various lymph node stations and sub-stations around the stomach, 31 at last count (Degiuli et al. 1998). Definitions
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for various nodal levels, originally N1 through N4, are expressed in terms of groupings of these numbered anatomically-defined nodal stations for tumors in various positions within the stomach. The N groupings have changed considerably over time. Current definitions include only node levels from N1 thorough N3 (i.e., no N4). With the 13th edition of the Japanese classification system, circa 1997, which has been translated into English (Japanese Gastric Cancer Association 1998), several major changes were instituted. For example, one major change involves the designation of node involvement at perigastric short gastric (#4a) and left paracardial (#2) sites as distant metastatic disease sites (M1) when they occur in the setting of an antral primary tumor. The same stations are N1 disease or N3 disease for other primary sites within the stomach. The reader should appreciate that the Japanese system bears scant relation to the more familiar UICC/AJCC TNM system described earlier (Greene et al. 2002). Japanese mandates for node dissection are classified according to the “D-level” system. Definitions for extent of lymphadenectomy in all but one of the trials we will discuss follow the Japanese mandates. According to the Japanese system, a “D1 lymphadenectomy” encompasses all anatomically defined N1 node stations for a given location of tumor, a “D2” all N2 nodes stations, and a “D3” all N3 node stations. To make matters still more confusing, all but one of the trials we shall discuss use D-level definitions based on pre1997 editions. Table 5.3 summarizes prospective randomized trials of various Japanese-defined lymphadenectomy schemes. Given the aforementioned changing definitions and resulting confusion, surgeons might consider themselves fortunate that the trials are largely negative. For the two large European trials, the MRC Trial (Cuschieri et al. 1996, 1999) and the Dutch Trial (Bonenkamp et al. 1995, 1999; Hartgrink et al. 2004) in-hospital surgical
Table 5.3 Prospective, randomized trials addressing extent of lymphadenectomy, as defined by D-level (note: changing definitions over time) TRIAL N Rand. Survival P Value 1. South African, ‘88 Dent et al., Br J Surg 1988; 75: 110–112
43 pts
D1 vs D2 p = n.s.
2. M.R.C., ‘98 Cushieri et al., Br J Cancer 1998; 79: 1522–1530
400 pts
D1 vs D2 p = n.s.
3. Dutch, ‘99 Bonenkamp et al., NEJM 1999; 340: 908–914
711 pts
D1 vs D2 p = n.s.
4. Taipei Veterans, ‘06 221 (“intent”) D2 vs. D3 p = 0.041 Wu CW et al., Lancet Oncol 2006; 7: 309–315 156 (“per protocol”) p = 0.056 523 5. Japanese JCOG9501, ‘06 Sasako et al, JCO 2006; 24(18s): 934s (abstract) Sasako et al. Scan J Surg 2006; 95: 232–235 Sasako M., Sano T, et al. NEJM 2008; 359: 453–462
D2 vs. D3 p = n.s.
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mortality rates for the D2 groups were quite high: 13 and 10%, respectively. Both trials showed higher mortality when pancreatic-splenic resection was performed, and this somewhat confounded the D-level question since, at the time of these trials, these were mandated procedures for the D-2 group when tumors were in the middle third or proximal third of the stomach. In the Dutch Trial, restricting subgroup analysis to patients who did not undergo pancreatic or splenic resection (a post-hoc, selected analysis), survival was higher for the D-2 group (59% for the D-1 group vs. 71% for the D-2 group, p = 0.02) (Hartgrink et al. 2004). An 11-year follow-on report for this trial indicates that of the 12% of cases with pathologic N-2 disease (N = 89 out of 711 total), there were nine 10-year survivors, and eight of the nine were in the D-2 group (p = 0.01 for this post-hoc analysis of the N-2 subgroup) (Hartgrink et al. 2004). Subgroup analysis notwithstanding, both European trials were negative. Whatever was supposedly gained as a result of D-2 lymphadenectomy was lost as a result of higher surgical mortality. In the borderline-positive, single-institution Wu Trial, conducted in Taiwan, surgical mortality was zero in both D-2 and D-3 groups. The confounding influence of pancreatectomy and splenectomy deserve mention. In the mid-1990s, as a result of key work by Maruyama and others (Maruyama et al. 1995; Kasakura et al. 2000; Uyama et al. 1996), Japanese surgeons abandoned the routine pancreatic–splenic resection, unless it was required to achieve a negative-margin resection. Recommendations for D2/D3 resections were changed accordingly, but too late for the aforementioned trials. Both the MRC and Dutch Trials verified the wisdom of this change (Cuschieri et al. 1996, 1999; Hartgrink et al. 2004).
5.6.4 “Low Maruyama Index” Lymphadenectomy is Associated with Improved Survival In the late 1980s, Keiichi Maruyama and colleagues at the National Cancer Center Hospital in Tokyo created a computer program (known as the “Maruyama Program”) which searched a meticulously-maintained 3,843-patient database of gastric cancer cases treated by extensive lymphadenectomy. The program is designed to match cases with characteristics similar to a given case, and report observed nodal dissemination risk, survival, and other information. With seven demographic and clinical inputs, all identifiable preoperatively or intraoperatively, the program predicts the statistical likelihood of nodal disease for each of the 16 main nodal stations around the stomach. Maruyama Program predictions have been assessed in Japanese, German, and Italian populations and found to be highly accurate (Kampschoer et al. 1989; Bollschweiler et al. 1992; Guadagni et al. 2000). The Maruyama Program is designed (Hundahl 2005) to be used by surgeons preoperatively or intraoperatively, as a convenient means of rationally planning a more data-driven extent of lymphadenectomy for a given patient. Since the late 1980s, the program has been used in exactly this way by many gastric cancer surgeons around the world. In an effort to expand use of this computerized tool, a CD-ROM with expanded case volume was prepared in 2000 (Siewert et al. 2000). In a prospectively planned surgical analysis of a large adjuvant chemoradiation trial in the U.S. (SWOG 9008, Intergroup 0116), the extent of surgical treatment was specifically
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assessed and prospectively coded. The prospectively planned surgical analysis of survival made use of a novel means of quantifying the adequacy of lymphadenectomy relative to the likely extent of nodal disease, the Maruyama Index of Unresected Disease (MI). MI was defined (by the author, SH) as the sum of Maruyama Program predictions for those Japanese-defined regional node stations (stations #1–#12) left in situ by the surgeon (Hundahl et al. 2002). On the basis of the trial’s entry criteria and the definition of MI, every case registered could have had an MI of zero; this variable was under the surgeon’s control. Median overall survival for the MI <5 subgroup was 91 months vs. 27 months for others (p = 0.005). By multivariate analysis, adjusting for treatment, T-stage and number of nodes positive, MI proved an independent predictor of survival (p = 0.0049). To further assess of the utility of the MI as a prognostic tool, the Dutch D1 vs. D2 Trial has been re-analyzed (Peeters et al. 2005). Blinded to survival and eliminating cases with incomplete information, 648 of the 711 patients treated with curative intent had MI assigned. Median MI was 26 (vs. median of 70 for the Macdonald Trial). Overall trial findings with respect to D-level were not affected by the absence of the 63 cases with incomplete data. In contrast to D level, MI <5 proved a strong predictor of survival by both univariate and multivariate analysis (see Fig. 5.1). MI was an independent predictor of both overall survival (p = 0.016, HR = 1.45, 95% CI 1.07–1.95) and relapse risk (p = 0.010, HR = 1.72, 95% CI 1.14–2.60). Strong “dose-response” with respect to MI and survival was also observed, and the effect was profound. Thus, the Dutch Trial findings with respect to MI largely confirmed what was observed in the Macdonald Trial. Based on results from these two trials, it appears that surgeons might better impact on patient survival by pursuing a “low Maruyama Index operation” instead of relying on D-level
Overall survival and DFS by “Maruyama Index of Unresected Disease” (MI) quartiles Overall survival
1,0 8
1,0 P < 0.01
P < 0.01
(logrank)
(logrank)
8
>70 (n = 61) >26 70 (n = 159)
4
5 26 (n = 164)
2
MI in quartiles Cum Survival
Cum Survival
MI in quartiles 6
6 4
2
<=5 (n = 164) 0,0
0
2 4 6 8 10 12 14 survival since surgery (yrs)
Disease-specific survival
>70 (n = 61) >26 70 (n = 159) 5 26 (n = 164) <=5 (n = 164)
0,0
0 2 4 6 8 10 12 14 disease free period since surgery (yrs)
Fig. 5.1 In the absence of adjuvant treatment, the impact of “Maruyama Index of Unresected Disease” (MI) is profound. This graph depicts the relationship between MI quartiles and survival. Lower MI is associated with higher survival (Peeters et al., 2005)
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guidance. By using the Maruyama Program to prospectively plan a given patient’s lymphadenectomy, achieving a “low Maruyama Index operation” is relatively straightforward. The compelling dose-response effect observed for MI also suggests it can also be viewed as a quantitative yardstick for the adequacy of lymphadenectomy in a given case of gastric cancer. As such a quantitative yardstick, it might someday be used to perhaps identify patients at greater or lesser risk of locore gional recurrence, and perhaps influence decisions on postoperative adjuvant therapy. At a minimum, we feel that strong consideration should be given to explicitly calculate and report MI for every patient who is entered into a future postoperative adjuvant trial.
5.7 Radiotherapy 5.7.1 Palliative Radiotherapy Radiotherapy is an effective palliative modality of local gastric cancer symptoms. Gastric outlet obstruction, pain from local tumor extension and/or lymph node encasement of celiac nerves, bleeding, and biliary obstruction are not infrequent problems confronting those afflicted with gastric cancer. These symptoms interfere with the tolerance of systemic therapy and certainly impact quality of life. Radiotherapy to symptomatic sites of disease will cause tumor reduction in the vast majority. Symptomatic relief is achieved in 65–80% (Moertel et al. 1964; Tey et al. 2007; Kim et al. 2008a, b; Hashimoto et al. 2009) of patients. The MD Anderson Group reported the results of palliative radiotherapy in 37 gastric patients (Kim et al. 2008b). Two-thirds received concurrent chemoradiation therapy. Bleeding, obstruction, and pain were controlled in 70, 80, and 86%, respectively. Furthermore, these symptoms were controlled without additional interventions for the patient’s remaining life expectancy in 70, 81, and 49%, respectively. Those who received concomitant chemotherapy had a trend towards improved median survival. Retrospective evaluations suggest that more moderate doses of radiotherapy (40–45 Gy) result in a higher palliative rate and longer duration of palliation (Kim et al. 2008b; Hashimoto et al. 2009). Certainly, decisions regarding duration of radiotherapy and concomitant systemic chemotherapy, with palliative radiation therapy, need to be individualized, based on clinical judgment.
5.7.2 Role of Radiotherapy in Potentially Curative Gastric Cancer 5.7.2.1 Patterns of Failure The role and implementation of radiotherapy in curative gastric cancer therapy largely flows from a consideration of failure patterns following gastric resection. Locoregional
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failure is defined as disease recurrence in the tumor bed, anastomosis, regional nodes, or, rarely, the operative wound. Autopsy series document locoregional failure in 83–93% (Horn 1955; McNeer et al. 1957; Stout 1943; Thomson and Robins 1952). Clinical series have also observed a significant incidence of locoregional failure. Among 130 patients receiving curative gastric resection at the Massachusetts General Hospital, locoregional failure was observed in 38%. There were 16% who developed locoregional failure alone as the sole site of identifiable disease relapse at the time of first failure (Landry et al. 1990). Finally, the University of Minnesota reoperative series provides important insight into failure following gastric resection (Gunderson and Sosin 1982; Gunderson 2002). There were 107 patients who had planned single or multiple reoperations following curative gastric resection. Locoregional relapse occurred in 67% of the entire cohort; and, importantly, 23% of the entire cohort failed only in the locoregional areas, without any other documented site of failure. In these patterns of failure analyses, the sites of relapse are quite consistent. Failure in the gastric bed occurs in 20–50%. Failure in the anastomosis or stump occurs in approximately 25%, and failure in the regional lymphatics occurs in 40% of the re-operative series and 50% of the autopsy series. These sites (tumor bed; anastomosis/stump; lymph nodes) constitute the target volumes treated in either preoperative (obviously excluding anastomosis considerations) or postoperative adjuvant radiotherapy trials. In view of the consistent risk of recurrence in the anastomosis and stump, as well as in the tumor bed, it is not surprising that efforts to increase dissection of lymph node stations alone have less than a dramatic impact on locoregional recurrence and overall survival. For example, in the Dutch randomized study of D1 vs. D2 lymph node dissection, locoregional recurrence occurred in 58% of the D1 group as well as fully in 45% of the D2 group at 11 years (Hartgrink et al. 2004; Jansen et al. 2005). The University of Minnesota reoperative series employed increasingly more extensive nodal dissection during the course of the series without clinically apparent impact on reduction of locoregional failure (Gunderson and Sosin 1982; Gunderson 2002). Anastomotic and/ or stump recurrence is felt to likely be a result of the propensity of gastric carcinoma to spread longitudinally along the submucosal and subserosal lymphatic systems. Tumor bed failure is related in large part to the instance of involved surgical margins seen in multiple surgical series. Eight series evaluating this issue report 260 of 1074 (24%) with positive surgical margins (Smalley and Gunderson 1996). It is important to note that the serosal investiture of the stomach is incomplete. The cardia, in particular, has incomplete serosal investiture and extension of tumor to inked radial margins in this location represents a true positive margin in the vast majority. The inferoposterior portion of the stomach (inferioroposterior to the antrum and pylorus) also has either no serosal lining or incomplete serosal lining; and careful communication between surgeons and pathologists is imperative in the evaluation of margin status. The University of Bologna (Mattioli et al. 2001) reported positive radial margins of excision in 32% of gastric cardia lesions out of 116 patients evaluated. Positive radial margins were associated with increased locoregional failure and decreased overall survival. The consistently observed locoregional failures of patients resected for gastric cancer in the tumor bed, anastomosis/ stump, and lymph node areas provide rationale for adjuvant radiotherapy either prior to or following surgery.
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5.7.3 Postoperative Adjuvant Radiation Three methodologically flawed but suggestive randomized phase III studies observed improved outcomes with postoperative adjuvant radiation. Takahashi and Abe (1986) randomly assigned patients to surgery alone vs. surgery plus intraoperative radiotherapy. Fiveyear survival was statistically improved by 15–20% in those with stages II–III disease, but randomization was susceptible to bias, and failed to stratify for important prognostic factors (Landry et al. 1990). Moertel and associates prospectively randomized 62 high-risk patients to receive surgery alone vs. surgery followed by postoperative external beam radiotherapy plus bolus 5-fluorouracil (5-FU). Those randomized to therapy had statistically significant improvements in relapse-free and overall survival. Overall survival was 23% with adjuvant therapy vs. 4% with surgery alone (p = 0.05). However, there were also methodologic problems with interpretation of this study (Moertel et al. 1969). The British Stomach Cancer Group randomized gastric cancer patients to receive surgery only vs. 5-FU, doxorubicin, and mitomycin-C chemotherapy alone vs. irradiation alone. Locoregional failure was substantially reduced with radiotherapy vs. the other two treatment arms, but no overall survival benefit was seen; and there were, again, substantial methodologic problems (Hallissey et al. 1994). The consistently observed locoregional failure following stomach resection as well as the intriguing phase III randomized trials discussed above set the stage for the Intergroup 0116 trial. There were 603 patients registered on this U.S.–Canadian study from 1991 to 1998 (Macdonald et al. 2001, 2009). Patients had to have complete margin-negative resection of a gastric cancer with either extension full-thickness through the muscularis propria and/or positive regional lymph nodes. There was no requirement for the performance of either a D1 or D2 resection. Complete resection was defined by the presence of tumor-free resection margins along with the operating surgeon’s report of no unresected cancer. Lymph nodes were positive for metastatic cancer in 85% of patients and 20% arose in the gastric cardia. Patients were randomized to either surgery alone vs. adjuvant radiochemotherapy. Radiation consisted of 45 Gy to the anastomosis/stump, regional lymphatics, and original tumor bed. Bolus 5-FU and leucovorin were given 4 weeks before radiation, during weeks one and five of radiation, as well as following radiation. Significantly, all radiotherapy fields were centrally reviewed and approved before radiotherapy initiation. Therapy produced significant acute morbidity (Kassem et al. 2005), but only 1% overall mortality as a result of therapy. With over 10 years of median follow-up, disease-free survival (p < 0.001) as well as overall survival (p = 0.004) favor chemoradiotherapy. Multiple subset analyses were performed, including demographic, TNM-stage, D-level of resection, and tumor origin. Chemoradiotherapy benefitted all subsets, with the exception of those with diffuse histology. The use of postoperative adjuvant radiotherapy increased significantly after the release of this information. The SEER database documented a doubling in the use of postoperative radiotherapy after the results of Intergroup 0116 were published, with statistically significant improvement in overall survival (Kozak and Moody 2008; Coburn et al. 2007). The benefit of adjuvant postoperative radiochemotherapy for gastric cancer has been observed in other series (Besa et al. 2006; Fiorica et al. 2007; Kim et al. 2005).
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Kim and others (2005) reported a large South Korean experience of 544 patients who received postoperative chemoradiotherapy. The outcomes in these patients were compared to outcomes in 446 patients matched for prognostic factors who received surgery alone in South Korea during the same time period. All patients underwent extensive D2 lymph node dissection. Radiochemotherapy was administered similar to Intergroup 0116. Relapse-free and overall survival was statistically significantly improved with radiochemotherapy in this large group, all of whom received D2 nodal dissection. Quality of life (QOL) was assessed in a Canadian trial of postoperative radiochemotherapy. As expected, radiochemotherapy was associated with clinical significant worsening in global and function scales at completion of radiation therapy. However, by 6–12 months post-therapy, none of the subscales showed clinically or statistically significant differences from baseline, on average.
5.7.4 Local Unresectable/Postoperative Residual Local Disease Fewer than half of patients with newly diagnosed gastric cancer are candidates for curative surgical resection and effective adjuvant therapy. Some present with no clinically evident metastatic disease, but with primary tumors that are too large to resect with curative intent. Increasingly, carefully planned multimodality therapy is being implemented to afford a minority the possibility of true cure, while simultaneously providing effective palliation to the majority. The MD Anderson group reported 39 patients with potentially resectable disease who received preoperative radiochemotherapy in anticipation of eventual curative resection. These patients failed to proceed to surgery usually because of development of distant metastases (primarily peritoneal) or other clinical contraindications. Median follow-up was 8 months and median and 1-year clinical local disease control were 11 months and 46%, respectively (Kim et al. 2008a). The majority, therefore, despite not being able to complete potentially curative surgery, were effectively palliated with respect to local symptoms, for the remainder of their lives (median survival 10 months).
5.7.5 Definitive Radiochemotherapy Several series (Moertel et al. 1969; Schein and Novak 1982; Holbrook 1974; Haas et al. 1983) have documented a small minority of cases with low-volume locally unresectable gastric cancer – in the range of 5–10% – who achieve long-term survival with a combination of moderate-dose radiotherapy and concomitant systemic chemotherapy. The Mayo Clinic evaluated concomitant 5-FU with radiation in a phase III trial of locally unresectable gastric adenocarcinomas. Patients received 45–40 Gy and were randomized to receive either 5-FU via bolus or saline placebo on the same schedule. Overall survival was substantially improved in the 5-FU group, with 12% of the 5-FU group surviving five years vs. none in the placebo arm (Holbrook 1974; Childs et al. 1968). The EORTC trial randomized 115 patients to receive radiotherapy alone vs. concomitant radiotherapy and 5-FU during radiotherapy alone vs. radiotherapy plus concomitant and post-radiotherapy 5-FU.
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An overall survival advantage was present in those receiving both 5-FU and irradiation (p = 0.04). Additionally, among those with incompletely resected tumors, all long-term survivors received combined modality therapy (Bleiberg et al. 1989). Finally, the Gastrointestinal Tumor Study Group (GTSG) performed a randomized trial in locally unresectable gastric cancer. Ninety patients were randomized to receive either chemotherapy alone (5-FU and methyl-CCNU (MeCCNU)) or external beam radiotherapy (50 Gy) combined to the same chemotherapy. Combined radiochemotherapy produced excessive morbidity and mortality during the first 26 weeks after randomization. However, with longer follow-up, those who received combined modality therapy had statistically significant improvement in long-term survival, with approximately 20% alive at follow-up after five years. Those who had prior debulking surgery but were left with residual local unresectable disease had improved outcome when compared to those who were not debulked prior to randomization (Schein and Novak 1982).
5.7.6 Neoadjuvant Chemotherapy for Locally Unresectable Gastric Cancer Table 5.4 summarizes several series (Yano et al. 2002; Menges et al. 2003; GallardoRincón et al. 2000; Melcher et al. 1996; Cascinu et al. 2004; Verschueren et al. 1988; Wilke et al. 1989) of locally unresectable, nonmetastatic gastric cancer treated with neoadjuvant chemotherapy. A variety of 5-FU–based chemotherapy regimens have been employed. Those displaying substantial clinical regression of disease have been explored, with some capable of undergoing potential curative resection. Several themes emerged from the data available to date. The rate of pathologic complete remission is, in most series, £5%. Outcome is clearly improved in those who undergo significant cytoreduction to allow R0 resections. Only a few series have evaluated locoregional failure in those presenting with locally unresectable disease downsized sufficiently to allow resection. However, in these series, locoregional relapse occurs in >50%. This highlights the potential role of adjuvant radiotherapy prior to or following surgical resection for those presenting
Table 5.4 Phase II trials of preoperative chemotherapy Series (ref) # pCR Operated 0%
Resected
R0 resections
42%
24%
64%
52% 8%
Yano (33)
34
Menges (34)
25
Gallardo-Rincon (35)
60
2%
18%
Melcher (36)
10
0%
10%
Cascinu (37)
82
5%
45%
Verschueren (38)
19
Wilke (39)
34
80%
15%
74%
37%
59%
53%
LRF
71% 44%
50%
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with locally unresectable tumors without clinically apparent metastases. Furthermore, as neoadjuvant chemotherapy is increasingly utilized, it is important to identify those in whom neoadjuvant chemotherapy alone is unlikely to permit an R0 resection, or those who receive an R0 resection, but manifest features associated with high risk of development of subsequent locoregional failure. Both of these subsets deserve consideration of the use of radiochemotherapy to increase the likelihood of R0 resection and/or decrease the risk of locoregional failure.
5.7.7 Preoperative Radiotherapy with/without Chemotherapy Preoperative radiotherapy as a component of neoadjuvant treatment has increasingly been explored in both unresectable but nonmetastatic gastric cancer as well as resectable, poorprognosis presentations. This is certainly not surprising in view of the substantial locoregional failure problem with gastric cancer. Other GI sites, such as the esophagus and rectum, have had more formal evaluations of neoadjuvant radiotherapy. Skoropad and others (2000) randomized 112 gastric cancer patients whose cancer was resectable but nonmetastatic to receive either surgery alone or preoperative and intraoperative radiation therapy. Overall, there was no survival benefit; but, among those at greatest risk of locoregional failure (either positive nodes or T3–T4 primary tumors), survival benefit was suggested on subset analysis. Zhang and colleagues (1998) prospectively randomized 370 patients with adenocarcinoma of the gastric cardia to receive surgery alone vs. preoperative radiotherapy as monotherapy to the primary tumor site and regional lymphatics. Overall survival was improved at 5 and 10 years in those receiving preoperative radiotherapy. Failure-site analysis was performed on all sites of failure occurring at any time in the patient’s follow-up after randomization. Tumor bed failure and regional lymphatic failure was dramatically reduced with preoperative treatment (p < 0.02 for both failure sites). Distant metastases were similar between the groups, occurring in 24.3% with preoperative radiotherapy vs. 24.7% with surgery alone. Several phase II trials of either neoadjuvant radiochemotherapy alone or induction chemotherapy followed by neoadjuvant radiochemotherapy have been reported and are summarized in Table 5.5 (Allal et al. 2005; Ajani et al. 2004a, b, 2005, 2006; Reed et al. 2008; Lowy et al. 2001; Safran et al. 2000; Saikawa et al. 2008). These series include those who have operable but poor-prognosis features evident preoperatively (Allal et al. 2005; Ajani et al. 2004a, b, 2005, 2006; Reed et al. 2008; Lowy et al. 2001) as well as those with nonmetastatic but unresectable tumors (Safran et al. 2000; Saikawa et al. 2008). Many of these series indicate that substantial pathologic evidence of tumor regression is powerfully associated with a reduction in locoregional failure (Reed et al. 2008) or with an improvement in overall survival (Ajani et al. 2004a, b, 2005). Ajani and others at the MD Anderson Cancer Center have defined a pathologic partial response (pPR) as <10% of residual cancer in the stomach. In the series cited above, this dramatic cytoreduction was also associated with very favorable overall survival outcome. Series utilizing only neoadjuvant radiochemotherapy (Allal et al. 2005; Lowy et al. 2001) seem to have a lower rate of pCR than those treated with induction chemotherapy followed by neoadjuvant
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radiochemotherapy. The approach of neoadjuvant induction chemotherapy followed by radiochemotherapy has been associated with pCR rates of 20–30% and R0 resection rates in excess of 70%. While these are unarguably excellent results, these regimens are toxic, and further evaluation in the setting of randomized control studies is important. The limited data addressing locally unresectable but nonmetastatic tumors (Safran et al. 2000; Saikawa et al. 2008) demonstrate that a meaningful minority can undergo significant cytoreduction without evidence of metastatic disease to allow R0 resections. While it is impossible to compare the phase II trials of preoperative chemotherapy alone (Table 5.4) vs. preoperative radiochemotherapy trials (Table 5.5), future trials will appropriately be careful to evaluate not only pCR and pPR rates, but also R0 resections and locoregional failure following primary tumor excision.
Table 5.5. Phase II trials of preoperative radiochemotherapy Series (ref) # pCR Operated Resected RO resections
LRF regimen
Neoadjuvant Radiochemotherapy for Resectable Gastric Cancer Allal (42)
19
5%
18%
Ajani (43)
33
30%
85%
Reed (44)
146
23%
Ajani (45)
43
Ajani (46)
18%
11%
Induction CDDP, 5-FU, LV then CDDP, 5-FU, LV + XRT
70%
9%
Induction 5-FU, LV, CDPP X 2; then 45 Gy XRT + 5-FU pvi various preoperative XRT regimens
75%
70%
13%
26%
83%
77%
Induction 5-FU, LV, CDDP × 2; then 45 Gy XRT + 5-FU pvi, paclitaxel
41
20%
98%
78%
Induction 5-FU, paclitaxel, CDDP × 2; then 45 Gy XRT + 5-FU pvi, paclitaxel
Ajani (47)
43
26%
91%
Induction CPT-11, CDDP; then 45 Gy XRT + 5-FU, paclitaxel
Lowy (48)
24
8%
Neoadjuvant 5-FU pvi + XRT
Neoadjuvant Radiochemotherapy for Unresectable Gastric Cancer Safran (49)
27
4%
Saikawa (50)
29
13%
48% 34%
37%
Neoadjuvant paclitaxel + XRT
34%
XRT + S-1; CDDP followed by S-1: CDDP
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5.8 Systemic Therapy in Advanced Disease Gastric cancer is a common disease worldwide. With approximately 800,000 new cases diagnosed annually throughout the world, gastric cancer is the second most common cancer diagnosed globally. In the United States, more than 21,000 new cases of gastric cancer are diagnosed each year, with approximately 35% having metastatic disease at the time of diagnosis (Garcia et al. 2007; Parkin et al. 2005). At the time of diagnosis, gastric cancers are localized in approximately 50% of patients, and primary management is based on surgical resection of the primary tumor. When the cancer is localized to the stomach, an early lesion with minimal invasion is detected with negative lymph nodes, and the cancer is confined to the mucosa or submucosa, surgical cure rates may exceed 80% (Parkin et al. 2005; Sue-Ling et al. 1993); however, as few patients have symptoms, the detection of early gastric cancer is rare in the United States and other Western countries. Gastric cancer is more commonly locally advanced at diagnosis, with tumor extension through the gastric wall and direct extension into other organs, with or without metastatic involvement of perigastric lymph nodes (Sasako et al. 1997; Siewert et al. 1993; Earle and Maroun 1999). In these circumstances, fewer than 30% of patients are cured by surgical means. Because many patients present with metastatic disease at the time of diagnosis, and this results in poor outcomes after surgery, with a significant number of patients having relapse of the disease, there has been interest in treating patients with systemic chemotherapy. In the setting of metastatic gastric cancer, many chemotherapeutic agents have resulted in positive response when used alone as monotherapy or in combination with other agents, that has resulted in improvement in overall survival rates, although the duration of response has remained limited (Fig. 5.2). Advances in systemic chemotherapy may predict response and guide treatment in metastatic gastric cancer.
Fig. 5.2 Progress in treatment of advanced gastric/esophagogastric cancer. FAM, 5-FU, doxorubicin, and mitomycin C; FAMTX, 5-FU, doxorubicin, leucovorin, and methotrexate; ECF, epirubicin, cisplatin, and 5-FU
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5.8.1 Single-Agent Chemotherapy Traditional chemotherapy agents used as monotherapy have resulted in variable response rates in patients with advanced or metastatic gastric cancer (Table 5.5). Single-agent chemotherapy has resulted in response rates from 10 to approximately 2.5% and included 5-FU; mitomycin C, doxorubicin, epirubicin, cisplatin, and carmustine (BCNU); methotrexate; etoposide; chlorambucil; hydroxyurea; docetaxel; irinotecan; and paclitaxel. Initial studies with 5-FU vs. best supportive care (BSC) established the role of chemotherapy in demonstrating objective responses and impact on progression and overall survival. 5-FU has been the most extensively studied chemotherapy agent in patients with metastatic gastric cancer. Reported response rates vary, but are up to 21%. Earlier trials used schedules with daily 5-FU administration by intravenous bolus injection for 5 consecutive days. Treatments using 5-FU by continuous infusion for several days up to several weeks have been reported. Although the response rates to infusional chemotherapy with 5-FU are similar to those of bolus 5-FU, the toxicity profiles are different. The major side effects of bolus 5-FU are neutropenia and diarrhea, and erythroderma of the palms and soles (hand–foot syndrome). The oral fluorinated pyrimidines ftorafur and uracil (UFT), S1, and capecitabine have also demonstrated significant efficacy as single agents in the treatment of metastatic gastric cancer.
5.8.2 Combination Chemotherapy Many phase II trials of combination chemotherapy were based on promising activity observed with a variety of single agents. Table 5.6 lists several combinations of recently published trials. Many of these regimens resulted in less activity and/or greater toxicities in subsequent phase II and phase III trials (Tables 5.7 and 5.8).
5.8.3 Nitrosourea Combinations The combination of a nitrosourea, such as BCNU or MeCCNU, with 5-FU represents one of the earlier approaches to combination chemotherapy in the treatment of metastatic gastric cancer. Although earlier response rates, up to 41%, were promising, the median duration of survival for the combination was 7.7 months, which was not significantly improved over each of the drugs when used alone (Ajani et al. 1998). Subsequent trials with combinations of BCNU and 5-FU showed lower response rates (Kovach et al. 1974). MeCCNU was also evaluated with 5-FU. In a randomized study comparing MeCCNU combined with 5-FU to 5-FU alone, the combination produced a 40% response rate and superior survival (Jamieson and Gill 1981), but subsequent studies with nitrosoureas failed to confirm these results (Moertel 1976). Nitrosourea compounds have the potential for causing significant severe toxicities and are no longer used in gastric cancer therapy.
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Table 5.6 Phase II trials of new agents in gastric cancer Agents Response rate (%) Pac-5-FU
56
Pac-Cis-5-FU
53
CPT-Cis
50
UFT-Cis
51
Cape-Cis
55
5-FU-Oxal
48
FOLFOX-4
45
DCF
54
Table 5.7 Phase III trials in gastric cancer Agents ELF vs
Response rate 9%
FAMTX vs
12%
Cis-5-FU
20%
FAMTX vs.
21%
E-Cis-5-FU
45%
Mito-Cis-5-FU vs
44%
E-Cis-5-FU
43%
EAP vs
20%, more toxic
FAMTX
33%
DCF vs
36%
CF
26%
CF cisplatin and fluorouracil; DCF docetaxel, cisplatin and 5-FU; Cis-5-FU cisplatin and 5-fluorouracil; E etoposide; EAP etoposide, doxorubicin, cisplatin; ELF etoposide, leucovorin, 5-FU; FAMTX 5-FU, doxorubicin, and methotrexate; Mito mitomycin
5.8.4 Mitomycin Regimens With single-agent therapy demonstrating activity of mitomycin C and doxorubicin, the triple-drug combination of 5-FU, doxorubicin, and mitomycin C (FAM) underwent phase II and III evaluations (Moertel and Lavin 1979). Initial studies demonstrated a 42%
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Table 5.8 Response rates to single-agent chemotherapy in patients with advanced and metastatic gastric adenocarcinoma Drug Number of patients Response rate (%) Antimetabolites Fluorouracil
416
21
Methotrexate
28
11
Gemcitabine hydrochloride
15
0
Oral antimetabolites UFT
188
28
S1
51
45
Capecitabine
31
28
Hydroxyurea (oral)
31
19
Tegafur (oral)
19
19
Mitomycin C
211
30
Doxorubicin hydrochloride
141
17
80
19
139
30
41
17
Antibiotics
Epirubicin hydrochloride Heavy metals Cisplatin Carboplatin Taxanes Paclitaxel 3 h 24 h Docetaxel
98
17 –
7
–
22
123
21
Irinotecan hydrochloride
66
23
Topotecan hydrochloride
33
6
Camptothecins
Targeted therapies Gefitinib
–
1.5
Erlotinib
–
5
UFT uracil and tegafur
response rate; however, subsequent phase III trials failed to demonstrate the response rate or a survival benefit (Schein et al. 1978). In a randomized trial of 5-FU, 27% to FA, and 38% to FAM, survival among the groups was similar, with 27 weeks for FA and 30 weeks for the other two regimens (Cullinan et al. 1985).
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5.8.5 5-Fluorouracil, Doxorubicin, Leucovorin, and Methotrexate Biochemical modulation of 5-FU by methotrexate and leucovorin led to the development of a regimen combining 5-FU, doxorubicin, leucovorin, and methotrexate (FAMTX). This combination was evaluated in metastatic gastric cancer, with responses exceeding 50% (Douglass et al. 1984; Klein et al. 1982). When compared to FAM, FAMTX showed a superior response rate with BSC (Cullinan et al. 1985). Subsequently FAMTX has been replaced by cisplatin-containing regimens.
5.8.6 Cisplatin-Based Combinations The in vitro synergy between cisplatin and 5-FU and the single-agent antitumor activity of cisplatin in metastatic gastric cancer led to the development of phase II studies of cisplatincontaining regimens (Fig. 5.3). In a phase II study, the response rate of the combination of 5-FU, doxorubicin, and cisplatin (FAP) was 35% (Moertel et al. 1986). A phase III study did not show an advantage of FAP compared to 5-FU (Cullinan et al. 1994). Cunningham et al. (1990) utilized epirubicin, cisplatin, and 5-FU (ECF), with response rates in phase II trials of 37–71%. In a randomized trial, the response rate of ECF was superior to FAMTX (46% vs. 21%, p = 0.0002), and median survival was longer (8.7 months vs. 6.1 months, p = 0.0009) (Cunningham et al. 1990; Waters et al. 1999). With the exception of emesis and alopecia, ECF demonstrated an overall better toxicity profile. At two years of follow-up, 14% of the ECF patients remained alive while only 5% of the FAMTX patients did likewise. Etoposide was added to cisplatin and doxorubicin (EAP), with a response rate of approximately 50% but with a mortality rate in the range of 10–14% (Preusser et al. 1989).
50
RR %
45
Median survival (months)
40
36
30
26 21
20
10
5.7
8.9
8.6
9.2
0 FAMTX
Epirubicin-CF
CF
Docetaxel-CF
Fig. 5.3 Metastatic gastric cancer: phase III. Adding a third drug to 5-fluorouracil (F) and cisplatin (C). FAMTX, 5-FU, doxorubicin, leucovorin, and methotrexate
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In a randomized study, similar response rates were demonstrated with FAMTX, but it also showed less toxicity (Kelsen et al. 1991). To decrease toxicity from the EAP regimen, this group developed a subsequent regimen of etoposide, leucovorin, and 5-FU (ELF), with a response rate of 53% and a median survival rate of 11 months (Wilke et al. 1990). In a phase III trial by the European Organization for Research and Treatment of Cancer, FAMTX was compared to ELF and to infusional 5-FU and cisplatin. There were differences in response rates and median survival rates (Vanhoefer et al. 2000).
5.8.7 Taxane-Based Regimen Several phase II studies demonstrated activity of docetaxel in metastatic gastric cancer. The Swiss Group for Clinical Cancer Research conducted a randomized phase II study comparing docetaxel and cisplatin (DC), docetaxel, cisplatin and 5-FU (DCF), and ECF in 119 chemotherapy-naïve patients that resulted in an ORR of 18.5, 36, and 25% respectively (Roth et al. 2007). In the phase III V325 study, 158 patients with metastatic gastric cancer received either DC or DCF, showing a higher response rate of 43% while DC resulted in ORR of 26%. The combination of docetaxel, cisplatin, and 5-FU (DCF) has been compared to cisplatin/5-FU, with DCF demonstrating a significantly longer time to tumor progression (5.6 months vs. 3.7 months), higher response rate (36% vs. 26%), longer time on therapy (19 months vs. 16 months), and marginal, but significantly longer, overall survival, as well as greater 1- and 2-year survival. Toxicity, however, was also greater in the DCF group, with more neutropenia (82% vs. 57%), neutropenic fever without granulocyte colony-stimulating factor (30% vs. 12%), diarrhea (19% vs. 8%), and lethargy (19% vs. 14%). The conclusion was that DCF improved clinical end points, but with greater toxicity (Moiseyenko et al. 2002). On the basis of these results, docetaxel in combination with cisplatin and 5-FU was approved by the FDA as a first-line treatment of patients with advanced gastric cancer.
5.8.8 Irinotecan-Based Therapy Multiple studies have demonstrated the activity of irinotecan with phase II response rates of irinotecan combinations in metastatic gastric cancer. The combination of irinotecan and bolus 5-FU demonstrated a response rate of 22% (Blanke et al. 2001). The combination of irinotecan and cisplatin has been reported in several phase II studies, with responses ranging from 30 to 60% (Baker et al. 2001; Ilson et al. 1999a, b). With infusional 5-FU, several phase II reports demonstrate responses of 35–40% (Hawkins et al. 2003; Moehler et al. 2003; Bouche et al. 2003). A recent phase III trial randomized patients to irinotecan, weekly infusional 5-FU, and leucovorin (IF), or conventional cisplatin and 5-FU. Although the response rate, time to tumor progression, and overall survival were all improved in the IF group, statistical significance was not reached. Toxicity was likewise less in the IF arm except for diarrhea (Dank et al. 2005).
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5.8.9 Epirubicin-Based Combinations In a phase II randomized trial, REAL-2, 1,002 patients with gastric cancer were assigned chemotherapy with one of four epirubicin-based regimens. The first was epirucibin, 5-FU, and cisplatin; the second, epirubicin, cisplatin, and capecitabine; third, epirubicin, oxaliplatin, and 5-FU (EOF); and fourth, epirubicin oxaliplatin, and capecitabine (EOX). The primary endpoint was noninferiority in overall survival for triplet therapeutic regimens containing oxaliplatin compared to cisplatin, and for those containing capecitabine compared to 5-FU. The median OS in the ECF, ECX, EOF, and ECF were demonstrated to be 9.9, 9.9, 9.3, and 11 months, respectively. Toxicities for both fluoropyrimidines, capecitabine and 5-FU, were quite similar. Higher incidences of grade 3 or 4 diarrhea and neuropathy were observed in oxaliplatin-treated patients compared to those treated with cisplatin. Although ORR, PFS, and median OS did not differ significantly among the four groups, median OS was longer with EOX compared to ECF (p = 0.02). The conclusions from this trial demonstrated that oxaliplatin is as effective as cisplatin and capecitabine as effective as 5-FU when given according to these gastric cancer regimens.
5.8.10 Chemotherapy vs. Best Supportive Care Because of debate over whether chemotherapy offered any advantages for patients with advanced gastric cancer, randomized trials were conducted in which patients with metastatic gastric cancer were assigned to receive chemotherapy or BSC (Table 5.9). There was variability in when chemotherapy was initiated, with treatment beginning at the time of symptomatic or objective progression or at the discretion of the physician. Although the studies were different, results consistently showed that patients randomized to receive chemotherapy immediately had better survival rates than those randomized to BSC, even if they received chemotherapy later. In one study of 40 patients with advanced gastric cancer receiving either BSC or an induction course of 5-FU, methotrexate, cyclophosphamide, and vincristine followed by weekly 5-FU and mitomycin C. The median survival in both groups was 2 months (Rake et al. 1976). The West Midlands group reported on 193 patients randomized to 5-FU/ MeCCNU or no treatment. For patients who received the minimum of one 6-week course of chemotherapy, the survival time was 25 weeks, compared to 22-week survival in control subjects. Median survival estimates for all patients, including early deaths, was in the 8- to 10-week range with no apparent difference between the two groups. A QOL analysis did favor the patients treated with chemotherapy (Kingston et al. 1978). In a group of 76 patients with T4 or M1 disease who were randomized to no treatment, localized radiotherapy, and thiotepa, median survival for all three groups was approximately 19 weeks (Dent et al. 1979). However, in another randomized trial in which patients were assigned to treatment with a modified FAMTX regimen or supportive care, the trial was stopped and all patients were assigned to treatment because of a significantly better outcome in those who received treatment. Median survival was 10 months for patients who were treated, vs. 3 months for the untreated controls (p = 0.001) (Murad et al. 1993).
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5 Gastric Cancer Table 5.9 Chemotherapy for advanced gastric cancer vs. best supportive care (BSC) Regimen Median survival (months) FMCV/FM
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BSC
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FU/MeCCNU
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BSC
22
Thiotepa
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BSC
19
FAMTX
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BSC
3
FEMTX
3.1
BSC
3.0
ELF/FU-LV
8
BSC
5
FAM
(1 year = 34.1%)
BSC
(1 year = 22.5%)
CV cisplatin and vinorelbine; ELF etoposide, leucovorin, 5-FU; FAM 5-FU, doxorubicin, and mitomycin C; FAMTX 5-FU, doxorubicin, and methotrexate; FEMTX 5-FU, epirubicin, and methotrexate; FM fludarabine and mitoxantrone; FU fluorouracil; LV leucovorin; MeCCNU, methyl-CCNU
In another trial, 41 patients were randomized to receive 5-FU, epirubicin, and methotrexate (FEMTX) plus vitamins A and E, vs. the same vitamins and BSC. Median time to progression was 5.4 months and 1.7 months (p = 0.0013), and median survival time was 3.1 months vs. 3.0 months, favoring treatment with FEMTX (Pyrhonen et al. 1995). In a study of 61 patients randomized between chemotherapy with lactoferrin or 5-FU/ leucovorin compared to BSC, survival was superior in the treatment group, with 8 months’ median survival vs. 5 months in the untreated patients (p = 0.003). The QOL also favored the treated patients (p < 0.05) (Glimelius et al. 1977). In the final trial, a retrospective study of 409 patients treated with FAM and 207 patients untreated, the 1-year survival rate was 34.1% in the treated patients vs. 22.5% in the untreated group (Park et al. 1997).
5.8.11 Targeted Therapy Research into the molecular biology of gastric cancer cells has revealed genetic and molecular targets that are being evaluated as predictive and prognostic markers in stomach cancer. Knowledge of molecular targets also allow for the development of targeted therapeutic interventions.
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5.8.12 Monoclonal Antibodies and Tyrosine Kinase Inhibitors Newer targeted therapies, such as the anti-HER2 monoclonal antibody, trastuzumab; the anti-vascular endothelial growth factor (VEGF) drug, bevacizumab; the anti-epidermal growth factor (EGF) receptor drugs, cetuximab and matuzumab; and signal transduction inhibitors, such as erlotinib and gefitinib, are currently being evaluated in gastric cancer. Cetuximab is being evaluated in the Cancer and Leukemia Group B 80403 trial, combining monoclonal antibody with chemotherapy as first-line treatment in a phase II trial of metastatic gastric cancer. As planned, this will be a randomized phase III trial of three different chemotherapy regimens combined with cetuximab: ECF; oxaliplatin, 5-FU, and leucovorin; and irinotecan with cisplatin (CALGB Clinical Trials (www. calgb.org)) Multiple phase II trials of chemotherapy combined with targeted therapies are ongoing. Promising outcomes from these studies will undoubtedly be tested in future phase III trials. Trastuzumab, a recombinant monoclonal antibody against HER2 plus chemotherapy has recently demonstrated benefit in patients with metastatic gastric cancer. In a prospective, randomized controlled phase III trial, 3,807 patients with recurrent, locally advanced, or metastatic gastroesophageal and gastric adenocarcinoma were evaluated. Tumor tissue was tested for HER2 status and 22.1% of tested cancers were found to be positive for HER2 expression. Patients were randomly assigned standard chemotherapy with 5-FU or capecitabine plus cisplatin or this standard chemotherapy plus trastuzumab. Trastuzumab was given until disease progression. The primary endpoint was OS; secondary endpoints included overall response rate, PFS, time to disease progression, duration of response, and safety. Compared with standard chemotherapy, trastuzumab plus standard chemotherapy resulted in increased OS, 13.8 months vs. 11.11 months (HR=0.74; 95% CI, 0.60–0.91). Additionally, trastuzumab plus chemotherapy was associated with an improved response rate, 47.3% vs. 34.5% p = 0.0017). Both regimens were tolerated well with no unusual toxicities or adverse events. The conclusions from this study suggested that this regimen offered another option for patients after testing for HER2 status based on protein expression or fluorescent in situ hybridization (VanCutsen et al. 2009, Bang 2010). However, an amended Hercept Test scoring system should be used to determine HER2 positivity in gastric cancer since there are differences between the results in stomach cancer and in breast cancer (Hofman 2008).
5.8.13 Chemotherapy in Resectable Gastric Cancer The use of chemotherapy in patients with resectable or potentially resectable gastric cancer should be considered in two clinical scenarios. The first is as postoperative adjuvant chemotherapy after resection in patients at risk for recurrence. The second clinical scenario in which chemotherapy is used is as perioperative treatment. In this situation chemotherapy is used both before and after gastrectomy.
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There has until recently been no convincing evidence that the postoperative use of cytotoxic chemotherapy benefits patients after gastrectomy with curative intent (Earle and Maroun 1999; Mari et al. 2000). The use of postoperative cytotoxic therapy has never been adopted as a standard of care in North America. In late 2007, the study of Sakuramoto and colleagues (2007) was published in the New England Journal of Medicine. This large (greater than 1,000 cases) phase III study of adjuvant chemotherapy in resected gastric cancer compared 1 year of postoperative therapy with the fluorinated pyrimidine S-1 to cases treated with surgical resection alone. Follow-up data showed that the 3-year overall survival rates were 80.1% in the S-1 group and 70.1% in the surgery-only group. The hazard ratio for death in cases receiving S-1 compared to that in the surgery-only group was 0.68 (0.52–0.87). The log rank p value was 0.003. S-1 was well tolerated with grade 3 or grade 4 adverse events occurring in less than 10% of cases. There was no question that the clinical trial of Sakuramoto et al. was well designed, well powered, and well executed. The benefit seen for S-1 therapy was highly statistically significant. However, when looked at from the perspective of western oncologists, there was concern that the S-1 results were not applicable to the gastric cancer cases seen in the United States and Europe. The striking finding of a 70% 3-year survival in the surgeryonly cases was very much higher than the 25–45% survivals seen in western studies of surgical resection alone (Macdonald et al. 2001). Although the Japanese cases had some better prognostic factors (more T2 and fewer T3 tumors and somewhat less nodal involvement) than seen in western series, a 70% 3-year survival is well beyond what could be attributed to differences in prognostic factors. In summary, although all agree that the S-1 study demonstrates benefit for the Japanese gastric cancer population, it appears that monotherapy with S-1 is not appropriate for western gastric cancer patients. Perioperative chemotherapy does have a role in the management of surgically resectable stomach cancer. In 2006, the results of a European phase III trial testing perioperative chemotherapy with the combination chemotherapy regimen ECF (epirubicin, cisplatin and 5-FU) was reported (Cunningham et al. 2006). The study (acronym: the MAGIC trial) reported by Cunningham et al. accrued patients with potentially resectable gastroesophageal cancer to surgery alone or perioperative chemotherapy. The chemotherapy consisted of pre- and postoperative ECF. The results of the trial convincingly demonstrated a benefit from the use of the ECF regimen. Five-year overall survival was 36% in the perioperativechemotherapy group and 23% in the surgery-only group (p = 0.008 by the log-rank test). This improvement in survival of 13% points corresponds to a 25% relative reduction in the risk of death. Progression-free survival also was improved by chemotherapy. Perioperative chemotherapy appeared to influence other outcomes. Encouraging trends, such as decreased tumor size and reduction in the extent of nodal metastases were noted in the ECF patients. There were significant toxicities, as would be expected, in the patients receiving ECF. These toxicities were manageable, and well over 90% of cases randomized to chemotherapy were able to receive preoperative chemotherapy. However, it is significant that, for a variety of reasons including chemotherapy toxicity, less than 50% of cases completed all the postoperative chemotherapy. The MAGIC study of Cunningham and colleagues is a significant step forward in the treatment of gastric cancer. As the INT0116 study (Macdonald et al. 2001) defined
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chemoradiation as a standard of care for patients identified postoperatively, MAGIC has now defined perioperative chemotherapy strategies as appropriate approaches for patients presenting with resectable gastric cancer.
5.8.14 Supportive Care Because a large percentage of patients with metastatic gastric cancer have experienced significant weight loss, supportive care with attention to obstruction, nutrition support, and pain control are important to enhance the ability of the patient to undergo chemotherapy (Table 5.10). Gastric outlet obstruction can often be treated with endoluminal stent or with laser therapy for exophytic tumor masses. Nutritional support can be achieved through feeding jejunostomy or percutaneous endoscopic gastrostomy tube placement or through parenteral alimentation. Pain management, including selective use of palliative radiation for bone metastases or obstructing or bleeding tumors, may also be necessary.
5.9 Conclusion Gastric cancer is a common disease worldwide, occurring in greater than 800,000 persons each year. The epidemiology, molecular carcinogenesis, diagnosis, and therapy of stomach cancer represent complex multifactorial problems. There is still a great deal to learn about this neoplasm. This chapter emphasized clinical aspects of the management of gastric cancer patients. There are several themes of importance. First, as is the case in all oncology at the start of the twenty-first century, an increasing understanding of the molecular biology and molecular genetics of carcinogenesis and tumor growth is beginning to supply clinicians with rationales for targeted approaches to be tested in clinical trials. Understanding some of the important factors in the biology of gastric carcinogenesis has led to strategies of disease prevention such as the elimination of H. pylori in high-risk populations. Targeted therapies and effective prevention strategies hold real promise for the future control of Table 5.10 Supportive care: symptom management Obstruction Endoluminal stent Endoscopic laser Nutritional support Feeding jejunostomy Percutaneous endoscopic gastrostomy (PEG) Parenteral alimentation Pain control Palliative irradiation
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stomach cancer. However, the major theme in the management of this neoplasm that has been communicated by this chapter is the importance of multispecialty care. The advances that have been demonstrated in the recent past have been the result of committed oncologists of various disciplines working together. The surgeon, radiation oncologist, and medical oncologist working together have led to perioperative and postoperative treatment strategies that have improved patient survival and have been widely adopted as standards of care. The accomplishments of teamwork in the multimodality management of gastric cancer are impressive. However, more impressive is the promise that this well-established clinical teamwork, melded with rapidly developing advances in translational science, holds for continued improvement in the treatment of stomach cancer.
References Ajani JA, Crane CH, Wu TT et al (2005) Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol 23:1237 Ajani JA, Fairweather J, Dumas P et al (1998) Phase II study of Taxol in patients with advanced untreated gastric carcinoma. Cancer J Sci Am 4(4):269–274 Ajani JA, Mansfield PF, Janjan N et al (2004a) Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol 22:2774 Ajani JA, Walsh G, Komaki R et al (2004b) Preoperative induction of CPT-11 and cisplatin chemotherapy followed by chemoradiotherapy in patients with locoregional carcinoma of the esophagus or gastroesophageal junction. Cancer 100:2347 Ajani JA, Winter K, Okawara GS et al (2006) Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol 24:3953 Allal AS, Swahlen D, Bründler MA et al (2005) Neoadjuvant radiochemotherapy for locally advanced gastric cancer: long-term results of a phase I trial. Int J Radiat Oncol Biol Phys 63:1286 Baker J, Ajani JA, Ho L et al (2001) CPT-11 plus cisplatin as second line therapy of advanced gastric or GE junction adenocarcinoma (AGC-AGEJC). Proc Am Soc Clin Oncol 20(suppl):A647 Bang YJ, Van Cutsem E, Chung H et al. (2010) Trastuzumab in combination with chemotherapy alone for the treatment of HER2 positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase III open label randomized control trial. The Lancet 376:687–697 Berlin J, Washington M (2006) Uncommon cancers of the stomach. In: Raghavan D, Blecher M, Johnson D (eds) Textbook of uncommon cancer, 3rd edn. Wiley, Chichester, England, pp 352–366 Besa P, Garrido M, Bustos M et al (2006) Adjuvant chemoradiotherapy for gastric adenocarcinoma, toxicity, survival, and prognostic factors. Int J Radiat Oncol Biol Phys 66:262 Blair V, Martin I, Shaw D et al (2006) Hereditary diffuse gastric cancer diagnosis and management. Clin Gastroenterol Hepatol 4(3):262–275 Blanke CD, Haller DG, Benson AB et al (2001) A phase II study of irinotecan with 5-fluorouracil and leucovorin in patients with previously untreated gastric adenocarcinoma. Ann Oncol 12(11):1575–1580 Bleiberg H, Goffin JC, Dalesio O et al (1989) Adjuvant radiotherapy and chemotherapy in resectable gastric cancer: a randomized trial of the gastrointestinal tract cancer cooperative group of the EORTC. Eur J Surg Oncol 15:535 Bollschweiler E, Boettcher K, Hoelscher AH, Sasako M, Kinoshita T, Maruyama K et al (1992) Preoperative assessment of lymph node metastases in patients with gastric cancer: evaluation of the Maruyama computer program. Br J Surg 79(2):156–160
132
J.S. Macdonald et al.
Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ; Dutch Gastric Cancer Group (1999) Extended lymph-node dissection for gastric cancer. N Engl J Med 340(12):908–914 Bonenkamp JJ, Songun I, Hermans J, Sasako M, Welvaart K, Plukker JT et al (1995) Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 345(8952):745–748 Bouche O, Raoul JL, Giovanini M et al (2003) Randomized phase II trial of LV5-FU2, LV5FU2-cisplatinum or LV5-FU2-irinotecan in patients with metastatic gastric or cardial adenocarcinoma: final results of study FFCD 9803. Proc Am Soc Clin Oncol 21(suppl):A1033 Bozzetti F, Marubini E, Bonfanti G, Miceli R, Piano C, Crose N et al; The Italian Gastrointestinal Tumor Study Group (1997) Total versus subtotal gastrectomy: surgical morbidity and mortality rates in a multicenter Italian randomized trial. Ann Surg 226(5):613–620 Bozzetti F, Marubini E, Bonfanti G, Miceli R, Piano C, Gennari L; Italian Gastrointestinal Tumor Study Group (1999) Subtotal versus total gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Ann Surg 230(2):170–178 Bozzetti F, Bonfanti G, Bufalino R, Menotti V, Persano S, Andreola S et al (1982) Adequacy of margins of resection in gastrectomy for cancer. Ann Surg 196(6):685–690 Cascinu S, Scartozzi M, Labiance R et al (2004) High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgrastim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Br J Cancer 90:1521 Childs DS Jr, Moertel CG, Holbrook MA et al (1968) Treatment of unresectable adenocarcinoma of the stomach with a combination of 5-fluorouracil and radiation. Am J Roentgenol 102:541 Coburn N, Govindarajan A, Law C et al (2007) State-specific effect of adjuvant therapy following gastric cancer resection: a population-based analysis of 4,041 patients. Ann Surg Oncol: Springer Science + Business Media, L.L.C. volume 15:500–507 Cullinan SA, Moertel CG, Fleming TR et al (1985) A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 253(14): 2061–2067 Cullinan SA, Moertel CG, Wieand HS et al (1994) Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. J Clin Oncol 12(2):412–416 Cunningham D, Cahn A, Menzies-Gow N (1990) Cisplatin, epirubicin and 5-flourouracil (CEF) has significant activity in advanced gastric cancer. Proc Am Soc Clin Oncol 9:123 Cunningham D, Allum WH, Stenning SP et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11–20 Cuschieri A, Fayers P, Fielding J, Craven J, Bancewicz J, Joypaul V et al (1996) Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: preliminary results of the MRC randomised controlled surgical trial. The Surgical Cooperative Group. Lancet 347(9007): 995–999 Cuschieri A, Weeden S, Fielding J, Bancewicz J, Craven J, Joypaul V et al (1999) Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer 79(9–10):1522–1530 Dank M, Zaluski J, Barone C et al (2005) Randomized phase 3 trial of irinotecan (CPT-11) + 5-FU/ folinic acid (FA) vs. CDDP + 5-FU in 1st line advanced gastric cancer patients. Proc Am Soc Clin Oncol 23(suppl):A4003 Degiuli M, Sasako M, Ponti A, Soldati T, Danese F, Calvo F (1998) Morbidity and mortality after D2 gastrectomy for gastric cancer: results of the Italian Gastric Cancer Study Group prospective multicenter surgical study. J Clin Oncol 16(4):1490–1493 Dent DM, Werner ID, Novis B et al (1979) Prospective randomized trial of combined oncological therapy for gastric carcinoma. Cancer 44(2):385–391
5 Gastric Cancer
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Dooley CP, Larson AN, Stace NA etal (1984) Double contrast barium meal and upper gastrointestinal endoscopy. Ann Intern Med 101: 538 Douglass HO Jr, Lavin PT, Goudsmit A et al (1984) An Eastern Cooperative Oncology Group evaluation of combinations of methyl-CCNU, mitomycin-C, Adriamycin, and 5-fluorouracil in advanced measurable gastric canter (EST 2277). J Clin Oncol 2(12):1372–1381 Earle CC, Maroun JA (1999) Adjuvant chemotherapy after curative resection for gastric cancer in nonAsian patients: revisiting a meta-analysis of randomised trials. Eur J Cancer 35(7):1059–1064 Fiorica F, Cartei F, Enea M et al (2007) The impact of radiotherapy on survival in resectable gastric carcinoma: a meta-analysis of literature data. Cancer Treat Rev 33:729 Gallardo-Rincón D, Oñate-Ocaña LF, Calderillo-Ruiz G (2000) Neoadjuvant chemotherapy with P-ELF (cisplatin, etoposide, leucovorin, 5-fluorouracil) followed by radical resection in patients with initially unresectable gastric adenocarcinoma: a phase II study. Ann Surg Oncol 7:45 Garcia M, Jemal A, Ward EM, Center MM, Hao Y, Siegel RL, Thun MJ (2007) Global cancer facts & figures 2007. American Cancer Society, Atlanta, GA Glimelius B, Ekstrom K, Hoffman K et al (1977) Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8(2):163–168 Gotoda T, Yanagisawa A, Sasako M, Ono H, Nakanishi Y, Shimoda T et al (2000) Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer 3(4):219–225 Gouzi JL, Huguier M, Fagniez PL, Launois B, Flamant Y, Lacaine F et al (1989) Total versus subtotal gastrectomy for adenocarcinoma of the gastric antrum. A French prospective controlled study. Ann Surg 209(2):162–166 Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG et al (eds) (2002) AJCC cancer staging manual. Springer, New York Guadagni S, de Manzoni G, Catarci M, Valenti M, Amicucci G, De Bernardinis G et al (2000) Evaluation of the Maruyama computer program accuracy for preoperative estimation of lymph node metastases from gastric cancer. World J Surg 24(12):1550–1558 Gunderson LL (2002) Gastric cancer – patterns of relapse after surgical resection. Semin Radiat Oncol 12:150 Gunderson LL, Sosin H (1982) Adenocarcinoma of the stomach: areas of failure in a reoperation series (second or symptomatic looks) clinicopathologic correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 8:1 Haas CD, Mansfield CM, Leichman LP et al (1983) Combined nonsimultaneous radiation therapy and chemotherapy with 5-FU, doxorubicin, and mitomycin for residual localized gastric adenocarcinoma: A Southwest Oncology Group pilot study. Cancer Treat Rep 67:421 Hallissey MT, Dunn JA, Ward LC et al (1994) Adjuvant chemotherapy in operable gastric cancer: 5-year follow-up of first British Stomach Cancer Group trial. Lancet 343:1309 Hartgrink HH, Van De Velde CJ, Putter H, Bonenkamp JJ, Klein Kranenbarg E, Songun I et al (2004) Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol 22:2069–2077 Hashimoto K, Mayahara H, Takashima A et al (2009) Palliative radiation therapy for hemorrhage of unresectable gastric cancer: a single institute experience. J Cancer Res Clin Oncol 135(8): 1117–1123 Hawkins R, Cunningham D, Soerbye H et al (2003) Randomized phase II trial of docetaxel plus irinotecan versus docetaxel plus 5-fluorouracil in patients with untreated advanced gastric adenocarcinoma. Am Soc Clin Oncol 22(suppl):A1032 Hiki Y (1996) Endoscopic mucosal resection (EMR) for early gastric cancer. Nippon Geka Gakkai Zasshi 97(4):273–278 Hofman M, Stoss, O Shi D et al. (2008) Assessment of a HER2 scoring system for gastric cancer. Results from avalidation study. Histopathology 52: 797–805
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Holbrook MA (1974) Radiation therapy: current concepts in cancer. Gastric cancer: treatment principles. JAMA 228:1289 Horn RC (1955) Carcinoma of the stomach: autopsy findings in untreated cases. Gastroenterology 29:515 Hundahl SA (2005) Evidence-based recommendations for local-regional control of gastric cancer. Cancer Invest 23(4):352–362 Hundahl SA, Macdonald JS, Benedetti J, Fitzsimmons T (2002) Surgical treatment variation in a prospective, randomized trial of chemoradiotherapy in gastric cancer: the effect of undertreatment. Ann Surg Oncol 9(3):278–286 Hundahl SA, Macdonald JS, Benedetti J (2004) Durable survival impact of “Low Maruyama Index Surgery” in a trial of adjuvant chemoradiation for gastric cancer. 2004 ASCO GI Symposium, San Francisco, 22 January 2004. Report No.: 48 Hundahl S, Macdonald J, Smalley S (2006) Stomach. In: Chang A, Ganz P, Hayes D et al (eds) Oncology: an evidence-based approach. Springer, New York, p 680–703 Ilson D, Enzinger P, Saltz L et al (1999a) Phase II trial of weekly irinotecan + cisplatin in advanced gastric cancer. Proc Am Soc Clin Oncol 18(suppl):A994 Ilson DH, Saltz L, Enzinger P et al (1999b) Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 17(10):3270–3275 Jamieson GG, Gill PG (1981) A prospective trial of 5-FU and BCNU in the treatment of advanced gastric cancer. Aust N Z J Surg 51(1):16–19 Jansen E, Boot H, Verheij M et al (2005) Optimal locoregional treatment in gastric cancer. J Clin Oncol 23:4509 (1995) Japanese classification of gastric carcinoma, first English edition. Kanehara company, Tokyo Japanese Gastric Cancer Association (1998) Japanese classification of gastric carcinoma – 2nd English edition. Gastric Cancer 1(1):10–24 Jemal A, Siegel R, Xu J, Ward E (2010) Cancer Statistics 2010. CA A Cancer Journal for Clinicians; 60:277–300 Kajitani T (1981) The general rules for the gastric cancer study in surgery and pathology. Part I. Clinical classification. Jpn J Surg 11(2):127–139 Kampschoer GH, Maruyama K, van de Velde CJ, Sasako M, Kinoshita T, Okabayashi K (1989) Computer analysis in making preoperative decisions: a rational approach to lymph node dissection in gastric cancer patients. Br J Surg 76(9):905–908 Kasakura Y, Fujii M, Mochizuki F, Kochi M, Kaiga T (2000) Is there a benefit of pancreaticosplenectomy with gastrectomy for advanced gastric cancer? Am J Surg 179(3):237–242 Kassam Z, MacKay H, Buckley C et al (2005) Quality of life during adjuvant chemoradiation for gastric adenocarcinoma. Int J Radiat Oncol Biol Phys 72:2193 Kaurah P, Huntsman D (2004) Hereditary diffuse gastric cancer. University of Washington, Seattle. http://www.genetests.org. Accessed 1 July 2006 Kelsen D, Atiq OT, Saltz L et al (1991) FAMTX (fluorouracil, methotrexate, Adriamycin) is as effective and less toxic than EAP (etoposide, Adriamycin, cisplatin): a random assignment trial in gastric cancer. Proc Am Soc Clin Oncol 10:137 Kim S, Lim DH, Lee J et al (2005) An observational study suggesting clinical benefit for adjuvant postoperative chemoradiation in a population of over 500 cases after gastric resection with D2 nodal dissection for adenocarcinoma of the stomach. Int J Radiat Oncol Biol Phys 63:1279 Kim MM, Mansfield PF, Das P et al (2008a) Chemoradiation therapy for potentially resectable gastric cancer: clinical outcomes among patients who do not undergo planned surgery. Int J Radiat Oncol Biol Phys 71:167 Kim MM, Rana V, Janjan NA et al (2008b) Clinical benefit of palliative radiation therapy in advanced gastric cancer. Acta Oncol 47:421 Kingston RD, Ellis DJ, Powell J et al (1978) The West Midlands gastric carcinoma chemotherapy trial: planning and results. Clin Oncol 4(1):55–69
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Klein HO, Dias Wickramanayake P, Dieterle F (1982) Chemotherapieprotokoll zur behandlung des metasierenden magenkarzinos: methotrexat, Adriamycin, 5-fluorouracil. Dtsch Med Woch enschr 107:1708–1715 Kobayashi T, Kazui T, Kimura T (2003) Surgical local resection for early gastric cancer. Surg Laparosc Endosc Percutan Tech 13(5):299–303 Kobayashi T, Gotohda T, Tamakawa K, Ueda H, Kakizoe T (2004) Magnetic anchor for more effective endoscopic mucosal resection. Jpn J Clin Oncol 34(3):118–123 Kovach JS, Moertel CG, Schutt AJ et al (1974) A controlled study of combined 1, 3-bis-(2-chlorethyl)1-nitrosourea and 5-fluorouracil therapy for advanced gastric and pancreatic cancer. Cancer 33(2):563–569 Kozak KR, Moody JS (2008) The survival impact of the Intergroup 0116 trial on patients with gastric cancer. Int J Radiat Oncol Biol Phys 72:517 Kuwano H, Mochiki E, Asao T, Kato H, Shimura T, Tsutsumi S (2004) Double endoscopic intraluminal operation for upper digestive tract diseases: proposal of a novel procedure. Ann Surg 239(1):22–27 Landry J, Tepper JE, Wood WC et al (1990) Analysis of survival and local control following surgery for gastric cancer. Int J Radiat Oncol Biol Phys 191:1357 Lowy AM, Feig BW, Janjan N et al (2001) A pilot study of preoperative chemoradiotherapy for resectable gastric cancer. Ann Surg Oncol 8:519 Macdonald J, Hill M, Roberts (1992) Gastric cancer: epidemiology, pathology, detection and staging. In: Ahlgren J, Macdonald J (eds) Gastrointestinal oncology. Lippincott, Philadelphia, PA, pp 151–158 Macdonald JS, Smalley SR, Benedetti J et al (2001) Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725–730 Macdonald JS, Smalley SR, Benedetti J et al (2009) Chemoradiation of resected gastric cancer: a 10-year follow-up of the phase III trial INT0116 (SWOG 9008). Jour Clin Oncol. 27:15a Abstract 4515 Manson S (2006) Mucosa-associated lymphoid tissue (MALT) lymphoma. Semin Oncol Nurs 22(2):73–79 Mari E, Floriani I, Tinazzi A et al (2000) Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials: a study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente). Ann Oncol 11: 837–843 Maruyama K, Sasako M, Kinoshita T, Sano T, Katai H, Okajima K (1995) Pancreas-preserving total gastrectomy for proximal gastric cancer. World J Surg 19(4):532–536 Mattioli S, Di Simone MP, Ferruzzi L et al (2001) Surgical therapy for adenocarcinoma of the cardia: modalities of recurrence and extension of resection. Dis Esophagus 14:104 McNeer G, Vandenberg H, Dong FY et al (1957) A critical evaluation of subtotal gastrectomy for the cure of cancer of the stomach. Ann Surg 134:2 Melcher AA, Mort D, Maughan TS (1996) Epirubicin, cisplatin, and continuous infusion 5-fluorouracil (ECF) as neoadjuvant chemotherapy in gastroesophageal cancer. Br J Cancer 74:1651 Menges M, Schmidt C, Lindemann W et al (2003) Low toxic neoadjuvant cisplatin, 5-fluorouracil, and folinic acid in locally advanced gastric cancer yields high R-0 resection rate. J Cancer Res Clin Oncol 129:423 Moehler MH, Siebler J, Hoehler T et al (2003) Safety and efficacy of CPT11/FA/5-FU (ILF) versus ELF in previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. Proc Am Soc Clin Oncol 22(suppl):A1034 Moertel CG (1976) Chemotherapy of gastrointestinal cancer. Clin Gastroenterol 5(3):777–793 Moertel CG, Lavin PT (1979) Phase II–III chemotherapy studies in advanced gastric cancer. Cancer Treat Rep 63(11–12):1863–1869
136
J.S. Macdonald et al.
Moertel CG, Childs DS Jr, Reitemeier RJ et al (1964) Combined 5-fluorouracil and supervoltage radiation therapy in the palliative management of advanced gastrointestinal cancer: a pilot study. Mayo Clin Proc 39:767 Moertel CG, Childs DS Jr, Reitemeier RJ et al (1969) Adjuvant radiotherapy or chemotherapy in resectable gastric cancer: 5-year follow-up of second British Stomach Cancer Group trial. Lancet 2:865 Moertel CG, Rubin J, O’Connell MJ et al (1986) A phase II study of combined 5-fluorouracil, doxorubicin, and cisplatin in the treatment of advanced upper gastrointestinal adenocarcinomas. J Clin Oncol 4(7):1053–1057 Moiseyenko VM, Van Cutsem E, Tjulandin S et al (2002) Docetaxel-cisplatin-5-FU (CD) versus cisplatin-5-FU (CF) as first line therapy for gastric cancer: interim analysis results on efficacy and safety in a multicenter randomized phase III study. Proc Am Soc Clin Oncol 21(suppl 1):A587 Murad AM, Santiago FF, Petroianu A et al (1993) Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72(1):37–41 Newman E, Mulholland M (2006) Prophylactic gastrectomy for hereditary diffuse gastric cancer syndrome. J Am Coll Surg 202(4):612–617 Ono H, Kondo H, Gotoda T, Shirao K, Yamaguchi H, Saito D et al (2001) Endoscopic mucosal resection for treatment of early gastric cancer. Gut 48(2):225–229 Park JO, Chung HC, Cho JY et al (1997) Retrospective comparison of infusional 5-fluorouracil, doxorubicin, and mitomycin-C (modified FAM) combination chemotherapy versus palliative therapy in treatment of advanced gastric cancer. Am J Clin Oncol 20(5):484–489 Parkin D, Bray F, Ferlay J, Pisani D (2005) Global cancer statistics, 2002. CA: Cancer J Clin 55:74–108 Pathirana A, Poston GJ (2001) Lessons from Japan – endoscopic management of early gastric and oesophageal cancer. Eur J Surg Oncol 27(1):9–16 Peeters KCMJ, Hundahl SA, Kranenbarg EK, Hartgrink H, vandeVelde CJH (2005) “LowMaruyama-Index” surgery for gastric cancer – a blinded re-analysis of the Dutch D1-D2 trial. World J Surg 29:1576–1584 Preusser P, Wilke H, Achterrath W et al (1989) Phase II study with combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol 7(9):1310–1317 Pyrhonen S, Kuitunen T, Nyandoto P et al (1995) Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71(3):587–591 Rake MO, Mallinson CN, Cocking JB et al (1976) Assessment of the value of cytotoxic therapy in the treatment of carcinoma of the stomach. Gut 17:832 Reed VK, Krishnan S, Mansfield PF et al (2008) Incidence, natural history, and patterns of locoregional recurrence in gastric cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 71:741 Robertson CS, Chung SC, Woods SD, Griffin SM, Raimes SA, Lau JT et al (1994) A prospective randomized trial comparing R1 subtotal gastrectomy with R3 total gastrectomy for antral cancer. Ann Surg 220(2):176–182 Roth AD, Fazio N, Stupp R et al (2007) Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol 25(22):3217–3223 Safran H, Wanebo HJ, Hesketh PJ et al (2000) Paclitaxel and concurrent radiation for gastric cancer. Int J Radiat Oncol Biol Phys 46:889 Saikawa Y, Kubota T, Kumagai K et al (2008) Phase II study of chemoradiotherapy with S-1 and low-dose cisplatin for inoperable advanced gastric cancer. Int J Radiat Oncol Biol Phys 71:173 Sakuramoto S, Sasako M, Yamaguchi T et al (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357:1810–1820
5 Gastric Cancer
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Sano T, Katai H, Sasako M, Maruyama K (2000) The management of early gastric cancer. Surg Oncol 9(1):17–22 Sasako M (1997) Treatment of early gastric cancer. Chir Ital 49(3):9–13 Sasako M, Sano T, Katai H, Maruyama K (1997) Radical surgery. In: Sugimura T, Sasako M (eds) Gastric cancer. Oxford University Press, Oxford, England, pp 223–248 Sayegh M, Takeshi S, Simon D et al (2004a) Gastric cancer. Springer, Tokyo, pp 140–148 Sayegh ME, Sano T, Dexter S, Katai H, Fukagawa T, Sasako M (2004b) TNM and Japanese staging systems for gastric cancer: how do they coexist? Gastric Cancer 7(3):140–148 Schein PS, Novak J (1982) A comparison of combination chemotherapy and combined modality therapy for locally advanced gastric carcinoma. Cancer 49:1771 Schein PS, Macdonald JS, Hoth D, Woolley PV (1978) Mitomycin C, experience in the United States, with emphasis on gastric cancer. Recent Results Cancer Res 63:148–151 Siewert JR, Bottcher K, Roder JD et al; German Gastric Carcinoma Study Group (1993) Prognostic relevance of systematic lymph node dissection in gastric carcinoma. Br J Surg 80(8): 1015–1018 Siewert JR, Kelsen D, Maruyama K, Feussner H, Omote K, Etter M et al (2000) Gastric cancer diagnosis and treatment – an interactive training program, 1st edn. Springer Electronic Media, Berlin, Germany Skoropad VY, Berdov BA, Mardynski YS et al (2000) A prospective, randomized trial of preoperative and intraoperative radiotherapy versus surgery alone in resectable gastric cancer. Eur J Surg Oncol 26:773 Smalley SR, Gunderson LL (1996) Stomach. In: Perez CA, Brady LW (eds) Principles and practice of radiation oncology, 3rd edn. Lippincott-Raven Publishers, Philadelphia, PA Stout AP (1943) Pathology of carcinoma of the stomach. Arch Surg 46:807 Sue-Ling HM, Johnston D, Martin IG et al (1993) Gastric cancer: a curable disease in Britain. BMJ 307(6904):591–596 Takahashi M, Abe M (1986) Intraoperative radiotherapy for carcinoma of the stomach. Eur J Surg Oncol 12:247 Tey J, Shakespeare TP, Mukherjee RK et al (2007) The role of palliative radiation therapy in symptomatic locally advanced gastric cancer. Int J Radiat Oncol Biol Phys 67:385 Thomson FB, Robins RE (1952) Local recurrence following subtotal resection for gastric carcinoma. Surg Gynecol Obstet 95:341 Uyama I, Ogiwara H, Takahara T, Kikuchi K, Iida S, Kubota T et al (1996) Spleen- and pancreaspreserving total gastrectomy with superextended lymphadenectomy including dissection of the para-aortic lymph nodes for gastric cancer. J Surg Oncol 63(4):268–270 van den Brandt P, Goldbohm R (2006) Nutrition in the prevention of gastrointestinal cancer. Best Pract Res Clin Gastroenterol 20(3):589–603 VanCutsen E, Kang Y, Chung L, Shen L, et al (2009) Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal groth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). ASCO:Abstract LBA4509 Vanhoefer U, Rougier P, Wilke H et al (2000) Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18(14):2648–2657 Verschueren R, Willemse P, Sleijfer D et al (1988) Combined chemotherapeutic-surgical approach of locally advanced gastric cancer. Proc Am Soc Clin Oncol 7:93 Waters JS, Norman A, Cunningham D et al (1999) Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer 80(1–2): 269–272
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Wilke H, Preusser P, Fink U et al (1989) Preoperative chemotherapy in locally advanced and nonresectable gastric cancer: a phase II study with etoposide, doxorubicin, and cisplatin. J Clin Oncol 7:1318 Wilke H, Preusser P, Fink U et al (1990) High dose folinic acid/etoposide/5-fluorouracil in advanced gastric cancer – a phase II study in elderly patients or patients with cardiac risk. Invest New Drugs 8(1):65–70 Wotherspoon A, Doglioni C, Diss T et al (1993) Regression of primary low-grade Bcell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 342:575 Wu-Williams A, Yu M, Mack T (1990) Life-style, workplace, and stomach cancer by subsite in young men of Los Angeles County. Cancer Res 50:2569–2576 Yamamoto H, Sekine Y, Higashizawa T, Kihira K, Kaneko Y, Hosoya Y et al (2001) Successful en bloc resection of a large superficial gastric cancer by using sodium hyaluronate and electrocautery incision forceps. Gastrointest Endosc 54(5):629–632 Yano M, Shiozaki H, Inoue M et al (2002) Neoadjuvant chemotherapy followed by salvage surgery: effect on survival of patients with primary noncurative gastric cancer. World J Surg 26:1155 Yoshikane H, Sakakibara A, Hidano H, Niwa Y, Goto H, Yokoi T (2001) Piecemeal endoscopic aspiration mucosectomy for large superficial intramucosal tumors of the stomach. Endoscopy 33(9):795–799 Zhang Z-X, Gu X-Z, Yin W-B et al (1998) Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of the gastric cardia (AGC) – report on 370 patients. Int J Radiat Oncol Biol Phys 42:929
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John R. Zalcberg, Desmond Yip, Christine Hemmings, Bruce Mann, and Charles D. Blanke
6.1 Epidemiology 6.1.1 Demographics Gastrointestinal stromal tumors (GISTs) are the commonest mesenchymal tumors of the gastrointestinal tract. Although they most frequently arise in the stomach (around 60% of cases) and small intestine (30–35%), GISTs can occur anywhere in the tubular organs of the gastrointestinal tract, though they uncommonly arise from colorectum and appendix (5%) and esophagus (<1%) (Miettinen and Lasota 2006b). Extraintestinal examples (e.g., omental, mesenteric or retroperitoneal tumors) also occur, but metastasis from an intestinal primary should be considered in these cases; it is thought that true primary extra-intestinal disease represents less than 1% of all GISTs. Rare examples have been reported in the gallbladder (Mendoza-Marin et al. 2002; Park et al. 2004). The overall incidence of GISTs has been estimated at anywhere from 10 to 20 per million if small,
J.R. Zalcberg (*) Division of cancer medicine, Peter MacCallum Cancer Centre and Dept of medicine University of Melbourne, Melbourne, VIC, Australia e-mail:
[email protected] D. Yip Medical Oncology Unit, The Canberra Hospital, ANU Medical School, Australian National University, Canberra, ACT, Australia C. Hemmings ACT Pathology, The Canberra Hospital, ANU Medical School, Australian National University, Canberra, ACT, Australia B. Mann Peter MacCallum Cancer Center, Melbourne, VIC, Australia C.D. Blanke Division of Medical Oncology, UBC, Vancouver, BC, Canada C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_6, © Springer-Verlag Berlin Heidelberg 2011
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incidentally discovered tumors are included. Sporadic GIST most commonly arises in the fifth and sixth decades, with a slight male preponderance, at least in terms of malignant tumors (Miettinen and Lasota 2006b). Recent autopsy series suggest around 20% of the general population harbor micro-GISTs, though only a small fraction will develop clinically significant tumors (Kawanowa et al. 2006). While GISTs are relatively rare tumors, their incidence has apparently increased in recent times, in part because of better recognition due to the characteristic CD117 immunohistochemical staining for the c-KIT receptor that is expressed on the majority of GISTs. An additional reason for the apparent higher incidence is the increased attention and research interest due to the recognition of the key role of oncogenic KIT gain-of-function mutations first recognized and described by Hirota (1998), coupled with the availability of novel targeted therapies such as imatinib for the condition. Finally, these tumors in the past have been misclassified as other soft tissue sarcomas such as leiomyosarcomas, leiomyomas or leimyoblastomas (Miettenen et al. 2002). For example a Dutch National Pathology Registry study found an incidence of 2.1 per million inhabitants in 1995 and one of 12.7 per million in 2003 (Goettsch et al. 2005). Similarly US SEER cancer registry data have documented an increase in cases from 2.8 per million population in 1992 to 6.9 per million in 2002. These changes are mainly due to reclassification of smooth muscle tumors as GIST, but there are also a noticeably increased number of cases of mesenchymal tumors diagnosed since 1992. Histopathological review of all cases of patients with potential GIST in western Sweden diagnosed between 1983 and 2000 determined an incidence of 14.5 per million (Nilsson et al. 2005). A similar Icelandic histopathological review of all gastrointestinal mesenchymal tumors diagnosed in the country between 1990 and 2003 has found an annual incidence of 11 per million population.
6.1.2 Special Types and Associations 6.1.2.1 Pediatric GIST Fewer than 1% of GISTs occur in children, and these tumors have a strong predilection for the stomach. In contrast to sporadic GIST in adults, tumors arising in children show a striking female preponderance (around 75%), with a median age of 12; they are also more commonly multifocal and have a tendency to involve regional lymph nodes more frequently. The majority of tumors have an epithelioid phenotype. Despite the majority of tumors expressing CD117 immunohistochemically, only around 15% show KIT mutations (Janeway et al. 2007). Pediatric GISTs have been shown to have a distinct transcriptional signature, with overexpression of BAALC, PLAG1, IGF1R, FGF4, and NELL1 (Agaram et al. 2008a). Most are wild type in mutational profile and in vitro studies show that kinase inhibitors such as nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib. Association with Carney triad (see below) seems infrequent, despite demographic and histologic similarities (Miettinen et al. 2005a).
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6.1.2.2 Familial GIST Familial GIST is a rare autosomal dominant condition arising as a result of germline KIT or PDGFR mutations and is characterized by multiple tumors arising throughout the gastrointestinal tract, often in association with interstitial cell of Cajal (ICC) hyperplasia. These tumors tend not to arise until middle age, and their behavior varies from indolent to malignant. Other manifestations of KIT activation including mastocytosis and increased cutaneous pigmentation may be seen (Miettinen and Lasota 2006b).
6.1.2.3 Syndromic GIST GIST cases are mostly sporadic but may also occur as part of a syndromic association such as Carney’s triad where GIST can be associated with extra-adrenal paragangliomas and pulmonary chondromas, typically affecting young females (Carney 1999). In these cases, the tumors are typically gastric in location, epithelioid in morphology and arise in girls or young women. The majority of these tumors are indolent, with prolonged survival even after the development of liver metastases (Miettinen and Lasota 2006b; Miettinen et al. 2005a). There is also an autosomal dominant familial inherited association with paraganglioma alone affecting both males and females, which is thought to be a separate syndrome (Carney and Stratakis 2002). These pediatric and syndromic GISTs tend to be wild type and have a more indolent clinical course (Miettinen et al. 2005b). GIST is relatively common in patients with neurofibromatosis, Type 1, accounting for around 5% of GIST cases (Miettinen et al. 2006). These tumors typically have a spindled morphology with few mitoses and lack CD117 expression but express CD34. They most often arise in the small intestine and are typically multiple and small (Miettinen and Lasota 2006a). They are often associated with diffuse ICC hyperplasia, and generally lack both KIT and PDGFR mutations (Miettinen and Lasota 2006b). Although they tend to be clinically indolent, in malignant examples primary imatinib resistance is common (Mussi et al. 2008b).
6.1.2.4 Other Associations GIST may also occur in patients with other tumors, either synchronously or metachronously and indeed many GISTs are discovered incidentally during investigation of unrelated disease. The frequency of second tumors reportedly ranges from 4.5 to 33%, when Carney triad and neurofibromatosis are excluded. Gastric GISTs are the ones most often associated with other tumors, reflecting their overall high frequency. The commonest second malignancies in one series were gastrointestinal tract carcinoma (47%), hematologic malignancies (7%), and carcinoma of prostate (9%), breast (7%), kidney (6%), lung (5%) or female genital tract (5%). Others included carcinoid tumor (3%), sarcoma (3%), melanoma (2%)
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and seminoma (2%). An association has been seen with myeloid leukemia (Miettinen et al. 2008). Collision tumors and metastases of carcinoma or sarcoma into GIST have also been reported (Agaimy et al. 2006).
6.2 Pathology 6.2.1 Gross Pathology GISTs are believed to originate from ICC, or their stem-cell like precursors. ICC have both myoid and neural features and function as gut pacemakers, regulating GI motility. They are KIT-dependent cells located around the myenteric plexus and in the muscularis propria throughout the GI tract. ICC may differentiate into smooth muscle cells if KIT signaling is disrupted (Torihashi et al. 1999). GISTs most often arise as intramural tumors, centered on muscularis propria. Tumor may erode overlying mucosa, classically producing a smooth nodule with central umbilication from which devastating hemorrhage may occur. GISTs vary widely in size, varying from less than 1 cm when discovered incidentally, to 30 cm or more (Hemmings, unpublished data). There is often relative constriction of tumor growth within muscularis propria, with bulging of larger tumors into submucosal and subserosal connective tissue, producing a “dumbbell” configuration. The cut surface of the tumor varies from myxoid to smooth, homogeneous, pale tumor with a soft fleshy texture, to firm and more fibrous, or more variegated with areas of hemorrhage and necrosis. Foci of calcification may produce a gritty texture on slicing.
6.2.2 Light Microscopy 6.2.2.1 Morphology The commonest histologic pattern is that of a moderately cellular spindle-cell neoplasm, typically centered on muscularis propria but often extending into submucosa and/or subserosa (Fig. 6.1). The cells recapitulate the ICC’s to varying degrees. Indeed, ICC hyperplasia may be identifiable in subjects with familial GIST. The degree of cellularity may vary considerably, as does the mitotic rate. Necrosis is an inconsistent finding but may be extensive. A subset of GIST has a more epithelioid morphology (Fig. 6.2), which may be seen exclusively or intermingled with areas of spindle cells. Some tumors, particularly those harboring PDGFR mutations, have abundant myxoid stroma (Fig. 6.3), which may appear chondroid and, on occasion, include true cartilaginous differentiation (Fig. 6.4). Metaplastic
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Fig. 6.1 Typical appearance of a spindle-cell GIST (H & E, original magnification ×200)
Fig. 6.2 Less commonly, the cells have a more epithelioid morphology (H & E, original magnification ×1,000)
osteoid or true ossification may also be seen (Fig. 6.5). Other less common findings include signet-ring, oncocytic or rhabdoid cells. Rhabdomyosarcomatous differentiation has been described following tyrosine kinase inhibitor therapy (Liegl et al. 2009).
6.2.2.2 Immunohistochemistry CD117 Most GISTs (approximately 95%) express KIT protein, and a mainstay of diagnosis in GIST has been immunoperoxidase staining for CD117, a cell surface antigen on the extracellular domain of KIT (Croom and Perry 2003). CD117 staining is typically strong and diffuse in most GISTs, though some KIT negative tumors may still harbor KIT gene mutations, strongly
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Fig. 6.3 Some tumors, particularly those harboring PDGFR mutations, exhibit abundant myxoid stroma (H & E, original magnification ×100)
Fig. 6.4 The stroma may appear chondroid and, on occasion, show true cartilaginous differentiation (H & E, original magnification ×200)
suggesting that KIT is still involved in tumorigenesis. Many KIT-negative GISTs harbor PDGFR mutations. In some intestinal tumors the staining may be patchy, and a minority label as paranuclear dots only (Miettinen and Lasota 2006b). Despite its relatively high sensitivity, CD117 staining should not be taken as definite evidence of GIST – a number of other tumors will show weak or focal positivity (particularly if antigen retrieval is employed; this should not be performed to reduce the risk of false positive staining). Particularly in unusual sites, other diagnoses such as solitary fibrous tumor (which is also typically positive for CD34) should be considered.
CD34 CD34 is a hemopoietic progenitor cell antigen which is also expressed in endothelial cells, some fibroblasts, and various mesenchymal neoplasms. Perhaps 70 (Miettinen and Lasota
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Fig. 6.5 Heterologous elements such as metaplastic osteoid or true ossification may also be seen (H & E, original magnification ×200)
2006b) to 85% (Miettinen and Lasota 2006a) of GIST express CD34, with almost universal positivity in tumors of the esophagus and rectum, whereas in the stomach epithelioid or sarcomatoid GIST may be negative.
PDGFR It has been suggested that immunohistochemical staining for PDGFR has diagnostic value, particularly in KIT-negative GIST (Rossi et al. 2005), however the currently available antibodies appear to be unreliable on paraffin-embedded tissue (Miettinen and Lasota 2006a), and its use is not widespread. Furthermore, PDGFR may also be expressed in a subset of abdominal fibromatosis (“desmoid tumor”) and is therefore not entirely specific (Rossi et al. 2005).
Protein Kinase C Theta Protein kinase C (PKC) theta is a downstream effector in the KIT signaling pathway and has been suggested as an immunohistochemical marker as well as a potential further therapeutic target in GIST, often staining KIT-negative tumors as well (Lee et al. 2008). Positivity in GIST is reported to range from perhaps 85–100% of tumors (Miettinen and Lasota 2006b) however, a number of other mesenchymal tumors also react with the antibody (Lee et al. 2008), which is again said to be “difficult” in everyday laboratory applications and has not gained widespread use for routine diagnosis.
DOG-1 Gene expression profiling found that the gene FLJ10261 Discovered On GIST-1 (DOG-1) was specifically expressed in GIST. Immunoreactivity was subsequently demonstrated in
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Fig. 6.6 Immunoperoxidase staining for DOG-1 is usually positive in GIST, including those that are negative for CD117. Mutational analysis of this case confirmed the presence of a PDGFR mutation, whereas kit was wild type (same case as Fig. 6.3). (DOG-1, original magnification ×200)
the vast majority of GIST, including in KIT-negative and PDGFR-mutant tumors. Very few non-GIST mesenchymal tumors have been shown to react with DOG-1 (West et al. 2004), which also appears to stain fewer cases of carcinoma, melanoma and seminoma than does CD117 (Espinosa et al. 2008). This antibody is now commercially available and provides a useful additional diagnostic tool in cases where CD117 staining is focal, weak or negative (Fig. 6.6).
6.2.2.3 Other Markers Other markers which may be expressed in GISTs include the myoid markers smooth muscle actin (SMA) (20–35%) and heavy-caldesmon (80%), whereas desmin is only occasionally positive (<5%). Perhaps surprisingly, expression of S-100 protein is relatively unusual in GIST, being rare in the stomach but somewhat more common (perhaps 14%) in the small intestine. Most GISTs express nestin, but this is of limited value clinically as it is also expressed in gastrointestinal schwannoma, whereas GFAP is negative in GIST. Keratin positivity (generally focal) may be observed, particularly with antibodies reacting to keratin 18, whereas CK7 and CK20 are generally negative (Miettinen and Lasota 2006a).
6.2.3 Electron Microscopy There are no diagnostic ultrastructural features specific to GISTs, and the appearances may vary somewhat according to anatomic location. Overall, gastric and omental tumors tend to have better developed myoid features than their intestinal counterparts. Cytoplasmic filaments and intercellular junctions are common, with filaments often forming paranuclear
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Fig. 6.7 Skeinoid fibers (bottom right, below the nucleus) are most often seen in small intestinal tumors (EM, original magnification ×20,000)
aggregates in epithelioid tumors. The cells tend to have surface filopodia and interdigitating cell processes, but these are often short in gastric and omental tumors whereas in the intestine they tend to be long and complex. External lamina is often poorly formed, and tends to be absent altogether in intestinal tumors. Pinocytotic vesicles are variable in frequency but tend to occur at all anatomic locations, whereas microtubules are more common in intestinal tumors but rare in the stomach or omentum. Skeinoid fibers occur in around one-third of small intestinal tumors, and appear to be largely confined to that location (Yantiss et al. 2002) see Fig. 6.7.
6.2.4 Molecular Biology and Mutational Analysis 6.2.4.1 KIT The majority of GISTs (perhaps 85%) harbor mutations in the gene encoding the transmembrane receptor tyrosine kinase KIT. These mutations cause functional changes in KIT protein, usually leading to ligand-independent dimerization and constitutive activation of KIT signaling and thereby activation of downstream effectors. These processes commonly involve signal transduction via the transfer of ATP to tyrosine residues on substrate proteins, by tyrosine kinase enzymes. The end result is to stimulate cellular proliferation and impede apoptosis, thereby culminating in neoplasia. KIT mutations most often arise in the juxtamembrane position at exon 11 (around 67% of GISTs, arising at all anatomic sites), with exons 9 (extracellular domain, 10%, occurring in a higher percentage of intestinal GISTs), 13 (kinase 1 domain, 1%) and 17 (activation loop, 1%) being less commonly affected (Miettinen and Lasota 2006b).
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6.2.4.2 PDGFR Most GISTs lacking KIT mutations are wild type (~10%), or have PDGFRA mutations (5–7%). KIT and PDGFR are highly homologous receptor tyrosine kinases. Both genes are located at 4q12, suggesting a common ancestral gene (Miettinen and Lasota 2006b). PDGFR mutations most often occur in exons 12 (juxtamembrane, approximately 1% of GISTs) or 18 (activation loop, 6%), and are commoner in gastric tumors, often having a myxoid and epithelioid phenotype (see Fig. 6.5). Activation loop mutations at D842V (5%) are often associated with extraintestinal location (mesentery and omentum), and imatinib resistance. KIT and PDGFR mutations appear to be mutually exclusive (Miettinen and Lasota 2006b). Thus molecular analysis for KIT and PDGFR mutations may be useful in establishing a diagnosis of GISTs in challenging cases, and should be performed at diagnosis in highrisk or metastatic GISTs, when it may serve to guide therapy (see below). Fully resected, low-risk GISTs need not be routinely tested.
6.2.4.3 IGF-1 IGF-1 and -2 bind to the IGF-1 receptor and lead to activation of MAPK and PI3K cascades. Braconi et al. (2008) found IGF-1R to be overexpressed in all 94 GISTs analyzed in a series. Strong IGF-1 expression correlated with higher mitotic index, larger size, and a higher risk of relapse and metastasis. IGF-1 and -2 expression both correlated with reduced disease-free survival, which was improved if both IGF-1 and -2 were negative. Immunohistochemistry, quantitative polymerase chain reaction (qPCR) and fluorescent in situ hybridization (FISH) of GISTs have demonstrated significant overexpression of IGF-1R and amplification of the IGFR1 gene in wild type or pediatric GIST compared to mutant types (Godwin et al. 2008). Inhibition of IGF-1R activity using NVP-AEW541 has been shown to result in cytotoxicity and induce apoptosis in GIST cell lines, via AKT and MAPK signaling (Tarn et al. 2008) suggesting that IGF-1 drives pathogenesis in the subset of GISTs which do not have KIT or PDGFR mutations, and offers another potential therapeutic target.
6.2.4.4 BRaf V600E A small subset of tumors studied by Agaram et al., (2008b) were found to harbor BRaf mutations at exon 15 (V600E). These tumors all arose in the small intestine and were classified as high risk and occurred in women aged 49–55 years, raising the possibility of a distinct subset of GISTs, providing an alternative mechanism of imatinib resistance and potentially offering another therapeutic target for some patients.
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6.2.4.5 Other As stated above, 20% of the population has micro-GISTs, with only a few becoming malignant. KIT gene mutation is known to be a very early event in tumor genesis, and it is felt additional alterations are necessary for progression to high-risk disease (e.g., loss of chromosomes 1p, 14q, 22q; telomerase reactivation, and microsatellite instability) (Kawanowa et al. 2006).
6.2.5 Behavior and Prognosis 6.2.5.1 Patterns of Metastasis GISTs most often metastasize within the abdomen, either intraperitoneally or hematogenously to the liver. Metastasis to extra-abdominal sites is rare, but distant metastases can occur in unusual sites including brain (Hughes et al. 2004), testis (Doric et al. 2007) or soft tissues (Pasku et al. 2008).
6.2.5.2 Prediction of Behavior Histology is an imperfect predictor of clinical behavior, which also varies according to primary site. Primary esophageal GISTs are rare, but most are malignant. Gastric tumors are commonest, with fundic tumors being more often malignant than those arising in the antrum. Small intestinal GISTs are more often malignant and although rare, primary colorectal GISTs frequently metastasize (around 50%) and often follow an aggressive clinical course. In comparison with gastric tumors, intestinal GIST tend to be larger at diagnosis, but even when controlling for size and mitotic count, intestinal tumors tend to be more aggressive, also reflected in differing gene expression profiles. Be that as it may, the two best-documented early criteria for assessment of biologic potential were size and mitotic count. NIH-consensus risk-group stratification criteria for risk of GIST recurrence following resection were published in 2002 (Fletcher et al. 2002) but these did not reflect the importance of location in predicting behavior or of the negative impact of tumor rupture (Joensuu 2008). More recently, the Armed Forces Institute of Pathology (AFIP) (Miettinen and Lasota 2006a) attempted to refine the criteria in terms of location as well as size and mitotic count, although data for rare sites such as esophagus and rectum are still limited. Gastric GISTs <10 cm and with five mitotic figures (mf) per 50 high-power fields (hpf) have a low risk for metastases, whereas those with >5 mf/50 hpf are at high risk. In contrast, intestinal GISTs >5 cm have at least a moderate risk of metastasis, and those with >5 mf/50 hpf are at high risk. Intestinal GISTs <5 cm or <5 mf/50 hpf are relatively at low risk. See Table 6.1.
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Table 6.1 Risk stratification of primary GIST by mitotic index, size and site (based on Miettinen and Lasota 2006a) Mitoses per 50 Size Gastric Duodenal Distal small Colorectal high-power fields bowel <5/50
<2 cm 2–5 cm 5–10 cm >10
None Very low Low Moderate
None Low Moderate High
None Low ID High
None Low ID High
>5/50
<2 cm 2–5 cm 5–10 cm >10
Nonea Moderate High High
Higha High High High
ID High ID High
High High ID High
ID insufficient data Small numbers
a
Furthermore, gastric GISTs may be subclassified histologically, which improves estimation of biologic potential. Sclerosing spindle cell GISTs are usually small, mitotically inactive and relatively paucicellular tumors with abundant collagenous matrix which may calcify. The prognosis of this subtype is excellent. Palisading spindle cell tumors reminiscent of schwannoma typically have a low mitotic rate but may attain larger size, despite which the prognosis is generally favorable. Hypercellular spindle cell GISTs without nuclear palisading tend to have more frequent mitoses (often >5 mf/50 hpf), and carry a moderate risk of metastasis. Sarcomatoid spindle cell GIST have diffuse atypia and increased mitoses (often >20 mf/50 hpf), and a greater tendency to metastasize. In the epithelioid group, sclerosing tumors with a somewhat syncytial appearance tend to have few mitoses and a low risk of metastasis. Dyshesive tumors with clearly defined cell borders are intermediate in behavior, whereas hypercellular and sarcomatoid tumors are more aggressive (Miettinen and Lasota 2006a). Other morphologic factors which may have adverse prognostic significance include the presence of multiple peritoneal nodules and fat infiltration (regardless of primary site), coagulative necrosis and/or ulceration, mucosal invasion (Miettinen and Lasota 2006a), serosal involvement (Goh et al. 2008), the presence of metastases at diagnosis, and tumor rupture (Joensuu 2008, Takahashi et al. 2007). On the other hand, nuclear palisading is statistically favorable in both gastric and intestinal GISTs (Miettinen and Lasota 2006a). Immunohistochemically, loss of p16 expression is common (perhaps 50% of cases), does not correlate with age, sex, histologic subtype, or the presence of necrosis, but appears to be an independent predictor of poor prognosis (Schneider-Stock et al. 2005). Although metastases may resemble the primary tumor histologically, they are often genetically heterogeneous, harboring a variety of secondary mutations not seen in the primary (Wardelmann et al. 2006). Response to targeted therapy may therefore vary between different tumor deposits (Cameron et al. 2009).
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6.3 Diagnosis and Staging 6.3.1 Clinical Presentation GISTs have a predilection for adults older than 50 years, with a peak at around 60 years. They arise slightly more commonly in men (Miettinen et al. 2005c). GISTs may have a variety of presentations. They may be incidentally detected at gastroscopy, abdominal imaging or laparotomy for unrelated conditions (Miettinen et al. 2005c). The most common presentation is with bleeding, which may manifest as iron deficiency anemia due to chronic blood loss, or as an acute gastrointestinal hemorrhage from the primary causing hematemesis or melena. Rarely rupture of the primary or a metastasis into the peritoneal cavity may produce hemoperitoneum. Obstructive symptoms may occur depending on the location of the primary. For example dysphagia may occur with esophageal GISTs and altered bowel habits in rectal primaries. Advanced disease may present with ascites and a palpable mass. Patients may have considerable disease bulk at initial diagnosis, though this occurs less commonly in modern series. The most common sites of spread are into the liver and the peritoneum. Lung, cutaneous, intracerebral, and bony involvement occur less commonly.
6.3.2 Investigations Incidental submucosal lesions may be encountered during endoscopy and a biopsy using forceps may be difficult to conduct. Endoscopic ultrasound (EUS) may be used to detect the component of the gastric wall from where the lesion is arising and also to determine echogenicity, which may allow lipomas to be distinguished (these are intensely hyperechoic and arise from the submucosa). Lesions may be observed if small and non-suspicious. If lesions are symptomatic or intramural and hypoechoic, then these are suspicious for malignancy and should be referred for resection (Hwang et al. 2006). Small bowel GISTs may be more difficult to detect. An abnormality may be found on a barium follow-through examination. Active bleeding sites in the small bowel may be localized by mesenteric angiography however video wireless capsule endoscopy is a more accurate way of diagnosing intraluminal small bowel lesions than conventional imaging modalities (Mazzarolo and Brady 2007). If lesions are deemed to be easily resectable, preoperative percutaneous biopsy may not be advisable due to the risk of tumor rupture or dissemination (The NCCN Clinical Practice Guidelines in Oncology 2008). A tissue diagnosis is always required however, before instituting neoadjuvant therapy or placing a patient onto a clinical trial. If GIST is suspected or confirmed, computed tomography (CT) with contrast of the chest, abdomen and pelvis is important in staging the patient to determine the local extent
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of disease as well as presence of metastases, with respect to planning further management. MRI imaging of the pelvis for rectal GISTs can give more anatomical information than CT scanning. Functional imaging with fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning is a very useful modality for initial staging as well as monitoring of treatment response to therapy and is complementary to CT imaging.
6.4 Clinical Management Similarly to other gastrointestinal malignancies, the management of GISTs is multidisciplinary, involving a number of different specialties.
6.4.1 Surgical Management The technical aspects of the surgery for GIST follow general surgical oncological principles with nuances specific to this tumor type. This means, surgeons with site-specific or diseasespecific expertise should be involved with elective surgical treatment. When GISTs present with acute bleeding, perforation, or obstruction and require emergency laparotomy by a general surgeon, pathological material should be available to guide further management.
6.4.1.1 Resectable Primary GIST Resection without definitive biopsy material is appropriate when the diagnosis of GIST is likely, except as discussed above. Endoscopic biopsy is often unable to definitively diagnose GIST, as a common result is normal overlying mucosa. EUS-guided fine-needle aspiration is usually inadequate to provide a definitive diagnosis (American Gastroenterological Association Institute 2006; Pidhorecky et al. 2000). Transperitoneal core biopsy in a patient with apparently resectable disease risks tumor rupture and seeding (Demetri et al. 2007; Gold and Dematteo 2006; Pidhorecky et al. 2000). A difficulty is when radiological imaging has GIST as one of a number of differential diagnoses, with lymphoma being another. These cases must be decided on an individual basis. All GISTs are considered potentially malignant, and resection should be considered even for small intramural lesion (£2 cm) (Blackstein et al. 2006; Blay et al. 2005; Corless et al. 2002). Most treatment guidelines mandate removal of lesions 2 cm in size of larger (Demetri et al. 2007).The decision to observe or remove will depend on the features of the tumor and also its location and the age and fitness of the patient. Small tumors that are not resected should be monitored with periodic EUS or computerized tomography (CT). The objective of GIST surgery is to remove the primary tumor with negative microscopic margins. This may require en bloc resection of adjacent organs and structures such as the spleen, tail of pancreas, diaphragmatic crus, etc. for gastric GISTs. Tumor handling
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should be minimized since tumor rupture is associated with poor outcome (Blackstein et al. 2006; Eisenberg and Judson 2004; Gold and Dematteo 2006; Pidhorecky et al. 2000). Open surgery has been standard, but, there is little evidence for avoiding laparoscopic resection of lesions (Everett and Gutman 2008).The principals of laparoscopic surgery are similar to those of open surgery-macroscopic tumor resection, minimal tumor handling, and protection from port-site implantation by the use of a specimen retrieval bag. As lymphatic spread is rare and nodal metastasis indicates advanced disease, lymphadenectomy is not part of standard surgery for GIST (Blackstein et al. 2006; Eisenberg and Judson 2004; Gold and Dematteo 2006). Clinically or radiologically involved nodes should be resected when feasible as part of the primary operation, but if there is nodal involvement, systemic disease is likely and preoperative systemic therapy would be appropriate. Postoperatively, patients with intermediate- or high-risk primary GIST should be considered for adjuvant imatinib therapy or for entry into an adjuvant trial (see Adjuvant imatinib therapy).
6.4.1.2 Borderline Resectable Disease Though highly likely to be GIST on imaging (or proven on biopsy) a disease of borderline resectability definitely requires referral to a surgeon with interest and experience in the field and consideration in an appropriate multidisciplinary setting. Options include attempted resection (which may include biopsy for confirmation if unresectable) or nonoperative biopsy and subsequent imatinib treatment. The role of preoperative imatinib is not clearly defined; however, in many patients the disease becomes resectable after response to imatinib. Situations where neoadjuvant therapy might be considered include: potentially resectable GIST where surgery would cause functional impairment (e.g., rectal GIST requiring abdominoperitoneal resection) or loss of organ function (e.g., total gastrectomy), or where a tumor is large and truly locally advanced (Blay et al. 2005).Close monitoring for possible tumor progression on treatment is necessary, though it would be unusual to worsen on short-term therapy. The surgical and medical oncologists should decide the optimal timing of the surgery. As 75% of responding patients achieved their maximal response by 23 weeks in clinical trials, the optimal time to operative after neoadjuvant treatment is at about 6 months (Blanke et al. 2008a). Surgery after treatment with imatinib follows similar principles as primary surgery. The tumor is usually quite soft, which may increase the risk of rupture; however, the vascularity may be reduced, which may facilitate surgery. Imatinib should be continued in patients who have had tumor resection following response to imatinib, and the patient may resume taking drug as soon as oral intake is feasible (Blay et al. 2005).
6.4.1.3 Surgery for Recurrence Before effective systemic therapy evolved, resection of recurrent disease in the liver and/ or peritoneal cavity was the only potential treatment and was routinely considered. While apparent complete resection was sometimes possible, the disease inevitably recurred, and
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so the role of surgery in metastatic GIST is uncertain. Resection may be considered in patients with disease responding to imatinib in whom the disease is apparently completely resectable, and in otherwise stable oligo- or multi-focal disease where one tumor mass is growing (clonal escape) and resection is feasible (Demetri et al. 2007; Eisenberg 2006). One report details a progression-free survival rate of 33% at 1 year with such an approach (Raut et al. 2006).The true impact of this approach on disease outcome is the subject of at least two ongoing or proposed clinical trials. Surgery in patients with evidence of generalized progression is associated with poor outcomes and is not recommended. Occasionally surgery may be useful for palliation of a particular lesion that is bleeding or obstructing. Such surgery is often difficult and potentially morbid, and should only be undertaken after consideration of other options, such as hepatic embolization.
6.4.2 Medical Management 6.4.2.1 Chemotherapy Historically conventional chemotherapy treatments have not been very successful in the treatment of GISTs. Cytotoxic agents active in soft tissue sarcomas have formerly been employed. A Mayo Clinic study compared patients with leiomyosarcomas with those with GIST treated with a schedule of dacarbazine, mitomycin, doxorubicin and cisplatin plus GM-CSF support. There was a one response seen in 21 patients with GISTs while a 67% (12/18) response rate was seen in leiomyosarcomas. Reviews of the MD Anderson Cancer Center experience of treatment of gastrointestinal leiomyosarcomas (most of which would be GISTs) found a response rate of 3.3% using doxorubicin containing regiments in 120 patients treated between 1948 and 1989 (Plager et al. 1991) and of 13.3% in 30 patients treated with ifosfamide between 1985 and 1989 (Patel et al. 1991). A more recent phase II trial by the same group found no responses to temozolamide in a group of 18 patents with GIST (Trent et al. 2003).
6.4.2.2 Imatinib mesylate (Glivec, Gleevec, (STI571) Novartis) Imatinib mesylate is an oral phenylaminopyrimidine tyrosine kinase inhibitor that inhibits the PDGFR receptor, KIT kinase, BCR-ABL and ABL kinases. Developed for its activity against the PDGFR receptor, it was also found to be effective against chronic myeloid leukemia. In vitro experiments found the drug to be a potent inhibitor of KIT and also of a GIST cell line (Tuveson et al. 2001). Imatinib selectively inhibits the tyrosine kinase activity associated with KIT, which forms the rationale for its use in GIST (Croom and Perry 2003). The proof of principle came with the treatment of a Finnish woman in 2000 with rapidly progressive advanced GIST refractory to chemotherapy (Joensuu et al. 2001). After a month of starting treatment there was a 52% reduction in tumor diameters in the
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liver on MRI imaging and loss of FDG uptake on PET scanning. Fine needle biopsy of the liver metastases showed decreased density of tumor cells as well as development of myxoid degeneration. This single case study led to the commencement of two early phase studies. The EORTC conducted a phase I study of imatinib with doses ranging from 300 to 1,000 mg/day in soft tissue sarcoma patients (van Oosterom et al. 2001). Thirty six patients with GIST were enrolled and dose limiting toxicity was seen at a dose of 500 mg bd with doses at 400 mg bd and below being more manageable in terms of side effects and less need for dose reduction. Most patients were seen to have major and rapid improvements in symptoms and performance status. Twenty-five patients had an objective response to treatment, with 19 of these being partial remissions. The US–Finland B2222 study conducted at the same time randomized 147 patients to receive either 400 or 600 mg/day of imatinib (Demetri et al. 2002). A partial response was seen in 53.7% of these patients with 27.9% having stable disease in the initial publication. PET imaging was again found to be a sensitive and rapid indicator of response or resistance to imatinib. An update of this study with a median of 63 months follow-up (and 71 months maximum follow-up) has found an overall response rate of 68% with two cases of complete remission seen (Blanke et al. 2008a). The median time to progression was 24 months. This gives an estimated 5-year survival of 57% with no differences in either overall response, time to progression, response duration or overall survival between the two doses. Twenty eight percent of the cohorts were still taking imatinib at the last follow-up, suggesting that long-term survival, even with advanced disease, is possible. The North American Sarcoma Intergroup S0033 phase III trial randomized 746 patients to two dose levels (400 vs. 800 mg) of imatinib (Blanke et al. 2008b). Crossover to the higher dose level was allowed on disease progression. At a median follow-up of 4.5 years, no difference was seen in the overall response rate in either arm of 45%. The median progression-free survivals were 18 and 20 months, respectively, and median overall survivals 55 and 51 months, respectively; neither of which were statistically different. A third of the patients on the standard arm who crossed over to the higher dose achieved an objective response or stabilization of their disease. Serious adverse events and possible treatment related deaths were higher on the 800-mg arm. The EORTC, Italian Sarcoma Group (ISG) and Australasian Gastrointestinal Trials Group (AGITG) conducted a parallel randomized study which enrolled 946 patients with advanced GIST to 400 vs. 400-mg bd of imatinib (Verweij et al. 2004). After approximately 25-months median follow-up, 56% of patients in the 400 mg arm were found to have disease progression compared to 50% in the higher dose arm (P = 0.026). However, at the 40-month median follow-up, there was no statistical difference in the progressionfree survivals of each arm (Casali et al. 2005). No differences were seen in the response rates in either arm and in total for the group there was a 5% complete remission rate, 47% partial remission and 32% stable disease. As expected there were a higher number of dose reductions (60 vs. 16%) and dose interruptions (64 vs. 40%) in the higher dose arm due to toxicity compared to the lower dose arm. Patients on this study were also allowed to cross over to the higher dose on progression if they were on the standard dose to start with. Fiftyfour percent of the patients who met protocol criteria for crossover (113/241) went over to the higher dose and only 17% required a subsequent dose reduction (Zalcberg et al. 2005).
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The partial response rate with dose escalation was 2 and 27% with stable disease. Eighteen percent were progression-free at 12 months following crossover. The licensed starting dose of imatinib for metastatic GIST is 400–600 mg/day. The EORTC-ISG-AGITG and the North American Intergroup S0033 trials both compared two dose levels of imatinib (400 vs. 800 mg/day). The studies were designed so that data could be combined in a preplanned meta-analysis, the MetaGIST project (Van Glabbeke et al. 2007). With a median follow-up of 45 months no difference in overall survival was seen in the arms but there was a small improvement in progression-free survival with the high dose arm (HR 0.89, P = 0.04). Multivariate analyses were carried out to determine whether there were any factors that influenced survival and to find subgroups that benefitted from the higher dose. Adverse prognostic factors were found to be male sex, poor performance status, bowel origin, low baseline hemoglobin and high baseline neutrophil counts. Exon mutational analysis was available from 47% of the cohort. This confirmed that exon 11 mutations had a better PFS and overall survival (26 and 60 months) than either exon 9 (13 and 31 months), wild type (16 and 43 months) and other mutations (16 vs. 34 months). The only factor that showed a benefit to high dose imatinib in improved PFS was exon 9 mutation status (HR 0.58, P = 0.017) but this did not translate into improved overall survival (numbers were small, however). This would support a strategy of using an imatinib starting dose of 800 mg/day (Casali et al. 2008). Where licensing restrictions prevent this, patients with the mutation may be able to start on 600 mg/day or alternatively they need closer monitoring for evidence of lack of disease control on the 400 mg dose so that dose escalation can be implemented on progression. Tumors with exon 11 mutations are often aggressive but tend to respond to imatinib because the mutation results in a conformational change in KIT which allows a better “fit” of the imatinib molecule into the ATP-binding pocket in the intracellular domain of the KIT molecule. Tumors with exon 11 duplication may be associated with better survival. Exon 9 mutations are more often seen in intestinal tumors rather than gastric, and are associated with aggressive behavior. Higher dose imatinib is indicated in these tumors (DebiecRychter et al. 2006). Many patients who initially respond to imatinib ultimately develop progressive disease. This secondary imatinib resistance often arises after around 2 years of therapy in primary exon 11 mutations (Heinrich et al. 2008) and is usually associated with secondary KIT or PDGFR mutations. Several distinctive secondary point mutations have been identified, generally affecting the same allele as the primary mutation (Antonescu et al. 2005). Furthermore, after mutated receptors are switched off, heterologous wild-type tyrosine kinase receptors may become an important means of maintaining signaling activation in imatinib-exposed GIST (Negri et al. 2009).
6.4.2.3 Toxicity of Imatinib The toxicities of imatinib mesylate are generally manageable (Harrison and Goldstein 2006). In many clinical trials gastrointestinal hemorrhage either into the gut or into the abdominal cavity has been observed in a small number of patients. This may be a result of
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direct mucosal disruption or of tumor response. The latter tends to affect patients with high tumor bulk and emergency surgical intervention may be indicated. In the US–Finland trial hemorrhage occurred in 5.4% of patients (Demetri et al. 2002). The S0033 trial reported significant bleeding in 5% of the low dose arm and 11% of the higher dose with four patients in the higher dose dying from the hemorrhage (Blanke et al. 2008b). Hematological toxicities are common and usually mild not requiring any treatment. It is dose related and on the clinical trials where a higher dose is used significant anemia, neutropenia and thrombocytopenia is observed which may require treatment interruption and dose reductions. The most commonly described nonhematological side effects are gastrointestinal, especially nausea and vomiting. These may respond to splitting the dose or taking the tablets with food and water or at night. Diarrhea may occur and respond to anti-diarrheal agents. An erythematous and pruritic maculopapular rash can occur which responds to treatment interruption and dose reduction as well as topical steroids and antihistamines. Superficial edema of the legs as well as in the periorbital region is common and usually does not required specific treatment. Severe cases may require use of diuretics. Liver function abnormalities can occur uncommonly and may be managed again by dose interruption and reduction; rarely systemic steroids are needed. Investigators from the EORTC-ISG-AGITG study have analyzed the relationship of toxicities to imatinib and pretreatment factors to see which are prognostic ones (Van Glabbeke et al. 2006). Anemia was found to correlate with dose and baseline hemoglobin, while neutropenia was found to correlate with baseline neutrophil count and hemoglobin level but was not dose dependent. Nonhematological toxicities were also dose related. High toxicity rates were found in female sex (edema, nausea and diarrhea), older age (edema, rash, fatigue), poor performance status (fatigue and nausea), prior cytotoxic treatment (fatigue), small lesions (rash) and identified gastrointestinal origin tumor (diarrhea). A predictive spreadsheet calculator incorporating this model has been validated on a separate dataset and is available from www.eortc.be/tools/imatinibtoxicity.
6.4.2.4 Dosing of Imatinib Mesylate The pharmacokinetics of imatinib may vary between individuals due to factors such as body weight, loss of absorptive surface of the small bowel due to resection, cytochrome P450 3A4 polymorphisms, P glycoprotein polymorphisms, OCT1 efflux pump activity, albuminemia and alpha1 acid glycoprotein binding (Gurney et al. 2007; White et al. 2006; Widmer et al. 2006). Over time serum levels in individual patients may also vary due to drug interactions (especially those that interact with cytochrome P450 3A4) and medication non-compliance. It has been found that there is a trend towards increased imatinib clearance with long-term exposure (Judson et al. 2005). Low plasma imatinib trough levels have been found to correlate with a lower overall response rate and time to progression in a subset of patients treated on the B2222 study where pharmacokinetic monitoring was carried out (von Mehren et al. 2008). Maintaining imatinib trough levels above 1110 ng/ mL may help to optimize dosing of the drug for therapeutic effect (Demetri et al. 2008).
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Excessively high plasma levels may provide an explanation for treatment toxicities and support implementation of dose reduction without an expected loss of efficacy.
6.4.2.5 Duration of Imatinib Therapy Imatinib may produce striking responses in metastatic GISTs, with marked tumor shrinkage and loss of functional tracer uptake on PET imaging. However, serial biopsies of responding lesions have shown that despite the development of myxoid degeneration there continued to be viable tumor cells present (Joensuu et al. 2001). The French Sarcoma Group BFR14 study attempted to assess the effect of treatment interruption of patients on imatinib vs. continuation (Blay et al. 2007). This trial enrolled 182 patients with advanced GIST and 58 of the 98 patients who had received a year of imatinib and were stable or responding were randomized to treatment interruption or discontinuation. At the date of analysis 8 of 26 patients in the continuation arm had progressed while 26 of 32 patients had progressed on the interruption arm. There were no differences observed in the quality of life, overall survival or the rate of resistance to reintroduction of imatinib. The trial has continued with another randomization of 50 patients (excluding patients who were interrupted at 1 year) who were still responding at 3 years (Adenis et al. 2008). Again it was found that there was a high rate of progression with 1 year PFS in the interruption arm being 23.7 vs. 87.7% for continuation. Another randomization is ongoing at the 5-year mark (Duffaud et al. 2009). All progressing patients were salvaged on reintroduction of imatinib and no impact on overall survival was seen. No difference so far has been seen in the time to development of secondary resistance on either arms of the study, and reintroduction of imatinib leads to reinduction of response in 93% of subjects (Duffaud et al. 2009). This study thus indicates that discontinuation of imatinib is associated with a high relapse rate and that maintenance treatment is recommended.
6.4.2.6 Management of Progression on Imatinib Isolated areas of tumor progression indicating the development of resistant clones may be treated by surgery or ablative procedures such as radiofrequency ablation whilst continuing imatinib to maintain control of sensitive clones. This is aimed at eliminating the drug resistant clones and may be associated with prolonging progression-free survival (Raut et al. 2006). See above Sect. 6.4.1.3. Generalized or multifocal progression should be first treated by dose escalation of imatinib to 400 mg bd if patients are already on the 400 mg/day dose. This may establish tumor control in about a third of patients (Verweij et al. 2004). Dose escalation is associated with increased side effects, but the rate of dose reduction required within 6 months with dose escalation from 400 to 800 mg/day is less if patients are initially started on the higher dose (17 vs. 50%) (Zalcberg et al. 2005). The median duration of benefit in dose escalation is estimated at 11.6 weeks (Zalcberg et al. 2005).
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If dose escalation is ineffective then use of the multi-kinase inhibitor sunitinib should be implemented outside of a clinical trial setting (see below). Continuation of imatinib until alternative therapy is started is recommended to prevent a flare response of the imatinib sensitive clones on withdrawal of the medication which may cause rapid clinical deterioration.
6.4.2.7 Sunitinib (Sutent (SU11248) Pfizer) Sunitinib is an oral multikinase inhibitor which blocks a number of targets including KIT, PDGFR, VEGFR, RET and CSF-1R. In a randomized phase III registration study, 312 advanced GIST patients with imatinib resistance or intolerance received either sunitinib or placebo in a 2:1 allocation in a 4-weeks on and 2-week off schedule of 50 mg/day (Demetri et al. 2006). Crossover of the placebo arm was allowed on tumor progression. The trial was unblinded early when planned interim analysis revealed a prolongation in time to progression with sunitinib. Median time to progression was 27.3 vs. 6.4 weeks with placebo. An overall response rate of 7% was seen with sunitinib and 0% with placebo. Stable disease lasting at least 22 weeks was seen in 17%. Despite the crossover overall survival was better in the upfront sunitinib group (HR 0.49, P = 0.007). As a result sunitinib is licensed for second line therapy of advanced GIST in the 4 week on and 2 week off schedule. Continuous daily dosing of sunitinib at 37.5 mg/day either in the evening or in the morning has been shown be safe and efficacious in a phase II study in patients with imatinib resistant or intolerant GIST (George et al. 2009). There were no other new toxicities seen and response rates as well as toxicity were similar to those reported in the 4 weeks on 2 weeks off schedule. Constant serum levels were maintained with no accumulation over time. Twenty-three percent of patients still required dose reductions to 25 mg daily. Sunitinib is associated with side effects of nausea, fatigue, diarrhea, mucositis, handfoot syndrome, and skin discoloration. The drug may also cause hematological toxicity in terms of anemia and neutropenia. These side effects were generally mild and manageable by dose delay or reduction. Hypertension may occur due to its anti-VEGF effect, and initiation or titration of an antihypertensive may be required. Hypothyroidism is well recognized as a complication of sunitinib therapy. In a series of 42 patients with advanced GIST treated with the drug, 62% exhibited TSH abnormalities with 38% becoming hypothyroid (Desai et al. 2006). Some patients were noted to have a transient fall in the TSH level before developing hypothyroidism and two patients were found to have absent thyroid tissue on neck ultrasound, suggesting that the mechanism for this is the induction of a destructive thyroiditis. It is thus important to measure monitor thyroid functioning and initiate thyroid replacement therapy if necessary. The effect of primary and secondary kinase genotypes in sunitinib response has been studied in a series of 97 patients with imatinib refractory GIST (Heinrich et al. 2008). The clinical benefit of sunitinib observed on patients with primary exon 9 or wild type mutations were higher than those with exon 11 mutations (58 vs. 56% vs. 34%). Similarly the
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overall response was higher in exon 9 than exon 11 (37 vs. 5%, P = 0.02). Longer median progression-free survivals were seen with exon 9 (19.4 months, P = 0.005) and wild type (19.0 months, P = 0.0356) compared to exon 11 (5.1 months). This translated into higher median overall survivals of exon 9 (26.9 months, P = 0.012) and wild type GISTs (30.5 months, P = 0.0132) compared to exon 11 (12.3 months). Secondary kinase mutations were seen more commonly in the primary exon 11 patients compared to exon 9 (73 vs. 19%) and no secondary mutations were observed in wild type GISTs on imatinib. Patients with acquired exon 13 or 14 mutations which encode the receptor ATP binding pocket had a median progression-free survival of 7.8 months compared to exon 17 or 18 which encode the activating loop (2.3 months, P = 0.0157) correlating with higher clinical benefit (61 vs. 15%, P = 0.011) with sunitinib. This is supported by in vitro autophosphorylation studies indicating that exon 13 and 14 mutations were sensitive to sunitinib while secondary exon 17 and 18 mutations were resistant.
6.4.3 Assessing Response to Therapy CT scan imaging may be used to monitor response to therapy. Scans should be performed with oral contrast (to outline bowel) and in triple phase (to detect hypervascular liver metastases). Conventional measurement of response to treatment in solid tumors is with the use of the response evaluation criteria in solid tumors (RECIST) criteria (Therasse et al. 2000). This relies on measuring change in maximal tumor diameters. However, a number of factors in GIST serve to make RECIST a less than ideal methodology for response measurement. Increase in tumor size may occur due to intratumoral hemorrhage or cystic changes developing due to myxoid degeneration in lesions as a result of treatment response. Localized intratumoral progression may occur with resistant clones causing a new ‘nodule within a mass’ to develop without increasing the size of the preexisting lesion (Shankar et al. 2005). Choi et al. (2007) have proposed a new set of CT scan criteria to measure response in GIST which incorporates changes in tumor density (quantified by change in Hounsfield units) and smaller changes in tumor sizes. This has been found to correlate well with functional response measured with PET scans. These criteria have been validated in a independent dataset (Benjamin et al. 2007). FDG-PET is useful in detecting early response to biological therapy if the tumors are FDG avid to begin with. A marked reduction in metabolic activity may be seen within days of initiation of therapy much earlier than can be detected on CT imaging (Stroobants et al. 2003). Changes in tumor density can cause apparently new lesions to appear on CT imaging on response to therapy and PET may determine these are hypofunctioning and not due to tumor progression. Conversely this modality is useful in detecting tumor relapse or progression. See Fig. 6.8. Dynamic contrast-enhanced Doppler ultrasound (DCE-US) is currently being developed as a functional imaging method of monitoring response of GIST to therapy. It involves the measurement of uptake of ultrasound microbubble contrast agents by tumor (Lamuraglia et al. 2006). This may become a less expensive method and more widely used functional imaging modality once validated.
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Fig. 6.8 FDG-PET/CT imaging of patient with metastatic GIST shows a baseline study with several metabolically-active peritoneal deposits. Highlighted are two pelvic lesions in the pelvis as visualized on volume-rendered PET/CT above and coronal PET images below. There is a larger and more intense abnormality at baseline (red arrow) and smaller, less intense lesion (blue arrow). One month following imatinib there was a complete metabolic response in all lesions. By 12 months there had been significant CT regression of most lesions except the left pelvic lesion. PET demonstrated recrudescent activity in the small right pelvic lesion as well as intense uptake in the previously lowgrade left pelvic lesion. These images emphasize the heterogeneity that can exist in biology at baseline evaluation and a variable response to therapy, suggesting clonal mutational variations
6.4.4 Radiotherapy There is paucity of data in the literature regarding the utility of radiotherapy in GIST. The location of GISTs and their pattern of spread usually make it difficult to deliver adequate doses of radiotherapy without causing toxicity to surrounding organs. There are some isolated reports of its use as adjuvant therapy after resection. In a prospective series of 50 patients from Toronto ten patients with small intestinal GIST were
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given adjuvant radiotherapy (Crosby et al. 2001). All the patients who received radiation subsequently relapsed with three of the cases being within the radiotherapy field and six outside the field. In the remaining patient it was not possible to determine where the recurrence was relative to the field. There is a case report of a rectal GIST patient with probable microscopic positive margins who remained disease free on 2-year follow-up after receiving radical radiotherapy (50.5 Gy) to the tumor bed (Pollock et al. 2001). A more recent series of 39 patients with primary or recurrent rectal or pararectal space, GISTs identified 6 patients who received radiotherapy. One patient achieved stabilization of disease after imatinib failure and out of five where post operative radiotherapy was received, only one developed a further recurrence (Mussi et al. 2008a). The consideration of use of palliative radiotherapy in symptomatic areas such as bony or cutaneous metastases would be reasonable, but data as to effectiveness are lacking.
6.4.5 Adjuvant Therapy for Resected Gastrointestinal Stromal Tumor Despite complete surgical resection of the primary GISTs, recurrence or metastases may occur in 40–90% of cases (Eisenberg and Judson 2004). The five-year survival rate from a series of patients who achieved gross resection of GIST from the Memorial Sloan Kettering Cancer Centre was 54% (DeMatteo et al. 2000). The risk of recurrence may be determined by stratification of patients on the basis of tumor characteristics such as the size and mitotic rate (Fletcher et al. 2002). A number of studies have been conducted on the use of imatinib in adjuvant systemic therapy of resected GISTs. The American College of Surgeons Oncology Group (ACOSOG) Z9001 study randomized patients with completely resected c-KIT positive GISTs measuring greater than or equal to 3 cm to placebo or imatinib 400 mg daily for 1 year (DeMatteo et al. 2007a). On relapse patients were allowed to crossover to the drug if on placebo or double the dose of imatinib if already on it. The trial was stopped early when interim analysis showed a significant advantage in reduction in relapse with the imatinib. One-year relapse free survival with imatinib vs. placebo was 97 vs. 83% and 2 year relapse free survival 90 vs. 71%. After unblinding, the placebo arm patients were allowed to go onto imatinib for a year. The patients had been stratified on the basis of tumor size only (with no consideration of mitotic rate) and the group that obtained the most benefit was the >10 cm group; however, patients with GISTs of all sizes statistically obtained improved results. No difference in overall survival has yet been seen. This may be due to the short period of follow-up or possibly that imatinib may be successfully reserved for salvage of relapsed disease. An earlier adjuvant study performed by the ACOSOG was the phase II Z9000 trial of imatinib 400 mg/day for 1 year in c-KIT positive patients with high risk resected GIST (DeMatteo et al. 2008). High risk was defined as tumors ³10 cm, ruptured or multifocal. At 3 years median follow-up relapse free survival at 1, 2, and 3 years have been reported as 94, 73, and 61% respectively. Overall survivals for the same time periods are 99, 97, and 97%. Nilsson has reported a small pilot series of 23 patients with high-risk resected GIST patients who were also treated for 1 year with imatinib (Nilsson et al. 2007). With a mean
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follow-up of 40 months only 1 (4%) of the patients has relapsed. This was compared to a matched historical control group of 48 patients derived from a population based series (Nilsson et al. 2005) where 32 patients (67%) relapsed. Mutational analysis was performed and interestingly the relapse in the pilot study was in a wild type pediatric GIST case. Another small multicentre single armed study has been reported early results from China where 57 patients with high risk GIST were enrolled to receive imatinib for at least 12 months (Zhan and China Gastrointestinal Cooperative, 2007). With about 75% of patients completing 12 months of treatment only two relapses have been seen. There are two other large phase III trials of adjuvant imatinib in resected GIST which have completed enrollment but are yet to report results. The first is the EORTC 62024 trial which randomized 750 patients with resected intermediate and high risk GIST to either observation or 2 years of imatinib 400 mg daily. The primary endpoint of this study was overall survival but this was subsequently amended to time to secondary resistance. Another trial the Scandinavian Sarcoma Group SSGXVIII trial enrolled 400 patients and compares 12 vs. 36 months of imatinib in high and very risk patients with the main endpoint being recurrence free survival. In summary, 12 months of imatinib mesylate does seem to reduce early recurrences. Longer follow-up will be required along with the results of ongoing randomized studies to determine whether this is sustained and whether this may translate into an overall survival benefit. The appropriate duration of adjuvant therapy will also be partly answered by these studies.
6.4.6 Neoadjuvant Therapy for Locally Advanced GISTs The use of neoadjuvant systemic biological therapy for locally advanced GISTs may be justified if the aim is to render initially inoperable tumors resectable by shrinkage (socalled conversion therapy) or if it allows preservation of organ function by allowing a less radical operation by shrinkage of the disease. A number of retrospective series have described this approach. A Polish series (Rutkowski et al. 2006) analyzed surgical resection of 32 out of 141 patients with inoperable or metastatic GIST who were treated with imatinib. Surgery was carried out either for residual disease after response (24 patients, 17%) or for salvage (eight patients) after progression on imatinib. In those patients who achieved complete remission after resection of downstaged tumor and did not continue imatinib the early relapse rate was high. Subsequent patients were continued on imatinib post surgery and more durable remissions were achieved. Despite the continuation of imatinib the results of salvage surgery was not good with five patients relapsing. A French paper (Bonvalot et al. 2006) reported surgery in 22 (12%) out of 180 advanced GIST patients treated with imatinib. Of these five patients, emergency operations were due to tumor rupture. The rest were planned resections either for the primaries or metastases. The observed progression-free survivals for downstaged tumors were however similar to that of nonoperated patients. An Italian series (Fiore et al. 2009) of 15 patients found that all patients responded to imatinib and underwent surgery with a 77% 3-year progression-free survival from commencement of imatinib. The recently published RTOG 0132 phase II
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trial examined the use of preoperative imatinib 600 mg daily in 63 patients potentially resectable GIST (Eisenberg et al. 2009). These were a mix of primary GIST and recurrent GIST. An additional 24 months of adjuvant imatinib was given post operatively. Operative complications and toxicity of therapy were found to be minimal. Likewise a Memorial Sloan Kettering Cancer Centre series described 40 patients who received tyrosine kinase therapy before proceeding to resection after a median of 15 months (DeMatteo et al. 2007b). All but one patient initially had disease stabilization or partial response. In the 20 patients who were responding at the time of resection, the 2-year progression-free survival and overall survival were 61 and 100%, respectively. Of the 13 patients who had surgery for focal progression the median time to progression was 12 months and the 2-year overall survival 36%. Multifocal disease progression was associated with poor outcomes with surgery in seven patients. The median time to progression was 3 months with 1-year survival of 36%. This would suggest that surgery in the context of multifocal progression is not indicated. The German APOLLO study is a phase II study to examine the benefit of neoadjuvant imatinib in locally advanced GIST. The primary endpoints are radiological and histological response, and secondary endpoints are achievement of R0 resection and organ preservation. The EORTC is conducting a randomized trial of surgery or no surgery in patients with locally advanced GIST who are downstaged to potential resectability.
6.4.7 Other Agents in Development 6.4.7.1 Nilotinib (AMN107, Tasigna, Novartis) Nilotinib is a second generation tyrosine kinase inhibitor with activity against KIT, PDFR and BCR-ABL. It achieves 7–10 times the intracellular concentration as imatinib. In vitro studies show some activity in imatinib resistant cell lines and also some synergy with imatinib. A phase I dose escalation study was conducted in 53 patients with imatinib refractory GIST (Von Mehren et al. 2007). Eighteen patients received nilotinib alone and 35 received it in combination with imatinib. The maximal tolerated dose (MTD) was established as being nilotinib 400 mg bd with imatinib 400 mg daily. In the monotherapy cohort of 18 patients 1 partial remission and 13 stable disease were seen (tumor control rate of 78%) with median duration of disease control being 158 days. In the MTD cohort of 16 patients 1 partial remission and 9 patients had stable disease (tumor control rate 62%) with median duration of control being 259 days (Blay et al. 2008). A retrospective analysis has been conducted for 42 patients with imatinib and sunitinib resistant GIST enrolled onto a multicountry European compassionate access program of nilotinib at a dose of 400 mg bd. Four partial remissions and 15 stable disease response were seen giving a clinical benefit of 45%. Toxicity led to cessation of the medication in 12%. The median overall survival was 211 days. A phase III study of third line nilotinib vs. best supportive care has been completed and results are awaited. A frontline phase III study of imatinib vs. nilotinib has also been initiated.
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6.4.7.2 Sorafenib (BAY 43 1006, Nexavar, Bayer) Sorafenib is an oral multikinase inhibitor that inhibits KIT, VEGFR, PDGFR and Raf kinases. In vitro inhibition of imatinib resistance GIST cell lines have been observed (Guo et al. 2007). Preliminary results of a phase II trial of sorafenib in patients with imatinib resistant and both imatinib and sunitinib resistant advanced GIST patients have shown activity of the drug (Wiebe et al. 2008). Three out of 24 patients have had a partial remission and 14 stable disease with disease control rate 71%. Median progression-free survival was 5.3 months and median survival 13 months. A European series has reported preliminary data on 24 GIST patients treated with sorafenib in the fourth line setting following failure of imatinib, sunitinib and nilotinib) (Gelderblom et al. 2009). Twenty percent have achieved partial remission and 50% stable disease. Half the patients had a clinical benefit in terms of improvement in performance status or symptoms.
6.4.7.3 Retaspimycin Hydrochloride (IPI-504, Infinity Pharmaceuticals) Retaspimycin is a water soluble heat shock protein 90 (HSP90) inhibitor. HSP90 is a protein chaperone that is responsible for the folding, stability and localization of mutated “client” proteins such as c-KIT and PDGFR. In vitro experiments have shown that HSP90 inhibition has inhibitory effects on imatinib sensitive and imatinib resistant GIST cell line KIT oncoproteins (Bauer et al. 2006). A phase I study has determined a dosing schedule of 400 mg twice weekly for 2 weeks out of three (Wagner et al. 2008). Forty-five patients with GIST were treated and 32 assessable for response. At 6 weeks the partial remission rate was 3% and stable disease 67% (70% disease control rate). The median progressionfree survival was 12 weeks. Commonly seen side effects were fatigue, headache, nausea, diarrhea, myalgia and first-degree heart block. A phase III double blind, placebo controlled study of retaspimycin (RING trial) in refractory GIST commenced enrolment of patients who have previously been treated with at least imatinib and sunitinib. This study was halted in April 2009 when early review of data found a higher than expected mortality in the study arm.
6.4.7.4 Everolimus (RAD001, Afinitor, Novartis) Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor. It has been found that in imatinib resistance that downstream kinase signaling pathways which include the AKT/mTOR and MAP kinase pathways remain activated (Fletcher et al. 2003). Synergism has been found between imatinib and everolimus in GIST cell lines leading to the conduct of a phase I/II trial of this combination in imatinib resistant GIST (van Oosterom et al. 2005). This established a safe tolerable dose of imatinib 600 mg and everolimus 2.5 mg daily. In the phase I part of this study 31 patients were treated in dif-
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ferent everolimus dose cohorts. Stable disease was observed in eight patients and two experienced partial remissions. The phase II part of the study enrolled patients in two strata; those following one line of prior therapy, and those who were second line failures (Dumez et al. 2008). Four-month progression-free survival was 17.4% in 23 evaluable out of 28 patients in the first stratum while it was 37.1% in the 35 of 47 evaluable patients in the second cohort. Common side effects included mild fatigue, diarrhea, vomiting, nausea, anemia, headache and rash.
6.4.7.5 Motesanib Diphosphate (AMG706, Amgen) Motesanib is an oral small molecule multi-kinase inhibitor targeting c-KIT, PDGFR and VEGFR1–3. Two phase II clinical trials have been performed with this agent in advanced imatinib refractory GIST patients. The first multinational study enrolled 139 patients of whom 120 were eligible on the basis of confirmed prestudy disease progression (Benjamin et al. 2006). The response rate on RECIST criteria was 3% with 46% of patients having stable disease as the best response. Durable stable disease of more than 22 weeks was seen in 24%. Median progression-free survival was 16 weeks and median overall survival was 14.8 months. FDG PET imaging was performed at 8 weeks and in the 89 patients who had baseline and week 8 scans the response was 30%. Choi criteria was also used to evaluate responses at week 8 and of the 96 patients evaluable for efficacy the response rate was 33% on the basis of reduced tumor density and/or tumor size. The second study was conducted in Japan and reported on the initial 35 patients who had received more than one dose of motesanib (Yamada et al. 2008). There was one partial response and seven patients had stable disease for more than 24 weeks. Median progression-free survival was 113 days.
6.5 Conclusion Great progress has been made in the understanding of the biological basis behind the pathogenesis of GISTs in the last 10 years. This understanding has translated directly into clinical breakthroughs in the management of this rare disease, which in the past had no effective therapies except surgery. These developments in targeted biological therapies have come at a rapid rate and made an enormous difference in the survival and quality of life of patients with advanced disease. The management of GIST is necessarily multidisciplinary and involves coordinated care of patients spanning gastroenterologists, surgeons, pathologists, scientists, radiologists, nuclear physicians and medical oncologists. Further advances in the understanding of the tumor biology will lead to progression of new agents from the laboratory to the clinic, thereby providing further therapeutic options for patients in the future.
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Acknowledgments The authors would acknowledge the assistance of Mark Koina of the Electron Microscopy Unit at ACT Pathology, The Canberra Hospital in supplying the electron microscopy image and Rod Hicks from the Centre for Molecular Imaging, Peter MacCallum Cancer Centre for providing the PET/CT images.
References Adenis A et al (2008) Does interruption of imatinib (IM) in responding patients after three years of treatment influence outcome of patients with advanced GIST included in the BFR14 trial? J Clin Oncol 26:10522 (Meeting Abstracts) Agaimy A et al (2006) Occurrence of other malignancies in patients with gastrointestinal stromal tumors. Semin Diagn Pathol 23:120–129 Agaram NP et al (2008a) Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res 14:3204–3215 Agaram NP et al (2008b) Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 47:853–859 American Gastroenterological Association Institute (2006) American Gastroenterological Association Institute medical position statement on the management of gastric subepithelial masses. Gastroenterology 130:2215–2216 Antonescu CR et al (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11:4182–4190 Bauer S et al (2006) Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res 66:9153–9161 Benjamin R et al (2006) Initial results of a multicenter single-arm phase 2 study of AMG706, an oral multikinase inhibitor, for the treatment of advanced imatinib-resistant gastrointestinal stromal tumors (GIST). In: 12th annual meeting of the connective tissue oncology society, Venice, Italy Benjamin RS et al (2007) We should desist using RECIST, at least in GIST. J Clin Oncol 25: 1760–1764 Blackstein ME et al (2006) Gastrointestinal stromal tumours: consensus statement on diagnosis and treatment. Can J Gastroenterol 20:157–163 Blanke CD et al (2008a) Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26:620–625 Blanke CD et al (2008b) Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26:626–632 Blay JY et al (2005) Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20–21 March 2004, under the auspices of ESMO. Ann Oncol 16:566–578 Blay JY et al (2007) Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol 25:1107–1113 Blay JY et al (2008) A phase I study of nilotinib alone and in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors (GIST): study update. J Clin Oncol 26:10553 (Meeting Abstracts) Bonvalot S et al (2006) Impact of surgery on advanced gastrointestinal stromal tumors (GIST) in the imatinib era. Ann Surg Oncol 13:1596–1603
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Braconi C et al (2008) Insulin-like growth factor (IGF) 1 and 2 help to predict disease outcome in GIST patients. Ann Oncol 19:1293–1298 Cameron S et al (2009) Analysis of a case with disappearance of the primary gastrointestinal stromal tumor and progressive liver metastases under long-term treatment with tyrosine kinase inhibitors. Med Oncol 27(2):213–218 Carney JA (1999) Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc 74:543–552 Carney JA, Stratakis CA (2002) Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 108:132–139 Casali P et al (2005) Imatinib mesylate in advanced gastrointestinal stromal tumors (GIST): survival analysis of the intergroup EORTC/ISG/AGITG randomized trial in 946 patients. Eur J Cancer Suppl 3:201 Casali PG et al (2008) Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 19(suppl 2):ii35–ii38 Choi H et al (2007) Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 25: 1753–1759 Corless CL et al (2002) KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 160:1567–1572 Croom KF, Perry CM (2003) Imatinib mesylate: in the treatment of gastrointestinal stromal tumours. Drugs 63:513–522, discussion 523–514 Crosby JA et al (2001) Malignant gastrointestinal stromal tumors of the small intestine: a review of 50 cases from a prospective database. Ann Surg Oncol 8:50–59 Debiec-Rychter M et al (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093–1103 DeMatteo RP et al (2000) Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 231:51–58 DeMatteo R et al (2007a) Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup Phase III trial ACOSOG Z9001. Proc Am Soc Clin Oncol (Abstr 10079) DeMatteo RP et al (2007b) Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor. Ann Surg 245:347–352 DeMatteo R et al (2008) Efficacy of adjuvant imatinib mesylate following complete resection of localized, primary gastrointestinal stromal tumor (GIST) at high risk of recurrence: The U.S. Intergroup phase II trial ACOSOG Z9000. In: ASCO Gastrointestinal Cancers Symposium (Abstr 8) Demetri GD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480 Demetri GD et al (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368:1329–1338 Demetri GD et al (2007) NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5(Suppl 2):S1–S29, quiz S30 Demetri G et al. (2008) Correlation of imatinib plasma levels with clinical benefit in patients (Pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST). In: ASCO Gastrointestinal Cancers Symposium Desai J et al (2006) Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 145:660–664
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Doric M et al (2007) Testicular metastasis of gastrointestinal stromal tumor of the jejunum. Bosn J Basic Med Sci 7:176–179 Duffaud F et al (2009) Time to secondary resistance (TSR) after interruption of imatinib: updated results of the prospective French Sarcoma Group randomized phase III trial on long-term survival. J Clin Oncol 27:10508 (Meeting Abstracts) Dumez H et al (2008) A phase I-II study of everolimus (RAD001) in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST). J Clin Oncol 26:10519 (Meeting Abstracts) Eisenberg BL (2006) Combining imatinib with surgery in gastrointestinal stromal tumors: rationale and ongoing trials. Clin Colorectal Cancer 6(Suppl 1):S24–S29 Eisenberg BL, Judson I (2004) Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy. Ann Surg Oncol 11:465–475 Eisenberg BL et al (2009) Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol 99:42–47 Espinosa I et al (2008) A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol 32:210–218 Everett M, Gutman H (2008) Surgical management of gastrointestinal stromal tumors: analysis of outcome with respect to surgical margins and technique. J Surg Oncol 98:588–593 Fiore M et al (2009) Preoperative imatinib for unresectable or locally advanced primary gastrointestinal stomal tumors (GIST). Eur J Canc Surg xx:1–7 Fletcher CD et al (2002) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33:459–465 Fletcher J et al (2003) Mechanisms of resistance to imatinib mesylate (IM) in advanced gastrointestinal stromal tumor (GIST) (abstract). Proc Am Soc Clin Oncol 22:815 Gelderblom H et al (2009) Sorafenib fourth-line treatment in imatinib, sunitinib, and nilotinib resistant metastatic GIST: a retrospective analysis. ASCO Gastrointestinal Cancers Symposium (Abstr 51) George S et al (2009) Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer 45(11):1959–1968 Godwin A et al (2008) Insulin-like growth factor 1 receptor (IGF-1R): a potential therapeutic target for gastrointestinal stromal tumors (GIST). J Clin Oncol 26:10507 (Meeting Abstracts) Goettsch WG et al (2005) Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer 41:2868–2872 Goh BK et al (2008) Which is the optimal risk stratification system for surgically treated localized primary GIST? Comparison of three contemporary prognostic criteria in 171 tumors and a proposal for a modified Armed Forces Institute of Pathology risk criteria. Ann Surg Oncol 15:2153–2163 Gold JS, Dematteo RP (2006) Combined surgical and molecular therapy: the gastrointestinal stromal tumor model. Ann Surg 244:176–184 Guo T et al (2007) Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor. Clin Cancer Res 13:4874–4881 Gurney H et al (2007) Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype. Clin Pharmacol Ther 82:33–40 Harrison ML, Goldstein D (2006) Management of metastatic gastrointestinal stromal tumour in the Glivec era: a practical case-based approach. Intern Med J 36:367–377 Heinrich MC et al (2008) Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 26:5352–5359 Hirota S et al (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580
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Hughes B et al (2004) Cerebral relapse of metastatic gastrointestinal stromal tumor during treatment with imatinib mesylate: case report. BMC Cancer 4:74 Hwang JH et al (2006) American Gastroenterological Association Institute technical review on the management of gastric subepithelial masses. Gastroenterology 130:2217–2228 Janeway KA et al (2007) Pediatric KIT wild-type and platelet-derived growth factor receptor alpha-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer Res 67:9084–9088 Joensuu H (2008) Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 39:1411–1419 Joensuu H et al (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056 Judson I et al (2005) Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time EORTC Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 55:379–386 Kawanowa K et al (2006) High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol 37:1527–1535 Lamuraglia M et al (2006) Dynamic contrast-enhanced Doppler ultrasound (DCE-US) is a useful radiological assessment to early predict the outcome of patients with gastrointestinal stromal tumors (GIST) treated with imatinib (IM). J Clin Oncol 24:9539 (Meeting Abstracts) Lee HE et al (2008) Characteristics of KIT-negative gastrointestinal stromal tumours and diagnostic utility of protein kinase C theta immunostaining. J Clin Pathol 61:722–729 Liegl B et al (2009) Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: a novel form of tumor progression. Am J Surg Pathol 33:218–226 Mazzarolo S, Brady P (2007) Small bowel capsule endoscopy: a systematic review. South Med J 100:274–280 Mendoza-Marin M et al (2002) Malignant stromal tumor of the gallbladder with interstitial cells of Cajal phenotype. Arch Pathol Lab Med 126:481–483 Miettenen M et al (2002) Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review. Eur J Cancer 38:S39–S51 Miettinen M, Lasota J (2006a) Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23:70–83 Miettinen M, Lasota J (2006b) Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 130:1466–1478 Miettinen M et al (2005a) Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol 29:1373–1381 Miettinen M et al (2005b) Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol 29:1373–1381 Miettinen M et al (2005c) Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 29:52–68 Miettinen M et al (2006) Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 30:90–96 Miettinen M et al (2008) A nonrandom association between gastrointestinal stromal tumors and myeloid leukemia. Cancer 112:645–649 Mussi C et al (2008a) Gastrointestinal stromal tumor of the rectum and rectovaginal space: a retrospective review. J Clin Oncol 26:10560 (Meeting Abstracts) Mussi C et al (2008b) Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin Cancer Res 14:4550–4555
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Negri T et al (2009) Oncogenic and ligand-dependent activation of KIT/PDGFRA in surgical samples of imatinib-treated gastrointestinal stromal tumours (GISTs). J Pathol 217: 103–112 Nilsson B et al (2005) Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era – a population-based study in western Sweden. Cancer 103:821–829 Nilsson B et al (2007) Adjuvant imatinib treatment improves recurrence-free survival in patients with high-risk gastrointestinal stromal tumours (GIST). Br J Cancer 96:1656–1658 Park JK et al (2004) Malignant gastrointestinal stromal tumor of the gallbladder. J Korean Med Sci 19:763–767 Pasku D et al (2008) Bilateral gluteal metastases from a misdiagnosed intrapelvic gastrointestinal stromal tumor. World J Surg Oncol 6:139 Patel S et al (1991) Evaluation of ifosfamide in metastastic leiomyosarcoma of gastrointestinal origin. Proc Am Soc Clin Oncol 10:352 Pidhorecky I et al (2000) Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management. Ann Surg Oncol 7:705–712 Plager C et al (1991) Adriamycin based chemotherapy for leiomyosarcoma of the stomach and small bowel. Proc Am Soc Clin Oncol 10:352 Pollock J et al (2001) Adjuvant radiotherapy for gastrointestinal stromal tumor of the rectum. Dig Dis Sci 46:268–272 Raut CP et al (2006) Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24:2325–2331 Rossi G et al (2005) PDGFR expression in differential diagnosis between KIT-negative gastrointestinal stromal tumours and other primary soft-tissue tumours of the gastrointestinal tract. Histopathology 46:522–531 Rutkowski P et al (2006) Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 93:304–311 Schneider-Stock R et al (2005) Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study. Clin Cancer Res 11:638–645 Shankar S et al (2005) Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. Radiology 235:892–898 Stroobants S et al (2003) 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer 39:2012–2020 Takahashi T et al (2007) An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors. Int J Clin Oncol 12: 369–374 Tarn C et al (2008) Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci U S A 105:8387–8392 The NCCN Clinical Practice Guidelines in Oncology (2008) Soft tissue sarcoma (V.2.2009). National Comprehensive Cancer Network, Fort Washington Therasse P et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216 Torihashi S et al (1999) Blockade of kit signaling induces transdifferentiation of interstitial cells of cajal to a smooth muscle phenotype. Gastroenterology 117:140–148 Trent J et al (2003) A two arm phase 2 study of temozolomide (T) in gastrointestinal stromal tumors (GISTs) and other soft-tissue sarcomas (STS). Proc Am Soc Clin Oncol 22:3298 Tuveson DA et al (2001) STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 20:5054–5058
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Van Glabbeke M et al (2006) Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: a study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG). Eur J Cancer 42:2277–2285 Van Glabbeke MM et al (2007) Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): a meta-analyis based on 1,640 patients (pts). J Clin Oncol 25:10004 (Meeting Abstracts) van Oosterom AT et al (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358:1421–1423 van Oosterom A et al (2005) A phase I/II trial of the oral mTOR-inhibitor everolimus (E) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM: study update. J Clin Oncol 23:9033 (Meeting Abstracts) Verweij J et al (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364:1127–1134 Von Mehren M et al (2007) A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) – study update. J Clin Oncol 25:10023 (Meeting Abstracts) von Mehren M et al (2008) Imatinib pharmacokinetics (PK) and its correlation with clinical response in patients with unresectable/metastatic gastrointestinal stromal tumor (GIST). J Clin Oncol 26:4523 (Meeting Abstracts) Wagner AJ et al (2008) Inhibition of heat shock protein 90 (Hsp90) with the novel agent IPI-504 in metastatic GIST following failure of tyrosine kinase inhibitors (TKIs) or other sarcomas: clinical results from phase I trial. J Clin Oncol 26:10503 (Meeting Abstracts) Wardelmann E et al (2006) Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12:1743–1749 West RB et al (2004) The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol 165:107–113 White DL et al (2006) OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 108:697–704 Widmer N et al (2006) Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein. Br J Clin Pharmacol 62:97–112 Wiebe L et al (2008) Activity of sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): a phase II trial of the University of Chicago Phase II Consortium. J Clin Oncol 26:10502 (Meeting Abstracts) Yamada Y et al (2008) Phase II study of motesanib diphosphate (AMG 706) in Japanese patients (pts) with advanced gastrointestinal stromal tumors (GISTs) who developed progressive disease or relapsed while on imatinib mesylate. Gastrointestinal Cancers Symposium (Abstr 107) Yantiss RK et al (2002) Gastrointestinal stromal tumors: an ultrastructural study. Int J Surg Pathol 10:101–113 Zalcberg JR et al (2005) Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 41:1751–1757 Zhan WH; China Gastrointestinal Cooperative Group (2007) Efficacy and safety of adjuvant postsurgical therapy with imatinib in patients with high risk of relapsing GIST. J Clin Oncol 25:10045 (Meeting Abstracts)
Multimodality Management of Localized and Borderline Resectable Pancreatic Adenocarcinoma
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Michael B. Ujiki, William Small, Robert Marsh, and Mark S. Talamonti
7.1 Introduction Adenocarcinoma of the pancreas continues to be a daunting clinical challenge, with approximately 42,000 deaths per year in the United States (Jemal et al. 2009). It is a disease characterized by its late presentation, rapid demise thereafter, and relatively ineffective systemic therapies. Despite this grim prognosis, appreciable progress has been made in the identification of patients with localized disease who may be candidates for potentially curative resections and in the understanding of the technical nuances and efficacy of aggressive surgical procedures. Following initial reports in the 1930s of successful resections for periampullary tumors, the technique known as the Whipple procedure, or pancreaticoduodenectomy, underwent several technical modifications and revisions (Brunschwig 1937; Halsted 1899; Whipple et al. 1935). With time also has come a better understanding of the considerable physiologic impact and sequelae of the procedure and its potential, albeit limited, for cure. The high in-hospital mortality rate during the first several decades after the development of the operation led some to propose that it be abandoned, with risks not sufficiently justified by the low overall survival rates (Crile 1970; Shapiro 1975). By the late 1980s and early
M.B. Ujiki Pritzker School of Medicine, University of Chicago, Chicago, IL, USA and Minimally Invasive Surgery, NorthShore University Health System, Evanston, IL 60201, USA W. Small Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA R. Marsh Pritzker School of Medicine, University of Chicago, Chicago, IL, USA and Gastrointestinal Oncology Section, NorthShore University Health System, Evanston, IL, USA M.S. Talamonti (*) Pritzker School of Medicine, University of Chicago, Chicago, IL, USA and Department of Surgery, NorthShore University Health System, Evanston, IL, USA e-mail:
[email protected] C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_7, © Springer-Verlag Berlin Heidelberg 2011
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1990s, series from experienced centers indicated that an aggressive surgical approach to periampullary tumors, of which pancreatic cancer is the most common, was justified. Morbidity and mortality rates dramatically improved and median survival rates began to significantly exceed the expected survival times of nonoperative treatment options (Crist et al. 1987; Trede et al. 1990). Today, the overall five-year survival rate is 15–25% for patients who undergo resection, compared with 1–5% for those who do not receive cancerdirected treatment (Bilimoria et al. 2007; Alexakis et al. 2004).
7.2 Clinical Staging and Preoperative Management From a surgical perspective, the first objective in the management of suspected or confirmed pancreatic cancer is to determine the potential for resection. Routine exploratory laparotomy for the purpose of operatively determining resectability has been diminished by modern three-dimensional radiographic imaging along with effective and sustainable nonoperative methods of palliation. Contrast-enhanced computed tomography (CT) accurately predicts resectability in 80–90% of patients (McCarthy et al. 1998; Chong et al. 1998; Vedantham et al. 1998; Roche et al. 2003; Gulliver et al. 1992; Freeny et al. 1993; Fuhrman et al. 1994). Careful correlation between preoperative CT findings and surgical results has better defined CT criteria for resectability. The critical aspects that need to be evaluated in a thorough radiographic assessment are: the presence or absence of peritoneal or hepatic metastases; the patency of the superior mesenteric vein (SMV) and portal vein and the relationship of these vessels and their tributaries to the tumor; the relationship of the tumor to the superior mesenteric artery, celiac axis, hepatic artery, and gastroduodenal artery; and the presence of any aberrant vascular anatomy (Wayne et al. 2002). Magnetic resonance imaging does not appear to have an advantage over CT except for revealing smaller hepatic metastases and for use in patients who cannot undergo contrast-enhanced CT (Ichikawa et al. 1997; Megibow et al. 1995). Unequivocal radiographic findings contraindicating resection include distant metastases, major venous thrombosis of the portal vein or SMV extending for several centimeters, and circumferential encasement of the superior mesenteric, celiac, or proximal hepatic arteries (Fuhrman et al. 1994). Patients without distant metastases and with slightly more advanced but still potentially localized disease may now be categorized as “borderline resectable.” Criteria for this group of patients include encasement of a short segment of the hepatic artery, without evidence of tumor extension to the celiac axis; tumor abutment of the superior mesenteric artery involving less than 180° of the artery circumference; and short-segment occlusion of the SMV–portal vein confluence beneath the neck of the pancreas. Whether these patients would benefit from an initial approach with chemoradiation, repeat staging studies, and subsequent exploration remains an area of investigation and will be discussed subsequently (Varadhachary et al. 2006). A recent consensus conference with representation from the Society of Surgical Oncology, the American Society of Clinical Oncology, and the American HepatoPancreatico-Biliary Association attempted to define reproducible and clinically relevant criteria to better categorize resection classifications for nonmetastatic pancreatic cancer
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(Callery et al. 2009). These classifications are listed below and are crucial if the efficacy of surgery and neoadjuvant strategies are to be carefully assessed and determined based on extent of disease. 1. Tumors considered localized and resectable should demonstrate the following: (a) No distant metastases (b) No radiographic evidence of SMV and portal vein abutment, distortion, tumor thrombus, or venous encasement (c) Clear fat planes around the celiac axis, hepatic artery, and SMA (Fig. 7.1) 2. Tumors considered borderline resectable include the following: (a) No distant metastases (b) Venous involvement of the SMV/portal vein demonstrating tumor abutment with or without impingement and narrowing of the lumen, encasement of the SMV/portal vein but without encasement of the nearby arteries, or short-segment venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and reconstruction (c) Gastroduodenal artery encasement up to the hepatic artery with either short-segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis (d) Tumor abutment of the SMA not to exceed 180° of the circumference of the vessel wall (Figs. 7.2 and 7.3) In patients without significant major comorbidities and in the absence of radiographic findings to suggest metastatic disease or locally advanced unresectable disease as outlined above, surgical resection should be considered feasible and likely to be achievable.
a
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Fig. 7.1 (a) Cross-sectional and (b) sagittal images of a localized, potentially resectable pancreatic cancer seen as a low-density lesion sparing the superior mesenteric vein (SMV) (arrow) and superior mesenteric artery
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Fig. 7.2 Borderline resectable pancreatic cancer with partial involvement of the SMV, and abutment but not encasement of the mesenteric artery (arrow). Patient underwent successful pancreaticoduodenectomy but required segmental resection of the involved vein and reconstruction using an internal jugular vein graft
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Fig. 7.3 Coronal image of a locally advanced, unresectable pancreatic cancer demonstrating 360° encasement of the superior mesenteric artery (arrow)
Positron emission tomography (PET) is an evolving technology, which as of yet does not have a specifically defined role in the evaluation of patients with suspected pancreatic cancer. PET may be useful for preoperative diagnosis of pancreatic carcinoma in patients with suspected cancer in whom CT fails to identify a discrete mass or in whom fine-needle aspiration (FNA) is nondiagnostic (Delbeke and Martin 2010). It does not appear to significantly alter the clinical approach in most patients staged by helical CT. It is also limited by the fact there is a relatively high rate of glucose intolerance in patients with pancreatic disease, which could contribute to a higher false negative rate (Diederichs et al. 1998). PET imaging is useful for M staging and restaging by detecting CT occult metastatic disease, allowing noncurative resection to be avoided in this group of patients. PET can differentiate post-therapy changes from recurrence and holds promise for monitoring neoadjuvant chemoradiation treatment responses. The technique is less useful in periampullary carcinoma and marginally helpful in staging except for M staging. PET should be
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considered complementary to morphologic imaging with CT (Delbeke and Martin 2010; Diederichs et al. 1998). Endoluminal ultrasonography (EUS) has become a powerful tool in the diagnostic evaluation of suspected pancreatic tumors. It is remarkably sensitive for detecting small pancreatic tumors and clarifying suspected vascular invasion (Owens and Savides 2010). EUS has also been shown to be accurate in the evaluation of peripancreatic adenopathy and ascites when combined with EUS-guided FNA (Rosch et al. 2000; Rosch 1995; Raut et al. 2003). With the development of neoadjuvant protocols for borderline resectable pancreatic cancer, preoperative tissue diagnosis is required to differentiate adenocarcinoma from neuroendocrine tumors and chronic pancreatitis. EUS is currently the procedure of choice for obtaining a tissue biopsy prior to the commencement of treatments. Furthermore, there is a theoretical oncologic advantage over percutaneous biopsy because the needle tract is contained in the eventual surgical specimen. The major limitation of EUS is the dependence on a skilled and experienced gastroenterologist to perform the procedure. Endoscopic retrograde cholangiopancreatography (ERCP) has both diagnostic and therapeutic roles in the evaluation of patients with suspected pancreatic cancers. ERCP provides suggestive evidence of malignancy when irregular, tight strictures are seen in the distal common bile duct and main pancreatic duct. Brush biopsies of such strictures are not particularly sensitive (60%), but they are highly specific when positive (98%) (Stewart et al. 2001). ERCP is applicable in the evaluation of patients with suspected intraductal papillary mucinous neoplasms of the pancreas. The procedure can accurately detect the presence of mucin in the pancreatic duct and may be helpful in localizing the extent of disease to the head, body, or tail of the pancreas (Tanaka 2004). ERCP is most valuable when decompression of biliary obstruction is required before surgery. Placement of a biliary stent preoperatively is controversial. Some reports have demonstrated increased morbidity and mortality rates when resection is performed following preoperative drainage (van der Gaag et al. 2010). These reports have not clearly delineated the differences between percutaneous biliary drainage vs. endoscopic stent placement, nor has the experience or the expertise of the unit performing the drainage procedures been accounted for on a regular basis. Other reports have found no significant effect on outcome except for a slight increase in the incidence of wound infections (Pisters et al. 2001a; Sewnath et al. 2001; Sohn et al. 2000). The expected decrease in serum bilirubin levels, increases in albumin and protein levels, and improvements in performance status have similarly not led to better surgical outcomes. Most studies regarding this issue have been retrospective, and therefore meaningful conclusions are difficult to draw. Most would agree that preoperative biliary decompression is not necessary if timely surgical therapy is anticipated and there are no significant metabolic or nutritional deficits. All patients presenting with obstructive jaundice and entered into a neoadjuvant trial do require biliary decompression. Most surgeons routinely prefer that this be done with endoscopic stent placement. In general, stents placed in patients with potentially resectable cancers should be plastic, not metal. CA 19-9 is a tumor-associated antigen frequently elevated in patients with pancreatic cancer (Ritts and Pitt 1998). Studies have attempted to evaluate its role in establishing the diagnosis of malignancy in a clinically suspicious presentation. Controversy exists regarding the correct cutoff used to establish the threshold level for malignancy. Forsmark et al. found accuracy rates of 85 and 95% in the diagnosis of pancreatic malignancy when levels were greater
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than 90 U/mL and greater than 200 U/mL, respectively (Forsmark et al. 1994). In combination with CT, a positive predictive value of 99% can be achieved when levels are greater than 120 U/mL (Ritts et al. 1994). Schlieman et al. found that CA 19-9 levels may be potentially useful as a marker for resectability (Schlieman et al. 2003). When a threshold level of 150 U/mL was used, the positive predictive value for determination of unresectable pancreatic cancer was 88%. Their recommendation was for additional staging modalities, such as diagnostic laparoscopy, in patients with abnormally high serum levels of CA 19-9. Katz found that levels greater than 680 U/mL were a significant prognostic predictor of overall survival (Katz et al. 1998). Most physicians caring for patients with pancreatic cancer use CA 19-9 levels as supportive evidence of malignancy in equivocal cases, as a parameter of therapeutic response, and as an indicator of recurrence. It should be noted that 5–15% of patients, who are Lewis a antigen negative, are incapable of expressing CA19-9 and may, therefore, have a falsely negative reading. Equally, a high bilirubin may falsely elevate the value. Some centers still routinely employ laparoscopy as part of the preoperative evaluation for patients with potentially resectable tumors. Early reports from high-volume centers demonstrated a 15–25% incidence of occult metastatic disease detected at the time of staging laparoscopy (Warshaw et al. 1986, 1990; Conlon et al. 1996). More recent series, using modern, contrastenhanced helical CT scans, have found a lower incidence (4–15%) of occult metastatic disease detected by laparoscopy (Friess et al. 1998; Barreiro et al. 2002; Pisters et al. 2001b; Jimenez et al. 2000; Nieveen van Dijkum et al. 2003). Differences also exist in its utility for tumors located in the head of the pancreas vs. those in the body and tail of the pancreas. The latter are associated with a higher incidence of occult metastatic disease (Barreiro et al. 2002). Rather than apply diagnostic laparoscopy in all patients, most surgeons now use it selectively. Laparoscopy is recommended prior to laparotomy for tumors larger than 5 cm, patients with preoperative CA 19-9 levels greater than 680 mg/dL, or tumors in the body or tail of the pancreas (Katz et al. 1998; Montgomery et al. 1997). Laparoscopy is also useful when CT suggests the presence of hepatic, peritoneal, or omental nodules that are too small to characterize or biopsy. Additionally, laparoscopic ultrasound may help identify vascular invasion, as well as hepatic metastases (John et al. 1995).
7.3 Principles of Surgical Management and Current Controversies The fundamental objectives of pancreatic cancer surgery are total extirpation of the primary tumor with microscopically clear resection margins, complete regional lymphadenectomy of appropriate peripancreatic nodal groups, and reconstruction of the gastrointestinal tract so as to facilitate early and sustained return of normal physiologic function. Subtotal pancreatic resection can be carried out as either a left (distal) or right pancreatectomy. The latter is also described as a pancreaticoduodenectomy or Whipple procedure. A standard pancreaticoduodenectomy involves resection of the distal stomach, distal common bile duct, gall bladder, duodenum, pancreatic head, uncinate process, proximal jejunum, and regional lymph nodes (Evans et al. 2001). More recent modifications include preservation of the distal stomach and proximal duodenum, the so-called pyloric-preserving Whipple. Most adenocarcinomas of the pancreas occur in the head of the gland and their resection requires pancreaticoduodenectomy.
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7.3.1 Extent of Regional Lymphadenectomy Given the high incidence of lymph node metastasis in patients with pancreatic cancer, there continues to be interest in the extent of lymphadenectomy done during pancreaticoduodenectomy. Data from Asia and Japan have suggested a survival benefit for extended lymph node dissections for esophageal and gastric cancers. Retrospective reviews of surgical experiences have shown a wide range in the number and location of lymph nodes removed during a routine pancreas resection with no definitive conclusions regarding the impact of nodal dissection on survival. Two recent surgical trials have attempted to address this issue. Neither showed any survival advantage to extended dissections that included more aggressive clearance of retroperitoneal soft tissues and nodes. Yeo et al. reported no significant difference in one-, three-, or five-year survival rates and median survival when comparing standard pancreaticoduodenectomy to more radical resection, but did find that complication rates were increased in the radical group (Yeo et al. 2002). In the most recent update of this trial, now with a median live patient follow-up of 5.3 years, the one- and five-year survival rates in the standard group were 75 and 13%, respectively, compared with 73 and 29% in the radical group (p = 0.13) (Riall et al. 2005). Pedrazzoli et al. also found that overall survival did not differ according to the magnitude of lymphadenectomy (Pedrazzoli et al. 1998). Predictors of long-term survival were tumor differentiation, tumor size, presence of lymph node metastases, and need for blood transfusions (Pedrazzoli et al. 1998). Standard lymph node basins resected in a typical pancreaticoduodenectomy include nodes along the common bile duct, nodes along the hepatic artery back toward the celiac trunk, posterior, and anterior pancreaticoduodenal nodes, and nodes along the superior mesenteric artery. Lymph nodes not routinely resected in the standard Whipple procedure include nodes at or above the bifurcation of the common hepatic duct, celiac axis nodes and the left gastric and splenic branch nodes, aortocaval nodes, and nodes along the distal superior mesenteric artery (Fig. 7.4). Complications resulting from extended lymphadenectomy may include exacerbated dumping syndromes and debilitating diarrhea (Yeo et al. 2002; Riall et al. 2005; Pedrazzoli et al. 1998). Results of clinical trials thus far suggest that nodal metastases are a strong predictor of subsequent systemic failure and that radical removal of regional nodes is unlikely to favorably impact overall survival. Outside the setting of a clinical trial, extended lymphadenectomy cannot be justified because of increased complication rates and lack of any convincing survival advantage.
7.3.2 Role of Vascular Resection The critical need for a complete margin-negative resection (R0) is highly evident when examining survival data. Most series suggest similar survival rates for margin-positive resections compared to nonoperative local-regional therapies in patients with locally advanced disease (Trede et al. 1990; Varadhachary et al. 2006; Evans et al. 2001). Data from the surgical group at the M.D. Anderson Cancer Center have demonstrated the
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CHD CBD
Hepatic artery
Celiac Axis & Branches
APD & PPD SMV & R-SMA
Aorto-Caval & Distal SMA
Fig. 7.4 Extent of lymphadenectomy during pancreaticoduodenectomy. Nodal basins designated in green represent those removed in a standard Whipple procedure. Nodal basins designated in red represent those not typically removed in a Whipple procedure but which may be part of an extended nodal dissection and are usually included in standard radiation treatment volumes. CBD common bile duct; APD anterior pancreaticoduodenectomy nodes; PPD posterior pancreaticoduodenal nodes; SMV superior mesenteric vein; R-SMA right lateral wall of the superior mesenteric artery; CHD common hepatic duct; celiac axis and branches celiac trunk at origin from aorta and splenic artery and left gastric artery branches; aorta-caval nodes between the inferior vena cava and abdominal aorta; distal SMA nodes along the distal superior mesenteric artery at the root of the small bowel mesentery
safety and utility of venous resection in highly selected patients with localized headof-pancreas cancers in which a margin-negative resection could only be accomplished by the addition of venous resection. Perioperative morbidity was low and ultimate survival rates were comparable to those of patients undergoing R0 resection without vein resection (Bold et al. 1999). The operative mortality rate was 1.6% and the overall complication rate was 22%. Median survival in both groups was approximately 22 months. CT scanning predicted the need for vein resection and reconstruction in approximately 85% of patients. This is critical since preoperative awareness of vascular involvement will facilitate intraoperative technical approaches and minimize the potential danger of adding a vascular procedure to the already formidable task at hand. Technical options for reconstruction include primary end-to-end repair, lateral venorrhaphy with vein patch from the saphenous or inferior mesenteric vein, or internal jugular vein interposition grafting, usually with splenic vein preservation (Fig. 7.5). Although superior mesenteric artery or hepatic artery encasement is a contraindication to resection, if gross tumor-free margins can be achieved, venous resection of the portal vein or SMV appears to be justified. In experienced hands, venous resection is not associated with reduced survival or increased complications (Bachellier et al. 2001; Sasson et al. 2002; Nakagohri et al. 2003; van Geenen et al. 2001). Since survival is improved relative to microscopic (R1 resection) or macroscopic (R2 resection) margin involvement, venous resection should be strongly considered if it would result in a margin negative resection (R0) (Bold et al. 1999; Harrison and Brennan 1998).
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Fig. 7.5 Intraoperative picture of vascular reconstruction of the superior mesenteric, splenic vein, and portal vein confluence using an internal jugular vein graft and facial vein side branch
7.3.3 Standard Gastrectomy vs. Pyloric-Preserving Whipple Conflicts regarding the use of the standard Whipple operation with distal gastrectomy vs. a pylorus-preserving Whipple procedure stem from concerns over the oncologic completeness of resection when preserving the pylorus and first portion of the duodenum vs. the potential physiologic side effects of gastric resection (Thomas and Ahmad 2010; Lin and Lin 1999). Sequelae of distal gastrectomy may include dumping syndromes, bile reflux, and marginal anastomotic ulcerations. Others have suggested that the incidence of delayed gastric emptying is higher after pyloric preservation and may result in longer postoperative length of stay. Suffice to say, no study has shown a markedly improved quality of life after either procedure, and more recent studies, with large cohorts, have shown the incidence of serious physiologic complications or clinically significant delayed gastric emptying to be equally common after either operation (Tran et al. 2004; Lerut et al. 1984). No significant differences have been observed in local recurrence rates, and overall survival between the two techniques also appears equivalent (Tran et al. 2004). The authors tend to use a selective approach to gastric resection and reconstruction. In patients undergoing the Whipple procedure for ampullary lesions, benign cystic neoplasms of the pancreas, and islet cell tumors, pyloric-preserving resections are chosen. If the resection is being done after neoadjuvant radiation or if postoperative radiation is anticipated, then a standard Whipple with distal gastrectomy and antecolic gastrojejunostomy is preferred. The advantage of this reconstruction is the location of the anastomosis in the left mid-abdomen and a reduction in
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the incidence of radiation gastritis and radiation jejunal strictures. Truncal vagotomy is no longer routinely done and pharmacologic acid suppression is usually sufficient to minimize the risk of marginal ulceration at the gastrojejunostomy.
7.3.4 Techniques for Pancreatic Reconstruction For several decades, the most feared complication after the Whipple procedure was the development of a pancreatic leak from the pancreatic-enteric anastomosis. Mortality rates secondary to a pancreatic leak have been reported to be as high as 40% (Lerut et al. 1984; Herter et al. 1982; Aston and Longmire 1973). Death was usually secondary to overwhelming sepsis or delayed hemorrhage. Mortality secondary to a pancreatic leak has markedly diminished with CT-guided drainage of abdominal fluid collections, advanced antibiotics, and nutritional support; however, improved outcomes are most likely due to better attention to technical factors affecting the integrity of the anastomosis. Technical approaches regarding reconstruction of the pancreatic-enteric anastomosis have included anatomic variations of the anastomosis such as a pancreaticogastrostomy instead of the traditional pancreaticojejunostomy. Retrospective studies have shown a slightly higher pancreatic leak rate and mortality rate in patients when a pancreaticojejunostomy was performed (Schlitt et al. 2002). However, randomized prospective studies have shown no difference in leak rates when a pancreaticogastrostomy or pancreaticojejunostomy is performed (Yeo et al. 1995). Other technical considerations include the type of pancreatic to intestinal anastomosis done with variations of an invagination technique (end of pancreas invaginated into either the end or side of the jejunum) vs. a duct-to-mucosa technique between the main pancreatic duct and the jejunal mucosa. All have proven to be safe and effective with no clear advantage of one over another (Sikora and Posner 1995). Randomized prospective trials have shown no difference in duct-to-mucosa or end-to-side anastomosis in patients who have a pancreaticojejunostomy after pancreaticoduodenectomy (Bassi et al. 2003). Anastomotic stents have also been used in the pancreatic duct but do not seem to affect fistula rates (Sikora and Posner 1995; Balcom et al. 2001). Prophylactic pharmacologic approaches employing somatostatin analogs have been used in Europe and the United States with conflicting results (Bassi et al. 2000; Yeo et al. 2000). Two recent prospective clinical trials from the M.D. Anderson Cancer Center and Johns Hopkins Hospital have failed to show any benefit for prophylactic octreotide therapy (Yeo et al. 2000; Lowy et al. 1997). Topical agents with sealants such as fibrin glue have not justified the extra costs with appreciable reductions in leak rates. Factors most likely associated with increased leak rates include the type of primary tumor and texture of the pancreatic gland remnant. Anastomotic leaks are, in general, more likely in patients with ampullary and primary duodenal neoplasms compared to those with primary pancreatic cancers. The latter are thought to induce a fibrotic, sclerosing reaction in the substance of the gland and therefore actually make the anastomotic suture lines more secure. Regardless of which technique is used, most pancreatic surgeons now pay careful attention to preserving the blood supply around the end of the pancreas and performing anastomosis with meticulous fine suture techniques. In patients receiving neoadjuvant or adjuvant chemoradiation, anastomotic complications are not significantly increased. However, these patients are at risk
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for the subsequent development of pancreatic enzyme insufficiency and require periodic clinical evaluations to avoid the potential metabolic consequences of malabsorption and steatorrhea (Ohtsuka et al. 2001).
7.3.5 Surgical Morbidity and Mortality Several studies have assessed the impact of referral to high-volume centers on morbidity and mortality after pancreaticoduodenectomy (Raval et al. 2010). The development of regional referral centers, with a high volume of procedures (>40 resections per year) performed by surgeons specializing in this operation is one of the main reasons for the decrease in mortality noted in recent series. In high-volume centers, perioperative mortality rates are 1–4%. Systemic, rather than surgical, complications now cause the majority of perioperative deaths. Predictors of surgical mortality include intraoperative blood loss, preoperative serum bilirubin level, diameter of the main pancreatic duct, and postoperative complications (Bilimoria et al. 2008). Not only postoperative mortality but also morbidity, hospital stay, and cost are reduced in high-volume centers. Most complications respond to nonoperative treatment; however, complications that require reoperation are still associated with a mortality rate of 23–67%. Resection rates in explored patients and overall survival rates are also significantly higher at high-volume centers. The most common complication following pancreatic resection is delayed gastric emptying, with an incidence of 50–70%. Although other complications, such as pancreatic leak, can predispose to delayed gastric emptying, it can occur without other morbidity. Intravenous erythromycin can reduce the incidence of delayed gastric emptying by up to 37%. The incidence of postoperative pancreatic fistula is 2–24%. However, the definition of a fistula varies (Ujiki and Talamonti 2005). Low-output fistulas, defined as fistulas of a volume less than 100 mL/day, even with elevated fluid amylase levels, are probably of little clinical significance. These problems rarely delay the resumption of normal oral intake and should not significantly delay discharge or adjuvant treatments. High-output fistulas with volumes greater than 100 cc/day and with amylase levels greater than 1,000 U/dL may require a period of conservative management with bowel rest, octreotide therapy, and nutritional support. In the absence of a complete dehiscence of the pancreatic-jejunal anastomosis, reoperation is rarely required. The mortality rate can be as high as 28% and the usual cause of death is retroperitoneal sepsis or hemorrhage. Most series have not identified a risk factor that predisposes to leakage; however, some report that soft pancreatic parenchyma, small pancreatic duct diameter, ampullary carcinoma, and the anastomotic method used are predisposing factors. Intra-abdominal abscess following pancreatic resection occurs in 1–12% of patients. The usual cause is a leak from the pancreatic-enteric anastomosis. CT usually diagnoses the abscess, and image-guided drainage is usually successful. Postoperative hemorrhage occurs in 2–15% of patients after pancreatic resection (Ujiki and Talamonti 2007). Bleeding within the first 24 h postoperatively is usually a result of inadequate intraoperative hemostasis or hemorrhage from one of the enteric anastomoses. Anastomotic hemorrhage can usually be treated conservatively; however, hemorrhage into
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the peritoneum requires re-exploration. Hemorrhage later in the postoperative period is usually due to stress ulceration or erosion of a retroperitoneal vessel from an anastomotic leak, the latter being much more serious with a mortality rate of up to 58%. In some cases, embolization alone may suffice as treatment; otherwise more dramatic measures such as re-exploration and revision of the anastomosis or, in the worse-case scenario, completion total pancreatectomy may be required. The impact of these complications has significant treatment implications. Delay in postoperative adjuvant therapy due to prolonged recovery is frequent following surgical complications (Bilimoria et al. 2009). Decline in general performance status and in the parameters used to measure nutritional status is the rule rather than the exception in patients with severe complications. Indeed, most clinical trials to assess the impact of adjuvant chemoradiation after pancreaticoduodenectomy find that 20–25% of patients are unable to complete a full course of planned therapy, secondary to the debilitating effects of operative complications.
7.4 Adjuvant Therapy for Pancreatic Adenocarcinoma Despite improved perioperative outcomes after surgical resection and improved estimated five-year survival rates after potentially curative surgery, the vast majority of patients experience recurrence. Significant risk factors for recurrence after surgical resection for pancreatic adenocarcinoma include lymph node-positive disease and involved surgical margins. Outcomes for these patients are significantly worse than those for patients with negative resection margins and lymph node-negative disease. Unfortunately, over 75% of resected specimens will demonstrate nodal metastases, microscopic margin involvement, or both, underscoring the imperative need for an effective adjuvant therapy. Results from the several published prospective and retrospective series evaluating the role of adjuvant chemoradiation are shown in Table 7.1. In the United States, adjuvant chemoradiation has been considered to be the standard of care for more than 20 years by many clinicians. The rationale for this, however, lies in the findings of the randomized Gastrointestinal Tumor Study Group (GITSG) study initially published in 1985 (Kalser and Ellenberg 1985). This trial, which randomized a total of 49 patients between 1974 and 1982, enrolled only patients with negative surgical margins and who had pancreatic adenocarcinoma confirmed by histology (excluding patients with periampullary carcinoma, islet cell carcinoma, or cystadenocarcinoma). Patients were randomized after resection to receive 5-fluorouracil (5-FU) chemotherapy plus radiotherapy or observation alone. Patients were stratified at the time of randomization by the type of surgical procedure, degree of differentiation, stage of disease, and location of primary tumor. Ninety-five percent of patients had primary cancer of the head of pancreas, and 28% had node-positive disease. Radiotherapy was given in two courses of 20 Gy each, separated by a two-week interval, for a total of 40 Gy. Chemotherapy with 5-FU (500 mg/m2 intravenous bolus) was administered at the beginning of each course of radiotherapy for three consecutive days and then continued on a once-weekly basis for two years or until disease recurrence was
Pancreas only
289
Multi-institutional, 2 × 2 factorial/ randomized, no therapy vs. chemotherapy vs. chemoradiotherapy
Multi-institutional, randomized therapy vs. no therapy
218
EORTC (Klinkenbijl Pancreatic head et al. 1999) (55%) or/ periampullary cancer
ESPAC-1 (Neoptolemos et al. 1997, 2001, 2004, 2009a)
Single-institution, prospective nonrandomized therapy vs. intensive therapy vs. no therapy
174
Pancreas only (head, neck, or uncinate)
Johns Hopkins (Yeo et al. 1997)
Multi-institutional, randomized therapy vs. no therapy
43
Pancreas only (95% head)
GITSG (Kalser and Ellenberg 1985)
5-FU 425 mg/m2 plus FA 20 mg/m2/day for 5 days every 28 days × 6
(continued)
Median overall survival: chemoRT vs. no chemoRT – 15.9 vs. 17.9 months p = not reported Chemotherapy vs. no chemo –20.1 vs. 15.5 months p = not reported
40 Gy split course 5-FU 500 mg/m2 for 3 – 20 Gy × 2, 2 days with each course weeks apart of RT or/
Median overall survival, therapy vs. none: 19.5 vs. 13.5 months p = 0.003 Median overall survival, intensive vs. regular: 17.5 vs. 21 months p = NS Median overall survival, therapy vs. none: 24.5 vs. 19.0 months p = 0.208 17.1 vs. 12.6 months p = 0.099 (head of pancreas only)
5-FU 500 mg/m2 for 3 days each, and then weekly for 4 months (std) vs. 5-FU 200 mg/m2 plus FA 5 mg/m2 5/7 days CI for 4 months (intense)
Median overall survival, therapy vs. none: 21 vs. 11 months p = 0.03 2 year survival: 43 vs. 19%
Results
40 Gy split course 5-FU 25 mg/kg for 3–5 days by CI with each – 20 Gy × 2, 2 course of RT only weeks apart
40–45 Gy split course (std) vs. 50–57 Gy continuous, plus 23–27 Gy to the liver (intense)
40 Gy split course 5FU 500 mg/m2 for 3 – 20 Gy × 2, 2 days with each course weeks apart of RT and then weekly for 2 years
Table 7.1 Results from recent prospective and retrospective series of adjuvant therapy for resected pancreatic cancer Study Disease sites Number of Design Radiation therapy Chemotherapy patients
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Multi-institutional, randomized, 5FU plus FA vs. GEM
Multi-institutional, randomized, 5-FU vs. GEM used pre- and post-5-FU/ RT
1,088
451 (388 head)
616
Pancreas only
Pancreas only, all sites and head only
ESPAC-3 (Neoptolemos et al. 2009b)
RTOG 97-04 (Regine et al. 2008)
Johns Hopkins Pancreas only (Herman et al. 2008)
Single institution, retrospective analysis of adjuvant chemoRT vs. none
Multi-institutional, randomized therapy vs. no therapy
368
Pancreas only
CONKO-001 (Neuhaus et al. 2008; Neoptolemos et al. 2009b)
Design
Number of patients
Disease sites
Table 7.1 (continued) Study
5-FU 425 mg/m2 plus FA 20 mg/m2 days 1–5 every 28 days GEM 1,000 mg/m2 Days 1, 8, and 15 every 4 weeks, both 6 months 5-FU 250 mg/m2 CI throughout RT (both arms)
None
45 Gy by continuous fractionation to tumor bed and nodes, with boost to 50.4 Gy tumor bed
Varied. Majority received 50 Gy by continuous fractionation
GEM 1,000 mg/m2 days 1, 8, and 15 every 4 weeks for 6 months
None
Varied. Majority received CI 5FU with RT followed by 5FU for 2–6 months
5-FU 250 mg/m2 CI; GEM 1,000 mg/m2 Days 1, 8, and 15 every 4 weeks, both 3 weeks before and 3 months after RT
Chemotherapy
Radiation therapy
Median overall survival, chemoRT vs. none: 21.2 vs. 14.4 months, p < 0.001
Median overall survival: no difference at 5 years; planned subset analysis of head of pancreas only, GEM vs. 5-FU: 20.5 vs. 16.9 months p = 0.09
Log-rank analysis=0.7, p = 0.39 HR (gem) = 0.94
Median overall survival, 5-FU/FA vs. GEM: 23.0 vs. 23.6 months
Median overall survival, therapy vs. none: 22.8 vs. 20.2 months p = 0.005 Median DFS, therapy vs. none: 13.4 vs. 6.9 months p < 0.001
Results
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Pancreas – head only
ACOSOG Z05031 (Picozzi et al. 2008)
89
472 – 466 eligible
Multi-institutional phase II study
Single institution, retrospective analysis of adjuvant chemoRT vs. none 50.4 Gy by continuous fractionation
Varied. 93% of patients received 45–55 Gy, median 50.4 Gy
Median overall survival, chemoRT vs. none: 25.2 vs. 19.2 months p = 0.001
Median overall survival: 27.1 months (95% confidence interval 23.4–33.6 months) 31.8 months if all treatment cycles begun
Varied. 98% received concurrent fluorouracil with RT and 10.4% received additional chemotherapy Cisplatin 30 mg/m2 weekly × 6, 5FU 175 mg/m2 CI days 1–38, INT 3 million units MWF during RT;
chemoRT chemotherapy plus radiation therapy; Gy gray; CI continuous infusion; HR hazard ratio; DFS disease free survival; INT interferon alpha; FA folinic acid; NS not significant; 5FU 5 fluorouracil; RT radiation therapy
Pancreas only
Mayo Clinic (Corsini et al. 2008)
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noted. With 43 patients in the final analysis, median survival was improved (21 vs. 11 months) with the addition of adjuvant therapy, and this did meet statistical significance (p = 0.035). This trial has been extensively criticized because of its small numbers, slow accrual, the use of outdated split course radiation, and a delay of more than 10 weeks in starting adjuvant therapy in 25% of patients. The only other prospective study in the United States that compared adjuvant chemoradiation with surgical resection alone for pancreatic adenocarcinoma is a nonrandomized study from Johns Hopkins (Yeo et al. 1997). Patients were allowed to choose between standard therapy (similar to that used in the GITSG study), intensified therapy (intensified radiation therapy to pancreatic bed and liver with infusional 5-FU), or observation alone. The majority of patients chose standard therapy and those that received adjuvant chemoradiation showed an improvement in overall survival (19.5 months vs. surgery, 13.5 months, p = 0.003), with no difference seen between the two chemoradiation arms. The Gastrointestinal Tract Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC) published a phase III trial comparing radiotherapy plus 5-FU with observation alone in the adjuvant setting (Klinkenbijl et al. 1999). Two hundred eighteen patients were randomized from 1987 to 1995, to receive either observation alone or a combination of 5-FU as a continuous infusion (CI) concomitantly with radiotherapy. After chemoradiation was completed, patients were followed and received no more chemotherapy unless they relapsed. The median survival was 19 months for the observation group and 24.5 months for the treatment group, but this result was not statistically significant (p = 0.208) and was further confounded by the inclusion in this trial of patients with periampullary tumors, who made up almost half of the cohort. In a subset analysis, there was a nonsignificant trend toward improved survival in the pancreatic cancer cohort when adjuvant therapy was given (17.1 vs. 12.6 months, p = 0.099) (Klinkenbijl et al. 1999). More recent data from European trials show a significant role for adjuvant systemic chemotherapy, but have raised considerable controversy regarding the role for adjuvant chemoradiation in pancreatic adenocarcinoma. The European Study Group for Pancreatic Cancer (ESPAC-1) trial was designed to answer several questions about adjuvant therapy for pancreatic cancer (Neoptolemos et al. 1997). This complex trial was initially constructed with a 2 × 2 factorial design to compare adjuvant chemoradiation, 6 months of adjuvant chemotherapy, and a combination of these, with an additional observation control arm. The results of this trial were published sequentially over the course of several years (Neoptolemos et al. 1997, 2001, 2004, 2009a). In the chemoradiation group, a course of 40 Gy was given with 5-FU as a sensitizing agent, using the same schedule and doses as were used in the GITSG trial. In the chemotherapy arm, patients received folinic acid with bolus 5-FU at a dose of 425 mg/m2 for five consecutive days every 28 days for six cycles. Patients randomized to both treatment arms were to receive chemoradiation first, followed by the full course of chemotherapy. Patients were stratified by margin status at initial randomization. For the overall group, the two-year survival for those receiving chemotherapy was 40% and for those not receiving chemotherapy, 30% (no p value reported). The two-year survival rate for patients receiving chemoradiation was 29%, compared with 40% for those not receiving chemoradiation. For chemotherapy randomization, a secondary end-point analysis demonstrated that the hazard ratio (HR) for death was statistically
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significantly improved in patients receiving chemotherapy compared with those not receiving chemotherapy (HR = 0.71, p = 0.0009), and median survival for the chemotherapy arm was 20.1 vs. 15.5 months for the no-chemotherapy arm, with no p values reported. The same analysis was performed in the chemoradiation arm, and this analysis suggested worse outcomes for patients receiving chemoradiation, with an HR for death of 1.28 (p = 0.05). Median survival was 15.9 months for patients receiving chemoradiation and 17.9 months for patients who did not receive chemoradiation. Five-year survival rate was 21% among patients who received chemotherapy and 8% among patients who did not receive chemotherapy (p = 0.009), and it was 10% among patients randomized to receive chemoradiation and 20% among patients who did not receive chemoradiation (p = 0.05). Patients in the 2 × 2 factorial design who received adjuvant chemoradiation actually fared significantly worse than those undergoing surgery alone. In contrast, however, those who received adjuvant systemic chemotherapy had an increased overall survival compared with those who underwent surgery alone. When both the 2 × 2 factorial arm and single randomization arms were analyzed for prognostic factors, the benefit of chemotherapy appeared most pronounced in patients with well-differentiated tumors, lymph node-positive disease, and margin-negative resections. The detrimental effects of chemoradiation in Europe aside, this study has been widely criticized in the United States because of its complicated design, the lack of statistical power in the 2 × 2 design, and the lack of radiation quality controls (Backlund et al. 2010). The Charite Onkologie (CONKO)-001 is a multicenter trial based in Germany comparing adjuvant chemotherapy with gemcitabine (GEM) vs. observation alone following pancreatic resection. Patients were randomized on a 1:1 basis and stratified for resection status (R0 vs. R1), T status (T1–2 vs. T3–4), and nodal status (N-positive vs. N-negative). Patients in the GEM group received three weekly infusions of GEM at a dose of 1,000 mg/m2 for three weeks on and one week off, for a total of six cycles. The primary endpoint of the trial was disease-free survival, with a secondary endpoint of overall survival. Estimated disease-free survival was 13.4 months in the GEM group compared with 6.9 months in the control group (p < 0.001), and this benefit was seen regardless of margin status, tumor size, or nodal involvement (Oettle et al. 2007). At the time of initial publication, there was no statistically significant benefit seen in overall survival numbers, but a subsequent update demonstrated that patients receiving adjuvant GEM had a median survival rate of 22.8 months vs. 20.2 months for patients receiving observation alone (p = 0.005). Estimated five-year survival for the GEM arm was 21% compared with 9% for the observation arm (Neuhaus et al. 2008). The ESPAC-3 trial evaluated the use of adjuvant 5-FU and leucovorin (425 and 20 mg/ m2, respectively, daily for five days per month) vs. GEM (1,000 mg/m2 weekly for three out of four weeks), both for six months in an attempt to clarify the optimal agent in the adjuvant setting (Neoptolemos et al. 2009b). Thousand hundred and eighty-eight patients were randomized and at 34 months, there was no statistical difference in the median survival (23 vs. 23.6 months). There was, however, more toxicity in the 5-FU/ leucovorin arm (10% vs. 0% grade 3–4 toxicity) and this suggests that GEM, when used as a single agent, is the superior therapy on the basis of similar results but less toxicity. The largest multigroup trial in the United States to address chemotherapy and chemoradiation was the Radiation Therapy Oncology Group (RTOG) Trial 97-04. RTOG 97-04
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was a large intergroup trial conducted by the RTOG, the Eastern Cooperative Oncology Group (ECOG), and the Southwest Oncology Group, inclusive of Canadian affiliates (Regine et al. 2008). This trial included 451 patients with pancreatic adenocarcinoma, with 75% of patients having T3 and T4 disease and approximately 66% of patients having node-positive disease. One-third of patients had positive margins. Randomization was performed after surgery and was stratified by tumor diameter (<3 cm or ³3 cm) and surgical margins (33% of patients had positive surgical margins). Patients were randomly assigned to either 5-FU (group 1) or GEM (group 2). Chemotherapy before chemoradiation in group 1 consisted of CI 5-FU (250 mg/m2) daily for 3 weeks, and in group 2 consisted of a 30-min infusion of GEM (1,000 mg/m2) once weekly for three weeks. Within the next two weeks, both groups began identical chemoradiation regimens (50.4 Gy with CI of 250 mg/m2 of 5-FU daily through the course of radiotherapy). An additional phase of chemotherapy was initiated 3–5 weeks after the completion of chemoradiation, with group 1 receiving three months of infusional 5-FU daily for the next three months (four weeks on and two weeks off for two cycles) and group 2 receiving three months of GEM (three weeks on and one week off). Prospective quality assurance procedures were used, including central review of preoperative CT scans and radiation therapy fields, before the initiation of chemoradiation. For the final analysis, 451 evaluable patients were included, and there was found to be no difference in the overall or disease-free survival rates among treatment groups. As part of the second primary objective study, a subgroup analysis of patients with tumors in the head of the pancreas was performed, and these patients had a median survival of 20.5 months and a three-year survival rate of 31% in the GEM group compared with 16.9 months and 22% in the 5-FU group (HR = 0.82, p = 0.09). However, after adjusting for prespecified stratification variables of nodal status, tumor diameter, and surgical margin status, the treatment effect yielded an HR of 0.80 (p = 0.05). Although complicated by crossover to treatment with GEM when recurrence developed, this study suggests a mild advantage for GEM over 5-FU in the adjuvant setting for tumors in the head of the pancreas (Regine et al. 2008). Recently, large retrospective series from Johns Hopkins and Mayo Clinic have suggested that the use of adjuvant 5-FU-based chemoradiation significantly improves overall survival compared with that in patients undergoing surgery alone (Corsini et al. 2008; Herman et al. 2008). In the study from Johns Hopkins, analysis of 616 patients showed that the benefit of chemoradiation was independent of several risk factors including tumor size, grade, margin, and nodal status. Adjuvant chemoradiation improved survival for both margin-negative and margin-positive patients (median 21.2 vs. 14.4 months, p < 0.001). In addition, lymph node-positive patients appeared to have significant benefit with adjuvant chemoradiation, and lymph node-negative patients did not. But by multivariate analysis, the interaction between nodal status and treatment was not significant (Herman et al. 2008). The recently reported Mayo Clinic experience of 472 patients who underwent R0 resection also showed a significant survival benefit with the use of adjuvant 5-FU based chemoradiation (median 25.2 vs. 19.2 months, p = 0.001). This benefit was present for both lymph node-positive and lymph node-negative disease (Picozzi et al. 2010). Although both these trials support the findings of a benefit of adjuvant chemoradiation, they were nonrandomized single-institution studies.
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A multi-institutional phase II study which provoked considerable interest was the recently reported ACOSOG study based on the adjuvant use of 5-FU (175 mg/m2 CI daily), interferon alpha (3 million units three times a week) and cisplatinum (30 mg/m2 weekly × 6 doses) with concurrent RT (50.4 Gy) (Picozzi et al. 2010). This was intended to be a confirmatory study based on an earlier single-institution evaluation of this regimen which had proven remarkably effective but also quite toxic. The original regimen was modified by decreasing the 5-FU and interferon dose, but study accrual was nonetheless terminated after accrual of 89 out of an intended 93 patients owing to excessive toxicity. Provocatively, at two years median follow-up, 67% of patients were alive 18 months from study registration. Median survival was 27.1 months overall (CI 23.4–33.6 months) and 31.8 months if all treatment cycles had been begun. The challenges in the study of adjuvant therapy after pancreaticoduodenectomy are readily apparent in the analysis of the above studies. Patient accrual is slow, and selection criteria are inconsistent and often poorly defined. Stratification criteria often inhibit adequate numbers of patients to enrollment and thus preclude sufficient power to determine significance between patient subgroups. Crossover treatment after recurrence prevents clear delineation between 5-FU vs. GEM-based protocols. Nonetheless, certain conclusions can probably be drawn from the above-mentioned studies, albeit with more than a modicum of restraint. Adjuvant therapy after potentially curative pancreatic resection appears warranted though the most effective form of therapy (chemotherapy alone vs. chemoradiation) remains to be determined. The benefit of local-regional control with added radiation therapy for patients at lower risk for early disseminated disease, but with concern for local recurrence, may justify the potential added morbidity of combined modality therapy. There does not appear to be a marked advantage to GEM over 5-FU as the best radiation sensitizer. Systemic therapy with full-dose GEM as the early or initial treatment for patients at risk for early distant recurrence appears warranted and probably has some survival advantage, though small, over surgery alone. Future trials will need to address the controversy of chemotherapy alone as the adjuvant therapy of choice vs. chemoradiation with or without systemic therapy before or after radiation. GEM should be considered the more effective baseline systemic chemotherapeutic agent by which to compare other treatment arms (Backlund et al. 2010).
7.5 Neoadjuvant Therapy for Localized and Borderline Resectable Pancreas Cancer The rationale for neoadjuvant therapy in pancreatic cancer is multifold. Preoperative chemotherapy or radiation may theoretically downstage disease by (1) sterilizing peripheral extent of tumor infiltration, resulting in fewer R1 margin-positive resections, (2) decreasing tumor volume such that borderline-resectable disease may become more easily resectable, and (3) minimizing regional nodal disease/tumor burden such that locoregional recurrence is reduced. Furthermore, patients who receive neoadjuvant therapy are more likely to complete their full course of chemotherapy and radiation
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when compared to patients given postoperative chemoradiation; between 21 and 30% of patients undergoing pancreaticoduodenectomy may not complete adjuvant chemoradiation due to postoperative morbidity or patient refusal (Spitz et al. 1997). Additionally, chemoradiation administered to undissected, well-oxygenated tissue may maximize any cytotoxic benefit gained from treatment. Perhaps most importantly, patients who exhibit disease progression during their neoadjuvant therapy self-select themselves as poor responders who are least likely to gain benefit from resection and may forego the morbidity of pancreatic resection. Lastly, preliminary analysis of the cost effectiveness of a neoadjuvant vs. adjuvant approach suggests that the neoadjuvant approach may be superior in this regard. Each of these clinical justifications is relevant in pancreatic cancer, as the aggressive and unforgiving nature of this disease leaves little margin for mismanagement or over/under treating (Abbott et al. 2010).
7.5.1 Resectable Disease Patients with clinically localized disease who undergo successful resection and on pathologic review are found to have clear resection margins (R0) and no evidence of nodal metastases have a relatively favorable prognosis compared to patients with either marginpositive resections (R1 or R2) or nodal and regional disease. Thus, those patients with limited disease found on noninvasive imaging are those most likely to survive, with a corollary that these patients are most likely to benefit further from advances in neoadjuvant therapies. There is a growing body of literature examining neoadjuvant strategies in this selected subgroup of patients who by definition have no imaging evidence of nodal disease, disruption of local planes, or extension of tumor outside the pancreas (Spitz et al. 1997; Abbott et al. 2010; Yeung et al. 1993; Hoffman et al. 1998; Moutardier et al. 2004; White and Tyler 2004; Mornex et al. 2006; Evans et al. 2008; Talamonti et al. 2006). In 1997, Spitz et al. reported the MD Anderson Cancer Center experience, providing preoperative 5-FU-based chemoradiation to patients with potentially resectable tumors based on high-quality imaging and comparing outcomes with those receiving postoperative combined modality therapy (Spitz et al. 1997). Of the 91 patients in the neoadjuvant therapy cohort, 26% exhibited disease progression during therapy and were not offered operative intervention. Of the remaining 67 patients, 41 were treated according to study protocol (chemoradiation followed by resection). Median survival in this cohort was 19.2 months compared to 22 months in the postoperative adjuvant cohort, despite postoperative therapy patients more frequently having a microscopically positive margin and positive regional lymph nodes on final histologic examination. This lack of survival benefit in the neoadjuvant cohort may be explained by bias in their selection criteria; to be included in this treatment arm, patients were required to have histologically proven pancreatic adenocarcinoma and a hypodense mass in the pancreatic head; those without CT evidence of a mass or biopsy-proven pancreatic cancer were given postoperative chemoradiation. Because the two treatment arms were neither matched nor randomized, it is difficult to derive definitive conclusions regarding efficacy from these data. Certainly, the study did confirm the feasibility and safety of a neoadjuvant approach. Of note, this study also
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detailed the high GI toxicity of standard 5.5-week radiation therapy (32% of patients required hospital admission) and the better tolerated two-week, rapid fractionation that evolved from this finding. Lowy, in his recent review of adjuvant and neoadjuvant therapy for pancreatic cancer, outlined twelve studies published between 1993 and 2006 that evaluate a variety of preoperative chemoradiation regimens (Lowy 2008). As noted, early studies were largely 5-FU-based, with or without mitomycin-C, while more recent investigations either added, or replaced 5-FU with, GEM. Radiation schema usually delivered between 30 and 50.4 Gy with fairly wide treatment fields including prophylactic regional nodal radiation. Primary outcomes reported include percent of patients resected following neoadjuvant therapy (range 38–85%) and median survival (range 12–36 months). No correlation between dose of preoperative radiation and resectability or survival has been demonstrated, nor was the addition of mitomycin-C to chemotherapeutic regimens related to increased survival. It is noteworthy that two of the three studies that added cisplatin to their 5-FU-based neoadjuvant therapy demonstrated survival at the higher end of the twelve-study range (23 and 27 months) (Moutardier et al. 2004; White and Tyler 2004). Furthermore, the use of GEM in the preoperative protocol of three studies was associated with 20-, 26-, and 34-month median survival, again much longer survival than most 5-FU-based reports (Evans et al. 2008; Talamonti et al. 2006; Lowy 2008; Meszoely et al. 2004). Talamonti reported 20 patients in a multicenter trial utilizing 36 Gy of limited field radiation and full-dose GEM (1, 000 mg/m2) (Talamonti et al. 2006). This trial reported an 85% resectability rate and a median survival of 26 months. These data are consistent with earlier Phase I trials and animal models which demonstrate that GEM is an excellent radiosensitizer (when compared to 5-FU) and that its use may portend increased survival for patients who are operative candidates. A large series from the MD Anderson Cancer Center expanded on these outcomes using GEM-based neoadjuvant chemoradiation. In 2008, Evans et al. described the administration of GEM (7 weeks, 400 mg/m2) and rapid-fraction radiation therapy (30 Gy over 2 weeks) in patients with resectable pancreatic cancer (Evans et al. 2008). While 26% of patients either exhibited disease progression or were deemed unresectable at surgery, a full 74% of patients underwent successful resection. Median survival for these patients was 34 months compared to only 7 months for patients who had unresectable disease. This substantial median survival compares very favorably to nearly all other neoadjuvant regimes, demonstrating the best median survival for patients undergoing neoadjuvant therapy for resectable pancreatic cancer. Varadhachary et al. reported outcomes in a cohort of patients who received four doses of GEM-cisplatin in addition to the standard preoperative GEM and rapid fractionation, 30-Gy radiation therapy (GEM 400 mg/m2 weekly × 4 concomitant with RT, and GEM 750 mg/ m2 with cisplatin 30 mg/m2 every 2 weeks × 4 prechemoRT) (Varadhachary et al. 2008). This extra treatment period did not adversely affect tumor progression, though patients did require more durable biliary decompression. In the 88% of patients who completed chemoradiation, 66% underwent resection. The median survival in resected patients was 31 months vs. only 10.5 months in the unresected group. The authors’ conclusions, when comparing median survival to the similar cohort described by Evans et al. (34 months) (Evans et al. 2008), were that the addition of GEM-cisplatin to GEM-based neoadjuvant chemoradiation was not efficacious in extending survival.
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The omission of radiation therapy and the accentuation of neoadjuvant chemotherapy is a novel strategy with recent support (Heinrich et al. 2008). Heinrich et al demonstrated the feasibility of delivering GEM with cis-platinum and no radiation therapy in a recent phase II trial. The regimen was well tolerated, graded histologic tumor responses were comparable to chemoradiation protocols, and there was no added surgical morbidity. This strategy of neoadjuvant chemotherapy alone for resectable pancreas cancer is under investigation in a current American College of Surgeons Oncology Group clinical trial, Z5041, which is examining GEM plus erlotinib both pre and postsurgery. In examining these data on neoadjuvant therapy for resectable pancreatic cancer on the whole, it is important to note that there are no randomized, prospective trials evaluating either 5-FU- or GEM-based chemoradiation in a neoadjuvant setting. Despite this shortcoming, many researchers have noted a median survival that exceeds traditionally recognized survival for operable pancreatic cancer and this should serve as the paradigm on which further clinical trials are based.
7.5.2 Borderline Resectable Strategies Most studies that address neoadjuvant chemoradiation for borderline resectable or locally advanced tumors prior to 2005 include patients who have visceral vessel abutment or encasement (again a vague distinction for study purposes) with relatively low subsequent resection rates ranging from 1 to 29% (Snady et al. 2000; Kim et al. 2002). In these reports, there was significant variability in treatment regimens, at times including the use of some or all of the following agents: external beam radiation therapy (EBRT), 5-FU, streptozotocin, cisplatin, mitomycin-C, leucovorin, and dipyridamole. Utilizing a variety of preoperative chemoradiation strategies, median survival ranged from 10 to 32 months depending on patient cohort and inclusion criteria used (Pipas et al. 2005; Kamthan et al. 1997; Ammori et al. 2003; Aristu et al. 2003; Joensuu et al. 2004). There are a number of more recent studies that have helped to refine our understanding of optimal neoadjuvant treatment strategies for borderline resectable disease. Two studies from Japan highlight their experience with preoperative chemoradiation for borderline resectable pancreatic cancer. In the first, 32 patients with <50% of SMA encasement and no cavernous transformation or thrombosis of the SMV–portal vein confluence were treated with EBRT (40 Gy) and either 5-FU/cisplatin- or GEM (400 mg/m2)-based chemotherapy (Takai et al. 2008). Twenty-four of the 32 patients underwent definitive resection, with median survival of 26 and 20 months for 5-FU/cisplatin and GEM treatment strategies, respectively (p = NS). A caveat in interpreting this study is the lack of clarity in the study arm, as patients may belong to either “resectable” or “borderline resectable” according to expert consensus criteria highlighted above. The second study from the same group retrospectively examined 68 patients with pancreatic adenocarcinoma who were initially found to have extra-pancreatic disease (T3/4 by AJCC staging) or borderline disease by previous NCCN criteria (Satoi et al. 2009). Utilizing the same neoadjuvant regimen described in their previous study (40 Gy EBRT with 5-FU/cisplatin or GEM at 400 mg/m2), 35 patients (19 potentially resectable and 16 locally advanced) received
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preoperative chemoradiation without adjuvant therapy. Following neoadjuvant therapy, 79% of patients underwent surgical resection. Median survival was 24.5 months in the resected group in the neoadjuvant arm compared to 18.5 months in a historical control surgery-alone group. A retrospective review from MD Anderson, published in 2008, details the preoperative classification, administration of therapy, and subsequent response (with or without the addition of surgery) in 160 patients (Katz et al. 2008). Many were deemed to have borderline resectable disease (proximity/abutment/encasement of visceral vessels – Group A). However, the authors submitted that two additional subsets of patients exist; those with questionable metastatic disease (Group B) and those who display either a suboptimal performance status or have prohibitive medical comorbidities and who are not initially surgical candidates (Group C). All 160 patients received either chemotherapy, chemoradiation, or both. This primarily consisted of either 50.4 or 30 Gy of EBRT with radiosensitizing doses of either 5-FU, paclitaxel, GEM, or capecitabine. Resection rates following neoadjuvant therapy were 38, 50, and 38% in groups A, B, and C, respectively. Furthermore, resected patients in groups A, B, and C exhibited 40/29/39-month median survivals compared with 15/12/13-month median survivals for unresected patients, respectively. This important study certainly does not demonstrate an obvious benefit of one treatment regimen vs. another, but does clearly make two salient points. Firstly, patients with stringently defined borderline resectable disease who respond to neoadjuvant therapy and undergo definitive surgical therapy have a significant survival advantage compared to patients with unresectable disease. Secondly, and perhaps more provocatively, there are further subsets of patients, not encompassed by traditional AJCC criteria, who may equally benefit from a trial of neoadjuvant chemotherapy or chemoradiation therapy. Further studies will need to be done to validate these findings, but the notion of expanding the indications for neoadjuvant therapy for this disease warrants further investigation. Two small retrospective studies with a similar design examined the use of GTX (GEM, Taxotere, capecitabine) chemotherapy alone for three cycles followed by either 5-FU, or capecitabine plus/minus oxaliplatin, combined with RT prior to surgery in borderline resectable disease (Takai et al. 2008; Satoi et al. 2009). In the first study, 9 of 17 patients were able to undergo surgery, and 8 of 9 had an R0 resection. In the second, 14 of 16 completed a pancreaticoduodenectomy and 12 of 14 had an R0 resection. The numbers are too small to draw any meaningful conclusions about survival, but the results show that an intensive neoadjuvant approach is both feasible and safe and that selected patients with initially borderline resectable disease may have an R0 resection by this approach. It is fairly apparent that the optimal management of borderline resectable disease is less clearly defined than that of resectable disease, as evidenced by both relatively fewer studies addressing the issue as well the wider variability in treatment regimens and outcomes. Most importantly, the lack of consistency in defining study participants makes interpretation particularly dangerous. Certainly as treatment strategies become more disease-stage specific, efficacious, tolerable, and consistent, better data will exist to guide ongoing management. Many high-volume centers will now accept radiographic findings of a borderline resectable tumor as an indication for a neoadjuvant treatment strategy based on the possible survival benefits vs. a primary surgical approach for these patients. There does not yet
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exist consensus agreement as to the optimal treatment schema for neoadjuvant therapy in borderline resectable disease, though most investigators would now agree on a GEMbased regimen.
7.6 Summary The management of localized pancreatic cancer has progressed from a nearly purely surgical approach to increasingly effective multimodality treatment strategies. State-of-theart care now involves coordination of exquisite staging by radiology, appropriate use of interventional gastroenterology, optimized surgical outcomes, and individualized applications of chemotherapy and radiation oncology predicated upon prognosis and risk for recurrence. For the patient presenting with signs and symptoms of pancreatic cancer, initial staging studies should include high-quality three-dimensional radiologic imaging with either CT or MRI. There now exist definable and objective radiographic criteria to accurately categorize a nonmetastatic tumor as localized and potentially resectable, or surgically borderline based on limited vascular involvement, vs. locally advanced and unresectable with extensive regional involvement that would preclude complete resection of all gross disease. Surgical treatment with improved outcomes has probably been the most significant contribution to these patients in the last 25 years. Surgical advances include a more refined understanding of the importance of the regional lymphadenectomy, the imperative need to achieve an R0 or R1 resection margin near the vascular structures, and the necessity to optimize long-term quality of life issues with more functional resections and reconstructions such as the pyloric-preserving Whipple. Adjuvant chemotherapy with a GEM-based regime should now be considered the standard of care for postoperative patients with a sufficient performance status after a reasonable recovery period. The role of adjuvant radiation therapy remains one of the most controversial debates in gastrointestinal oncology. Data from several large European trials demonstrate that most patients do not derive marked benefit from adjuvant chemoradiation and may actually suffer a diminution in quality and length of life. Conversely, data from US trials and single-institution series suggest there are certain patients with relatively lower risk of early distant disease who would benefit from radiation for improved local and regional control. Developing criteria for these patients and defining the roles of adjuvant chemotherapy and chemoradiation will be the challenge and mandate for future trials. Patients with surgically borderline tumors as described in previous sections would most likely require advanced surgical techniques such as vascular resection and reconstructions if a complete resection is to be achieved. These are optimal candidates for novel neoadjuvant strategies that may improve resectability rates and the margin status of these surgical specimens. The impact of such aggressive strategies appears to be justified by currently available reports. Clearly, pancreatic cancer remains one of the most formidable challenges in medicine today. Advances have been made, but future improvements will come only with well-designed clinical trials addressing the roles of combined treatment strategies and the development of more effective biologic and chemotherapeutic agents.
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References Abbott DE, Baker MS, Talamonti MS (2010) Neoadjuvant therapy for pancreatic cancer: a current review. J Surg Oncol 101(4):315–320 Alexakis N, Halloran C, Raraty M, Ghaneh P, Sutton R, Neoptolemos JP (2004) Current standards of surgery for pancreatic cancer. Br J Surg 91(11):1410–1427 Ammori JB, Colletti LM, Zalupski MM, Eckhauser FE, Greenson JK, Dimick J et al (2003) Surgical resection following radiation therapy with concurrent gemcitabine in patients with previously unresectable adenocarcinoma of the pancreas. J Gastrointest Surg 7(6): 766–772 Aristu J, Canon R, Pardo F, Martinez-Monge R, Martin-Algarra S, Manuel Ordonez J et al (2003) Surgical resection after preoperative chemoradiotherapy benefits selected patients with unresectable pancreatic cancer. Am J Clin Oncol 26(1):30–36 Aston SJ, Longmire WP Jr (1973) Pancreaticoduodenal resection. Twenty years’ experience. Arch Surg 106(6):813–817 Bachellier P, Nakano H, Oussoultzoglou PD, Weber JC, Boudjema K, Wolf PD et al (2001) Is pancreaticoduodenectomy with mesentericoportal venous resection safe and worthwhile? Am J Surg 182(2):120–129 Backlund DC, Berlin JD, Parikh AA (2010) Update on adjuvant trials for pancreatic cancer. Surg Oncol Clin N Am 19(2):391–409 Balcom JHT, Rattner DW, Warshaw AL, Chang Y, Fernandez-del Castillo C (2001) Ten-year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization. Arch Surg 136(4):391–398 Barreiro CJ, Lillemoe KD, Koniaris LG, Sohn TA, Yeo CJ, Coleman J et al (2002) Diagnostic laparoscopy for periampullary and pancreatic cancer: what is the true benefit? J Gastrointest Surg 6(1):75–81 Bassi C, Falconi M, Salvia R, Caldiron E, Butturini G, Pederzoli P (2000) Role of octreotide in the treatment of external pancreatic pure fistulas: a single-institution prospective experience. Langenbecks Arch Surg 385(1):10–13 Bassi C, Falconi M, Molinari E, Mantovani W, Butturini G, Gumbs AA et al (2003) Duct-tomucosa versus end-to-side pancreaticojejunostomy reconstruction after pancreaticoduodenectomy: results of a prospective randomized trial. Surgery 134(5):766–771 Bilimoria KY, Bentrem DJ, Ko CY, Tomlinson JS, Stewart AK, Winchester DP et al (2007) Multimodality therapy for pancreatic cancer in the U.S.: utilization, outcomes, and the effect of hospital volume. Cancer 110(6):1227–1234 Bilimoria KY, Talamonti MS, Sener SF, Bilimoria MM, Stewart AK, Winchester DP et al (2008) Effect of hospital volume on margin status after pancreaticoduodenectomy for cancer. J Am Coll Surg 207(4):510–519 Bilimoria KY, Bentrem DJ, Lillemoe KD, Talamonti MS, Ko CY (2009) Assessment of pancreatic cancer care in the United States based on formally developed quality indicators. J Natl Cancer Inst 101(12):848–859 Bold RJ, Charnsangavej C, Cleary KR, Jennings M, Madray A, Leach SD et al (1999) Major vascular resection as part of pancreaticoduodenectomy for cancer: radiologic, intraoperative, and pathologic analysis. J Gastrointest Surg 3(3):233–243 Brunschwig A (1937) A one-stage pancreaticoduodenectomy. Surg Gynecol Obstet 65:681–684 Callery MP, Chang KJ, Fishman EK, Talamonti MS, William Traverso L, Linehan DC (2009) Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol 16(7):1727–1733 Chong M, Freeny PC, Schmiedl UP (1998) Pancreatic arterial anatomy: depiction with dual-phase helical CT. Radiology 208(2):537–542
198
M.B. Ujiki et al.
Conlon KC, Dougherty E, Klimstra DS, Coit DG, Turnbull AD, Brennan MF (1996) The value of minimal access surgery in the staging of patients with potentially resectable peripancreatic malignancy. Ann Surg 223(2):134–140 Corsini MM, Miller RC, Haddock MG, Donohue JH, Farnell MB, Nagorney DM et al (2008) Adjuvant radiotherapy and chemotherapy for pancreatic carcinoma: the Mayo Clinic experience (1975–2005). J Clin Oncol 26(21):3511–3516 Crile G Jr (1970) The advantages of bypass operations over radical pancreatoduodenectomy in the treatment of pancreatic carcinoma. Surg Gynecol Obstet 130(6):1049–1053 Crist DW, Sitzmann JV, Cameron JL (1987) Improved hospital morbidity, mortality, and survival after the Whipple procedure. Ann Surg 206(3):358–365 Delbeke D, Martin WH (2010) PET and PET/CT for pancreatic malignancies. Surg Oncol Clin N Am 19(2):235–254 Diederichs CG, Staib L, Glatting G, Beger HG, Reske SN (1998) FDG PET: elevated plasma glucose reduces both uptake and detection rate of pancreatic malignancies. J Nucl Med 39(6):1030–3 Evans DB, Lee JE, Pisters PW (2001) Pancreaticoduodenectomy (Whipple operation) and total pancreatectomy for cancer. In: Baker RJ, Fischer JE (eds) Mastery of surgery. Lippincott Williams & Wilkins, Philadelphia, pp 1299–1318 Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW et al (2008) Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 26(21):3496–3502 Forsmark CE, Lambiase L, Vogel SB (1994) Diagnosis of pancreatic cancer and prediction of unresectability using the tumor-associated antigen CA19-9. Pancreas 9(6):731–734 Freeny PC, Traverso LW, Ryan JA (1993) Diagnosis and staging of pancreatic adenocarcinoma with dynamic computed tomography. Am J Surg 165(5):600–606 Friess H, Kleeff J, Silva JC, Sadowski C, Baer HU, Buchler MW (1998) The role of diagnostic laparoscopy in pancreatic and periampullary malignancies. J Am Coll Surg 186(6):675–682 Fuhrman GM, Charnsangavej C, Abbruzzese JL, Cleary KR, Martin RG, Fenoglio CJ et al (1994) Thin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg 167(1):104–111; discussion 11–13 Gulliver DJ, Baker ME, Cheng CA, Meyers WC, Pappas TN (1992) Malignant biliary obstruction: efficacy of thin-section dynamic CT in determining resectability. AJR Am J Roentgenol 159(3):503–507 Halsted W (1899) Contributions to the sugery of the bile passages, especially the common bile duct. Boston Med Surg J 141:645–654 Harrison LE, Brennan MF (1998) Portal vein resection for pancreatic adenocarcinoma. Surg Oncol Clin N Am 7(1):165–181 Heinrich S, Schafer M, Weber A, Hany TF, Bhure U, Pestalozzi BC et al (2008) Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg 248(6):1014–1022 Herman JM, Swartz MJ, Hsu CC, Winter J, Pawlik TM, Sugar E et al (2008) Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. J Clin Oncol 26(21):3503–3510 Herter FP, Cooperman AM, Ahlborn TN, Antinori C (1982) Surgical experience with pancreatic and periampullary cancer. Ann Surg 195(3):274–281 Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson AB III (1998) Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study. J Clin Oncol 16(1):317–323 Ichikawa T, Haradome H, Hachiya J, Nitatori T, Ohtomo K, Kinoshita T et al (1997) Pancreatic ductal adenocarcinoma: preoperative assessment with helical CT versus dynamic MR imaging. Radiology 202(3):655–662
7 Multimodality Management of Localized and Borderline Resectable Pancreatic Adenocarcinoma
199
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249 Jimenez RE, Warshaw AL, Rattner DW, Willett CG, McGrath D, Fernandez-del Castillo C (2000) Impact of laparoscopic staging in the treatment of pancreatic cancer. Arch Surg 135(4):409– 414; discussion 14–15 Joensuu TK, Kiviluoto T, Karkkainen P, Vento P, Kivisaari L, Tenhunen M et al (2004) Phase I-II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 60(2):444–452 John TG, Greig JD, Carter DC, Garden OJ (1995) Carcinoma of the pancreatic head and periampullary region. Tumor staging with laparoscopy and laparoscopic ultrasonography. Ann Surg 221(2):156–164 Kalser MH, Ellenberg SS (1985) Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection Arch Surg 120(8):899–903 Kamthan AG, Morris JC, Dalton J, Mandeli JP, Chesser MR, Leben D et al (1997) Combined modality therapy for stage II and stage III pancreatic carcinoma. J Clin Oncol 15(8):2920–2927 Katz A, Hanlon A, Lanciano R, Hoffman J, Coia L (1998) Prognostic value of CA 19-9 levels in patients with carcinoma of the pancreas treated with radiotherapy. Int J Radiat Oncol Biol Phys 41(2):393–396 Katz MH, Pisters PW, Evans DB, Sun CC, Lee JE, Fleming JB et al (2008) Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg 206(5):833– 846; discussion 46–48 Kim HJ, Czischke K, Brennan MF, Conlon KC (2002) Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer? J Gastrointest Surg 6(5):763–769 Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH et al (1999) Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 230(6):776–782; discussion 82–84 Lerut JP, Gianello PR, Otte JB, Kestens PJ (1984) Pancreaticoduodenal resection. Surgical experience and evaluation of risk factors in 103 patients. Ann Surg 199(4):432–437 Lin PW, Lin YJ (1999) Prospective randomized comparison between pylorus-preserving and standard pancreaticoduodenectomy. Br J Surg 86(5):603–607 Lowy AM (2008) Neoadjuvant therapy for pancreatic cancer. J Gastrointest Surg 12(9):1600–1608 Lowy AM, Lee JE, Pisters PW, Davidson BS, Fenoglio CJ, Stanford P et al (1997) Prospective, randomized trial of octreotide to prevent pancreatic fistula after pancreaticoduodenectomy for malignant disease. Ann Surg 226(5):632–641 McCarthy MJ, Evans J, Sagar G, Neoptolemos JP (1998) Prediction of resectability of pancreatic malignancy by computed tomography. Br J Surg 85(3):320–325 Megibow AJ, Zhou XH, Rotterdam H, Francis IR, Zerhouni EA, Balfe DM et al (1995) Pancreatic adenocarcinoma: CT versus MR imaging in the evaluation of resectability – report of the Radiology Diagnostic Oncology Group. Radiology 195(2):327–332 Meszoely IM, Wang H, Hoffman JP (2004) Preoperative chemoradiation therapy for adenocarcinoma of the pancreas: The Fox Chase Cancer Center experience, 1986–2003. Surg Oncol Clin N Am 13(4):685–696, x Montgomery RC, Hoffman JP, Riley LB, Rogatko A, Ridge JA, Eisenberg BL (1997) Prediction of recurrence and survival by post-resection CA 19-9 values in patients with adenocarcinoma of the pancreas. Ann Surg Oncol 4(7):551–556 Mornex F, Girard N, Scoazec JY, Bossard N, Ychou M, Smith D et al (2006) Feasibility of preoperative combined radiation therapy and chemotherapy with 5-fluorouracil and cisplatin in potentially resectable pancreatic adenocarcinoma: the French SFRO-FFCD 97-04 Phase II trial. Int J Radiat Oncol Biol Phys 65(5):1471–1478
200
M.B. Ujiki et al.
Moutardier V, Magnin V, Turrini O, Viret F, Hennekinne-Mucci S, Goncalves A et al (2004) Assessment of pathologic response after preoperative chemoradiotherapy and surgery in pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys 60(2):437–443 Nakagohri T, Kinoshita T, Konishi M, Inoue K, Takahashi S (2003) Survival benefits of portal vein resection for pancreatic cancer. Am J Surg 186(2):149–153 Neoptolemos JP, Kerr DJ, Beger H, Link K, Pederzoli P, Bassi C et al (1997) ESPAC-1 trial progress report: the European randomized adjuvant study comparing radiochemotherapy, 6 months chemotherapy and combination therapy versus observation in pancreatic cancer. Digestion 58(6):570–577 Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H et al (2001) Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 358(9293):1576–1585 Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H et al (2004) A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350(12):1200–1210 Neoptolemos JP, Stocken DD, Tudur Smith C, Bassi C, Ghaneh P, Owen E et al (2009a) Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials. Br J Cancer 100(2):246–250 Neoptolemos J, Buchler M, Stocken D et al (2009b) ESPAC-3(v2): a multicenter, international open-label, randomized, controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/ FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal adenocarcinoma. J Clin Oncol 27:18s [suppl; abstr LBA4505] Neuhaus P RH, Post S et al (2008) Deutsche krebsgesellschaft. CONKO-001: final results of the randomized, prospective, multiceneter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC). J Clin Oncol 26(Suppl):4504 Nieveen van Dijkum EJ, Romijn MG, Terwee CB, de Wit LT, van der Meulen JH, Lameris HS et al (2003) Laparoscopic staging and subsequent palliation in patients with peripancreatic carcinoma. Ann Surg 237(1):66–73 Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K et al (2007) Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297(3):267–277 Ohtsuka T, Yamaguchi K, Chijiiwa K, Tanaka M (2001) Postoperative pancreatic exocrine function influences body weight maintenance after pylorus-preserving pancreatoduodenectomy. Am J Surg 182(5):524–529 Owens DJ, Savides TJ (2010) Endoscopic ultrasound staging and novel therapeutics for pancreatic cancer. Surg Oncol Clin N Am 19(2):255–266 Pedrazzoli S, DiCarlo V, Dionigi R, Mosca F, Pederzoli P, Pasquali C et al (1998) Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: a multicenter, prospective, randomized study. Lymphadenectomy Study Group. Ann Surg 228(4):508–517 Picozzi VJ, Abrams RA, Decker PA, Traverso W et al (2010) Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, and interferon-alfa-2bbased chemoradiation: ACOSOG Trial Z05031. Ann Oncol [Epub ahead of print] Pipas JM, Barth RJ Jr, Zaki B, Tsapakos MJ, Suriawinata AA, Bettmann MA et al (2005) Docetaxel/ gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol 12(12):995–1004 Pisters PW, Hudec WA, Hess KR, Lee JE, Vauthey JN, Lahoti S et al (2001a) Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated morbidity in 300 consecutive patients. Ann Surg 234(1):47–55 Pisters PW, Lee JE, Vauthey JN, Charnsangavej C, Evans DB (2001b) Laparoscopy in the staging of pancreatic cancer. Br J Surg 88(3):325–337
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Raut CP, Grau AM, Staerkel GA, Kaw M, Tamm EP, Wolff RA et al (2003) Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration in patients with presumed pancreatic cancer. J Gastrointest Surg 7(1):118–126; discussion 27–28 Raval MV, Bilimoria KY, Talamonti MS (2010) Quality improvement for pancreatic cancer care: is regionalization a feasible and effective mechanism? Surg Oncol Clin N Am 19(2):371–390 Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A et al (2008) Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA 299(9): 1019–1026 Riall TS, Cameron JL, Lillemoe KD, Campbell KA, Sauter PK, Coleman J et al (2005) Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma-part 3: update on 5-year survival. J Gastrointest Surg 9(9):1191–1206 Ritts RE, Pitt HA (1998) CA 19-9 in pancreatic cancer. Surg Oncol Clin N Am 7(1):93–101 Ritts RE Jr, Nagorney DM, Jacobsen DJ, Talbot RW, Zurawski VR Jr (1994) Comparison of preoperative serum CA19-9 levels with results of diagnostic imaging modalities in patients undergoing laparotomy for suspected pancreatic or gallbladder disease. Pancreas 9(6):707–716 Roche CJ, Hughes ML, Garvey CJ, Campbell F, White DA, Jones L et al (2003) CT and pathologic assessment of prospective nodal staging in patients with ductal adenocarcinoma of the head of the pancreas. AJR Am J Roentgenol 180(2):475–480 Rosch T (1995) Staging of pancreatic cancer. Analysis of literature results. Gastrointest Endosc Clin N Am 5(4):735–739 Rosch T, Dittler HJ, Strobel K, Meining A, Schusdziarra V, Lorenz R et al (2000) Endoscopic ultrasound criteria for vascular invasion in the staging of cancer of the head of the pancreas: a blind reevaluation of videotapes. Gastrointest Endosc 52(4):469–477 Sasson AR, Hoffman JP, Ross EA, Kagan SA, Pingpank JF, Eisenberg BL (2002) En bloc resection for locally advanced cancer of the pancreas: is it worthwhile? J Gastrointest Surg 6(2): 147–157; discussion 57–58 Satoi S, Yanagimoto H, Toyokawa H, Takahashi K, Matsui Y, Kitade H et al (2009) Surgical results after preoperative chemoradiation therapy for patients with pancreatic cancer. Pancreas 38(3):282–288 Schlieman MG, Ho HS, Bold RJ (2003) Utility of tumor markers in determining resectability of pancreatic cancer. Arch Surg 138(9):951–955; discussion 5–6 Schlitt HJ, Schmidt U, Simunec D, Jager M, Aselmann H, Neipp M et al (2002) Morbidity and mortality associated with pancreatogastrostomy and pancreatojejunostomy following partial pancreatoduodenectomy. Br J Surg 89(10):1245–1251 Sewnath ME, Birjmohun RS, Rauws EA, Huibregtse K, Obertop H, Gouma DJ (2001) The effect of preoperative biliary drainage on postoperative complications after pancreaticoduodenectomy. J Am Coll Surg 192(6):726–734 Shapiro TM (1975) Adenocarcinoma of the pancreas: a statistical analysis of biliary bypass vs Whipple resection in good risk patients. Ann Surg 182(6):715–721 Sikora SS, Posner MC (1995) Management of the pancreatic stump following pancreaticoduodenectomy. Br J Surg 82(12):1590–1597 Snady H, Bruckner H, Cooperman A, Paradiso J, Kiefer L (2000) Survival advantage of combined chemoradiotherapy compared with resection as the initial treatment of patients with regional pancreatic carcinoma. An outcomes trial. Cancer 89(2):314–327 Sohn TA, Yeo CJ, Cameron JL, Pitt HA, Lillemoe KD (2000) Do preoperative biliary stents increase postpancreaticoduodenectomy complications? J Gastrointest Surg 4(3):258–267; discussion 67–68 Spitz FR, Abbruzzese JL, Lee JE, Pisters PW, Lowy AM, Fenoglio CJ et al (1997) Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol 15(3):928–937
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Stewart CJ, Mills PR, Carter R, O’Donohue J, Fullarton G, Imrie CW et al (2001) Brush cytology in the assessment of pancreatico-biliary strictures: a review of 406 cases. J Clin Pathol 54(6):449–455 Takai S, Satoi S, Yanagimoto H, Toyokawa H, Takahashi K, Terakawa N et al (2008) Neoadjuvant chemoradiation in patients with potentially resectable pancreatic cancer. Pancreas 36(1): e26–e32 Talamonti MS, Small W Jr, Mulcahy MF, Wayne JD, Attaluri V, Colletti LM et al (2006) A multiinstitutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol 13(2):150–158 Tanaka M (2004) Intraductal papillary mucinous neoplasm of the pancreas: diagnosis and treatment. Pancreas 28(3):282–288 Thomas RM, Ahmad SA (2010) Current concepts in the surgical management of pancreatic cancer. Surg Oncol Clin N Am 19(2):335–358 Tran KT, Smeenk HG, van Eijck CH, Kazemier G, Hop WC, Greve JW et al (2004) Pylorus preserving pancreaticoduodenectomy versus standard whipple procedure: a prospective, randomized, multicenter analysis of 170 patients with pancreatic and periampullary tumors. Ann Surg 240(5):738–745 Trede M, Schwall G, Saeger HD (1990) Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality. Ann Surg 211(4):447–458 Ujiki MB, Talamonti MS (2005) Surgical management of pancreatic cancer. Semin Radiat Oncol 15(4):218–225 Ujiki MB, Talamonti MS (2007) Guidelines for the surgical management of pancreatic adenocarcinoma. Semin Oncol 34(4):311–320 van der Gaag NA, Rauws EA, van Eijck CH, Bruno MJ, van der Harst E, Kubben FJ et al (2010) Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 362(2): 129–137 van Geenen RC, ten Kate FJ, de Wit LT, van Gulik TM, Obertop H, Gouma DJ (2001) Segmental resection and wedge excision of the portal or superior mesenteric vein during pancreatoduodenectomy. Surgery 129(2):158–163 Varadhachary GR, Tamm EP, Abbruzzese JL, Xiong HQ, Crane CH, Wang H et al (2006) Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol 13(8):1035–1046 Varadhachary GR, Wolff RA, Crane CH, Sun CC, Lee JE, Pisters PW et al (2008) Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol 26(21):3487–3495 Vedantham S, Lu DS, Reber HA, Kadell B (1998) Small peripancreatic veins: improved assessment in pancreatic cancer patients using thin-section pancreatic phase helical CT. AJR Am J Roentgenol 170(2):377–383 Warshaw AL, Tepper JE, Shipley WU (1986) Laparoscopy in the staging and planning of therapy for pancreatic cancer. Am J Surg 151(1):76–80 Warshaw AL, Gu ZY, Wittenberg J, Waltman AC (1990) Preoperative staging and assessment of resectability of pancreatic cancer. Arch Surg 125(2):230–233 Wayne JD, Abdalla EK, Wolff RA, Crane CH, Pisters PW, Evans DB (2002) Localized adenocarcinoma of the pancreas: the rationale for preoperative chemoradiation. Oncologist 7(1):34–45 Whipple AO, Parsons WB, Mullins CR (1935) Treatment of carcinoma of the ampulla of Vater. Ann Surg 102(4):763–779 White RR, Tyler DS (2004) Neoadjuvant therapy for pancreatic cancer: the Duke experience. Surg Oncol Clin N Am 13(4):675–684, ix–x Yeo CJ, Cameron JL, Maher MM, Sauter PK, Zahurak ML, Talamini MA et al (1995) A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy. Ann Surg 222(4):580–588; discussion 8–92
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Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH et al (1997) Pancreati coduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 225(5):621–633; discussion 33–36 Yeo CJ, Cameron JL, Lillemoe KD, Sauter PK, Coleman J, Sohn TA et al (2000) Does prophylactic octreotide decrease the rates of pancreatic fistula and other complications after pancreaticoduodenectomy? Results of a prospective randomized placebo-controlled trial. Ann Surg 232(3):419–429 Yeo CJ, Cameron JL, Lillemoe KD, Sohn TA, Campbell KA, Sauter PK et al (2002) Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg 236(3):355–366; discussion 66–68 Yeung RS, Weese JL, Hoffman JP, Solin LJ, Paul AR, Engstrom PF et al (1993) Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma. A phase II study. Cancer 72(7):2124–2133
Unresectable Pancreatic Cancer
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Daniel Renouf, Laura A. Dawson, and Malcolm Moore
8.1 Introduction Pancreatic adenocarcinoma is the fourth leading cause of cancer death in North America, with approximately 35,000 deaths annually (Jemal et al. 2008). Advanced pancreatic cancer is an aggressive and lethal disease; the median survival without treatment is less than 3 months and one-year survival is less than 5% (Glimelius et al. 1996). The disease is relatively resistant to cytotoxic chemotherapy; even with treatment, median survival is approximately 6 months and one-year survival is 20–25% (Moore et al. 2007). The majority of patients with pancreatic cancer are diagnosed with locally advanced or metastatic disease. Around 15–20% of patients have localized disease amenable to surgical resection, though even with successful surgery, the disease usually recurs. A major improvement in outcome can only come through better systemic therapy or earlier detection. Screening programs are being studied but show little promise. Locally advanced pancreatic cancer (LAPC) includes tumors that invade into or are adherent to adjacent structures, such as the celiac and superior mesenteric vasculature, and are thus difficult to resect with negative margins. Borderline resectable tumors are often defined as having focal tumor abutment of the vasculature (Katz et al. 2008). The treatment of borderline resectable tumors may still involve surgery (with or without preoperative systemic and radiation therapy), and is addressed in the previous chapter on resectable disease, while this chapter focuses on truly unresectable tumors. The treatment modalities for LAPC evaluated include systemic therapy, radiation therapy, systemic therapy given concurrently with radiation (chemoradiotherapy), or a combination of both approaches.
D. Renouf and M. Moore (*) Department of Medical Oncology, Princess Margaret Hospital, 5-708, 610 University Avenue, Toronto, ON, M5G 2M9, Canada e-mail:
[email protected] L.A. Dawson Department of Radiation Oncology, Princess Margaret Hospital, 5-708, 610 University Avenue, Toronto, ON, M5G 2M9, Canada C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_8, © Springer-Verlag Berlin Heidelberg 2011
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Metastatic pancreatic cancer refers to tumors that have spread beyond the pancreas and regional lymph nodes. The main treatment modality for metastatic pancreatic cancer is systemic therapy. This chapter reviews the current data on local and systemic therapies in unresectable pancreatic adenocarcinoma and discusses future directions for the treatment of this challenging disease. Given the unsatisfactory results of therapy for all stages of pancreatic cancer, clinical research is a critical part of the approach to these patients.
8.2 Locally Advanced Pancreatic Cancer 8.2.1 Radiation and Chemoradiotherapy There is evidence from small older studies that treatment of LAPC improves outcomes compared with best supportive care. Shinchi et al. (2002) compared chemoradiotherapy (with 5-FU and radiation therapy) to best supportive care. This was a randomized study of only 31 patients, and treatment with chemoradiotherapy improved median survival, from 6.4 to 13.2 months. Several studies have compared radiotherapy alone with chemoradiotherapy for the treatment of LAPC. Moertel et al. 1981) randomized 194 patients to receive radiotherapy (to a total dose of 60 Gy) or radiotherapy (to a total dose of 40 or 60 Gy) given with 5-FU. Overall survival was significantly better in the chemoradiotherapy arms, and there was no difference between the higher and lower doses of radiation. A second study compared radiotherapy and chemoradiotherapy, in which the chemotherapy used was 5-FU and mitomycin C. In this trial no significant difference was noted between the two arms, although there was a trend toward improved survival in the chemoradiotherapy arm (Cohen et al. 2005). The method of 5-FU administration (intermittent high dose rather then continuous infusion), and the use of mitomycin C may have contributed to the poor outcomes in the chemoradiotherapy arm. Two meta-analyses have been performed, using the data from these two trials, as well as also data from previous smaller studies (Yip et al. 2006; Sultana 2007). Both concluded that chemoradiotherapy significantly improved survival, compared with radiation therapy alone. This conclusion was further supported by a retrospective study of 1,700 elderly patients with LAPC derived from the Medicare/SEER database which found an adjusted mean survival for patients who had undergone chemoradiotherapy of 47 weeks, vs. 29 weeks for those who had undergone radiation therapy alone (Krzyzanowska et al. 2003). Selection bias may have contributed to these results as it was not a randomized trial. A recent systemic review (Huguet et al. 2009) concluded that chemoradiotherapy with 5-FU and radiotherapy to a total dose of 50 Gy increases survival and quality of life in patients with LAPC compared with best supportive care (level of evidence C); that chemoradiotherapy increases overall survival compared with radiotherapy alone (level of evidence B1); and that chemoradiotherapy is more toxic then radiotherapy (level of evidence A).
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8.2.2 Different Chemoradiotherapy Protocols 8.2.2.1 Radiotherapy Protocols Modifications of radiation dose and technique have been tested in an attempt to improve the efficacy of chemoradiotherapy. A recent review concluded that the optimal dose of radiotherapy is unclear, and the association between dose and local control and survival has not been evaluated prospectively. The maximum tolerable dose of radiation depends on the dose, schedule, and drug given concurrently. When radiation is given with 5-FU, 50–54 Gy is usually given in standard fractionation (over 5–6 weeks) (Huguet et al. 2009). The volume irradiated is also important and older studies have included regional nodal irradiation. As toxicity is related to the volume of normal tissues irradiated, there is movement towards a more involved field approach. When strong potent sensitizers are used concurrently with radiation therapy (e.g., gemcitabine or targeted agents), smaller volume irradiation is recommended (to include the gross primary and nodal targets without extensive elective nodal radiation therapy). Original studies of radiation therapy used 2D radiation therapy. CT-based 3D conformal therapy is now widely available and allows a reduced exposure to normal tissues. Other modern radiation therapy techniques include intensitymodulated radiation therapy (IMRT) where the fluence patterns of photons varies across each beam angle, allowing more flexibility regarding where dose is deposited (and sparing normal tissues). Stereotactic body radiotherapy (SBRT), allows high-dose conformal radiation therapy to be delivered to small volumes in far fewer fractions than standard radiation therapy. Image guidance and breathing motion management need to be used with SBRT to ensure that the doses are delivered to the tumor as planned. Studies of SBRT in LAPC (Hoyer et al. 2005; Chang et al. 2009) have been disappointing with substantial toxicity and unimpressive median survivals. This is in part due to doses delivered to tumors involving or directly adjacent to the duodenum (a common situation), causing an increase in duodenal bleeding. Lower-dose SBRT may be an option for palliation of pancreatic cancer. Intraoperative radiation (IORT) allows for the delivery of high-dose radiation directly to areas of tumor and thus potentially may reduce side effects of the radiation. Results have been inconclusive and at this time this technique is not routinely used outside of clinical trials. (Ruano-Ravina 2008).
8.2.2.2 Chemotherapy Given Concurrently Fluoropyrimidines, either bolus or infusional 5-FU, or more recently the oral agent capecitabine, have been the standard chemotherapy given with radiation therapy. Gemcitabine, active in advanced pancreatic cancer, is a potent radiosensitizer even at lower doses. Studies have demonstrated the feasibility of combining radiation with weekly or biweekly gemcitabine with doses ranging from 40 to 1,000 mg/m2 (Blackstock et al. 2003).
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A small comparative study by Li and colleagues compared gemcitabine (600 mg/m2/week) with 5-FU, both given concurrently with radiotherapy, and demonstrated a survival benefit for the gemcitabine arm (14.5 vs. 6.7 months) although the confidence limits are wide due to the small sample size (Li et al. 2003). Wilkowski et al. (2009) conducted a larger randomized phase II trial that revealed no difference in survival between chemoradiotherapy with gemcitabine and cisplatin or 5-FU-based chemoradiotherapy. In the absence of any phase III trials to compare gemcitabine or 5-FU-based chemoradiotherapy, a recent review concluded that 5-FU remains the reference chemotherapy to be given in combination with radiotherapy in LAPC (level of evidence B1) (Huguet et al. 2009). There are data from several studies to support capecitabine as a potential replacement for infusional 5-FU, as a radiation sensitizer (Saif et al. 2005; Schneider et al. 2005). An ongoing large phase III study comparing capecitabine-based chemoradiotherapy vs. 5-FU based chemoradiotherapy in rectal cancer will more clearly define the role of capecitabine in this setting (Hofheinz et al. 2009). More intensive chemoradiotherapy strategies have been or are currently being explored. The Eastern Cooperative Oncology Group (ECOG) performed a phase I/II trial of 5-FU, gemcitabine (50–100 mg/m2/week), plus radiotherapy that closed early due to excess toxicity (Talamonti et al. 2000). The treatment volumes included elective regional nodes, which contributed to the high toxicity observed. This study provides further support for the use of smaller radiation fields when radiation therapy is used concurrently with gemcitabine or combination chemotherapy. This combination, but with lower radiation dose and volumes (50.4 vs. 59.4 Gy), was evaluated in a phase II study conducted by the Cancer and Leukemia Group B (CALGB). There was acceptable toxicity and a median survival of 11.4 months (Mamon et al. 2005). The Radiation Therapy Oncology Group (RTOG) evaluated paclitaxel 50 mg/m2/week with concurrent radiotherapy in 122 patients with LAPC. There were seven clinically complete responses, 28 partial responses, and a median survival of 11.2 months (Rich et al. 2004).
8.2.3 Chemotherapy Alone Several large studies have compared chemoradiotherapy to chemotherapy alone in LAPC (Table 8.1). Earlier studies found no difference in survival between 5-FU-based chemoradiotherapy and 5-FU-based chemotherapy alone (Hazel et al. 1981; Klaassen et al. 1985). The gastrointestinal tumor study group (GITSG) compared chemotherapy with 5-FU, streptomycin, and mitomycin vs. chemoradiotherapy with 5-FU followed by 5-FU, streptomycin, and mitomycin. The chemoradiotherapy arm had a trend towards improved median survival (10.5 vs. 8 months) that did not reach statistical significance, and a statistically significant improvement in one-year survival (41 vs. 19%, p < 0.02) (Gastrointestinal Tumor Study Group 1988). More recent studies have used gemcitabine as the chemotherapy platform for comparison with chemoradiotherapy. Chauffert et al. (2000) conducted a randomized phase III trial comparing chemoradiotherapy with 5-FU and cisplatin followed by maintenance gemcitabine, vs. gemcitabine alone. The patients who received gemcitabine alone had a significantly
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Table 8.1 Selected trials comparing chemoradiotherapy vs. chemotherapy for locally advanced unresectable pancreatic cancer Reference Treatment Median survival (months) Hazel et al. (1981)
5-FU chemoradiotherapy followed by Methyl CCNU vs. 5-FU and Methyl CCNU
7.8 vs. 7.3 (p = NS)
Klaassen et al. (1985)
5-FU chemoradiotherapy vs. 5-FU alone
8.3 vs. 8.2 (p = NS)
Gastrointesinal tumor study group (1988)
5-FU chemoradiotherapy followed by streptozocin, mitomycin, and 5-FU vs. streptozocin, mitomycin, and 5-FU
10.5 vs. 8 (p = NS)
Chauffert et al. (2000)
5-FU and cisplatin chemoradiotherapy followed by maintenance gemcitabine vs. gemcitabine alone
8.6 vs. 13 (p = 0.03)
Loehrer et al. (2008)
Gemcitabine chemoradiotherapy followed by maintenance gemcitabine vs. gemcitabine alone
11 vs. 9.2 (p = 0.044)
longer overall survival than those receiving chemoradiotherapy (13 vs. 8.6 months). The high dose of radiation therapy used (60 Gy compared to more usual 54 Gy), and the concurrent cisplatin led to increased toxicity and likely contributed to the poor outcome of the chemoradiotherapy arm. At the 2008 American Society of Clinical Oncology (ASCO) meeting, Loehrer et al. (2008) presented the results of a phase III trial comparing chemoradiotherapy with gemcitabine followed by maintenance gemcitabine, vs. gemcitabine alone. This trial closed early due to poor accrual, but results were reported on the 74 patients who were randomized. The chemoradiotherapy arm had an improved overall survival compared with chemotherapy alone (11 vs. 9.2 months; p = 0.044). Higher rates of grade 4 toxicity were observed with chemoradiotherapy (41.2 vs. 5.7%). A meta-analysis that included most of the aforementioned trials (but not Loehrer’s study) concluded that there is no significant difference in overall survival between chemoradiotherapy vs. chemotherapy alone (Sultana 2007). A systematic review (Huguet et al. 2009) recently concluded that concurrent chemoradiotherapy is not superior to chemotherapy alone in terms of survival (level of evidence B1) and increases treatment-related toxicity (level of evidence A). Until recently, clinical trials evaluating systemic therapy for advanced pancreatic cancer included patients with both metastatic and locally advanced disease. This demonstrates that many investigators consider systemic therapy alone an appropriate option. LAPC has a better survival rate than metastatic disease and the results of a study can be influenced by the proportion of patients with LAPC included; it has ranged from 10 to 40% in recent trials. This practice has inhibited the study of LAPC as a unique subset of pancreatic cancer, and in the future, metastatic disease and LAPC will be studied separately by most expert groups.
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8.2.4 Chemotherapy Followed by Chemoradiotherapy A popular current approach to LAPC is induction chemotherapy followed by chemoradiotherapy. This strategy screens out those patients with rapidly growing systemic disease, and allows selection of patients with true localized disease who may receive a greater benefit from local control. Ko et al. (2007) treated 25 LAPC patients with induction chemotherapy with gemcitabine and cisplatin for six cycles, followed by capecitabine with radiotherapy. They found a median survival of 13.5 months for all patients, and 17 months for the 12 patients who completed the two phases of treatment. Two retrospective studies evaluated induction chemotherapy followed by chemoradiotherapy, in LAPC. Krishnan et al. (2007) examined a regimen consisting of induction chemotherapy with gemcitabine or gemcitabine and cisplatin, followed by gemcitabinebased chemoradiotherapy. Median overall survival was significantly longer in patients who received chemotherapy followed by chemoradiotherapy. Huguet et al. (2007) also retrospectively examined the efficacy of a regimen consisting of induction chemotherapy followed by chemoradiotherapy and found that patients who received chemoradiotherapy had a significant improvement in median progression-free survival (10.8 vs. 7.4 months), and overall survival (15 vs. 11.7 months). These results have to be interpreted with caution as these were not derived from randomized studies. A systemic review concluded that induction chemotherapy before concurrent chemoradiotherapy improves survival in patients with LAPC (level of evidence C) (Huguet et al. 2009). This method also potentially spares patients with rapidly progressive disease from potentially toxic radiotherapy, and may help to define which patients benefit from chemoradiotherapy. The Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) LAP07 phase III trial will test this therapeutic strategy. Patients with LAPC will initially receive induction chemotherapy (gemcitabine vs. gemcitabine and erlotinib) for four cycles, and those with a controlled tumor will be randomly assigned between two additional cycles of chemotherapy vs. chemoradiotherapy (conformal radiation therapy with a total dose of 54 Gy and concomitant capecitabine). At the end of this second phase patients who received erlotinib during induction will continue erlotinib as maintenance treatment until progression. The GERCOR study highlights much of the uncertainty that exists about the optimal management of locally advanced disease in 2010. These include fundamental questions such as whether local therapy has any role, what the optimal timing would be, and the role of maintenance therapy. As trials move toward exclusively being performed in the locally advanced population, these issues should be answered, and therapy will become better defined.
8.2.5 Targeted Therapy A number of the newer “targeted” agents can function as radiosensitizers. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have activity in advanced pancreatic cancer (Sect. 8.2.5). There is preclinical evidence that inhibiting EGFR may sensitize tumor cells to ionizing radiation, through increasing the proportion of cells in the G1 phase
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of the cell cycle (Huang and Harari 2000), restoration of apoptosis (Ciardiello et al. 2001; Baumann et al. 2007), or potentially antiangiogenic mechanisms (Baumann et al. 2007). There is also clinical data from the head and neck literature that combining EGFR inhibitors with radiation improves outcomes vs. radiotherapy alone (Bonner et al. 2006). The EGFR tyrosine kinase inhibitor gefinitib given in combination with chemoradiotherapy was found to be associated with significant toxicity and minimal efficacy (Czito et al. 2006; Maurel et al. 2006). Toxicity was also seen when the anti-EGFR monoclonal antibody cetuximab was given with IMRT and gemcitabine, but there was also promising efficacy, with one study finding a rate of complete plus partial response of 35.5% (Munter et al. 2008). A phase II study tested escalating doses of erlotinib with gemcitabine, paclitaxel, and radiation followed by maintenance erlotinib in locally advanced and margin positive patients (Iannitti et al. 2005). In this study the partial response rate was 46% and the median survival was 14 months. Another study, performed by Duffy and colleagues, assessed escalating doses of erlotinib with radiation and biweekly gemcitabine, followed by weekly maintenance gemcitabine and erlotinib (Duffy et al. 2008). The results of this study were also encouraging, with 53% of patients having stable disease, 35% having partial responses, and a median survival of 18.7 months emerging. The incorporation of targeted agents into current chemoradiotherapy protocols is an area that requires more study. Whether these efforts should be restricted to agents that have established activity in advanced disease is unknown. One critical aspect of these trials will be correlative studies to define molecular predictive and prognostic markers (Chang and Saif 2009).
8.2.6 Summary and Future Directions Despite close to 10,000 patients in North America a year presenting with LAPC limited progress has been made, and clinical trial activity lags behind what is ongoing in metastatic disease. One may conclude, however, that chemoradiotherapy is superior to radiotherapy alone and that fluoropyrimidines combined with radiation therapy represent a reasonable current standard for chemoradiotherapy, but not that chemoradiotherapy clearly adds to what can be achieved using chemotherapy alone. A reasonable approach would be to start with chemotherapy alone for 2–6 months and proceed to chemoradiotherapy in patients without progressive disease. This selects patients who have a higher likelihood of benefit from local therapy. As discussed previously, at this time there is a move toward separating patients with locally advanced disease from those with metastatic disease for ongoing clinical trials (traditionally these were grouped together). If chemoradiotherapy is not shown to have incremental benefit in the GERCOR study, then the current approach of separating LAPC and metastatic disease could stop and both could be combined in studies of systemic therapies. If chemoradiotherapy has benefits, then the challenge will be how to develop and evaluate new protocols, particularly those incorporating targeted agents. At present there is no agreed-upon methodology for doing this, and the heterogeneity of this population limits the conclusions that can be drawn from phase II studies.
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8.3 Metastatic Pancreatic Cancer 8.3.1 Chemotherapy Many cytotoxic agents have been studied in advanced pancreatic cancer (Table 8.2). Early studies used response as a primary endpoint, although this is unreliable and few drugs were able to reproducibly demonstrate meaningful rates of tumor response. Fluorouracil (5-FU) was considered the best of these drugs (Glimelius et al. 1996; Palmer et al. 1994; Mallinson et al. 1980; Crown et al. 1991) and many subsequent studies evaluated 5-FU combinations. Until gemcitabine was approved, no drug or combination had clearly demonstrated an improvement in survival or quality of life in advanced disease over 5-FU alone. In 1997 the results of a landmark trial in 126 patients comparing gemcitabine with 5-FU were reported (Burris et al. 1997). Both drugs were given weekly and the gemcitabine arm had an improvement in clinical benefit (a composite of measurements of pain, analgesic usage, Table 8.2 Selected trials comparing chemotherapy regimens for unresectable and metastatic pancreatic cancer Reference Treatment Median survival (months) Burris et al. (1997)
Gemcitabine vs. 5-FU
5.7 vs. 4.4 (p = 0.0025)
Poplin et al. (2009)
Gemcitabine vs. gemcitabine FDR vs. gemcitabine and oxaliplatin
4.8 vs 6.2 (p = 0.04) vs. 5.7 (p = 0.22)
Heinemann et al. (2006)
Gemcitabine vs. gemcitabine and cisplatin
6 vs. 7.5 (p = NS)
Colucci et al. (2009)
Gemcitabine vs. gemcitabine and cisplatin
8.3 vs. 7.2 (p = NS)
Louvet et al. (2002)
Gemcitabine vs. gemcitabine and oxaliplatin
7.1 vs. 9 (p = NS)
Herrmann et al. (2007)
Gemcitabine vs. gemcitabine and capecitabine
7.2 vs. 8.4 (p = NS)
Cunningham et al. (2009)
Gemcitabine vs. gemcitabine and capecitabine
6.2 vs. 7.1 (p = NS)
Rocha Lima et al. (2004)
Gemcitabine vs. gemcitabine and irinotecan
6.3 vs. 6.6 (p = NS)
Stathopoulous et al. (2004)
Gemcitabine vs. gemcitabine and irinotecan
6.4 vs. 6.5 (p = NS)
Oettle et al. (2005)
Gemcitabine vs. gemcitabine and pemetrexed
6.3 vs. 6.2 (p = NS)
O’Reilly et al. (2004)
Gemcitabine vs. gemcitabine and exatecan
6.2 vs. 6.7 (p = NS)
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and performance status), and survival when compared with 5-FU. The response rate to gemcitabine was less than 10%, there was an overall disease control rate (PR + SD) of 45 vs. 19% with 5-FU, the time to progression doubled from 1.9 to 3.8 months, the median survival increased from 4.4 to 5.7 months, and the one-year survival improved from 2 to 18% (p < 0.002). While clinical benefit was the primary endpoint, it was the improvement in one-year survival that was most impressive and led to the approval of gemcitabine as first-line treatment of metastatic pancreatic cancer in many jurisdictions. Gemcitabine has since been regarded as the standard backbone of systemic therapy for pancreatic cancer. Subsequent trials focused on modulation of gemcitabine, and on combinations of gemcitabine with various cytotoxic or targeted agents. The standard dose of gemcitabine is 1,000 mg/m2 given over 30 min at an infusion rate of 33 mg/m2/min. Gemcitabine is metabolized intracellularly to its active metabolite (dFdCTP), a rate limited process saturated at infusion rates of 10 mg/m2/min. Gemcitabine by fixed dose rate infusion (FDR) involved giving gemcitabine at 10 mg/m2/min for 150–180 min to increase intracellular levels of the active metabolite (Hochster 2003). Pharmacological studies demonstrated that the FDR dosing strategy did increase intracellular dFdCTP. Initial studies showed greater toxicity but also suggested a greater efficacy when compared to the standard 30-min infusion (Touroutoglou et al. 1998; Tempero and Plunkett 2003). However, when FDR gemcitabine was evaluated in a large phase III study it did not meaningfully improve survival compared to standard-dose gemcitabine and its use has been largely abandoned (Poplin et al. 2009). Numerous phase II and III trials have evaluated cytotoxic agents in combination with gemcitabine. The most commonly evaluated agents were fluoropyrimidines and the platins (cisplatin and oxaliplatin). The results have been generally disappointing. Several phase II studies of gemcitabine plus cisplatin showed early promise (Brodowicz et al. 2000; Heinemann et al. 2000; Philip et al. 2001; Cascinu et al. 2003). Two underpowered phase III trials of gemcitabine ± cisplatin demonstrated higher response rates and a trend towards an improvement in survival with the combination arm and a meta-analysis suggested benefit in the good performance status population (Heinemann et al. 2006, 2007; Colucci et al. 2002). However, in 2009, Colucci and colleagues presented results from a randomized phase III trial comparing gemcitabine ± cisplatin in over 450 patients (Colucci et al. 2009). There was no improvement in overall or progression-free survival for all patients, and even in the good performance status subset, no improvements were seen. Quality of life was somewhat worse on the gemcitabine-cisplatin arm. A phase II study of gemcitabine with oxaliplatin reported a response rate of 30.6% and a promising median survival of 9.2 months (Alberts et al. 2003; Louvet et al. 2002). The survival results were probably influenced by the high proportion of patients with locally advanced disease included in the study. This led to two randomized trials to evaluate the addition of oxaliplatin to gemcitabine (Poplin et al. 2006; Louvet et al. 2005). Louvet and colleagues demonstrated a nonsignificant trend for an improvement in the median survival in a study of over 300 patients that did not reach statistical significance (Klaassen et al. 1985). A larger study conducted by ECOG compared standard gemcitabine to FDR gemcitabine and to FDR gemcitabine plus oxaliplatin in over 800 patients (Blackstock et al. 2003). Neither FDR gemcitabine nor gemcitabine + oxaliplatin improved overall survival beyond that achieved with gemcitabine alone. One potential problem with the combination
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of gemcitabine + oxaliplatin is the overlapping myelotoxicity, which often leads to a reduction in dose for both drugs. For the fluoropyrimidines, all studies using intravenous 5-FU with gemcitabine have been negative. One combination that showed initial promise was capecitabine and gemcitabine. In 2003, Hess and colleagues reported the results of a phase I/II study demonstrating that this combination is tolerable and has promising activity (Hess et al. 2003). Scheithauer et al. (2003) also reported on a randomized phase II study that showed this combination to be well tolerated, and found a trend towards improved survival benefit. This stimulated the conduct of two large phase III randomized controlled trials comparing gemcitabine alone with gemcitabine in combination with capecitabine (Cunningham 2005; Herrmann et al. 2007; Cunningham et al. 2009). The first study published by Hermann and colleagues did not meet its primary endpoint of an overall improvement in survival but reported a trend towards better survival, especially in patients with good performance status (Herrmann et al. 2007). The second study used a higher dose of capecitabine and was initially presented as a positive study by Cunningham and colleagues at the European Cancer Conference in 2005. At the final analysis and reporting, the trial was no longer positive for survival (7.4 vs. 6 months with gemcitabine alone: HR 0.86 (0.72–1.02), p = 0.08) (Cunningham et al. 2009). A meta-analysis combining data from the two phase III studies and the prior phase II data did demonstrate a modest survival benefit over gemcitabine alone (hazard ratio of 0.86 (0.75–0.98), p = 0.02). Numerous other cytotoxic agents (Rocha Lima et al. 2004; Oettle et al. 2005; O’Reilly et al. 2004; Shepard et al. 2004; Stathopoulos et al. 2006) including irinotecan, pemetrexed, exatecan, and docetaxel have not shown benefit when combined with gemcitabine. A Cochrane meta-analysis of studies in advanced pancreatic cancer did not find a significant difference in one-year survival between gemcitabine combinations and gemcitabine alone. It is reasonable to conclude that single-agent gemcitabine is equivalent to combination chemotherapy and remains a standard of care in clinical trials. There may be benefit from combination therapy in selected patients, but the characteristics of this population have not been determined. If benefit can only be shown in meta-analyses done on thousands of patients, then the absolute benefits of combination therapy are quite small and probably not justifiable given the incremental toxicity of combination chemotherapy.
8.3.2 Targeted Therapy A better understanding of the biology of pancreatic cancer has led to the identification of pathways that are potential targets for drug therapy. There is now a wealth of preclinical data demonstrating growth inhibition by drugs that inhibit these targets. The majority of early phase trials in pancreatic cancer now evaluate these targeted therapies either alone or in combination with traditional cytotoxic agents, and there have been numerous phase II and phase III trials examining the efficacy of targeted agents in metastatic pancreatic cancer (Table 8.3). The EGFR pathway is important in pancreatic tumorigenesis and preclinical data suggest that it may be activated in patients with pancreatic cancer. Anti-EGFR agents have
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Table 8.3 Selected trials comparing chemotherapy vs. biological therapy ± chemotherapy for unresectable and metastatic pancreatic cancer Reference Treatment Median survival (months) Moore et al. (2003)
Gemcitabine vs. gemcitabine and erlotinib
5.9 vs. 6.2 (p = 0.038)
Philip et al. (2007)
Gemcitabine vs. gemcitabine and cetuximab
6 vs. 6.5 (p = NS)
Cascinu et al. (2008)
Gemcitabine and cisplatin vs. gemcitabine, cisplatin, and cetuximab
7.5 vs. 78 (p = NS)
Kindler et al. (2008)
Gemcitabine vs. gemcitabine and bevacizumab
5.7 vs. 6 (p = NS)
Kindler et al. (2008)
Gemcitabine, bevacizumab and erlotinib vs. gemcitabine, bevacizumab, and cetuximab
7.2 vs. 7.8 (p = NS)
Van Cutsem et al. (2004)
Gemcitabine and erlotinib vs. gemcitabine, erlotinib and bevacizumab
6 vs. 7.1 (p = NS)
Van Cutsem et al. (2004)
Gemcitabine vs. gemcitabine and tipifarnib
6.1 vs. 6.4 (p = NS)
Bramhall et al. (2002)
Gemcitabine vs. gemcitabine and marimastat
5.5 vs. 5.5 (p = NS)
Moore et al. (2003)
Gemcitabine vs. BAY 12-9566
6.7 vs. 3.7 (p < 0.001)
been successfully used in the treatment of colon and lung cancer (Jonker et al. 2007; Van Cutsem et al. 2007a; Shepherd 2005). The NCIC.PA.3 trial compared the EGFR tyrosine kinase inhibitor erlotinib plus gemcitabine vs. gemcitabine alone (Moore et al. 2007). Five hundred and sixty-nine patients were randomized and while median survival in the erlotinib-gemcitabine arm was modestly improved (6.24 vs. 5.91 months with gemcitabine alone) the overall survival (HR 0.82, p = 0.038) (Fig. 8.1), and the one-year survival, which improved from 17 to 23% (p = 0.023) were significantly better. The major toxicities were an increase in the incidence of grade 3 and 4 skin rashes (6 vs. 1%) and diarrhea (6 vs. 2%). The incidence of interstitial lung disease was 2%. Progression-free survival was longer in the erlotinib arm (HR 0.77, p = 0.004) and the disease control rate (response rate + stable disease) increased from 49 to 59%. The presence of EGFR expression in tumor specimens did not predict for a benefit from erlotinib, but the patients who experienced a grade 2 or greater skin rash had a median survival of 10.3 months and a one-year survival of 43%. A molecular analysis of KRAS mutation status and EGFR expression using fluorescent in situ hybridization (FISH) was conducted in a subset of patients who had specimens available. The hazard ratio for gemcitabine + erlotinib in the 21% of patients who had wild type KRAS was 0.66 as compared
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Fig. 8.1 Overall survival-Gemcitabine vs Gemcitabine + Erlotinib in advanced pancreatic cancer’
to 1.07 in the KRAS mutants. This is consistent with data in colorectal cancer where EGFR inhibitors have no effect in the presence of a KRAS mutation. The relationship suggested between rash and activity of EGFR inhibitors in pancreatic cancer (Moore et al. 2007; Xiong et al. 2004), and also in other cancers treated with EGFR inhibitors is being further explored (Van Cutsem et al. 2007b). Smoking status may also play a role in metabolism of these drugs, as Hughes and colleagues demonstrated that maximum tolerated dose for erlotinib is higher in smokers than nonsmokers, possibly due to induction of the CYP1A1/1A2 enzymes involved in erlotinib metabolism (Hughes et al. 2009). The concept of erlotinib dose escalation to rash is being tested in the ongoing first-line RACHEL study (comparing dose-escalated erlotinib (to rash) in combination with gemcitabine vs. standard dose erlotinib with gemcitabine). Cetuximab, a monoclonal antibody to EGFR, was studied in combination with gemcitabine in a phase II study in patients whose tumors had immunohistochemical evidence of EGFR expression (Xiong et al. 2004). The disease control rate was 76% (12% partial response and 64% disease stabilization) with a median overall survival of 7.1 months and a one-year survival of 32%. Cascinu et al. (2008) evaluated gemcitabine and cisplatin ± cetuximab in a phase II study. There were no significant differences noted in response rate, progression-free survival, or median overall survival (7.5 vs. 7.8 months). A randomized phase III trial compared gemicitabine ± cetuximab in 735 patients with advanced pancreatic cancer. The addition of cetuximab did not significantly improve objective response rate, progression-free survival, or overall survival (Philp et al. 2007). Pancreatic cancer is not a vascular tumor but as with other solid tumors such as colorectal and lung cancers, a number of trials targeting the vascular endothelial growth factor (VEGF) pathway were undertaken (Hurwitz et al. 2004; Sandler et al. 2006). The final results have been universally negative and some excess toxicity was seen. A phase II study of bevacizumab, a monoclonal antibody against VEGF, plus gemcitabine as first-line therapy in 52
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advanced pancreatic cancer patients at the University of Chicago looked promising with 21% with partial response, 46% with stable disease, a median progression-free survival of 5.4 months and a median survival of 8.8 months (Kindler et al. 2005). The CALGB then conducted a randomized phase III study comparing bevacizumab and gemcitabine to gemcitabine alone. Six hundred and two patients were enrolled, and based on a protocol-specified interim analysis the study data were released because a futility boundary was crossed (Kindler et al. 2007). The results revealed no benefit of the addition of bevacizumab to gemcitabine. The promising phase II data was likely due to a high percentage of ECOG performance status 0 and 1 patients being included, plus other exclusion criteria that then selected out a population of patients with a more favorable biology. A randomized phase II study of gemcitabine ± axitinib (an orally active selective inhibitor of VEGF 1, 2, and 3) did show a trend favoring the combination (Spano et al. 2008), and a randomized phase III trial was conducted. In early 2009 it was announced that this trial had also crossed a futility boundary and was negative. Aflibercept or VEGF-trap is a soluble VGF receptor and acts as a potent antiangiogenic agent. A phase III study of gemcitabine ± aflibercept was also recently announced to be negative. Given the molecular complexity of pancreatic cancer, there is strong rationale for combining targeted agents to achieve greater efficacy. Kindler and colleagues recently presented the results of a phase II study examining the efficacy of gemcitabine, bevacizumab, and erlotinib vs. gemcitabine, bevacizumab, and cetuximab (Kindler et al. 2008). The median survival was 7.2 months in the erlotinib arm and 7.8 months in the cetuximab arm. The AVITA study was a large randomized phase III trial exploring the efficacy of adding bevacizumab to gemcitabine and erlotinib (Van Cutsem et al. 2009). Six hundred and seven patients with previously untreated metastatic pancreatic cancer were randomly assigned to gemcitabine and erlotinib and either bevacizumab or placebo. While the addition of bevacizumab to gemcitabine/erlotinib improved Progression-Free Survival (PFS) (4.6 vs. 3.6 months), there was no improvement in overall survival. Further studies of antivascular therapy do not seem justified at this point. Other targeted therapies with biological rationale and preclinical activity that have been inactive in human testing include the mTOR inhibitor RAD001 (everolimus) (Wolpin et al. 2009), the NF-kB inhibitor curcumin (Dhillon et al. 2008), the farnesyltransferase inhibitor tipifarnib (Van Cutsem et al. 2004), and the matrix metalloproteinase inhibitors marimastat (Bramhall et al. 2002) and BAY 12-9566 (Moore et al. 2003).
8.3.3 Second-Line Therapy Once patients have progressed after gemcitabine-based chemotherapy, there is minimal evidence to suggest a benefit from further systemic therapy. Additionally, many patients will not be of adequate performance status to receive further therapy. A small randomized study with a combination of 5-FU and oxaliplatin demonstrated a modest survival benefit from treatment and further studies of this combination are under way (Pelzer et al. 2008). Small studies have also suggested that single-agent erlotinib may have
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modest activity in this setting, and the results of correlative studies to define the molecular features of those who achieve disease control are awaited (Kulke et al. 2007; Tang et al. 2009). Kulke and colleagues demonstrated a response rate of 10%, and a median survival of 6.5 months in a phase II study of erlotinib and capecitabine in 30 patients. Paradoxically, the survival in second-line studies was comparable to or greater than that seen in first line, likely due to selection of a better group of patients who maintain a decent performance status despite failing first-line therapy. Patients with adequate performance status who have progressed after first-line therapy should certainly be considered for clinical trials.
8.3.4 Summary and Future Directions Despite a high level of clinical trial activity over the past decade, effective therapies for advanced metastatic pancreatic cancer remain elusive. Almost all the phase III studies conducted were negative, suggesting that better clinical trial methodologies and criteria for the phase II/III transition are required. Standard options for first-line treatment include gemcitabine alone, or gemcitabine combined with erlotinib. 5-FU with oxaliplatin demonstrated a survival benefit in one study in the second-line setting. Patients with reasonable performance status should be enrolled onto clinical trials if feasible. While it has been a discouraging decade for new therapeutics development in pancreatic cancer, there is cause for some optimism. A greater understanding of the genetic complexity and heterogeneity of the disease is emerging. The International Genome Sequencing Consortium will characterize the entire genome of 500 human pancreatic cancers and create xenografts for preclinical testing of new therapies. This will be an invaluable resource to better understand the development and progression of this disease. Jones and colleagues from Johns Hopkins sequenced over 20,000 protein coding genes in 24 pancreatic cancers (Jones et al. 2008). The average number of genetic mutations was 63 and while there was marked heterogeneity in the pathways affected and the mutations in those pathways, they were clustered into abnormalities in 12 core signaling pathways. These were apoptosis, K-ras signaling, DNA damage control, hedgehog signaling, regulation of G1/S transition, integrin signaling, homophilic cell adhesion, JNK signaling, regulation of invasion, TGF-b signaling, Wnt/Notch signaling and non K-ras GTPase dependent signaling. The pathways are important clues to unlocking the mystery of pancreatic cancer and drugs targeting most of these key pathways are now coming into phase I and II testing. The clinical trials need to be linked to the genetics and biology of pancreatic cancer. Tissue collection to define predictive markers needs to be included in these studies as has been done with EGFR inhibitors in colorectal cancer (Jones et al. 2008; Lynch et al. 2004; Karapetis et al. 2008; Peeters et al. 2009). This will provide better therapeutic and economic efficiency (Van Cutsem et al. 2007c). Given the genetic complexity, it seems likely that effective control of pancreatic cancer will require combinations of targeted agents and a personalized approach to treatment based on the individual genotype and phenotype.
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8.4 Summary Pancreatic cancer is a common and deadly disease. Most patients present with unresectable locally advanced or metastatic disease and the median survival is 6–9 months. For LAPC, standard approaches include gemcitabine-based chemotherapy alone or in combination with 5-FU-based chemoradiotherapy. Treatments under investigation include induction chemotherapy followed by chemoradiotherapy, and the use of biological therapy with radiotherapy in locally advanced disease. For metastatic pancreatic cancer the standard treatments include systemic therapy with gemcitabine or gemcitabine combined with the EGFR tyrosine kinase inhibitor erlotinib. Ongoing and future trials are assessing novel targeted agents alone or in combination. There have been significant advances in the understanding of pancreatic cancer biology but these are yet to translate to better therapies at the bedside. Important areas of future research will include attempts to better understand the link between tumor biology and the clinical course of the disease, and to develop clinical and molecular predictive models that better define therapy for the individual patient.
References Alberts SR, Townley PM, Goldberg RM et al (2003) Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a north central cancer treatment group phase II study. Ann Oncol 14:580–585 Baumann M, Krause M, Dikomey E et al (2007) EGFR-targeted anti-cancer drugs in radiotherapy: preclinical evaluation of mechanisms. Radiother Oncol 83:238–248 Blackstock AW, Tepper JE, Niedwiecki D et al (2003) Cancer and leukemia group B (CALGB) 89805: phase II chemoradiation trial using gemcitabine in patients with locoregional adenocarcinoma of the pancreas. Int J Gastrointest Cancer 34:107–116 Bonner JA, Harari PM, Giralt J et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578 Bramhall SR, Schulz J, Nemunaitis J et al (2002) A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 87:161–167 Brodowicz T, Wolfram RM, Kostler WJ et al (2000) Phase II study of gemcitabine in combination with cisplatin in patients with locally advanced and/or metastatic pancreatic cancer. Anticancer Drugs 11:623–628 Burris HA III, Moore MJ, Andersen J et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413 Cascinu S, Labianca R, Catalano V et al (2003) Weekly gemcitabine and cisplatin chemotherapy: a welltolerated but ineffective chemotherapeutic regimen in advanced pancreatic cancer patients. A report from the Italian group for the study of digestive tract cancer (GISCAD). Ann Oncol 14:205–208 Cascinu S, Berardi R, Labianca R et al (2008) Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol 9:39–44
220
D. Renouf et al.
Chang BW, Saif MW (2009) Combining epidermal growth factor receptor inhibitors and radiation therapy in pancreatic cancer: small step or giant leap? JOP 10:231–236 Chang DT, Schellenberg D, Shen J et al (2009) Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. Cancer 115:665–672 Chauffert B, Mornex F, Bonnetain F et al (2008) Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 19:1592–1599 Ciardiello F, Caputo R, Troiani T et al (2001) Antisense oligonucleotides targeting the epidermal growth factor receptor inhibit proliferation, induce apoptosis, and cooperate with cytotoxic drugs in human cancer cell lines. Int J Cancer 93:172–178 Cohen SJ, Dobelbower R Jr, Lipsitz S et al (2005) A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys 62:1345–1350 Colucci G, Giuliani F, Gebbia V et al (2002) Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the gruppo oncologia dell’italia meridionale. Cancer 94:902–910 Colucci G, Labianca R, Costanza V et al (2009) A randomized trial of gemcitabine versus gemcitabine plus cisplatin in chemotherapy-naive advanced pancreatic adenocarcinoma: the GIP-1 (gruppo italiano pancreas- GOIM/GISCAD/GOIRC) study. J Clin Oncol 27 (Abstr 4504) Crown J, Casper ES, Botet J et al (1991) Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma. J Clin Oncol 9:1682–1686 Cunningham D, Chau I, Stocken D et al (2005) Phase III randomised comparison of gemicitabine (GEM) with gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer Suppl 3:12 Cunningham D, Chau I, Stocken DD et al (2009) Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 27:5513–5518 Czito BG, Willett CG, Bendell JC et al (2006) Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results. J Clin Oncol 24:656–662 Dhillon N, Aggarwal BB, Newman RA et al (2008) Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14:4491–4499 Duffy A, Kortmansky J, Schwartz GK et al (2008) A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma. Ann Oncol 19:86–91 Gastrointestinal Tumor Study Group (1988) Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 80:751–755 Glimelius B, Hoffman K, Sjoden PO et al (1996) Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 7:593–600 Hazel JJ, Thirlwell MP, Huggins M et al (1981) Multi-drug chemotherapy with and without radiation for carcinoma of the stomach and pancreas: a prospective randomized trial. J Can Assoc Radiol 32:164–165 Heinemann V, Wilke H, Mergenthaler HG et al (2000) Gemcitabine and cisplatin in the treatment of advanced or metastatic pancreatic cancer. Ann Oncol 11:1399–1403 Heinemann V, Quietzsch D, Gieseler F et al (2006) Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 24: 3946–3952 Heinemann V, Labianca R, Hinke A et al (2007) Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic
8 Unresectable Pancreatic Cancer
221
c ancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a german multicenter study. Ann Oncol 18:1652–1659 Herrmann R, Bodoky G, Ruhstaller T et al (2007) Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 25:2212–2217 Hess V, Salzberg M, Borner M et al (2003) Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: a phase I/II trial. J Clin Oncol 21:66–68 Hochster HS (2003) Newer approaches to gemcitabine-based therapy of pancreatic cancer: fixeddose-rate infusion and novel agents. Int J Radiat Oncol Biol Phys 56:24–30 Hofheinz R, Wenz F, Post S et al (2009) Capecitabine (cape) versus 5-fluorouracil (5-FU)-based neo-adjuvant chemotherapy for locally advanced rectal cancer (LARC): safety results of a randomized, phase III trial. J Clin Oncol 27:4014 Hoyer M, Roed H, Sengelov L et al (2005) Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol 76:48–53 Huang SM, Harari PM (2000) Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res 6:2166–2174 Hughes AN, O’Brien ME, Petty WJ et al (2009) Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers. J Clin Oncol 27:1220–1226 Huguet F, Andre T, Hammel P et al (2007) Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol 25:326–331 Huguet F, Girard N, Guerche CS et al (2009) Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol 27:2269–2277 Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342 Iannitti D, Dipetrillo T, Akerman P et al (2005) Erlotinib and chemoradiation followed by maintenance erlotinib for locally advanced pancreatic cancer: a phase I study. Am J Clin Oncol 28:570–575 Jemal A, Siegel R, Ward E et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96 Jones S, Zhang X, Parsons DW et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806 Jonker DJ, O’Callaghan CJ, Karapetis CS et al (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048 Karapetis CS, Khambata-Ford S, Jonker DJ et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765 Katz MH, Pisters PW, Evans DB et al (2008) Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg 206:833–846; discussion 846–848 Kindler HL, Friberg G, Singh DA et al (2005) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23:8033–8040 Kindler H, Niedzwiecki D, Hollis D et al (2007) A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine puls placebo (P) in patients (pts) with a dvanced pancreatic cancer (PC): a preliminary analysis of cancer and leukemia group B (CALGB). J Clin Oncol 25 (Abstr 4508) Kindler HL, Gangadhar T, Karrison T et al (2008) Final analysis of a randomized phase II study of bevacizumab (B) and gemcitabine (G) plus cetuximab (C) or erlotinib (E) in patients (pts) with advanced pancreatic cancer (PC). J Clin Oncol 26 (Abstr 4502) Klaassen DJ, MacIntyre JM, Catton GE et al (1985) Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil – an Eastern Cooperative Oncology Group study. J Clin Oncol 3:373–378
222
D. Renouf et al.
Ko AH, Quivey JM, Venook AP et al (2007) A phase II study of fixed-dose rate gemcitabine plus low-dose cisplatin followed by consolidative chemoradiation for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 68:809–816 Krishnan S, Rana V, Janjan NA et al (2007) Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer 110:47–55 Krzyzanowska MK, Weeks JC, Earle CC (2003) Treatment of locally advanced pancreatic cancer in the real world: population-based practices and effectiveness. J Clin Oncol 21:3409–3414 Kulke MH, Blaszkowsky LS, Ryan DP et al (2007) Capecitabine plus erlotinib in gemcitabinerefractory advanced pancreatic cancer. J Clin Oncol 25:4787–4792 Li CP, Chao Y, Chi KH et al (2003) Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study. Int J Radiat Oncol Biol Phys 57:98–104 Loehrer PJ, Powell ME, Cardenes HR et al (2008) A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer. J Clin Oncol 26:4506 Louvet C, Andre T, Lledo G et al (2002) Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study. J Clin Oncol 20:1512–1518 Louvet C, Labianca R, Hammel P et al (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509–3516 Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139 Mallinson CN, Rake MO, Cocking JB et al (1980) Chemotherapy in pancreatic cancer: results of a controlled, prospective, randomised, multicentre trial. Br Med J 281:1589–1591 Mamon HJ, Niedzwiecki D, Hollis DR et al (2005) Preliminary analysis of cancer and leukemia group B (CALGB) 80003: a phase II trial of gemcitabine, 5-fluorouracil (5FU), and radiation therapy (RT) in locally advanced non-metastatic pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys 63:s13 Maurel J, Martin-Richard M, Conill C et al (2006) Phase I trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion, in locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 66:1391–1398 Moertel CG, Frytak S, Hahn RG et al (1981) Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: the gastrointestinal tumor study group. Cancer 48:1705–1710 Moore MJ, Hamm J, Dancey J et al (2003) Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the national cancer institute of Canada clinical trials group. J Clin Oncol 21:3296–3302 Moore MJ, Goldstein D, Hamm J et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966 Munter M, Timke C, Abdollahi A et al (2008) Final results of a phase II trial [PARC-study ISRCTN56652283] for patients with primary inoperable locally advanced pancreatic cancer combining intensity-modulated radiotherapy (IMRT) with cetuximab and gemcitabine. J Clin Oncol 26 (Abstr 4613) Oettle H, Richards D, Ramanathan RK et al (2005) A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 16:1639–1645
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O’Reilly R, Abou-Alfa G, Letourneau R et al (2004) A randomized phase III trial of DX-8951f (exatecan mesylate; DX) and gemicitabine (GEM) vs. gemcitabine alone in advanced pancreatic cancer (APC). J Clin Oncol 23 (Abstr LBA4006) Palmer KR, Kerr M, Knowles G et al (1994) Chemotherapy prolongs survival in inoperable pancreatic carcinoma. Br J Surg 81:882–885 Peeters M, Siena S, Van Cutsem E et al (2009) Association of progression-free survival, overall survival, and patient-reported outcomes by skin toxicity and KRAS status in patients receiving panitumumab monotherapy. Cancer 97(11):1469–1474 Pelzer U, Kubica K, Stieler J et al (2008) A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. J Clin Oncol 26 (Abstr 4508) Philip PA, Zalupski MM, Vaitkevicius VK et al (2001) Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma. Cancer 92:569–577 Philp P, Benedetti J, Fenoglio-Preiser C et al (2007) Phase III study of gemcitabine [G] plus cetuximan [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. J Clin Oncol 25 (Abstr LBA4509) Poplin E, Levy D, Berlin J et al (2006) Phase III trial of gemitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion [FDR] versus gemcitabine + oxaliplatin (GEMOX) in patients with advanced pancreatic cancer (E6201). J Clin Oncol 25 (Abstr LBA4004) Poplin E, Feng Y, Berlin J et al (2009) Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27:3778–3785 Rich T, Harris J, Abrams R et al (2004) Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12. Am J Clin Oncol 27:51–56 Rocha Lima CM, Green MR, Rotche R et al (2004) Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22: 3776–3783 Ruano-Ravina A, Almazan Ortega R, Guedea F (2008) Intraoperative radiotherapy in pancreatic cancer: a systematic review. Radiother Oncol 87:318–325 Saif MW, Eloubeidi MA, Russo S et al (2005) Phase I study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: expression analysis of genes related to outcome. J Clin Oncol 23:8679–8687 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 355:2542–2550 Scheithauer W, Schull B, Ulrich-Pur H et al (2003) Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann Oncol 14:97–104 Schneider BJ, Ben-Josef E, McGinn CJ et al (2005) Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 63:1325–1330 Shepard RC, Levy DE, Berlin JD et al (2004) Phase II study of gemcitabine in combination with docetaxel in patients with advanced pancreatic carcinoma (E1298). A trial of the Eastern Cooperative Oncology Group. Oncology 66:303–309 Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al (2005) Erlotinib in previously treated nonsmall-cell lung cancer. N Engl J Med 353:123–132 Shinchi H, Takao S, Noma H et al (2002) Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 53:146–150 Spano JP, Chodkiewicz C, Maurel J et al (2008) Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 371:2101–2108
224
D. Renouf et al.
Stathopoulos GP, Syrigos K, Aravantinos G et al (2006) A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer 95:587–592 Sultana A, Tudur Smith C, Cunningham D et al (2007) Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy. Br J Cancer 96:1183–1190 Talamonti MS, Catalano PJ, Vaughn DJ et al (2000) Eastern Cooperative Oncology Group phase I trial of protracted venous infusion fluorouracil plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer: a regimen with unexpected early toxicity. J Clin Oncol 18:3384–3389 Tang P, Gill S, Au HJ et al (2009) Phase II trial of erlotinib in advanced pancreatic cancer. J Clin Oncol 27:4609 Tempero M, Plunkett W, Ruiz Van Haperen V et al (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21:3402–3408 Touroutoglou N, Gravel D, Raber MN et al (1998) Clinical results of a pharmacodynamicallybased strategy for higher dosing of gemcitabine in patients with solid tumors. Ann Oncol 9:1003–1008 Van Cutsem E, van de Velde H, Karasek P et al (2004) Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430–1438 Van Cutsem E, Peeters M, Siena S et al (2007a) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapyrefractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664 Van Cutsem E, Humblet Y, Gelderblom H et al (2007) Cetuximab dose-escalation study in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): pharmacokinetic and efficacy data of a randomized study. Proceedings of the Gastrointestinal Cancers Symposium (Abstr 237) Van Cutsem E, Verslype C, Grusenmeyer PA (2007c) Lessons learned in the management of advanced pancreatic cancer. J Clin Oncol 25:1949–1952 Van Cutsem E, Vervenne WL, Bennouna J et al (2009) Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 27:2231–2237 Wilkowski R, Boeck S, Ostermaier S et al (2009) Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer – a multi-centre randomised phase II study. Br J Cancer 101:1853–1859 Wolpin BM, Hezel AF, Abrams T et al (2009) Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol 27:193–198 Xiong HQ, Rosenberg A, LoBuglio A et al (2004) Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol 22:2610–2616 Yip D, Karapetis C, Strickland A et al (2006) Chemotherapy and radiotherapy for inoperable advanced pancreatic cancer. Cochrane Database Syst Rev 3:CD002093
Liver Cancer
9
Joseph D. Thomas, George A. Poultsides, Timothy M. Pawlick, and Melanie B. Thomas
9.1 Introduction The most common primary malignancy of the liver in adults is hepatocellular carcinoma (HCC). It is currently the fifth most common solid tumor worldwide, and the third leading cause of cancer-related death (Jemal et al. 2005). HCC is a particularly lethal disease, as evidenced by roughly equal annual incidence and mortality rates (Jemal et al. 2004). A majority of HCC patients have underlying cirrhosis and hepatic dysfunction, which significantly complicates patient care. HCC is a highly heterogeneous malignancy and due to this prevalence of cirrhosis, HCC patients present the challenges of “one patient with two diseases.” Multidisciplinary management of HCC patients is critical to safely and effectively optimizing the available treatment options for HCC patients. Encouraging progress has been made in several aspects of HCC management, such as improved treatment of viral hepatitis, increased screening of patients at high-risk for developing HCC, improved patient selection for liver transplantation and surgical resection, and approval of the oral anti-cancer agent sorafenib for treatment of advanced HCC.
9.2 Epidemiology and Risk Factors The prevalence of HCC varies greatly depending on geographic location, but 80% of new HCC cases occur in developing countries, principally in Eastern Asia and SubSaharan Africa (Bosch et al. 2004). The incidence of HCC is rising in economically developed regions, including Japan, Western Europe, and the United States. In the United
J.D. Thomas, G.A. Poultsides, T.M. Pawlick, and M.B. Thomas (*) Hollings Cancer Center, A National Cancer Institute Designated Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA e-mail:
[email protected] C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_9, © Springer-Verlag Berlin Heidelberg 2011
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States, an estimated 22,620 new cases of primary liver cancer are expected in 2009 (El-Serag 2002). This incidence is predicted to rise significantly in ensuing years due to the estimated 4,000,000 hepatitis-C virus exposed individuals in the U.S (El-Serag and Rudolph 2007; NIH 2002). In addition to variations in HCC by geographical location, the incidence of HCC has been shown to differ based on age, gender, and race. Men are typically affected two to three times as often as women, Asians are affected twice as often as African Americans, and Caucasians are affected two to three times less than African Americans. There has also been a recent shift in incidence off HCC from the elderly population to younger patients. The mean age of patients diagnosed with HCC in the US is 65, with the peak incidence between 70 and 75 years (El-Serag 2002). However, recent trends show the greatest increase in incidence has now shifted to men between the ages of 40 and 60. The primary risk factor for HCC is hepatic cirrhosis, but a moderate number of patients develop HCC in the absence of cirrhosis. HCC is most commonly associated with chronic viral hepatitis (HBV and HCV). Worldwide, the hepatitis B virus is the most frequent underlying cause of HCC, and case control studies have estimated that chronic HBV carriers were at a 5–15 times increase risk of and it has been estimated that the risk of HCC could be increased up to 17 times in an HCV infected patient (Chu and Liaw 2006). Other diseases that result in liver cell injury and lead to fibrosis also increase the risk of HCC. HCC has been demonstrated in alpha 1 antitrypsin deficiency, hereditary tyrosinemia, Wilson’s disease, and Primary Biliary Cirrhosis, each with variable risk. Hemochromatosis is a significant risk factor for HCC with an increased relative risk of 200 times that of the normal population. Other risk factors identified include nonalcoholic fatty liver disease, excessive alcohol consumption, and environmental toxins such as aflatoxin B1 a carcinogenic mycotoxin ubiquitous to contaminated food in the developing world. The combination of insulin resistance, hypertension, and hypercholesterolemia, termed “metabolic syndrome,” along with diabetes, obesity, steroid abuse, and long-term use of estrogen-containing drugs have been identified as risk factors as well (Smedile and Bugianesi 2005; Oh et al. 2005; El-Serag et al. 2006; Nissen and Martin 2002).
9.3 Clinical Presentation The clinical presentation of HCC varies greatly depending on both time of diagnosis, as well as geographical region of the world (Bialecki and Di Bisceglie 2002, 2005). In developed countries such as the US, HCC is rare before age 40, and is usually found as a part of routine screening tests of high-risk individuals, or as a result of hepatic decompensation and clinical deterioration. However, in high risk areas such as Africa, patients often present with large painful masses in their early 20s and 30s. Several studies have acknowledged a difference in presentation, depending on whether the HCC presents in the setting of cirrhosis. Cirrhotic patients often present with hepatic decompensation, which leads to ascites, encephalopathy, jaundice, and variceal bleeding.
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Noncirrhotic patients are more likely to present with more constitutional symptoms such as weight loss, anorexia, or malaise. Abdominal pain is the most frequent complaint of both noncirrhotic and cirrhotic patients, while cirrhotic patients are more likely to have hepatomegaly on physical exam, and noncirrhotics are more likely to have abdominal distension. Other symptoms at time of presentation include paraneoplastic syndromes, hypoglycemia, diarrhea, nausea or vomiting, painless jaundice secondary to obstruction, cholangitis, fever, and in rare cases peritonitis from tumor rupture. Other patients are relatively asymptomatic, and they are diagnosed as a result of a screening test or radiological exam for another condition.
9.4 Liver Disease and HCC A majority of HCC (60–80%) arise in a background of chronic hepatitis and cirrhosis, which is characterized by inflammatory cell infiltration, hepatocyte regeneration, necrosis, and parenchymal remodeling. Liver injury triggers activation of hepatic stellate cells (SCs), which are resting fibroblasts and a major storage site in the liver for retinoids and extracellular matrix. SC activation results in release of chemotactic cytokines, inflammatory cell recruitment and infiltration, growth factor upregulation, and release of proteases. Residual hepatocytes are stimulated to proliferate, and eventually, there is remodeling of the hepatic sinusoids and subdivision of liver parenchyma by fibrous septae, resulting in cirrhosis (Hino et al. 2002). Cirrhosis can have a profound impact on tolerance and efficacy of anticancer drug therapy. The liver is central to the metabolism of virtually every foreign and endogenous substance in the body. Hepatic metabolism involves oxidative pathways, primarily via the CYP450 enzyme system, and additional metabolic steps, which include conjugation to a glucuronide, a sulfate, or glutathione. In cirrhosis, the total liver cell mass is reduced and distortion of the microcirculation of the liver and collagen deposition leads to impaired sinusoidal transport and reduced extraction of protein-bound substances. Hepatic cirrhosis not only decreases drug metabolizing enzyme activity, but it also alters the absorption, plasma protein binding, distribution, and renal excretion of drugs. Intrahepatic vascular shunts that develop as a consequence of cirrhosis, allow drugs to be routed around hepatocytes, thus decreasing their first-pass extraction. However, all routes of hepatic metabolism are not equally impaired. As hepatic dysfunction progresses in cirrhotic patients, reduced synthesis of albumin occurs that leads to a decrease in plasma protein binding of drugs. For drugs that are more than 90% protein-bound, this increase in the free drug fraction may be substantial and may have clinical consequences. The CYP3A4 subfamily, the most common hepatic enzyme in adult humans, oxidizes over 50% of currently used drugs. Several studies have shown significant decreases in the CYP3A protein levels in patients with cirrhosis, although contradictory data does exist. Therefore, it is difficult to predict the disposition of a drug in liver disease, and each agent must be studied individually to provide a rationale for adjusting doses (Elbekai et al. 2004).
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9.5 Diagnosis and Staging With the varying clinical presentations of HCC, several imaging modalities can assist in the diagnosis of HCC. Ultrasound and serum alpha-fetoprotein (AFP) levels are most often used as screening tests in high risk individuals, while imaging studies such as computed tomography (CT) scan and MRI have become the diagnostic procedures of choice (Befeler and Di Bisceglie 2002). The development of tri-phasic CT scanning and improved MRI equipment has led to greater sensitivity and specificity in diagnosis and many patients are now being diagnosed at an asymptomatic stage. Core biopsy of the liver is also used as a histological means to confirm the diagnosis, but is not being performed as routinely as it was in the past because of the increasing availability of advanced radiological techniques.
9.6 Alpha Fetoprotein Serum AFP is most commonly used as a screening test; however it has been shown to have a poor positive predictive value, as well as a low sensitivity and specificity (Gambarin-Gelwan et al. 2000; Nakamura et al. 2006). AFP levels can be normal in up to 30% of patients at time of diagnosis. Serum AFP levels of 400–500 mg/mL are considered diagnostic for HCC, although elevations of AFP can also be seen in other diseases such as germ cell tumors, gastric cancer, lung cancer, as well as chronic inflammatory states such as viral hepatitis. Several studies have demonstrated that significantly elevated levels of AFP related to HCC correlate with tumor size, aggressiveness, and a worsening prognosis with a lower median survival rate. AFP can also be useful as a way to monitor tumor progression, the response to treatment, or detecting the recurrence of disease. AFP has a short half-life and the level will change within a few days after proliferation, removal or destruction of tumor cells (Sassa et al. 1999).
9.6.1 Ultrasound Ultrasound of the abdomen is a noninvasive, safe imaging modality that is commonly used for screening individuals at risk for developing HCC, due to its relatively high sensitivity to detect very small intrahepatic lesions (Liao et al. 2008). Abdominal US with the addition of Doppler are frequently used for the assessment of vascular invasion of HCC, and can differentiate tumor invasion into the portal vein from a bland or non-tumor thrombus. US also can visualize the biliary structures, ductal dilatation, as well as detect hilar adenopathy, which is helpful in the staging process. The role of US in diagnosis of HCC is limited however, because of the improvement and wide availability of CT and MRI, as well as a low sensitivity and predictive value of US in the setting of cirrhosis. US is an imaging option for patients in whom iodinated contrast media is contraindicated.
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9.6.2 MRI The use of MRI in the diagnosis of HCC has increased substantially with the development and improvement of MRI scanners, software, and techniques. For some physicians, MRI has become the preferred diagnostic procedure because of its ability to detect and characterize hepatic lesions. Gadolinium enhancement of HCC during various stages of hepatic circulation, help improve characterization of HCC, and because of its ability to detect vascular invasion, it is the best tool to differentiate HCC from hepatic hemangioma (Secil et al. 2008). MRI sensitivity is lowest when evaluating small tumors less than 2 cm, but overall it is more accurate than CT or US in detecting HCC and estimating actual tumor size. It is also more effective than CT in detecting HCC in patients with cirrhosis.
9.6.3 CT In addition to MRI, CT scanning is another advanced imaging technique used for the diagnosis and staging of HCC. Evaluation for HCC has improved greatly with the use of spiral CT scanners and advanced imaging protocols. Spiral scanners allow for very rapid imaging of the liver, while the use of triphasic imaging provides images during three different phases of contrast administration. HCC is typically supplied with blood from the hepatic artery while the surrounding liver parenchyma receives both arterial and portal venous blood. Therefore, triphasic CT scanning is able to differentiate tumor cells from normal tissue utilizing images before contrast, during the arterial phase, as well as the portal venous phase. HCC is a hypervascular tissue and tends to enhance during the first 2–40 s of contrast administration, or the arterial phase, while the liver parenchyma enhances most notably at 50–90 s after contrast administration, or during the portal venous phase. HCC frequently can be found with satellite nodules surrounding the primary lesion, and typically appears heterogeneous on CT, secondary to the fibrotic and/or necrotic characteristics of the tumor tissue (Shinmura et al. 2008; Kitamura et al. 2008).
9.6.4 Liver Biopsy Liver biopsy is still the gold standard when diagnosing HCC, as histological examination is the only true way to confirm the diagnosis. It is superior to any other diagnostic test in sensitivity and specificity, and is a safe, efficient, and an effective confirmatory test. A fine needle aspiration biopsy is performed most frequently with CT or US guidance, but depending on the circumstances, an open surgical biopsy can also be performed. Recently, liver biopsy has become somewhat controversial because of case reports of HCC being spread along biopsy needle tracks. These case reports are rare, but with the increasing availability of CT and MRI, some specialists argue that when patients can potentially be cured by liver transplantation or resection, biopsy is unnecessary after a thorough radiological, clinical, and laboratory evaluation.
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9.7 Staging and Prognostic Systems in HCC HCC staging is an important prognostic tool that provides a classification framework, to help guide and plan treatment. Over the years, various staging systems have been developed, none of which is universally adopted. HCC is more difficult to stage and prognosticate than other solid tumors, because most HCC patients have underlying liver dysfunction in addition to a tumor burden. The amount of liver dysfunction and degree of cirrhosis is one of the most important variables in predicting survival, and helps determine what treatment can be offered. Knowledge of the various HCC staging systems is important to understanding the heterogeneity of HCC patients, and as a basis for treatment decision making. The Okuda classification for HCC is the most widely used classification system and has been in place for over a decade It is a point based system based on bilirubin, albumin, ascites, and tumor size (>50%, <50%). It was the first classification system to account for both severity of liver dysfunction as well as tumor burden. One of the limitations of the system, however, is that it has a very narrow definition of tumor size, and does not include other factors which have prognostic significance such as vascular invasion, or multifocality. It has also been shown to have lower predictive capacity, when compared to some of the newer staging systems. The Childs–Pugh and TMN staging systems are uni-dimensional prognostic systems that only account for one of the two prognostic variables of HCC. TMN only addresses the tumor itself, while Childs–Pugh only accounts for degree of hepatic dysfunction. Childs– Pugh uses ascites, encephalopathy, serum bilirubin, serum albumin, and prothrombin time as variables, but despite its limitations, has been shown to offer significant prognostic information. The TMN system, as modified in 2002, describes tumor morphology, vascular invasion, and metastasis, but does not account for any abnormalities in liver functional status. This limitation has restricted its use, which is often limited to the surgical setting. The Chinese University Prognostic Index (CUPI) considers six variables and divides patients into three stages. The tumor itself is evaluated by the TNM staging system and AFP level, while liver function is evaluated on the basis of ascites, bilirubin, alkaline phosphatase, and fibrosis. It is one of the newer staging systems that has shown promise when compared to the Okuda and Cancer of the Liver Italian Program (CLIP) staging systems, but it is now as widely accepted as some of the other staging systems while still being validated. The Barcelona Clinic Liver Cancer Staging System (BCLC) is a four stage system that links variables related to tumor stage, liver functional status, physical status, and cancer related symptoms, into a complex treatment algorithm. It is currently the only staging system to account for the patients’ performance status, and is clinically useful because of its treatment algorithm. CLIP is a seven stage classification system based upon four variables. It uses the Childs–Pugh class to evaluate hepatic dysfunction, but also addresses tumor characteristics including tumor morphology, portal vein thrombosis, and alpha- fetoprotein (AFP) levels (Tables 9.1 and 9.2).
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Three stage system, based on four variables (1) Bilirubin: <3 (0 points) >3 (1 point) (2) Albumin: >3 (0 points) <3 (1 point) (3) Ascites: Absent (0 points) Present (1 point) (4) Tumor Size on cross section: <50% (0 points) >50% (1 point) Stage 1: 0 total points Stage 2: 1–2 total points Stage 3: 3–4 total points
Childs–Pugh
Classification system divided into Class A, B, C, based on a score that is calculated from five variables (1) Ascites: Absent (1 point) Mild/diuretic responsive (2 points) Severe/diuretic resistant (3 points) (2) Encephalopathy: None (1 point) Grade 1–2 (2 points) Grade 3–4 (3 points) (3) Bilirubin: <2 mg/dL (1 point) 2–3 mg/dL (2 points) >3 mg/dL (3 points) (4) International normalized ratio (INR): <1.7 (1 point) 1.7–2.3 (2 points) >2.3 (3 points) (5) Albumin: >3.5 g/dL (1 point) 2.8–3.5 g/dL (2 points) <2.8 g/dL (3 points) Class A: 5–6 total points Class B: 7–9 total points Class C: 10–15 total points
Cancer of the Liver Italian program (CLIP)
Seven Stage Score (0–6) based on four variables (1) Childs–Pugh: A (0 points) B (1 point) C (2 points)
References Okuda et al. (1985)
The Cancer of the Liver Italian Program (CLIP) Investigators (2000) (continued)
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Features
References
(2) Alpha fetoprotein (AFP): <400 ng/dL (0 points) >400 ng/dL (1 point) (3) Portal vein thrombosis: Yes (0 points) No (1 point) (4) Tumor extension/morphology: Uninodular and extension less than or equal to 50% (0 points) Multinodular and extension less than or equal to 50% (1 point) Massive or extension >50% (2 points) Leung et al. (2002)
Chinese University Prognostic Index (CUPI)
Three stage system group into three risk groups, low, intermediate and high (1) TMN stage I and II (−3 points) IIIa and IIIb (−1 points) IVa and IVb (0 points) (2) Serum bilirubin (mmol/L) <34 (0 points) 34–51 (3 points) ³52 (4 points) (3) Serum alkaline phosphatase ³200 (3 points) (4) Serum AFP ³500 ng/dL (2 points) (5) Ascites Yes (3 points) (6) Asymptomatic on presentation Yes (−4 points) Low risk: Score £1 Intermediate risk: Score 2–7 High risk: Score ³8
American Joint Committee on Cancer (AJCC) TNM
Categorical staging system with stages I–IV based on Vauthey et al. (2002) tumor size and number (T), lymph nodes involved (N), and presence of metastasis (M), does not use any laboratory values or account for cirrhosis T (primary tumor size, number and location) T0 No evidence of primary tumor T1 Solitary tumor £2 cm without vascular invasion T2 Solitary tumor £2 cm with vascular invasion OR Multiple tumors in 1 lobe £2 cm without vascular invasion OR Solitary tumor >2 cm without vascular invasion
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Features T3 Solitary tumor >2 cm with vascular invasion OR Multiple tumors in one lobe £2 cm with vascular invasion OR Multiple tumors in one lobe >2 cm with or without vascular invasion T4 Multiple tumors in more than one lobe OR Invasion of a major branch of hepatic or portal vein OR Invasion of adjacent organs other than the gallbladder OR Perforation of visceral peritoneum N (nodal metastasis) N0 No regional lymph node metastasis N1 Regional lymph node metastasis M (distant metastasis) M0 No distant metastasis M1 distant metastasis Fibrosis score (F)a F0 Fibrosis score 0–4 (none to moderate fibrosis) F! Fibrosis score 5–6 ( severe fibrosis or cirrhosis) Stages Stage I T1N0M0 Stage II T2N0M0 Stage IIIA T3N0M0 Stage IIIB T1N1M0 or T2N1M0 or T3N1M0 Stage IVA T4, any N, M1 Stage IVB Any T, any N, M1
Barcelona Cancer Liver Clinic (BCLC)
Four stage (A–D) categorical staging system, only staging system to account for performance status Stage A: all criteria need to be met Stage B: all criteria need to be met Stage C: Must include either Performance Status 1–2, or extrahepatic spread/vascular invasion Stage D: Must include either Performance Status 3–4 or Okuda III/ Childs–Pugh C (Llovet et al. 1999a)
Fibrosis score as defined by Ishak (Ishak H hepatol 1995)
a
References
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Table 9.2 Barcelona Cancer of the Liver Clinic Staging System Stage Performance Tumor stage Okuda Liver functional status status Stage A: early HCC A1
0
Single, <5 cm
I
Bilirubin normal and no portal hypertension
A2
0
Single, <5 cm
I
Bilirubin normal and portal hypertension
A3
0
Single, <5 cm
I
Bilirubin increased and portal hypertension
A4
0
Three nodules <3 cm I–II
Child–Pugh class A or B
Stage B: intermediate 0 HCC
Multinodular
I–II
Child–Pugh class A or B
Stage C: advanced HCC
1–2
Vascular invasion or extrahepatic spread
I–II
Child–Pugh class A or B
Stage D: end-stage HCC
3–4
Any
III
Child–Pugh class C
9.8 Treatment of HCC The optimal management of patients with HCC requires multidisciplinary care, including potential input from surgical oncology, liver transplantation, diagnostic imaging, interventional radiology, anatomic pathology, and medical oncology. Many academic centers have established multidisciplinary liver clinics and/or liver conferences which can address this important need. Since as discussed previously, there are several staging and prognostic systems for HCC, but at present not one that has been validated across a wide spectrum of HCC patients, nor universally accepted, the evidence-based management of HCC patients follows a treatment “algorithm” at many institutions (Fig. 9.1).
9.9 Surgical Resection The standard surgical management for HCC consists of resection or liver transplantation. However, of patients initially presenting with HCC only 10–30% will be eligible for surgery (Choi et al. 2006). Patients with cirrhosis may be candidates for limited surgical
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9 Liver Cancer
Assess tumor size, location ? extrahepatic metastases
Potentially resectable
Assess serverity of liver disease
Unresectable
Child-pugh C
Liver transplant candidate? Yes
No Child-pugh A/B*
Optimize medical therapy, consider PVE
Intraoperative evaluation
Resect
Evaluate for transplant
Liver only
Tumor Size, number
>5 cm Systemic therapy
Unresectable Single £5 cm
Consider intraopertive ETOH injetion, RFA, cryoablation
RFA PEI/cryoblation, TACE, stereotactic radiotheraphy, or radiotherapeutic microspheres may be alternatives depending on tumor charcteristics, location, and local expertise
Consider “bridging” therapy,eg, TACE
Extrahepatic mets
Multiple £5 cm
>4 lesions
£4 lesions
Fig. 9.1 General treatment algorithm for hepatocellular carcinoma (HCC) (Clark et al. 2005); (Palavecino et al. 2009). PVE portal vein embolization; RFA radiofrequency ablation; PEI percutaneous ethanol injection; TACE transarterial chemoembolization. * Suitability of patients with Child–Pugh B cirrhosis for surgical resection is highly controversial. Systemic therapy options include participation in a clinical trial (preferred) or sorafenib
resection, liver transplantation, or locoregional ablative treatment, depending on the severity of the cirrhosis. In general, the treatment of HCC is predicated on not only the extent of underlying tumor, but also the level of hepatic dysfunction. Specifically, in patients with
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no evidence of cirrhosis, hepatic resection has been the mainstay of surgical treatment. In patients with severely cirrhotic livers (Child–Pugh class B or C) transplantation is optimal therapy for HCC, as it addresses simultaneously the neoplasm and the underlying liver dysfunction. The ideal treatment strategy for small HCC in patients with mild cirrhosis may involve resection or transplantation, and is more controversial. However, due to lack of organ availability as well as cultural and economic reasons, surgical resection is the primary therapy for many patients with HCC worldwide. The selection of patients for surgical resection is based on several criteria, including the absence of extrahepatic disease, the degree of hepatic dysfunction, and technical considerations such as the adequacy of the Future Liver Remnant (FLR), and tumor involvement of major vascular structures, such as the portal vein or vena cava. Patients with normal liver parenchyma are usually eligible for extensive resection, whereas patients with compensated cirrhosis may be candidates for minor or major hepatectomy in selected cases. Surgery in patients with underlying cirrhosis can be associated with substantial morbidity and mortality. Although perioperative mortality can be as high as 30–50% in patients who are Child–Turcotte–Pugh B or C, Child–Turcotte–Pugh A patients have an associated surgical mortality of only 5–10%. Pawlik et al. (2005a) have reported a series of patients who underwent resection of HCC >10 cm with a perioperative mortality of 5%. Ng et al. (2005) evaluated 40 patients with small (<5 cm) and 380 patients with large or multinodular tumors and noted a similar morbidity (27 and 23%, respectively) and mortality (2.4 and 2.7%, respectively) between the two groups studied. More recently, with the combination of better patient selection, as well as better preoperative optimization, peri-operative mortality has further decreased following hepatic resection in well-compensated cirrhotics. Factors limiting the safety of resection include preexisting portal hypertension and decreased hepatic reserve. A potentially severe complication of resection is exacerbation of portal hypertension, which may result in a precipitous decline in hepatic function. In 1999, Llovet et al. (1999b) reported the importance of portal hypertension as a prognostic indicator in cirrhotic patients undergoing resection of HCC. The 5-year survival of resection patients without portal hypertension was 74%, compared to 25% in those with clinically relevant hypertension. The model for end-stage liver disease (MELD) has recently been shown to be a very accurate and easy way to predict accurately postoperative liver failure and mortality. The calculated MELD is based on the patient’s age, serum creatinine, serum bilirubin, and international normalized ratio (INR) levels. Patients with MELD score <9 had a reported mortality rate of zero in two recent large institutional series of patients undergoing resection of HCC (Cucchetti et al. 2006; Teh et al. 2005). For patients with cirrhosis being considered for surgical resection, CT volumetry can be helpful. Accurate identification of patients with an inadequate FLR may allow for subsequent utilization of portal vein embolization (PVE) and offer a safer resection in a subset of patients (Tu et al. 2007). In general, PVE is advocated for patients with underlying cirrhosis who have an FLR less than 40–50% of the total liver volume. PVE in this subset of patients may allow for preoperative hypertrophy of the remnant liver, thereby decreasing the risk of liver insufficiency and failure in the postoperative period. These advancements in patient selection and preoperative optimization have resulted in contemporary perioperative rates of 0–5% for patients with compensated cirrhosis who undergo resection of early HCC (Ng et al. 2005; Pawlik et al. 2005b; Fan et al. 1999; Katz et al. 2009).
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In addition to being safe, surgical resection can be an efficacious therapy for early HCC. In most series, surgical resection of early HCC reported 5-year survival rates of 45–50%, compared with 65–70% for transplantation (Cunningham et al. 2009). However, direct comparison of resection vs. transplantation survival data can be difficult to interpret. The better results with transplantation may reflect – in part – the more stringent selection of patients. In fact, investigators from both the United States (Cha et al. 2003) and Asia (Poon et al. 2002) have reported that partial hepatectomy in patients with early HCC, who were otherwise eligible for transplantation, was associated with a 5-year overall survival rate of 69–70%, which is comparable to that reported for liver transplantation. Other data have similarly confirmed that certain patients with early HCC can have durable long term survival following surgical resection. For example, Izumi et al. (1994) reported a 5-year survival of more than 75% in patients with a solitary HCC tumor without vascular invasion following hepatic resection. In aggregate, these data serve to emphasize that certain subsets of patients can enjoy excellent long-term prognosis following hepatic resection. Some patients with HCC who undergo resection may have smaller and solitary tumors with low histologic grade and no associated vascular invasion (Cho et al. 2008; Nathan et al. 2009; Pawlik et al. 2005c). Unlike transplantation which requires strict tumorspecific criteria for eligibility (e.g., solitary tumor £5 cm or three tumors, the largest being £3 cm), patients being considered for resection, however, may also have more advanced tumor characteristics. Specifically, some patients with advanced HCC who otherwise would not be candidates for transplantation may sometimes be considered for surgical resection. Pawlik et al. (2005a) reported on 300 patients who underwent hepatic resection for HCC 10 cm or larger. In this study, median overall survival was 20 months, and the 5-year actuarial survival rate was 27%. Perhaps more importantly, those patients with large HCC that was solitary and had no vascular invasion had a 5-year survival of greater than 45%. In a separate study, Ng et al. (2005) reported that patients with large or multinodular HCC had a 5-year survival rate of 39%. In contrast, while hepatic resection for HCC with major vascular invasion has been reported to be associated with median survival exceeding historical survival in patients not treated surgically, the 5-year survival rate following resection is only 10% (Pawlik et al. 2005c). Unlike advanced HCC, early HCC (e.g., solitary tumor £5 cm or three tumors, the largest being £3 cm) may often be treated surgical with either resection or transplantation. Resection of early HCC may offer several advantages over transplantation, including more immediate therapy, the availability of pathologic analysis of the resected tumor to better guide the appropriateness of liver transplantation, and, in cases of eventual transplantation, a delay of exposure to the morbidity and mortality of transplantation and immunosuppression. For those patients who have disease progression after resection, salvage transplantation may be a potential treatment option. Reporting on over 450 patients who underwent resection of early HCC, Poon et al. (2002) noted that 80% of patients who recurred had a transplantable recurrence using the same criteria as for primary transplantation. In addition, Belghiti et al. (2003) reported that salvage liver transplantation was as safe and efficacious as primary liver transplantation. Specifically, in this series, global morbidity and perioperative mortality were comparable between primary and salvage liver transplantation. In addition, primary vs. salvage liver transplantation was associated with similar long-term survival rates (59% vs. 61% at 5 years) (Belghiti et al. 2003). The use of
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different therapeutic approaches that incorporate hepatic resection or transplantation should be dictated by the clinical situation (Kim and Hemming 2009; Pawlik 2009). It is important to note that the exact proportion of patients who may qualify for salvage transplantation remains unclear. Whereas some studies (Poon et al. 2002) have estimated that salvage transplantation may be feasible in up to 75–80% of patients with recurrence following hepatic resection, other studies (Del Gaudio et al. 2008; Facciuto et al. 2008) have reported a significantly lower salvage rate in the range of 20%. Further studies will be needed to define the true applicability of salvage transplantation for patients who recur following hepatic resection.
9.10 Liver Transplantation A major pattern of failure after surgical resection for HCC is recurrence with the development of de novo intrahepatic disease. It has been suggested that the hepatic fibrosis, as well as chronic active hepatitis, is responsible for the tendency of the remaining liver to generate new HCCs. As such, while 5-year overall survival rates following resection may be close to 70% following resection of early, “transplantable” HCC, disease-free survival rates have been reported to be low as 36–48% at 5 years (Cha et al. 2003; Poon et al. 2002). For this reason, liver transplantation has been proposed as definitive treatment for HCC, to treat both the tumor as well as the damaged liver parenchyma at risk. Initial results for orthotopic liver transplantation (OLT) for “all stage” HCC were associated with high early recurrence (18%) and lower 5-year survival rates (40%) as compared to other indications for OLT (Ringe et al. 1991). As a result of these discouraging experiences, HCC was considered a contraindication to OLT in many transplantation centers in the early 1990s. Subsequently, on examination of liver explants, it was observed that incidental small HCC, not detected by preoperative imaging, had no adverse impact on the posttransplantation outcome. This observation led to the formulation of the Milan criteria (Bismuth 2000; Mazzaferro et al. 1996). Patients with HCC meeting these criteria (a single tumor less than 5 cm in diameter, or two to three tumors each less than 3 cm) had similar posttransplant survival compared with patients without HCC, with 4-year and recurrence-free survival rates of 75 and 83%, respectively (Mazzaferro et al. 1996). These results have been corroborated by multiple centers and have led to the acceptance of liver transplantation for HCC in cirrhotic patients who fit these criteria. While there exists an interest in expanding the criteria for liver transplantation of patients with HCC to include patients with larger and more numerous tumors (Silva et al. 2008; Yao et al. 2001; Takada et al. 2007), these criteria have not been universally accepted or adopted. One major deterrent to the widespread application of liver transplantation for early HCC is organ availability. In one series, cumulative probabilities for dropout from the liver transplantation list (due to death or the appearance of contraindications) were 7.3, 25.3, and 43.6% at 6, 12, and 24 months, respectively (Yao et al. 2002). Furthermore, in a study of 347 patients from the University of Toronto, although survival associated with liver transplantation was better than resection when measured from the time of surgery, survival
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from time of listing or hepatic resection (intention-to-treat analysis) was not different between the two groups (Shah et al. 2007).This group also noted that patients who waited longer than 4 months for transplantation had over a twofold higher risk of death (Shah et al. 2007). One proposed method of ameliorating the prolonged wait times has been the introduction of live-donor liver transplantation (LDLT); largely pioneered in Asia, where adult-to-adult right lobe liver transplantation is performed more frequently than in the United States or Europe. Although recent studies have reported favorable outcomes for LDLT (Todo et al. 2004), it remains unclear whether these outcomes will be equivalent to that of deceased-donor liver transplantation (DDLT) (Lo et al. 2007).
9.11 Nonresectional Locoregional Therapies For selected patients with HCC confined to the liver, whose disease is not amenable to resection or transplantation, nonresectional locoregional therapies can be considered. These include percutaneous ethanol injection (PEI), cryotherapy, radiofrequency ablation (RFA), and transarterial chemoembolization (TACE). While nonresectional locoregional therapies are generally not considered potentially “curative,” these approaches do allow for destruction of tumors while preserving nontumorous liver parenchyma, and the potential to serve as a bridge to more definitive therapy, such as liver transplantation, or as salvage treatment for postresection recurrence. PEI and cryotherapy have been largely replaced by RFA, secondary to their decreased efficacy (Lin et al. 2005), and associated risks of cholangitis and myoglobinuria-related renal failure, respectively. RFA uses radio waves delivered via an electrode directly inserted into a tumor to create a zone of thermal necrosis to destroy the tumor. Using US or CT guidance, a needle electrode is inserted into the tumor and delivers a high-frequency alternating current, generating rapid vibration of ions, which leads to frictional heat, and eventually coagulative tissue necrosis. RFA can be performed percutaneously, laparoscopically, or through an open incision and is most effective in tumors <3 cm in diameter. Larger tumors generally require multiple overlapping ablations or the use of multiple-array probes. RFA can be an alternative to resection for small resectable HCC, but the equivalence of RFA to surgery has not been consistently supported. Traditionally, RFA (and any ablative technique) has been limited by the inability to accurately evaluate treatment margins in all three dimensions. In fact, in a nonrandomized comparative study of 148 patients with solitary, small (<4 cm) HCC, the rate of local (near the margin of ablation) recurrence was found to be as high as 7.3% after RFA, compared with 0% after surgery (Hong et al. 2005). However, in a recent prospective randomized trial of 180 patients with a solitary HCC <5 cm, percutaneous RFA and surgical resection were associated with similar overall (68% vs. 64%) and disease-free (46 and 52%) survival rates at 4 years (Chen et al. 2006).It has been suggested that RFA may be more effective in patients with cirrhosis, because the fibrotic liver can act as insulation and confine the heat to the tumor, creating the so-called “oven effect” (Livraghi et al. 1999). Nevertheless, there is no consensus regarding the efficacy of RFA as first-line treatment for HCC, and to
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date this technique is generally accepted as the best treatment for small HCC in the patient whose tumor cannot be resected safely, as a means of preventing tumor progression prior to liver transplantation, or as salvage treatment for patients who have tumor recurrence after surgical treatment. TACE is another form of locoregional therapy that combines intraarterially infused chemotherapy and hepatic artery embolization. It is based on the fact that HCCs larger than 2 cm predominantly receive their blood supply from the hepatic arterial circulation. Chemotherapy agents may be either infused into the liver before embolization or impregnated in the gelatin sponges used for the embolization. Lipiodol has also been used in conjunction with TACE because this agent will remain selectively in HCCs for an extended period, allowing the delivery of locally concentrated therapy. Transarterial (bland) embolization (TAE) can also be performed omitting the chemotherapeutic agent. The superiority of TACE compared to best supportive care has been established in two randomized control trials. The first study from the University of Hong-Kong randomized 80 patients with advanced HCC to TACE with an emulsion of cisplatin in lipiodol and gelatin-sponge particles or conservative management (Lo et al. 2002). Two-year survival rates were significantly higher for TACE compared with the control group (31% vs. 11%, p = 0.006). In the second trial performed by the BCLC group, the TACE group received doxorubicin combined with lipiodol and gelfoam (Llovet et al. 2002).The 112 nonsurgical candidates with HCC in this trial had more favorable characteristics than the Hong-Kong study, but again, the 2-year survival rates were significantly better for the TACE than the symptomatic control group (63% vs. 27%, p = 0.009). Morbidity rates have been reported to be as high as 23% after TACE especially among patients with HCCs >10 cm in diameter. Moreover, postembolization syndrome, including fever, nausea, and pain, is common. Other complications, such as fatal hepatic necrosis and liver failure, have rarely been reported. TACE is generally contraindicated in patients with ascites (Choi et al. 2006). Given that it is well-tolerated and has proven efficacy over best-supportive care, TACE has secured a role as standard of care for HCC patients who are not candidates for resection or transplantation.
9.12 Systemic Therapy Until recently there has been no published evidence that systemic chemotherapy improves overall survival in any subset of HCC patients. HCCs are clinically chemotherapy-resistant tumors; this observation is supported by low response rates (RR) across a wide variety of cytotoxic chemotherapy agents (Simonetti et al. 1997; Watanuki et al. 2002; Anna et al. 1994; Chan and Lung 2004). The most widely used agent has been adriamycin, both as a single agent and in chemotherapeutic combinations. A pivotal phase III trial of adriamycin vs. combination chemotherapy (cisplatinum, interferon, adriamycin, and 5-fluorouracil, PIAF) showed a statistically significant difference in RR favoring PIAF, but no survival difference (Yeo et al. 2005). Over the course of the last several decades, numerous clinical trials of a wide variety of chemotherapeutic and hormonal agents has shown little or no
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activity in this complex malignancy (Table 9.3), and a sense of skepticism of ever developing effective systemic therapy for HCC, pervaded the field. A large Phase II, single arm trial of sorafenib in advanced HCC patients conducted by Abou-Alfa and colleagues, indicated that this novel oral agent did not induce tumor responses (RR 2.2%), however the median overall survival was 9.3 months, which was very favorable compared to historical controls. These encouraging results led to an international placebo-controlled international phase III trial of sorafenib in HCC patients with Childs–Pugh A cirrhosis. The SHARP (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol) trial showed superior survival in the sorafenib arm compared to placebo (10.7 months vs. 7.9 months, p = 0.00058) (Llovet et al. 2008). Sorafenib is a multikinase inhibitor with activity against Raf kinase and several other cellular receptors including vascular endothelial growth factor 2 (VEGF2), platelet-derived growth factor receptor (PDGFR), FLT3, and c-Kit. In HCC cell lines sorafenib inhibits proliferation and induces apoptosis (Liu et al. 2006). The approval of the oral agent sorafenib for the treatment of patients with HCC in 2007 in both the United States and the European Union represents a true paradigm shift in the treatment of advanced HCC, and a significant step forward in providing effective therapeutic options for the many individuals with advanced HCC. Despite the fact that sorafenib does not yield radiographic tumor shrinkage, the traditional measure of anti-tumor activity, it clearly does impact carcinogenic activity in HCC, based on prolongation of both time to tumor progression and overall survival. The demonstration of improved patient outcome of a targeted chemotherapeutic agent in this very challenging malignancy has also generated renewed enthusiasm in the field, and an explosion of clinical research efforts worldwide. Sorafenib also provides a platform on which to build future comparative, adjuvant, and combination clinical trials, to further improve patient outcome. The challenge going forward is to identify those agents that in combination with sorafenib have the greatest potential for improved efficacy while maintaining patient safety. Several other novel “targeted” or biologic agents are now being tested in HCC patients. Hepatocarcinogenesis is a complex multistep, process, which results in a large number of heterogeneous molecular abnormalities, and thus numerous potential targets for existing therapeutic agents. There are several molecular pathways that represent rational targets in HCC for novel therapies, summarized below. The MAPK (mitogen-activated protein kinase) which is responsible for cellular proliferation and differentiation (Ito et al. 1998; McKillop et al. 1997; Feng et al. 2001). Therapeutic agents that target this pathway include sorafenib (targets both raf and vascular endothelial growth factor receptor (VEGFR)) and farnesyltransferase inhibitors (targeting ras). The MAPK pathway involves a cascade of phosphorylation of four major cellular kinases; ras, raf, MAP and Erk (MAP, MAPK; ERK, extracellular-signal-regulated kinase), which is responsible for cellular proliferation and differentiation. These intermediates are found to be elevated in both HCC cell lines and human specimens. Therapeutic agents that target this pathway include sorafenib (targets both raf and VEGFR) and farnesyltransferase inhibitors (targeting ras). A Phase II trial of sorafenib demonstrated antitumor activity in advanced HCC patients. This study did not meet its primary endpoint of response based on WHO criteria, with limited RR of 2.2%. However, many patients (33.6%) had stable disease for at least 4 months, with many showing central tumor “necrosis.” Based on the encouraging overall survival of 9.2 months reported in the phase II trial, a placebo-controlled
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international phase III trial was conducted in HCC patients with Childs–Pugh A cirrhosis (Llovet et al. 2008). The PI3K/Akt/mTOR pathway (Phosphoinositide-3 kinase/Protein Kinase B/mammalian target of rapamycin) is a kinase cascade responsible for cellular proliferation and apoptosis, and is closely linked to cell cycle. PI3K is associated with cell surface growth factor receptors, and upon ligand binding can trigger formation of PIP3, which in turn activates Akt and leads to a number of downstream events (mTOR being one of the targets). PI3K is associated with cell surface growth factor receptors, and upon ligand binding can trigger formation of PIP3, which in turn activates Akt and leads to a number of downstream events (mTOR being one of the targets). This pathway is known to be up-regulated in a subset of HCC patients. Molecular targeted therapy such as rapamycin, a naturally occurring mTOR inhibitor, showed promising results in HCC cell lines (Sahin et al. 2004; Treiber 2009; Villanueva et al. 1983; Tam et al. 2009). However, no published results from clinical trials of any agents that target mTOR in HCC patients are available.
9.13 Growth Factors as Therapeutic Targets in Hepatocellular Carcinoma Both the EGFR (epidermal growth factor receptor) and VEGFR families of growth factors are upregulated in HCC (Fausto 1991; Hisaka et al. 1999).The EGFR is frequently expressed in human hepatoma cells and EGF may be one of the mitogens that are needed for the growth of hepatoma cells. Several agents the inhibit EGF signaling are clinically available, including gefitinib, cetuximab, erlotinib and panitumumab. Erlotinib is an orally active and selective inhibitor of the EGFR/HER1-related tyrosine kinase enzyme. EGFR/HER1 expression was detected in 88% of the patients in a phase II study of erlotinib. In two phase II studies of this agent, the RR was less than 10% but the disease control rate was more than 50%, and median survival times were 10.75 and 13 months, respectively (Thomas et al. 2007; Philip et al. 2005). Other studies of anti-EGFR agents in HCC are summarized in Table 9.3. HCCs are generally hypervascular, and vascular endothelial growth factor (VEGF) promotes HCC development and metastasis (Yamaguchi et al. 2006; Li et al. 1999). Various agents targeting the VEGF circulating ligand or transmembrane receptor, including bevacizumab (Avastin®), sorafenib (Nexavar®), and TSU-68, have been studied in patients with HCC. Bevacizumab, a monoclonal antibody inhibitor of VEGF ligand, has been investigated in phase II studies alone or combination with other agents. These studies showed a high disease control rate of over 80% and a median PFS of more than 6 months. Sorafenib, an oral multikinase inhibitor, blocks tumor cell proliferation mainly by targeting Raf/MEK/ERK signaling at the level of Raf kinase, and exerts an antiangiogenic effect by targeting VEGFR-2/-3. TSU-68 is an oral antiangiogenesis compound that blocks VEGFR-2, PDGFR (platelet-derived growth factor receptor), and FGFR (fibroblast growth factor receptor); a phase I/II study has been conducted in Japan.
Gefitinib
O’Dwyer et al. (2006)
Combination cytotoxic + biologic therapy Sun et al. (2007) Capecitabine, oxaliplatin, bevacizumab Zhu et al. (2006) GEMOX + bevacizumab
Sorafenib vs. placebo Sorafenib Erlotonib Erlotonib Bevacizumab + erlotonib Cetuximab
“Targeted” biologic therapy Llovet et al. (2008) Abou-Alfa et al. (2006) Philip et al. (2005) Thomas et al. (2007) Thomas et al. (2009) Zhu et al. (2007)
30 33
II
31
602 137 38 40 34 30
94/94 37/17 169/170 444 37 35
Sample size
II
II
III II II II II II
III II II/III III II II
Cytotoxic chemotherapy Yeo et al. (2005) Mok et al. (2002) Gish et al. (2007) Gish et al. (2007) Patt et al. (2005) Pastorelli et al. (2006)
PIAF vs. adriamycin Nolatrexed vs. adriamycin TI38067 vs. adriamycin Nolatrexed vs. adriamycin Thalidomide Pegylated adriamycin + gemcitabine
Phase
Table 9.3 Selected clinical trials in patients with advanced HCC Study Regimen
20
11%
3%
2.3% 2.2 9% 0% 20.6% 0%
20.9 vs. 10.5 0 NA 1.4 vs. 4.0 6% 23%
Response rate (RR) %
9.6
PFS 5.4 months
10.7 vs. 7.9 (p = 0.00058) 9.3 13 10.75 19 (PFS 9 months) PFS 6 weeks; OS 22 weeks PFS 2.8 months; OS 6.5 months
8.6 vs. 6.83 4.9 vs. 3.7 5.7 vs. 5.6 5.5 vs. 8 (p = 0.0068) 6.8 8.8 months
Median survival (months)
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9.14 Summary and Conclusions As noted previously, the availability in the clinic of several novel biologic agents and the urgent need for effective therapies for the majority of HCC with advanced HCC has led to the evaluation of many of these agents in HCC, principally in phase II trials. The efficacy and safety of sorafenib in patients with poorer performance status and more advanced hepatic dysfunction, is yet to be established. A key objective for future clinical trials in HCC is to continue assessing new biologic agents in combination with sorafenib, across the broad spectrum of HCC patients seen in the clinic. The traditional approach is to evaluate new agents in single arm phase II studies and use classic radiological response criteria such as WHO or RECIST as a measure of activity and thereby identify promising agents to take forward into phase III clinical trial testing against an appropriate control group. This approach, however, is being questioned because traditional radiographic tumor responses may not occur with biologic agents although they may cause other anticancer effects that may lead to meaningful patient benefit. This is especially true in HCC where radiological assessment is notoriously difficult due to poor delineation of tumors in the liver and tumor necrosis may occur without any change in overall tumor dimensions. Many investigators are evaluating novel radiological imaging techniques that assess changes in blood flow as criteria by which to assess biologic activity of antiangiogenic therapies. Conducting controlled clinical trials of systemic chemotherapy regimens in HCC patients is challenging. Obstacles include the multiple comorbidities of patients with cirrhosis, the intrinsic chemo-resistance of HCC, the advanced nature of HCC at presentation in a majority of patients, the pharmacotherapeutic challenges of treating a cancer that arises in an already-damaged liver, and the distribution of the majority of patients primarily in developing nations where multidisciplinary treatment of HCC may not be available. Hepatocellular cancer is a heterogeneous disease in terms of its etiology, underlying associations, and biologic and clinical behavior, which further complicates clinical trial design. The need for newer effective systemic therapies for HCC patients remains evident, and making continued progress in this disease requires the collaboration and expertise of all of the medical disciplines involved in the care of HCC patients.
References Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A et al (2006) Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24(26): 4293–4300 Anna CH, Maronpot RR, Pereira MA, Foley JF, Malarkey DE, Anderson MW (1994) ras protooncogene activation in dichloroacetic acid-, trichloroethylene- and tetrachloroethylene-induced liver tumors in B6C3F1 mice. Carcinogenesis 15(10):2255–2261 Befeler AS, Di Bisceglie AM (2002) Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 122(6):1609–1619
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Belghiti J, Cortes A, Abdalla EK, Regimbeau JM, Prakash K, Durand F et al (2003) Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg 238(6):885–892; discussion 892–893 Bialecki ES, Di Bisceglie AM (2005) Clinical presentation and natural course of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 17(5):485–489 Bismuth H (2000) Multimodal therapy concepts in hepatocellular carcinoma. Zentralbl Chir 125(7):647–649 Bosch FX, Ribes J, Diaz M, Cleries R (2004) Primary liver cancer: worldwide incidence and trends. Gastroenterology 127(5 suppl 1):S5–S16 Cha CH, Ruo L, Fong Y, Jarnagin WR, Shia J, Blumgart LH et al (2003) Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg 238(3):315–321; discussion 321–323 Chan KT, Lung ML (2004) Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. Cancer Chemother Pharmacol 53(6):519–526 Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ et al (2006) A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 243(3):321–328 Cho CS, Gonen M, Shia J, Kattan MW, Klimstra DS, Jarnagin WR et al (2008) A novel prognostic nomogram is more accurate than conventional staging systems for predicting survival after resection of hepatocellular carcinoma. J Am Coll Surg 206(2):281–291 Choi E, Rodgers S, Ahmad S, Abdalla E (2006) Hepatobiliary cancers. In: Feig B, Berger D, Fuhrman G (eds) The MD Anderson surgical oncology handbook. Lippincott Williams & Wilkins, Philadelphia, PA, pp 320–366 Chu CM, Liaw YF (2006) Hepatitis B virus-related cirrhosis: natural history and treatment. Semin Liver Dis 26(2):142–152 Clark HP, Carson WF, Kavanagh PV, Ho CP, Shen P, Zagoria RJ (2005) Staging and current treatment of hepatocellular carcinoma. Radiographics 25(suppl 1):S3–S23 Cucchetti A, Ercolani G, Vivarelli M, Cescon M, Ravaioli M, La Barba G et al (2006) Impact of model for end-stage liver disease (MELD) score on prognosis after hepatectomy for hepatocellular carcinoma on cirrhosis. Liver Transpl 12(6):966–971 Cunningham SC, Tsai S, Marques HP, Mira P, Cameron A, Barroso E et al (2009) Management of early hepatocellular carcinoma in patients with well-compensated cirrhosis. Ann Surg Oncol 16(7):1820–1831 Del Gaudio M, Ercolani G, Ravaioli M, Cescon M, Lauro A, Vivarelli M et al (2008) Liver transplantation for recurrent hepatocellular carcinoma on cirrhosis after liver resection: University of Bologna experience. Am J Transplant 8(6):1177–1185 Elbekai RH, Korashy HM, El-Kadi AO (2004) The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes. Curr Drug Metab 5(2):157–167 El-Serag HB (2002) Hepatocellular carcinoma and hepatitis C in the United States. Hepatology 36(5 suppl 1):S74–S83 El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576 El-Serag HB, Hampel H, Javadi F (2006) The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 4(3):369–380 Facciuto ME, Koneru B, Rocca JP, Wolf DC, Kim-Schluger L, Visintainer P et al (2008) Surgical treatment of hepatocellular carcinoma beyond Milan criteria. Results of liver resection, salvage transplantation, and primary liver transplantation. Ann Surg Oncol 15(5):1383–1391 Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, Yeung C et al (1999) Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg 229(3):322–330 Fausto N (1991) Growth factors in liver development, regeneration and carcinogenesis. Prog Growth Factor Res 3(3):219–234
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Feng DY, Zheng H, Tan Y, Cheng RX (2001) Effect of phosphorylation of MAPK and Stat3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance. World J Gastroenterol 7(1):33–36 Gambarin-Gelwan M, Wolf DC, Shapiro R, Schwartz ME, Min AD (2000) Sensitivity of commonly available screening tests in detecting hepatocellular carcinoma in cirrhotic patients undergoing liver transplantation. Am J Gastroenterol 95(6):1535–1538 Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A et al (2007) Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol 25(21):3069–3075 Hino O, Kajino K, Umeda T, Arakawa Y (2002) Understanding the hypercarcinogenic state in chronic hepatitis: a clue to the prevention of human hepatocellular carcinoma. J Gastroenterol 37(11):883–887 Hisaka T, Yano H, Haramaki M, Utsunomiya I, Kojiro M (1999) Expressions of epidermal growth factor family and its receptor in hepatocellular carcinoma cell lines: relationship to cell proliferation. Int J Oncol 14(3):453–460 Hong SN, Lee SY, Choi MS, Lee JH, Koh KC, Paik SW et al (2005) Comparing the outcomes of radiofrequency ablation and surgery in patients with a single small hepatocellular carcinoma and well-preserved hepatic function. J Clin Gastroenterol 39(3):247–252 Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F et al (1995) Histological grading and staging of chronic hepatitis. J Hepatol 22:696–699 Ito Y, Sasaki Y, Horimoto M, Wada S, Tanaka Y, Kasahara A et al (1998) Activation of mitogenactivated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology 27(4):951–958 Izumi R, Shimizu K, Ii T, Yagi M, Matsui O, Nonomura A et al (1994) Prognostic factors of hepatocellular carcinoma in patients undergoing hepatic resection. Gastroenterology 106(3):720–727 Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E et al (2004) Cancer statistics, 2004. CA Cancer J Clin 54(1):8–29 Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al (2005) Cancer statistics, 2005. CA Cancer J Clin 55(1):10–30 Katz SC, Shia J, Liau KH, Gonen M, Ruo L, Jarnagin WR et al (2009) Operative blood loss independently predicts recurrence and survival after resection of hepatocellular carcinoma. Ann Surg 249(4):617–623 Kim RD, Hemming AW (2009) Hepatocellular carcinoma: resection or transplantation. J Gastrointest Surg 13(6):1023–1025 Kitamura T, Ichikawa T, Erturk SM, Nakajima H, Sou H, Araki T et al (2008) Detection of hypervascular hepatocellular carcinoma with multidetector-row CT: single arterial-phase imaging with computer-assisted automatic bolus-tracking technique compared with double arterialphase imaging. J Comput Assist Tomogr 32(5):724–729 Leung TW, Tang AM, Zee B, Lau WY, Lai PB, Leung KL et al (2002) Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients. Cancer 94(6):1760–1769 Li XM, Tang ZY, Qin LX, Zhou J, Sun HC (1999) Serum vascular endothelial growth factor is a predictor of invasion and metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res 18(4):511–517 Liao AH, Cheng YC, Weng CH, Tsai TF, Lin WH, Yeh SH et al (2008) Characterization of malignant focal liver lesions with contrast-enhanced 40 MHz ultrasound imaging in hepatitis B virus X transgenic mice: a feasibility study. Ultrason Imaging 30(4):203–216 Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC (2005) Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 54(8): 1151–1156
9 Liver Cancer
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Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D et al (2006) Sorafenib blocks the RAF/ MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66(24):11851–11858 Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Solbiati L, Gazelle GS (1999) Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 210(3):655–661 Llovet JM, Bru C, Bruix J (1999a) Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19(3):329–338 Llovet JM, Fuster J, Bruix J (1999b) Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30(6):1434–1440 Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J et al (2002) Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial [see comment]. Lancet 359(9319):1734–1739 Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390 Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT et al (2002) Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35(5):1164–1171 Lo CM, Fan ST, Liu CL, Chan SC, Ng IO, Wong J (2007) Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg 94(1):78–86 Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F et al (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334(11):693–699 McKillop IH, Schmidt CM, Cahill PA, Sitzmann JV (1997) Altered expression of mitogenactivated protein kinases in a rat model of experimental hepatocellular carcinoma. Hepatology 26(6):1484–1491 Mok TS, Wong H, Zee B, Yu KH, Leung TW, Lee TW et al (2002) A Phase I-II study of sequential administration of topotecan and oral etoposide (toposiomerase I and II inhibitors) in the treatment of patients with small cell lung carcinoma. Cancer 95(7):1511–1519 Nakamura S, Nouso K, Sakaguchi K, Ito YM, Ohashi Y, Kobayashi Y et al (2006) Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size. Am J Gastroenterol 101(9):2038–2043 Nathan H, Schulick RD, Choti MA, Pawlik TM (2009) Predictors of survival after resection of early hepatocellular carcinoma. Ann Surg 249(5):799–805 Ng KK, Vauthey JN, Pawlik TM, Lauwers GY, Regimbeau JM, Belghiti J et al (2005) Is hepatic resection for large or multinodular hepatocellular carcinoma justified? Results from a multiinstitutional database. Ann Surg Oncol 12(5):364–373 (2002) NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements 19(3):1–46 Nissen NN, Martin P (2002) Hepatocellular carcinoma: the high-risk patient. J Clin Gastroenterol 35(5 suppl 2):S79–S85 O’Dwyer PJ, Giantonio BJ, Levy DE, Kauh JS, Fitzgerald DB, Benson AB (2006) Gefitinib in advanced unresectable hepatocellular carcinoma: Results from the Eastern Cooperative Oncology Group’s Study E1203. J Clin Oncol 24:4143 Oh KC, Park SH, Park JC, Jin DK, Park CS, Kim KO et al (2005) Is the prevalence of cryptogenic hepatocellular carcinoma increasing in Korea? Korean J Gastroenterol 45(1):45–51 Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H et al (1985) Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 56(4):918–928 Palavecino M, Chun YS, Madoff DC, Zorzi D, Kishi Y, Kaseb AO et al (2009) Major hepatic resection for hepatocellular carcinoma with or without portal vein embolization: perioperative outcome and survival. Surgery 145(4):399–405
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J.D. Thomas et al.
Pastorelli D, Cartei G, Zustovich F, Marchese F, Artioli G, Zovato S et al (2006) Gemcitabine and liposomal doxorubicin in biliary and hepatic carcinoma (HCC) chemotherapy: preliminary results and review of the literature. Ann Oncol 17(suppl 5):v153–v157 Patt YZ, Hassan MM, Lozano RD, Nooka AK, Schnirer II, Zeldis JB et al (2005) Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer 103(4): 749–755 Pawlik TM (2009) Debate: resection for early hepatocellular carcinoma. J Gastrointest Surg 13(6):1026–1028 Pawlik TM, Poon RT, Abdalla EK, Zorzi D, Ikai I, Curley SA et al (2005a) Critical appraisal of the clinical and pathologic predictors of survival after resection of large hepatocellular carcinoma. Arch Surg 140(5):450–457; discussion 457–458 Pawlik TM, Delman KA, Vauthey JN, Nagorney DM, Ng IO, Ikai I et al (2005b) Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma. Liver Transpl 11(9):1086–1092 Pawlik TM, Poon RT, Abdalla EK, Ikai I, Nagorney DM, Belghiti J et al (2005c) Hepatectomy for hepatocellular carcinoma with major portal or hepatic vein invasion: results of a multicenter study. Surgery 137(4):403–410 Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G et al (2005) Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 23(27):6657–6663 Poon RT, Fan ST, Lo CM, Liu CL, Wong J (2002) Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 235(3):373–382 The Cancer of the Liver Italian Program (CLIP) Investigators (2000) Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology 31(4):840–845 Ringe B, Pichlmayr R, Wittekind C, Tusch G (1991) Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation in 198 patients. World J Surg 15(2):270–285 Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M (2004) mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 10(24):8421–8425 Sassa T, Kumada T, Nakano S, Uematsu T (1999) Clinical utility of simultaneous measurement of serum high-sensitivity des-gamma-carboxy prothrombin and Lens culinaris agglutinin A-reactive alpha-fetoprotein in patients with small hepatocellular carcinoma. Eur J Gastroenterol Hepatol 11(12):1387–1392 Secil M, Obuz F, Altay C, Gencel O, Igci E, Sagol O et al (2008) The role of dynamic subtraction MRI in detection of hepatocellular carcinoma. Diagn Interv Radiol 14(4):200–204 Shah SA, Cleary SP, Tan JC, Wei AC, Gallinger S, Grant DR et al (2007) An analysis of resection vs transplantation for early hepatocellular carcinoma: defining the optimal therapy at a single institution. Ann Surg Oncol 14(9):2608–2614 Shinmura R, Matsui O, Kadoya M, Kobayashi S, Terayama N, Sanada J et al (2008) Detection of hypervascular malignant foci in borderline lesions of hepatocellular carcinoma: comparison of dynamic multi-detector row CT, dynamic MR imaging and superparamagnetic iron oxideenhanced MR imaging. Eur Radiol 18(9):1918–1924 Silva M, Moya A, Berenguer M, Sanjuan F, Lopez-Andujar R, Pareja E et al (2008) Expanded criteria for liver transplantation in patients with cirrhosis and hepatocellular carcinoma. Liver Transpl 14(10):1449–1460 Simonetti RG, Liberati A, Angiolini C, Pagliaro L (1997) Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol 8(2):117–136 Smedile A, Bugianesi E (2005) Steatosis and hepatocellular carcinoma risk. Eur Rev Med Pharmacol Sci 9(5):291–293
9 Liver Cancer
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Sun W, Haller DG, Mykulowycz K, Rosen M, Soulen M, Capparo M et al (2007) Combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): A phase II study. J Clin Oncol 25(18):4574 Takada Y, Ito T, Ueda M, Sakamoto S, Haga H, Maetani Y et al (2007) Living donor liver transplantation for patients with HCC exceeding the Milan criteria: a proposal of expanded criteria. Dig Dis 25(4):299–302 Tam KH, Yang ZF, Lau CK, Lam CT, Pang RW, Poon RT (2009) Inhibition of mTOR enhances chemosensitivity in hepatocellular carcinoma. Cancer Lett 273(2):201–209 Teh SH, Christein J, Donohue J, Que F, Kendrick M, Farnell M et al (2005) Hepatic resection of hepatocellular carcinoma in patients with cirrhosis: Model of End-Stage Liver Disease (MELD) score predicts perioperative mortality. J Gastrointest Surg 9(9):1207–1215; discussion 1215 Thomas MB, Chadha R, Glover K, Wang X, Morris J, Brown T et al (2007) Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 110(5):1059–1067 Thomas MB, Morris JS, Chadha R, Iwasaki M, Kaur H, Lin E et al (2009) Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol 27(6):843–850 Todo S, Furukawa H; Japanese Study Group on Organ T (2004) Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 240(3): 451–459; discussion 459–461 Treiber G (2009) mTOR inhibitors for hepatocellular cancer: a forward-moving target. Expert Rev Anticancer Ther 9(2):247–261 Tu R, Xia LP, Yu AL, Wu L (2007) Assessment of hepatic functional reserve by cirrhosis grading and liver volume measurement using CT. World J Gastroenterol 13(29):3956–3961 Vauthey JN, Lauwers GY, Esnaola NF, Do KA, Belghiti J, Mirza N et al (2002) Simplified staging for hepatocellular carcinoma. J Clin Oncol 20(6):1527–1536 Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C et al (1983) Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 135(6):1972–1983 Watanuki A, Ohwada S, Fukusato T, Makita F, Yamada T, Kikuchi A et al (2002) Prognostic significance of DNA topoisomerase IIalpha expression in human hepatocellular carcinoma. Anticancer Res 22(2B):1113–1119 Yamaguchi R, Yano H, Nakashima O, Akiba J, Nishida N, Kurogi M et al (2006) Expression of vascular endothelial growth factor-C in human hepatocellular carcinoma. J Gastroenterol Hepatol 21(1 pt 1):152–160 Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A et al (2001) Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 33(6):1394–1403 Yao FY, Bass NM, Nikolai B, Davern TJ, Kerlan R, Wu V et al (2002) Liver transplantation for hepatocellular carcinoma: analysis of survival according to the intention-to-treat principle and dropout from the waiting list. Liver Transpl 8(10):873–883 Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY et al (2005) A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 97(20): 1532–1538 Zhu AX, Blaszkowsky LS, Ryan DP, Clark JW, Muzikansky A, Horgan K et al (2006) Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 24(12):1898–1903 Zhu AX, Stuart K, Blaszkowsky LS, Muzikansky A, Reitberg DP, Clark JW et al (2007) Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 110(3): 581–589
Carcinoma of the Biliary Tract
10
Sean P. Cleary, Jennifer Knox, and Laura Ann Dawson
10.1 Introduction The gallbladder and bile ducts share a common embryologic origin and are lined with a simple columnar epithelium. Most malignancies of the biliary tract are adenocarcinomas that arise from the malignant transformation of this columnar epithelium. Adenocarcinomas of the bile ducts are often referred to as cholangiocarcinomas. Malignant transformation can occur anywhere along the biliary system from the ampulla of Vater to the terminal intrahepatic bile ducts. Gallbladder cancers arise from the epithelium of the gallbladder or cystic duct. Intrahepatic cholangiocarcinoma (ICC) develops in bile ducts within the liver and proximal to the lobar hepatic ducts and hepatic duct confluence. Extrahepatic bile duct cancer develops in the biliary tree from the ampulla of Vater to the hepatic duct confluence. Extrahepatic bile duct tumors can be further subdivided into intrapancreatic cholangiocarcinoma, which are managed similarly to other periampullary malignancies (and are not discussed here), and proximal or hilar cholangiocarcinoma. Adenocarcinomas of the bile ducts and gallbladder have traditionally been associated with a poor prognosis. The malignancies often present late as locally advanced or metastatic disease due to the lack of early symptoms and effective screening strategies. The management of these cancers is hampered by the complexity of the hepatic, vascular and biliary anatomy; the traditionally high morbidity and mortality of hepatobiliary resection and lack of proven adjuvant treatment. As an uncommon malignancy, the majority of experience in the management
L.A. Dawson (*) Department of Radiation Oncology, University Health Network, Princess Margaret Hospital, 610 University Ave, Toronto, ON, M5G 2M9, Canada e-mail:
[email protected] S.P. Cleary Division of General Surgery, Department of Surgery, University Health Network, Toronto General Hospital, Toronto, ON, Canada J. Knox Department of Medical Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_10, © Springer-Verlag Berlin Heidelberg 2011
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of these cancers has generally been limited to few high-volume centers. Over the last two decades, enhanced understanding of hepatic and biliary anatomy, improved radiologic assessment, the development of adjunctive interventional radiologic techniques such as biliary drainage and portal vein embolization, and improved peri-operative care have all combined to increase the safety of hepatic and biliary resections. This improvement in perioperative outcomes has permitted the application of an increasingly aggressive surgical approach towards these cancers that has paralleled improvements in long-term survival observed over time. While cancers of the gallbladder and bile duct share a common embryologic origin and many similarities; the natural history, diagnosis and management of cancers from different regions of the biliary tree are dissimilar enough that they are highlighted separately.
10.2 Gallbladder Cancer 10.2.1 Epidemiology and Risk Factors Gallbladder cancer is a rare malignancy in North America affecting 1–2 people per 100,000 with approximately 2,000–5,000 cases diagnosed each year (Jemal et al. 2006). It is the fifth most common cancer of the gastrointestinal tract (Canadian Cancer Society/National Cancer Institute of Canada 2008). The incidence of gallbladder cancer shows a substantial gender, geographic and ethnic variation. High incidence areas include East Asia, Northern India and Pakistan, Eastern Europe and South America (Randi et al. 2006). Gallbladder cancer is more common in females with a female: male ratio of 2–3:1, with a more apparent gender discrepancy in India and South America vs. Asia and Eastern Europe (Randi et al. 2006). By comparison, North America is a low incidence area in this disease, with increased risk seen among Hispanics and Native Americans. The most commonly cited risk factor for gallbladder cancer is gallstones. Between 60 and 100% of patients with gallbladder cancer also have gallstones (Perpetuo et al. 1978), and gallstones are associated with a 4–7-fold increase in the risk of cancer (Lowenfels et al. 1985, 1999); this risk may be higher for patients with symptomatic gallstone disease, those with large stones, and in high risk geographic regions or ethnic groups (Lowenfels et al. 1989; Diehl 1980; Zatonski et al. 1997). The mechanistic link between gallstones and cancer is poorly understood but likely involves longstanding chronic inflammation leading to dysplasia and neoplastic changes in the mucosa either alone or in combination with other factors (Serra and Diehl 2002; Wistuba and Gazdar 2004). Similarly, longstanding inflammation leading to dysplastic changes may be implicated in the association between chronic infections with Salmonella (S. typhi and S. paratypi) (Shukla et al. 2000; Dutta et al. 2000; Nath et al. 1997) and possibly Helicobacter (H. pylori and H. bilis) species (Bulajic et al. 2002) and gallbladder malignancy. Finally, endocrine and metabolic factors associated with gallbladder cancer include increasing parity and gravidity (Zatonski et al. 1997; Pandey and Shukla 2003) and obesity (Calle et al. 2003; Moller et al. 1994; Serra et al. 2002; Strom et al. 1995).
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10.2.2 Pathology of Gallbladder Cancer Since gallbladder cancer is often diagnosed at an advanced stage and associated with an overall poor prognosis, there is considerable interest in identifying premalignant lesions and defining the malignant progression in this disease. To date, gallbladder adenomas and dysplasia have been identified as premalignant lesions, while adenomyomatosis as well as cholesterol and inflammatory polyps are not believed to be associated with cancer risk. Up to 1% of cholecystectomy specimens will contain an adenoma; these lesions may resemble normal gallbladder mucosa or show evidence of pyloric gland metaplasia or intestinal metaplasia (Koga et al. 1988; Kozuka et al. 1982). Malignant changes have been identified in 39% of adenomas, and 19% of carcinomas contain adjacent adenomatous elements. Furthermore, a correlation between polyp size and risk of malignancy may exist with benign histology in virtually all polyps <1 cm, with malignant features in some adenomas >1.2 cm, and invasive cancers in some polyps >3 cm (Koga et al. 1988; Kozuka et al. 1982). As a result the risk of malignancy in a gallbladder polyps is thought to be negligible in lesions <1 cm. Dysplasia is considered as a premalignant gallbladder lesion that is often flat with poorly defined borders, may have a villous or granular appearance, and may be solitary or multifocal. These lesions may demonstrate varying degrees of pseudostratification, nuclear atypia, loss of polarity and mitotic figures without evidence of invasion. Dysplastic mucosal areas are often difficult to identify on gross examination, as a result there is a wide range in estimates of the frequency of these lesions varying from 0.4 to 33.8% (Sasatomi et al. 2000). Dysplasia can be graded as mild, moderate to severe, with dysplasia and carcinoma-in situ often found adjacent to, or in continuity with invasive cancer (Nakajo et al. 1990; Yamaguchi and Enjoji 1988; Roa et al. 2006). Indirect estimates of the time for progression from dysplasia-to-carcinoma-in situ-to-carcinoma indicate that invasive cancer may develop over a period of 10–15 years (Roa et al. 2006). Ninety-eight percent of carcinomas of the gallbladder are of epithelial origin, with over 90% identified as adenocarcinomas. Nonepithelial tumors include sarcomas, lymphomas, carcinoid tumors and metastases; other epithelial types include adenosquamous, squamous and small-cell carcinomas (Henson et al. 1992). Histologic subtypes of adenocarcinoma include papillary, intestinal, mucinous, signet-cell and clear cell variants (Henson et al. 1992). The papillary subtype of adenocarcinoma is noteworthy since these lesions tends to be exophytic with fibrovascular stalks that fill the gallbladder lumen before invading through the gallbladder wall and are associated with more indolent biologic behavior and favorable long-term prognosis (Albores-Saavedra et al. 2005). On gross examination, about 60% of cancers arise in the fundus of the gland, with 30% developing in the body and 10% in the neck (Levy et al. 2001), and they develop as an asymmetric thickening of the gallbladder wall with diffuse infiltration of surrounding structures. Based on macroscopic characteristics, cancers can be categorized into infiltrative, nodular, papillary or mixed forms. Infiltrative tumors are most common and exhibit early and extensive infiltration of the subserosal plane leading to involvement of the entire gallbladder wall. Nodular tumors are characterized by early invasion through the gallbladder wall into adjacent organs and liver. The growth of papillary tumors is predominantly
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intraluminal, resulting in a polypoid or cauliflower-like lesion. These tumors are less prone to local invasion and lymph node metastases and are therefore associated with a better prognosis (Sumiyoshi et al. 1991). Gallbladder carcinomas spread via lymphatic, vascular, perineural, intraperitoneal and intraductal routes as well as by direct invasion; understanding these modes of spread is important in considering an approach to surgical resection of these tumors. Lymphatic drainage from the gallbladder occurs first into the cystic duct node followed by lymph nodes along the common bile duct, in the pancreaticoduodenal region, posterior to the portal vein and along the common hepatic artery. From there, lymphatic drainage proceeds to the celiac, superior mesenteric and para-aortic lymph nodes (Fahim et al. 1962). The next most common site of spread is to the adjacent liver via direct invasion or by invasion of veins which drain from the gallbladder into the adjacent liver segments, particularly segments IVb and V (Fahim et al. 1962; Misra et al. 2003). Intraductal spread is commonly seen in papillary cancers, and perineural spread often follows the course of the arterial anatomy of the region. Direct invasion of the cancers can also occur along the hilar plate and Glisson’s capsule towards the liver hilum; this mode of spread is particularly challenging when considering surgical resection and can often render tumors unresectable based on early hepatic vascular invasion. Other organs which can become involved by direct invasion include the anterior abdominal wall, duodenum, colon, diaphragm and hepatic ducts.
10.2.3 Diagnosis of Gallbladder Cancer The diagnosis of gallbladder cancer can be challenging due to the lack of specific signs and symptoms of early disease, particularly in the elderly that are most commonly affected in this disease. The clinical manifestation of gallbladder malignancy can often overlap with gallstone disease and other benign upper gastrointestinal disorders. As a result, most cases are not diagnosed until the disease is advanced. The most common symptom for patients with gallbladder cancer is right upper quadrant pain, followed by weight loss, anorexia, nausea and vomiting. Chronic or recurring pain may be due to associated gallstone disease or can be the result of locally invasive disease. A palpable mass, jaundice, gastrointestinal obstruction and the development of constitutional symptoms such as anorexia and weight loss are all indicators of advanced disease. Alternatively, malignancy may be detected in cases of complicated gallstone disease such as chronic cholecystitis, Mirrizzi’s syndrome or even as an incidental finding after cholecystectomy performed for presumed benign indications (Misra et al. 2003; Liu et al. 1997; Redaelli et al. 1997). Radiologic investigations play a critical role in the detection and staging of gallbladder malignancies. Ultrasound (U/S) is the most common imaging modality used to investigate biliary tract symptoms. Thickening of the gallbladder wall can be seen in both benign inflammation and malignancy, but findings of discontinuous thickening or diffuse thickening >12 mm can be suggestive of cancer. The observation of a mass protruding into the gallbladder lumen, a fixed mass, mural calcifications and loss of the normal interface between the gallbladder and the liver parenchyma can all be indicators of malignancy seen on U/S (Wibbenmeyer et al. 1995a; Pandey et al. 2000). The diagnostic sensitivity of
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conventional U/S for the detection of cancer approaches 80% and can reliably detect hepatic parenchymal invasion; the addition of duplex vascular assessment can improve this sensitivity by demonstrating vascular flow within lesions and enhance the ability to detect vascular involvement (Bach et al. 1998; Chijiiwa et al. 1991). Contrast-enhanced computed tomography (CT) has a high sensitivity (90%) for detecting more advanced tumors (>T2) but its utility in detecting early lesions is uncertain (Yoshimitsu et al. 2002; Ohtani et al. 1996). Gallbladder cancers usually appear as a low-attenuation mass or eccentric thickening of the gallbladder wall. CT is the predominant imaging modality for staging gallbladder cancer and determining resectability and is highly accurate in determining local extent, vascular involvement, invasion of adjacent structures as well as detecting the presence of metastatic disease. Magnetic resonance imaging (MRI) can provide similar information to CT, although current image resolution of this technique limits its detection of small early lesions. Gallbladder cancers appear hypointense on T1-weighted images and hyperintense on T2-weighted images. The role of positron emission tomography (PET) and PET-CT has not been fully established in this disease, although recent reports suggest a promising role for this imaging modality in the detection of the primary tumor and metastatic disease (Petrowsky et al. 2006; Rosenbaum et al. 2006). The use of biochemical serum markers to improve the diagnostic accuracy in gallbladder cancer has been investigated. In a series comparing patients undergoing upper abdominal surgery to patients with gallbladder cancer, a serum carcino-embryonic antigen (CEA) level >4.0 ng/mL had a specificity of 93% but had a limited sensitivity of 50%. A CA19-9 level >20 U/mL had a sensitivity and specificity of 80%. The use of both CEA and CA19-9 either in parallel or in series did not improve the diagnostic yield (Strom et al. 1990; Ritts et al. 1994).
10.2.4 Staging of Gallbladder Cancer The original staging system for gallbladder cancer was proposed by Nevin et al. (1976) but has been largely replaced by the TNM system proposed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) 5th edition in 1997 (Fleming et al. 1997) and revised in the 6th edition in 2002 (Greene et al. 2002). The UICC/ AJCC 6th edition was designed to be clinically relevant with T3 tumors considered to be locally invasive but potentially resectable tumors and T4 tumors as unresectable in most cases. Stage 2 is divided into locally advanced resectable tumors (stage 2a), and tumors with lymph node metastases (stage 2b). Stage 3 tumors are considered unresectable in most cases, whereas stage 4 represents distant metastatic disease (Tables 10.1 and 10.2).
10.2.5 Surgical Resection of Gallbladder Cancer Surgical resection is the only potentially curative treatment modality for gallbladder cancer. Until recently, surgery for this disease has been hampered by high peri-operative complication rates and poor long-term results. Widespread reviews of surgical cases from the 1970s
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Table 10.1 UICC/AJCC staging system for gallbladder cancer 6th edition 2002 T stage T0 no evidence of primary tumor Tis carcinoma in situ T1 tumor invades lamina propria or muscle layer T1a tumor invades lamina propria T1b tumor invades muscle layer T2 tumor invades perimuscular connective tissue w/no extension beyond serosa or into liver T3 tumor perforates serosa (visceral peritoneum) And/or directly invades liver And/or invades adjacent or structure such as Duodenum, stomach, colon, pancreas, omentum Or bile ducts T4 tumor invades main portal vein or hepatic artery Or multiple extrahepatic organs or structures N stage Nx regional lymph nodes cannot be assessed N0 no regional lymph node metastasis N1 regional lymph node metastasis M stage Mx distant metastases cannot be assessed M0 no distant metastases M1 distant metastases Table 10.2 Gallbladder cancer tumor stage Stage 0 Tis
N0
M0
Stage 1A
T1
N0
M0
Stage 1B
T2
N0
M0
Stage 2A
T3
N0
M0
Stage 2B
T1–3
N1
M0
Stage 3
T4
Any N
M0
Stage 4
Any T
Any N
M1
and 1980s demonstrated that few cases underwent potentially curative resections and 5-year survival rates of 5–17% (Cubertafond et al. 1994; Piehler and Crichlow 1978; Wilkinson 1995). Since those reports, developments in preoperative evaluation, intraoperative technique and postoperative care have substantially reduced the rates of peri-operative morbidity and mortality with an associated increase in long-term survival. Developments in imaging have permitted better staging and improved operative planning. Improvements in surgical technique, intraoperative anesthesia, and postoperative care have enabled the performance of more complex resections while reducing the perioperative mortality rate to <5%.
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The surgical resection of gallbladder cancers must take into account the anatomic and pathologic characteristics of this disease and include hepatic resection with regional lymphadenectomy and potentially resection of the biliary system. Malignancies of the gallbladder invade the liver through local extension or via the venous drainage of the gallbladder into segments IVB and V. As a result, these segments are the most common site of hepatic involvement, but tumors may extend further into segment IVa or the right and caudate lobes (Sumiyoshi et al. 1991; Nimura et al. 1991). In conservative series, early tumors with no obvious intrahepatic extension have been managed with resection of the gallbladder with a rim of 2–3 cm of liver tissue around the gallbladder bed. For tumors with limited liver invasion, some centers have advocated resection of segments IVb and V as a formal anatomic resection with vascular control of the portal inflow along the umbilical fissure and segmental portal vein branch, respectively, and ligation of the middle hepatic vein at the apex of the resection. Segmental resection of segments IVb and V is limited in its ability to achieve an adequate radial margin while preserving the integrity of the remaining right hemi-liver by the proximity of the gallbladder neck to the bifurcation of the right portal pedicle, which can be as little as 2 mm (Yamaguchi et al. 1998). As a result, many centers have argued that improved oncologic clearance can be obtained by extended right hepatectomy with resection of segments IVb, V–VIII (Nimura et al. 1991; Nakamura et al. 1989, 1994; Todoroki et al. 1999a). In addition to hepatic invasion, gallbladder cancers can invade the hepatoduodenal ligament into or along bile ducts (intraductal or periductal invasion) and spread along the lymphatic channels in the porta hepatis (Kaneoka et al. 2003). Invasion of the biliary ducts is often associated with jaundice; however periductal spread occurs via perineural invasion and may not cause biliary obstruction. The role of resection of the extrahepatic biliary tree in gallbladder cancer is the subject of considerable debate (Pawlik et al. 2007; Shimizu et al. 2004). The rate of lymph node metastases appears to correlate with the depth of primary tumor invasion (T-stage) and can range from 10 to 62% (Misra et al. 2003; Ogura et al. 1991; Fong et al. 1998; Shirai et al. 1992a; Bartlett 2000). The overall objective in the surgical management of gallbladder cancer is the complete resection of all macro- and microscopic disease and achievement of an R0 resection. While a standardized operation may not be beneficial for all cases and patients (D’Angelica et al. 2009), the surgical approach should be tailored to the clinical setting in which cancer is identified, the extent of the tumor, and the operative risk in each individual patient. Due to the rarity of these tumors, these cases are best managed at high-volume hepatobiliary surgical oncology centers.
10.2.5.1 Management of Known Gallbladder Cancer Malignancies of the gallbladder can remain asymptomatic until they have reached an advanced stage. As a result, most lesions diagnosed on the development of symptoms or detected on imaging investigations tend to be T3 lesions or greater and many of these lesions are unresectable at presentation. Although unusual, early T1/2 lesions can be detected preoperatively on imaging as an incidental finding or on investigations for associated gallstone
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disease. The management of lesions detected preoperatively should be determined by the stage and location of the tumor. The challenge in managing early gallbladder cancers without adjacent organ involvement (T1 or T2 lesions) is differentiating these lesions from chronic inflammatory changes in the gallbladder and properly staging these lesions. The dissection for simple cholecystectomy proceeds along the subserosal plane; while cholecystectomy alone may be sufficient treatment for Tis and T1a lesions, it should be avoided in cases where malignancy is suspected. For early T1 and T2 lesions, cholecystectomy with resection of the adjacent liver parenchyma has been established as the minimum treatment required to reliably obtain an R0 radial margin. The extent of liver resection is the subject of some debate and may depend on the individual case. Options include: cholecystectomy with a wedge of hepatic parenchyma which may be adequate for an early T1 lesions in the fundus, formal resection of segments IVb and V for early T1/2 lesions in the fundus, to extended right hepatectomy which may be necessary for T2 lesions in the neck of the gallbladder. A conservative approach to hepatic resection can be considered in cancers exhibiting an expansive or nodular growth pattern but avoided in cases of infiltrative tumors where more extensive resection is required (Ogura et al. 1998). Since lymph node metastases can be seen in up to 10% of T1b lesions and 60% of T2 lesions, resection of even early malignancies should include regional lymphadenectomy of the nodes in the porta hepatis (Misra et al. 2003; Ogura et al. 1991; Fong et al. 1998; Shirai et al. 1992a; Bartlett 2000). The role of bile duct resection in these cases is controversial with some centers advocating routine biliary resection (Nakamura et al. 1989; Shimizu et al. 2004), while others advocate a selected approach where bile duct resection is performed in cases with jaundice or a positive cystic duct margin (Pawlik et al. 2007; D’Angelica et al. 2009). Five year survival rates of 60–100% has been documented for T2 lesions treated with cholecystectomy, hepatic resection with lymphadenectomy and possible biliary resection compared to 19–50% for cholecystectomy alone (Dixon et al. 2005; Matsumoto et al. 1992; Shirai et al. 1992b; de Aretxabala et al. 1997). Aggressive resection is indicated in T3 tumors and selected T4 cancers, where resection of all macro and microscopic disease is feasible. For many tumors an extended right hepatectomy, portal lymphadenectomy and possible bile duct resection is required for R0 resection. This aggressive approach has been enabled by the increasing safety of hepatobiliary surgery, has led to an increasing use of extended resections, and has improved overall survival at many Asian and North American centers; 5 year survival rates for stage III and IV disease now approach 69 and 25%, respectively (Nimura et al. 1991; Nakamura et al. 1989, 1994; Todoroki et al. 1999a; Dixon et al. 2005; Kondo et al. 2002). For selected T3 tumors that invade the pancreas or have extensive periductal invasion, several centers have reported combined hepatectomy, bile duct resection and pancreaticoduodenectomy with 5-year survival rates of up to 30% (Kaneoka et al. 2003; Kondo et al. 2002; Todoroki et al. 1999b; Chijiiwa and Tanaka 1994; Sasaki et al. 2006). These improved peri-operative and long-term results have significantly improved the outlook for patients diagnosed with gallbladder cancer. While some may advocate a dogmatic approach to routine formalized extended resection, recent publications have stressed that negative margins status (R0), and not the extent of resection, is predictive of survival and proposed that the surgical treatment of gallbladder cancers be tailored in each individual case to obtain complete macro and microscopic disease clearance (Pawlik et al. 2007; D’Angelica et al. 2009; Pawlik and Choti 2009).
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10.2.5.2 Management of Incidental Gallbladder Cancer Laparoscopic cholecystectomy is a common surgical procedure performed with increasing frequency for benign gallbladder conditions. The unexpected findings of malignancy in a laparoscopic cholecystectomy may occur during the procedure or, more commonly, as a finding on histopathologic examination of the gallbladder specimen. Due to the subserosal plane of dissection in a standard cholecystectomy, the incidental finding of cancer presents a unique and challenging clinical dilemma. Intraoperatively, the index of suspicion for malignancy should be raised in cases of a thickened gallbladder wall, or when the tissue planes are obscured and dissection is difficult, particularly in an older patient. Malignancy can be an unexpected finding on pathologic examination of the specimen in 0.3–2% of cases (Misra et al. 2003). This finding should prompt a thorough pathologic review including the determination of radial and cystic duct margin status, depth of tumor invasion (T-stage), presence of perineural/vascular/lymphatic invasion, and presence/status of the cystic duct node. The presence of gallbladder injury and bile spillage are associated with increased rates of local, peritoneal and port-site recurrence (Wibbenmeyer et al. 1995b; Wakai et al. 2002; Weiland et al. 2002; Suzuki et al. 1998). Once the specimen has been thoroughly reviewed, the subsequent management of incidental gallbladder cancers is determined by the T-stage and other pathologic characteristics of the tumor. T1a lesions, that invade the lamina propria only, have a very good prognosis with a 5-year survival of 90–100% when treated with simple cholecystectomy (Wakai et al. 2002; Shirai et al. 1992b; Toyonaga et al. 2003). Perineural, vascular and lymphatic invasion is extremely rare in T1a lesions and more extensive resections do not improve outcome (Ogura et al. 1991; Taner et al. 2004; Ouchi et al. 2002). The management of incidental T1b tumors is somewhat controversial. Two series report excellent survival for T1b cancer with an 85–90% 10-year survival, and no benefit to radical resection (Shirai et al. 1992b; Wakai et al. 2001). In comparison, many groups have recommended reexploration and radical reresection for incidental T1b lesions with reports of 5-year survival rates of 72–100% (Ouchi et al. 1994; Ogura et al. 1991; Matsumoto et al. 1992). Supporters of reexploration cite the 15% incidence of lymph node metastases, 10% incidence of residual disease in the gallbladder fossa and a 37% incidence of any residual disease upon reexploration as evidence to support the role for exploration and extended resection in these cases (Pawlik et al. 2007; Ogura et al. 1991; de Aretxabala et al. 1992). The management of more advanced incidental lesions, T2 or greater, is less controversial as these tumors are associated with a 20–62% incidence of lymph node metastases and 40–76% incidence of residual disease at reexploration (Misra et al. 2003; Fong et al. 1998; Shirai et al. 1992a; Bartlett 2000; de Aretxabala et al. 1992). For this reason, several series have demonstrated a significant survival benefit with extended resection compared to cholecystectomy alone for T2 lesions (Fong et al. 1998; Shirai et al. 1992a; de Aretxabala et al. 1997; Wakai et al. 2002; Chijiiwa et al. 2001). Cases undergoing reresection have been associated with 5-year survival rates of 70–80% and 30–45% for T2 and T3 lesions, respectively (Shirai et al. 1992a; Fong et al. 2000; Suzuki et al. 2004; Oertli et al. 1993). Initial reports on high rates of port-site recurrences led many to advocate abdominal wall resection of port sites at reexploration (Wakai et al. 2002; Schaeff et al. 1998; Paolucci
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2001; Lundberg and Kristoffersson 1999), but more recent series have shown no increase risk in abdominal wall recurrences compared to open surgery (Paolucci et al. 2003; Lundberg and Kristoffersson 2000). In summary, in cases where cancer is found incidentally on examination of a specimen after simple cholecystectomy, patients with tumors T1b or greater should be considered for reexploration and extended resection. Surprisingly, there is no evidence that survival in patients treated with cholecystectomy and reexploration is inferior to those who undergo primary extended resection (Fong et al. 2000; Suzuki et al. 2000). Despite this evidence, population-based studies show that only the minority of patients with potentially curable gallbladder tumors undergo extended resection (Paolucci et al. 2003; Coburn et al. 2008).
10.2.6 Radiation Therapy in Gallbladder Cancer The historical role of radiation therapy (RT) in gallbladder cancer has been palliative. Reasons for the limited historical experience in using RT as adjuvant, neoadjuvant or definitive therapy include challenges in defining the extent of tumor, the proximity of sensitive normal tissues to the biliary system, and technical demands with delivery of precise high dose radiation to the biliary targets that move with breathing. Specialized techniques including transcatheter brachytherapy, intraoperative radiation therapy (IORT), conformal radiation therapy (CRT), and intensity modulated radiation therapy (IMRT) allow tumorcidal doses to be delivered safely to some gallbladder and biliary cancers. IORT is most often delivered using electrons intraoperatively, immediately after resection, while the abdominal cavity is open. Brachytherapy is often delivered using 192-Iridium within biliary catheters placed in malignant bile ducts. Advantages of IORT and brachytherapy are that the high dose radiation falls off quickly, however this advantage also limits the utility to superficial targets. IORT and brachytherapy have often been used in addition to external beam RT to increase the dose to the highest risk regions. The delivery of high radiation doses that conform around the tumor is now possible with external beam RT, delivered using CRT or IMRT, combined with strategies to reduce organ motion and imaging at the time of radiation delivery to ensure it is targeted appropriately. There are no randomized trials of RT in gallbladder cancer. Most retrospective and prospective series include heterogeneous patient populations (bile duct and gall bladder), treated with heterogeneous therapy (external beam RT, IORT and/or brachytherapy, with or without chemotherapy or surgery). This heterogeneity and the potential for selection bias makes it impossible to accurately quantify the benefits of RT.
10.2.6.1 Adjuvant Radiation Therapy for Gallbladder Cancer Although there is an increased propensity for metastases to develop following resection for gallbladder cancer vs. bile duct cancer, several series suggest a benefit to adjuvant local regional RT. In most series, adjuvant RT has consisted of 45–55 Gy delivered over
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4–5 weeks using conventional external beam, RT delivered to the gallbladder fossa, adjacent liver and regional nodal areas. Vaittenim et al. found an improved median survival following surgery and adjuvant RT compared to no adjuvant therapy (median survival 63 vs. 29 months) for gallbladder cancer (Vaittenim 1970). However, surgery most often consisted of a simple cholecystectomy. Todoroki et al. found a significant improvement of 5 year survival in 85 patients with stage IV gallbladder carcinoma following resection and adjuvant RT (n = 47) compared to resection alone (8.9 vs. 2.9%, p = 0.002) (Todoroki et al. 1999b). Local control was also improved from 36 to 59% (p = 0.05). Long term survival was observed in patients with microscopic residual disease after surgery who were treated with RT (p = 0.003). Kresl et al. reported improved survival in patients with complete resection vs. microscopic and gross residual disease (median survival 5.1, 1.4, and 0.6 years, respectively, p = 0.02) in patients who received 5-FU-based chemotherapy and RT following surgery (Kresl et al. 2002). Radiotherapy doses greater than 54 Gy were associated with improved local control. Bosset et al. reported that five of seven resected gallbladder cancer patients were without recurrence 5–58 months following 46 Gy, followed by 9 Gy to the high risk volume (Bosset et al. 1989). Czito et al. observed a median survival of 1.9 years and local control of 65% in 22 patients with resected gallbladder cancer who received adjuvant RT (median dose 45 Gy) and concurrent 5-FU chemotherapy (n = 18) (Czito et al. 2005). Morrow et al. reported an improved median survival from 3 to 4.5 months for patients receiving adjuvant chemotherapy or RT or both compared to those treated with surgery alone, demonstrating how patient selection can greatly alter outcomes (Morrow et al. 1983). In a national cancer database review of 2,500 patients with gallbladder cancer treated between 1989 and 1990, patients who underwent surgery, RT and chemotherapy had better survival than those who underwent surgery alone (hazard ratio 0.625, 95% CI 0.52–0.75) (Donohue et al. 1998).
10.2.6.2 Radiation Therapy for Unresectable Gallbladder Cancer RT can palliate bleeding or pain from locally advanced gallbladder cancer. Moderate dose RT for locally advanced gallbladder cancer is generally well tolerated, and some series have suggested improved survival with RT compared to palliative resection, although survival remains poor (median survival 6–8 months) (Houry et al. 1989; Uno et al. 1996). In one series, in patients in whom complete resection was not feasible, there was a trend toward improved survival with the addition of RT (13 vs. 8 months, p < 0.10) (Vaittenim 1970). In another series, patients with unresectable gallbladder cancer treated with RT had an improvement in their symptoms (Mahe et al. 1994). Fuller et al. showed the possibility for escalating doses to gallbladder cancers with image guided IMRT (median dose 60 Gy, range 54–70 Gy) in ten patients with no prior surgery (Randi et al. 2006), cholecystectomy with (Canadian Cancer Society/National Cancer Institute of Canada 2008) or without (Lowenfels et al. 1985) hepatoduodenectomy; two of the seven resected patients had R1 resections. Five received concurrent 5FU chemotherapy. One patient developed grade 3 gastrointestinal toxicity. Median survival was 16.7 months (Fuller et al. 2006). Others have also delivered doses up to 70 Gy to gallbladder
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cancers (Silk et al. 1989). There are rare case reports of long term survivors following RT for locally advanced gallbladder cancer (Sugimoto et al. 2005; Montemaggi et al. 1996).
10.3 Carcinoma of the Extrahepatic Bile Duct 10.3.1 Epidemiology and Risk Factors Carcinomas of the extrahepatic biliary tree, commonly known as Klatskin tumors, are rare malignancies that account for up to 3% of all gastrointestinal cancers. At an incidence rate of 0.5–2 cases per 100,000, it is estimated that there are between 2,500 and 4,000 new cases per year in the United States (Strom et al. 1995; Khan et al. 2005; Rajagopalan et al. 2004). Of all cholangiocarcinomas, approximately 2/3 are hilar or extrahepatic, 20–30% are distal or intrapancreatic, and 5–10% are intrahepatic (Nakeeb et al. 1996). The management of intrapancreatic cholangiocarcinoma is better addressed within the description of pancreatic malignancies and ICC will be discussed in a subsequent section. There are several recognized risk factors for cholangiocarcinoma, although the vast majority of cancers are seen in patients with no readily identifiable predisposing condition. Primary sclerosing cholangitis (PSC) is an autoimmune condition that causes bile duct inflammation resulting in scarring and fibrosis. This chronic inflammation is thought to lead dysplastic and ultimately neoplastic changes in the bile ducts. The risk of cholangiocarcinoma in patients with PSC is thought to be over a 1,000-fold higher than the general population, and is thought to be 0.5–1% per year or 10–40% lifetime risk (Burak et al. 2004). There does not appear to be a relationship between the duration of disease or the concomitant presence of inflammatory bowel disease and the risk of cancer in PSC (Chalasani et al. 2000; Broome et al. 1996). Congenital cystic dilatations of the biliary ducts, or choledochal cysts, have a risk of developing cancer that is proportional to the duration of disease or age of the patient. The mechanism of cancer development in these cysts is not certain but is likely related to bile stasis and infection as well as reflux of pancreatic secretions leading to chronic inflammation, dysplasia and cancer. The median age of cancer diagnosis in patients with these lesions is 30–35 years old, compared to the overall peak incidence of 70–75 years of age of sporadic cases (Shaib and El-Serag 2004). The risk of cancer is thought to be <1% per year in these lesions with an overall lifetime cancer incidence of 28% if cysts are left untreated (Lipsett et al. 1994; Chijiiwa and Koga 1993). Other known risk factors for cholangiocarcinoma include exposure to thorium dioxide found in Thorotrast, a radiologic contrast agent used in the 1950s, liver fluke Opisthorcis viverrini infections (Shaib and El-Serag 2004; Watanapa and Watanapa 2002; Chaimuangraj et al. 2003; Thamavit et al. 1978), and inherited BRCA2 mutations (The Breast Cancer Linkage Consortium 1999). Epidemiologic studies have suggested associations between Clonorchis sinensis infection, dioxide exposure, cirrhosis and cancer but the evidence supporting these is not as strong (Shaib and El-Serag 2004; Lipshutz et al. 2002).
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10.3.2 Pathology of Extrahepatic Bile Duct Cancer The vast (>90%) majority of Klatskin tumors are adenocarcinomas; occasionally adenosquamous or squamous carcinomas may be seen in cases of choledochal cysts or common bile duct stones (Rossi et al. 1987). Histologically and macroscopically they can be further classified as nodular, sclerosing and papillary subtypes (Weinbren and Mutum 1983). The papillary subtype is characterized by intraluminal growth of papillary projections of tumor. These papillary growths are often friable so that some cases will present with intermittent jaundice due to transient bile duct obstruction due to either tumor debris or mucin produced by these lesions. Papillary tumors have a lower propensity to invade through the duct wall into adjacent structures and are therefore associated with a better prognosis (Lim and Park 2004; Lim et al. 2003). The sclerosing subtype is characterized by intraductal and periductal tumor growth with significant associated desmoplastic reaction causing obstruction of the affected bile ducts with little or no perceptible mass on imaging, while the nodular subtype often is seen as a mass that arises from and obstructs the bile duct lumen (Lim and Park 2004; Choi et al. 2004).
10.3.3 Diagnosis of Extrahepatic Bile Duct Cancer The present symptoms and the stage at which the disease presents, is dependent on the location and extent of the tumor. As a result, the anatomic relationships between the tumor and bile duct as well as its pattern of invasion and spread, impact not only the stage at which the disease is recognized but also the treatment strategy and outcomes. The most common presenting sign for Klatskin tumors is obstructive jaundice which is often accompanied by pruritus, acholic stool and dark urine; for this to occur the tumor must occlude the common hepatic duct or the hepatic ducts bilaterally. In a patient with normal liver function, unilateral hepatic duct obstruction will not result in jaundice but may cause abnormalities in hepatic transaminases or alkaline phosphatase which may be picked up incidentally. Serum tumor markers such as CEA, Ca-125 and Ca19-9 are of limited use in the initial diagnosis due to low sensitivity and specificity. Elevated Ca19-9 levels can be seen in benign biliary tract disease, but a Ca19-9 level >100 U/mL has some utility in detecting cancer in patients with PSC (Nichols et al. 1993; Patel et al. 2000). Symptoms of cholangitis such as fever and sepsis are unusual as initial symptoms unless there has been prior manipulation of the biliary tree. RUQ pain, weight loss, nausea, and fatigue are nonspecific symptoms which are often seen in these cases, particularly among those with advanced disease (Malhi and Gores 2006). The radiologic assessment of Klatskin tumors should include the delineation of the location and extent of biliary ductal involvement, an assessment of local invasion of liver, vascular structures and adjacent organs, the assessment of liver volumes including the presence of hepatic hypertrophy or atrophy, and the identification of local and distant metastatic disease. Endoscopic U/S is a commonly used imaging modality in the assessment of patients with obstructive jaundice. U/S is useful in determining the proximal level of
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biliary ductal dilatation and obstruction as well as ruling out benign causes of jaundice such as gallstone disease. U/S may be limited in its ability to define the distal level of ductal involvement, the detection of mass component or differentiate between benign and malignant strictures. Doppler U/S can be very reliable in detecting vascular involvement in the porta hepatis (Choi et al. 2004; Bach et al. 1996; Hann et al. 1996). Cholangiography can be invaluable in delineating the extent of biliary tract involvement and can be performed though either a percutaneous (PTC) or endoscopic approach (ERCP). Both techniques have the advantage of determining the proximal and distal extent of malignant obstruction but also provide an opportunity to establish biliary decompression and drainage as well as obtaining samples for cytologic diagnosis (Brugge 2005). MR cholangiography (MRCP) has largely replaced endoscopic and percutaneous procedures for diagnostic purposes in many centers and has the distinct advantage of providing three dimensional reconstructions of the biliary tree and accurately depicting its relationship to vascular structures (Manfredi et al. 2004; Zidi et al. 2000; Hekimoglu et al. 2008). Extensive experience with the use of 18 FDG-PET and PET-CT in the staging of Klatskin tumors is limited. PET may identify not only the primary tumor, but also sites of extrahepatic disease that may be missed on conventional imaging (Petrowsky et al. 2006). The sensitivity and specificity of PET may approach 80% and may be more useful in nodular tumors compared to mucinous or sclerosing cancers, as these are more 18FDG avid (Kluge et al. 2001; Anderson et al. 2004). False positive PET findings can be seen in regions of acute inflammation such as PSC and following biliary stent insertion (Keiding et al. 2000).
10.3.4 Staging Extrahepatic Bile Duct Cancer The original classification system for cancers of the extrahepatic bile duct was proposed by Bismuth and Corlette (1975), and describes the location and extent of bile duct involvement. Type 1 tumors are midbile duct lesions that are proximal to the bifurcation. Type 2 tumors extend up to the hepatic duct confluence but do not involve either the right or left hepatic ducts. Type 3 tumors occlude the common hepatic duct as well as its confluence and extend into the right (Type 3A) or left (Type 3B) hepatic ducts. Type 4 tumors are classified as tumors that occlude the hepatic duct, its confluence and extend into both the left and right hepatic ducts, or tumors with multifocal duct involvement. It is possible that in early series, many Type 1 tumors were actually gallbladder cancers with periductal involvement that were misclassified as arising from the bile duct. The Bismuth-Corlette classification system has endured and is still used today because of its simplicity, and utility in predicting the extent of biliary and hepatic resection likely required to achieve complete tumor clearance, but does not account for issues such as local invasion, resectability and long-term outcome. The AJCC 6th edition (Greene et al. 2002) staging system for extrahepatic bile duct cancer is shown in Table 10.3; this system describes the extent of local invasion, the presence of lymph node or distant metastases and begins to address issues of resectability since T3 tumors may be resectable whereas, most T4 tumors would be considered unresectable. While the AJCC 6th edition staging has not been validated in terms of clinical outcomes, lack of associations between the AJCC 5th edition staging and resectability or survival led
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10 Carcinoma of the Biliary Tract Table 10 3 AJCC 6th edition (Greene et al. 2002) TNM staging for bile duct cancer AJCC 6th edition TNM Description T stage T0 Tis T1 T2 T3 T4
N stage N0 N1 M stage M0 M1
No evidence of primary tumor Carcinoma in situ Tumor confined to the bile duct histologically Tumor invades beyond the bile duct wall Tumor invades the liver, gallbladder, pancreas and/or unilateral branches of the portal vein or hepatic artery Tumor invades any of the following: main portal vein or its branches bilaterally, common hepatic artery or adjacent structures (colon, stomach, duodenum, abdominal wall) No regional lymph node metastases Regional lymph node metastases No distant metastases Distant metastases
Table 10.4 AJCC 6th edition (Greene et al. 2002) stage grouping for bile duct cancer AJCC 6th edition stage Definition Stage 0
Tis
N0
M0
Stage 1A
T1
N0
M0
Stage 1B
T2
N0
M0
Stage 2A
T3
N0
M0
Stage 2B
T1–3
N1
M0
Stage 3
T4
Any N
M0
Stage 4
Any T
Any N
M1
Jarnagin et al. (2001) to suggest a new staging system (see Tables 10.4 and 10.5) which introduced the incorporation of lobar atrophy into the staging of bile duct cancers. Lobar atrophy can occur due to prolonged biliary obstruction or vascular occlusion; its presence indicates that removal of the lobe is required for tumor clearance and may be associated with improved perioperative outcomes by inducing hypertrophy of the contralateral lobe (Jarnagin and Shoup 2004). The system proposed by Jarnagin associated with resectability and overall survival in the original series of patients, (Jarnagin et al. 2001) but was not associated with outcome in other series (Hemming et al. 2005) (Table 10.6).
10.3.5 Surgical Resection of Extrahepatic Bile Duct Cancer The surgical management of Klatskin tumors is extremely challenging; extensive experience in the treatment of this disease is limited to a few high-volume hepatobiliary oncology
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Table 10.5 Criteria for unresectability proposed by Jarnagin et al. (2001), Jarnagin and Shoup (2004), and Sicklick and Choti (2005) Criteria of unresectability for hilar cholangiocarcinoma Patient factors Medically unfit or otherwise unable to tolerate a major operation Hepatic cirrhosis Insufficient remnant liver volume to maintain adequate hepatic function Local tumor-related factors Tumor extension to secondary (2°) biliary radicles bilaterally Encasement or occlusion of main portal vein or its bifurcationa Atrophy of one hepatic lobe with contralateral portal vein branch encasement or occlusiona Atrophy of one hepatic lobe with contralateral tumor extension to 2° biliary radicles Unilateral tumor extension to 2° biliary radicles with contralateral portal vein branch encasement or occlusion Metastatic disease Histologically proven metastases in N2 lymph nodesb Lung, liver or peritoneal metastases onsidered relative contraindications in centers with experience in portal vein resection and C reconstruction b N2 lymph nodes are defined as the peripancreatic, periduodenal, celiac, superior mesenteric or posterior pancreaticoduodenal lymph nodes in the AJCC 5th edition staging system. Metastases to N1 lymph nodes (cystic duct, pericholedochal, hilar or portal nodes) are considered resectable a
Table 10.6 Clinical T-stage criteria proposed by Jarnagin et al. (2001) Clinical stage Criteria T1
Tumor involving biliary confluence ± unilateral extension into 2° biliary radicles
T2
Tumor involving biliary confluence ± unilateral extension into 2° biliary radicles and ipsilateral portal vein involvement ± ipsilateral hepatic lobar atrophy
T3
Tumor involving biliary confluence + bilateral extension into 2° biliary radicles, unilateral extension into 2° biliary radicles with contralateral portal vein involvement, unilateral extension into 2° biliary radicles with contralateral hepatic lobar atrophy, or main portal vein involvement
centers. Early surgical experiences were hampered by high perioperative morbidity and mortality as well as low rates of R0 resection (Cameron et al. 1990; Gerhards et al. 2000). Increasing safety of hepatic resection and an aggressive approach to resection have improved peri-operative and long-term results in this disease. Thorough preoperative imaging and staging is crucial to proper preoperative planning as approximately 30% of tumors will be unresectable at diagnosis and a further 30–50% will be deemed unresectable at laparotomy with a high correlation between tumor stage and resectability (Jarnagin et al. 2001; Hemming et al. 2005; Mansfield et al. 2005; Launois et al. 1999). Preoperative laparoscopy may be
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useful in detecting peritoneal spread or intrahepatic metastases but has limited utility in determining local factors affecting resectability (Weber et al. 2002). The role of preoperative biliary drainage of the future remnant liver (FRL) using percutaneous transhepatic cholangiography (PTC) is the subject of some debate. While PTC has largely been replaced by MRCP as a diagnostic modality, preoperative biliary drainage of the FRL has the potential advantage of relieving biliary obstruction and controlling infection. This may not only improve hepatic function and patient’s nutritional status prior to surgery, but may also improve renal function and liver hypertrophy thus reducing the risk of postoperative liver failure and morbidity. While preoperative biliary drainage is advocated by many centers, its benefits have not been conclusively demonstrated (Ebata et al. 2003; Smith et al. 1985; Wig et al. 1999; Hatfield et al. 1982; McPherson et al. 1984; Laurent et al. 2008; Nimura 2008). The preoperative assessment of patients with hilar cholangiocarcinoma should include an evaluation of the volume of the FRL. Since many cases require extensive hepatic resection, FRL volumes of <20% of total liver volume are associated with higher rates of postoperative liver failure and complications (Abdalla 2001; Shoup 2003). Preoperative embolization of the contralateral portal vein and segment four branches can induce hypertrophy of the FRL and increase the safety of extensive hepatic resections (Madoff et al. 2003; Abdalla et al. 2002a; Palavecino et al. 2009). An aggressive surgical approach to Klatskin tumors to improve R0 resection rates was pioneered by Japanese centers (Nishio et al. 2005; Kosuge et al. 1999; Miyazaki et al. 1999) and has gained acceptance throughout North America (Jarnagin and Shoup 2004; Hemming et al. 2005; Ito et al. 2008) and Europe (Neuhaus et al. 1999). Resection of the extrahepatic bile duct combined with portal lymphadenectomy and extended hepatectomy including caudate lobe resection can achieve complete microscopic tumor clearance (R0 resection) in 50–80% and 5-year survival in 30–50% of cases with a perioperative mortality rate of 5–10% and is considered the standard of care for surgical resection of hilar cholangiocarcinoma (Jarnagin and Shoup 2004; Hemming et al. 2005; Nishio et al. 2005; Kosuge et al. 1999; Miyazaki et al. 1999; Ito et al. 2008; Neuhaus et al. 1999; Tsao et al. 2000). Routine resection of the caudate lobe has been advocated due to its variable biliary drainage pattern, its proximity to the hepatic duct confluence and the observation that the caudate is a common site of tumor recurrence (Tsao et al. 2000; Abdalla et al. 2002b; Parikh et al. 2005; Nimura et al. 1990; Ogura et al. 1993). In selected cases with extensive intra and periductal tumor extension into the intrapancreatic bile duct, combined hepatic resection and pancreaticoduodenectomy (Whipple procedure) may be performed to achieve complete tumor clearance in appropriate patients (Sasaki et al. 2006; Jarnagin et al. 2001; Nishio et al. 2005). Due to its proximity to the bile duct, tumor invasion of the portal vein is commonly seen and was previously considered to be a contraindication to resection due to high complication rates associated with complex vascular resections and reconstruction. Resection of the portal vein to achieve an R0 resection has been performed safely and effectively in many centers; cases where portal vein resection is performed appear to have similar long-term outcomes with minimal increases in peri-operative morbidity and mortality compared to cases resected without vascular involvement (Ebata et al. 2003; Nishio et al. 2005; Neuhaus et al. 1999; Hemming et al. 2006). While controversial, liver transplantation has been suggested as a treatment option in selected cases of cholangiocarcinoma that are deemed unresectable due to the presence of
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bilateral liver involvement, extensive vascular invasion or preexisting liver disease such as PSC. Transplantation can achieve complete tumor clearance in cases where the disease is confined to the liver and porta hepatis and allows complete inflow vascular resection and reconstruction (Iwatsuki et al. 1998). Initial reports of transplantation in unresectable or incidental cholangiocarcinoma were hampered by early tumor recurrence and poor overall survival (Robles et al. 2004; Shimoda et al. 2001; Zheng et al. 2002) even when transplantation was combined with pancreaticoduodenectomy to improve tumor clearance (Cherqui et al. 1995; Jonas et al. 1998; Anthuber et al. 1996). Recently, neoadjuvant chemotherapy with external beam RT ± brachytherapy followed by liver transplantation has been shown in selected centers to be associated with 5-year survival of up to 80% (Rea et al. 2005; Sotiropoulos et al. 2004; Sudan et al. 2002). As a result of these recent results, several centers are reevaluating the potential role of transplantation in the management of cholangiocarcinoma.
10.3.6 Radiation Therapy in Bile Duct Cancer Cholangiocarcinomas tend to spread along the bile duct system and locally via direct extension into adjacent structures (more common in intrahepatic and perihilar tumors), regionally to pericholedochal, peripancreatic, hilar, and cystic lymph nodes and distantly to the liver and peritoneum. In contrast to gallbladder cancers, most recurrences following resection of extrahepatic cholangiocarcinoma are locoregional within the liver, tumor bed, and regional lymph nodes in the porta hepatic or pancreaticoduodenal system and the celiac axis, providing stronger rationale for adjuvant RT for biliary cancers vs. gallbladder cancers. In general, the potential benefits of RT to distal bile duct cancers are less than those to proximal bile duct cancers, in part due to the challenges in delivering tumorcidal doses to more distal cancers and in part due to the proximity to the duodenum and other luminal gastrointestinal tissues. Similar to gallbladder cancer, most experience with radiotherapy for biliary cancer has been with conventional (nonconformal) adjuvant RT (40–55 Gy), to a large volume, sometimes with chemotherapy (Kim et al. 2002a; Morganti et al. 2003). CRT, IORT or brachytherapy are sometimes used to increase the doses to the highest risk regions (to 60–66 Gy).
10.3.6.1 Adjuvant Radiation Therapy for Perihilar Cholangiocarcinomas The majority of series suggest a benefit to adjuvant RT in bile duct cancers. The European Organization for Research and Treatment of Cancer (EORTC) reported improved survival (median 19 vs. 8.3 months, p = 0.0005) in 38 patients with Klatskin tumors after curative resection, external beam RT and brachytherapy vs. 17 patients who underwent surgery alone (Gonzalez et al. 1990). Gerhards et al. also observed improved survival in 71 patients with resected hilar cholangiocarcinoma who received adjuvant radiotherapy (external
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beam and brachytherapy) compared with 20 who had resection alone (24 vs. 8 months) (Gerhards et al. 2000). Complications such as cholangitis were more common in patients receiving brachytherapy vs. no radiation or external beam RT alone (63 vs. 40 vs. 32%, respectively, p = 0.03). Improved survival was also seen in 28 Japanese patients with stage IV Klatskin tumor treated with external beam RT, IORT or both compared with 19 patients who had resection alone (33.9 vs. 13.5%, p = 0.014) (Todoroki et al. 2000). Locoregional control was improved from 31 to 80% with postoperative RT. No change in survival was seen following adjuvant radiotherapy in the patients without lymph node involvement and negative margins. For 24 patients with positive lymph nodes, survival was better in patients treated with external beam RT plus IORT compared to IORT alone (Kurosaki et al. 1999). In another series, locoregional recurrences were seen in 47% of 91 patients with extrahepatic bile duct cancer treated with postoperative RT (40–45 Gy over 4–5 weeks), with or without concurrent 5-FU chemotherapy (Kim et al. 2002b). Twenty-five patients had positive resection margins and 12 had gross residual tumor following surgery. Five year survival was approximately 30% in patients with negative margins and positive margins, suggesting a benefit to postoperative RT used more often in patients with microscopic residual tumor (Kim et al. 2002b). Borghero et al. compared outcomes of 42 high risk patients with resected extrahepatic cholangiocarcinoma (with microscopically positive resection margins or pathologically involved nodes) who received adjuvant chemo-RT to those of 21 lower risk patients (with negative resection margins and negative nodes) who did not receive adjuvant RT. Survival and local recurrence rates were similar in both groups (5 year survival 36 vs. 42%, p = 0.6; 5 year locoregional recurrence rate 38 vs. 37%, p = 0.13, for adjuvant and no adjuvant therapy groups respectively). The lack of a significant difference in outcomes suggests that adjuvant chemo-RT may have benefited patients with higher risk extrahepatic cholangiocarcinoma (Borghero et al. 2008). In contrast to the above series, other studies have failed to show a benefit of RT following surgery (Lillemore and Cameron 2000; Zlotecki et al. 1998). In a matched control study, Pitt et al. found no survival difference in patients with perihilar cholangiocarcinoma treated with or without postoperative RT (median survival 18.4 vs. 20.1 months) (Pitt et al. 1995). Selection bias plays a role in the above series in that patients with better performance status and recovery from surgery are more likely to be offered RT. It is also likely that patients with worse prognostic factors would be more likely to be offered adjuvant therapy. Overall, most series suggest a benefit to adjuvant RT, with most marked differences seen in patients with positive margins or involved nodes.
10.3.6.2 Neoadjuvant Radiation Therapy for Cholangiocarcinomas Neoadjuvant therapy for cholangiocarcinoma may benefit borderline resectable cancers by making them resectable. Also, the volume irradiated in the neoadjuvant setting is smaller, with less risk of toxicity. McMasters et al. reported that preoperative chemo-RT was well tolerated in nine patients who went on to have R0 resections. In contrast, margin-negative resections were only seen in 54% of patients who did not receive preoperative therapy
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(p < 0.01). Six unresectable patients became resectable following preoperative therapy, three with a pathologic complete response (McMasters et al. 1997). Three minor wound infections were seen postoperatively. No anastomotic leaks or serious complications were observed. None of the five patients with proximal bile duct cancers recurred, and one was disease free at 32 months. Gerhards et al. evaluated the role of preoperative RT (3.5 Gy × 3) in minimizing the risk of implantation metastases in 21 patients who underwent resection of proximal cholangiocarcinomas (Gerhards et al. 2000). With a follow-up time of 2–79 months, no patient developed implantation metastases, compared to 20% of patients who did following endoscopic biliary drainage in a prior study.
10.3.6.3 Radiation Therapy for Unresectable Cholangiocarcinoma Extrahepatic cholangiocarcinoma and portal or pancreaticoduodenal lymph node metastases may precipitate biliary obstruction and jaundice. Palliative low dose RT to this region may alleviate biliary obstruction in some patients. As edema and precipitation of obstruction is possible following RT, it is most successful in conjunction with a bypass procedure or percutaneous stent. Cameron et al. found that 1 year survival was improved in patients treated with RT in addition to palliative stenting (38 vs. 9%, p < 0.05), suggesting a palliative benefit to RT (Cameron et al. 1990). In addition to palliation of symptoms, several studies have suggested improved outcomes with RT with or without chemotherapy for unresectable cancers. The median survival of patients with locally advanced bile duct cancers treated with RT alone or chemotherapy ranges from 7 to 24 months, with a suggestion that outcomes are better with more intense treatment (Monson et al. 1992). Ben-David et al. reviewed 81 patients with extrahepatic cholangiocarcinomas and gallbladder carcinoma treated with RT (52 unresectable or with gross residual disease) and concurrent chemotherapy in 50% of patients. The median survival and progression-free survival rates were 13.1 and 7.9 months, respectively (Ben-David et al. 2006). Grove et al. reported significantly increased median survival in patients with unresectable extrahepatic bile duct cancer receiving RT vs. those who underwent surgical decompression alone (12.2 vs. 2.2 months, p = 0.05) (Grove et al. 1991). Tollenaar et al. also found increased survival with RT following surgical decompression compared to surgical decompression alone (16 vs. 3 months, p < 0.001) in 55 patients (Tollenaar et al. 1991). In a study by Crane et al, 1-year survival in 52 unresectable patients undergoing primarily RT was 44% (Crane et al. 2002). Local control was improved with higher doses. In another study of 31 patients with extrahepatic bile duct cancer treated with external beam RT alone (median 50.5 Gy over 5 weeks, n = 17) or with brachytherapy (5 Gy × 3, n = 14), higher doses were also associated with a longer time to recurrence (9 vs. 5 months, p = 0.06) and survival (21 vs. 0% 2 year survival, p = 0.015) (Shin et al. 2003). Others have also seen improved outcomes following higher RT doses and occasional long term survivors (Foo et al. 1984; Grove et al. 1991), but this has not been a universal finding (Flickinger et al. 1991) (Table 10.8).
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Although brachytherapy is an attractive strategy to increase RT dose, it has been associated with an increased risk of cholangitis, duodenal ulcer and duodenal stenosis. Brachytherapy likely has the most value in unresectable hilar cholangiocarcinomas where the irradiated segment is at a distance of at least 2 cm from the duodenum. A metal stent can be placed across the obstructed segment following brachytherapy and can help prevent scarring and reduce the risk of cholangitis. IORT has also been used to boost the highest risk regions (by 10–25 Gy) (Kurosaki et al. 1999). Toxicity is more likely with a combination of external RT and IORT with a 13–25% risk of serious toxicity in the original IORT series. Various chemotherapy regimens (mostly 5 FU based) have been used as radiation sensitizers (Minsky et al. 1990; Morganti et al. 2000). When RT (45 Gy) was combined with doxifluridine (600 mg/m2) daily, intravenous paclitaxel (50 mg/m2) weekly (before RT) in 19 patients with unresectable extrahepatic bile duct cancer, the local response rate was 90% with a median survival time of 14 months. One case of gastrointestinal bleeding was seen (Park et al. 2006). RT and gemcitabine have also been investigated in the setting of local-regional radiotherapy for distal biliary malignancies. As the volume of tissue required to be irradiated increases, the maximal dose of weekly gemcitabine should be reduced (e.g., to 250 mg/m2) (Morganti et al. 2003). Overall, the use of external beam RT with or without brachytherapy, IORT or chemotherapy results in a median survival of 12–14 months in patients with unresectable cholangiocarcinoma. Long-term survival is possible, reported in up to 10% of selected patients with unresectable or recurrent biliary malignancies (Gonzalez et al. 1990; Grove et al. 1991; Minsky et al. 1990; Fogel and Weissberg 1984; Veeze-Kuijpers et al. 1990; Fritz et al. 1994; Alden and Mohiuddin 1994; Kopelson et al. 1977) (Fig. 10.1).
a
Baseline CT
b
3 months post RT
Change due to RT
c
2 years post RT
Fibrosis due to high dose RT
Fig. 10.1 (a) Intrahepatic cholangiocarcinoma refractory to chemotherapy (gemcitabine and capecitabine), treated with conformal RT (CRT) (33 Gy in six fractions). (b) Three months following RT, there is hypodense change in liver within the high dose irradiated volume. (c) Two years following RT, the tumor remains stable with less enhancement
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10.4 Intrahepatic Cholangiocarcinoma 10.4.1 Epidemiology and Risk Factors ICC are adenocarcinomas arising from the epithelial cells of the intrahepatic (second order and higher) bile ducts. ICC have also been referred to as “peripheral cholangiocarcinomas” due to their origin from the higher order biliary ducts and location within the liver parenchyma. After hepatocellular cancer (HCC), ICC is the second most common primary liver malignancy accounting for 10–20% of liver cancers (Shaib and El-Serag 2004; Welzel et al. 2006; Yamasaki 2003). ICC is a somewhat enigmatic cancer as it is often a diagnosis of exclusion once secondary malignancies are excluded and is often classified along with HCC in cancer registries, though its genetic origin and biologic behavior is vastly different from either HCC or metastases. With an increasing appreciation for this malignancy, studies from multiple continents have shown a consistent increase in the incidence and mortality of ICC beyond what would be expected by increased detection and improved classification alone, and has an incidence of approximately 0.85 per 100,000 in the United States (Patel 2002; Khan et al. 2002a; Wood et al. 2003; Shaib and El-Serag 2004). Traditional risk factors for ICC include PSC, ulcerative colitis, choledochal cysts, liver fluke infection, thorium dioxide exposure hepatolithiasis and cholodocholithiasis; as well as viral (B and C) hepatitis, alcoholic liver disease, cirrhosis are also risk factors for extrahepatic cholangiocarcinoma and HCC, respectively (Sorensen et al. 1998). Combined, these risk factors suggest that chronic biliary ductal inflammation and/or chronic liver disease and cirrhosis lead to the development of ICC. It is possible that research on the progenitor cells of HCC, ICC and an intermediary tumor cholangiolocarcinoma may yield further incites into the origin of the cancer, and whether common and/or distinct oncologic pathways exist for HCC and ICC. Furthermore, recent studies have suggested that smoking, diabetes, obesity, peptic ulcer disease, chronic pancreatitis, and HIV infection may be additional risk factors for ICC (Welzel et al. 2007; Shaib et al. 2005); the increase in prevalence of these predisposing conditions may partially explain the increasing worldwide incidence of ICC (Welzel et al. 2007).
10.4.2 Pathology of Intrahepatic Cholangiocarcinoma ICCs are adenocarcinomas containing tubular or papillary patterns of duct structures surrounded by an abundance of desmoplastic stroma. Tumors can be classified as scirrhoustype or nonscirrhous type based on the amount of desmoplastic reaction seen on histologic examination (Kajiyama et al. 1999). Based on macroscopic appearances and behavior, the Liver Cancer Study Group of Japan (LCSGJ) classified ICCs into mass-forming, periductal infiltrating, and intraductal infiltrating types (Liver Cancer Study Group of Japan 2003). The mass-forming subtype is seen as a well defined mass with distinct margins in
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the hepatic parenchyma; this subtype demonstrates a nodular, exophytic or expansive growth pattern and has a lower propensity to infiltrate along biliary ducts towards the porta hepatis. The mass forming subtype is prone to invasion of the portal venous system and as a result is at higher risk of intrahepatic recurrence after resection. The periductal infiltrating subtype forms a more poorly defined mass that has a sclerosing growth pattern and infiltrates along the biliary ducts and may invade both the hepatic parenchyma and portal vascular structures. The intraductal infiltrating type is characterized by a prominent papillary growth within the bile duct lumen that extends proximally towards the porta hepatis with limited superficial extraductal extension (Weinbren and Mutum 1983; Liver Cancer Study Group of Japan 2003; Nakajima et al. 1988; Sasaki et al. 1998).
10.4.3 Diagnosis of Intrahepatic Cholangiocarcinoma Unlike hilar cholangiocarcinomas which commonly presents early, with jaundice, ICC can progress to a very advanced stage before they become symptomatic. Most curable lesions are detected incidentally by identification of abnormal liver enzymes or a mass on imaging studies. When symptoms do develop, vague abdominal pain, fatigue, weight loss and weakness are the most common complaints (Chen et al. 1999; DeOliveira et al. 2007; Paik et al. 2008). Tumor markers CEA and Ca19-9 are most commonly evaluated in ICC patients. Ca19-9 is elevated in 29% of ICC cases and, when abnormal have a sensitivity of 89% and a specificity of 86%. The use of Ca19-9 as a diagnostic tool is limited by fact that the sensitivity of this test drops to 53% in cases with concomitant PSC and the enzyme may be elevated in cholangitis, chronic liver disease and other GI malignancies. Significant elevations of Ca19-9 may be indicative of advanced unresectable disease (Nichols et al. 1993; Patel et al. 2000; Paik et al. 2008; Levy et al. 2005) (Fig. 10.2). Radiologic assessment of ICC often requires the utilization of multiple complementary noninvasive imaging techniques. U/S can detect and localize suspected masses and color
Post op conformal RT plan 50Gy
Fig. 10.2 Example of a CRT plan for a pT3N1 R1 hilar cholangiocarcinoma treated with hepatectomy and biliary reconstruction. Fifty gray in 25 fractions was delivered with concurrent 5FU chemotherapy, followed by oral capecitabine. The patient remains alive with no evidence of recurrence 4.5 years following surgery
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Doppler can identify associated vascular compression or invasion. Proximal biliary dilatation can be difficult to identify with peripheral lesions but may be easily detected by U/S on more central lesions arising in more proximal regions of the biliary tree. On CT ICCs appear as hypodense lesions on venous phase with occasional peripheral arterial rim enhancement. CT can be valuable in detecting intrahepatic metastases, vascular invasion, lymphadenopathy, and may be used in the assessment of liver volumetry prior to resection. However, CT may underestimate the extent of infiltrative cancers, particularly periductal infiltrating lesions, due to the poorly defined borders of these tumors and the sclerosis and fibrosis in surrounding hepatic parenchyma (Zhang et al. 1999; Khan et al. 2002b). MRI and MRCP have the ability to define the malignant mass in relation to the biliary system. The ability to accurately visualize strictures within the bile ducts may be particularly useful when evaluating patients with PSC. With enhanced abilities to discriminate tissue characteristics, MRI and MRCP may be able to provide insight into the extent of infiltrative lesions but can still under-stage lesions (Manfredi et al. 2004; Braga et al. 2001; Zidi et al. 2000; Peterson et al. 1998). There is limited data on the use of FDG-PET and PET/CT in ICC. PET-based imaging appears to reliably detect mass forming ICC >1 cm in diameter with a sensitivity and specificity similar to contrast-CT (Petrowsky et al. 2006). PET may have higher specificity in diagnosing malignant lymphadenopathy and may be more sensitive in detecting distant metastases than the traditional CT and MRI (Anderson et al. 2004; Kim et al. 2008). The need for percutaneous needle biopsy is relatively common in cases of ICC vs. other hepatic lesions, due to the similarities in radiographic appearance between ICC and either metastatic lesions or HCC with cholangiohepatoma features. The diagnostic yield of percutaneous biopsy must always be weighed against the risk of bleeding, needle track seeding, and inconclusive pathologic examination. Immunohistochemical examination of ICC usually demonstrates staining with CK7, CK19 and CEA with variable staining of CK20; staining with Hepatocyte-1 would indicate a hepatocellular differentiation (Endo et al. 2008). A search for primary malignancies including upper and lower endoscopy, CT chest and abdomen as well as mammography for females is undertaken to rule out metastatic disease in cases of ICC where either radiologic or histologic examination is inconclusive.
10.4.4 Staging of Intrahepatic Cholangiocarcinoma The appropriate staging system for ICC has been the subject of considerable debate in North America and Asia. The AJCCUICC 6th edition TNM staging system (Greene et al. 2002) for ICC was based on prognostic data derived from patients with HCC, not cholangiocarcinoma. Due to the etiologic and prognostic differences between these two malignancies, it was felt that this staging system might not provide an accurate prediction of survival in ICC. As a result, three alternate staging systems have been proposed by two groups in Japan as well as one group in North America (Nathan et al. 2009) based on ICC cases in the respective region; a comparison of these staging systems can be seen in Table 10.7. In 2001, Okabayashi et al. (2001) modified and simplified the AJCC system and developed a staging system for mass-forming ICC based on clinical, diagnostic and
Regional lymph node metastases
3C-any T N1
Any T any N M1
Direct invasion of adjacent organs (other than gallbladder) Perforation of visceral peritoneum
3B-T4N0
4
Multiple tumors >5 cm Tumor invading main portal or hepatic vein branch
3A-T3N0
3
Metastatic disease
Solitary tumor with vascular invasion Multiple tumors, all <5 cm
T2N0
2
Solitary tumor without vascular invasion
T1N0
1
Metastatic disease
4A-T4N0-meets 0/4 requirements Any T N1-lymph node metastases 4B-any T any N M1-Metastatic disease
Any T any N M1 – metastatic disease
T3N0 – tumors with extrahepatic extension Any T N1 – lymph node metastases
T3N0 – meets 1/3 requirements
3A-multiple tumors with or without vascular invasion 3B-regional lymph node metastases
T2N0 tumors with vascular invasion and/or multiple tumors
T1N0 single tumor without vascular invasion
Nathan et al. (2009)
T2N0 – meets 2/3 requirements
T1N0 meets three requirements Single nodule Tumor £2 cm No venous or serous membrane invasion
Liver cancer study group of Japan
Solitary tumor with vascular invasion
Solitary tumor without vascular invasion
Table 10.7 Comparison of staging systems for intrahepatic cholangiocarcinoma Stage AJCC Okabayashi
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pathologic features of 60 cases of resected ICC. In multivariate analysis multiple tumors, vascular invasion and lymph node metastases were independent predictors of survival and were incorporated into the staging system. The LCSGJ proposed a staging system for mass forming ICC based on three factors: solitary vs. multiple tumors, size £2 cm, portal or hepatic venous invasion and serosal invasion (Liver Cancer Study Group of Japan 2003). Nathan et al. (2009) attempted to validate the AJCC and Japanese staging systems on 598 histologically confirmed resected cases of ICC obtained through the United States SEER database. In this analysis, tumor size did not predict survival and as a result the AJCC T-stage system failed to accurately differentiate patient’s prognosis. Multiple tumors, vascular invasion and lymph node metastases were all predictive of survival in their analysis. While the Okabayashi staging system had an improved ability over AJCC to discriminate between T2 and T3 lesions, due to the elimination of size criteria, there was no difference in survival according to stage using LCSGJ system.
10.4.5 Surgical Resection of Intrahepatic Cholangiocarcinoma Complete resection with negative microscopic margins (R0 resection) offers the best chance of cure in patients with ICC. Noncurative resection with macroscopic (R2) or microscopic (R1) positive margins are frequently associated with rapid tumor recurrence within months (median=3 months), poor long-term survival (5-year survival <7%), and offer little to no improvement in survival over conservative or palliative management (Khan et al. 2005; Yamamoto et al. 1992, 2001; Ohashi et al. 1994). Curative resection in ICC is hampered by the often advanced stage of disease at which the disease is discovered, with many series reporting resectability rates are commonly <40% (DeOliveira et al. 2007; Endo et al. 2008; Yang and Yan 2008). Furthermore, infiltrating tumors often have poorly defined borders which presents a challenge in planning and achieving a resection with an adequate margin. Therefore, the surgical approach to ICC includes hepatectomy that achieves complete tumor resection with negative microscopic margins, which leaves an adequate functioning liver remnant offers the best opportunity for curative resection. In general, an adequate liver remnant consists of two contiguous liver segments which constitute at least 20% of the total liver volume and have adequate vascular inflow/outflow and biliary drainage (Pawlik et al. 2004; Vauthey et al. 2000). There are many factors which impact remnant liver function, its assessment and the actual volume required including preexisting liver disease and chemotherapy (Clavien et al. 2007). If an inadequate liver remnant is anticipated, hypertrophy of these segments can be induced by preoperative portal vein embolization with both the final remnant volume and the degree of hypertrophy associated with improved peri-operative outcomes (Ribero et al. 2007). The vast majority of publications on surgical resection of ICC consist of small (most <60 patients) single-center experiences. While there is some variability between these series, aggressive curative resection is associated with a perioperative mortality rate of <5%, and 1-year survival rates of 50–75% and 5-year survival rates of 40–60% (Nakeeb et al. 1996; Chen et al. 1999; DeOliveira et al. 2007; Paik et al. 2008; Endo et al. 2008; Okabayashi et al. 2001; Yamamoto et al. 1992). Since lymphatic spread is common in this
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disease, the role of lymphadenectomy with hepatic resection for ICC is the subject of some debate. Routine hilar lymphadenectomy is more commonly practiced in Asia while many North American centers perform a lymphadenectomy on a selected basis in cases where lymphatic spread is suspected or in highly advanced lesions (Endo et al. 2008; Yang and Yan 2008). At this time there is little evidence that routine lymphadenectomy improves survival as most recurrences occur in the remnant liver (Chu and Fan 1999; Shimada et al. 2001). Further extension of surgery for ICC to include routine vascular resection and/or pancreaticoduodenectomy has not yielded improvements in outcome (Yamamoto et al. 1999; Urahashi et al. 2007). Liver transplantation has been suggested as a treatment modality for ICC in cases deemed unresectable due to tumor extent and invasion or underlying liver disease. Initial experience of transplantation for ICC was hampered by early recurrences and poor outcomes (Pichlmayr et al. 1995), since then several centers have reported 5-year survival rates of approximately 20%. However, two recent studies by Robles et al. (2004) and Becker et al. (2008) reporting 5-year survival rates of up to 40% following transplantation and the experience of in hilar tumors (Rea et al. 2005; Rosen et al. 2008) may lead to an expansion of the role of transplantation in this disease.
10.4.6 Radiation Therapy for Intrahepatic Cholangiocarcinoma Unresectable ICC has been treated with CRT, delivered in a variety of fractionations. At the University of Michigan, hyperfractionated RT, delivered in 1.5 Gy twice daily, with concurrent FuDR, was used to treat patients with ICC. Individualized prescription doses were used, and up to 90 Gy was delivered, dependent on the volume of liver irradiated. The median survival of 46 cholangiocarcinoma patients was 13 months (Ben-Josef et al. 2005). At the Princess Margaret Hospital in Toronto, ten ICC patients were treated with individualized hypofractionated RT delivered in six fractions (median dose 32.5 Gy, range 28–48 Gy) (Hekimoglu et al. 2008). Two patients developed transient biliary obstruction following the first few fractions, leading to a policy of pretreatment steroids for subsequent patients with central tumors. No other serious treatment-related toxicity was seen. The median survival was 15.0 months (95% CI 6.5–29.0). Local control was common, but recurrences outside the irradiated fields were frequent, providing rationale for combining RT with systemic therapy.
10.5 Systemic Therapy in Biliary Cancers 10.5.1 Metastatic Disease While surgical resection of the primary tumor is potentially curative therapy, less than 25% of patients will be resectable at presentation and amongst those, relapse rates are high
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(Oertli et al. 1993; Alexander et al. 1984; Wade et al. 1997; de Groen et al. 1999). Those with unresectable or metastatic disease will receive variable palliative therapy with a median survival most often less than 1 year. Biliary bypass or decompression stenting is crucial if chemotherapy metabolized or cleared by the hepatobiliary system is contemplated. Once adequate biliary drainage is achieved, there must be no evidence of infection at the start of each cycle of chemotherapy. Generally there has not been an accepted standard chemotherapy regimen in advanced biliary cancer. Data from a recent phase III trial evaluating a gemcitabine-cisplatin doublet (Valle et al. 2010). Historically, chemotherapy has had limited proven impact on the natural history of this disease. This is due in part to the absence of agents with substantial activity compared with chemotherapy in other solid tumors, limited data on the optimal therapeutic approach and the overall morbidity of treatment for this patient population. Practices vary considerably between institutions and regions, and range from no chemotherapy offered, due to concern over lack of efficacy and detrimental toxicity, to offering patients multiple-drug, potentially toxic regimens without demonstrated efficacy. Clinical trials in cholangiocarcinomas and gallbladder cancer have suffered from the relative rarity of these tumors and the inclination to lump them with other difficult and anatomically related cancers such as pancreas or hepatocellular carcinomas. In addition the difficulty in obtaining a histological diagnosis, the propensity to not always have measurable disease and the generally morbidity of this older patient population have made standard chemotherapy trials more difficult to complete. While many small studies have been completed, more multicenter cooperation is required for larger randomized trials. Carcinomas of the biliary tract and gallbladder may have biologic sufficient differences leading to different sensitivities to chemotherapy. However, most studies to date show similar response rates. A shorter median survival for gallbladder cancer patients is seen compared with cholangiocarcinomas. This probably reflects a more aggressive biology of gallbladder cancer. Due to their relative rarity it may not be practical to separate the biliary cancers in chemotherapy clinical trials, but planned randomized studies should include biliary tumor type in the stratification strategy.
10.5.1.1 Early Chemotherapy Studies Fluoropyrimidines have been considered the basis of palliative chemotherapy despite response rates (seen in small phase III trials) in the range of 0–10% (Falkson et al. 1984; Takada et al. 1994; Kajanti and Pyrhonen 1994). Older combination chemotherapy including 5-FU, has not demonstrated a clear superiority over single agent 5-FU but resulted in added toxicity (Table 10.8). However, Glimelius et al. (1996) showed there was improved quality of life for biliary cancer patients treated with 5-FU-based chemotherapy vs. bestsupportive care. Cisplatin; the platinum analog, is a drug that has had an important impact on many solid tumors. It synergizes with other drugs and is rarely used as a single agent. Regimens containing cisplatin, often combined with gemcitabine or 5-FU, evaluated in phase II studies
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10 Carcinoma of the Biliary Tract Table 10.8 Randomized chemotherapy trials in advanced biliary cancer References Treatment ORR (%) Median n survival (months)
QOL
Falkson (1984)
87
5-FU vs. 5-FU + STZ vs. 5-FU + MeCCNU
10 12 10
2.5–5 NS
NR
Takada (1994)
36
5-FU vs. FAM
0
NR
NR
5-FU/LV ± Etoposide vs. BSC
11 0
6.5 2.5 NS
33% vs. 5% p < 0.01
Glimelius (1996) 37
Rao (2005)
54
ECF vs. FELV
19 15
9 12 NS
Symptomatic relief both arms
Valle (2010)
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Gemcitabine vs. Cisplatin/Gem
15 26
8.1 11.7 p < 0.001, HR 0.62
Pending
STZ streptozocin; MeCCNU methyl CCNU; LV leucovorin; FAM 5-FU, doxorubicin, and mitomycin; NR not reported; BSC best supportive care; NS not significant; ECF epirubicin, cisplatin, and infused 5-FU; FELV bolus 5-FU, etoposide, leukovorin
of biliary cancer have in general reported higher response rates than those seen previously (20–45%), but also have more toxicity (20–50% ³ grade 3 toxicity) which may limit their general applicability in this patient population (Reyes-Vidal et al. 2003; Doval et al. 2004; Taieb et al. 2002; Mitry et al. 2002; Patt et al. 2001; Rao et al. 2005). Rao et al. (2005) compared two triplet chemotherapy regimens in a small phase III trial, designed primarily to evaluate if a cisplatin containing regimen improved survival over a regimen without cisplatin. Epirubicin, cisplatin and infused 5-FU (ECF) was compared to the bolus 5-FU, etoposide and leukovorin (FELV) combination. The primary endpoint of overall survival was 9 months for ECF and 12 months for FELV (p = 0.20). While this study of 54 patients was underpowered to detect small differences in efficacy, it did show that the ECF regimen may actually have been better tolerated than FELV. The authors concluded that both arms achieved good symptomatic relief for patients with advanced disease. Many other small studies evaluating cisplatin combined with gemcitabine are discussed below.
10.5.1.2 The Newer Chemotherapy Agents Numerous small phase II trials in biliary cancer reflects not only the lack of consensus on the best treatment but also an increase in research interest to evaluate new therapeutics in biliary cancer. What has emerged with some newer chemotherapeutic agents is a level of chemosensitivity which was not previously seen. Gemcitabine (Reyes-Vidal et al. 2003;
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Doval et al. 2004; Gallardo et al. 2001; Kubicka et al. 2001; Penz et al. 2001; Raderer et al. 1999; Gebbia et al. 2001; Hsu et al. 2004; Knox et al. 2004, 2005; Riechelmann et al. 2007), newer 5-FU regimens (Raderer et al. 1999; Gebbia et al. 2001; Hsu et al. 2004), capecitabine (Lozano et al. 2000; Kornek et al. 2004; Nehls et al. 2003) and platinum analogs (Reyes-Vidal et al. 2003; Doval et al. 2004; Taieb et al. 2002; Mitry et al. 2002; Patt et al. 2001; Rao et al. 2005; Nehls et al. 2003; Sanz-Altamira et al. 1998) all appear to be active, and perhaps more so in combinations. Larger phase II trials report objective radiological response rates (ORRs) ranging from 15 to 45%. Median survivals in general are over 1 year, which appear superior to older series. Significant differences in response rates between gallbladder and cholangiocarcinoma have not been seen, however, some series report poorer overall survival for patients with gallbladder cancer compared to cholangiocarcinoma (Reyes-Vidal et al. 2003; Doval et al. 2004; Knox et al. 2005). Many of these investigators have also reported preliminary data correlating the tumor marker; CA-19-9 with clinical response. The nucleoside analog gemcitabine is a chemotherapeutic agent with a favorable therapeutic profile. It has been established as the standard agent in advanced pancreas cancer, and has activity in a number of other solid cancers. Gallardo et al. (2001) showed promising single agent activity in gallbladder cancer with a response rate of 35%. Other series have shown ORRs ranging from 15 to 30% in mixed biliary cancers, with gemcitabine appearing consistently active and well-tolerated as a single agent (Kubicka et al. 2001; Penz et al. 2001; Gebbia et al. 2001). It has been studied in patients with preserved or decompressed livers and does not appear to contribute to any permanent liver damage. To quantitate the impact on overall survival, a prospective trial with best supportive care as the comparator arm is required but that trial is not likely to be done. A pooled analysis of 104 chemotherapy trials involving over 1,300 advanced biliary cancer patients conducted between the years 1999 and 2006 (Eckel and Schmid 2007) concludes that gemcitabine appears to be the most active single systemic agent. A second large review (Yonemoto et al. 2007) also supported gemcitabine as a potential standard chemotherapy despite the lack of phase III data. Both these reviews also concluded gemcitabine combined with a platinum containing agent has shown consistently higher ORRs than other regimens. Similarly, the gemcitabine-capecitabine (GemCap) couplet also looked very promising when compared to other combinations (ORRs of 30%, median survivals of over a year and mild toxicity) (Knox et al. 2005; Townsley and Knox 2005; Cho et al. 2005; Iyer et al. 2005; Koeberle et al. 2008). Whether Gemcitabine used in combination with other active agents improves patient outcomes further required evaluation in a phase III trial. Mounting a large phase III trial in biliary cancer has been difficult. Two large, well-designed phase III trials were planned in the early 2000s and are described below. One of the earliest trials planned was led by the National Cancer Institute of Canada (NCIC)’s Clinical Trials Group to evaluate the GemCap combination in a phase III trial with single agent gemcitabine as the comparator arm and overall survival as the primary endpoint. This design is stratified for gallbladder vs. bile duct cancer as well as performance status and extent of disease. This trial suffered from multiple delays to activate and reluctance of international partners to join a trial of a relatively rarer tumor type. It finally opened in late 2008 but closed in 2009 when new data from the British ABC-02 suggested the control arm of single agent gemcitabine may no longer be adequate.
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The National Cancer Research Network in Great Britain recently conducted a successful randomized trial of gemcitabine vs. a gemcitabine-cisplatin doublet (ABC-02) (Valle et al. 2010). This is the largest randomized chemotherapy clinical trial in biliary cancer to date. The control arm of single agent gemcitabine was delivered at a standard 1,000 mg/m2 days 1, 8, 15 q 28 days (Takahashi et al. 2004), while the experimental doublet combined gemcitabine 1,000 mg/m2 day 1, eight with low dose cisplatin at 25 mg/m2 dL, d8 all q 21 days (CisGem). A preliminary analysis at 86 patients showed both arms to be active but with a trend to improved responses time-to-progression and 6 month progression-free survival in the combination arm. An increase in toxicity, especially lethargy was seen with the combination (Valle et al. 2006). A preplanned expansion continued to accrue over 400 patients in order to have 80% power to detect an increase in median overall survival from 8 to 11 months (2-sided a at 5% level). Patients were randomized 1:1 and stratified by primary site of disease, center enrolled, performance status and disease extent. Three hundred and twenty-four patients were accrued between May 2005 and September 2008. The initial 86 patients in the preliminary study were included in the final analysis for a total of 410 patients evaluated with intention-to-treat analysis. Eligible patients for ABC-02 had histologically or cytologically verified nonresectable or recurrent/metastatic cholangiocarcinoma, gallbladder or ampullary carcinoma and receiving first-line systemic therapy. They required ECOG performance status of 0–2, adequate biliary drainage and were free of infection at enrollment. Screening biochemistry included total bilirubin <1.5× the upper limit of normal (ULN) and AST, ALT and ALP <3× ULN. The trial met its primary endpoint demonstrating a median overall survival of 11.7 months for the CisGem doublet over 8.1 months for gemcitabine alone (p < 0.001, HR 0.64 (0.52–0.8)). This is the first clear demonstration of an overall survival advantage with chemotherapy in biliary cancer, representing a 36% risk reduction in death. Exploratory sub-group analysis favored CisGem across all stratified groups including primary site, extent of disease and performance status. Progression-free survival was 8.4 months vs. 6.5 also favoring CisGem (p < 0.001, HR 0.63 (0.51–0.77)), and objective response rates were 26 vs. 15% (Table 10.8). Quality of life analysis is pending (Fig. 10.3). ABC-02 toxicity to date has been reported as grade 3/4 adverse events on study and was very similar and modest between the two arms. Myelosuppression by gemcitabine vs. CisGem (% grade 3/4) was as follows: neutropenia; 17 vs. 25, thrombocytopenia; 7 vs. 9, anemia; 3 vs. 8, infection with neutropenia; 7 vs. 10. Other notable toxicity (Gem vs. CisGem (% grade 3/4)) included: lethargy; 17 vs. 19, nausea and vomiting; 9 vs. 9. Overall no significant serious toxicity differences were noted between the two arms. There may be significant differences in
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Overall Survival (%)
Fig. 10.3 ABC-001 survival curve and progression-free survival (Figure courtesy of
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Hazard ratio for death, 0.64 (95% CI, 0.52–0.80) P<0.001
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care in colon cancer. In combination with either gemcitabine (GEMOX) (Andre et al. 2004) or capecitabine (XELOX) (Nehls et al. 2003) promising response rates were seen in phase II trials, with encouraging median survivals ranging from 9 to 15 months. GEMOX was further evaluated in a 70 patient multicenter phase II trial of both intra and extrahepatic cholangiocarcinomas and gallbladder cancers (Andre et al. 2006). ORR persisted in the 30% range, overall survival was 8.3 months. Toxicity was moderate but quite manageable. At this time it is not clear whether GEMOX offers an advantage over gemcitabinecisplatin regimens.
10.5.1.3 Targeted Therapies Many advances are being made with targeted therapy in various solid tumor adenocarcinomas. Strategies include blockade of angiogenesis-related signaling, Akt survival pathways
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or the epidermal growth factor receptor (EGFR) signaling. While evaluating these strategies in biliary cancer are barely underway, it is likely that lessons learned from more common cancers will translate eventually into cholangiocarcinomas and gallbladder cancers. Philip et al. evaluated the oral EGFR tyrosine kinase inhibitor; erlotinib, in advanced biliary cancer (Philip et al. 2006). Over half of the patients had received one prior chemotherapy. EGFR expression by immunohistochemistry was detected in 81% of the patients’ tumors. Three patients had partial responses (7%) and 17% of patients were progression free at 6 months. These results suggest a therapeutic benefit to EGFR blockade with erlotinib in some patients with biliary cancer. Activity of EGFR inhibition should be reevaluated in biliary cancer in light of emerging data of influence of k-ras mutation and lack of response to EGFR inhibitors seen in colon cancer. It may be possible to identify a more susceptible subpopulation. Recent focus on the Raf and MAPK/Erk kinase (Hemming et al. 2006) pathway in drug development may advance biliary cancer. A MEK 1/2 inhibitor, AZD 6244 showed promise in a phase II trial of advanced biliary patients who had failed prior chemotherapy. ORRs and potentially prolonged PFS were reported in abstract form (Bekaii-Saab et al. 2009). This and other MEK targeted agents warrant priority investigation in biliary cancers.
10.5.2 Adjuvant Systemic Therapy In any cancer, where the cure rates with resection are poor and at least modestly effective metastatic systemic therapy is available, a strong argument for adjuvant therapy can be made. The current paradigm of developing such a treatment starts first with establishing a safe, well-tolerated regimen that prolongs life in the advanced disease. Development of adjuvant therapy in biliary cancer has been hindered by the lack of consensus as to what chemotherapy standard for advanced disease, should be brought forward for adjuvant evaluation. The recent data on the CisGem regimen should change that. It is also a rare tumor, where relatively few patients are resectable at presentation, and so it would be difficult to complete a large randomized adjuvant trial. The data surrounding adjuvant chemotherapy are very limited. The largest trial to date was conducted in Japan by Takada et al. and published in 2002 (Takada et al. 2002). This phase III multicenter randomized trial accrued patients with resected pancreaticobiliary cancers to postoperative chemotherapy consisting of mitomycin C and 5-FU given IV at surgery followed by oral 5-FU until progressive disease (MF arm) vs. surgery alone. Patients were stratified by tumor site and whether R0 resection was achieved. The trial accrued 118 patients with bile duct cancers, 112 patients with gallbladder cancer and 48 patients with carcinoma of the ampulla of Vater. The 5-year survival rate in gallbladder cancer in per protocol analysis was significantly better on the MF arm than the control arm (26 vs. 14%, p = 0.0367). This was not statistically different in the intention-to treat analysis. There were no significant differences between patients with bile duct or ampulla of Vater carcinomas between the MF and control arms (5-year survival MF vs. control: 27 vs. 24% in bile duct cancer and 34 vs. 28% in the ampullary cancers). A third to one half of patients on study did not have a R0 resection, and so this trial did not ask a pure adjuvant
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question. It makes sense that adjuvant chemotherapy might impact on gallbladder cancer due to its high rate of metastatic spread. A confirmatory trial in gallbladder cancer has not been done. Further adjuvant chemotherapy data specific to distal bile duct cancers may be forthcoming from the European Study Group for Pancreatic Cancer-3 trial (ESPAC-3), a large intergroup randomized adjuvant pancreas cancer trial. There is a planned subset analysis of distal bile duct cancers resected with pancreaticoduodenectomy with clear margins and randomized to 5-FU or gemcitabine or no therapy. This trial completed accrual but the analysis has not been presented to date. At this time the literature does not support routine adjuvant chemotherapy in biliary cancer, although it is often offered to patients with high risk disease and a good performance status. As previously discussed, there have been numerous series of adjuvant or neo-adjuvant chemo-RT with differing conclusions and no level I evidence to mandate adjuvant therapy as a standard practice (see Sects. 3.6.1 and 3.6.2 for further discussion). A recently activated South Western Oncology Group (SWOG)-led phase II study of adjuvant therapy for 80 resected extrahepatic biliary and gallbladder cancer patients should provide insight regarding outcomes, toxicity and feasibility of a multidisciplinary standardized adjuvant treatment regimen (12 weeks of Gemcitabine/capecitabine followed by CRT or IMRT (52–29 Gy) delivered over 6 weeks with concurrent capecitabine) in these patients.
10.6 Conclusions and Future Work Gallbladder and bile duct cancers are challenging cancers to treat with an overall poor prognosis. Treatment should be multidisciplinary and limited to tertiary centers. Supportive care and appropriate use of biliary stents are crucial for all patients with biliary cancers as biliary decompression is often a priority. Aggressive surgery to obtain negative microscopic margins (R0 resection) offers the best option for cure in biliary tract and gallbladder cancer. Extended hepatic resection with portal lymphadenectomy and biliary tract resection is the current standard of care for resection of hilar cholangiocarcinoma. The extent of surgery required for to reliably obtain an R0 resection in gallbladder cancer remains the subject of some debate and research, and may depend on the stage and clinical presentation. Hepatic resection remains the mainstay for treatment of ICC, but the role of lymphadenectomy and bile duct resection remain controversial and may depend on the stage and macroscopic tumor subtype. Vascular resection and multivisceral resection can now be performed safely with good long-term outcome and have permitted a surgical approach to more advanced tumors. Recent results have led to a reappraisal of the use of transplantation with neoadjuvant chemoradiotherapy in hilar and intrahepatic cholangiocarcinoma; patient selection appears to be of critical importance and requires further study. There is rationale for increased use of RT and chemotherapy, in combination with surgery, as outcomes remain poor overall. Advanced RT techniques allow higher doses to be delivered safely, and improved outcomes following RT and chemotherapy in the adjuvant setting and for unresectable disease have been suggested, especially for patients without R0 resections or with positive nodes.
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With the completion of the large randomized phase III trial (ABC-02), a new chemotherapy standard of care has been established for advanced, unresectable biliary cancer. The cisplatin/gemcitabine couplet was demonstrated to improve overall survival over single agent gemcitabine, with a hazard ratio of 0.64 (Valle et al. 2010). Toxicity appears acceptable for this patient population. It is expected that this Cis/Gem doublet will be adapted as a first-line chemotherapy globally in suitable patients. It is also expected that with this success more clinical research aimed at defining the most optimal management of biliary subtypes, evaluating combinations with targeted therapy or in the second-line setting and with RT will gain support. A safe and effective standard in advanced disease should spur on prospective adjuvant and neoadjuvant studies. Future ambitious proposals will require multiinstitutional and international collaboration to accrue sufficient numbers of patients, continued support from clinical trial cooperative groups and the ongoing commitment from industry to help develop treatments for this orphan tumor site.
References Abdalla EK, Barnett CC, Doherty D, Curley SA, Vauthey JN (2002a) Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg 137(6):675–680; discussion 671–680 Abdalla EK, Vauthey JN, Couinaud C (2002b) The caudate lobe of the liver: implications of embryology and anatomy for surgery. Surg Oncol Clin N Am 11(4):835–848 Albores-Saavedra J, Tuck M, McLaren BK, Carrick KS, Henson DE (2005) Papillary carcinomas of the gallbladder: analysis of noninvasive and invasive types. Arch Pathol Lab Med 129(7):905–909 Alden ME, Mohiuddin M (1994) The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. Int J Radiat Oncol Biol Phys 28(4):945–951 Alexander F, Rossi RL, O’Bryan M, Khettry U, Braasch JW, Watkins E Jr (1984) Biliary carcinoma. A review of 109 cases. Am J Surg 147(4):503–509 Anderson CD, Rice MH, Pinson CW, Chapman WC, Chari RS, Delbeke D (2004) Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. J Gastrointest Surg 8(1):90–97 Andre T, Tournigand C, Rosmorduc O, Provent S, Maindrault-Goebel F, Avenin D, Selle F, Paye F, Hannoun L, Houry S, Gayet B, Lotz JP, de Gramont A, Louvet C (2004) Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol 15(9):1339–1343 Andre T, Reyes-Vidal J, Fartoux L (2006) EXIBIT: an international multicenter phase II trial of gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary cancer. Proc Am Soc Clin Oncol 24(18):4135 Anthuber M, Schauer R, Jauch KW, Kramling HJ, Schildberg FW (1996) Experiences with liver transplantation and liver transplantation combined with Whipple’s operation in Klatskin tumor. Langenbecks Arch Chir Suppl Kongressbd 113:413–415 Bach AM, Hann LE, Brown KT, Getrajdman GI, Herman SK, Fong Y, Blumgart LH (1996) Portal vein evaluation with US: comparison to angiography combined with CT arterial portography. Radiology 201(1):149–154 Bach AM, Loring LA, Hann LE, Illescas FF, Fong Y, Blumgart LH (1998) Gallbladder cancer: can ultrasonography evaluate extent of disease? J Ultrasound Med 17(5):303–309 Bartlett DL (2000) Gallbladder cancer. Semin Surg Oncol 19(2):145–155
286
S.P. Cleary et al.
Becker NS, Rodriguez JA, Barshes NR, O’Mahony CA, Goss JA, Aloia TA (2008) Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 12(1):117–122 Bekaii-Saab T, Phelps M, Li X, Saji M, Kosuri K, Goff L, Kauh J, O’Neil B, South C, Thomas J, Balsom S, Chattah N, Balint C, Liersemann R, Vasko V, Marsh W, Doyle L, Ellison G, Ringel M, Villalona-Calero M (2009) A multi-institutional study of AZD6244 (ARRY-142886) in patients with advanced biliary cancers. AACR 2009 Abstract LB129 ed Ben-David MA, Griffith KA, Abu-Isa E, Lawrence TS, Knol J, Zalupski M, Ben-Josef E (2006) External-beam radiotherapy for localized extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys 66(3):772–779 Ben-Josef E, Normolle D, Pan C, Tatro D, Ten Haken RK, Knol J, Walker S, Dawson LA, Ensminger WD, Lawrence TS (2005) A phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol, 23(24):8739–8747 Bismuth H, Corlette MB (1975) Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver. Surg Gynecol Obstet 140(2):170–178 Borghero Y, Crane CH, Szklaruk J, Oyarzo M, Curley S, Pisters PW, Evans D, Abdalla EK, Thomas MB, Das P, Wistuba II, Krishnan S, Vauthey JN (2008) Extrahepatic bile duct adenocarcinoma: patients at high-risk for local recurrence treated with surgery and adjuvant chemoradiation have an equivalent overall survival to patients with standard-risk treated with surgery alone. Ann Surg Oncol 15(11):3147–3156 Bosset JF, Mantion G, Gillet M, Pelissier E, Boulenger M, Maingon P, Corbion O, Schraub S (1989) Primary carcinoma of the gallbladder. Adjuvant postoperative external irradiation. Cancer 64(9):1843–1847 Braga HJ, Imam K, Bluemke DA (2001) MR imaging of intrahepatic cholangiocarcinoma: use of ferumoxides for lesion localization and extension. AJR Am J Roentgenol 177(1):111–114 Broome U, Olsson R, Loof L, Bodemar G, Hultcrantz R, Danielsson A, Prytz H, Sandberg-Gertzen H, Wallerstedt S, Lindberg G (1996) Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 38(4):610–615 Brugge WR (2005) Endoscopic techniques to diagnose and manage biliary tumors. J Clin Oncol 23(20):4561–4565 Bulajic M, Maisonneuve P, Schneider-Brachert W, Muller P, Reischl U, Stimec B, Lehn N, Lowenfels AB, Lohr M (2002) Helicobacter pylori and the risk of benign and malignant biliary tract disease [see comment]. Cancer 95(9):1946–1953 Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD (2004) Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol 99(3):523–526 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults [see comment]. New Engl J Med 348(17):1625–1638 Cameron JL, Pitt HA, Zinner MJ, Kaufman SL, Coleman J (1990) Management of proximal cholangiocarcinomas by surgical resection and radiotherapy. Am J Surg 159(1):91–97; discussion 97–98 Canadian Cancer Society/National Cancer Institute of Canada (2008) Canadian cancer statistics. Canadian Cancer Society, Toronto Chaimuangraj S, Thamavit W, Tsuda H, Moore MA (2003) Experimental investigation of opisthorchiasis-associated cholangiocarcinoma induction in the Syrian hamster – pointers for control of the human disease. Asian Pac J Cancer Prev 4(2):87–93 Chalasani N, Baluyut A, Ismail A, Zaman A, Sood G, Ghalib R, McCashland TM, Reddy KR, Zervos X, Anbari MA, Hoen H (2000) Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study [see comment]. Hepatology 31(1):7–11 Chen MF, Jan YY, Jeng LB, Hwang TL, Wang CS, Chen SC, Chao TC, Chen HM, Lee WC, Yeh TS, Lo YF (1999) Intrahepatic cholangiocarcinoma in Taiwan. J Hepatobiliary Pancreat Surg 6(2):136–141
10 Carcinoma of the Biliary Tract
287
Cherqui D, Alon R, Piedbois P, Duvoux C, Dhumeaux D, Julien M, Fagniez PL (1995) Combined liver transplantation and pancreatoduodenectomy for irresectable hilar bile duct carcinoma. Br J Surg 82(3):397–398 Chijiiwa K, Koga A (1993) Surgical management and long-term follow-up of patients with choledochal cysts. Am J Surg 165(2):238–242 Chijiiwa K, Tanaka M (1994) Carcinoma of the gallbladder: an appraisal of surgical resection. Surgery 115(6):751–756 Chijiiwa K, Sumiyoshi K, Nakayama F (1991) Impact of recent advances in hepatobiliary imaging techniques on the preoperative diagnosis of carcinoma of the gallbladder. World J Surg 15(3):322–327 Chijiiwa K, Nakano K, Ueda J, Noshiro H, Nagai E, Yamaguchi K, Tanaka M (2001) Surgical treatment of patients with T2 gallbladder carcinoma invading the subserosal layer. J Am Coll Surg 192(5):600–607 Cho JY, Paik YH, Chang YS, Lee SJ, Lee DK, Song SY, Chung JB, Park MS, Yu JS, Yoon DS (2005) Capecitabine combined with gemcitabine (CapGem) as first-line treatment in patients with advanced/metastatic biliary tract carcinoma. Cancer 104(12):2753–2758 Choi BI, Lee JM, Han JK (2004) Imaging of intrahepatic and hilar cholangiocarcinoma. Abdom Imaging 29(5):548–557 Chu KM, Fan ST (1999) Intrahepatic cholangiocarcinoma in Hong Kong. J Hepatobiliary Pancreat Surg 6(2):149–153 Clavien PA, Petrowsky H, DeOliveira ML, Graf R (2007) Strategies for safer liver surgery and partial liver transplantation. N Engl J Med 356(15):1545–1559 Coburn NG, Cleary SP, Tan JCC, Law CHL (2008) Surgery for gallbladder cancer: a populationbased analysis. J Am Coll Surg 207(3):371–382 Crane C, Macdonald K, Vauthey J et al (2002) Limitations of conventional doses of chemoradiation for unresectable biliary cancer. Int J Radiat Oncol Biol Phys 53:969 Cubertafond P, Gainant A, Cucchiaro G (1994) Surgical treatment of 724 carcinomas of the gallbladder. Results of the French Surgical Association Survey. Ann Surg 219(3):275–280 Czito BG, Hurwitz HI, Clough RW, Tyler DS, Morse MA, Clary BM, Pappas TN, Fernando NH, Willett CG (2005) Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys 62(4):1030–1034 D’Angelica M, Dalal KM, DeMatteo RP, Fong Y, Blumgart LH, Jarnagin WR (2009) Analysis of the extent of resection for adenocarcinoma of the gallbladder [see comment]. Ann Surg Oncol 16(4):806–816 de Aretxabala X, Roa I, Burgos L, Araya JC, Fonseca L, Wistuba I, Flores P (1992) Gallbladder cancer in Chile. A report on 54 potentially resectable tumors. Cancer 69(1):60–65 de Aretxabala XA, Roa IS, Burgos LA, Araya JC, Villaseca MA, Silva JA (1997) Curative resection in potentially resectable tumours of the gallbladder. Eur J Surg 163(6):419–426 de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM (1999) Biliary tract cancers. N Engl J Med 341(18):1368–1378 DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, Choti MA, Yeo CJ, Schulick RD (2007) Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 245(5):755–762 Diehl AK (1980) Epidemiology of gallbladder cancer: a synthesis of recent data. J Natl Cancer Inst 65(6):1209–1214 Dixon E, Vollmer CM Jr, Sahajpal A, Cattral M, Grant D, Doig C, Hemming A, Taylor B, Langer B, Greig P, Gallinger S (2005) An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: a 12-year study at a North American Center. Ann Surg 241(3):385–394 Donohue JH, Stewart AK, Menck HR (1998) The National Cancer Data Base report on carcinoma of the gallbladder, 1989–1995. Cancer 83(12):2618–2628
288
S.P. Cleary et al.
Doval DC, Sekhon JS, Gupta SK, Fuloria J, Shukla VK, Gupta S, Awasthy BS (2004) A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Br J Cancer 90(8):1516–1520 Dutta U, Garg PK, Kumar R, Tandon RK (2000) Typhoid carriers among patients with gallstones are at increased risk for carcinoma of the gallbladder [see comment]. Am J Gastroenterol 95(3):784–787 Ebata T, Nagino M, Kamiya J, Uesaka K, Nagasaka T, Nimura Y (2003) Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases. Ann Surg 238(5): 720–727 Eckel F, Schmid RM (2007) Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 96(6):896–902 Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D’Angelica M, DeMatteo RP, Fong Y, Schwartz L, Kemeny N, O’Reilly E, Abou-Alfa GK, Shimada H, Blumgart LH, Jarnagin WR (2008) Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 248(1):84–96 Fahim RB, McDonald J, Richards JC, Ferris DO (1962) Carcinoma of the gallbladder: a study of its modes of spread. Ann Surg 156:114–124 Falkson G, Macintyre JM, Moertel CG (1984) Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer 54:965–969 Fleming ID, Cooper JS, Henderson DE (1997) AJCC cancer staging manual, 5th edn. Springer, New York Flickinger JC, Epstein AH, Iwatsuki S, Carr BI, Starzl TE (1991) Radiation therapy for primary carcinoma of the extrahepatic biliary system. An analysis of 63 cases. Cancer 68(2): 289–294 Fogel TD, Weissberg JB (1984) The role of radiation therapy in carcinoma of the extrahepatic bile ducts. Int J Radiat Oncol Biol Phys 10(12):2251–2258 Fong Y, Heffernan N, Blumgart LH (1998) Gallbladder carcinoma discovered during laparoscopic cholecystectomy: aggressive reresection is beneficial. Cancer 83(3):423–427 Fong Y, Jarnagin W, Blumgart LH (2000) Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg 232(4):557–569 Foo M, Gunderson L, Bender C et al (1984) External radiation therapy in carcinoma of the extrahepatic bile ducts. Int J Radiat Oncol Biol Phys 10:2251 Fritz P, Brambs HJ, Schraube P, Freund U, Berns C, Wannenmacher M (1994) Combined external beam radiotherapy and intraluminal high dose rate brachytherapy on bile duct carcinomas. Int J Radiat Oncol Biol Phys 29(4):855–861 Fuller CD, Thomas CR Jr, Wong A, Cavanaugh SX, Salter BJ, Herman TS, Fuss M (2006) Imageguided intensity-modulated radiation therapy for gallbladder carcinoma. Radiother Oncol 81(1):65–72 Gallardo JO, Rubio B, Fodor M, Orlandi L, Yanez M, Gamargo C, Ahumada M (2001) A phase II study of gemcitabine in gallbladder carcinoma. Ann Oncol 12(10):1403–1406 Gebbia V, Giuliani F, Maiello E, Colucci G, Verderame F, Borsellino N, Mauceri G, Caruso M, Tirrito ML, Valdesi M (2001) Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol 19(20):4089–4091 Gerhards MF, van Gulik TM, de Wit LT, Obertop H, Gouma DJ (2000) Evaluation of morbidity and mortality after resection for hilar cholangiocarcinoma – a single center experience. Surgery 127(4):395–404 Glimelius B, Hoffman K, Sjoden PO (1996) Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 7:593–600 Gonzalez D, Gerard J, Maners A (1990) al e. Results of radiation therapy in carcinoma of the proximal bile duct (Klatskin tumor). Semin Liver Dis 10:131
10 Carcinoma of the Biliary Tract
289
Greene FL, Page DL, Fleming ID (2002) AJCC cancer staging manual, 6th edn. Springer, New York Grove MK, Hermann RE, Vogt DP, Broughan TA (1991) Role of radiation after operative palliation in cancer of the proximal bile ducts. Am J Surg 161(4):454–458 Hann LE, Fong Y, Shriver CD, Botet JF, Brown KT, Klimstra DS, Blumgart LH (1996) Malignant hepatic hilar tumors: can ultrasonography be used as an alternative to angiography with CT arterial portography for determination of resectability? J Ultrasound Med 15(1):37–45 Hatfield AR, Tobias R, Terblanche J, Girdwood AH, Fataar S, Harries-Jones R, Kernoff L, Marks IN (1982) Preoperative external biliary drainage in obstructive jaundice. A prospective controlled clinical trial. Lancet 2(8304):896–899 Hekimoglu K, Ustundag Y, Dusak A, Erdem Z, Karademir B, Aydemir S, Gundogdu S (2008) MRCP vs. ERCP in the evaluation of biliary pathologies: review of current literature. J Dig Dis 9(3):162–169 Hemming AW, Reed AI, Fujita S, Foley DP, Howard RJ (2005) Surgical management of hilar cholangiocarcinoma. Ann Surg 241(5):693–699; discussion 699–702 Hemming AW, Kim RD, Mekeel KL, Fujita S, Reed AI, Foley DP, Howard RJ (2006) Portal vein resection for hilar cholangiocarcinoma. Am Surg 72(7):599–604; discussion 595–604 Henson DE, Albores-Saavedra J, Corle D (1992) Carcinoma of the gallbladder. Histologic types, stage of disease, grade, and survival rates. Cancer 70(6):1493–1497 Houry S, Schlienger M, Huguier M, Lacaine F, Penne F, Laugier A (1989) Gallbladder carcinoma: role of radiation therapy. Br J Surg 76(5):448–450 Hsu C, Shen YC, Yang CH, Yeh KH, Lu YS, Hsu CH, Liu HT, Li CC, Chen JS, Wu CY, Cheng AL (2004) Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract. Br J Cancer 90(9): 1715–1719 Ito F, Agni R, Rettammel RJ, Been MJ, Cho CS, Mahvi DM, Rikkers LF, Weber SM (2008) Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence. Ann Surg 248(2):273–279 Iwatsuki S, Todo S, Marsh JW, Madariaga JR, Lee RG, Dvorchik I, Fung JJ, Starzl TE (1998) Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic resection or transplantation. J Am Coll Surg 187(4):358–364 Iyer RV, Gibbs DL, Soehnlein N (2005) A phase II study of gemcitabine and capecitabine in advanced cholangiocarcinoma and gallbladder carcinoma gastrointeshinal cancers symposium Abst 139 Jarnagin WR, Shoup M (2004) Surgical management of cholangiocarcinoma. Semin Liver Dis 24(2):189–199 Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BJ, Youssef BM, Klimstra D, Blumgart LH (2001) Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 234(4):507–517; discussion 509–517 Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56(2):106–130 Jonas S, Kling N, Guckelberger O, Keck H, Bechstein WO, Neuhaus P (1998) Orthotopic liver transplantation after extended bile duct resection as treatment of hilar cholangiocarcinoma. First long-terms results. Transpl Int 11(Suppl 1):S206–S208 Kajanti M, Pyrhonen S (1994) Epirubicin-sequential methotrexate-5-fluorouracil-leucovorin treatment in advanced cancer of the extrahepatic biliary system. A phase II study. Am J Clin Oncol 17(3):223–226 Kajiyama K, Maeda T, Takenaka K, Sugimachi K, Tsuneyoshi M (1999) The significance of stromal desmoplasia in intrahepatic cholangiocarcinoma: a special reference of “scirrhoustype” and “nonscirrhous-type” growth. Am J Surg Pathol 23(8):892–902 Kaneoka Y, Yamaguchi A, Isogai M, Harada T, Suzuki M (2003) Hepatoduodenal ligament invasion by gallbladder carcinoma: histologic patterns and surgical recommendation. World J Surg 27(3):260–265
290
S.P. Cleary et al.
Keiding S, Hansen SB, Rasmussen HH, Gee A, Kruse A, Roelsgaard K, Tage-Jensen U, Dahlerup JF (2000) Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography. Ugeskr Laeg 162(6):782–785 Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC (2002a) Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol 37(6):806–813 Khan SA, Davidson BR, Goldin R, Pereira SP, Rosenberg WM, Taylor-Robinson SD, Thillainayagam AV, Thomas HC, Thursz MR, Wasan H (2002b) Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 51(Suppl 6):7–9 Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD (2005) Cholangiocarcinoma. Lancet 366(9493):1303–1314 Kim BS, Ha HK, Lee IJ, Kim JH, Eun HW, Bae IY, Kim AY, Kim TK, Kim MH, Lee SK, Kang W (2002a) Accuracy of CT in local staging of gallbladder carcinoma [see comment]. Acta Radiol 43(1):71–76 Kim JH, Kim TK, Eun HW, Kim BS, Lee MG, Kim PN, Ha HK (2002b) Preoperative evaluation of gallbladder carcinoma: efficacy of combined use of MR imaging, MR cholangiography, and contrastenhanced dual-phase three-dimensional MR angiography. J Magn Reson Imaging 16(6):676–684 Kim JY, Kim MH, Lee TY, Hwang CY, Kim JS, Yun SC, Lee SS, Seo DW, Lee SK (2008) Clinical role of 18F-FDG PET-CT in suspected and potentially operable cholangiocarcinoma: a prospective study compared with conventional imaging. Am J Gastroenterol 103(5):1145–1151 Kluge R, Schmidt F, Caca K, Barthel H, Hesse S, Georgi P, Seese A, Huster D, Berr F (2001) Positron emission tomography with [(18)F]fluoro-2-deoxy-D-glucose for diagnosis and staging of bile duct cancer. Hepatology 33(5):1029–1035 Knox JJ, Hedley D, Oza A, Siu LL, Pond GR, Moore MJ (2004) Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: a review of the Princess Margaret Hospital experience. Ann Oncol 15(5):770–774 Knox JJ, Hedley D, Oza A, Feld R, Siu LL, Chen E, Nematollahi M, Pond GR, Zhang J, Moore MJ (2005) Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol 23(10):2332–2338 Koeberle D, Saletti P, Borner M, Gerber D, Dietrich D, Caspar CB, Mingrone W, Beretta K, Strasser F, Ruhstaller T, Mora O, Herrmann R (2008) Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine: a multicenter, phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol 26(22):3702–3708 Koga A, Watanabe K, Fukuyama T, Takiguchi S, Nakayama F (1988) Diagnosis and operative indications for polypoid lesions of the gallbladder. Arch Surg 123(1):26–29 Kondo S, Nimura Y, Hayakawa N, Kamiya J, Nagino M, Uesaka K (2002) Extensive surgery for carcinoma of the gallbladder. Br J Surg 89(2):179–184 Kopelson G, Harisiadis L, Tretter P, Chang CH (1977) The role of radiation therapy in cancer of the extra-hepatic biliary system: an analysis of thirteen patients and a review of the literature of the effectiveness of surgery, chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 2(9–10):883–894 Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K, Depisch D, Lang F, Scheithauer W (2004) Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol 15(3):478–483 Kosuge T, Yamamoto J, Shimada K, Yamasaki S, Makuuchi M (1999) Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg 230(5):663–671 Kozuka S, Tsubone N, Yasui A, Hachisuka K (1982) Relation of adenoma to carcinoma in the gallbladder. Cancer 50(10):2226–2234 Kresl JJ, Schild SE, Henning GT, Gunderson LL, Donohue J, Pitot H, Haddock MG, Nagorney D (2002) Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma. Int J Radiat Oncol Biol Phys 52(1):167–175
10 Carcinoma of the Biliary Tract
291
Kubicka S, Rudolph KL, Tietze MK, Lorenz M, Manns M (2001) Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology 48(39):783–789 Kurosaki H, Karasawa K, Kaizu T, Matsuda T, Okamoto A, Sato T, Ebara T, Tanaka Y (1999) Intraoperative radiotherapy for resectable extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys 45(3):635–638 Launois B, Terblanche J, Lakehal M, Catheline JM, Bardaxoglou E, Landen S, Campion JP, Sutherland F, Meunier B (1999) Proximal bile duct cancer: high resectability rate and 5-year survival. Ann Surg 230(2):266–275 Laurent A, Tayar C, Cherqui D (2008) Cholangiocarcinoma: preoperative biliary drainage (Con). HPB (Oxford) 10(2):126–129 Levy AD, Murakata LA, Rohrmann CA Jr (2001) Gallbladder carcinoma: radiologic-pathologic correlation [erratum appears in Radiographics 2001;21(3):766]. Radiographics 21(2):295–314; questionnaire Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD (2005) The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci 50(9):1734–1740 Lillemore KD, Cameron JL (2000) Surgery for hilar cholangiocarcinoma: the Johns Hopkins approach. J Hepatobiliary Pancreat Surg 7:115–121 Lim JH, Park CK (2004) Pathology of cholangiocarcinoma. Abdom Imaging 29(5):540–547 Lim JH, Kim MH, Kim TK, Lee MG, Lee SS, Lee JW, Lee KT, Lee JK, Lim HK (2003) Papillary neoplasms of the bile duct that mimic biliary stone disease. Radiographics 23(2):447–455 Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL (1994) Choledochal cyst disease. A changing pattern of presentation. Ann Surg 220(5):644–652 Lipshutz GS, Brennan TV, Warren RS (2002) Thorotrast-induced liver neoplasia: a collective review. J Am Coll Surg 195(5):713–718 Liu KJ, Richter HM, Cho MJ, Jarad J, Nadimpalli V, Donahue PE (1997) Carcinoma involving the gallbladder in elderly patients presenting with acute cholecystitis. Surgery 122(4):748–754; discussion 746–754 Liver Cancer Study Group of Japan (2003) General rules for the clinical and pathologic study of primary liver cancer, 2nd edn. Kanehara Press, Tokoyo Lowenfels AB, Lindstrom CG, Conway MJ, Hastings PR (1985) Gallstones and risk of gallbladder cancer. J Natl Cancer Inst 75(1):77–80 Lowenfels AB, Walker AM, Althaus DP, Townsend G, Domellof L (1989) Gallstone growth, size, and risk of gallbladder cancer: an interracial study. Int J Epidemiol 18(1):50–54 Lowenfels AB, Maisonneuve P, Boyle P, Zatonski WA (1999) Epidemiology of gallbladder cancer. Hepatogastroenterology 46(27):1529–1532 Lozano RD, Patt YZ, Hassan MM (2000) Oral capecitabine (Xeloda) for the treatment of hepatobiliary cancers (hepatocellular carcinoma, cholangiocarcinoma and gallbladder cancer). Proc Am Soc Clin Oncol 19:264a Lundberg O, Kristoffersson A (1999) Port site metastases from gallbladder cancer after laparoscopic cholecystectomy. Results of a Swedish survey and review of published reports. Eur J Surg 165(3):215–222 Lundberg O, Kristoffersson A (2000) Wound recurrence from gallbladder cancer after open cholecystectomy. Surgery 127(3):296–300 Madoff DC, Hicks ME, Abdalla EK, Morris JS, Vauthey JN (2003) Portal vein embolization with polyvinyl alcohol particles and coils in preparation for major liver resection for hepatobiliary malignancy: safety and effectiveness – study in 26 patients. Radiology 227(1):251–260 Mahe M, Stampfli C, Romestaing P, Salerno N, Gerard JP (1994) Primary carcinoma of the gallbladder: potential for external radiation therapy. Radiother Oncol 33(3):204–208 Malhi H, Gores GJ (2006) The modern diagnosis and therapy of cholangiocarcinoma. Aliment Pharmacol Ther 23(9):1287–1296
292
S.P. Cleary et al.
Manfredi R, Barbaro B, Masselli G, Vecchioli A, Marano P (2004) Magnetic resonance imaging of cholangiocarcinoma. Semin Liver Dis 24(2):155–164 Mansfield SD, Barakat O, Charnley RM, Jaques BC, O’Suilleabhain CB, Atherton PJ, Manas D (2005) Management of hilar cholangiocarcinoma in the North of England: pathology, treatment, and outcome. World J Gastroenterol 11(48):7625–7630 Matsumoto Y, Fujii H, Aoyama H, Yamamoto M, Sugahara K, Suda K (1992) Surgical treatment of primary carcinoma of the gallbladder based on the histologic analysis of 48 surgical specimens. Am J Surg 163(2):239–245 McMasters KM, Tuttle TM, Leach SD, Rich T, Cleary KR, Evans DB, Curley SA (1997) Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg 174(6): 605–608; discussion 608–609 McPherson GA, Benjamin IS, Hodgson HJ, Bowley NB, Allison DJ, Blumgart LH (1984) Preoperative percutaneous transhepatic biliary drainage: the results of a controlled trial. Br J Surg 71(5):371–375 Minsky BD, Wesson MF, Armstrong JG, Kemeny N, Reichman B, Botet J, Nori D (1990) Combined modality therapy of extrahepatic biliary system cancer. Int J Radiat Oncol Biol Phys 18(5):1157–1163 Misra S, Chaturvedi A, Misra NC, Sharma ID (2003) Carcinoma of the gallbladder [see comment]. Lancet Oncol 4(3):167–176 Mitry E, Van Cutsem E, Van Laethem J (2002) A randomized phase II trial of weekly high dose 5-FU (HD-FU) with and without folinic acid (FA) and cisplatin (P) in patients with advanced biliary tract carcinoma: the EORTC 40955 trial. Proc Am Soc Clin Oncol 22:175 Miyazaki M, Ito H, Nakagawa K, Ambiru S, Shimizu H, Okaya T, Shinmura K, Nakajima N (1999) Parenchyma-preserving hepatectomy in the surgical treatment of hilar cholangiocarcinoma. J Am Coll Surg 189(6):575–583 Moller H, Mellemgaard A, Lindvig K, Olsen JH (1994) Obesity and cancer risk: a Danish recordlinkage study. Eur J Cancer 30A(3):344–350 Monson JR, Donohue JH, Gunderson LL, Nagorney DM, Bender CE, Wieand HS (1992) Intraoperative radiotherapy for unresectable cholangiocarcinoma – the Mayo Clinic experience. Surg Oncol 1(4):283–290 Montemaggi P, Morganti AG, Dobelbower RR Jr, Brizi G, Smaniotto D, Costamagna G, Cellini N, Marano P (1996) Role of intraluminal brachytherapy in extrahepatic bile duct and pancreatic cancers: is it just for palliation? Radiology 199(3):861–866 Morganti AG, Trodella L, Valentini V, Montemaggi P, Costamagna G, Smaniotto D, Luzi S, Ziccarelli P, Macchia G, Perri V, Mutignani M, Cellini N (2000) Combined modality treatment in unresectable extrahepatic biliary carcinoma. Int J Radiat Oncol Biol Phys 46(4):913–919 Morganti AG, Trodella L, Valentini V, Macchia G, Alfieri S, Smaniotto D, Luzi S, Costamagna G, Doglietto GB, Cellini N (2003) Concomitant gemcitabine (Gemzar) and extended nodes irradiation in the treatment of pancreatic and biliary carcinoma: a phase I study. Onkologie 26(4):325–329 Morrow C, Sutherland D, Florack G (1983) Primary gallbladder carcinoma: significance of subserosal lesions and results of aggressive surgical treatment and adjuvant chemotherapy. Surgery 94:709 Nakajima T, Kondo Y, Miyazaki M, Okui K (1988) A histopathologic study of 102 cases of intrahepatic cholangiocarcinoma: histologic classification and modes of spreading. Hum Pathol 19(10):1228–1234 Nakajo S, Yamamoto M, Tahara E (1990) Morphometrical analysis of gall-bladder adenoma and adenocarcinoma with reference to histogenesis and adenoma-carcinoma sequence. Virchows Arch A Pathol Anat Histopathol 417(1):49–56 Nakamura S, Sakaguchi S, Suzuki S, Muro H (1989) Aggressive surgery for carcinoma of the gallbladder. Surgery 106(3):467–473 Nakamura S, Nishiyama R, Yokoi Y, Serizawa A, Nishiwaki Y, Konno H, Baba S, Muro H (1994) Hepatopancreatoduodenectomy for advanced gallbladder carcinoma. Arch Surg 129(6):625–629
10 Carcinoma of the Biliary Tract
293
Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, Hruban RH, Lillemoe KD, Yeo CJ, Cameron JL (1996) Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 224(4):463–473; discussion 465–473 Nath G, Singh H, Shukla VK (1997) Chronic typhoid carriage and carcinoma of the gallbladder. Eur J Cancer Prev 6(6):557–559 Nathan H, Aloia TA, Vauthey JN, Abdalla EK, Zhu AX, Schulick RD, Choti MA, Pawlik TM (2009) A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol 16(1):14–22 Nehls O, Oettle H, Hartmann J-T (2003) Multicenter phase II trial of oxaliplatin plus capecitabine (XELOX) in advanced biliary system adenocarcinomas (study CCC/GBC-01). Proc Am Soc Clin Oncol 22:280 Neuhaus P, Jonas S, Bechstein WO, Lohmann R, Radke C, Kling N, Wex C, Lobeck H, Hintze R (1999) Extended resections for hilar cholangiocarcinoma. Ann Surg 230(6):808–818; discussion 819 Nevin JE, Moran TJ, Kay S, King R (1976) Carcinoma of the gallbladder: staging, treatment, and prognosis. Cancer 37(1):141–148 Nichols JC, Gores GJ, LaRusso NF, Wiesner RH, Nagorney DM, Ritts RE Jr (1993) Diagnostic role of serum CA 19-9 for cholangiocarcinoma in patients with primary sclerosing cholangitis. Mayo Clin Proc 68(9):874–879 Nimura Y (2008) Preoperative biliary drainage before resection for cholangiocarcinoma (Pro). HPB (Oxford) 10(2):130–133 Nimura Y, Hayakawa N, Kamiya J, Kondo S, Shionoya S (1990) Hepatic segmentectomy with caudate lobe resection for bile duct carcinoma of the hepatic hilus. World J Surg 14(4): 535–543; discussion 544 Nimura Y, Hayakawa N, Kamiya J, Maeda S, Kondo S, Yasui A, Shionoya S (1991) Hepatopan creatoduodenectomy for advanced carcinoma of the biliary tract. Hepatogastroenterology 38(2):170–175 Nishio H, Nagino M, Nimura Y (2005) Surgical management of hilar cholangiocarcinoma: the Nagoya Experience. HPB 7(4):259–262 Oertli D, Herzog U, Tondelli P (1993) Primary carcinoma of the gallbladder: operative experience during a 16 year period. Eur J Surg 159(8):415–420 Ogura Y, Mizumoto R, Isaji S, Kusuda T, Matsuda S, Tabata M (1991) Radical operations for carcinoma of the gallbladder: present status in Japan. World J Surg 15(3):337–343 Ogura Y, Mizumoto R, Tabata M, Matsuda S, Kusuda T (1993) Surgical treatment of carcinoma of the hepatic duct confluence: analysis of 55 resected carcinomas. World J Surg 17(1):85–92; discussion 83–92 Ogura Y, Tabata M, Kawarada Y, Mizumoto R (1998) Effect of hepatic invasion on the choice of hepatic resection for advanced carcinoma of the gallbladder: histologic analysis of 32 surgical cases. World J Surg 22(3):262–266; discussion 266–267 Ohashi K, Nakajima Y, Tsutsumi M, Kanehiro H, Fukuoka T, Hisanaga M, Taki J, Nakae D, Konishi Y, Nakano H (1994) Clinical characteristics and proliferating activity of intrahepatic cholangiocarcinoma. J Gastroenterol Hepatol 9(5):442–446 Ohtani T, Shirai Y, Tsukada K, Muto T, Hatakeyama K (1996) Spread of gallbladder carcinoma: CT evaluation with pathologic correlation. Abdom Imaging 21(3):195–201 Okabayashi T, Yamamoto J, Kosuge T, Shimada K, Yamasaki S, Takayama T, Makuuchi M (2001) A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer 92(9):2374–2383 Ouchi K, Suzuki M, Tominaga T, Saijo S, Matsuno S (1994) Survival after surgery for cancer of the gallbladder. Br J Surg 81(11):1655–1657 Ouchi K, Mikuni J, Kakugawa Y (2002) Laparoscopic cholecystectomy for gallbladder carcinoma: results of a Japanese survey of 498 patients. J Hepatobiliary Pancreat Surg 9(2):256–260 Paik KY, Jung JC, Heo JS, Choi SH, Choi DW, Kim YI (2008) What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol 23(5):766–770
294
S.P. Cleary et al.
Palavecino M, Abdalla EK, Madoff DC, Vauthey JN (2009) Portal vein embolization in hilar cholangiocarcinoma. Surg Oncol Clin N Am 18(2):257–267, viii Pandey M, Shukla VK (2003) Lifestyle, parity, menstrual and reproductive factors and risk of gallbladder cancer. Eur J Cancer Prev 12(4):269–272 Pandey M, Sood BP, Shukla RC, Aryya NC, Singh S, Shukla VK (2000) Carcinoma of the gallbladder: role of sonography in diagnosis and staging. J Clin Ultrasound 28(5):227–232 Paolucci V (2001) Port site recurrences after laparoscopic cholecystectomy. J Hepatobiliary Pancreat Surg 8(6):535–543 Paolucci V, Neckell M, Gotze T, Workgroup Surgical Endoscopy GSoS (2003) Unsuspected gallbladder carcinoma – the CAE-S/CAMIC registry. Zentralbl Chir 128(4):309–312 Parikh AA, Abdalla EK, Vauthey JN (2005) Operative considerations in resection of hilar cholangiocarcinoma. HPB 7(4):254–258 Park JY, Park SW, Chung JB, Seong J, Kim KS, Lee WJ, Song SY (2006) Concurrent chemoradiotherapy with doxifluridine and paclitaxel for extrahepatic bile duct cancer. Am J Clin Oncol 29(3):240–245 Patel T (2002) Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2:10 Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ (2000) The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol 95(1):204–207 Patt YZ, Hassan MM, Lozano RD, Waugh KA, Hoque AM, Frome AI, Lahoti S, Ellis L, Vauthey JN, Curley SA, Schnirer II, Raijman I (2001) Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and 5-fluorouracil for biliary tract cancer. Clin Cancer Res 7(11):3375–3380 Pawlik T, Choti M (2009) Biology dictates prognosis following resection of gallbladder carcinoma: sometimes less is more. Ann Surg Oncol 16(4):787–788 Pawlik TM, Scoggins CR, Thomas MB, Vauthey JN (2004) Advances in the surgical management of liver malignancies. Cancer J 10(2):74–87 Pawlik T, Gleisner A, Vigano L, Kooby D, Bauer T, Frilling A, Adams R, Staley C, Trindade E, Schulick R, Choti M, Capussotti L (2007) Incidence of finding residual disease for incidental gallbladder carcinoma: implications for re-resection. J Gastrointest Surg 11(11): 1478–1487 Penz M, Kornek GV, Raderer M, Ulrich-Pur H, Fiebiger W, Lenauer A, Depisch D, Krauss G, Schneeweiss B, Scheithauer W (2001) Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol 12(2):183–186 Perpetuo MD, Valdivieso M, Heilbrun LK, Nelson RS, Connor T, Bodey GP (1978) Natural history study of gallbladder cancer: a review of 36 years experience at M.D. Anderson Hospital and Tumor Institute. Cancer 42(1):330–335 Peterson MS, Murakami T, Baron RL (1998) MR imaging patterns of gadolinium retention within liver neoplasms. Abdom Imaging 23(6):592–599 Petrowsky H, Wildbrett P, Husarik DB, Hany TF, Tam S, Jochum W, Clavien PA (2006) Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol 45(1):43–50 Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, Donehower RC, Fitch T, Picus J, Erlichman C (2006) Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 24(19):3069–3074 Pichlmayr R, Lamesch P, Weimann A, Tusch G, Ringe B (1995) Surgical treatment of cholangiocellular carcinoma. World J Surg 19(1):83–88 Piehler JM, Crichlow RW (1978) Primary carcinoma of the gallbladder. Surg Gynecol Obstet 147(6):929–942 Pitt HA, Nakeeb A, Abrams RA, Coleman J, Piantadosi S, Yeo CJ, Lillemore KD, Cameron JL (1995) Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg 221(6):788–797; discussion 788–797 Raderer M, Hejna MH, Valencak JB, Kornek GV, Weinlander GS, Bareck E, Lenauer J, Brodowicz T, Lang F, Scheithauer W (1999) Two consecutive phase II studies of 5-fluorouracil/leucovorin/
10 Carcinoma of the Biliary Tract
295
mitomycin C and of gemcitabine in patients with advanced biliary cancer. Oncology 56(3):177–180 Rajagopalan V, Daines WP, Grossbard ML, Kozuch P (2004) Gallbladder and biliary tract carcinoma: a comprehensive update, part 1. Oncology 18(7):889–896 Randi G, Franceschi S, La Vecchia C (2006) Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 118(7):1591–1602 Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, Ross PJ, Oates J, Norman AR (2005) Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer 92(9):1650–1654 Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, Gores GJ, Nagorney DM (2005) Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 242(3):451–458; discussion 458–461 Redaelli CA, Buchler MW, Schilling MK, Krahenbuhl L, Ruchti C, Blumgart LH, Baer HU (1997) High coincidence of Mirizzi syndrome and gallbladder carcinoma [see comment]. Surgery 121(1):58–63 Reyes-Vidal J, Gallardo J, Yanez E (2003) Gemcitabine and cisplatin in the treatment of patients with unresectable or metastatic gallbladder cancer: results of the phase II Gocchi study 2000–13. Proc Am Soc Clin Oncol 22:273 Ribero D, Abdalla EK, Madoff DC, Donadon M, Loyer EM, Vauthey JN (2007) Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome. Br J Surg 94(11):1386–1394 Riechelmann R, Townsley C, Chin S, Pond G, Knox J (2007) Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer 110:1307–1312 Ritts RE Jr, Nagorney DM, Jacobsen DJ, Talbot RW, Zurawski VR Jr (1994) Comparison of preoperative serum CA19-9 levels with results of diagnostic imaging modalities in patients undergoing laparotomy for suspected pancreatic or gallbladder disease. Pancreas 9(6):707–716 Roa I, de Aretxabala X, Araya JC, Roa J (2006) Preneoplastic lesions in gallbladder cancer. J Surg Oncol 93(8):615–623 Robles R, Figueras J, Turrion VS, Margarit C, Moya A, Varo E, Calleja J, Valdivieso A, Valdecasas JC, Lopez P, Gomez M, de Vicente E, Loinaz C, Santoyo J, Fleitas M, Bernardos A, Llado L, Ramirez P, Bueno FS, Jaurrieta E, Parrilla P (2004) Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg 239(2):265–271 Rosen CB, Heimbach JK, Gores GJ (2008) Surgery for cholangiocarcinoma: the role of liver transplantation. HPB (Oxford) 10(3):186–189 Rosenbaum SJ, Stergar H, Antoch G, Veit P, Bockisch A, Kuhl H (2006) Staging and follow-up of gastrointestinal tumors with PET/CT. Abdom Imaging 31(1):25–35 Rossi RL, Silverman ML, Braasch JW, Munson JL, ReMine SG (1987) Carcinomas arising in cystic conditions of the bile ducts. A clinical and pathologic study. Ann Surg 205(4):377–384 Sanz-Altamira PM, Ferrante K, Jenkins RL, Lewis WD, Huberman MS, Stuart KE (1998) A phase II trial of 5-fluorouracil, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma. Cancer 82(12):2321–2325 Sasaki A, Aramaki M, Kawano K, Morii Y, Nakashima K, Yoshida T, Kitano S (1998) Intrahepatic peripheral cholangiocarcinoma: mode of spread and choice of surgical treatment. Br J Surg 85(9):1206–1209 Sasaki R, Itabashi H, Fujita T, Takeda Y, Hoshikawa K, Takahashi M, Funato O, Nitta H, Kanno S, Saito K (2006) Significance of extensive surgery including resection of the pancreas head for the treatment of gallbladder cancer – from the perspective of mode of lymph node involvement and surgical outcome. World J Surg 30(1):36–42 Sasatomi E, Tokunaga O, Miyazaki K (2000) Precancerous conditions of gallbladder carcinoma: overview of histopathologic characteristics and molecular genetic findings. J Hepatobiliary Pancreat Surg 7(6):556–567
296
S.P. Cleary et al.
Schaeff B, Paolucci V, Thomopoulos J (1998) Port site recurrences after laparoscopic surgery. A review. Dig Surg 15(2):124–134 Serra I, Diehl AK (2002) Number and size of stones in patients with asymptomatic and symptomatic gallstones and gallbladder carcinoma [comment]. J Gastrointest Surg 6(2):272–273; author reply 273 Serra I, Yamamoto M, Calvo A, Cavada G, Baez S, Endoh K, Watanabe H, Tajima K (2002) Association of chili pepper consumption, low socioeconomic status and longstanding gallstones with gallbladder cancer in a Chilean population [erratum appears in Int J Cancer 2003;104(6):798]. Int J Cancer 102(4):407–411 Shaib Y, El-Serag HB (2004) The epidemiology of cholangiocarcinoma. Semin Liver Dis 24(2):115–125 Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA (2005) Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 128(3):620–626 Shimada M, Yamashita Y, Aishima S, Shirabe K, Takenaka K, Sugimachi K (2001) Value of lymph node dissection during resection of intrahepatic cholangiocarcinoma. Br J Surg 88(11): 1463–1466 Shimizu Y, Ohtsuka M, Ito H, Kimura F, Shimizu H, Togawa A, Yoshidome H, Kato A, Miyazaki M (2004) Should the extrahepatic bile duct be resected for locally advanced gallbladder cancer? Surgery 136(5):1012–1017; discussion 1018 Shimoda M, Farmer DG, Colquhoun SD, Rosove M, Ghobrial RM, Yersiz H, Chen P, Busuttil RW (2001) Liver transplantation for cholangiocellular carcinoma: analysis of a single-center experience and review of the literature. Liver Transpl 7(12):1023–1033 Shin H, Seong J, Kim W et al (2003) Combination of external beam irradiation and high-dose-rate intraluminal brachytherapy for inoperable carcinoma of the extrahepatic bile ducts. Int J Radiat Oncol Biol Phys 57:105–112 Shirai Y, Yoshida K, Tsukada K, Muto T, Watanabe H (1992a) Radical surgery for gallbladder carcinoma. Long-term results. Ann Surg 216(5):565–568 Shirai Y, Yoshida K, Tsukada K, Muto T, Watanabe H (1992b) Early carcinoma of the gallbladder. Eur J Surg 158(10):545–548 Shoup M (2003) J Gastrointest Surg Shukla VK, Singh H, Pandey M, Upadhyay SK, Nath G (2000) Carcinoma of the gallbladder – is it a sequel of typhoid? Dig Dis Sci 45(5):900–903 Sicklick JK, Choti MA (2005) Controversies in the surgical management of cholangiocarcinoma and gallbladder cancer. Semin Oncol 32(6 Suppl 9):S112–S117 Silk YN, Douglass HO Jr, Nava HR, Driscoll DL, Tartarian G (1989) Carcinoma of the gallbladder. The Roswell Park experience. Ann Surg 210(6):751–757 Smith RC, Pooley M, George CR, Faithful GR (1985) Preoperative percutaneous transhepatic internal drainage in obstructive jaundice: a randomized, controlled trial examining renal function. Surgery 97(6):641–648 Sorensen HT, Friis S, Olsen JH, Thulstrup AM, Mellemkjaer L, Linet M, Trichopoulos D, Vilstrup H, Olsen J (1998) Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology 28(4):921–925 Sotiropoulos GC, Lang H, Niebel W, Malago M, Broelsch CE (2004) 10-year tumor-free survival after intraoperative radiation therapy and secondary liver transplantation for hilar cholangiocarcinoma. Transplantation 77(10):1625 Strom BL, Maislin G, West SL, Atkinson B, Herlyn M, Saul S, Rodriguez-Martinez HA, RiosDalenz J, Iliopoulos D, Soloway RD (1990) Serum CEA and CA 19-9: potential future diagnostic or screening tests for gallbladder cancer? Int J Cancer 45(5):821–824 Strom BL, Soloway RD, Rios-Dalenz JL, Rodriguez-Martinez HA, West SL, Kinman JL, Polansky M, Berlin JA (1995) Risk factors for gallbladder cancer. An international collaborative case-control study [see comment]. Cancer 76(10):1747–1756
10 Carcinoma of the Biliary Tract
297
Sudan D, DeRoover A, Chinnakotla S, Fox I, Shaw B Jr, McCashland T, Sorrell M, Tempero M, Langnas A (2002) Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant 2(8):774–779 Sugimoto K, Ohzato H, Tomita N, Tamura S, Aihara T, Okamura S, Miki H, Nakata K, Kim C, Takiuchi D, Okada K, Takatsuka Y (2005) Two cases of successful local control with intermittent hepatic arterial infusion therapy using 5-FU and external radiation therapy for unresectable advanced gall bladder cancer. Gan To Kagaku Ryoho 32(11):1855–1858 Sumiyoshi K, Nagai E, Chijiiwa K, Nakayama F (1991) Pathology of carcinoma of the gallbladder. World J Surg 15(3):315–321 Suzuki K, Kimura T, Ogawa H (1998) Is laparoscopic cholecystectomy hazardous for gallbladder cancer? Surgery 123(3):311–314 Suzuki K, Kimura T, Ogawa H, Suzuki K, Kimura T, Hashimoto H, Nishihira T, Ogawa H, Suzuki K, Kimura T, Ogawa H (2000) Long-term prognosis of gallbladder cancer diagnosed after laparoscopic cholecystectomy port site recurrence of gallbladder cancer after laparoscopic surgery: two case reports of long-term survival. Is laparoscopic cholecystectomy hazardous for gallbladder cancer? Surg Endosc 14(8):712–716 Suzuki S, Yokoi Y, Kurachi K, Inaba K, Ota S, Azuma M, Konno H, Baba S, Nakamura S (2004) Appraisal of surgical treatment for pT2 gallbladder carcinomas. World J Surg 28(2):160–165 Taieb J, Mitry E, Boige V, Artru P, Ezenfis J, Lecomte T, Clavero-Fabri MC, Vaillant JN, Rougier P, Ducreux M (2002) Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Ann Oncol 13(8):1192–1196 Takada T, Kato H, Matsushiro T et al (1994) Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas. Oncology 51:396–400 Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, Nagakawa T, Nakayama T (2002) Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 95(8):1685–1695 Takahashi T, Shivapurkar N, Riquelme E, Shigematsu H, Reddy J, Suzuki M, Miyajima K, Zhou X, Bekele BN, Gazdar AF, Wistuba II (2004) Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis. Clin Cancer Res 10(18 Pt 1):6126–6133 Taner CB, Nagorney DM, Donohue JH (2004) Surgical treatment of gallbladder cancer. J Gastrointest Surg 8(1):83–89; discussion 89 Thamavit W, Bhamarapravati N, Sahaphong S, Vajrasthira S, Angsubhakorn S (1978) Effects of dimethylnitrosamine on induction of cholangiocarcinoma in Opisthorchis viverrini-infected Syrian golden hamsters. Cancer Res 38(12):4634–4639 The Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91(15):1310–1316 Todoroki T, Takahashi H, Koike N, Kawamoto T, Kondo T, Yoshida S, Kashiwagi H, Otsuka M, Fukao K, Saida Y (1999a) Outcomes of aggressive treatment of stage IV gallbladder cancer and predictors of survival. Hepatogastroenterology 46(28):2114–2121 Todoroki T, Kawamoto T, Takahashi H, Takada Y, Koike N, Otsuka M, Fukao K (1999b) Treatment of gallbladder cancer by radical resection [see comment]. Br J Surg 86(5):622–627 Todoroki T, Ohara K, Kawamoto T, Koike N, Yoshida S, Kashiwagi H, Otsuka M, Fukao K (2000) Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma. Int J Radiat Oncol Biol Phys 46(3):581–587 Tollenaar RA, van de Velde CJ, Taat CW, Gonzalez Gonzalez D, Leer JW, Hermans J (1991) External radiotherapy and extrahepatic bile duct cancer. Eur J Surg 157(10):587–589
298
S.P. Cleary et al.
Townsley C, Knox J (2005) An expanded phase II study combining gemcitabine and capecitabine in patients with advanced biliary cancer. In: International society of gastrointestinal oncology (ISGIO) second annual conference. Arlington, Virginia Toyonaga T, Chijiiwa K, Nakano K, Noshiro H, Yamaguchi K, Sada M, Terasaka R, Konomi K, Nishikata F, Tanaka M (2003) Completion radical surgery after cholecystectomy for accidentally undiagnosed gallbladder carcinoma. World J Surg 27(3):266–271 Tsao JI, Nimura Y, Kamiya J, Hayakawa N, Kondo S, Nagino M, Miyachi M, Kanai M, Uesaka K, Oda K, Rossi RL, Braasch JW, Dugan JM (2000) Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience. Ann Surg 232(2):166–174 Uno T, Itami J, Aruga M, Araki H, Tani M, Kobori O (1996) Primary carcinoma of the gallbladder: role of external beam radiation therapy in patients with locally advanced tumor. Strahlenther Onkol 172(9):496–500 Urahashi T, Yamamoto M, Ohtsubo T, Katsuragawa H, Katagiri S, Takasaki K (2007) Hepatopan creatoduodenectomy could be allowed for patients with advanced intrahepatic cholangiocarcinoma. Hepatogastroenterology 54(74):346–349 Vaittenim E (1970) Carcinoma of the gallbladder. Ann Chir Gynaecol 168:1 Valle JW, Wasan H, Johnson P (2006) Gemcitabine, alone or in combination with cisplatin, in patients with advanced or metastatic cholangiocarcinoma and other biliary tract tumors: a multicenter, randomized phase II (the UK ABC-01) study. Proc Am Soc Clin Oncol 24:336s Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Levson T, Hughes S, Pereira SF, Roughton M, Bridgewater J (2010) ABC-02 Trial Investigators Cisplatin plus Gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362(14):1273–1281 Vauthey JN, Chaoui A, Do KA, Bilimoria MM, Fenstermacher MJ, Charnsangavej C, Hicks M, Alsfasser G, Lauwers G, Hawkins IF, Caridi J (2000) Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery 127(5):512–519 Veeze-Kuijpers B, Meerwaldt JH, Lameris JS, van Blankenstein M, van Putten WL, Terpstra OT (1990) The role of radiotherapy in the treatment of bile duct carcinoma. Int J Radiat Oncol Biol Phys 18(1):63–67 Wade TP, Prasad CN, Virgo KS, Johnson FE (1997) Experience with distal bile duct cancers in U.S. Veterans Affairs hospitals: 1987–1991. J Surg Oncol 64(3):242–245 Wakai T, Shirai Y, Yokoyama N, Nagakura S, Watanabe H, Hatakeyama K (2001) Early gallbladder carcinoma does not warrant radical resection. Br J Surg 88(5):675–678 Wakai T, Shirai Y, Hatakeyama K (2002) Radical second resection provides survival benefit for patients with T2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy. World J Surg 26(7):867–871. Epub 2002 Apr 2018 Watanapa P, Watanapa WB (2002) Liver fluke-associated cholangiocarcinoma. Br J Surg 89(8):962–970 Weber SM, DeMatteo RP, Fong Y, Blumgart LH, Jarnagin WR (2002) Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg 235(3):392–399 Weiland ST, Mahvi DM, Niederhuber JE, Heisey DM, Chicks DS, Rikkers LF (2002) Should suspected early gallbladder cancer be treated laparoscopically? J Gastrointest Surg 6(1):50–56; discussion 56–57 Weinbren K, Mutum SS (1983) Pathological aspects of cholangiocarcinoma. J Pathol 139(2):217–238 Welzel TM, McGlynn KA, Hsing AW, O’Brien TR, Pfeiffer RM (2006) Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst 98(12):873–875 Welzel TM, Graubard BI, El-Serag HB, Shaib YH, Hsing AW, Davila JA, McGlynn KA (2007) Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol 5(10):1221–1228 Wibbenmeyer LA, Sharafuddin MJ, Wolverson MK, Heiberg EV, Wade TP, Shields JB (1995a) Sonographic diagnosis of unsuspected gallbladder cancer: imaging findings in comparison with benign gallbladder conditions. AJR Am J Roentgenol 165(5):1169–1174
10 Carcinoma of the Biliary Tract
299
Wibbenmeyer LA, Wade TP, Chen RC, Meyer RC, Turgeon RP, Andrus CH (1995b) Laparoscopic cholecystectomy can disseminate in situ carcinoma of the gallbladder. J Am Coll Surg 181(6): 504–510 Wig JD, Kumar H, Suri S, Gupta NM (1999) Usefulness of percutaneous transhepatic biliary drainage in patients with surgical jaundice – a prospective randomised study. J Assoc Physicians India 47(3):271–274 Wilkinson DS (1995) Carcinoma of the gall-bladder: an experience and review of the literature. Aust N Z J Surg 65(10):724–727 Wistuba II, Gazdar AF (2004) Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer 4(9):695–706 Wood R, Brewster DH, Fraser LA, Brown H, Hayes PC, Garden OJ (2003) Do increases in mortality from intrahepatic cholangiocarcinoma reflect a genuine increase in risk? Insights from cancer registry data in Scotland. Eur J Cancer 39(14):2087–2092 Yamaguchi K, Enjoji M (1988) Carcinoma of the gallbladder. A clinicopathology of 103 patients and a newly proposed staging. Cancer 62(7):1425–1432 Yamaguchi K, Chijiiwa K, Shimizu S, Yokohata K, Tsuneyoshi M, Tanaka M (1998) Anatomical limit of extended cholecystectomy for gallbladder carcinoma involving the neck of the gallbladder. Int Surg 83(1):21–23 Yamamoto J, Kosuge T, Takayama T, Shimada K, Makuuchi M, Yoshida J, Sakamoto M, Hirohashi S, Yamasaki S, Hasegawa H (1992) Surgical treatment of intrahepatic cholangiocarcinoma: four patients surviving more than five years. Surgery 111(6):617–622 Yamamoto M, Takasaki K, Yoshikawa T (1999) Extended resection for intrahepatic cholangiocarcinoma in Japan. J Hepatobiliary Pancreat Surg 6(2):117–121 Yamamoto M, Takasaki K, Otsubo T, Katsuragawa H, Katagiri S (2001) Recurrence after surgical resection of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 8(2):154–157 Yamasaki S (2003) Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepatobiliary Pancreat Surg 10(4):288–291 Yang J, Yan LN (2008) Current status of intrahepatic cholangiocarcinoma. World J Gastroenterol 14(41):6289–6297 Yonemoto N, Furuse J, Okusaka T, Yamao K, Funakoshi A, Ohkawa S, Boku N, Tanaka K, Nagase M, Saisho H, Sato T (2007) A multi-center retrospective analysis of survival benefits of chemotherapy for unresectable biliary tract cancer. Jpn J Clin Oncol 37(11):843–851 Yoshimitsu K, Honda H, Shinozaki K, Aibe H, Kuroiwa T, Irie H, Chijiiwa K, Asayama Y, Masuda K (2002) Helical CT of the local spread of carcinoma of the gallbladder: evaluation according to the TNM system in patients who underwent surgical resection. AJR Am J Roentgenol 179(2):423–428 Zatonski WA, Lowenfels AB, Boyle P, Maisonneuve P, Bueno de Mesquita HB, Ghadirian P, Jain M, Przewozniak K, Baghurst P, Moerman CJ, Simard A, Howe GR, McMichael AJ, Hsieh CC, Walker AM (1997) Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH Program of the International Agency for Research on Cancer. J Natl Cancer Inst 89(15):1132–1138 Zhang Y, Uchida M, Abe T, Nishimura H, Hayabuchi N, Nakashima Y (1999) Intrahepatic peripheral cholangiocarcinoma: comparison of dynamic CT and dynamic MRI. J Comput Assist Tomogr 23(5):670–677 Zheng SS, Huang DS, Wang WL, Liang TB, Zhang M, Shen Y, Xu X, Wu J, Yan S, Guo H, Lu AW (2002) Orthotopic liver transplantation in treatment of 77 patients with end-stage hepatic disease. Hepatobiliary Pancreat Dis Int 1(1):8–13 Zidi SH, Prat F, Le Guen O, Rondeau Y, Pelletier G (2000) Performance characteristics of magnetic resonance cholangiography in the staging of malignant hilar strictures. Gut 46(1): 103–106 Zlotecki RA, Jung LA, Vauthry JN et al (1998) Carcinoma of the extrahepatic biliary tract: surgery and radiotherapy for curative and palliative intent. Radiat Oncol Investig 6:240–247
Neuroendocrine Cancers
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John A. Jakob, Carlo Mario Contreras, Eddie K. Abdalla, Alexandria Phan, and James C. Yao
Abbreviations 5-HIAA 5-HT 5-HTP ACTH CGA CGH CHD CT DOTA DTPA EGF FAS FDG HACE HAE IFN a LOH MEN1 MRI mTOR NCCN NET NF1
5-Hydroxyindoleacetic acid 5-Hydroxytryptophan 5-Hydroxytryptamine Adrenocorticotropic hormone Chromogranin A Comparative genomic hybridization Carcinoid heart disease Computed tomography Tetraazacyclo-dodecanetetra-acetic acid Diethylenetriamine pentaacetic acid Epidermal growth factor 5-Fluorouracil, doxorubicin, and streptozocin 2-Fluoro-2-deoxy-D-glucose Hepatic artery chemoembolization Hepatic artery embolization Interferon a Loss of heterozygosity Multiple endocrine neoplasia type 1 Magnetic resonance imaging Mammalian target of rapamycin National comprehensive cancer network Neuroendocrine tumor Neurofibromatosis type 1
J.A. Jakob, A. Phan, and J.C. Yao (*) Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA e-mail:
[email protected] C.M. Contreras and E.K. Abdalla Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_11, © Springer-Verlag Berlin Heidelberg 2011
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NSE NYHA PDGF PET PFS RFA SEER SNP TGF b TSC2 TTP VEGF VHL VIP ZES
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Neuron-specific enolase New York Heart Association Platelet-derived growth factor Positron emission tomography Progression-free survival Radiofrequency ablation Surveillance, Epidemiology, End Results Single nucleotide polymorphism Transforming growth factor b Tuberous sclerosis complex 2 Time to progression Vascular endothelial growth factor von Hippel–Lindau syndrome Vasoactive intestinal peptide Zollinger-Ellison syndrome
11.1 Introduction Neuroendocrine tumors (NETs) originate from neuroendocrine cells which are located throughout the body. This chapter focuses on low- to intermediate-grade NETs of the gastrointestinal tract, though the term “neuroendocrine tumor” can also denote other diseases such as small-cell carcinoma of pulmonary and extrapulmonary origins, thyroid medullar carcinoma, neuroblastoma, and Merkel cell tumors. Islet cell carcinomas, also known as pancreatic endocrine tumors, pancreatic NETs, or pancreatic carcinoid, arise from the islets of Langerhans. Low- to intermediate-grade NETs arising from other sites are generally called carcinoids and are most commonly localized in the gastrointestinal tract and bronchopulmonary tree. Both of these tumor groups share the capacity for hormone production and usually have indolent clinical courses. Presenting symptoms, when present, are caused by excess hormones, local tumor growth, and metastasis. Surgical resection is the curative approach for localized disease. In unresectable, metastatic disease, the introduction of somatostatin analogs such as octreotide have significantly improved quality of life, and the potential tumor stabilization properties of newer, targeted agents are the subject of ongoing phase III trials. Nonetheless, advanced NETs remain largely incurable and often require the concerted efforts of a multidisciplinary team for effective palliation.
11.2 Epidemiology The incidence of NETs varies with gender, age, and race. The overall incidence in the United States is estimated at 5.25 cases per 100,000 (Yao et al. 2008a). Most NETs progress slowly and may remain undiagnosed for many years. Carcinoid tumors were
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Table 11.1 Organ distribution of neuroendocrine tumors (carcinoids and pancreatic islet cell tumors) Distribution (%) Pulmonary
27
Gastrointestinal Stomach Small intestine Appendix Colon Rectum Pancreas
58 6 17 3 4 17 6
Unknown/other
15
Adapted from analysis of SEER 17 registry, 2000–2004 in Yao et al. (2008a).
found in 0.65–1.2% patients during unselected small intestine necropsy (Moertel et al. 1961; Berge and Linell 1976). These tumors are usually diagnosed in the sixth and seventh decades. NETs have been described as more common among African Americans owing to a higher incidence of rectal carcinoid (Modlin et al. 2003; Yao et al. 2008a). The gastrointestinal tract is the most common primary site of NETs. It accounts for 58% of all carcinoid tumors (Yao et al. 2008a). The distribution of NETs is illustrated in Table 11.1.
11.3 Prognosis The overall prognosis of patients with NETs varies by histologic grade, extent of disease, and site of primary tumor. High-grade NETs have high metastatic potential and an aggressive growth pattern. Treatment strategy is similar to that for small cell carcinoma of the lung. Most low- to intermediate-grade NETs have a more favorable prognosis than adenocarcinoma of the same primary site. The median overall survival of patients with localized low- to intermediate-grade NETs is 223 months, according to a recent analysis of the Surveillance Epidemiology and End Results (SEER) database of patients registered from 1973 to 2004. For those patients with regional disease, defined as involvement of regional lymph nodes or extension to adjacent tissue or both, median overall survival is 111 months. For metastatic disease, median overall survival plummets to 33 months (Yao et al. 2008a). The prognoses of NETs by anatomical site will be discussed in Sects. 11.7 and 11.8.
11.4 Pathogenesis and Molecular Biology NETs may occur sporadically or in the context of an inherited disorder. Little is known about the pathogenesis of sporadic NETs. The multiple endocrine neoplasia type 1 (MEN1) gene, mutated in Multiple Endocrine Neoplasia, type I, whose germline mutation
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p redisposes to inherited islet cell carcinomas does manifest mutation (20%) and loss of heterozygosity (LOH) (70%), in sporadic islet cell carcinomas (Toumpanakis and Caplin 2008). Menin, the protein product of the MEN1 gene, appears to exert its tumor suppressor action via multiple mechanisms, including transcription regulation/chromatin remodeling via interaction with histone methyltransferases, direct regulation of cell cycle progression via interaction with the genetic loci of the cyclin-dependent kinase inhibitors p18ink4c, and p27kip1, as well as facilitation of apoptosis by increased production of caspase 8 (Yang and Hua 2007). Interestingly, the two most frequently mutated tumor suppressors in human cancer, p53 and PTEN, are not altered in NETs of the gastroenteropancreatic system. p53 mutations have been reported in atypical pulmonary carcinoids (Schnirer et al. 2003). PTEN protein expression was not altered in a limited sample size of nine assayed carcinoid lesions, although expression was lost in poorly differentiated neuroendocrine carcinomas (Wang et al. 2002). The elevated expression of various angiogenesis and tumor growth factors, such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), and their receptors, is found in carcinoid tumors (Terris et al. 1998; Krishnamurthy and Dayal 1997; Chaudhry et al. 1992). In addition, somatostatin receptors are expressed in the majority of carcinoids. Investigators have employed positional cloning techniques to identify novel candidate tumor suppressor or oncogene loci for sporadic NETs, without finding specific candidate genes. In a series of 12 foregut tumors (mostly islet cell carcinomas) and 14 midgut tumors (mostly carcinoids of the ileum), comparative genomic hybridization (CGH) identified gain of chromosome arm 20q as the most common chromosome imbalance in the foregut tumors (58%), and gain of 17p and 19q as the most common imbalance in midgut tumors (57% each). This study also demonstrated loss of chromosome arm 18q in 43% of midgut carcinoid tumors (Tonnies et al. 2001). A separate investigation of 18 midgut carcinoids with CGH revealed loss of 18q22-qter as the most common chromosomal abnormality (Kytola et al. 2001). Higher-resolution, single-nucleotide polymorphism (SNP)-based array technology has recently confirmed frequent loss of chromosome 18 (34%) (Kim et al. 2008). As of early 2009, however, no oncogene or tumor suppressor candidates unique to sporadic NETs have been identified via positional cloning or related technologies. A significant minority of NETs, 5–10%, occur in the context of multiple endocrine neoplasia, type I (MEN1), an autosomal dominant disorder characterized by pituitary tumors, hyperparathyroidism, and islet cell carcinomas. MEN1 syndrome-related NET disease differs from sporadic disease insofar as it consists of a unique pattern of symptomatic and nonsymptomatic lesions. Symptomatic lesions include duodenal gastrinomas, which are the cause of Zollinger-Ellison syndrome, a condition that afflicts nearly 60% of MEN1 patients with peptic ulcers, gastroesophageal reflux, and diarrhea. Characteristic nonsymptomatic lesions include small, duodenal foci of somatostatin expression and pancreatic microadenomas and macroadenomas. These pancreatic lesions tend to be asymptomatic and express glucagon or pancreatic polypeptide (PP). Roughly 20% of MEN1-associated pancreatic macroadenomas are “insulinomas,” causing hyperinsulinemic hypoglycemic syndrome. Of note, approximately 10% of pancreatic islet cell carcinomas are associated with MEN1 syndrome (Anlauf et al. 2007).
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Other inherited disorders, such as neurofibromatosis type 1 (NF1), von Hippel–Lindau syndrome (VHL), and tuberous sclerosis complex 2 (TSC2), predispose to NETs. Carcinoids of the ampulla of Vater, mediastinum, and duodenum are seen in roughly 1% of patients with NF1; islet cell carcinomas are associated with 5–17% and <1% of VHL and TSC2 patients, respectively. These diseases account for far less NET disease burden then sporadic and MEN1-related tumors (Anlauf et al. 2007).
11.5 Pathologic Classification NETs are derived from neuroectodermal cells and are characterized by monotonous sheets of small round cells with uniform nuclei and cytoplasm (Fig. 11.1). Neuroendocrine cells store endocrine or paracrine substances in membrane-bound vesicles, releasing them by a process of exocytosis. Typical carcinoid cells have minimal mitotic activity, cytological atypia, or nuclear polymorphism. Pulmonary carcinoid with more than two mitoses per ten high power fields are considered “atypical” and are more likely to metastasize and recur. Tumors with high mitotic activity or necrosis are called poorly differentiated, anaplastic,
Fig. 11.1 Histologic appearance of neuroendocrine tumors (NETs). Microscopic appearance of low grade NET. (a) Standard microscopy showing few mitoses, no necrosis, and large number of tumor vessels. (b) Immunohistochemical staining for chromogranin A
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or high-grade neuroendocrine carcinoma. They have a behavior similar to small cell carcinoma of the lung and have a poor prognosis. If tumor grade cannot be determined based on available tumor specimen, a repeat core needle biopsy is recommended because the results may determine treatment options.
11.6 Clinical Presentation of NETs and Diagnostic Work Up The classic symptoms associated with hormonal production such as flushing and diarrhea in carcinoid syndrome are typically present in the setting of metastases. These symptoms can be insidious in onset and present years before diagnosis. Symptoms of local and regional carcinoid and islet cell carcinoma disease, with the exception of hypoglycemia in insulinoma, tend to be vague. Symptoms often occur secondary to acute obstruction from primary tumor, mesenteric fibrosis, or ischemia secondary to mesenteric vascular involvement. Multiple diagnostic procedures are frequently performed, including computed tomography (CT) of the abdomen and pelvis, esophagogastroduodenoscopy, and colonoscopy, sometimes without achieving a definitive diagnosis. This situation is particularly frustrating when clinical suspicion of carcinoid syndrome is great; fortunately, serum and urine laboratory markers, described below in Sect. 11.6.1, are frequently performed in parallel with more invasive testing and can confirm the diagnosis, if not localize the primary lesion.
11.6.1 Neuroendocrine Tumor Laboratory Tests and Markers Frequently measured tumor markers in carcinoid disease include serum chromogranin A (CGA) and 5-hydroxyindoleacetic acid (5-HIAA) levels in a 24-h urine sample. Tryptophanrich food should be avoided during urine collection for 5-HIAA levels (Feldman and Lee 1985). False-positive results occur with the consumption of serotonin-rich foods such as plantains, pineapples, bananas, kiwifruit, plums, tomatoes, butternuts, walnuts, shagbark hickory nuts, mockernut, pecans, and sweet pignuts. Common medications that affect urinary 5-HIAA levels include guaifenesin, acetaminophen, and salicylates. Serum CGA level is a very sensitive, but nonspecific, marker for all NETs. Elevations are frequently seen among patients on proton pump inhibitors or with poor renal function. Urine 5-HIAA and serum CGA may also serve as biochemical markers for monitoring the disease progression and the treatment response. Immunohistochemical markers used to confirm a carcinoid diagnosis on actual tumors include neuron-specific enolase (NSE), CD56, CGA and synaptophysin (summarized in Table 11.2). In addition to the above markers, NETs also synthesize many bioactive amines and peptides such as 5-hydroxytryptamine (5-HTP), 5-hydroxytryptophan (5-HT), serotonin,
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11 Neuroendocrine Cancers Table 11 2 Immunohistochemical markers of neuroendocrine carcinoma Marker Significance Neuron-specific enolase
Cytoplasmic glycolytic enzyme, neuroendocrine marker
Synaptophysin
Presynaptic vesicle membrane glycoprotein, present on normal and neoplastic neuroendocrine cells
Chromogranin A
Acidic protein, universal marker for neuroendocrine tissue
CD56
Neural adhesion molecule
insulin, gastrin, glucagon, somatostatin, vasoactive intestinal polypeptide (VIP), growth hormone, adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone, PP, calcitonin, substance P, pancreastatin, and various growth factor such as transforming growth factor-b, (TGF-b) and PDGF (Schnirer et al. 2003).
11.6.2 Imaging 11.6.2.1 Endoscopy Endoscopic techniques are designed to localize tumors and to facilitate biopsy retrieval. Upper endoscopy can often locate gastric and duodenal carcinoid tumors. Colonoscopy is used in the identification of colorectal carcinoids. Conventional endoscopy is generally not useful in patients with jejunal or ileal tumors. Instead, double-balloon enteroscopy and capsule endoscopy are emerging techniques that could play a prominent role for tumors in these locations. The disadvantages of endoscopy include the requirement for patient sedation and the difficulty in visualizing small, submucosal lesions. Endoscopic ultrasound is useful in the assessment, visualization, and biopsy of pancreatic and some small duodenal NETs.
11.6.2.2 Computed Tomography and Magnetic Resonance Imaging Both CT and magnetic resonance imaging (MRI) can be used for diagnostic workup. The utility of CT and MRI imaging for diagnosis of a typical small bowel carcinoid of the ileum is limited at best; usually the presence of such lesions can only be inferred by the presence of luminal narrowing, adenopathy, and mesenteric fibrosis. CT and MRI technologies are far more useful in the detection of hepatic metastases, which frequently present more convenient sites for biopsy to confirm diagnosis.
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CT and MRI technologies are more adept in the detection of primary pancreatic islet cell carcinomas; sensitivities of CT and MRI are 64–82% and 74–100%, respectively (Tamm et al. 2007).
11.6.2.3 OctreoScan Somatostatin receptor scintigraphy has improved the visualization of NETs. OctreoScan utilizes a somatostatin analog, 111In-labeled diethylenetriamine penta-acetic acid octreotide (DTPA-D-Phe1-octreotide) to visualize somatostatin receptor-positive tumors. Compared with routine CT or MRI, OctreoScan detects additional metastases in about one third of patients. In addition, OctreoScan may help to identify insulinoma and gastrinoma when conventional scans are negative. The overall sensitivity of OctreoScan is 80–90% (Krenning et al. 1994).
11.6.2.4 Positron Emission Tomography (PET) There is little experience with positron emission tomography (PET) imaging in the evaluation of NETs. Because 2-fluoro-2-deoxy-D-glucose (FDG) PET scan only identifies tumors with moderate to high proliferative activity, false-positive and false-negative results are common. 11C-labeled 5-HT PET is used to image tryptophan metabolism and is superior to routine FDG PET or CT scan (Eriksson et al. 1993, 2002). Currently, 11C-labeled 5-HT PET is not available in North America.
11.6.2.5 Other Nuclear Scintigraphy Techniques Metaidobenzyguanidine (MIBG) is absorbed by carcinoid tumor cells. 131Iodine-labeled MIBG (131I-MIBG) has an overall sensitivity of 55–70% (Krenning et al. 1994; Vinik et al. 1989; Feldman 1989; Hanson et al. 1989). Although 131I-MIBG is less sensitive than OctreoScan, it may be used in patients who are treated by long-acting octreotide.
11.7 Carcinoid Clinical Behavior by Site 11.7.1 Gastric Carcinoid Gastric carcinoid tumors are divided into three distinct groups. Group one (75%) is associated with chronic atrophic gastritis, group two (5–10%) with Zollinger-Ellison syndrome (5–10%); and group three (15–25%) is sporadic gastric carcinoid tumors (Nilsson 1996). Group three has the worse prognosis of the subtypes, frequently presenting with metastatic
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11 Neuroendocrine Cancers Table 11 3 The clinical features of gastric carcinoid by group Clinical Clinical feature Tumor size feature (cm)
Metastasis
Prognosis
Group 1
Chronic gastritis
<1
10 %
Good
Group 2
ZES, gastrinoma
<1.5
25%
Intermediate
Group 3
Atypical carcinoid
>1
Frequent
Poor
ZES, Zollinger Ellison syndrome.
disease. Analysis of the SEER database demonstrates a median overall survival of just 13 months for patients with metastatic gastric carcinoid (Yao et al. 2008a). Clinical features of the three types of gastric carcinoids are summarized in Table 11.3.
11.7.2 Small Intestine Carcinoid Small intestine carcinoid tumors, the carcinoid most frequently associated with typical symptoms of carcinoid syndrome, are usually found in the distal ileum within 60 cm of the ileocecal valve. At diagnosis, multiple putative “primary” lesions tend to be present in multiple sites. Analysis of SEER data from 1973 to 2004 demonstrates that jejunum and ileum carcinoids (30%) were far more likely then rectal (5%) or appendiceal (9%) lesions to be diagnosed with distant metastases. Of note, only 9% of duodenal carcinoids present with distant metastases. The median overall survival for duodenal and jejunum/ileum carcinoids is 107 and 111 months, respectively, in localized disease and 57 and 56 months, respectively, with metastases (Yao et al. 2008a).
11.7.3 Appendiceal Carcinoid Carcinoid tumors are found incidentally in 1 out of 200–300 appendectomies in young adults. For appendiceal carcinoid of less than 1cm in diameter, surgical resection is sufficient. For tumors >2 cm in diameter, a significantly higher risk of metastasis exists and a right hemicolectomy is recommended. The optimal treatment of lesions between 1 and 2 cm is controversial, but right hemicolectomy is recommended if high risk features such as vascular invasion are observed. (Stinner and Rothmund 2005). Median overall survival of disease restricted to the appendix is greater than 360 months; individuals with metastatic disease at diagnosis fare far worse, with a median overall survival of only 27 months (Yao et al. 2008a).
11.7.4 Rectal Carcinoid Rectal carcinoids occur most frequently in middle-aged adults. These tumors are found incidentally in approximately 1 in 2,500 proctoscopies as a small yellow-gray submucosal nodule in the walls of the rectum. The majority of rectal carcinoids are less than 1 cm in diameter and do not metastasize, whereas 60–80% of lesions larger than 2 cm do. Local excision is
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adequate for rectal carcinoids <1 cm. Lesions measuring 1–1.9 cm without evidence of highrisk features such as muscularis, lymphovascular, or perineural invasion can also be excised locally (Kwaan et al. 2008). Patients with tumors displaying any of these high-risk features should prompt consideration of a more aggressive segmental rectal resection, sphincter-sparing if possible. In patients with metastatic rectal carcinoid at diagnosis, excision is generally performed with palliative, not curative intent (Wang and Ahmad 2006). The median overall survival of patients with metastatic rectal carcinoid is just 22 months (Yao et al. 2008a).
11.8 Clinical Features of Islet Cell Tumors 11.8.1 Insulinomas Insulinomas are the most common type of islet-cell tumor. The peak incidence of insulinomas occurs in patients between 30 and 60 years of age, and these tumors are more frequent in women. These tumors are usually benign (90%), intrapancreatic (nearly 100%), solitary, and small (<2 cm). About 5% of these tumors are associated with the MENI syndrome; screening of the family members of an MEN1 index case should be considered (Toumpanakis and Caplin 2008). Hyperinsulinism causes obesity and neurological or psychiatric disturbances in many patients. A recent series of four patients demonstrated efficacy of everolimus, whose frequent side effect is hyperglycemia, in the treatment of the hypoglycemia of advanced, progressive insulinoma (Kulke et al. 2009). The insulinoma diagnosis is made with detection of inappropriately high concentrations of both insulin and C peptide in the blood at a blood glucose level of less than 50 mg/dL together with symptoms of hypoglycemia. Conventional CT, transabdominal ultrasonography, and selective arteriography fail to localize an insulinoma in about 40% of cases, though >90% sensitivity can be achieved with combinations of MRI, thin-section pancreatic protocol CT scan, and endoscopic ultrasound. OctreoScan is another noninvasive modality available to assist in the localization of insulinoma. Portal venous sampling and arterial calcium stimulation are technically demanding, invasive procedures that are not widely available. When preoperative studies fail to definitively localize the insulinoma, surgical exploration with intraoperative ultrasonography can be considered (Tucker et al. 2006). At the authors’ institution, radiologic innovations have rendered blind surgical exploration unnecessary.
11.8.2 Gastrinomas Gastrinomas cause Zollinger-Ellison syndrome and their clinical hallmark is multiple recurrent peptic ulcers. Most gastrinomas are located in the “gastrinoma triangle,” which encompasses the duodenum, pancreatic head, and hepatoduodenal ligament. Gastrinomas of the duodenum are often small submucosal tumors and can easily be missed during routine
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upper gastrointestinal endoscopy; gastrinomas of the pancreas can exceed 1 cm in size (Fendrich et al. 2007). The diagnostic workup for gastrinoma often involves two steps. An elevated concentration of gastrin in a blood sample from a fasting patient and increased basal gastric acid output (>15 mEq/h) suggest the presence of gastrinoma. A secretin stimulation test is required to differentiate gastrinomas from other causes of gastrin elevation. Octreotide scan has 77% sensitivity for gastrinoma. Fifty percent of gastrinomas have metastases at diagnosis. Their median survival time is between 3 and 6 years. Roughly one fifth of gastrinomas occur in the context of MEN1 syndrome (Fendrich et al. 2007).
11.8.3 Glucagonomas Glucagonomas are rare alpha-cell tumors of the pancreas that occur in people between 50 and 70 years of age. These tumors are primarily located within the pancreas; most are malignant. They penetrate the pancreatic capsule and invade the regional lymph nodes. Symptoms may not appear until the tumor is larger than 5 cm in diameter. At diagnosis, 50–80% of tumors have metastasized to liver. Serum glucagon levels are usually quite elevated (>1,000 pg/mL; normal range, 150–200 pg/mL) and assist in diagnosis. Mild glucose intolerance is the most common feature. A characteristic skin rash called necrolytic erythema migrans may precede the diagnosis by at least 5 years. The initial lesion consists of red papules or pale brown macules on the face, abdomen, groin, perineum, or extremities. The erythematous areas form superficial bullae that eventually break down and become encrusted. Anemia, thromboembolic disease with venous thrombosis or pulmonary emboli, and psychiatric disturbances are other clinical features of glucagonoma. Anticoagulation therapy is recommended in individuals with glucagon excess (Doherty 2005).
11.8.4 Somatostatinoma Somatostatinoma is very rare. Most are found in the pancreas or duodenum. Patients often present with diabetes mellitus, cholelithiasis, diarrhea, steatorrhea, hypochlorhydria, anemia, and weight loss. These tumors are generally malignant and are usually diagnosed late in their course. Metastases to lymph nodes, liver, and bone may be found at diagnosis (Doherty 2005).
11.8.5 VIPoma VIPoma is characterized by symptoms of watery diarrhea of >3 L/day, hypokalemia, and achlorhydria; symptoms are mediated by VIP as well as other peptides secreted by malignant islet cells. VIPomas are located in the pancreas in adults and in extrapancreatic sites
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in children. They are often metastatic at diagnosis. The stool is essentially isotonic, and the diarrhea persists even during fasting with nasogastric suction. Large amounts of potassium and bicarbonate are lost in the stool, leading to hypokalemia and metabolic acidosis. Diagnosis is made by typical clinical presentation, presence of large pancreatic mass per imaging, and elevated plasma VIP levels. Somatostatin analogs are effective in the control of hormonal syndrome (Schonfeld et al. 1998).
11.8.6 Pancreatic Polypeptidomas PP is synthesized and released from PP cells in the normal pancreas. Pancreatic polypeptideomas are often found unexpectedly in patients with symptoms produced by metastases to the liver and bone (Sakai et al. 1993).
11.9 Carcinoid Syndrome, Carcinoid Heart Disease, and Carcinoid Crisis 11.9.1 Carcinoid Syndrome Carcinoid syndrome is often observed in patients with metastatic disease or when the primary tumor site allows secreted amines to escape into the enterohepatic circulation (Table 11.4). Common symptoms include flushing, diarrhea, abdominal cramping, and less frequently wheezing, heart valve dysfunction, and pellagra, all of which result from synergistic interactions between 5-HTP metabolites, kinins and prostaglandins. The Table 11.4 Symptoms of carcinoid syndrome Symptom Frequency Characteristics (%)
Involved mediators
Flushing
85–90
Foregut: long-lasting, purple Midgut: short-lasting, pink
Killirein, 5-HTP, histamine, substance P, prostaglandins
Diarrhea
70
Secretory
Gastrin, 5-HTP, histamine, prostaglandins, VIP
Abdominal pain
35
Progressive
Small bowel obstruction, hepatomegaly, ischemia
Telangiectasia
25
Face
Unknown
Bronchospasm
15
Wheezing
Histamine, 5-HTP
Pellegra
5
Dermatitis, diarrhea, dementia
Niacin deficiency
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i ncidence of carcinoid syndrome ranges from 10% in localized carcinoid to 40–50% in advanced tumors. As we will discuss in more detail in Sect. 11.12.1, somatostatin analogs such as octreotide are the mainstay of medical therapy for carcinoid syndrome.
11.9.2 Carcinoid Heart Disease Carcinoid heart disease (CHD) is due to fibrosis of endocardium of the right heart and occasionally leads to tricuspid regurgitation and right heart failure. However, the relationship between CHD and frank heart failure in the somatostatin analog era is unclear. A recent study of 150 patients with carcinoid syndrome and midgut lesions described a 20% prevalence of carcinoid valve disease as determined by echocardiography. Of those with valve disease by echocardiogaphy, 53% were assessed clinically as New York Heart Association (NYHA) heart failure class I or II. Surprisingly, 27% of the patients with moderate or severe valvular disease by echocardiography were NYHA class I, or essentially asymptomatic. Notably, more than 70% of all patients in the study were maintained on somatostatin analogs, though there was no relationship demonstrated between somatostatin analog use and the presence of CHD or heart failure. Patients with CHD did exhibit increased urine 5-HIAA and serum CGA levels, supporting a role for these metabolites in pathogenesis (Bhattacharyya et al. 2008). Currently, the United States National Comprehensive Cancer Network (NCCN) guidelines suggest echocardiography of patients with carcinoid syndrome and clinical signs/ symptoms of heart failure or in whom major surgery is planned (NCCN 2009).
11.9.3 Carcinoid Crisis Carcinoid crisis is caused by a massive release of bioactive products to the systemic blood, and is characterized by profuse hypotension, watery stools, and abdominal cramps. Characteristic symptoms such as itching, palpitations, and facial edema are related to large amounts of histamine, kinins, and prostaglandins. Carcinoid crisis is often precipitated by a surgery or procedure; treatment consists of prompt intravenous delivery of octreotide, with initiation of octreotide infusion at 50–100 mg/h as needed. Premedication of carcinoid patients with additional octreotide, in subcutaneous or intravenous form is often used to prevent or mitigate carcinoid crises caused by interventions (Dierdorf 2003).
11.10 General Approach to Treatment of Localized and Advanced Neuroendocrine Tumors The indolent features and lack of response to existing chemotherapy complicate treatment decisions for patients with NETs. Localized NETs should be surgically excised whenever possible. In asymptomatic or mildly symptomatic patients with advanced NETs, that is,
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those with lesions that are surgically unresectable or metastatic, treatment should be delayed and patients should be monitored every 3–6 months. For advanced, well to moderately differentiated, and asymptomatic NETs of the midgut, we recommend surgical resection of all gross disease that can be reasonably removed. There are multiple indications for palliative surgical interventions for advanced NETs. These indications extend beyond the commonly appreciated complications of refractory intestinal obstruction and bleeding. Patients with locally advanced tumors are often associated with bulky mesenteric lymphadenopathy; these nodes can cause mesenteric vascular compromise manifesting as visceral ischemia. Surgical intervention can also alleviate symptomatic, refractory hormone-mediated symptoms. In addition, surgical resection of a pancreatic NET can prevent pancreatitis and/or biliary obstruction. Ideally, the palliative resections include excision of primary tumor mass and removal of mesenteric nodal burden. Intestinal bypass is another strategy, but this does not address bulky mesenteric lymphadenopathy. The mainstays of medical treatment for symptomatic advanced carcinoid and VIPoma are somatostatin analogs. When carcinoid syndrome symptoms persist with somatostatin analog therapy, or mass effect symptoms worsen, debulking or ablation surgery, as discussed in the above paragraph and in Sect. 11.12.1, may be used to reduce tumor load and provide effective palliation. Interferon a (IFN a) can also offer palliation after somatostatin analog failure. For patients with unresectable disease confined to the liver, liver-directed therapy, such as hepatic artery embolization and radiofrequency ablation (RFA) (discussed at length in Sects. 11.12.4 and 11.12.5, respectively) should be considered for bulky disease, progression, or symptom palliation. A general approach for the therapy of unresectable disease is depicted in Fig. 11.2. In general, NETs respond poorly to conventional chemotherapy. However, two situations are appropriate for the initiation of conventional cytotoxic therapy. High-grade NETs, because of their rapid rate of growth and likely responsiveness to platinum-based chemotherapy, are reasonable candidates for prompt initiation of systemic treatment. The second situation appropriate for cytotoxic therapy in advanced NETs is progressive, symptomatic, metastatic, or unresectable islet cell carcinoma. The University of Texas M. D. Anderson Cancer Center has noted radiographic response rates of nearly 40% in a series of 84 such patients, using a regimen of 5-fluorouracil, doxorubicin, and streptozocin (FAS). Importantly, several patients with radiographic responses in this series became surgical candidates for potentially curative resection after chemotherapy (Kouvaraki et al. 2004).
11.11 Treatment of Resectable Neuroendocrine Tumors Surgery is the only treatment for NETs offering definitive cure. The surgical management of gastrointestinal NETs is dependent on multiple factors. The most important considerations are the site and histology of the primary tumor, the extent of the detectable disease,
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High grade
Platinum-based chemotherapy
FAS chemotherapy or clinical trials
Islet cell NET
Low volume, asymptomatic
Observation or clinical trials
Carcinoid
High volume or symptomatic
octreotide+/-IFN a or HAE/HACE or clinical trials or targeted therapy, off protocol
Progression
Low grade
octreotide+/-IFN a or HAE/HACE or clinical trials or targeted therapy, off protocol
Fig. 11.2 Approach for the therapy of advanced NETs. NET, neuroendocrine tumor. Islet cell, islet cell carcinoma of pancreas. Carcinoid, pulmonary or gastrointestional carcinoid. FAS chemotherapy, 5-fluouroracil, doxorubicin, streptozocin systemic chemotherapy. IFN a interferon a; HAE hepatic artery embolization; HACE hepatic artery chemoembolization. Targeted therapy, see Sect. 11.12.9, “Targeted therapy” for specific single- and double-agent regimens. Modified from Talamonti et al. (2004)
and the clinical presentation of the patient. Types I and II gastric carcinoids measuring less than 2 cm can be removed endoscopically while gastrectomy should be considered for patients with tumors >2 cm. Type III gastric carcinoids have a more aggressive course with a five-year survival less than 50%. Small intestine carcinoids should be managed with resection of the intestinal segment and its associated mesentery due to the risk of nodal involvement even with small tumors. The rest of the intestinal tract should be carefully examined, as 20% of these tumors are accompanied by a second primary malignancy (Memon and Nelson 1997). Appendiceal carcinoid tumors measuring <2 cm can be treated with appendectomy provided they do not display any high-risk features. As discussed in Sect. 11.7.3, larger lesions should be treated with right hemicolectomy. Similarly, carcinoid tumors of the colon and rectum are successfully treated with a formal hemicolectomy adhering to the usual techniques of mesenteric lymphadenectomy as with colon adenocarcinoma. The surgical approach of rectal carcinoids is outlined in Sect. 11.7.4. Noncarcinoid colon NETs (i.e., small cell and large cell neuroendocrine carcinoma) are rare and aggressive and have a worse outcome than colonic adenocarcinomas; patients with these lesions have a median survival of approximately 10 months (Bernick et al. 2004). As such, these patients rarely benefit from resection and are usually treated with chemotherapy.
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11.12 Treatment of Advanced Neuroendocrine Tumors The current goal of treatment of advanced NETs, that is, unresectable or metastatic tumors, is the amelioration of hormone-related symptoms. The reduction of tumor burden is also desirable, but the ultimate aim is palliation of the symptoms. The current standard of care for hormone-related symptom control remains a somatostatin analog, with or without adjunct IFN a. Other therapeutic methods, including systemic chemotherapy, hepatic artery embolization or hepatic artery chemoembolization, and an emerging technology, peptide receptor radionuclide therapy, are occasionally useful. Identifying targeted therapies with the potential to alter the natural history of advanced NET and extend survival remains a key research effort.
11.12.1 Surgical Resection of Hepatic Metastases There are several important considerations in the evaluation of a patient with isolated hepatic metastases of an NET. In general, liver metastases are resectable if two basic criteria are satisfied: (a) all tumors in the liver can be completely resected and (b) an adequate volume (20% of the standardized total liver volume) of liver with adequate biliary drainage, arterial inflow, and venous outflow can be preserved. If the locoregional and hepatic tumor burden is completely resectable, then this is the preferred management of metastatic NETs whether functional or nonfunctional. Hepatic resection is most effective for patients with low-grade NETs (Cho et al. 2008). Unique to functional NETs is the concept of incomplete resection, or “debulking.” Debulking at least 90% of the hepatic tumor burden in patients with functional metastases prolongs survival and improves endocrinopathy-related symptoms (Que et al. 1995). Patients with unresectable hepatic NET metastases may benefit from liver-directed therapies such as RFA (alone or in combination with resection), hepatic artery infusion, bland hepatic artery embolization or hepatic artery chemoembolization; the latter two interventions are discussed in depth in Sect. 11.12.4. Of note, hepatic artery embolization and surgical resection are equally effective in ameliorating pain and symptoms of hormonal excess (Chamberlain et al. 2000).
11.12.2 Somatostatin Analogs Somatostain analogs such as octreotide, depot octreotide, and lanreotide are the “front-line” medications for symptom control of advanced/nonresectable, symptomatic carcinoid and VIPoma; these agents may also have tumor stabilization properties in NETs. Octreotide is an intermediate-acting somatostatin analog that can be administered subcutaneously every 6–12 h. It provides a complete resolution or partial relief of flushing or diarrhea in about 85%
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of patients with carcinoid syndrome, and produces a biochemical response rate of up to 72% (Schnirer et al. 2003). The dose of octreotide varies from 50 to 500 mg, three times a day. Long-acting somatostatin analogs have obviated the need for multiple daily injections in most patients. Depot octreotide (10, 20, and 30 mg) is given intramuscularly once a month (Rubin et al. 1999). An intermediate-acting somatostatin analog should be used to supplement long-acting agents until a steady state is reached. Rarely, sinus bradycardia and cardiac conduction abnormalities have been observed. Caution should be observed in patients with preexisting cardiac disease. Gallbladder stones and sludge may develop with chronic use of somatostatin analogs. Hypoglycemia and, more commonly, hyperglycemia may occur especially among patients with brittle diabetes. Steatorrhea may also occur but can be managed with the use of pancreatic enzymes. Lanreotide is a somatostatin analog more frequently used in Europe than in the United States, and in extended release form, is administered subcutaneously once a month in doses of 60, 90, and 120 mg. Somatostatin analogs may also have cytostatic activity. Stabilization of growing NETs has been reported in nonrandomized phase II studies (Saltz et al. 1993; Arnold et al. 1993). Interim analysis of a phase III, randomized trial of depot octreotide 30 mg monthly in untreated, metastatic carcinoids of the midgut demonstrated significantly increased time to progression (TTP) in treated patients vs. placebo (14.3 vs. 6 months, p < 0.001), though this benefit was restricted to patients with less than 10% hepatic volume replaced by tumor (Arnnold et al. 2009). In addition, an international phase III trial is now under way to test the effect of lanreotide (120 mg, every 28 days) on progression-free survival (PFS) in patients with nonfunctioning NETs. Secondary end points include overall survival at 48 and 96 weeks (Clincaltrials.gov 2006a).
11.12.3 Biotherapy IFN a can induce biochemical response in most patients with carcinoid syndrome (Schnirer et al. 2003). In addition, the combination of octreotide and IFN a may have a synergistic effect on symptom control and biochemical responses in NETs (Janson et al. 1992a, b, 1993; Frank et al. 1999). However, IFN a is much more toxic than somatostatin analogs. Fatigue, fever, anorexia, psychiatric side effects, and weight loss are common. The use of IFN a is usually reserved for patients with symptoms refractory to somatostatin analog-only therapy.
11.12.4 Hepatic Artery Embolization and Hepatic Artery Chemoembolization The liver is the most common metastatic site of NETs, making hepatic artery embolization (HAE) and hepatic artery chemoembolization (HACE) feasible approaches to improve symptom control and reduce metastatic disease burden. These percutaneous catheter-based approaches can also be useful in reducing the volume or hormonal function of liver metastases
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with the intent of then performing a potentially curative resection in a patient who initially presents with “unresectable” disease, or particularly when hormone syndrome depresses performance status such that resection is not feasible on this basis alone. Common embolization agents include gelfoam or polyvinyl alcohol particles; when performed without chemotherapy agents, this process is referred to as “bland embolization.” Chemoembolization employs traditional cytotoxic agents such as cisplatin or doxorubicin along with the above-mentioned nonchemotherapy agents for embolization of arterial flow. To prevent carcinoid crisis, somatostatin analogs should be given before these procedures, which are performed in the inpatient setting. Many patients experience a transient postembolization syndrome, which can include severe abdominal pain, nausea, fever, fatigue, elevation of liver enzymes, and even death. Other major complications are gastrointestinal bleeding, gastric or duodenal ulceration, hepatic abscesses, ischemic necrosis of gallbladder and small intestine, sepsis, renal failure, portal vein thrombosis, arterial thrombosis, and arrhythmias. The efficacies of HAE and HACE for symptom and disease-burden control in metastatic NETs are commonly evaluated in nonrandomized, retrospective studies because of the invasive nature and palliative goals of these procedures. In addition, these studies generally include a significant proportion of patients who have undergone prior systemic chemotherapy as well as previous, concurrent, and subsequent octreotide treatment, further complicating assessment of the clinical benefit of HACE and HAE. In a retrospective, nonrandomized analysis of 81 patients undergoing HAE or HACE at the authors’ institution (The University of Texas M.D. Anderson Cancer Center), radiographic response rate was 67%, median PFS was 19 months, and median overall survival was 31 months. Of note, 63% of patients experienced symptomatic relief post procedure (Gupta et al. 2003). Other series have observed similar results, though sometimes with a higher frequency of symptom control (Bloomston et al. 2007; Ho et al. 2007). The clinical benefit of HACE vs. HAE in metastatic NETs has not been studied in randomized trials. However, a retrospective, nonrandomized analysis of 123 HAE- and HACE-treated patients in follow-up to the study described in the above paragraph demonstrated decreased response rate in carcinoid patients treated with HACE vs. HAE (44 vs. 81%, p < 0.003); differences observed in overall survival (33.8 vs. 33.2 months) and PFS (23.9 vs. 20.9 months) were not statistically significant. However, the same analysis reported statistically insignificant trends toward improved overall survival (31.5 vs. 18.2 months) and radiographic response (50 vs. 25%) in HACE vs. HAE treated islet cell carcinomas (Gupta et al. 2005).
11.12.5 Radiofrequency Ablation RFA involves the application of microwaves to eradicate diseased tissue, or in the case of a patient with advanced NET, specific metastases of the liver. This technique can be applied percutaneously or intraoperatively under ultrasound guidance. RFA has demonstrated some effectiveness in reducing hepatic metastases of less than 4 cm in NET patients (Hellman et al. 2002).
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11.12.6 Additional Symptom Control Methods Carcinoid symptoms may also be controlled or even eliminated by avoiding stress, minimizing tryptophan-rich foods, and supplementing dietary nicotinamide. Medical management of carcinoid symptoms can include bronchodilator for bronchospasm, loperamide or diphenoxylate for frequent, loose bowel movements, and diuretics for fluid overload secondary to valvular dysfunction. A proton pump inhibitor should be used for managing gastric hypersecretion in patients of gastrinoma.
11.12.7 Chemotherapy 11.12.7.1 Effectiveness of Chemotherapy in Carcinoids Carcinoids are resistant to conventional cytotoxic chemotherapy (Strosberg et al. 2008).
11.12.7.2 Effectiveness of Chemotherapy Islet Cell Carcinomas As discussed above in Sect. 11.10, triple agent therapy with FAS has activity in islet cell carcinomas (Kouvaraki et al. 2004). The FAS regimen is typically employed when islet cell carcinoma patients become symptomatic despite octreotide therapy. Scant data exist to support the use of FAS in metastatic carcinoid.
11.12.8 Biochemotherapy The combination of chemotherapy (streptozocin and doxorubicin or 5FU) plus IFN a does not improve response rate in NETs (Saltz et al. 1994; Janson et al. 1992a, b).
11.12.9 Peptide Receptor Radionuclide Therapy Lutetium-labeled octreotate (a derivative of octreotide) via tetraazacyclo-dodecanetetraacetic acid (DOTA) has shown promise in the treatment of advanced NETs. A recent Dutch study of 310 advanced NET patients with significant uptake on [111In-DTPA0octreotide] scintigraphy demonstrated an impressive PFS of 33 months for all patients treated with [177Lu-DOTA0,Tyr3]octreotate (Kwekkeboom et al. 2008).
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11.12.10 Targeted Therapy The identification of effective, molecularly targeted therapy for NETs is an active area of research. Phase II trials of modern molecular targeted therapies as single agents are summarized in Table 11.5; response rates have generally been as low as single-agent trials of older therapies. A study comparing VEGF inhibitor bevacizumab and monthly depot octreotide vs. pegylated IFN a and depot octreotide in 44 patients with metastatic carcinoid demonstrated 95% PFS at 18 weeks in the former vs. 68% in the latter. In addition, an 18% radiographic response was observed in the bevacizumab/depot octreotide arm as compared to no responses in the IFN a depot octreotide arm (Yao et al. 2008b). Inhibition of the VEGF receptor by sunitinib has also shown promise in a recent phase II trial. Kulke et al. reported a 16% overall response rate in advanced islet cell carcinoma as well as a median TTP of 7.7 and 10.2 months in advanced islet cell carcinomas and carcinoids respectively (Kulke et al. 2008). Everolimus or RAD001, an inhibitor of the mammalian target of rapamycin (mTOR), has proven efficacious when combined with octreotide depot. In a recent phase II study of advanced carcinoid and islet cell carcinoma patients, overall response rates of 22% and PFS of 60 weeks were observed (Yao et al. 2008c). Current, ongoing multicenter phase III studies of modern targeted agents’ effect on PFS include: bevacizumab/octreotide vs. IFN a octreotide in advanced carcinoid patients (Clincaltrials.gov 2007a), sunitinib vs. placebo in islet cell carcinoma (Clincaltrials.gov 2007b), everolimus/octreotide vs. placebo/octreotide in advanced carcinoid (Clincaltrials. gov 2006b), and everolimus vs. placebo in islet cell carcinoma (Clincaltrials.gov 2007c). Table 11.5 Phase II trials of targeted, molecular agents in advanced carcinoid and islet cell carcinoma Agent(s) Number Median PFS CR/PR/OR References of patients Bevacizumab + octreotide LAR
22
66 weeks
0/18/18%
Yao et al.( 2008b)
Bortezomib
16
N/A
0/0/0%
Shah et al. (2004)
Everolimus + octreotide LAR
60
60 weeks
0/22/22%
Yao et al. (2008c)
Gefitinib
37
30% at 6 months (carcinoid) 14% at 6 months (islet cell)
0/4/4%
Hobday et al. (2006)
Imatinib
27
24 weeks
0/3/3%
Yao et al. (2007)
Sunitinib
107
10.2 months, carcinoid (TTP) 7.7 months, islet cell (TTP)
0/11/11%
Kulke et al. (2008)
6 months (TTP)
0/5.5/5.5%
Temsirolimus
36
Islet cell: 0/16.7/16.7% Duran et al. (2006)
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11.13 Conclusion The multidisciplinary approach to effective, efficient diagnosis and treatment of patients with localized and advanced NETs is paramount. The care of the patient with localized NET disease requires the expertise of both the surgeon and the pathologist. The advanced NET patient presents the physician with different challenges, and interventional radiologists in addition to medical oncologists have a role to play in symptom control. Unfortunately, the options presently available to the medical oncologist to halt or prolong the natural history of advanced NET disease are limited. However, several ongoing phase III trials address the effectiveness of newer and promising targeted therapies to delay the progression of disease in advanced NET patients. Specific targets include VEGF (bevacizumab), the VEGF receptor (sunitinib), and mTOR (everolimus). Noteably, the clinical utility of several targeted agents is being evaluated both as single-agent therapy and in combination with depot octreotide. In addition, the potential of somatostatin analogs alone to alter the natural history of advanced NETs is the subject of ongoing clinical investigation. This research will hopefully produce an evidence-based strategy, possibly employing targeted therapy and/or somatostatin analogs, to prolong overall survival in patients with advanced NETs.
References Anlauf M, Garbrecht N, Bauersfeld J et al (2007) Hereditary neuroendocrine tumors of the gastroenteropancreatic system. Virchows Arch 451(Suppl 1):S29–S38 Arnnold R, Muller H, Schage-Brittinger C et al (2009) Placebo-controlled, double-blind, prospective, randomized study of the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID study group. J clin Oncol 27(28):4656–4663 Arnold R, Benning R, Neuhaus C et al (1993) Gastroenteropancreatic endocrine tumours: effect of Sandostatin on tumour growth. The German Sandostatin Study Group. Digestion 54:72–75 Berge T, Linell F (1976) Carcinoid tumours. Frequency in a defined population during a 12-year period. Acta Pathol Microbiol Scand A 84:322–330 Bernick P, Klimstra D, Shia J et al (2004) Neuroendocrine carcinomas of the colon and rectum. Dis Colon Rectum 47:163–169 Bhattacharyya S, Toumpanakis C, Caplin ME et al (2008) Analysis of 150 patients with carcinoid syndrome seen in a single year at one institution in the first decade of the twenty-first century. Am J Cardiol 101:378–381 Bloomston M, Al-Saif O, Klemanski D et al (2007) Hepatic artery chemoembolization in 122 patients with metastatic carcinoid tumor: lessons learned. J Gastrointest Surg 11:264–271 Chamberlain R, Canes D, Brown K et al (2000) Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg 190:432–445 Chaudhry A, Papanicolaou V, Oberg K et al (1992) Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system. Cancer Res 52: 1006–1012
322
J.A. Jakob et al.
Cho C, Labow M, Tang L et al (2008) Histologic grade is correlated with outcome after resection of hepatic neuroendocrine neoplasms. Cancer 113:126–134 Clincaltrials.gov (2006a) Phase III, randomised, double-blind, stratified comparative, placebo controlled, parallel group, multi-centre study to assess the effect of deep subcutaneous injections of lanreotide autogel 120 mg administered every 28 days on tumour progression free survival in patients with non-functioning entero-pancreatic endocrine tumour. http://www.clinicaltrials. gov/ct2/show/NCT00353496. Accessed 9 Jan 2009 Clincaltrials.gov (2006b) A randomized, double-blind placebo-controlled, multicenter phase III study in patients with advanced carcinoid tumor receiving octreotide depot and everolimus 10 mg/day or octreotide depot and placebo. http://clinicaltrials.gov/ct2/show/NCT00412061. Accessed 29 May 2009 Clincaltrials.gov (2007a) Phase III prospective, randomized comparison of depot octreotide plus interferon alpha versus depot octreotide plus bevacizumab (NSC #704865) in advanced, poor prognosis carcinoid patients. http://clinicaltrials.gov/ct2/show/NCT00569127. Accessed 29 May 2009 Clincaltrials.gov (2007b) A phase III randomized, double-blind study of sunitinib (SU011248, sutent) versus placebo in patients with progressive advanced/metastatic well-differentiated pancreatic islet cell tumors. http://clinicaltrials.gov/ct2/show/NCT00428597. Accessed 14 May 2009 Clincaltrials.gov (2007c) A randomized double-blind phase III study of RAD001 10 mg/d plus best supportive care versus placebo plus best supportive care in the treatment of patients with advanced pancreatic neuroendocrine tumor (NET). http://clinicaltrials.gov/ct2/show/ NCT00510068. Accessed 29 May 2009 Dierdorf SF (2003) Carcinoid tumor and carcinoid syndrome. Curr Opin Anaesthesiol 16: 343–347 Doherty GM (2005) Rare endocrine tumours of the GI tract. Best Pract Res Clin Gastroenterol 19:807–817 Duran I, Kortmansky J, Singh D et al (2006) A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95:1148–1154 Eriksson B, Bergstrom M, Lilja A et al (1993) Positron emission tomography (PET) in neuroendocrine gastrointestinal tumors. Acta Oncol 32:189–196 Eriksson B, Bergstrom M, Sundin A et al (2002) The role of PET in localization of neuroendocrine and adrenocortical tumors. Ann N Y Acad Sci 970:159–169 Feldman JM (1989) Carcinoid tumors and the carcinoid syndrome. Curr Probl Surg 26:835–885 Feldman J, Lee E (1985) Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid. Am J Clin Nutr 42:639–643 Fendrich V, Langer P, Waldmann J et al (2007) Management of sporadic and multiple endocrine neoplasia type 1 gastrinomas. Br J Surg 94:1331–1341 Frank M, Klose KJ, Wied M et al (1999) Combination therapy with octreotide and alpha-interferon: effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors. Am J Gastroenterol 94:1381–1387 Gupta S, Yao JC, Ahrar K et al (2003) Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience. Cancer J 9:261–267 Gupta S, Johnson MM, Murthy R et al (2005) Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors. Cancer 104: 1590–1602 Hanson MW, Feldman JM, Blinder RA et al (1989) Carcinoid tumors: Iodine-131 MIBG scintigraphy. Radiology 172:699–703 Hellman P, Ladjevardi S, Skogseid B et al (2002) Radiofrequency tissue ablation using cooled tip for liver metastases of endocrine tumors. World J Surg 26:1052–1056
11 Neuroendocrine Cancers
323
Ho AS, Picus J, Darcy MD et al (2007) Long-term outcome after chemoembolization and embolization of hepatic metastatic lesions from neuroendocrine tumors. AJR Am J Roentgenol 188:1201–1207 Hobday T, Holen K, Donehower R et al (2006) A phase II trial of gefitinib in patients (pts) with progressive metastatic neuroendocrine tumors (NET): a phase ii consortium (P2C) study. J Clin Oncol [ASCO Annual Meeting Proceedings] 24:189s Janson EM, Ahlstrom H, Andersson T et al (1992a) Octreotide and interferon alfa: a new combination for the treatment of malignant carcinoid tumours. Eur J Cancer 10:1647–1650 Janson ET, Ronnblom L, Ahlstrom H et al (1992b) Treatment with alpha-interferon versus alphainterferon in combination with streptozocin and doxorubicin in patients with malignant carcinoid tumors: a randomized trial. Ann Oncol 3:635–638 Janson ET, Kauppinen HL, Oberg K (1993) Combined alpha- and gamma-interferon therapy for malignant midgut carcinoid tumors. A phase I-II trial. Acta Oncol 32:231–233 Kim DH, Nagano Y, Choi IS et al (2008) Allelic alterations in well-differentiated neuroendocrine tumors (carcinoid tumors) identified by genome-wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors. Genes Chromosomes Cancer 47:84–92 Kouvaraki MA, Ajani JA, Hoff P et al (2004) Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22:4762–4771 Krenning EP, Kooij PPM, Bakker WH et al (1994) Radiotherapy with a radiolabeled somatostatin analogue, [111In-DTPA-D-Phe1]-octreotide. Ann N Y Acad Sci 733:496–506 Krishnamurthy S, Dayal Y (1997) Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor receptor in gastrointestinal carcinoids. Am J Surg Pathol 21:327–333 Kulke MH, Lenz HJ, Meropol NJ et al (2008) Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26:3403–3410 Kulke MH, Bergsland EK, Yao JC (2009) Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med 360:195–197 Kwaan M, Goldberg J, Bleday R et al (2008) Rectal carcinoid tumors: review of results after endoscopic and surgical therapy. Arch Surg 143:471–475 Kwekkeboom DJ, de Herder WW, Kam BL et al (2008) Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 26:2124–2130 Kytola S, Hoog A, Nord B et al (2001) Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids. Am J Pathol 158:1803–1808 Memon M, Nelson H (1997) Gastrointestinal carcinoid tumors: current management strategies. Dis Colon Rectum 40:1101–1118 Modlin IM, Lye KD, Kidd M (2003) A 5-decade analysis of 13,715 carcinoid tumors. Cancer 97:934–959 Moertel CG, Sauer WG, Docherty MB et al (1961) Life history of the carcinoid tumor of the small intestine. Cancer 14:291–293 NCCN (2009) Neuroendocrine tumors. http://www.nccn.org/professionals/physician_gls/PDF/ neuroendocrine. Accessed 12 Dec 2009 Nilsson O (1996) Gastrointestinal carcinoids – aspects of diagnosis and classification. APMIS 104:481–492 Que F, Nagorney D, Batts KP et al (1995) Hepatic resection for metastatic neuroendocrine tumors. Am J Surg 169:36–42 Rubin J, Ajani J, Schirmer W et al (1999) Octreotide acetate long-acting formulation versus openlabel subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 17: 600–606
324
J.A. Jakob et al.
Sakai H, Kodaira S, Ono K et al (1993) Disseminated pancreatic polypeptidioma. Intern Med 32:737–741 Saltz L, Trochanowski B, Buckley M et al (1993) Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors. Cancer 72:244–248 Saltz L, Kemeny N, Schwartz G et al (1994) A phase II trial of alpha-interferon and 5-fluorouracil in patients with advanced carcinoid and islet cell tumors. Cancer 74:958–961 Schnirer II, Yao JC, Ajani JA (2003) Carcinoid – a comprehensive review. Acta Oncol 42:672–692 Schonfeld WH, Eikin EP, Woltering EA et al (1998) The cost-effectiveness of octreotide acetate in the treatment of carcinoid syndrome and VIPoma. Int J Technol Assess Health Care 14:514–525 Shah MH, Young D, Kindler HL et al (2004) Phase II study of the proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors. Clin Cancer Res 10:6111–6118 Stinner B, Rothmund M (2005) Neuroendocrine tumours (carcinoids) of the appendix. Best Pract Res Clin Gastroenterol 19:729–738 Strosberg JR, Nasir A, Hodul P et al (2008) Biology and treatment of metastatic gastrointestinal neuroendocrine tumors. Gastrointest Cancer Res 2:113–125 Talamonti M, Stuart K, Yao J (2004) Neuroendocrine tumors of the gastrointestinal tract: how aggressive should we be? In: Perry M (ed) American society of clinical oncology 2004 education book. American Society of Clinical Oncology, Alexandria, pp 206–215 Tamm EP, Kim EE, Ng CS (2007) Imaging of neuroendocrine tumors. Hematol Oncol Clin North Am 21:409–432, vii Terris B, Scoazec JY, Rubbia L et al (1998) Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology 32:133–138 Tonnies H, Toliat MR, Ramel C et al (2001) Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation. Gut 48:536–541 Toumpanakis CG, Caplin ME (2008) Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Am J Gastroenterol 103:729–732 Tucker ON, Crotty PL, Conlon KC (2006) The management of insulinoma. Br J Surg 93: 264–275 Vinik AI, Thompson N, Eckhauser F et al (1989) Clinical features of carcinoid syndrome and the use of somatostatin analogue in its management. Acta Oncol 28:389–402 Wang AY, Ahmad NA (2006) Rectal carcinoids. Curr Opin Gastroenterol 22:529–535 Wang L, Ignat A, Axiotis C (2002) Differential expression of the PTEN tumor suppressor protein in fetal and adult neuroendocrine tissues and tumors: progressive loss of PTEN expression in poorly differentiated neuroendocrine neoplasms. Appl Immunohistochem Mol Morphol 10:139–146 Yang Y, Hua X (2007) In search of tumor suppressing functions of menin. Mol Cell Endocrinol 265–266:34–41 Yao JC, Zhang JX, Rashid A et al (2007) Clinical and in vitro studies of imatinib in advanced carcinoid tumors. Clin Cancer Res 13:234–240 Yao JC, Hassan M, Phan A et al (2008a) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063–3072 Yao JC, Phan A, Hoff PM et al (2008b) Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol 26:1316–1323 Yao JC, Phan AT, Chang DZ et al (2008c) Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 26:4311–4318
Colon Cancer
12
Sharlene Gill, Carl Brown, Robert Miller, and Oliver Bathe
12.1 Introduction Cancers of the colon represent the third leading cause of neoplasia-related morbidity and mortality in the United States and Canada (Committee CCSS 2009; Jemal et al. 2009). The lifetime risk for colon cancer is estimated to be 1 in 20 persons, with a median age of diagnosis of 71 years (Jemal et al. 2009). Over the past three decades, the overall incidence of colon cancer has diminished slightly by 2.2% in women and 2.8% in men (Jemal et al. 2008), yet there has been an increasing relative incidence of proximal, particularly cecal, colonic adenocarcinoma (Troisi et al. 1999). While this is partly explained by increased endoscopic screening, the etiology of this proximal shift is not entirely understood. Encouragingly, 5-year survival rates have notably improved over this time period, from 52% in 1975 to 65% in 2004 (Jemal et al. 2009). In metastate disease, 5-year survival has improved from 9% in 2000 to 19% in 2006 (Kopetz et al. 2009)
12.2 Pathogenesis, Pathology and Prognosis Four major anatomic divisions of the colon have been defined: (1) the right colon, subdivided into the cecum (intraperitoneal and measuring about 6 × 9 cm) and the ascending S. Gill (*) Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada e-mail:
[email protected] C. Brown Colorectal Surgery, St. Paul’s Hospital, Vancouver, BC, Canada R. Miller Radiation Oncology, Mayo Clinic, Rochester, MN, USA O. Bathe Surgical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_12, © Springer-Verlag Berlin Heidelberg 2011
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Table 12.1 World Health Organization classification of colorectal carcinoma Adenocarcinoma Medullary carcinoma Mucinous (colloid) adenocarcinoma (>50% mucinous) Signet ring cell carcinoma (>50% signet ring cells) Squamous cell (epidermoid) carcinoma Adenosquamous carcinoma Small-cell (oat cell) carcinoma Undifferentiated carcinoma Other (e.g., papillary carcinoma)
colon (retroperitoneal and measuring 15–20 cm long); (2) the middle (transverse) colon; (3) the left (descending) colon, and (4) the sigmoid colon, originating at the mesosigmoid and terminating at the rectum (Compton 2003). The overwhelming majority of colon cancers are adenocarcinomas with other histologies rarely occurring (Table 12.1). Based upon limited data, signet ring cell and small-cell histologies are considered unfavorable, and medullary and mucinous carcinomas are considered favorable, but the true independent prognostic impact of histology subtype alone remains unclear. In addition, the presence of tumor lymphatic or vascular invasion has been associated with poor prognosis on univariate analysis; however, in multivariate analyses, the significance has been uncertain (Compton et al. 2000a, b). On the other hand, histologic grade has been shown to have stage-independent prognostic value in a number of analyses (Compton et al. 2000b; Gill et al. 2004) with high-grade disease (defined as poorly differentiated or undifferentiated), associated with inferior outcomes. Likewise, the presence of perineural invasion is a significant adverse prognostic feature but, unfortunately, this is often inconsistently reported in colon cancer pathology reports (Liebig et al. 2009). Of increasing interest in recent years is the evaluation of molecular determinants of prognosis. The multistep progression of colon carcinogenesis from an adenoma to a carcinoma, as originally defined by Fearon and Vogelstein (1990), is characterized by the development of genomic instability wherein DNA integrity is compromised. The major known mechanisms of genomic instability are chromosomal and microsatellite. The pathway of chromosomal instability (CIN), also known as the “suppressor” pathway, represents the more common pathway of genomic instability and is characterized by sequential inactivation of tumor-suppressor genes, such as APC (located on chromosome 5q), p53 (chromosome 17p), and DCC (chromosome 18q) through widespread loss of heterozygosity (LOH) and by gain-of-function mutations, resulting in activation of oncogenes such as RAS (Kinzler and Vogelstein 1996; Lengauer et al. 1997). The less common second pathway of microsatellite instability (MSI), also known as the “mutator” pathway, is observed in 15–20% of colon cancers and is associated with defects in DNA mismatch repair. This can be due to germline mutations in genes involved the mismatch repair genes (hMLH1, hMSH2, hMSH6, or PMS2) which characterize hereditary Lynch syndrome (previously known as Hereditary
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Nonpolyposis Colon Cancer or HNPCC), or, more commonly, may arise in sporadic colon cancers from inactivation of hMLH1 due to a CpG Island Methylator Phenotype (CIMP) associated with epigenetic instability from aberrant promoter hypermethylation with consequent transcriptional silencing (Liu et al. 1995, 1996; Lynch and Smyrk 1996; Goel et al. 2003). Sporadic CRCs with evidence of hMLH1 promoter hypermethylation have also been found to commonly carry a V600E mutation in the BRAF gene (Bessa et al. 2008). Clinicopathologic differences have been identified in the phenotypes of these two pathways. Tumors with high levels of microsatellite instability-high (MSI-H) are more likely to arise from the proximal colon, are more common in females and, pathologically, associated with poor differentiation, mucinous features, node-negative status and prominent lymphocytic infiltration (Rodriguez-Bigas et al. 1997; Thibodeau et al. 1993). Elucidation of these pathways has led to the identification of a number of putative prognostic molecular markers in colon cancer. Unfortunately, these advances have yielded few clinically validated biomarkers which may be used in practice to inform current-day treatment decision making. One such potential marker is 18q LOH, which has been implicated as a negative prognostic feature, particularly in stage II. However, results from several retrospective analyses have been inconsistent, and its use as a prognostic marker is not presently recommended outside of clinical trials (Jen et al. 1994; Popat et al. 2005, 2007; Ogino et al. 2009a). Likewise, mutation of the KRAS oncogene was previously believed to be associated with a poor prognosis however, recent studies have failed to demonstrate any prognostic utility to KRAS status (Ogino et al. 2009b; Roth et al. 2010). In contrast, MSI-H has been demonstrated as an independent favorable prognostic feature in early stage colon cancer in a number of retrospective studies (Thibodeau et al. 1993; Popat et al. 2005; Watson et al. 1998). A systematic review of 32 studies including 1,277 colorectal cancers with MSI found a combined hazard ratio (HR) estimate for overall survival (OS) of 0.65 (95% confidence interval [CI], 0.59–0.71) (Popat et al. 2005). Despite the interest in MSI status as a prognostic marker, the 2006 American Society of Clinical Oncology guidelines update on the use of tumor markers for gastrointestinal cancers do not endorse the use of MSI as a prognostic marker in clinical practice, citing the largely retrospective nature of the available data (Locker et al. 2006). The use of biomarkers as predictive factors to determine efficacy of treatment is discussed later in this chapter.
12.3 Risk Factors for Colon Cancer 12.3.1 Inherited Predisposition Family history of CRC in a first-degree relative is an important risk factor and accounts for up to 20% of all affected patients. The relative risk (RR) associated with a single firstdegree relative with adenomas is 1.74 (95% CI 1.24–2.45) over that of the general population (Ahsan et al. 1998). Fewer than 10% of colon cancers are associated with a true inherited polyposis-related predisposition. The most common hereditary colorectal cancers
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are Lynch syndrome and familial adenomatous polyposis (FAP). Less well-known are the hamartomatous polyposis syndromes, including Peutz-Jeghers syndrome, Cowden syndrome and Juvenile Polyposis. Management of inherited syndromes must not only address the management and surveillance of an affected individual but also the identification and management of family members not yet affected. Lynch Syndrome is an autosomal dominant syndrome caused by a germline mutation in one of the genes involved in DNA mismatch repair and accounts for up to 3% of all CRC. It is molecularly characterized by MSI and clinically characterized by early-onset proximal colon cancers (median age 45 years), and extracolonic neoplasms such as endometrial, transitional cell carcinoma of the ureter and renal pelvis, small bowel, gastric, ovarian, pancreatic and biliary cancers (Lynch et al. 2009). The accepted clinical criteria for diagnosis are known as the Amsterdam Criteria (Vasen et al. 1999) and the criteria to identify affected high-risk individuals who may benefit from MSI testing are known as the Bethesda Guidelines (Laghi et al. 2004) (Table 12.2). Immunohistochemistry for protein expression of the MMR gene products (particularly for MSH2 and MLH1) have demonstrated high sensitivity and specificity for the MSI phenotype and are widely accepted as an initial step for Lynch screening (Lindor et al. 2002). Patients who fulfill Bethesda guidelines with MSI-H tumors would be offered genetic counseling and germline testing for MMR gene mutations (Lynch et al. 2007). Subtotal colectomy is recommended in affected mutation-carriers undergoing surgical resection of a colorectal cancer but the role of prophylactic colectomy in unaffected mutationcarriers is controversial (Lindor et al. 2006). Prophylactic hysterectomy and oophorectomy, on the other hand, is supported by the available evidence (Schmeler et al. 2006). Table 12.2 Lynch syndrome clinical criteria Amsterdam II criteria for diagnosis (Vasen et al. 1999) At least three relatives with an hereditary nonpolyposis colorectal cancer (HNPCC)-associated cancer (colorectal cancer, endometrial, stomach, ovary, ureter/renal pelvis, brain, small bowel, hepatobiliary tract, and skin [sebaceous tumors]):
One is a first-degree relative of the other two At least two successive generations affected At least one of the syndrome-associated cancers should be diagnosed at <50 years of age FAP should be excluded in any colorectal cancer cases Tumors should be verified whenever possible
Bethesda guidelines for tumor MSI testing (Laghi et al. 2004) Colorectal cancer diagnosed in a patient who is <50 years of age Presence of synchronous or metachronous colorectal, or other syndrome-associated tumorsa regardless of age Colorectal cancer with microsatellite instability-high (MSI-H) histology diagnosed in a patient who is <60 years of age Colorectal cancer or syndrome-associated tumor diagnosed under age 50 years in at least one first-degree relative Colorectal cancer or syndrome-associated tumor diagnosed at any age in two first- or second-degree relatives (HNPCC)-associated tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, gliomas (in Turcot’s syndrome) sebaceous gland adenomas and keratoacanthomas (in Muir-Torre syndrome), and carcinoma of the small bowel a
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FAP is an autosomal dominant syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene and accounts for less than 1% of all CRCs. It is characterized by literally thousands of early-onset colorectal polyps with 100% penetrance for colorectal cancer, in addition to extracolonic manifestations of hypertrophy of the retinal pigment epithelium, osteomas, sebaceous and epidermoid cysts, and desmoids tumors (Gardner’s syndrome) (Kinzler and Vogelstein 1996). FAP carries an increased risk of adenocarcinomas of the duodenum, jejunum, pancreas and biliary tree in addition to thyroid cancers and gliomas (associated with Turcot’s syndrome) (Offerhaus et al. 1992). Variants include an attenuated, later-onset variant of FAP (AFAP) and a recessively inherited MUTYH-associated polyposis (MAP). Guidelines recommend APC genetic testing for FAP in all patients with clinical evidence of greater than 100 colorectal adenomas, and for all first-degree relatives of FAP patients (Giardiello et al. 2001). The surgical management of FAP is dictated by prophylactic total colectomy. Chemoprevention with COX2 inhibitors may play a role in preventing the progression of duodenal adenomas (Phillips et al. 2002). Peutz-Jeghers syndrome is a rare autosomal dominant disorder involving mutations in a gene encoding STK-11, a serine threonine kinase, and is characterized by multiple hamartomatous polyps throughout the gastrointestinal tract, and hyperpigmented lesions affecting the buccal mucosa and lips. It is associated with increased risk of multiple cancers including the colorectum, small intestine, stomach, pancreas, breast, lung, ovary, and endometrium (Giardiello et al. 2000). Management is directed at intensive screening for at-risk first-degree relatives and surveillance for affected patients (Giardiello and Trimbath 2006).
12.3.2 Inflammatory Bowel Disease The association between inflammatory bowel disease, particularly ulcerative colitis, and CRC is well accepted. Based upon retrospective cohort analyses, left-sided disease is associated with a threefold increase in cancer risk and pan-colitis renders an almost 15-fold increase in risk beginning about 8 years after initial diagnosis (Ekbom et al. 1990; Greenstein et al. 1979). This risk is further magnified in the presence of primary sclerosing cholangitis (Brentnall et al. 1996) and pseudopolyps (Velayos et al. 2006). A similar magnitude increased risk is implicated for Crohn’s colitis but this is a much less common presentation (Gillen et al. 1994). Annual surveillance colonoscopy with random biopsies has been recommended after 8 years of colitis, with colectomy recommended in the presence of high grade dysplasia (Winawer et al. 2003).
12.3.3 Acquired Risk Factors Sporadic colon cancer accounts for over 65% of all new diagnoses. There is a 25-fold variation in the incidence of colon cancers worldwide with lower incidences in Asia and Africa relative to North America, Western Europe and Australia (Parkin et al. 2005). This
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geographic variability has fueled interest in the role of dietary and lifestyle factors in colon carcinogenesis. The available evidence supporting the role of diet patterns and physical activity is largely retrospective and hence ascertainment of a causative role has been problematic. The association between a Western diet, namely a diet low in fruits and vegetables and high in red meat and animal fat, has been the subject of numerous cohort studies yet remains contentious. In a pooled analysis including over 14 studies with more than 750,000 participants, fruit and vegetable intake was associated with a 26% relative reduction in risk of distal colon cancers, but not with overall colon cancer risk (Koushik et al. 2007). Similarly, high intake of red and processed meat has been associated with an increased risk of distal colon cancers (Larsson et al. 2005; Chao et al. 2005) but these findings have not been consistently reproducible. Dietary fiber has been postulated to be protective by absorbing fecal carcinogens, altering bile acid metabolism and reducing colonic transit time (Kritchevsky 1995). Despite cohort studies supporting an association, a systematic review of five randomized trials evaluating dietary fiber for prevention of colorectal cancers demonstrated no evidence of reduced risk of colorectal adenomas with increased fiber intake (Asano and McLeod 2002). Folic acid, a water-soluble vitamin of the B family, is essential for DNA synthesis and DNA methylation. Since it cannot be endogenously synthesized, it must be provided in the diet with major sources including citrus fruits, dark-green vegetables and dried beans. In a Nurses’ Health Study, folate intake exceeding 400 mg/day (from supplements and food) was associated with a 31% reduced risk for colon cancer – this reduction became statistically significant after 15 years of use (Giovannucci et al. 1998). However, two subsequent controlled trials unfortunately failed to demonstrate a reduced risk of colorectal adenomas with an intervention of folic acid supplementation and, in fact, one study suggested an increased risk of adenomas (Cole et al. 2007; Logan et al. 2008). The epidemiologic evidence supporting the benefit of physical activity and reduced risk of colon cancer is more robust. The biologic rationale is underscored by the mitogenic potential of hyperinsulinemia which is directly related to lack of physical activity, central adiposity and high body mass index (Giovannucci 1995). Moreover, insulin-like growth factors have also been linked to cellular proliferative and antiapoptotic effects (Aaronson 1991). In a metaanalysis of 52 studies examining physical activity in primary prevention of colorectal cancer, there was a 24% RR reduction of colon cancer when comparing the most vs. the least active individuals across all studies (RR 0.76, 95% CI 0.72–0.81) (Wolin et al. 2009).
12.4 Screening Symptoms of colon cancer (i.e., bleeding, obstruction) typically occur in the later stages of the natural history of the disease, particularly in proximal colon cancer. Furthermore, colon cancer mortality is mostly influenced by the stage of the disease at diagnosis; 5-year mortality in stage I disease is less than 10%, whereas stage IV colon cancer has a greater than
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90% 5-year mortality. Thus, identifying colon cancers prior to the development of symptoms is critical in reducing mortality. Conventional principles of screening encompass the following:
• Natural history, where the disease can be identified at an earlier, more easily treatable stage
• Safe, cost effective and acceptable screening measures that is sensitive and specific • Treatment must be acceptable to most patients • Disease must have a prevalence that is significant In colon cancer, all of these principles apply. Currently, there are two different classes of screening modalities for identifying colon cancers and advanced adenomas: indirect and direct. Indirect modalities include fecal occult blood testing (FOBT) and fecal immunochemistry tests (FIT). Direct modalities include flexible sigmoidoscopy (FS), colonoscopy, double contrast barium enema (DCBE), and computed tomography colonography (CTC).
12.4.1 Fecal Occult Blood Test The conceptual basis of the FOBT is that a colon cancer (or advanced polyp) is more likely to bleed than healthy mucosa. While there are several variants of the FOBT, they are all guaiac-based tests that test for peroxidase activity. Other substances with peroxidase or pseudoperoxidase (e.g., red meat, some fruits) can cause false positive test results. Similarly, common drugs that can cause mucosal irritation and bleeding, like nonsteroidal antiinflammatory drugs (NSAIDs) can also lead to a false positive test. Vitamin C can interfere with peroxidase activity, leading to the possibility of false negative tests in patients consuming large amounts of vitamin C. As cancers may bleed intermittently, the sensitivity of the test can be increased by taking more than a single sample over time. Typically, two samples are taken from three consecutive bowel movements. The sensitivity increases with each additional sample tested. Furthermore, the chances of finding an advanced neoplastic polyp are 23% with one positive test and over 50% with three positive tests (Lieberman and Weiss 2001). FOBT is recommended as either a yearly or biennial screening test in patients over age 50 years old. Hewitson et al. performed a metaanalysis of four randomized controlled trials comparing screening with annual FOBT with no screening and concluded that this strategy results in a 16% reduction in CRC mortality (RR 0.84, 95% CI 0.78–0.90) (Hewitson et al. 2008). Similarly, there was a 15% RR reduction (RR 0.85, 95% CI 0.78– 0.92) in CRC mortality for studies that used biennial screening. Furthermore, when adjusted for only those individuals who attended at least one round of screening, there was a 25% RR reduction (RR 0.75, 95% CI 0.66–0.84). However, there was no difference in all-cause mortality (RR 1.00, 95% CI 0.99–1.02) or all-cause mortality excluding CRC (RR 1.01, 95% CI 1.00–1.03).
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12.4.2 Fecal Immunochemistry Tests FIT tests are antibody based tests that are designed to identify human hemoglobin, globin or other blood components. Thus, dietary restrictions are unnecessary. Furthermore, some of these tests use automated devices to interpret the tests, eliminating human error. A recent review evaluated nine cohort studies and estimated the sensitivity of FIT for an advanced neoplasia to be 61–91% and specificity 91–98% (Whitlock et al. 2008). While the sensitivity is better than conventional FOBT (25–38%), the specificity of FIT is a little lower than the 98–99% reported for most guaiac based tests. However, optimized FOBT with specimen rehydration appears to have similar sensitivity and specificity as FIT (Levin et al. 2008). In summary, FIT may have better test characteristics than guaiac based FOBTs. Even though it has not been tested in large randomized controlled studies, it can be considered a reasonable alternative to FOBT.
12.4.3 Barium Enema While single contrast barium enema may detect tumors, it is substantially less sensitive than DCBE and should not be recommended. Patients must have complete colon preparation prior to the procedure. The radiologist uses a flexible rectal catheter to infuse barium followed by pressurized air to coat the bowel wall with barium. The test can take up to 1 h to complete and can be uncomfortable for the patient. The risk of colonic perforation is 1 in 25,000. Current literature would suggest the sensitivity of DCBE to identify lesions ³1 cm ranges from 48 to 70% (Canon 2008). All DCBE tests that demonstrate a suspicious finding mandate a subsequent colonoscopy for confirmation of a lesion, polyp removal and/or biopsy. False positive tests, caused by large haustral folds or retained stool, occur in up to 10% of patients. DCBE does not evaluate the very distal rectum well, because of the infusion catheter placement and difficulties in imaging the low pelvis. Thus, it is often recommended in the combination with FS for screening purposes. This strategy for CRC screening has never been tested in a controlled trial for mortality reduction. In the era of CTC, the role of DCBE has been questioned. Currently, DCBE is used predominantly in patients who have an incomplete colonoscopy rather than screening (Ferrucci 2006). Furthermore, radiologists are more confident interpreting CTC than DCBE. Thus, as CTC becomes more available, DCBE will likely be abandoned.
12.4.4 CT Colonography CTC, also known as “virtual” colonoscopy, involves thin slice (~1 mm) CT scanning of the abdomen. The patient must perform full bowel preparation prior to the procedure and the radiologist must infuse air via a flexible rectal catheter to distend the colon for evaluation.
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Whitlock et al. summarized the results of two recent large studies evaluating 3,751 patients (Whitlock et al. 2008). They demonstrated that pooled sensitivity for large adenomas (³1.0 cm) in these two studies was 92% (CI, 87–96%), with no statistical heterogeneity detected between the studies (I2 = 0%; p = 0.42). A metaanalysis of CTC (n = 6,393) demonstrated a slightly lower sensitivity of 85% (CI, 79–91%) for polyps >9 mm and specificity of 97% (CI, 96–97%) (Mulhall et al. 2005). This is similar to sensitivities reported for colonoscopic examination. The risk of bowel perforation from air infusion is likely similar to DCBE. The risk of radiation in these patients is unclear, but in patients over 50 years old undergoing CTC for surveillance the risk of radiation related malignancy is certainly less than 0.1%. CTC can demonstrate unexpected extracolonic findings in up to 50% of patients. While this may lead to early treatment of diseases unrelated to colon cancer, it is also possible that the investigation of these abnormalities may lead to complications (e.g., bleeding after percutaneous biopsy). While there are no controlled clinical trials demonstrating reduced disease specific or overall mortality with CTC, it is likely to supplant DCBE as a colon cancer screening modality.
12.4.5 Flexible Sigmoidoscopy FS is the simplest direct method for screening of colon cancer. The patient prepares for the test by utilizing one or two packages of phospha-soda enemas, instilled per rectum and the test requires no sedation. The endoscopist then inserts the colonoscope and advances it to at least 40 cm from the anal verge to be considered a “complete” FS. However, depending on the length of the colon, this may reach as far as the distal transverse colon, or as distal as the proximal sigmoid colon. Sensitivity of FS has been estimated at 70% for detection of all adenomas (Hakama et al. 2005). This implies that approximately 20% of adenomas occur in the proximal colon and up to 10% of polyps would be missed with either FS or colonoscopy. Two large trials have demonstrated an increased risk of proximal adenoma that warrants colonoscopic evaluation in all patients discovered to have a distal adenoma (Lieberman and Weiss 2001; Imperiale et al. 2000). In a population-based study, Rabenek et al. identified 39,762 patients who had an FS for apparent screening. The authors demonstrated a significantly lower incidence of colorectal cancer for up to 7 years after the investigation when compared to a similar unscreened population (Rabeneck et al. 2008). Similarly, Lieberman and Weiss demonstrated that FOBT and FS in combination can detect 75.8% of patients with an advanced adenoma or cancer (Lieberman and Weiss 2001). Most recently, in the UK, FS randomized controlled screening trial, a single FS offered between the ages of 55 and 64 years reduced the incidence of CRC by 23% (HR 0.77, 95% CI 0.70–0.84) and remarkably reduced the mortality by 31% (HR 0.69, 95% CI 0.59–0.82) (Atkin et al. 2010). While FS is more sensitive than FOBT alone, it is also riskier (1 in 20,000 risk of bowel perforation). Furthermore, patient attendance in several large studies has ranged from 40 to 49%, implying that it is less acceptable to patients than FOBT.
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12.4.6 Colonoscopy Colonoscopy involves direct endoscopic evaluation of the entire colon, from the cecum to the anus. It is the only screening modality that allows evaluation, prevention (via endoscopic polypectomy), and diagnosis (via biopsy) for CRC. A complete bowel cleansing is required the evening prior to the test and sedation is typically used. Colonoscopy is the gold standard by which other screening modalities are measured, so determining the sensitivity of colonoscopy is a challenge. However, two studies of patients undergoing back to back colonoscopies suggest that polyps bigger than 1 cm can be missed in 6–14% of patients (Heresbach et al. 2008; Rex et al. 1997). However, the “miss” rate of invasive cancer is considered to be much lower than 10%. There is evidence to suggest that prolonging the withdrawal time by at least 6 min during colonoscopy can improve neoplasia detection rates (Barclay et al. 2006). Furthermore, there are several technical maneuvers that can reduce miss rates (Rex 2006). Thus, colonoscopy screening should be performed by experienced surgeons and gastroenterologists in a center where there are clear performance benchmarks. Despite the possibility of missed lesions, a completed colonoscopy has been demonstrated to reduce the risk of death from colon cancer by nearly 50% in large case controlled studies (Baxter et al. 2009; Mulier et al. 2005). However, no prospective trials have been conducted to confirm this mortality benefit. Colonoscopy has the highest risk of complication among the available screening modalities. A recent population based study of 97,091 colonoscopies in patients 50–75 years old demonstrated the risk of bleeding was 1.64 per 1,000 and the risk of perforation was 0.85 per 1,000 (Rabeneck et al. 2008). The risk of death was 1 in 14,000.
12.4.7 Current Screening Recommendations In 2008, the American Cancer Society, in collaboration with the US Multi Society Task Force on Colorectal Cancer and the American College of Radiology, updated their guidelines for screening and surveillance for colorectal cancer and adenomatous polyps (see Table 12.3) (Levin et al. 2008). Presently, less than 30% of eligible patients in the United States are being screened for colorectal cancer (Klabunde et al. 2007). Clearly, physician and patient education initiatives are necessary to ensure that patients have access to this potentially life-saving practice.
12.5 Staging Colonoscopy remains the most commonly utilized diagnostic evaluation. It offers the opportunity to identify and biopsy colonic lesions, as well as to identify synchronous
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12 Colon Cancer Table 12 3 Current guidelines for colorectal cancer screening Risk category Recommended Average risk
Interval
FOBT FIT Flexible sigmoidoscopy to 40 cm or splenic flexure DCBE CT colonography Colonoscopy
Annual Annual Every 5 years
Colonoscopy Colonoscopy
5–10 years 3 years
Colonoscopy Colonoscopy
<3 years 3–6 months
Previous history of colon cancer Perioperative
Colonoscopy
Postoperative
Colonoscopy
Prior to surgery or within 6 months after surgery 1 year after perioperative colonoscopy Subsequent evaluations should be at 3 years and then 5 years, if all evaluations are normal
Every 5 years Every 5 years Every 10 years
Increased risk Previous history of polyp 1–2 small tubular adenomas 3–10 small adenomas or 1 adenoma >1 cm or Polyp with villous or high grade dysplasia >10 adenomas Sessile adenomas removed piecemeal
Family history of colorectal cancer or adenomatous polyps One first degree relative who developed Colonoscopy at neoplasia <60 years old, or ³2 first degree relatives who developed 40 years old or neoplasia at any age 10 years younger than the One first degree relative who developed neoplasia ³60 years old, or ³2 second degree relatives who developed cancer at any age High risk Genetic or suspected diagnosis of FAP
youngest relative with colorectal cancer Any screening modality used in patients with average risk
Flexible sigmoidoscopy at 10–12 years old
5 years
5 years
Annual
(continued)
336 Table 12.3 (continued) Risk category Genetic or suspected diagnosis of HNPCC
Chronic ulcerative colitis or Crohn’s disease
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Recommended
Interval
Colonoscopy Age 20–25 years old or 10 years younger than youngest family member at diagnosis Colonoscopy with biopsies for dysplasia
Annual or Biennial
Annual or Biennial
FOBT fecal occult blood test; FIT fecal immunochemistry test; DCBE double contrast barium enema; FAP familial adenomatous polyposis; HNPCC hereditary nonpolyposis colorectal cancer
malignancies or polyps. Once the diagnosis is confirmed, an accurate staging assessment is required. Stage of disease at diagnosis remains the strongest predictor of CRC survival and defines the clinical management strategy. The tumor, node, metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) is the recognized standard for CRC staging and is widely used at the bedside and by regional and national tumor registries in the US and Canada. The application of a uniform staging assessment allows for the evaluation of population-based treatment effects and outcomes. In the TNM system, pathologic staging (designated with the prescript “p”) is derived from resection specimens of the primary tumor, and is considered the most accurate assessment of local disease. Clinical classification (designated by the prescript “c”) is based upon clinical evaluation which may include physical examination, radiologic imaging and surgical exploration. The AJCC released the seventh edition of the Staging Manual in 2010 (AJCC 2010). As illustrated in Table 12.4, notable changes from the sixth edition included the further subdivision of stage II and III colon cancer, based upon new survival and relapse data (Gunderson et al. 2010), subclassification of M1 disease to differentiate single vs. multiple metastatic sites and a recommendation to include expanded reporting of pathologic and molecular prognostic features including the presence of perineural invasion, MSI and KRAS gene analysis.
12.6 Clinical Management 12.6.1 Malignant Polyps Adenomatous polyps occur in close to 20% of adults over the age of 60 years old who live in western countries (Correa 1978). Most of these premalignant adenomatous polyps are amenable to endoscopic removal for definitive treatment. Colonoscopic removal of these polyps has been shown to reduce the risk of colon cancer. However, up to 5% of polyps that appear grossly benign will contain invasive cancer (O’Brien et al. 1990). The risk of cancer correlates to the size of the polyp (see Table 12.5).
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12 Colon Cancer Table 12.4 TNM staging classification for cancers of the colon and rectum, AJCC (2010) Primary tumor (T) Tx T0 Tis T1 T2 T3 T4a T4b
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ: intraepithelial or invasion of lamina propria Tumor invades submucosa Tumor invades muscularis propria Tumor invades through the muscularis propria into pericolorectal tissues Tumor penetrates to the surface of the visceral peritoneum Tumor directly invades or is adherent to other organs or structures
Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1a Metastasis in one regional lymph node N1b Metastasis in 2–3 regional lymph nodes N1c Tumor deposit(s) in the subserosa, mesentery or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis N2a Metastasis in 4–6 regional lymph nodes N2b Metastasis in seven or more regional lymph nodes Distant metastasis (M) M0 No distant metastasis M1 Distant metastasis M1a Metastasis confined to one organ or site (e.g., liver, lung, ovary, nonregional node) M1b Metastases in more than one organ/site or the peritoneum Staging classification 0 I IIA IIB IIC IIIA IIIB
IVA IVB
Tis T1–T2 T3 T4a T4b T1–T2 T1 T4a T3–T4a T4b Any T Any T
N0 N0 N0 N0 N0 N1a–N1c N2a N2a N2b N1–N2 Any N Any N
M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1a M1b
Pathologically, a malignant polyp is defined by adenocarcinoma that invades into (but no deeper than) the submucosal layer of the bowel wall. By definition, a malignant polyp is a T1 colon cancer. It is important to distinguish a malignant polyp from a polyp with carcinoma in situ or high grade dysplasia. These entities have no appreciable metastatic potential and are cured by polypectomy if the pathologic assessment is adequate and the specimen can be removed in total.
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Table 12.5 Risk of invasive adenocarcinoma in an adenomatous polyp Study Size of polyp <1.0 cm 1.0–2.0 cm
>2.0 cm
Muto (1975) (n = 2,489)
1%
9%
46%
Shinya (1979) (n = 18,286)
0.5%
5%
11%
Hermanek (1987) (n = 6,793)
0.3%
7%
53%
Odom (2005) (n = 4,443)
0.07%
2%
19%
In a malignant polyp that has been removed with negative margins, the main reason to proceed with a formal segmental resection is to harvest the associated lymph nodes in the mesentery. The risk of lymph node metastasis in malignant polyps is 8–15% (Hassan et al. 2005; Robert 2007). This is a relatively low risk, and in some patients this risk approaches the mortality associated with colon resection. In 1985, Haggitt proposed a classification of malignant polyps designed to predict lymph node metastasis (Haggitt et al. 1985). In 64 patients who had a malignant polyp, Haggitt demonstrated that polyps with invasive cancer at the base of a pedunculated polyp or any sessile polyp had a 25% risk of lymph node involvement, while all other polyps had <5% risk of lymphatic spread. While the role of Haggitt’s classification has been superceded by other important pathologic features, this study represents an important early attempt to delineate patients who might be spared major surgery. In 2004, Ueno et al. evaluated 292 patients with malignant polyps who subsequently underwent either segmental colonic resection or close clinical follow up for recurrent cancer (Ueno et al. 2004). The authors evaluated Haggitt level, tumor grade, depth of submucosal invasion, tumor budding and lymphovascular invasion and found that the three features most predictive of adverse outcomes (lymph node metastasis or recurrence with clinical follow up) were tumor grade, tumor budding and lymphovascular invasion. In the absence of any of these features, the risk of adverse outcome is less than 1%. However, if the malignant polyp had any one of these features, the risk of adverse outcome was 20%. If the polyp had two or more of these features, the risk of adverse outcomes increased to 36%. Prospective evaluation of this scoring system may better define patients who can be spared major surgery. Presently, the American College of Gastroenterology guidelines (Bond 2000) state that malignant polyps may be treated with endoscopic removal and close surveillance when:
• The polyp is completely excised. • The polyp can be accurately assessed with respect to the depth of invasion, grade of differentiation, and completeness of excision of the carcinoma. • The cancer is not poorly differentiated. • There is no vascular or lymphatic involvement. • The margin of excision is not involved.
All other malignant polyps should be considered for surgical resection. However, even with some high risk features, patients with malignant polyps and serious medical comorbidities are best managed with close surveillance and nonsurgical treatment.
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12.6.2 Early-Stage Colon Cancer (Stage I–III Disease) 12.6.2.1 Surgical Management of the Primary Tumor There are three primary objectives in the surgical treatment of colon cancer: to cure, to stage and to palliate. Despite advances in adjuvant therapy, surgical removal of primary cancer and all macroscopic disease is necessary to achieve cure. In most cases, this involves removing the involved colon, its lymphatic basin, and any adjacent structures that are directly invaded by the tumor. Removing the entire lymph node basin is critical to cure the disease, as lymph nodes with tumor deposits are likely to grow and cause local recurrence. Furthermore, adequate lymphadenectomy is critical to accurately distinguish patients with early stage (I or II) disease from patients with stage III colon cancer. Palliation, or the relief of symptoms, is usually associated with surgery for incurable disease. However, many patients with colon cancer present with symptoms of either bleeding or obstruction. Thus, palliation is an important but often overlooked objective in the surgical treatment of patients, regardless of whether cure is possible. Segmental resection of the colon is the preferred treatment of most colon cancers. At the time of initial surgery, intramural spread of the tumor rarely exceeds 2 cm from the edge of the gross lesion (Hughes et al. 1983; Williams et al. 1983). Thus, gross margins of 5 cm or more are generally recommended (Hida et al. 2005). Furthermore, removal of the entire lymph node basin is critical in removing all gross disease, preventing recurrence and providing adequate tissue for lymph node assessment. Lymphatic drainage of the colon follows the same pattern as the arterial blood supply and venous outflow (see Figs. 12.1 and 12.2). Thus, proximal ligation of the segmental blood supply of the colon and removal of the mesenteric fat is the accepted oncologic strategy for harvesting lymph nodes.
Surgical Procedures for Colon Cancer Conventional procedures for solitary colon cancers are illustrated in Fig. 12.2. For most colon cancers, segment resection is the most appropriate surgical treatment. In patients with synchronous colon cancers, surgeons must decide between two separate segment resections, subtotal colectomy and ileorectal anastomosis, and total proctocolectomy and permanent ileostomy or ileal pouch anal reconstruction (see Fig. 12.3). In elderly patients, those with marginal fecal continence and those with frequent bowel movements, two segmental resections, are usually favored. However, this approach does increase the risk of anastomotic leak, a complication that has a high mortality. In younger patients, the perception of increased risk of metachronous lesions and the known capacity for bowel adaptation often leads to the recommendation of subtotal or total colectomy. Patients with underlying conditions (e.g., ulcerative colitis, Crohn’s colitis, FAP, HNPCC) that predispose to colon cancer are offered more extensive surgery to remove colon risk. In ulcerative colitis and FAP, the procedure of choice is proctocolectomy and ileal pouch anal anastomosis. In patients with Crohn’s colitis, ileo-anal reconstruction is not an option, so the extent of colectomy is determined by the minimal surgery required to
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Fig. 12.1 Lymphatic drainage of the colon
resect the colon involved by the cancer and colitis. Often, this can only be achieved by a proctocolectomy and permanent ileostomy. In patients with HNPCC, segmental colectomy, subtotal colectomy, and ileorectal anastomosis or proctocolectomy and ileal pouch anal anastomosis are all options for the treatment of a cancer or advanced polyp. In these patients, balancing the ongoing risk of metachronous cancer and the possible functional consequences of extensive colectomy are the primary considerations and must be individualized in discussions between the surgeon and the patient.
Lymphadenectomy There is controversy regarding the importance of extended lymphadenectomy and its impact on the oncologic outcomes in colon cancer. Chang et al. conducted a systematic review of retrospective studies evaluating the impact of lymph node harvest on 5-year survival (Chang et al. 2007a). The authors analyzed two nested cohort studies, five population-based studies, and ten single institution case series. In 16 of 17 studies evaluating patients with stage II colon cancer, increased lymph node retrieval/identification was associated better survival. This improved survival can be partially attributed to stage migration. Stage migration is the phenomenon whereby the distribution of stage in a particular cancer is influenced by either a change in staging system or a technical improvement that facilitates more accurate identification of spread of the disease. In this case, better lymph node harvest leads to fewer patients with undiagnosed stage III cancer being erroneously considered to have stage II disease. Johnson et al. used Surveillance, Epidemiology and End Results (SEER) data to analyze the impact of the number of disease-free lymph nodes harvested on survival in patients with stage III colon cancer (Johnson et al. 2006). In 20,702 patients with stage III disease,
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Fig. 12.2 Arterial blood supply of the colon
patients with >13 negative lymph nodes had better survival than patients with fewer than three negative lymph nodes. Furthermore, in patients with stage IIIB and IIIC colon cancer, there was a statistically significant reduction in survival with fewer lymph nodes retrieved. These data suggest that lymph node harvest impacts more than just staging accuracy. Improved survival in stage III patients with better lymph node retrieval and identification may be related to better surgery and pathology. However, this association may be explained by the biology of the cancer and its interaction with the host immune system; in other words, patients with larger, more easily identified lymph nodes may be experiencing a more robust immune response to the cancer, leading to locoregional containment of the disease. In a randomized controlled trial enrolling 260 patients (Rouffet et al. 1994), very high ligation (i.e., ligation at takeoff from the aorta) of the arterial blood supply of the colon did
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Fig. 12.3 Standard surgical resections for colon cancer. (a) Oncologic resection of cecal and ascending colon carcinoma. (b) Oncologic resection of hepatic flexure carcinoma, in which the distance between the tumor and left branch of the middle colic vessels is greater than 10 cm. (c) Shown is oncologic resection of proximal transverse colon carcinoma, in which the distance between the tumor and the left branch of the middle colic vessels is less than 10 cm. (d) Depicted are two options for resection of transverse colon carcinoma: transverse colectomy (A) and extending right hemicolectomy (A plus B). (e) Depicted are two options for resection of splenic flexure carcinoma: splenic flexure resection (A) and left hemicolectomy (A plus B). (f) Oncologic resection of descending colon carcinoma. (g) Oncologic resection of sigmoid colon carcinoma
not result in improved 5-year survival when compared to a slightly less proximal vascular ligation. However, all procedures were performed by experienced cancer surgeons who were performing wide mesenteric excisions, even in the control arm of the study. The College of American Pathologists recommend that a minimum of 12 lymph nodes should be identified after segmental resection for colon cancer (Compton 2006). Baxter
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et al. reviewed SEER data from all stage I–III colon cancer patients between 1988 and 2001 (Baxter et al. 2005). They found that only 37% of patients had 12 or more lymph nodes assessed. Furthermore, only 41% of patients with stage II colon cancer had adequate lymph node staging. These data suggest many patients with colon cancer might have had inadequate surgery and inadequate adjuvant therapy based on poor staging. Fortunately, there is evidence that colon cancer surgery can be improved. Wright et al. performed a study where community surgeons were exposed to a standardized lecture regarding surgical technique to optimize lymph node retrieval (Wright et al. 2008). The authors demonstrated a significant improvement in lymph node harvest after the intervention. Surgeons performing surgery for colon cancer need to monitor the lymph node harvest in patients with colon cancer and work closely with pathologists to maintain the minimum standard of 12 lymph node assessment.
Laparoscopic Surgery While laparoscopy has revolutionized selected major abdominal surgeries, the impact on colon surgery has been less extreme. While operating times are longer with the laparoscopic approach, hospital stay and postoperative pain are consistently better with minimally invasive surgery (Brown and Raval 2008). A recent Cochrane review evaluated 12 trials in which 3,346 patients were randomized to either open or laparoscopic surgery (Kuhry et al. 2008). At minimum 2-year follow-up, there was no difference in cancer related mortality (OR 0.84, 95% CI 0.76–1.06). Presently, not every general surgeon who performs surgery for colon cancer is qualified to perform laparoscopic colon resection. Specific training in laparoscopic colon surgery and a minimum of 20 laparoscopic colon resections for benign disease are recommended before proceeding with laparoscopic colon cancer surgery. As laparoscopic surgery is integrated into residency and fellowship training, laparoscopic colon cancer surgery will become more common.
12.6.3 Radiotherapy Considerations in Resected High-Risk Colon Cancer In contrast to rectal cancer, neoadjuvant and adjuvant radiotherapy has no proven role in the treatment of colon cancer. The anatomical constraints of operating in the lower pelvis and pattern of lymphatic drainage of the rectum are largely absent for colon malignancies and the addition of radiotherapy as adjuvant therapy for resectable colon cancer as a whole has not demonstrated a significant benefit in prolonging survival or reducing local or regional relapses. However, the select use of radiotherapy, both external beam radiotherapy (EBRT) given with radiosensitizing 5-fluorouracil (5-FU) as well as EBRT with 5-FU in conjunction with intraoperative electron beam radiotherapy (IOERT) has been proposed in situations where the advanced stage of the primary tumor or its anatomic location might compromise resection and lead to a higher risk of local or regional recurrence than is normally seen in colon carcinoma. These would include T4NxM0 tumors, T3N1-2M0 tumors of the proximal ascending, distal descending, and sigmoid colon, and locally extensive tumors arising in the setting of a fistula or abscess where en bloc surgical extirpation is
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difficult. This approach has been based on patterns of failure data from the University of Minnesota reoperation series which demonstrated a high rate of local and regional recurrence following surgery alone for high risk colon cancers (Gunderson et al. 1985) and a single institution study that suggested a benefit to postoperative radiotherapy and 5-FU chemotherapy in high risk colon cancer (Willett et al. 1993). However, the single phase III, multiinstitutional randomized clinical trial to have been performed to date (INT 013) failed to show a benefit of postoperative radiochemotherapy in high risk colon cancer patients randomized to 45.0–50.4 Gy of EBRT with 5-FU and levamisole vs. 5-FU and levamisole alone (5-year OS 58% vs. 62%, p > 0.50). This study closed after accruing only 222 of a planned 700 patients, leaving it underpowered to evaluate its primary endpoint. Additionally, this study was performed without the benefit of modern imaging and radiotherapy treatment planning in a significant number of patients (Martenson et al. 2004). In summary, although no level I evidence supports the routine use of radiochemotherapy as neoadjuvant or adjuvant therapy for resectable colon cancer, some investigators have supported its use in situations for locally advanced tumors of the very proximal and distal colon, as well as for T4NxM0 tumors or those arising from abscesses or fistuli. In such situations, a typical treatment regimen would include careful radiotherapy treatment planning using CT-based simulation to delineate the gross tumor or preoperative tumor volume and normal anatomic and lymphatic structures at risk for tumor adherence or involvement. Intensity modulated radiotherapy may offer a benefit in delivering therapeutic doses of radiotherapy to structures at risk while sparing the considerable small bowel volumes that traditionally would receive high dose radiotherapy during EBRT for colon cancer. Radiotherapy doses have traditionally been limited to 45.0–50.4 Gy in 1.8 Gy/day fractions because of the limits of small bowel tolerance. 5-FU given either as a bolus at the beginning and end of EBRT or as a continuous infusion through EBRT, has typically been employed as a radiosensitizing agent (Gunderson et al. 1994). In unresectable, nonmetastatic colon cancers where potentially curative surgical resection is a consideration but where a concern exists regarding the radial margin status because of local extension of the tumor into an unresectable structure, the combination of EBRT and chemotherapy, followed by maximal resection and IOERT, has been employed. Patients at the Mayo Clinic who present with primary or recurrent colon carcinoma who are unresectable at cure because of involvement by the primary or malignant lymphadenopathy of critical, unresectable structures such as the inferior vena cava or root of the mesentery. Patients typically receive maximal systemic therapy, followed by neoadjuvant EBRT (median dose of 50.4 Gy) with radiosensitizing 5-FU, and then undergo restaging at approximately 4 week after completion of EBRT. Following maximal resection of the tumor, IOERT to doses of 10.0–20.0 Gy (median dose 12.5 Gy) are delivered to the site of adherence and/or residual tumor following close consultation between the radiation oncologist, colorectal surgeon, and pathologist. In 40 primary colon carcinoma patients receiving such therapy, OS was approximately 52% and disease-free survival was 49% at 5 years, with 13% of patients (in a combined analysis of colon and rectal cancer patients) demonstrating local failure (Mathis et al. 2008). A similar approach has been used to salvage primary and nodal failures of colon cancer. Patients with isolated pelvic and retroperitoneal nodal failures of colonic primaries treated with irradiation, complete resection, and IORT had a median OS of 53 months and 5-year survival of 49% (Haddock et al. 2001, 2003).
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12.6.4 Adjuvant Chemotherapy for Resected High-Risk Colon Cancer Patients with early-stage colon cancer (stage I) have a very high cure rate with surgery alone and are rarely, if ever, considered for adjuvant systemic therapy. Patients with stage II or greater tumors may be offered additional testing and/or therapy.
12.6.4.1 5-FU Monotherapy In the preadjuvant chemotherapy era over two decades ago, when surgery alone was the standard of care, only 50% of stage III colon cancer patients remained recurrence-free at 3 years (Moertel et al. 1990). In current day, with the routine use of adjuvant therapy, patients with stage III colon cancer have 75% likelihood that they will be disease-free at 3 years and, most will be cured of their disease (Andre et al. 2004). The first definitive data supporting adjuvant chemotherapy came from parallel trials performed by the North Central Cancer Treatment Group (NCCTG) and the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated in the late 1970s. NSABP investigators showed that treatment with the combination of methyl-CCNU, vincristine, and 5-FU (MOF) led to a clinically and statistically significant disease-free (DFS) and overall 5-year survival (OS) advantage (59%) for Stage III patients over surgery alone (50%) (Wolmark et al. 1988). A similar improvement was seen using 5-FU modulated by either levamisole or leucovorin (Moertel et al. 1995). 5-FU and leucovorin subsequently became the standard of care in the next generation of studies (O’Connell et al. 1997; Wolmark et al. 1993). The largest American study to date, Intergroup 0089, randomized 3,759 patients with stage II and III colon cancer to 5-FU plus levamisole for 12 months, 5-FU plus high-dose leucovorin (HDLV) administered weekly for 6 of 8 weeks for 4 cycles (the Roswell Park Regimen), 5-FU plus low-dose leucovorin (LDLV) administered daily for 5 days every 4–5 weeks for 6 cycles (the Mayo regimen) and 5-FU plus LDLV plus levamisole (Haller et al. 2005). This study showed that either 5-FU + HDLV or 5-FU + LDLV led to a survival advantage for patients with stage III colon cancer, and that levamisole added toxicity without incremental benefit. More importantly, this study demonstrated six to be as effective as 12 months of adjuvant therapy. The overall relative benefit of adjuvant 5-FU-based monotherapy for all patients with stage II and III colon cancer and for substages based on T and N characteristics, was estimated in a pooled individual patient data analysis including seven adjuvant trials with surgery alone control arms (Gill et al. 2004). In this metaanalysis, adjuvant therapy with modulated 5-FU for stage II and III colon cancer decreased the risk of recurrence by 30% (HR, 0.70; range, 0.63–0.78) and decreased the risk of death by 26% at 5 years (HR 0.74; range, 0.66–0.83). While bolus regimens remained the preferred 5-FU platform in North America, the combination of both a bolus loading dose of 5-FU followed by 5-FU infusion was pursued by European investigators, in part because 5-FU is cell cycle specific in its action and appears to have a dual mechanisms of action related to inhibition of thymidylate synthetase and incorporation of the abnormal pyrimidine into RNA (Sobrero et al. 1997). The LV5-FU2 regimen initiated by de Gramont and colleagues admistered LV 200 mg/m2, 5-FU 400 mg/m2 bolus followed by 600 mg/m2 infused continuously for 22 h with
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treatment repeated on days 1 and 2 of every 2 weeks was compared again at the Mayo Clinic regimen, and was found to have comparable efficacy (Andre et al. 2003). Convenience would make an oral fluoropyrimidine an attractive alternative to either bolus or infusional 5-FU, if equivalent efficacy could be assured. Capecitabine is an oral prodrug that undergoes a series of enzymatic conversions to 5-FU (Schuller et al. 2000). The X-ACT trial compared capecitabine at a dose of 1,250 mg/m2 b.i.d. to the Mayo Clinic regimen in resected stage III colon cancer (Twelves et al. 2005). The HR for 3-year DFS of 0.87 (95% CI 0.75–1.00) met the primary endpoint for noninferiority and established capecitabine as a preferred option for patients receiving adjuvant 5-FU monotherapy.
12.6.4.2 5-FU and Oxaliplatin MOSAIC was the pivotal first trial to evaluate the combination of oxaliplatin with 5-FU/LV (FOLFOX4) to LV5-FU2 and enrolled 2,246 patients with stages II and III colon cancer (Andre et al. 2004). FOLFOX4 adds biweekly oxaliplatin at a dose of 85 mg/m2/day to the LV5-FU2 backbone as described previously. In the final analysis, the addition of oxaliplatin significantly improved 5-year DFS (73.3 vs. 67.4%, p = 0.003) and 6-year OS (78.5 vs. 76%, p = 0.046) (Andre et al. 2009). In stage III disease, 5-year DFS improved by 7.5% (66.4 vs. 58.9%, p = 0.005) and 6-year OS improved by 4.2% (72.9 vs. 68.7%, p = 0.023). Oxaliplatin caused significantly more peripheral sensory neuropathy, neutropenia, thrombocytopenia, nausea and vomiting, and allergic reactions (Andre et al. 2004). Out of the 12% of patients who developed sensory neuropathy interfering with function, only 1% of patients continued to have residual severe neuropathy 1 year later. NSABP C-07 which randomized 2,492 patients with stages II and III colon cancer to receive the Roswell Park regimen of bolus 5-FU/ LV with or without oxaliplatin (FLOX), confirmed these findings (Kuebler et al. 2007). Three year DFS increased from 71.8 to 76.1% (HR for DFS 0.79). Grade 3 or greater side effects were observed in 51% of patients on 5-FU/LV compared with 61% of patients receiving FLOX. Of note the FLOX regimen prescribes approximately 2/3 of the cumulative oxaliplatin dose specified by the FOLFOX4 regimen suggesting that less exposure to oxaliplatin than the cumulative dose of 1,020 mg/m2 delivered through the administration of 12 fortnightly doses of FOLFOX4 may be sufficient to achieve the same benefit. MOSAIC and NSABP C-07 have solidly shifted the standard of care to adjuvant oxaliplatin plus 5-FU/LV for patients with resected high-risk colon cancer. The subsequent XELOXA randomized study validated the efficacy of oxaliplatin in the adjuvant setting when combined with capecitabine (XELOX) vs. 5-FU/LV (3-year DFS in stage III 70.9 vs. 66.5%, p = 0.0045) (Haller et al. 2010).
12.6.4.3 Negative Trials in Adjuvant Colon Cancer It is worthwhile to acknowledge that irinotecan has no proven role in the adjuvant setting. The Cancer and Leukemia Group B (CALGB) chaired a U.S. Intergroup study comparing the bolus 5-FU based IFL regimen to bolus 5-FU/LV (Saltz et al. 2004). Accrual of C89803
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was discontinued prematurely and outcomes were reported earlier than planned after a protocol specified interim analysis indicated that IFL could not be proven superior to 5-FU/ LV. In the Pan European Trial in Adjuvant Colon Cancer (PETACC)-3, the addition of irinotecan to infusional 5-FU/LV favored but did not significantly improve 3-year DFS (p = 0.091) (Van Cutsem et al. 2009a). The third study examining the potential benefits of adjuvant irinotecan was the French ACCORD2 trial (Ychou et al. 2009). This study limited its enrollment to 400 stage III patients with high risk of recurrence because of N2 disease or N1 disease with concomitant perforation or obstruction. Again the irinotecan plus 5-FU arm failed to provide a benefit over 5-FU/LV. Irinotecan-based regimens should not be administered to patients in the adjuvant setting. Perhaps even more disappointing is the lack of incremental efficacy observed in recently completed trials evaluating the combination of FOLFOX and targeted therapies with demonstrated efficacy in the advanced setting. Bevacizumab is a monoclonal antibody (mAb) to vascular endothelial growth factor (VEGF) and has been shown to improve survival when combined with 5-FU based chemotherapy for the treatment of metastatic disease (see later Sect. 12.6.6.2). In NSABP C-08, a randomized trial of FOLFOX and bevacizumab vs. FOLFOX alone for resected stage II and III colon cancer, no significant improvement in DFS was observed (Wolmark et al. 2009). Confirmatory trials are pending. A similar negative finding has been reported with cetuximab, a mAb to the epidermal growth factor receptor (EGFR) which has survival efficacy in the metastatic setting when used in previously treated patients with tumors with a wild-type KRAS status (see later Sect. 12.6.6.2). The NCCTG-led N0147 trial of FOLFOX and cetuximab vs. FOLFOX alone in wild-type KRAS stage III colon cancer failed to reach its primary endpoint of DFS (Alberts et al. 2010). At present, an understanding of why biologic therapies have failed to improve outcomes in the adjuvant setting is lacking. Further studies including a careful evaluation of molecular determinants of response and outcomes, will be required to better elucidate the reasons for these disappointing findings.
12.6.4.4 Considerations in Stage II Colon Cancer While adjuvant treatment is clearly the standard of care for patients with stage III colon cancers, the treatment benefit for stage II disease remains the subject of debate. As most adjuvant studies enroll relatively fewer stage II patients, these studies have been underpowered to detect statistically significant benefits in this node-negative subgroup. Pooled analyses have been the typical methodology employed to judge the benefits of therapy in this group. The stage II controversy was initially fueled by two conflicting pooled analyses from the late 1990s: the NSABP pooled analysis of four trials reported a 30% reduction in mortality for stage II (Mamounas et al. 1999), whereas the International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) failed to demonstrate a statistically significant benefit for stage II tumors (International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators 1999). These data as well as a literaturebased metaanalysis (Figueredo et al. 2004) led a panel convened by ASCO in 2004 to conclude that routine administration of adjuvant therapy in stage II colon cancers was not
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recommended, but that patients should discuss their case on an individual basis with their physicians (Benson et al. 2004). The British QUASAR investigators (Quick and Simple and Reliable) enrolled 3,238 patients, 91% of whom were Dukes B and 71% of whom had colon cancer in one out of three 5-FU treatment arms or to observation (Gray et al. 2004). The study demonstrated significant improvement in DFS, and an analysis of the stage II patients (n = 2,948) indicated that there was a 3–4% absolute improvement in OS at 5 years for the treatment vs. control arm (p = 0.04). Interpretation of this study is confounded by the inclusion of patients with rectal cancer, a disease with higher stage-specific rates of recurrence. These results have been interpreted by some as evidence that adjuvant chemotherapy should be offered to all stage II patients with a clear description of the risks and benefits, so that the individual patient might make an informed choice. In addition, subgroup analyses from the MOSAIC trial demonstrate no significant interaction between stage of disease and treatment, supporting the position that FOLFOX benefited both stage II and stage III colon cancer patients compared to LVS-FU2 (Andre et al. 2004). Based upon these data, the question has been redirected from whether or not we should treat stage II patients, to whether we can select stage II patients who might benefit most from treatment. The ASCO expert panel that provided recommendations for adjuvant therapy of stage II colon cancer concluded that treatment may be considered for patients with higher than average risk, including those with inadequately sampled nodes (<13), T4 primary lesions, perforation, obstruction, lymphovascular invasion or poorly differentiated tumors but should not be administered as a matter of routine (Benson et al. 2004). Additional molecular markers of interest have since emerged to support this risk-adapted approach to adjuvant therapy in stage II disease. As previously discussed, MSI-H tumors are associated with a more favorable prognosis. In addition, recent studies have indicated that MSI-H tumors may be less responsive to 5-FU chemotherapy (Ribic et al. 2003). Most commonly cited among these is a retrospective pooled correlative analysis by Sargent et al. which found that patients with MSI-H tumors (deficient MMR) treated with 5-FU had a 5-year DFS which was similar to patients treated with surgery alone (70 vs. 67%, p = 0.30) (Sargent et al. 2010). In an ongoing stage II trial led by the Eastern Cooperative Oncology Group (ECOG 5202), a strategy of risk stratification by MSI and 18qLOH status to determine need for adjuvant chemotherapy is now being prospectively evaluated. In the meantime, the development and validation of a gene signature to predict recurrence in stage II colon cancer may have promising clinical utility in the near future. A recurrence score based upon a 7-gene RT-PCR assay has been validated as an independent predictor of recurrence beyond conventional pathologic features and MSI status (Kerr et al. 2009).
12.6.4.5 Adjuvant Therapy in the Elderly Over half of all newly diagnosed, cases of colon cancer are over the age of 70 years. The degree to which age may influence benefit from adjuvant chemotherapy remains an active topic. In 2001, the findings from a trial-based individual patient data analysis evaluating age as a predictive factor for adjuvant 5-FU chemotherapy were published in the New England Journal of Medicine (Sargent et al. 2001). Sargent et al. demonstrated that patients older than
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70 years received the same proportional benefit from 5-FU adjuvant therapy as their younger counterparts, without a noticeable increase in toxicity. The standard of care for adjuvant chemotherapy then switched from 5-FU to 5-FU plus oxaliplatin based upon the MOSAIC and NSABP C-07 findings (Andre et al. 2009; Kuebler et al. 2007). ACCENT is a multinational collaborative effort to pool individual patient data from phase 3 adjuvant colon cancer trials. In 2009, the ACCENT study group presented an analysis of older age on the efficacy of using new therapies beyond 5-FU alone (Mcleary et al. 2009). With 15% of 4,680 trial subjects over age 70, a somewhat surprising significant negative interaction of age by treatment effect was observed for disease-free survival and OS in the trials evaluating oxaliplatin-based adjuvant therapy. This was not observed for the endpoint of time to colon cancer recurrence (where deaths without recurrence are censored at the time of death, p = 0.21) suggesting interplay with competing risks. These data imply that adjuvant oxaliplatin does not translate into a survival benefit in patients over 70 years of age. Unfortunately, the ACCENT database does not capture toxicity and comorbidity data. Contradictory to these findings, an age-by-treatment analysis of the XELOXA study (Haller et al. 2010) showed no detrimental impact of age on oxaliplatinbased treatment effect. Thus, the clinical implications of these age-by-treatment analyses remain debatable. Ultimately, age alone cannot be the sole arbitrator of treatment decision making. Patient functional status, comorbidities, support and preferences must be carefully considered when determining the optimal adjuvant strategy for an individual patient.
12.6.5 Advanced Colon Cancer (Stage IV Disease) 12.6.5.1 Management of the Primary Tumor in Metastatic Colon Cancer The management and prognosis of patients with metastatic colon cancer has changed significantly over the past 10 years. Median survival has nearly doubled and subsets of patients with resectable metastatic disease may be cured with aggressive surgical and medical management. Management of the primary tumor in patients with stage IV disease is dependent on whether the cancer is symptomatic or asymptomatic. In patients with symptoms, surgical intervention is generally recommended for palliation. The most common symptom is bowel obstruction, occurring in nearly 30% before death. Except in patients whose life expectancy is very short, the preferred choice in this situation is resection of the primary tumor. In patients with unresectable colon cancer due to local invasion of critical structures, surgical bypass (anastomosis of proximal bowel to colon distal to obstructing lesion) may be possible. While restoration of gastrointestinal continuity is preferred, this may not be advisable in patients with a significant intraabdominal tumor burden. Thus, a colostomy or ileostomy may be necessary. In patients with short life expectancy and/or high surgical risk, colonic stenting is an option in centers with appropriate expertise. In a pooled analysis of case series including 791 patients stented for palliation, technical success was achieved in a median of 96% of patients (interquartile range 77–100%) (Sebastian et al. 2004). The majority of these patients had left colon obstruction, and most technical failures occurred proximal to the splenic
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flexure. In the overall group of patients treated with stents (n = 1,198), 7.3% developed a recurrent obstruction in a median of 24 weeks (IQ 1–52 weeks) after stent placement. Of these, 72% were managed with either argon beam ablation of tumor ingrowth or repeat stent placement for relief of obstruction and managed to avoid major abdominal surgery. The risk of perforation and death with the procedure was 3.8 and 0.6%, respectively. The role of surgery for patients with asymptomatic colon cancer and unresectable metastatic disease is less clear. Surgical resection is often recommended to avoid subsequent obstruction, which may occur at a time when both the primary tumor and the metastatic disease has progressed and the patient is less fit to survive surgical intervention. Furthermore, there is data to suggest that patients with metastatic disease may have a survival advantage with resection of the primary tumor. Ruo et al. reported 127 patients who were asymptomatic when they had their primary tumor resected, and compared them to 103 of patients who did not have their primary tumor resected between 1996 and 1999 (Ruo et al. 2003). It is unknown what proportion of patients in the nonresected group had symptoms. At baseline, the two groups had important differences; the resection group had fewer patients with two or more sites of distant metastases (32 vs. 47%), fewer patients with left sided and rectal tumors (54 vs. 72%) and less tumor burden in their liver (percentage of patients with >25% burden was 41 vs. 55%), and slightly more patients with comorbidities (32 vs. 20%). Nonetheless, the median survival was 16 months in the resection group compared to 9 months (p < 0.001) in the no resection group. These data are often used to justify resection in patients with incurable disease. However, there are emerging data suggesting that improvements in chemotherapy that have led to longer median survival may also affect the primary tumor. Armbrust et al. reported on four patients with stage IV colon cancer treated with systemic chemotherapy and no surgical intervention and the primary tumor remained stable at reevaluation 6, 23, 26, and 48 months later, respectively (Armbrust et al. 2007). Furthermore, Benoist et al. reported on 27 patients with incurable stage IV colon cancer treated with chemotherapy alone and compared them to 32 patients matched for important determinants of cancerspecific and overall mortality (Benoist et al. 2005). The authors demonstrated no significant difference in 2-year actuarial survival (41 vs. 44%, p = 0.75). Of the 27 unresected patients, only four patients developed bowel obstruction requiring surgery. The role of palliative surgery in asymptomatic patients remains unclear. While patients are living longer with improved systemic therapies, there is insufficient data to determine if the antitumor effects of chemotherapy will adequately suppress the growth of the primary tumor to prevent future obstruction. Thus, the potential risks, benefits and alternatives of surgical resection must be discussed with the patient and treatment individualized based on patient preference and the estimated risk of impending bowel obstruction.
12.6.5.2 Locoregional Management of Liver-Limited Metastatic Colon Cancer Colon cancer has a propensity to spread to liver and, about 25% of the time, only liver metastases are apparent. Untreated, liver metastases are almost uniformly fatal at 5 years (Bengtsson et al. 1981; Wagner et al. 1984). In recent years, treatment options have
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expanded dramatically as a consequent of advances in ablative technologies as well as systemic therapies. Liver resection for colorectal cancer was once controversial, but has been shown to be cost effective (Gazelle et al. 2003) and is now considered standard of care. Because of the segmental anatomy of the liver, it is technically possible to remove multiple lesions from different regions of the liver. Technical surgical advances including improved techniques for obtaining vascular control, development of new technologies for parenchymal dissection, and anesthetic advances, have made liver resection much safer. In institutions in which high volumes of liver surgery are performed, liver resections for colorectal metastases are associated with mortalities of <5% (Fernandez et al. 2004; Fong et al. 1997; Gayowski et al. 1994; Jarnagin et al. 2002; Pawlik et al. 2006). A SEER-based analysis of the last two decades has confirmed profound improvements in the outcome of patients with metastatic CRC directly correlated to sequential increases in the use of hepatic resection, in conjunction with advances in systemic therapy (Kopetz et al. 2009). Candidates for resection must be of sufficiently good health to tolerate major surgery, particularly surgery in which hemodynamic fluctuations and major blood loss is a risk. In general, it must be technically possible to remove all gross disease. For this reason, the presence of extrahepatic disease represents a contraindication for resection. Exceptions to that tenet may include patients with synchronous primary tumors as well as highly selected patients with synchronous lung metastases (Lee et al. 2008). Finally, the residual liver must have sufficient functional reserve. While cirrhosis is rare in this patient population, the effects of chemotherapy on liver function must be considered (Karoui et al. 2006; Kooby et al. 2003; Vauthey et al. 2006) as discussed below. The diagnostic work-up for proper selection of candidates focuses on identifying contraindications to resection. Total bilirubin, liver enzymes, albumin and INR are required for assessment of liver function. A colonoscopy is required (if not recently done) to ensure that the primary tumor is controlled. A triphasic CT scan or a liver MRI will define the extent of the intrahepatic disease and the technical feasibility of resection. A CT of the chest, abdomen and pelvis are required to evaluate for extrahepatic disease. Recently, FDG-PET has been advocated as a more sensitive and comprehensive way of ruling out extrahepatic disease (Fernandez et al. 2004; Zealley et al. 2001). With resection of hepatic metastases alone, the median survival is 30–46 months and 5-year survival is 30–38% (Fong et al. 1997; Gayowski et al. 1994; Doci et al. 1991; Seifert et al. 2000). A number of investigations have attempted to identify prognostic factors which may guide the selection of patients for resection. Perhaps the most commonly cited prognostic factors are the factors that comprise the Clinical Risk Score, described by Fong (see Table 12.6): nodal status of the primary tumor, disease-free interval, number of metastases, size of the largest metastasis, and preoperative CEA (Fong et al. 1999). Several independent investigators have confirmed the prognostic value of this Clinical Risk Score (Arru et al. 2008; Mala et al. 2002; Mann et al. 2004). A high Clinical Risk Score correlates with an increased likelihood of identifying extrahepatic disease with FDG-PET (Schussler-Fiorenza et al. 2004) and with diagnostic laparoscopy (Jarnagin et al. 2001). However, additional factors have also been reported as prognostic including tumor grade (Arru et al. 2008; Rees et al. 2008; Tan et al. 2008). In a large series reported by Pawlik et al., disease-free interval and nodal status of the primary tumor were not found to be prognostic on multifactorial analysis (Pawlik et al. 2005) Recent data suggest that a more
352 Table 12.6 Clinical risk score for recurrence after hepatic resection (Fong et al. 1999)
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Score
5-year survival (%)
0
60
1
44
2
40
3
20
4
25
5
14
One point each for: node positive primary, disease-free interval <12 months, >1 tumor, size >5 cm, CEA > 200 ng/mL
exuberant host inflammatory response to the tumor may portend a worse prognosis (Gomez et al. 2008; Ishizuka et al. 2007; Neal et al. 2009). In practice, while it is desirable to identify patients who will most likely benefit from resection, most hepatobiliary surgeons do not exclude patients for liver resection on the basis of any prognostic index alone. On the other hand, it is possible that patients with worse prognostic factors should be more strongly encouraged to receive perioperative systemic therapy, although the rationale for this has never been supported by experimental evidence. Some groups have taken a particularly aggressive approach at resecting colorectal liver metastases. Even before the advent of more effective systemic therapies, resection of four or more metastases was associated with a 5-year survival of 24–37% (Fong et al. 1997; Bolton and Fuhrman 2000; Minagawa et al. 2000). Extensive resections in which it is anticipated that the residual liver mass is less than 25% may benefit from portal vein embolization, in which the portal vein flow is eliminated in the segments containing tumor in an effort to induce hypertrophy in the uninvolved hepatic remnant (Covey et al. 2005, 2008). Alternatively, two-stage liver resections can be undertaken, whereby the diseased segments are removed in two separate operations (Adam et al. 2007; Mentha et al. 2009; Wicherts et al. 2008). During the course of a staged resection, the portal vein may be ligated, which has similar effects on the hepatic remnant as portal vein embolization (Capussotti et al. 2008). Finally and with increasing occurrence, chemotherapy has been administered to patients with extensive intrahepatic disease in an effort to downstage to a point where all gross disease is technically resectable. With contemporary multiagent chemotherapy regimens, unresectable disease can be converted to a resectability in 5–23% (Table 12.7). In series where resection was accomplished following chemotherapy for the purpose of downstaging, 5 year survival rates were 33–40% (Adam et al. 2001, 2004; Bismuth et al. 1996). The current emphasis is to evaluate the role of biologics in combination with chemotherapy to achieve resection in patients with initially unresectable or borderline-resectable liver metastases. In a recent randomized phase 2 trial of combination chemotherapy with cetuximab (CELIM study), response rates of 57–68% were observed with an encouraging 60% hepatic resectability rate (Folprecht et al. 2010). A number of ablative technologies have emerged that enable the ablation of liver lesions without surgery. These include cryoablation, radiofrequency ablation, microwave coagulation therapy, and laser-induced thermotherapy. Cryoablation has largely been supplanted by
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Table 12.7 Incidence of successful hepatic metastasectomy in first-line chemotherapy trials for c olorectal cancer References Agents RP (%) % Liver n resection Levi (1999)
5-FU, LV, oxaliplatin
90
66
23
De Gramont (2000)
5-FU, LV, oxaliplatin
210
54
7
Giacchetti (2003)
5-FU, LV, oxaliplatin
100
53
32
Scheithauer (2003)
Capecitabine, oxaliplatin
89
48
9
Teufel (2004)
5-FU, LV, CPT-11
35
31
9
Tournigand et al. (2004)
FOLFIRI? FOLFOX
109
56
9
Tournigand et al. (2004)
FOLFOX? FOLFIRI
111
54
22
Sorbye (2004)
5-FU, LV, oxaliplatin
82
62
11
Bajetta (2004)
Capecitabine, CPT-11
140
46
6
Cassidy (2004)
Capecitabine, oxaliplatin
96
55
5
Kohne (2005)
5-FU, LV, CPT-11
214
62
7
Falcone et al. (2007)
FOLFIRI FOLFOXIRI
122 122
41 66
6 15
Taberno (2007)
FOLFOX + cetuximab
43
72
23
thermal ablation because of the adverse systemic effects associated with cryotherapy (Pearson et al. 1999). Radiofrequency ablation is the most widely available technology. The general indications for ablation are similar to those for liver resection. Selected patients typically include those who cannot tolerate surgery; those who have prohibitive anatomy or small hepatic remnants from previous resections (Elias et al. 2002); and those with bilateral disease (in which case RFA may be used in conjunction with resection) (Abdalla et al. 2004; Elias et al. 2005). Technical success rates and local recurrence rates vary widely in the literature for colorectal liver metastases (Table 12.8). Large tumors and lesions directly adjacent to large vessels are associated with particularly high risks of local recurrence (Mulier et al. 2005; Machi et al. 2001). While outcomes for selected patients undergoing ablation are promising, local recurrences are much more likely with ablation, and the data are not yet available to suggest that ablation is equivalent to resection. In 2009, ASCO convened a panel to evaluate the utility of radiofrequency ablation for hepatic metastases from CRC (Wong et al. 2009). The panel acknowledged that evidence supports a survival benefit with hepatic resection, with wide variability in recurrence and survival rates across ablation studies and reported a compelling need for more research to determine the efficacy and utility of ablation to improve survival outcomes in this setting. Incremental improvements in survival following resection of liver metastases may be attributed to several factors. The wide availability of FDG-PET scan to exclude extrahepatic disease may enhance the proper selection of individuals who would benefit from resection. Fernandez et al. described a cohort of 100 consecutive patients who were selected using
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Table 12.8 Outcomes following radiofrequency ablation for colorectal liver metastases Series Number of Number of Local recurrence Survival patients lesions rate (%) Solbiati et al. (2001)
117
Machi et al. (2001)
179
39.1
130
9.2
46% (3 years)
Bowles et al. (2001)
39
39
30.8
25 months (median)
Kosari et al. (2002)
76
76
6.6
Bleicher et al. (2003)
59
59
18.3
Aloia et al. (2006)
30
30
37
27% (5 years)
Abdalla et al. (2004)
57
110
9
22% (4 years)
FDG-PET as part of the diagnostic work-up (Fernandez et al. 2004). The 5-year survival was 58%. While this was attributed to the superior capability of FDG-PET to select patients without extrahepatic disease, results from a definitive study of the influence of FDG-PET on survival are still unavailable. Likely of greater import are the temporal in systemic therapy for advanced colon cancer. In practice, the majority of patients who undergo resection of colorectal liver metastases have received chemotherapy at some time in the perioperative period. At present, it is unknown whether neoadjuvant chemotherapy or adjuvant chemotherapy is the optimal approach. There are rationales for each approach, and each approach has its advantages and disadvantages. Administering chemotherapy after resection more closely resembles the practices associated with treatment of the primary tumor, in which adjuvant therapy has consistently been shown to provide a survival advantage in reducing risk of recurrence. This approach also is less likely to detrimentally impact on the conduct of liver surgery. Unfortunately, this practice is largely based upon extrapolation from adjuvant studies and the evidence from adjuvant chemotherapy for resected liver metastases is sparse (Power and Kemeny 2010). Perhaps the most compelling data are derived from a trial by Portier et al., which was stopped prematurely due to slow accrual (Portier et al. 2006). A total of 171 patients were randomized to receiving 5-FU/LV or observation. Median disease-free survival was significantly greater in patients who received adjuvant chemotherapy (24.4 vs. 17.6 months), but OS was not significantly improved. In addition to this trial, a retrospective evaluation of outcomes from 792 liver resections from two major centers revealed an improved survival in patients who had received 5-FU-based adjuvant chemotherapy compared to patients who had not received chemotherapy, even after controlling for Clinical Risk Score (Parks et al. 2007). Administration of chemotherapy was associated with a median survival of 47 months, whereas the median survival in the cohort which had not received chemotherapy was 36 months. Further studies are required to elucidate the benefits of a postoperative “adjuvant” therapy approach after resection of colorectal cancer liver metastases, although it is unlikely that a trial employing a “no chemotherapy arm” will be feasible. Administration of chemotherapy prior to resection of otherwise resectable hepatic metastases has a number of potential advantages. It provides measurable information on the in vivo chemosensitivity of a given tumor. One might argue that progression during
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preoperative chemotherapy is a relative contraindication to postoperative treatment with the same agents and this has been associated with a less favorable prognosis (Abdalla et al. 2004; Gruenberger et al. 2008a; Small et al. 2009). The rationale for neoadjuvant chemotherapy has spurred a number of trials, mostly phase II trials. In sum, these trials have demonstrated that it is feasible and safe to administer chemotherapy prior to liver resection in a setting in which there is good multidisciplinary collaboration (Chua et al. 2010). The European Organization for Research and Treatment of Cancer (EORTC)-led EPOC study wherein 364 patients with four or less resectable liver metastases were randomized to perioperative FOLFOX or surgery alone (Nordlinger et al. 2008). Perioperative chemotherapy was associated with an 8.1% improvement in progression-free survival at 3 years, but no significant improvement in OS was observed. While this result was compelling, it did not demonstrate a definitive advantage to perioperative chemotherapy. Another limitation in the interpretation of the results is that the trial included mostly patients with favorable prognostic factors. Therefore, it is difficult to extrapolate the potential effects of chemotherapy on patients with worse prognostic factors. In addition, preoperative chemotherapy is not without risk. Chemotherapy is associated with alterations in the hepatic parenchyma such as sinusoidal dilatation, hyperbilirubinemia, steatosis, and steatohepatitis (Karoui et al. 2006; Vauthey et al. 2006). Irinotecan-containing regimens have been implicated with a relatively greater risk of steatosis (Vauthey et al. 2006), which is associated with increased surgical morbidity (Kooby et al. 2003). The use of portal vein embolization in tandem with administration of chemotherapy has been considered to prevent postoperative liver failure (Covey et al. 2008). While an increase in adverse events was not seen in an institutional series (Reddy et al. 2008), a phase II trial of preoperative XELOX and bevacizumab when surgery was performed more than 5 weeks after the last dose of systemic therapy (Gruenberger et al. 2008b), it will be important to continue to evaluate the safety of antiVEGF agents in this setting. As more than 50% of recurrences following resection of colorectal liver metastases appear in the liver (Ballantyne and Quin 1993), it has been reasoned that exposing the liver to a high dose of chemotherapy would be beneficial following hepatic resection. Hepatic artery infusion (HAI) represents an attempt at providing regional chemotherapy. The rationale for this approach is that liver metastases derive their blood supply from the hepatic arteries and normal hepatocytes derive most of their blood supply from the portal vein (Ackerman 1974). This gained attention when Kemeny et al. reported on a survival advantage in patients who received HAI (Kemeny et al. 1999). At the time of resection of colorectal liver metastases, 156 patients were randomly assigned to HAI with floxuridine and dexamethasone plus intravenous 5-FU/LV or systemic 5-FU/LV alone. At 2 years, the actuarial survival was 86% in the group which received HAI and 72% in the control group, which was significant. Clancy et al. performed a metaanalysis of trials in an attempt to better delineate the value of HAI following liver resection (Clancy et al. 2005). Seven trials met the inclusion criteria, and six of those consisted of randomized controlled trials. There was considerable heterogeneity in the chemotherapy administered, as well as in the control arms of the studies included in the metaanalysis. A small but statistically insignificant survival advantage was seen in the group that had received HAI. The authors concluded that adjuvant HAI could not be routinely recommended following resection of colorectal liver metastases, but further study was warranted. Since the development of
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numerous systemic chemotherapy regimens and drug combinations that include biological agents with high response rates, HAI is now infrequently administered, particularly in the setting of resectable liver metastases.
12.6.5.3 Stereotactic Body Radiotherapy In recent years, stereotactic body radiotherapy (SBRT), also referred to as radiosurgery, has become increasingly used as a noninvasive means of controlling isolated liver metastases arising from colorectal carcinoma primaries. Interest arose in developing a noninvasive treatment for liver metastases following publication of successful surgical excision of liver metastases. SBRT relies on delivering very high doses of radiotherapy to small treatment volumes with high precision, relying on recent developments in image-guided radiotherapy for accuracy. The combination of shortened treatment times, usually delivered in one to five fractions of SBRT, higher doses, and ability to avoid excess radiotherapy to normal tissues, such as the liver, combine to permit an ablative dose of radiotherapy to be focused on a small tumor within the liver with little risk of toxicity and a high likelihood of local control (Timmerman et al. 2007; Olsen et al. 2009). Additionally, advances in diagnostic imaging, such as positron emission scanning, allow for appropriate selection of patients with oligometastatic disease that might be appropriate for locally aggressive therapy in the setting of liver metastases (Kavanagh et al. 2006a; MacDermed et al. 2008). A number of investigators have reported excellent long term local control in patients undergoing SBRT for liver metastases (Blomgren et al. 1995). Although early reports have included liver metastases treated with SBRT arising from a number of primary sites, colonic primaries have predominated. Treatment of liver metastases is complicated by respiratory motion of the liver, which can be accounted for with abdominal compression, respiratory gating, breath holding techniques, and other methods. The University of Heidelberg has reported the results of a phase I/II trial of liver tumors treated with SBRT in which 30 of 60 tumors were liver metastases. Eligibility criteria included unresectable liver tumors less than 6 cm in maximum dimension that were at least 6 mm from the GI tract in patients with a Karnofsky performance status greater than 80%. Patients received doses from 14 to 26 Gy in a single fraction. Toxicity was minimal and local control was 81% at 5 years in last 54 patients treated (Herfarth et al. 2001). Wulf et al. have reported similar findings using a hypofractionated regimen consisting of three fractions of 10.0– 12.5 Gy, four fractions of 7.0 Gy, and one fraction of 26.0 Gy (Wulf et al. 2006). Twenty four of 51 treated lesions in the series were colorectal metastases. Local control was improved in the higher effective dose regimens, with half of patients receiving 10 Gy failing locally. In the high dose group, three fractions 12.0–12.5 Gy or one fraction of 26.0 Gy, local control was 82% at 2 years. OS was 22% at 3 years and freedom from progression was 19% at 2 years. Toxicity was also minimal. The University of Colorado reported the results of a phase I/II trial treating 36 patients with 1–3 liver metastases £6 cm in size with three fractions of 20.0 Gy in the phase II component of the trial. Local control was 93% in the 28 patients evaluable after 6 months (Kavanagh et al. 2006b). A report from Rotterdam utilizing three fractions of 12.5 Gy for liver metastases, 14 of 17 patients from colorectal
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primaries, found an 86% rate of local control at 2 years for metastatic patients (Mendez Romero et al. 2006). A reanalysis of data on liver metastases treated with SBRT at Heidelberg suggested that colorectal metastases treated with SBRT who previously had received oxaliplatin and/or CPT-11 had a worse outcome in relation to other histologies, although a similar analysis by Romero did not confirm this (Mendez Romero et al. 2006; Herfarth and Debus 2005).
12.6.6 Unresectable Metastatic Disease 12.6.6.1 Radiotherapy Considerations to Palliate Advanced Unresectable Disease Radiotherapy can be used palliatively for control of bone metastasis pain and for treatment of spinal cord compression. Some degree of pain relief is noted in approximately two-thirds of patients treated and complete pain relief in approximately one-quarter, with maximum pain reduction being reached over a period of weeks after treatment is complete. Typical EBRT courses range from 8 Gy in 1 fraction to 30 Gy in 10 fractions to 40 Gy in 20 fractions. No single regimen has proven superior to others in terms of dose and fractionation (Chow et al. 2007; Brown et al. 1999; Fairchild and Chow 2007). In previously irradiated patients with spinal metastases, stereotactic body radiosurgery may be an option for treatment (Yin et al. 2004; Chang and Timmerman 2007; Chang et al. 2007b). For patients with disseminated bone metastases that demonstrated activity on a technetium-99 nuclear bone scan, radiopharmaceutical treatment with strontium-89 and samarium-153 may be options to treat multiple sites of pain causing metastases (Bauman et al. 2005). Brain metastases in the setting of colon cancer are relatively less common and tend to occur later in the course of the illness in comparison to brain metastases arising from other primary sites. In a series of 916 patients with brain metastases from Freiburg, median time from primary diagnosis to diagnosis for brain metastases from colorectal cancer was 22.6 vs. 8.0 months for metastases arising from other sites. Additionally, patients with gastrointestinal primaries had fewer metastases at diagnosis compared with nongastrointestinal primary tumors (Bartelt et al. 2004). Options for treatment and expected survival depend on the numbers of metastases, presence of active systemic malignant disease outside the central nervous system, patient age, and performance status. Treatment is typically whole brain radiotherapy, administered over a period’s weeks. However, for patients with solitary brain metastases, good performance status, and controlled systemic disease, surgical resection or stereotactic radiosurgery may be considered an option in addition to whole brain radiotherapy. If reversible edema-induced neurological symptoms are present, reaction may be the treatment of choice patients treated, but OS remains poor for most patients after a diagnosis of brain metastases from colonic origin. No dose fractionation regimen for whole brain radiotherapy has been demonstrated to be superior to any other (Bartelt et al. 2004; Amichetti et al. 2005; Tsao et al. 2005a, b).
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12.6.6.2 Systemic Therapy for Advanced Unresectable Colon Cancer While selected patients with liver and/or lung limited oligometastases may be amenable to curative-intent resection, systemic therapy remains the mainstay treatment. Recent improvements in the survival of patients with advanced disease have been significant and meaningful, with median survivals approaching up to 2 years on treatment (Grothey et al. 2004) compared to an estimated survival of 6 months with best supportive care alone. The current armamentarium of cytotoxic agents with demonstrable efficacy which will be reviewed here include: fluoropyrimidines (intravenous 5-FU or oral capecitabine), oxaliplatin and irinotecan. While 5-FU and irinotecan have single agent efficacy, oxaliplatin is best used in combination with 5-FU. In a review of phase 3 trials over the last 10 years, access to all three active agents is strongly correlated with improved survival (Grothey and Sargent 2005). Chemotherapy regimens referred to in this section are summarized in Table 12.9. In addition, two classes of biologic agents will be discussed: the antiVEGF mAb, bevacizumab, and the antiEGFR mAbs: cetuximab and panitumumab.
First and Second-Line Chemotherapy N9741 was an Intergroup trial comparing three random-assignment allocations: FOLFOX4, IROX, and IFL, the standard first-line regimen for metastatic CRC at the time of this study (Goldberg et al. 2004). FOLFOX4 was associated with superior time to progression (TTP) (8.7 vs. 6.9 months, p = 0.0014), response rate (RR) (45 vs. 31%, p = 0.002) and median survival (19.5 vs. 14.8 months, p = 0.0001) compared to IFL. IFL also resulted in more diarrhea, vomiting, nausea and febrile neutropenia while patients on FOLFOX4 experienced higher rates of paresthesias. The use of IFL as an irinotecan-5-FU doublet has been replaced by irinotecan with infusional 5-FU (FOLFIRI). In a French intergroup (GERCOR) study, two hundred and twenty patients with metastatic CRC were randomly assigned to a sequence of FOLFIRI followed by FOLFOX6 or the reverse (Tournigand et al. 2004). Both strategies (FOLFOX6-FOLFIRI or FOLFIRI-FOLFOX6) achieved impressive equivalent first-line RRs (54 and 56%, respectively) and median survivals (20.6 and 21.5 months). Equivalent RR efficacy was also demonstrated in the randomized trial of first-line FOLFOX4 (36%) vs. FOLFIRI (34%) reported by Colucci et al. (2005). In both trials, toxicity varied with nausea, mucositis, and alopecia more frequent with FOLFIRI, and neutropenia and paresthesias more frequent with FOLFOX. Hence, the most widely accepted cytotoxic strategy is to employ FOLFOX or FOLFIRI in the first-line with a planned switch to the alternate regimen at progression or treatment intolerance. This switch to a second-line regimen will occur in the majority but not all patients. Ultimately, this will be influenced by toxicity concerns, performance status and patient preference. With no new classes of cytotoxics on the horizon, multiple strategies to optimize the use of available chemotherapies have been evaluated. To address the question of upfront doublets vs. sequential therapy, the UK MRC FOCUS randomized trial (Seymour et al. 2007) and the Dutch CAIRO trial (Koopman et al. 2007) demonstrated that a sequential approach
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12 Colon Cancer Table 12 9 Description of commonly used chemotherapy regimens Regimen Agents and doses (given IV unless specified)
Cycle frequency
LV5-FU2
Leucovorin 400 mg/m2 on day 1 with bolus 5-FU 400 mg/m2 bolus followed by a 46 h infusion of 5-FU 2,400–3,000 mg/m2
Every two weeks
IFL
Irinotecan 125 mg/m2 with bolus 5-FU 500 mg/m2 and leucovorin 20 mg/m2 on days 1, 8, 15, and 22
Every 6 weeks
IROX
Oxaliplatin 85 mg/m2 on day 1 with bolus 5-FU 400 mg/m2 and leucovorin 200 mg/m2 followed by a 22 h infusion of 5-FU 600 mg/m2 on days 1 and 2
Every 2 weeks
FOLFOX4
Oxaliplatin 85 mg/m2 on day 1 with bolus 5-FU 400 mg/m2 and leucovorin 200 mg/ m2 followed by a 22 h infusion of 5-FU 600 mg/m2 on days 1 and 2
Every 2 weeks
FOLFOX6
Oxaliplatin 100 mg/m2 with bolus 5-FU 400 mg/ m2 and leucovorin 400 mg/m2 followed by a 46 h infusion of 5-FU 2,400 mg/m2
Every 2 weeks
mFOLFOX6
Oxaliplatin 85 mg/m2 with bolus 5-FU 400 mg/ m2 and leucovorin 400 mg/m2 followed by a 46 h infusion of 5-FU 2,400 mg/m2
Every 2 weeks
FOLFOX7
Oxaliplatin 130 mg/m2, leucovorin 400 mg/m2 and a 46 h infusion of 5-FU 2,400 mg/m2
Every 2 weeks
FOLFIRI
Irinotecan 180 mg/m2 with bolus 5-FU 400 mg/ m2 and leucovorin 400 mg/m2 followed by a 46 h infusion of 5-FU 2,400 mg/m2
Every 2 weeks
FUFOX
Oxaliplatin 50 mg/m2 with leucovorin 500 mg/ m2 and a 24 h infusion of 5-FU 2,000 mg/m2 on days 1, 8, 15, and 22
Every 5 weeks
FOLFOXIRI
Irinotecan 165 mg/m2, oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 followed by a 48 h infusion of 5-FU 3,200 mg/m2
Every 2 weeks
CAPIRI
Capecitabine 1,000 mg/m2 p.o. b.i.d. days 1–14 plus irinotecan 80 mg/m2 on days 1 and 8
Every 3 weeks
CAPOX
Capecitabine 1,000 mg/m2 p.o. b.i.d. days 1–14 oxaliplatin 70 mg/m2 days 1 and 8
Every 3 weeks
XELIRI
Capecitabine 1,000 mg/m2 p.o. b.i.d. days 1–14 plus irinotecan 250 mg/m2 on day 1
Every 3 weeks
XELOX
Capecitabine 1,000 mg/m2 p.o. b.i.d. days 1–14 plus oxaliplatin 130 mg/m2 on day 1
Every 3 weeks
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did not compromise OS although first-line response rates were inferior. Of concern in both these studies was the lower than expected survival for all treatment arms, suggesting an overall poorer prognosis study cohort. While upfront doublets remain the preferred standard, FOCUS and CAIRO do suggest that a sequential approach, particularly in patients not well suited for doublet therapy, is not unreasonable. The amelioration of treatmentrelated toxicity is also a priority. The major dose-limiting toxicity of oxaliplatin is cumulative neuropathy. The OPTIMOX1 trial (Tournigand et al. 2006) randomly assigned patients to FOLFOX4 until progression or to OPTIMOX1, a strategy of six cycles of modified FOLFOX7 followed by maintenance LV5-FU2 for 12 cycles. For patients with nonprogressive disease, FOLFOX7 was then reintroduced. Overall RR, PFS and survival were similar despite the decreased use of oxaliplatin in the OPTIMOX1 arm. The OPTIMOX2 study aimed to evaluate a chemotherapy-free interval with no maintenance LV5-FU2 (Chibaudel et al. 2009). PFS (8.6 vs. 6.6 months) and duration of disease control were superior with the maintenance strategy confirming that while oxaliplatin-free intervals are feasible, caution and close follow-up must be exercised when considered complete chemotherapy holidays. The next generation of OPTIMOX trials will examine the integration of molecular targeted therapies (OPTIMOX3). Finally, the use of an oral fluoropyrimidine backbone in lieu of infusional 5-FU may also improve patient acceptability and tolerability. In a phase III trial designed to demonstrate equivalence of XELOX vs. FOLFOX, the PFS of XELOX was shown to be noninferior to FOLFOX (median 8.0 vs. 8.5 months) (Cassidy et al. 2008). Recognizing that exposure to all three active chemotherapy agents extends survival (Grothey et al. 2004) and that a proportion of patients may not be suitable for second-line therapy, the strategy of combining oxaliplatin, irinotecan and 5-FU in a single first-line regimen can be of interest. In an Italian randomized trial of FOLFOXIRI vs. FOLFIRI, the triplet combination yielded superior RR (60 vs. 34%, p < 0.0001), PFS (9.8 vs. 6.9 months, p = 0.0006) and OS (22.6 vs. 16.7 months, p = 0.03) (Falcone et al. 2007). A combined analysis of triplet regimen studies reaffirms improved response rates, PFS, OS and hepatic resection rates compared to FOLFIRI therapy, but at the expense of increased toxicity, notably diarrhea, vomiting and neutropenia (Montagnani et al. 2010).
First and Second-Line Targeted Therapies in Advanced Disease Table 12.10 summarizes the key trials assessing the combination of available biologic therapies with first- and second-line chemotherapies. These trials are discussed below.
Bevacizumab Bevacizumab is a humanized mAb to the VEGF-A ligand, thus halting the VEGF signaling pathway. Available evidence suggests that the efficacy of bevacizumab is mediated by antiVEGF induced vascular normalization which may alleviate hypoxia and improve delivery of the chemotherapy backbone to the tumor (Jain 2005). The pivotal trial was a randomized comparison of first-line IFL plus placebo with IFL plus bevacizumab 5 mg/kg every 2 weeks (Hurwitz et al. 2004). Median survival was increased from 15.6 to 20.3 months (p < 0.001) with the addition of bevacizumab, as were TTP (10.6 vs. 6.2 months, p < 0.001) and RR (45
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Table 12.10 Selected first and second-line phase 3 studies of biologics in combination with chemotherapy Study-Author Chemotherapy Biologic Primary efficacy endpoint First-line AVF2107g, Hurwitz et al. (2004)
IFL
Bevacizumab
Second-line E3200, Giantonio et al. (2007)
FOLFOX
Bevacizumab
EPIC, Sobrero et al. (2008)
Irinotecan
181, Peeters et al. (2010)
FOLFIRI
NO16966, Saltz et al. (2008) CRYSTAL, Van Cutsem et al. (2009b) PRIME, Siena et al. (2010)
Median OS 20.3 vs. 15.6 months HR 0.66, p < 0.001 FOLFOX/XELOX Bevacizumab Median PFS 9.4 vs. 8.0 months HR 0.83, p = 0.0023 FOLFIRI Cetuximab Median PFS 9.3 vs. 8.7 months (wtKRAS) HR 0.68, p = 0.02 FOLFOX Panitumumab Median PFS 9.6 vs. 8.0 months (wtKRAS) HR 0.80, p = 0.02 Median OS 12.9 vs. 10.8 months HR 0.75, p = 0.0011 Cetuximab Median OS 10.7 vs. 9.9 months HR 0.975, p = 0.71 Panitumumab Median PFS 5.9 vs. 3.9 months (wtKRAS) HR 0.73, p = 0.004
vs. 35%, p = 0.004). Notable and expected toxicity with bevacizumab was limited to grade 3 hypertension (10.3 vs. 2.3%), increased risk of arterial thrombo-embolic events, and rare reports of gastrointestinal perforation and wound dehiscence. Bevacizumab in combination with first-line 5-FU/LV monotherapy has been evaluated in two phase II trials (Kabbinavar et al. 2003, 2005a) and as a third treatment arm of the Hurwitz trial which was discontinued after a planned interim analysis established acceptable safety for the IFL plus bevacizumab arm (Hurwitz et al. 2005). In a combined efficacy analysis of these three cohorts, the addition of bevacizumab to 5-FU/LV resulted in an improvement in survival (17.9 vs. 14.6 months, p = 0.008), TTP (8.8 vs. 5.6 months, p < 0.0001) and RR (34 vs. 24%, p = 0.019) (Kabbinavar et al. 2005b). NO16966 was a randomized phase III 2X2 factorial trial of firstline FOLFOX vs. XELOX with or without bevacizumab (Saltz et al. 2008). While the primary endpoint of superior PFS was met in this study, the magnitude of benefit was lower than anticipated. This was partly attributed to methodologic concerns pertaining to treatment discontinuations in the absence of progressive disease, and variability in the definition of the primary PFS endpoint. When compared to the Hurwitz/IFL findings, a differential efficacy of bevacizumab with an irinotecan vs. oxaliplatin backbone has also been speculated. Despite these issues, the use of bevacizumab in combination with either FOLFOX or FOLFIRI remains the current standard of care for first-line therapy.
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To investigate the role of bevacizumab in second-line, a randomized trial of FOLFOX with or without bevacizumab was conducted in patients with IFL-refractory metastatic CRC (Giantonio et al. 2007). Survival, TTP and RR with FOLFOX plus bevacizumab (10 mg/kg every 2 weeks) was superior to FOLFOX alone (respectively 12.9 vs. 10.8 months, p = 0.0018, 7.2 vs. 4.8 months, p < 0.001 and 22 vs. 9%, p < 0.001). No meaningful activity was seen with single-agent bevacizumab (RR 3%). The addition of bevacizumab to second-line chemotherapy is therefore an appropriate option in bevacizumab-naïve patients. In clinical reality, this represents a minority of patients. In fact, there exists considerable interest in evaluating the role of continued bevacizumab therapy beyond progression of first-line chemotherapy. This is sparked primarily from the results of the phase IV bevacizumab registry study (BRiTE) which reported a remarkable 31.8 month survival in patients who went to receive postprogression chemotherapy with continued bevacizumab (Grothey et al. 2008). While impressive, this strategy requires prospective, controlled validation.
C etuximab and Panitumumab Cetuximab is a chimeric mAb against the extracellular domain of EGFR. Panitumumab is a fully human mAb against the same EGFR target. Both agents have demonstrated singleagent efficacy and approved indications in the chemotherapy-refractory setting with lack efficacy in tumors with mutated KRAS, as discussed in the next section. The initial investigation of the role of antiEGFR therapy in treatment-naïve disease focused on the strategy of combining cetuximab or panitumumab to the current standard of chemotherapy plus bevacizumab. Unfortunately, this dual-antibody approach yielded negative outcomes and was promptly abandoned in light of evidence of harm in two large phase 3 trials: the PACCE trial (Hecht et al. 2009) (HR for PFS 1.27; 95% CI, 1.06–1.52 with the addition of panitumumab) and the CAIRO2 trial (Tol et al. 2009) (HR for PFS 1.22; 95% CI, 1.04–1.43 with the addition of cetuximab). A number of randomized trials evaluating the combination of first-line chemotherapy with cetuximab or panitumumab compared to chemotherapy alone have been completed within the last 2 years (see Table 12.10). These phase 3 trials have consistently demonstrated enhanced response rates and improved PFS with the addition of cetuximab or panitumumab in tumors with wild type (wild-type KRAS) (Bokemeyer et al. 2009; Siena et al. 2010; Van Cutsem et al. 2009b). Ongoing randomized trials including a phase 3 CALGB/SWOG-led by North American Intergroup trial (C80405) are presently directly comparing the efficacy of doublet chemotherapy with cetuximab or panitumumab to a standard of chemotherapy plus bevacizumab in the first-line treatment of unresectable, metastatic wild-type KRAS colorectal cancer.
12.6.7 Management of Chemotherapy-Refractory Disease Therapeutic options are limited once a patient has exhausted 5-FU, irinotecan, oxaliplatin and bevacizumab. The BOND trial was a UK MRC randomized (2:1 assignment) phase II trial of irinotecan plus cetuximab (400 mg/mg2 loading dose then weekly 250 mg/m2) or cetuximab alone in irinotecan-refractory metastatic CRC (Cunningham et al. 2004). Over 60% of enrolled patients had also previously progressed on oxaliplatin. Response rates
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(primary endpoint), TTP and survival were respectively 23%, 4.1 and 8.6 months for irinotecan plus cetuximab and 11%, 1.5 and 6.9 months for cetuximab alone. Cetuximab use was associated with an acneiform rash. Despite the lack of phase III survival data, cetuximab was approved in 2004 in the US and European Union for second or subsequent-line therapy in patients with EGFR-positive, irinotecan-refractory metastatic CRC, recognizing that this was an area of an unmet medical need. The National Cancer Institute of Canada – Clinical Trials Group Study CO-17 randomized patients with chemotherapy-refractory disease between cetuximab and best supportive care (Jonker et al. 2007). A modest but statistically significant improvement in OS was observed with cetuximab (median survival 6.1 vs. 4.6 months, HR 0.77, p = 0.005). A study in a similar population was performed with panitumumab (Van Cutsem et al. 2007) which demonstrated an improved PFS (HR 0.54, p < 0.0001) but was unable to prove an OS benefit as this endpoint was confounded by a 76% cross-over rate. During this time, retrospective analyses emerged which led to the breakthrough of KRAS status as a determinant of treatment benefit with antiEGFR therapy (Benvenuti et al. 2007; Lievre et al. 2006). The KRAS-RAF-MAPK signaling pathway is activated downstream of EGFR. Mutation of KRAS causes constitutive oncogenic activation of this downstream cascade resulting in cell proliferation, antiapoptotic effect and angiogenesis (Bardelli and Siena 2010). The consequent independence from upstream signaling results in a failure to respond to blockade of the transmembrane EGFR receptor vis-à-vis cetuximab or panitumumab. KRAS mutation, specifically a mutation in codons 12 or 13, is observed in up to 40% of CRC. While no longer felt to unequivocally be a marker of poor prognosis, the negative predictive value of mutant KRAS has been confirmed in multiple KRAS correlative reanalyses of cetuximab and panitumumab phase 2 and 3 clinical trials. Notably, the CO.17 KRAS analysis demonstrated an extraordinary 4.7 month improvement in OS with the use of third-line cetuximab in the wtKRAS subset (median survival 9.5 vs. 4.8 months, HR 0.55, p < 0.001) (Karapetis et al. 2008). In accordance with the 2009 ASCO guidelines for KRAS testing, if KRAS mutation in codon 12 or 13 is detected, then patients should not receive antiEGFR antibody therapy (Allegra et al. 2009). The demonstration of the predictive utility of KRAS has heralded an era of intense investigation for additional genetic determinants to further tailor therapies for colon cancer. KRAS and BRAF mutations are mutually exclusive in CRC. Mutations in the BRAF V600E allele may account for up to 15% of wt KRAS nonresponders, based upon an initial retrospective study of 113 cases treated with antiEGFR therapy (Di Nicolantonio et al. 2008) and later studies with similar results (Laurent-Puig et al. 2009; Loupakis et al. 2009). Based upon these findings, evaluation of BRAF status in addition to KRAS mutational status is now recommended by the 2010 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for the management of colon cancer. However, recent re-analyses confirm the negative prognostic value of BRAF mutations but fail to confirm that it is a negative predictive marker for antiEGFR theraphy (Bokemeyer 2010). Hence, it is not clear that patients whos tumors harbor BRAF mutations do not benefit from therapy with cetuximab or panitumumab. The last decade has witnessed remarkable strides in the management of patients with advanced colorectal cancer. The optimal approach is continually being redefined with previous distinct lines of therapy now blurred into individualized treatment strategies which employ locoregional and surgical therapies where appropriate, in combination with tailored systemic
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and targeted chemotherapies. A personalized approach to cancer management with rational selection of therapies will hopefully continue to improve as advances are made in our understanding of the molecular predictors of prognosis and treatment efficacy in colon cancer.
References Aaronson SA (1991) Growth factors and cancer. Science 254:1146–1153 Abdalla EK, Vauthey JN, Ellis LM et al (2004) Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 239:818–825; discussion 817–825 Ackerman NB (1974) The blood supply of experimental liver metastases. IV. Changes in vascularity with increasing tumor growth. Surgery 75:589–596 Adam R, Avisar E, Ariche A et al (2001) Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 8:347–353 Adam R, Delvart V, Pascal G et al (2004) Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 240:644– 657; discussion 648–657 Adam R, Miller R, Pitombo M et al (2007) Two-stage hepatectomy approach for initially unresectable colorectal hepatic metastases. Surg Oncol Clin North Am 16:525–536, viii Ahsan H, Neugut AI, Garbowski GC et al (1998) Family history of colorectal adenomatous polyps and increased risk for colorectal cancer. Ann Intern Med 128:900–905 AJCC (2010) American Joint Committee on Cancer – cancer staging manual, 7th edn. Springer, New York Alberts S, Sargent DJ, Smyrk T et al (2010) Adjuvant mFOLFOX6 with or without cetuximab in KRAS wild-type patients with resected stage III colon cancer: results from NCCTG Intergroup Phase III Trial N0147. J Clin Oncol 28:7s Allegra CJ, Jessup JM, Somerfield MR et al (2009) American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27:2091–2096 Aloia T, Sebagh M, Plasse M et al (2006) Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 24:4983–4990 Amichetti M, Lay G, Dessi M et al (2005) Results of whole brain radiation therapy in patients with brain metastases from colorectal carcinoma. Tumori 91:163–167 Andre T, Colin P, Louvet C et al (2003) Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 21:2896–2903 Andre T, Boni C, Mounedji-Boudiaf L et al (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351 Andre T, Boni C, Navarro M et al (2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109–3116 Armbrust T, Sobotta M, Fuzesi L, Grabbe E, Ramadori G (2007) Chemotherapy-induced suppression to adenoma or complete suppression of the primary in patients with stage IV colorectal cancer: report of four cases. Eur J Gastroenterol Hepatol 19:988–994 Arru M, Aldrighetti L, Castoldi R et al (2008) Analysis of prognostic factors influencing long-term survival after hepatic resection for metastatic colorectal cancer. World J Surg 32:93–103
12 Colon Cancer
365
Asano T, McLeod RS (2002) Dietary fibre for the prevention of colorectal adenomas and carcinomas. Cochrane Database Syst Rev CD003430 Atkin WS, Edwards R, Kralj-Hans I et al (2010) Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 375: 1624–1633 Bajetta E, Di Bartolomeo M, Mariani L, Cassata A, Artale S, Frustaci S, Pinotti G, Bonetti A, Carreca I, Biasco G, Bonaglia L, Marini G, Iannelli A, Cortinovis D, Ferrario E, Beretta E, Lambiase A, Buzzoni R; Italian Trials in Medical Oncology (I.T.M.O.) Group (2004) Randomized multicenter Phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma Cancer 100(2):279-287 Ballantyne GH, Quin J (1993) Surgical treatment of liver metastases in patients with colorectal cancer. Cancer 71:4252–4266 Barclay RL, Vicari JJ, Doughty AS, Johanson JF, Greenlaw RL (2006) Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med 355:2533–2541 Bardelli A, Siena S (2010) Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol 28:1254–1261 Bartelt S, Momm F, Weissenberger C, Lutterbach J (2004) Patients with brain metastases from gastrointestinal tract cancer treated with whole brain radiation therapy: prognostic factors and survival. World J Gastroenterol 10:3345–3348 Bauman G, Charette M, Reid R, Sathya J (2005) Therapeutic Radiopharmaceutical Guidelines Group of Cancer Care Ontario’s Program in Evidence-based C. Radiopharmaceuticals for the palliation of painful bone metastases – a systematic review. Radiother Oncol 75:258–270 Baxter NN, Virnig DJ, Rothenberger DA, Morris AM, Jessurun J, Virnig BA (2005) Lymph node evaluation in colorectal cancer patients: a population-based study. J Natl Cancer Inst 97:219–225 Baxter NN, Goldwasser MA, Paszat LF, Saskin R, Urbach DR, Rabeneck L (2009) Association of colonoscopy and death from colorectal cancer. Ann Intern Med 150:1–8 Bengtsson G, Carlsson G, Hafstrom L, Jonsson PE (1981) Natural history of patients with untreated liver metastases from colorectal cancer. Am J Surg 141:586–589 Benoist S, Pautrat K, Mitry E, Rougier P, Penna C, Nordlinger B (2005) Treatment strategy for patients with colorectal cancer and synchronous irresectable liver metastases. Br J Surg 92:1155–1160 Benson AB III, Schrag D, Somerfield MR et al (2004) American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22: 3408–3419 Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F et al (2007) Oncogenic activation of the RAS/ RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67:2643–2648 Bessa X, Balleste B, Andreu M et al (2008) A prospective, multicenter, population-based study of BRAF mutational analysis for Lynch syndrome screening. Clin Gastroenterol Hepatol 6:206–214 Bismuth H, Adam R, Levi F et al (1996) Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 224:509–520; discussion 502–520 Bleicher RJ, Allegra DP, Nora DT, Wood TF, Foshag LJ, Bilchik AJ (2003) Radiofrequency ablation in 447 complex unresectable liver tumors: lessons learned. Ann Surg Oncol 10:52–58 Blomgren H, Lax I, Naslund I, Svanstrom R (1995) Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol 34:861–870 Bokemeyer C, Bondarenko I, Makhson A et al (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671
366
S. Gill et al.
Bokemeyer C, Kohne C, Rougier P, Stroh C, Schlichting M, Van Cutsem E (2010) Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. [abstract 3506] J Clin Oncol 28:15s Bolton JS, Fuhrman GM (2000) Survival after resection of multiple bilobar hepatic metastases from colorectal carcinoma. Ann Surg 231:743–751 Bond JH (2000) Polyp guideline: diagnosis, treatment, and surveillance for patients with colorectal polyps. Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 95:3053–3063 Bowles BJ, Machi J, Limm WM et al (2001) Safety and efficacy of radiofrequency thermal ablation in advanced liver tumors. Arch Surg 136:864–869 Brentnall TA, Haggitt RC, Rabinovitch PS et al (1996) Risk and natural history of colonic neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis. Gastroenterology 110:331–338 Brown CJ, Raval MJ (2008) Advances in minimally invasive surgery in the treatment of colorectal cancer. Expert Rev Anticancer Ther 8:111–123 Brown PD, Stafford SL, Schild SE, Martenson JA, Schiff D (1999) Metastatic spinal cord compression in patients with colorectal cancer. J Neurooncol 44:175–180 Canon CL (2008) Is there still a role for double-contrast barium enema examination? Clin Gastroenterol Hepatol 6:389–392 Capussotti L, Muratore A, Baracchi F et al (2008) Portal vein ligation as an efficient method of increasing the future liver remnant volume in the surgical treatment of colorectal metastases. Arch Surg 143:978–982; discussion 982 Cassidy J, Tabernero J, Twelves C et al (2004) XELOX (capecitabine plus oxaliplatin): Active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084–2091 Cassidy J, Clarke S, Diaz-Rubio E et al (2008) Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26:2006–2012 Chang CH, Timmerman R (2007) Stereotactic body radiation therapy: a comprehensive review. Am J Clin Oncol 30:637–644 Chang GJ, Rodriguez-Bigas MA, Skibber JM, Moyer VA (2007a) Lymph node evaluation and survival after curative resection of colon cancer: systematic review. J Natl Cancer Inst 99: 433–441 Chang EL, Shiu AS, Mendel E et al (2007b) Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine 7:151–160 Chao A, Thun MJ, Connell CJ et al (2005) Meat consumption and risk of colorectal cancer. JAMA 293:172–182 Chibaudel B, Maindrault-Goebel F, Lledo G et al (2009) Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol 27:5727–5733 Chow E, Harris K, Fan G, Tsao M, Sze WM (2007) Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 25:1423–1436 Chua TC, Saxena A, Liauw W, Kokandi A, Morris DL (2010) Systematic review of randomized and nonrandomized trials of the clinical response and outcomes of neoadjuvant systemic chemotherapy for resectable colorectal liver metastases. Ann Surg Oncol 17: 492–501 Clancy TE, Dixon E, Perlis R, Sutherland FR, Zinner MJ (2005) Hepatic arterial infusion after curative resection of colorectal cancer metastases: a meta-analysis of prospective clinical trials. J Gastrointest Surg 9:198–206 Cole BF, Baron JA, Sandler RS et al (2007) Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297:2351–2359
12 Colon Cancer
367
Colucci G, Gebbia V, Paoletti G et al (2005) Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 23:4866–4875 Committee CCSS (2009) Canadian cancer statistics 2009. Canadian Cancer Society, Toronto Compton CC (2003) Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol 16:376–388 Compton CC (2006) Key issues in reporting common cancer specimens: problems in pathologic staging of colon cancer. Arch Pathol Lab Med 130:318–324 Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP (2000a) American Joint Committee on Cancer prognostic factors consensus conference: Colorectal Working Group. Cancer 88:1739–1757 Compton CC, Fielding LP, Burgart LJ et al (2000b) Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 124:979–994 Correa P (1978) Epidemiology of polyps and cancer. Major Probl Pathol 10:126–152 Covey AM, Tuorto S, Brody LA et al (2005) Safety and efficacy of preoperative portal vein embolization with polyvinyl alcohol in 58 patients with liver metastases. AJR Am J Roentgenol 185:1620–1626 Covey AM, Brown KT, Jarnagin WR et al (2008) Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal metastases. Ann Surg 247:451–455 Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345 De Gramont (2000) J Clin Oncol Di Nicolantonio F, Martini M, Molinari F et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705–5712 Doci R, Gennari L, Bignami P, Montalto F, Morabito A, Bozzetti F (1991) One hundred patients with hepatic metastases from colorectal cancer treated by resection: analysis of prognostic determinants. Br J Surg 78:797–801 Ekbom A, Helmick C, Zack M, Adami HO (1990) Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 323:1228–1233 Elias D, De Baere T, Smayra T, Ouellet JF, Roche A, Lasser P (2002) Percutaneous radiofrequency thermoablation as an alternative to surgery for treatment of liver tumour recurrence after hepatectomy. Br J Surg 89:752–756 Elias D, Baton O, Sideris L et al (2005) Hepatectomy plus intraoperative radiofrequency ablation and chemotherapy to treat technically unresectable multiple colorectal liver metastases. J Surg Oncol 90:36–42 Fairchild A, Chow E (2007) Role of radiation therapy and radiopharmaceuticals in bone metastases. Curr Opin Support Palliat Care 1:169–173 Falcone A, Ricci S, Brunetti I et al (2007) Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 25:1670–1676 Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767 Fernandez FG, Drebin JA, Linehan DC, Dehdashti F, Siegel BA, Strasberg SM (2004) Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 240:438– 447; discussion 447–450 Ferrucci JT (2006) Double-contrast barium enema: use in practice and implications for CT colonography. AJR Am J Roentgenol 187:170–173 Figueredo A, Charette ML, Maroun J, Brouwers MC, Zuraw L (2004) Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in evidence-based care’s gastrointestinal cancer disease site group. J Clin Oncol 22:3395–3407
368
S. Gill et al.
Folprecht G, Gruenberger T, Bechstein WO et al (2010) Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 11:38–47 Fong Y, Cohen AM, Fortner JG et al (1997) Liver resection for colorectal metastases. J Clin Oncol 15:938–946 Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH (1999) Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 230:309–318; discussion 318–321 Gayowski TJ, Iwatsuki S, Madariaga JR et al (1994) Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathologic risk factors. Surgery 116:703–710; discussion 701–710 Gazelle GS, Hunink MG, Kuntz KM et al (2003) Cost-effectiveness of hepatic metastasectomy in patients with metastatic colorectal carcinoma: a state-transition Monte Carlo decision analysis. Ann Surg 237:544–555 Giacchetti S, Perpoint B, Zidani N et al (2003) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18(1):136-147 Giantonio BJ, Catalano PJ, Meropol NJ et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25: 1539–1544 Giardiello FM, Trimbath JD (2006) Peutz-Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol 4:408–415 Giardiello FM, Brensinger JD, Tersmette AC et al (2000) Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119:1447–1453 Giardiello FM, Brensinger JD, Petersen GM (2001) AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 121:198–213 Gill S, Loprinzi CL, Sargent DJ et al (2004) Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 22: 1797–1806 Gillen CD, Walmsley RS, Prior P, Andrews HA, Allan RN (1994) Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 35:1590–1592 Giovannucci E (1995) Insulin and colon cancer. Cancer Causes Control 6:164–179 Giovannucci E, Stampfer MJ, Colditz GA et al (1998) Multivitamin use, folate, and colon cancer in women in the Nurses’ Health Study. Ann Intern Med 129:517–524 Goel A, Arnold CN, Niedzwiecki D et al (2003) Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res 63:1608–1614 Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30 Gomez D, Morris-Stiff G, Wyatt J, Toogood GJ, Lodge JP, Prasad KR (2008) Surgical technique and systemic inflammation influences long-term disease-free survival following hepatic resection for colorectal metastasis. J Surg Oncol 98:371–376 Gray RG, Barnwell J, Hills R et al (2004) QUASAR: A randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. J Clin Oncol 22:3408–3419 Greenstein AJ, Sachar DB, Smith H et al (1979) Cancer in universal and left-sided ulcerative colitis: factors determining risk. Gastroenterology 77:290–294 Grothey A, Sargent D (2005) Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 23:9441–9442
12 Colon Cancer
369
Grothey A, Sargent D, Goldberg RM, Schmoll HJ (2004) Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209–1214 Grothey A, Sugrue MM, Purdie DM et al (2008) Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol 26:5326–5334 Gruenberger B, Scheithauer W, Punzengruber R, Zielinski C, Tamandl D, Gruenberger T (2008a) Importance of response to neoadjuvant chemotherapy in potentially curable colorectal cancer liver metastases. BMC Cancer 8:120 Gruenberger B, Tamandl D, Schueller J et al (2008b) Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 26:1830–1835 Gunderson LL, Sosin H, Levitt S (1985) Extrapelvic colon – areas of failure in a reoperation series: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 11:731–741 Gunderson L, Martenson J, Smalley S, Garton G (1994) Lower gastrointestinal cancers: rationale, results, and techniques of treatment. Front Radiat Ther Oncol 28:140–154 Gunderson LL, Jessup JM, Sargent DJ, Greene FL, Stewart AK (2010) Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol 28:264–271 Haddock MG, Gunderson LL, Nelson H et al (2001) Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients. Int J Radiat Oncol Biol Phys 49:1267–1274 Haddock MG, Nelson H, Donohue JH et al (2003) Intraoperative electron radiotherapy as a component of salvage therapy for patients with colorectal cancer and advanced nodal metastases. Int J Radiat Oncol Biol Phys 56:966–973 Haggitt RC, Glotzbach RE, Soffer EE, Wruble LD (1985) Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic polypectomy. Gastroenterology 89:328–336 Hakama M, Hoff G, Kronborg O, Pahlman L (2005) Screening for colorectal cancer. Acta Oncol 44:425–439 Haller DG, Catalano PJ, Macdonald JS et al (2005) Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of intergroup 0089. J Clin Oncol 23:8671–8678 Haller DG, Cassidy J, Tabernero J et al (2010) Efficacy findings from a randomized phase III trial of capecitabine plus oxaliplatin versus bolus 5-FU/LV for stage III colon cancer (NO16968): no impact of age on disease-free survival. In: Proceedings of the American society of clinical oncology GI cancers symposium, Orlando Hassan C, Zullo A, Risio M, Rossini FP, Morini S (2005) Histologic risk factors and clinical outcome in colorectal malignant polyp: a pooled-data analysis. Dis Colon Rectum 48:1588–1596 Hecht JR, Mitchell E, Chidiac T et al (2009) A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27:672–680 Heresbach D, Barrioz T, Lapalus MG et al (2008) Miss rate for colorectal neoplastic polyps: a prospective multicenter study of back-to-back video colonoscopies. Endoscopy 40:284–290 Herfarth KK, Debus J (2005) Stereotactic radiation therapy for liver metastases. Chirurg 76:564–569 Herfarth KK, Debus J, Lohr F et al (2001) Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol 19:164–170 Hermanek P (1987) Adenoma/dysplasia –carcinoma sequence in the small intestine. Z Gastroenerol 25(3): 166-167 (German) Hewitson P, Glasziou P, Watson E, Towler B, Irwig L (2008) Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterol 103:1541–1549
370
S. Gill et al.
Hida J, Okuno K, Yasutomi M et al (2005) Optimal ligation level of the primary feeding artery and bowel resection margin in colon cancer surgery: the influence of the site of the primary feeding artery. Dis Colon Rectum 48:2232–2237 Hughes TG, Jenevein EP, Poulos E (1983) Intramural spread of colon carcinoma. A pathologic study. Am J Surg 146:697–699 Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342 Hurwitz HI, Fehrenbacher L, Hainsworth JD et al (2005) Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502–3508 Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge JD, Ransohoff DF (2000) Risk of advanced proximal neoplasms in asymptomatic adults according to the distal colorectal findings. N Engl J Med 343:169–174 International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators (1999) Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol 17:1356–1363 Ishizuka M, Nagata H, Takagi K, Horie T, Kubota K (2007) Inflammation-based prognostic score is a novel predictor of postoperative outcome in patients with colorectal cancer. Ann Surg 246:1047–1051 Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62 Jarnagin WR, Conlon K, Bodniewicz J et al (2001) A clinical scoring system predicts the yield of diagnostic laparoscopy in patients with potentially resectable hepatic colorectal metastases. Cancer 91:1121–1128 Jarnagin WR, Gonen M, Fong Y et al (2002) Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg 236:397–406; discussion 397–406 Jemal A, Thun MJ, Ries LA et al (2008) Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 100:1672–1694 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249 Jen J, Kim H, Piantadosi S et al (1994) Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331:213–221 Johnson PM, Porter GA, Ricciardi R, Baxter NN (2006) Increasing negative lymph node count is independently associated with improved long-term survival in stage IIIB and IIIC colon cancer. J Clin Oncol 24:3570–3575 Jonker DJ, O’Callaghan CJ, Karapetis CS et al (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048 Kabbinavar F, Hurwitz HI, Fehrenbacher L et al (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60–65 Kabbinavar FF, Schulz J, McCleod M et al (2005a) Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 23:3697–3705 Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S (2005b) Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 23:3706–3712 Karapetis CS, Khambata-Ford S, Jonker DJ et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765 Karoui M, Penna C, Amin-Hashem M et al (2006) Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 243:1–7
12 Colon Cancer
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Kavanagh BD, McGarry RC, Timmerman RD (2006a) Extracranial radiosurgery (stereotactic body radiation therapy) for oligometastases. Semin Radiat Oncol 16:77–84 Kavanagh BD, Schefter TE, Cardenes HR et al (2006b) Interim analysis of a prospective phase I/ II trial of SBRT for liver metastases. Acta Oncol 45:848–855 Kemeny N, Huang Y, Cohen AM et al (1999) Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341:2039–2048 Kerr D, Gray R, Quirke P et al (2009) A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study [abstract 4000]. J Clin Oncol 27:15s Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170 Klabunde CN, Lanier D, Breslau ES et al (2007) Improving colorectal cancer screening in primary care practice: innovative strategies and future directions. J Gen Intern Med 22:1195–1205 Kohne CH, Van Cutsem E, Wils J et al (2005) Phase III Study of Weekly High-Dose Infustional Fluorouracil Plus Folinic Acid With or Without Irinotecan in Patients With Metastatic Colorectal Cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986 JCO Aug 1 4856-4865 Kooby DA, Stockman J, Ben-Porat L et al (2003) Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg 237:860–869; discussion 869–870 Koopman M, Antonini NF, Douma J et al (2007) Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 370:135–142 Kopetz S, Chang GJ, Overman MJ et al (2009) Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 27:3677–3683 Kosari K, Gomes M, Hunter D, Hess DJ, Greeno E, Sielaff TD (2002) Local, intrahepatic, and systemic recurrence patterns after radiofrequency ablation of hepatic malignancies. J Gastrointest Surg 6:255–263 Koushik A, Hunter DJ, Spiegelman D et al (2007) Fruits, vegetables, and colon cancer risk in a pooled analysis of 14 cohort studies. J Natl Cancer Inst 99:1471–1483 Kritchevsky D (1995) Epidemiology of fibre, resistant starch and colorectal cancer. Eur J Cancer Prev 4:345–352 Kuebler JP, Wieand HS, O’Connell MJ et al (2007) Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 25:2198–2204 Kuhry E, Schwenk WF, Gaupset R, Romild U, Bonjer HJ (2008) Long-term results of laparoscopic colorectal cancer resection. Cochrane Database Syst Rev CD003432 Laghi L, Bianchi P, Roncalli M, Malesci A (2004) Re: revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:1402–1403; author reply 1403–1404 Larsson SC, Rafter J, Holmberg L, Bergkvist L, Wolk A (2005) Red meat consumption and risk of cancers of the proximal colon, distal colon and rectum: the Swedish mammography cohort. Int J Cancer 113:829–834 Laurent-Puig P, Cayre A, Manceau G et al (2009) Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 27:5924–5930 Lee WS, Yun HR, Yun SH et al (2008) Treatment outcomes of hepatic and pulmonary metastases from colorectal carcinoma. J Gastroenterol Hepatol 23:e367–e372 Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386:623–627 Levi F, Zidani R, Brienza S, Dogliotti L, Perpoint B, Rotarski M, Letourneau Y, Llory JF, Chollet P, Le Rol A, Focan C (1999) A multicenter evaluation of intensified, ambulatory, chronomodulated
372
S. Gill et al.
chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma: International Organization for Cancer Chronotherapy. Cancer 85:2532–2540 Levin B, Lieberman DA, McFarland B et al (2008) Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 58:130–160 Lieberman DA, Weiss DG (2001) One-time screening for colorectal cancer with combined fecal occult-blood testing and examination of the distal colon. N Engl J Med 345:555–560 Liebig C, Ayala G, Wilks J et al (2009) Perineural invasion is an independent predictor of outcome in colorectal cancer. J Clin Oncol 27:5131–5137 Lievre A, Bachet JB, Le Corre D et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995 Lindor NM, Burgart LJ, Leontovich O et al (2002) Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20:1043–1048 Lindor NM, Petersen GM, Hadley DW et al (2006) Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 296: 1507–1517 Liu B, Nicolaides NC, Markowitz S et al (1995) Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet 9:48–55 Liu B, Parsons R, Papadopoulos N et al (1996) Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med 2:169–174 Locker GY, Hamilton S, Harris J et al (2006) ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 24:5313–5327 Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR (2008) Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 134:29–38 Loupakis F, Ruzzo A, Cremolini C et al (2009) KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 101:715–721 Lynch HT, Smyrk T (1996) Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 78:1149–1167 Lynch HT, Boland CR, Rodriguez-Bigas MA, Amos C, Lynch JF, Lynch PM (2007) Who should be sent for genetic testing in hereditary colorectal cancer syndromes? J Clin Oncol 25:3534–3542 Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR (2009) Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 76:1–18 MacDermed DM, Weichselbaum RR, Salama JK (2008) A rationale for the targeted treatment of oligometastases with radiotherapy. J Surg Oncol 98:202–206 Machi J, Uchida S, Sumida K et al (2001) Ultrasound-guided radiofrequency thermal ablation of liver tumors: percutaneous, laparoscopic, and open surgical approaches. J Gastrointest Surg 5:477–489 Mala T, Edwin B, Gladhaug I et al (2002) A comparative study of the short-term outcome following open and laparoscopic liver resection of colorectal metastases. Surg Endosc 16: 1059–1063 Mamounas E, Wieand S, Wolmark N et al (1999) Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 17:1349–1355 Mann CD, Metcalfe MS, Leopardi LN, Maddern GJ (2004) The clinical risk score: emerging as a reliable preoperative prognostic index in hepatectomy for colorectal metastases. Arch Surg 139:1168–1172
12 Colon Cancer
373
Martenson JA Jr, Willett CG, Sargent DJ et al (2004) Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of intergroup protocol 0130. J Clin Oncol 22:3277–3283 Mathis KL, Nelson H, Pemberton JH, Haddock MG, Gunderson LL (2008) Unresectable colorectal cancer can be cured with multimodality therapy. Ann Surg 248:592–598 Mcleary N, Meyerhardt J, Green E et al (2009) Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients with stage II/IIII colon cancer: findings from the ACCENT database. Proc Am Soc Clin Oncol Mendez Romero A, Wunderink W, Hussain SM et al (2006) Stereotactic body radiation therapy for primary and metastatic liver tumors: a single institution phase I–II study. Acta Oncol 45:831–837 Mentha G, Terraz S, Morel P et al (2009) Dangerous halo after neoadjuvant chemotherapy and two-step hepatectomy for colorectal liver metastases. Br J Surg 96:95–103 Minagawa M, Makuuchi M, Torzilli G et al (2000) Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: long-term results. Ann Surg 231:487–499 Moertel CG, Fleming TR, Macdonald JS et al (1990) Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352–358 Moertel CG, Fleming TR, Macdonald JS et al (1995) Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med 122:321–326 Montagnani F, Chiriatti A, Turrisi G, Francini G, Fiorentini G (2010) A systematic review of FOLFOXIRI chemotherapy for the first-line treatment of metastatic colorectal cancer: improved efficacy at the cost of increased toxicity. Colorectal Dis Mulhall BP, Veerappan GR, Jackson JL (2005) Meta-analysis: computed tomographic colonography. Ann Intern Med 142:635–650 Mulier S, Ni Y, Jamart J, Ruers T, Marchal G, Michel L (2005) Local recurrence after hepatic radiofrequency coagulation: multivariate meta-analysis and review of contributing factors. Ann Surg 242:158–171 Muto T, Bussey HJ, Morson BC (1975) The evolution of cancer of the colon and rectum. Cancer 36(6): 2251-2270 Neal CP, Mann CD, Sutton CD et al (2009) Evaluation of the prognostic value of systemic inflammation and socioeconomic deprivation in patients with resectable colorectal liver metastases. Eur J Cancer 45:56–64 Nordlinger B, Sorbye H, Glimelius B et al (2008) Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 371:1007–1016 O’Brien MJ, Winawer SJ, Zauber AG et al (1990) The National Polyp Study. Patient and polyp characteristics associated with high-grade dysplasia in colorectal adenomas. Gastroenterology 98:371–379 O’Connell MJ, Mailliard JA, Kahn MJ et al (1997) Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 15:246–250 Odom SR, Duffy SD, Barone JE, Ghevariya V, McClane SJ (2005) The rate of adenocarcinoma in endoscopically removed colorectal polyps. Ann Surg 71(12): 1024-1026 Offerhaus GJ, Giardiello FM, Krush AJ et al (1992) The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology 102:1980–1982 Ogino S, Nosho K, Irahara N et al (2009a) Prognostic significance and molecular associations of 18q loss of heterozygosity: a cohort study of microsatellite stable colorectal cancers. J Clin Oncol 27:4591–4598 Ogino S, Meyerhardt JA, Irahara N et al (2009b) KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res 15:7322–7329
374
S. Gill et al.
Olsen CC, Welsh J, Kavanagh BD et al (2009) Microscopic and macroscopic tumor and parenchymal effects of liver stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 73: 1414–1424 Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108 Parks R, Gonen M, Kemeny N et al (2007) Adjuvant chemotherapy improves survival after resection of hepatic colorectal metastases: analysis of data from two continents. J Am Coll Surg 204:753–761; discussion 753–761 Pawlik TM, Scoggins CR, Zorzi D et al (2005) Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 241:715–722; discussion 714–722 Pawlik TM, Abdalla EK, Ellis LM, Vauthey JN, Curley SA (2006) Debunking dogma: surgery for four or more colorectal liver metastases is justified. J Gastrointest Surg 10:240–248 Pearson AS, Izzo F, Fleming RY et al (1999) Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies. Am J Surg 178:592–599 Peeters M, Price T, Hotko Y et al (2010) Randomized phase III study of panitumumab with FOLFIRI versus FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28:15s, 2010 (suppl; abstr 3565) Proceedings of the American Society of Clinical Oncology – GI symposium: abstract 282 Phillips RK, Wallace MH, Lynch PM et al (2002) A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 50:857–860 Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23:609–618 Popat S, Zhao D, Chen Z et al (2007) Relationship between chromosome 18q status and colorectal cancer prognosis: a prospective, blinded analysis of 280 patients. Anticancer Res 27:627–633 Portier G, Elias D, Bouche O et al (2006) Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 24:4976–4982 Power DG, Kemeny NE (2010) Role of adjuvant therapy after resection of colorectal cancer liver metastases. J Clin Oncol 28:2300–2309 Rabeneck L, Paszat LF, Hilsden RJ et al (2008) Bleeding and perforation after outpatient colonoscopy and their risk factors in usual clinical practice. Gastroenterology 135:1899–1906 Reddy SK, Morse MA, Hurwitz HI et al (2008) Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. J Am Coll Surg 206:96–106 Rees M, Tekkis PP, Welsh FK, O’Rourke T, John TG (2008) Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 247:125–135 Rex DK (2006) Maximizing detection of adenomas and cancers during colonoscopy. Am J Gastroenterol 101:2866–2877 Rex DK, Cutler CS, Lemmel GT et al (1997) Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 112:24–28 Ribic CM, Sargent DJ, Moore MJ et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257 Robert ME (2007) The malignant colon polyp: diagnosis and therapeutic recommendations. Clin Gastroenterol Hepatol 5:662–667 Rodriguez-Bigas MA, Boland CR, Hamilton SR et al (1997) A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89:1758–1762
12 Colon Cancer
375
Roth AD, Tejpar S, Delorenzi M et al (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 28:466–474 Rouffet F, Hay JM, Vacher B et al (1994) Curative resection for left colonic carcinoma: hemicolectomy vs. segmental colectomy. A prospective, controlled, multicenter trial. French Association for Surgical Research. Dis Colon Rectum 37:651–659 Ruo L, Gougoutas C, Paty PB, Guillem JG, Cohen AM, Wong WD (2003) Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for asymptomatic patients. J Am Coll Surg 196:722–728 Saltz LB, Niedzwiecki D, Hollis D et al (2004) Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803). J Clin Oncol 22:246 Saltz LB, Clarke S, Diaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019 Sargent DJ, Goldberg RM, Jacobson SD et al (2001) A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345:1091–1097 Sargent DJ, Marsoni S, Monges G, et al (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28(20): 3219–3226 Scheithauer W, McKendrick J, Begbie S et al (2003) Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: Safety results of a randomized, phase III trial. Ann Oncol 14:1735-1743 Schmeler KM, Lynch HT, Chen LM et al (2006) Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 354:261–269 Schuller J, Cassidy J, Dumont E et al (2000) Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45:291–297 Schussler-Fiorenza CM, Mahvi DM, Niederhuber J, Rikkers LF, Weber SM (2004) Clinical risk score correlates with yield of PET scan in patients with colorectal hepatic metastases. J Gastrointest Surg 8:150–157; discussion 157–158 Sebastian S, Johnston S, Geoghegan T, Torreggiani W, Buckley M (2004) Pooled analysis of the efficacy and safety of self-expanding metal stenting in malignant colorectal obstruction. Am J Gastroenterol 99:2051–2057 Seifert JK, Bottger TC, Weigel TF, Gonner U, Junginger T (2000) Prognostic factors following liver resection for hepatic metastases from colorectal cancer. Hepatogastroenterology 47:239–246 Shinya H, Wolff WI (1979) Morphology, anatomic distribution and cancer potential of colonic polyps. Ann Surg 190(6): 679-683 Seymour MT, Maughan TS, Ledermann JA et al (2007) Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 370:143–152 Siena S, Cassidy J, Tabernero J et al (2010) Randomized phase III study of panitumumab (pmab) with FOLFOX4 compared to FOFLOX4 alone as first-line treatment for metastatic colorectal cancer: PRIME trial [abstract 283]. J Clin Oncol Small RM, Lubezky N, Shmueli E et al (2009) Response to chemotherapy predicts survival following resection of hepatic colo-rectal metastases in patients treated with neoadjuvant therapy. J Surg Oncol 99:93–98 Sobrero AF, Aschele C, Bertino JR (1997) Fluorouracil in colorectal cancer – a tale of two drugs: implications for biochemical modulation. J Clin Oncol 15:368–381 Sobrero AF, Maurel J, Fehrenbacher L et al (2008) EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26:2311–2319
376
S. Gill et al.
Solbiati L, Livraghi T, Goldberg SN et al (2001) Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients. Radiology 221:159–166 Sorbye H, Glimelius B, Berglund Å et al (2004) Multicentre phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 22:31–38 Tabernero J, Van Cutsem E, Díaz-Rubio E (2007) Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 25(33):5225–5232 Tan MC, Castaldo ET, Gao F et al (2008) A prognostic system applicable to patients with resectable liver metastasis from colorectal carcinoma staged by positron emission tomography with [18F]fluoro-2-deoxy-D-glucose: role of primary tumor variables. J Am Coll Surg 206: 857–868; discussion 859–868 Teufel A, Steinmann S, Siebler J et al (2004) Irinotecan plus folinic acid/continuous 5-fluorouracil as simplified bimonthly FOLFIRI regimen for first-line therapy of metastatic colorectal cancer. BMC Cancer 4:38 Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819 Timmerman R, Bastasch M, Saha D, Abdulrahman R, Hittson W, Story M (2007) Optimizing dose and fractionation for stereotactic body radiation therapy. Front Radiat Ther Oncol 40:352–365 Tol J, Koopman M, Cats A et al (2009) Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360:563–572 Tournigand C, Andre T, Achille E et al (2004) FOLFIRI followed by FOLFOX6 or the Reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22:2 Tournigand C, Cervantes A, Figer A et al (2006) OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer – a GERCOR Study. J Clin Oncol 24:394–400 Troisi RJ, Freedman AN, Devesa SS (1999) Incidence of colorectal carcinoma in the U.S.: an update of trends by gender, race, age, subsite, and stage, 1975–1994. Cancer 85:1670–1676 Tsao MN, Lloyd NS, Wong RKS, Rakovitch E, Chow E, Laperriere N (2005a) Radiotherapeutic management of brain metastases: a systematic review and meta-analysis. Cancer Treat Rev 31:256–273 Tsao M, Lloyd N, Wong R (2005b) The Supportive Care Guidelines Group of Cancer Care Ontario’s Program in Evidence-based C. Clinical practice guideline on the optimal radiotherapeutic management of brain metastases. BMC Cancer 5:34 Twelves C, Wong A, Nowacki MP et al (2005) Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696–2704 Ueno H, Mochizuki H, Hashiguchi Y et al (2004) Risk factors for an adverse outcome in early invasive colorectal carcinoma. Gastroenterology 127:385–394 Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapyrefractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664 Van Cutsem E, Labianca R, Bodoky G et al (2009a) Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 27:3117–3125 Van Cutsem E, Kohne CH, Hitre E et al (2009b) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417 Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453–1456 Vauthey JN, Pawlik TM, Ribero D et al (2006) Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 24: 2065–2072
12 Colon Cancer
377
Velayos FS, Loftus EV Jr, Jess T et al (2006) Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study. Gastroenterology 130:1941–1949 Wagner JS, Adson MA, Van Heerden JA, Adson MH, Ilstrup DM (1984) The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 199:502–508 Watson P, Lin KM, Rodriguez-Bigas MA et al (1998) Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members. Cancer 83:259–266 Whitlock EP, Lin JS, Liles E, Beil TL, Fu R (2008) Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 149:638–658 Wicherts DA, Miller R, de Haas RJ et al (2008) Long-term results of two-stage hepatectomy for irresectable colorectal cancer liver metastases. Ann Surg 248:994–1005 Willett CG, Fung CY, Kaufman DS, Efird J, Shellito PC (1993) Postoperative radiation therapy for high-risk colon carcinoma. J Clin Oncol 11:1112–1117 Williams NS, Dixon MF, Johnston D (1983) Reappraisal of the 5 centimetre rule of distal excision for carcinoma of the rectum: a study of distal intramural spread and of patients’ survival. Br J Surg 70:150–154 Winawer S, Fletcher R, Rex D et al (2003) Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 124:544–560 Wolin KY, Yan Y, Colditz GA, Lee IM (2009) Physical activity and colon cancer prevention: a meta-analysis. Br J Cancer 100:611–616 Wolmark N, Fisher B, Rockette H et al (1988) Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst 80:30–36 Wolmark N, Rockette H, Fisher B et al (1993) The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 11:1879–1887 Wolmark N, Yothers G, O’Connell M et al (2009) A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: results of NSABP protocol C-08 [abstract LBA4]. J Clin Oncol 27:18s Wong SL, Mangu PB, Choti MA et al (2009) American Society of Clinical Oncology 2009 clinical evidence review on radiofrequency ablation of hepatic metastases from colorectal cancer. J Clin Oncol 28:493–508 Wright FC, Gagliardi AR, Law CH et al (2008) A randomized controlled trial to improve lymph node assessment in stage II colon cancer. Arch Surg 143:1050–1055; discussion 1055 Wulf J, Guckenberger M, Haedinger U et al (2006) Stereotactic radiotherapy of primary liver cancer and hepatic metastases. Acta Oncol 45:838–847 Ychou M, Raoul JL, Douillard JY et al (2009) A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol 20:674–680 Yin FF, Ryu S, Ajlouni M et al (2004) Image-guided procedures for intensity-modulated spinal radiosurgery. Technical note. J Neurosurg 101(Suppl 3):419–424 Zealley IA, Skehan SJ, Rawlinson J, Coates G, Nahmias C, Somers S (2001) Selection of patients for resection of hepatic metastases: improved detection of extrahepatic disease with FDG pet. Radiographics 21 Spec No:S55–S69
Rectal Cancer
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Claus Rödel, Dirk Arnold, and Torsten Liersch
13.1 Introduction The treatment of rectal cancer is as variable as its clinical presentations. It can occur as an early tumor suitable for local excison, a locally advanced tumor that requires major surgery plus (neo)adjuvant therapy, one invading adjacent organs with no evidence of distant metastases, and lastly, one presenting with distant metastases. New data have been collected and progress has been made both in surgery as well as in radiotherapy and chemotherapy. Better knowledge of radial microscopic lymphatic spread within the so-called mesorectum has led to the use of total mesorectal excision (TME). With this type of surgery, local control rates have been markedly increased and local failure rates above 15% are now no longer acceptable. Technical advances in radiotherapy and improvements in the sequencing of radiotherapy, chemotherapy, and surgery allow a further increase in the therapeutic ratio. Moreover, additional agents, for example, capecitabine, oxaliplatin, or irinotecan as well as targeted therapies, are currently incorporated into multimodality concepts. In addition, advances in both pathology and imaging have further contributed to the multidisciplinary management.
C. Rödel () Department of Radiotherapy and Oncology, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany e-mail:
[email protected] D. Arnold Department of Haematology and Oncology, University Halle-Wittenberg, Halle, Germany T. Liersch Department of General Surgery, University of Göttingen, Göttingen, Germany
C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_13, © Springer-Verlag Berlin Heidelberg 2011
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13.2 Epidemiology Colorectal cancer is the third most frequently diagnosed cancer in men and women in Europe and the U.S.A., with an estimated 40,840 new cases diagnosed in the U.S.A. in 2009 (Jemal et al. 2009). High incidence rates are found in North America, Western Europe, and Australia (»40–45 cases/100,000 population), and intermediate rates in Eastern Europe (»26/100,000), with the lowest rates found in Africa (»3–8/100,000). Approximately two-thirds of cases occur in the colon and one-third in the rectum. Within the U.S.A., little difference in incidence exists among whites, African Americans, and Asian Americans. The occurrence of sporadic colorectal cancer increases continuously above the age of 45–50 years for both genders and peaks in the seventh decade. Subgroups of patients, including those with inherited syndromes, such as familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), or hamartomatous polyposis conditions (e.g., the Peutz–Jeghers syndrome), can experience colorectal cancer at a much earlier age.
13.3 Etiology The etiology appears to be multifactorial in origin and includes both environmental factors and a genetic component. Approximately 75–85% of colorectal cancers are sporadic; 15–20% develop in those with either a positive family history or a personal history of colorectal cancer or polyps (Learn and Kahlenberg 2009). The remaining cases occur in people with certain genetic predispositions, such as HNPCC (4–7%) or FAP (1%), or in people with inflammatory bowel disease, particularly chronic ulcerative colitis (1%). The fundamental role of environmental factors is supported by observations in migrant populations. Generally, migrants from low-incident regions in Africa and Asia to the highincident regions of North America or Australia assume the incidence of the host country within one generation (Whittemore et al. 1990). Specifically, a high-fat, low-fiber diet is implicated in the development of colorectal cancer. Conversely, the ingestion of a highfiber diet and fish appears to be protective against colorectal cancer. Fiber causes the formation of a soft, bulky stool that dilutes out carcinogens; it also decreases colonic transit time, allowing less time for carcinogenic substances to contact the mucosa. The more sedentary lifestyle in western countries, prolonged cigarette smoking, and alcohol consumption also appear to be linked with the risk of colorectal neoplasia (Norat et al. 2005; Cho et al. 2004). Most colorectal cancers arise from benign, adenomatous polyps lining the wall of the bowel, with those that grow to a large size (>2 cm) and have villous appearance or contain dysplastic cells being most likely to progress to cancer. This progression from adenoma to carcinoma is associated with an accumulation of genetic alterations, including the activation of oncogenes and inactivation of tumor suppressor genes (Leslie et al.
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2002). One of the early steps in this process is the interruption of the APC/b-catenin/ TCF-4 pathway allowing unchecked cellular replication at the crypt surface. This can occur in the germline of FAP patients with the second allele being inactivated somatically or in sporadic cancers for which both alleles are somatically inactivated. At least two pathways exist to develop colorectal cancer: chromosomal instability (CIN) and microsatellite instability (MSI). CIN is the genetic reason for tumor formation in about 80–85% of colorectal cancer and the mechanism operative in FAP. It is typically coupled with mutations in K-ras and p53, ultimately leading to loss of heterozygosity of p53 and malignant transformation. MSI is found not only in >90% of HNPCCs that carry a germline inactivation in DNA mismatch repair genes, but also in 15% of sporadic cancer, in which epigenetic hypermethylation silences gene transcription of hMLH1 (Grady and Carethers 2008). With MSI, multiple frameshift mutations at microsatellite sequences occur, including those in exon coding sequences of the transforming growth factor b receptor II, the proapoptotic gene BAX, and DNA mismatch repair genes (hMSH3 and hMSH6). Clinically, tumors with MSI are located preferentially in the right colon, tend to be diploid, exhibit a mucinous histology with a lymphoid reaction around the tumor, and have a more favorable stage-matched prognosis compared with non-MSI tumors.
13.4 Prevention and Early Detection 13.4.1 Primary Prevention Primary prevention involves the identification and elimination of factors which cause or promote colorectal cancer or interfere with adenoma-to-carcinoma cascade. Dietary and lifestyle approaches employ higher-fiber/lower-fat components and increased physical activity. Other dietary components, such as selenium, carotenoids, and vitamins A, C, and E, may also have protective effects by scavenging free-oxygen radicals. Folic acid, a component of fresh fruits and green vegetable, supplies methyl groups necessary for nucleotide synthesis and gene regulation. Prospective studies generally support an inverse association between folate intake and colorectal cancer risk (Lashner et al. 1997). Chemopreventive strategies are based on population-based studies that strongly support an inverse relationship between use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, sulindac, or the new selective COX-2 inhibitors, and the risk of colorectal adenomas or carcinomas (Williams et al. 1999). COX-2 is commonly overexpressed in more than 50% of adenoma and 80–85% of adenocarcinoma. The protective role of aspirin and NSAIDs, however, has to be counterpoised with the adverse effects of these drugs that preclude any recommendation that they should be commonly used for chemoprevention. Currently under way are trials that focus on FAP patients, those with resection of early-stage colorectal carcinoma and those with a history of adenomatous polyps.
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13.4.2 Screening for Early Detection The process of malignant transformation from adenoma to carcinoma takes several years. The goal of screening is to prevent rectal cancer mortality through the detection and treatment of benign or premalignant lesions and curable-stage cancer. For the average-risk population, screening should begin at age 50 and should follow one of the following testing options: colonoscopy (preferably) every 10 years, or fecal occult blood testing every year and flexible sigmoidoscopy every 5 years, or double-contrast barium enema every 5 years. If there is an affected first-degree relative, a family history of FAP or HNPCC, or a personal history of adenomatous polyps, colorectal cancer, or chronic inflammatory bowel disease, screening should begin earlier and/or such patients should undergo screening more often than the average-risk group. Two promising but investigational approaches of screening tools include virtual colonoscopy and molecular stool testing. The first employs virtual reality technology from cross-sectional CT or MRI scans, the second is based on the molecular detection of neoplasm-specific DNA from exfoliated cancer cells (Huerta 2008; Yee 2009).
13.5 Clinical Manifestations Rectal cancer is usually symptomatic prior to diagnosis. Common symptoms include gross red blood in stool (mixed or covering stool, or by itself, sometimes accompanied by the passage of mucus) and a change in bowel habits such as unexplained constipation, diarrhea, or reduction in stool caliber. Hemorrhoidal bleeding should always be a diagnosis of exclusion. Obstructing rectal cancers frequently present with diarrhea rather than constipation. In cases of locally advanced rectal cancer with circumferential growth and extensive transmural penetration, urgency, inadequate emptying, and tenesmus is seen. Urinary symptoms and buttock or perineal pain from posterior extension are grave signs.
13.6 Diagnostic Evaluation and Imaging 13.6.1 Pretreatment Staging The standard workup for rectal cancer is seen in Table 13.1. The pretreatment evaluation of a patient with rectal cancer should include a careful history and physical examination. Through digital rectal examination (DRE; the average finger can reach approximately 8 cm above the anal verge), tumors can be assessed for size, ulceration, and fixation to surrounding structures. DRE also permits a cursory evaluation of the patient’s sphincter
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Including family history of colorectal cancer or polyps
Physical exam
Including assessment of size, minimum diameter of the lumen, mobility, distance from the anal verge, and cursory evaluation of sphincter function
Rigid rectoscopy
Including assessment of mobility, minimum diameter of the lumen, and distance from the anal verge. Allows diagnostic biopsy of the primary tumor (preferably performed after or 1 week before rectal ultrasound to avoid false positive classification of lymph nodes in the mesorectal compartment)
Colonoscopy or Enema
To detect possible synchronous neoplasm; barium is only allowed if there is no stenotic tumor. In cases of stenotic tumor enema with water soluble contrast is favored
Endorectal ultrasound
Considering a local excision or preoperative therapy; allows determination of the infiltration depth into the rectal wall and LN status, offers the surgeon, who should perform the ERUS, the possibility to clarify the surgical strategy (low anterior resection with sphincter preservation or coloanal anastomosis, APR)
Pelvic CT or MRI
To assess the extent of the primary tumor and lymph node involvement (for accuracy of transrectal ultrasound, CT, MRI for T and N staging, see Table 13.2)
Abdominal/lung-CT
To detect possible metastatic disease
CEA
To obtain baseline CEA level (a prognostic factor and important for follow-up)
Complete blood count
Anemia secondary to bleeding
function, which is critical when determining whether a patient is a candidate for a sphincter-sparing procedure. Additionally, anal manometry should be used to quantify the function of the internal and external sphincters. The anal pressures can be measured at 1-cm intervals, first in the resting state and then during periods of voluntary contraction of the external anal sphincter. In normal adults, intra-anal pressure is usually doubled during voluntary contraction. For the assessment of the anal pressure profile, the recording probe must be withdrawn from the rectum continuously at a constant rate. This continuous pullthrough technique allows an appropriate assessment of the anal pressure profile and functional sphincter length. As determined by this method the length of the high-pressure zone varies between 2.5 and 5 cm. Rigid proctosigmoidoscopy allows direct visualization of the lesion and provides an estimation of the size of the lesion and degree of obstruction. This procedure is used to obtain biopsies and gives an accurate measurement of the distance of the lesion from the anal verge and the linea dentata. A complete evaluation of the large bowel, preferably by colonoscopy, should also be done to rule out synchronous intraluminal neoplasms. The primary imaging modalities to assess the extent of the primary tumor are endorectal ultrasound (ERUS), multidetector 4–16 slice CT, and phased array MRI. ERUS is the most
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Table 13.2 Estimates of sensitivity and specificity for pelvic CT, MRI and ERUS: a meta-analysis by Bipat et al. (2004), encompassing 90 studies from 1985 to 2002 Stage Imaging modality Sensitivity (%) Specificity (%) Muscularis propria invasion
ERUS MRI CT
94 94 NA
86 69 NA
Perirectal tissue invasion
ERUS MRI CT
90 82 79
75 76 78
Adjacent organ invasion
ERUS MRI CT
70 74 72
97 96 96
Lymph node involvement
ERUS MRI CT
67 66 55
78 76 74
accurate tool in predicting T stage of rectal cancers, especially T1 vs. T2 (Table 13.2; Fig. 13.1) (Bipat et al. 2004; Puli et al. 2009). Thus, ERUS has been recommended as the investigation of choice in selection of potentially curative local excision which should be restricted to patients with T1 (sm1/sm2) tumors without further risk factors, as well as in the selection of patients with early T3 tumors (vs. T2) for neoadjuvant treatment. ERUS cannot be reliably used in patients with high or stenosing tumors. Noteably, overestimation of staging with this technique occurs more often than understaging. In the German CAO/ARO/AIO-94 study, 18% of patients in the immediate surgery arm – clinically staged by ERUS to have T3 and/or N+ disease – had lymph node negative tumors confined to the rectal wall (pT1/2 pN0) on
Mass
Fig. 13.1 Endorectal ultrasound (ERUS) visualizes the rectal wall as alternating hyperechoic and hypoechoic layers of tissue. The first layer is the hyperechoic water-filled balloon or mucosal interface, which is bounded by the hypoechoic mucosa and muscularis mucosa, the hyperechoic submucosa, the hypoechoic muscularis propria, and, finally, the hyperechoic muscularis propria or perirectal fat interface. Depth of penetration is determined by identifying which of these layers is disrupted by the tumor. The figure shows a mass infiltrating beyond the muscularis propria (thick arrow) into the perirectal fat (bright area in the lower part), indicating a uT3-rectal tumor
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pathologic assessment of the resected specimen (Sauer et al. 2004). This probably is due to the inflammatory and desmoplastic processes caused by the tumor (or by tumor biopsy taken within 1 week before ERUS was performed), but is also operator dependent. Endorectal coil MRT is an alternative to ERUS but appears not to be superior to ERUS for T staging. Because of limited acoustic penetration by ERUS, invasion of bulky tumors into the perirectal fat and adjacent organs and pelvic side walls is better evaluated by multislice-CT scan and phased array MRI. The involvement of the anal sphincter and levator ani muscles cannot be truly seen on CT scans, whereas high-resolution MRI techniques using phasedarray coils have led to better spatial resolution and particularly have been shown to identify the anal sphincter, puborectalis, and particularly the mesorectal fascia (Beets-Tan and Beets 2008) (Fig. 13.2a, b). This latter is an important feature to predict negative circumferential margins between the tumor and the mesorectal fascia, and makes phase array MRI superior to CT especially for lower third rectal tumors. Moreover, substaging of T3 tumors (T3a/b with tumor spread £5 mm into the mesorectal compartment) has been validated prospectively by the MERCURY Study Group (2007) and has shown direct agreement between pretreatment imaging and corresponding pathology. The identification of positive lymph nodes is more difficult. Involvement is mainly assessed by size criteria (>8 mm), although enlarged lymph nodes are not pathognomonic of tumor involvement, and morphological features such as the presence of mixed signal intensity and irregularity of the borders of the lymph nodes may be more reliable. The overall accuracy in detecting positive lymph nodes with the above techniques is approximately 60–75% (Table 13.2). The accuracy of MRI is similar to CT; however, it may be
male, 65 years, cT3 cN+ rectal caner,
F
E
A
A
G H C
C B D
a
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Fig. 13.2 (a) MRI scan of the pelvis: Rectal cancer of the lower third of the rectum. A bladder, B os pubis, C rectal cancer of the lower third of the rectum, uT3 uN+, D sphincter area, E mesorectum, F ossis coccygeus, G glandulae spermaticae, H venae of the pelvis. (b) MRI scan of the pelvis: Rectal cancer of the upper third of the rectum. A bladder, B os pubis, C rectal cancer of the lower third of the rectum, uT3 uN+, D sphincter area, E mesorectum, F ossis coccygeus, G glandulae spermaticae, H venae of the pelvis
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male, 74 years, cT3 cN+ rectal cancer,
E A
F
H
A
C
G
C E
B D
b
F
Fig. 13.2 (continued)
further enhanced with the use of superparamagnetic iron oxide particles (Lahaye et al. 2008). Likewise, the accuracy of ERUS for the detection of involved perirectal lymph nodes may be augmented if combined with fine needle aspiration. However, adequate clinical detection of lymph node involvement remains a challenge that is critically important with respect to the increasing use of preoperative treatment strategies. Screening for distant metastatic disease is accomplished routinely by chest X-ray and abdominal contrast-enhanced CT or MRI. Thoracic CT is recommended for high-risk rectal cancer and suspicious findings on chest X-ray. Bone scan and brain imaging are required for clinical symptoms only. The major advantage of a positron emission tomography (PET) scan is to differentiate between recurrent tumor and scar tissue by measuring tissue metabolism of an injected glucose-based substance. Scar tissue is inactive, whereas tumor generally is hypermetabolic. This test generally is not used in a routine preoperative metastatic workup.
13.6.2 Imaging After Radio(Chemo)therapy Although ERUS, CT, and MRI can be used to assess downstaging of the tumor after neoadjuvant multimodal treatment, it is not accurate in distinguishing between ypT0, ypT1, ypT2 or ypT3 residual cancers. Overstaging is common, especially when there is a fibrotic thickening of the rectal wall. A reasonably high level of accuracy has been observed by phased array MRI for differentiating ypT0–2 vs. ypT3 (Barbaro et al. 2009). Diffusion-weighted MRI has been investigated to monitor therapy response and to predict outcome to preoperative therapy; however, further studies are needed. For the identification of responders to neoadjuvant therapy, 18FDG (18F fluoro-2-deoxy-d-glucose)-PET has a larger role (Fig. 13.3). Many studies have reported a significant decrease in standardized uptake values (SUV) on postradiation FDG-PET in responders when compared to nonresponders, but the clinical value of this information remains to be determined (Calvo et al. 2004).
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a
b
Fig. 13.3 [18F]FDG-PET for response prediction in rectal cancer treated with preoperative chemoradiotherapy (CRT). (a) Whole-body (focused on the pelvis) [18F]FDG-PET scan with 300 MBq prior to preoperative 5-FU-based CRT: enhanced uptake in cUICC-III rectal cancer. (b) [18F] FDG-PET with 300 MBq after 3 weeks of ongoing preoperative 5-FU-based CRT: there was only a physiological uptake in the rectum; no signs for viable cancer were detectable and the patient was classified as a complete responder. After surgery the FDG-PET result was confirmed by histopathological findings (ypT0 ypN0 M0)
13.7 Pathology 13.7.1 Anatomy and Pathway of Spread The rectum is approximately 16 cm in length. Because of differences in treatment and prognosis the rectum is subdivided into three parts according to the distance of the lower margin of the tumor from the anal verge (assessed by rigid rectoscopy): upper third 12–16 cm, middle third 6 to £12 cm, and lower third <6 cm. In reporting results, it should be stated whether the reference point is the anal verge (i.e., lowermost portion of the anal canal), the dentate line, or the anorectal ring. Distances measured from the anal verge are approximately 2 cm greater than distances from the dentate line. The anorectal ring is at the level of the puborectalis sling and levators, representing the pelvic floor from within the pelvis. The anterior peritoneal reflection represents the point at which the rectum exits the peritoneal cavity and becomes retroperitoneal (approximately 8–12 cm from the anal verge, extremely variable between females and males). Below this level there is a mesorectal, or circumferential, resection margin all around the rectum. While distal intramural spread usually extends no more than some millimeters beyond the grossly recognizable margin of the tumor, microscopic tumor nodules, so-called satellites, are found in the mesorectum predominantly in the radial direction, but also distal, some centimeters from the lower tumor margin (Quirke et al. 1986; Hermanek
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et al. 2003). A layer of visceral fascia (fascia propria) encloses both rectum and mesorectum and thus forms a separate compartment within the pelvis. With TME, this entire package is removed by sharp retroperitoneal dissection within the anatomically defined avascular (“holy”) plane between the visceral and parietal pelvic fascia. The sharp dissection is performed under direct vision between the fascia propria of the mesorectum and the fascia presacralis (Waldeyer’s fascia). Anteriorly, the Denonvilliers’ fascia (in men) or the rectovaginal septum (in women) should be used as the standard plane of dissection, unless an anterior or circumferential tumor dictates a wider resection margin (en bloc resection), such as resection of the posterior vaginal wall The dissection is performed until the levator muscles are visible laterally and posteriorly to the rectum (Fig. 13.4a, b). The major portion of the lymphatic drainage of the rectum passes along the superior hemorrhoidal arterial trunk toward the inferior mesenteric artery. Only a few lymphatics follow the inferior mesenteric vein. The pararectal nodes above the level of the middle rectal valve drain exclusively along the superior hemorrhoidal lymphatic chain. Below this level (approximately 7–8 cm above the anal verge), some lymphatics pass to the lateral rectal pedicle. These lymphatics are associated with nodes along the middle hemorrhoidal artery, obturator fossa, and hypogastric and common iliac arteries. Extensive lymphatics are also present contiguous with the rectovaginal septum in women, and along Denonvilliers’ fascia in men. The venous drainage of the upper rectum is to the inferior mesenteric vein via the superior hemorrhoidal and then to the portal system, whereas the lower rectum can, in addition, drain to the internal iliac veins and inferior vena cava. Therefore, either liver or lung metastases or both can occur with rectal cancers.
13.7.2 Histopathology The vast majority (over 90%) of colorectal cancers are adenocarcinoma. Mucinous and signet ring carcinoma are both variants of adenocarcinoma and account for some 10% of all colorectal cancer. This subdivison appears to confer no independent prognostic value. Other histologic types are rare and include carcinoid tumors, leiomyosarcomas, lymphomas, and squamous cell cancers. The grading system used for adenocarcinomas refers to the degree of differentiation and anaplasticity (good, moderate, poor) of the untreated primary. Despite substantial inter- and intraobserver variability in tumor grading, poorly differentiated tumors have consistently been found to be associated with a worse prognosis in multivariate analysis.
13.7.3 TNM Classification System In 1988, the American Joint Commission on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) proposed a joint TNM staging system. This was based on the fifth edition of the AJCC TNM staging system. The sixth edition of the AJCC TNM staging system is seen in Table 13.3. There are four major changes from the fifth edition. These
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a
ventral view
dorsal view
A. mesenterica inferior
A. mesenterica inferior Peritoneal fold
Distal resection margin with Contour®-stapler
b Plexus hypogastricus sinister Left ureter
Cavity of sacrum Promontorium
Plexus hypogastricus dexter
Fig. 13.4 (a) Total mesorectal excision (TME) specimen after preoperative CRT and perioperatively performed staining with methylenblue via A. mesenterica inferior. (b) Situs after TME. The task for surgeons: to perform an extended oncological R0 resection and to preserve organs and their function
include the following: (1) A revised description of the anatomy of the colon and rectum which better delineates the data regarding the boundaries between the colon, rectum, and anus is provided. (2) Smooth metastatic nodules in the pericolic or perirectal fat are considered nodal metastasis. In contrast, irregularly contoured metastatic nodules in the peritumoral fat are considered vascular invasion and are coded as a subcategory of the T stage as V1 (microscopic vascular invasion) if microscopically visible or V2 (macroscopic vascular
Regional nodes cannot be assessed No regional nodes Metastasis to 1–3 regional lymph nodes Metastasis to >4 regional lymph nodes Distant metastasis cannot be assessed No distant metastasis Distant metastasis Cannot be assessed No lymphatic vessel invasion Lymphatic vessel invasion present Cannot be assessed No venous invasion Microscopic venous invasion present Macroscopic venous invasion present
Distant metastasis (M) Mx M0 M1
Lymphatic vessel invasionf Lx L0 L1
Venous invasion (V)f Vx V0 V1 V2
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ: intraepithelial or invasion of the lamina propriaa Tumor invades submucosab Tumor invades muscularis propria Tumor invades through the muscularis propria into the subserosa, or into nonperitonealized pericolic or perirectal tissuesc Tumor directly invades other organs or structures, and/or perforates the visceral peritoneumd,e
Regional lymph nodes (N) Nx N0 N1 N2
T4
Primary tumor (T) Tx T0 Tis T1 T2 T3
Table 13.3 American Joint Commission on Cancer (AJCC) TNM staging system for colorectal cancer (sixth edition)
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T Tis T1–2 T3 T4 T1–2 T3–4 Tany Tany
N N0 N0 N0 N0 N1 N1 N2 Nany
M M0 M0 M0 M0 M0 M0 M0 M1
a
Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosa into the submucosa b T1 Classification modified by Nivatvongs (2000): Sm1: invasion only into the upper third of the submucosa, Sm2: invasion into middle third of submucosa; Sm3: invasion into lower third of submucosa c Additional classification by the UICC 2001: T3a: invasion £1 mm, T3b: invasion >1–5 mm, T3c: invasion >5–15 mm, T3d: invasion >15 mm (Wittekind et al 2001) d Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum e Tumor that is adherent to other organs or structures, macroscopically, is classified as T4. However, if no tumor is present in the adhesion, microscopically, the classification should be pT3. The V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion f A tumor nodule in the pericolonic adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule is classified in the pN category as a regional lymph node metastasis if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular contour, it should be classified in the T category and also coded as V1 (microscopic venous invasion) or as V2 (if it was grossly evident), because there is a strong likelihood that it represents venous invasion g Additional descriptors: Although they do not effect the stage grouping, additional prefixes are used which indicate the need for additional analysis. Suffix vs. Reason: m the presence of multiple primary tumors in a single site and is recorded in parenthesis: pT(m)NM; y When classification is performed during or following initial radiation and/or chemotherapy and is based on the amount of tumor present at the time of the examination, and not an estimate of tumor prior to therapy: ycTNM or ypTNM; r indicates recurrent tumor: rTNM; a indicates the stage at autopsy: aTNM
Stage groupingsg Stage 0 I IIA IIB IIIA IIIB IIIC IV
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invasion) if grossly visible. (3) Stage group II is subdivided into IIA (pT3 pN0 M0 disease) and IIB (pT4 pN0 M0 disease). (4) Stage group III is subdivided into IIIA (pT1–2 pN1 M0 disease), IIIB (pT3–4 pN1 M0 disease), and IIIC (pTany pN2 M0 disease). The prognostic validity of this latter change was supported by both the pooled analysis of Intergroup and NSABP postoperative trials and the retrospective analysis of the American College of Surgeons (National Cancer Database (NCDB)) database (Gunderson et al. 2004; Greene et al. 2004). The five-year survival by stages IIIA, IIIB, and IIIC in the pooled analysis was 81, 57, and 49%, and in the NCDB database was 55, 35, and 25%, respectively. Recently, however, concerns regarding the use of the sixth edition of the TNM staging system have been expressed, especially with respect to the definitions of lymph nodes and venous invasion, that may be associated with marked interobserver variations in defining stage II and III disease (Quirke et al. 2007).
13.7.4 Circumferential Resection Margin Surgeons create margins that can be involved by tumor spread at a variety of sites. The most well known are the proximal and distal margins of a resection. However, only 1−2% of cases in randomized trials show involvement of these margins. By far the most important margin is that created around the mesorectum (circumferential resection margin, CRM). This margin is under threat not only by direct involvement but also by the incomplete removal of lymph nodes that lie just under the mesorectal fascia, and any small deviation from the correct surgical plane could enter them, potentially compromising cure (Fig. 13.5). Studies by Quirke and others have shown that local recurrence is greatly increased and survival halved when tumor can be visualized at or within 1 mm from the radial surgical plane of resection (CRM+) (Quirke et al. 1986; Nagtegaal and Quirke 2008).
CRM
Fig. 13.5 Mesorectum and circumferential resection margin (CRM). This margin is under threat by direct tumor (TU) involvement but also by the incomplete removal of lymph nodes (LN) that lie just under the mesorectal fascia
TU
Mesorectum
LN
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13.7.5 Recording of Surgical Quality The recording of the frequency of involvement of the surgical CRM and the plane of surgery is important as an indicator of the quality of surgery and of prognosis for the patient. Quirke first introduced the concept of pathological audit of the quality of surgery in the MRC CLASSIC and CR07 studies (Table 13.4). The concept was also adopted in the Dutch TME trial. In the latter trial, despite extensive surgical training, only 57% of cases were judged to be good/complete excisions, with nearly one quarter of all cases (24%) assessed as a poor/incomplete excision – with early evidence of prognostic value (Nagtegaal and Quirke 2008). In the recently published MRC CR07 trial, the plane of surgery achieved was classified as good (mesorectal) in 52% of 1,156 included patients, intermediate (intramesorectal) in 34%, and poor (muscularis propria plane) in 13% (Table 13.5) (Quirke et al. 2009). The plane of surgery achieved was significantly associated with the risk of local recurrence both in univariate and multivariate analysis, and should therefore be assessed and reported routinely. Moreover, the assessment of the abdominoperineal excision specimens to measure the amount of tissue removed at the anorectal junction and to determine whether levator muscle is included in the resection is also strongly recommended
Table 13.4 Grading of surgical TME specimen (M.E.R.C.U.R.Y. criteria) Good (grade 1): intact mesorectum with only minor irregularities of a smooth mesorectal surface; no defects larger than 5 mm; no coning on specimen; smooth CRM on slicing Moderate (grade 2): moderate bulk to mesorectum but irregularity of the mesorectal surface; moderate coning of the specimen towards the distal margin; at no site is the muscularis propria visible with the exception of the area of insertion of levator muscles; moderate irregularity of the CRM Poor (grade 3): little bulk of mesorectum with defects down into muscularis and/or very irregular CRM
Table 13.5 Local failure rates of the British MRC (Medical Research Council) CR07-trial for rectal cancer according to TME quality grading Grading Three-year local recurrence rates N of TME-specimen preop. RT Surgery (+post. + surgery (%) CRT if pCRM+) (%) Poor plane of surgery: Defects down onto muscularis propria
154 (13%)
10
16
Moderate plane of surgery: Intramesorectal excision
398 (34%)
4
10
Good plane of surgery: Intact mesorectum
604 (52%)
1
7
Patients either received preoperative 5 × 5 Gy (arm 1) or selective postoperative CRT only in case of a positive circumferential resection margin (CRM+, defined as tumor within £1 mm from the CRM) (Sebag-Montefiore et al. 2009)
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(West et al. 2008). Guidelines of the Royal College of Pathologists in the United Kingdom for dissection and reporting of rectal cancer specimens are available at http://www.rcpath. org/resources/pdf/colorectalcancer.pdf.
13.7.6 Tumor Regression There is good evidence that neoadjuvant radio(chemo)therapy is able to induce T-level downsizing and UICC or nodal downstaging in locally advanced rectal cancers. In approximately 5–30% of cases, this can lead to complete disappearance of tumor cells, i.e., a pathological complete response (pCR, ypT0 ypN0), and patients with pCR have consistently been shown to have better outcomes (Rödel et al. 2005; Capirci et al. 2008). Variation in sampling protocols may explain some of the differences in reporting pCR-rates. Moreover, various tumor regression grading systems (TRG), based on the relative amount of tumor cells and fibrotic reactions, have been proposed. These classifications were often derived from esophageal or gastric cancer, and little information on the extent of inter- and intraobserver variability in defining TRG has been published. Recently, a four-point scale has been proposed (0 = complete histomorphologic regression, 1 = major histomorphologic regression with few hard to find scattered microscopic foci <2 mm, 2 = minor histomorphologic regression with fibrosis outweighing residual cancer cells, 3 = minimal histomorphologic regression with no/ negligible evidence of any tumor response) (Glynne-Jones and Anyemene 2009). This classification system needs to be prospectively tested on multiple datasets to validate the predictive value in terms of long-term outcome, and its reproducibility in the wider setting.
13.8 Surgery During the last two decades, locoregional tumor control in rectal cancer surgery has changed dramatically. On the basis of improved interdisciplinary pretherapeutical staging procedures, the development of very differentiated concepts in oncological surgery started with the introduction of new techniques like Transanal Endoscopic Microsurgery (TEM) and more precise, but extended surgical procedures following embryonic planes in the pelvic organ (TME). Considerable progress has been made not only in the treatment of small tumors without an endosonographically verified spread into the rectal wall but also in the treatment of locally advanced rectal cancer with broad invasion into the mesorectal compartment.
13.8.1 Local Excision: pT1-Low Risk Rectal Cancer Early rectal cancer is limited to the rectal wall (c/pT1 N0 M0) and represents accompanied 3–5% of rectal cancers. So-called low-risk pT1 cancers comprise small mobile tumors
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b
c
d
Fig. 13.6 Transanal endoscopic microsurgery (TEM) procedure. Since the optic of the operative rectoscope has an angle of 400, the tumor should always be in 6 o`clock lithotomy position on the operating table. For TEM the patient was positioned according to the location of the tumor and after gentle extension of the sphincter, the TEM equipment (Wolff, Knittlingen, Germany) was inserted (a). Under continuous distension of the rectal cavity by pressure-controlled CO2 insufflation, the lesion was identified centrally with an attempted macroscopically tumor-free margin of 1 cm (b). The resection was performed as full thickness excision (c). The wound was closed transversely with a single continuous suture of polyglactin (not shown). The completely resected tumor has been fixed to a cork board for specific evaluation of the resection margins (d)
without prognostic adverse histopathological parameters, such as high-grade differentiation (G3–G4), blood or lymphatic vessel invasion (V1, L1), invasion into the lower third of submucosa (sm3), or colloid histology. These low-risk pT1 (sm1, sm2; G1/2) cancers can be cured by local removal of the full thickness of the rectal wall, accomplished either by TEM (Fig. 13.6) for lesions localized 5–16 cm above the anal verge or with transanal excision alone (0–5 cm above anal verge) (Guerrieri et al. 2008; Langer et al. 2003). In general, local excison is associated with less anorectal and genitourinary dysfunction and better quality of life compared with radical transabdominal surgery. These methods are limited, however, to non-obstructing tumors with a dimension of less than half of the lumen and/or a size of <4 cm in diameter. The resected full wall specimen (no piecemeal procedures!) has to be examined meticulously by the pathologist to evaluate its integrity, the depth of tumor invasion into the rectal wall, the absence of margin infiltration both laterally and deeply, and the presence of other adverse pathological parameters, like high-grade differentiation and blood and/or lymphatic vessel invasion. In cases of high-risk pT1 and pT2 cancers, there is a substantial risk of positive lymphatic nodes, ranging from 10% in pT1 and up to 20% in pT2 rectal cancers. Therefore, local
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excision alone is oncologically not appropriate, and these patients require transabdominal resection, performed either as (low) anterior resection or as an abdominoperineal excision. Only in cases where major surgery is contraindicated or refused by the patient, local excision for high-risk T1 or T2 tumors can be performed on the basis of the patient’s decision, preferably then accompanied with combined multimodal treatment (Borschitz et al. 2008; Lezoche et al. 2008).
13.8.2 Standard Resection (Including Total Mesorectal Excision): High-Risk pT1- and pT2-Rectal Cancer In high-risk pT1 and pT2 rectal cancer, the standard transabdominal resection (anterior or low anterior resection and abdominoperineal resection (APR)), including TME, is the adequate treatment of choice. Provided the lymph nodes are negative (pN0) as a result of histopathological workup of the resected specimen, no further adjuvant treatment is required. In cases of positive lymph nodes (pN+, UICC stage III), postoperative 5-fluorouracil (5-FU)-based radio-chemotherapy (RCT) is indicated.
13.8.3 Surgical Treatment in Locally Advanced Rectal Cancer (UICC Stages II and III) From the clinical point of view, intermediate tumor stages are defined as neoplasms extending beyond the rectal wall into the mesorectal compartment but without unresectable infiltration to surrounding organs (c/pT3–4 or N1–2 M0). After TME alone for pT3–4 pN1–2 rectal cancers in the middle and lower third of the rectum, local recurrence rates range between 15 and 21% in randomized trials (Peeters et al. 2007; Sebag-Montefiore et al. 2009). It is well known that the efficacy of the TME procedure is closely related to the training and volume of cases per year of the individual surgeon. Thus, the surgeon represents one of the major prognostic factors for the treatment of rectal cancer patients (Martling et al. 2002). According to surgical standard procedures, the surface features of the resected mesorectum should be photodocumented during surgery and later analyzed pathologically. A further improvement of the quality of TME can be achieved by stain marking of the mesorectum (Sterk et al. 2000), which allows the surgeon to test intraoperatively for lesions in mesorectal fascia and the mesorectum itself. Such lesions bear the risk of locoregional relapse. It is generally accepted that by using low anterior resection with TME, radical surgery with negative margins can be achieved also for distal lesions since rectal cancer rarely grows more than a few millimeters distally from the macroscopic margin in the bowel wall. This indicates that a distal resection margin of 1 cm will probably be sufficient for local cure in terms of intramural spread. If such an approach is considered, frozen section (during the surgical intervention) is mandatory to decide if an abdominoperineal excison is necessary or not. To avoid a conversion of the surgical strategy intraoperatively, and to provide oncological safety, preoperative staging procedures should have allowed a definite
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decision about an initially planned sphincter preservation. If the tumor is felt to impinge on the puborectalis muscle, this patient is not a candidate for a sphincter-preserving operation. On the other hand, coloanal anastomosis is reserved for a highly defined group of patients. After complete TME transabdominally, this procedure consists of a perianally primary hand-sewn anastomosis and is usually performed with interrupted sutures of 2–0 or 3–0 vicryl including the internal anal sphincter. In all the cases of coloanal anastomosis, a diverting ileostomy or colostomy is performed in anticipation of poor immediate functional results with severe perineal irritation and excoriation (Cavaliere et al. 1995). Population-based registries have demonstrated that improvements in outcome after TME procedure occur mainly in patients <75 years of age. The 6-month postoperative mortality after TME is significantly increased in elderly patients (>75 years of age) and should be restricted to those patients with good physical and mental status and low comorbidity (Rutten et al. 2008). Furthermore, TME may be associated with an increased risk of anastomotic leakage with increased morbidity and mortality in the postoperative period (den Dulk et al. 2009). Based on an associated decreased local tumor control and survival (Law et al. 2007), the rate of anastomotic leakage has been considered as one of the important quality indicators of surgical performance. Recently, a multicenter analysis (pooled data from the Swedish Rectal Cancer Trial, Dutch TME trial, German CAO/ARO/AIO-94 trial, EORTC 22921 trial, and the Polish Rectal Cancer Trial) of oncological and survival outcomes following anastomotic leakage after rectal cancer surgery showed that, in multivariate analysis, cancer-specific survival was not reduced significantly by leakage but was overall survival (den Dulk et al. 2009). In summary, anastomotic leakage cannot be completely avoided in rectal cancer surgery, but its life-threatening consequences can be limited by a diverting stoma and/or pelvic drain (Matthiessen et al. 2007). From the clinical point of view, prompt diagnosis and immediate surgical re-intervention is mandatory for an effective treatment of anastomotic leakage in order to reduce morbidity and mortality in rectal cancer patients. The TME procedure is recommended for patients with locally advanced rectal cancer localized in the middle (6 to £12 cm from anal verge) and lower third (<6 cm) of the rectum. It is known that metastatic involvement of lymph nodes and other tumor deposits can be found in the mesorectal compartment up to 4 cm distally from the lower pole of the rectal cancer. Therefore, complete removal of the mesorectum is always indicated for these tumor locations (Heald and Ryall 1986), and should be further extended in cases of sphincter infiltration as wide abdominoperineal excision (West et al. 2008; Holm et al. 2007). Recently pathological studies of the CRM at the level of the anorectal junction and anal sphincters showed a high risk of tumor involvement (Nagtegaal et al. 2005). The quality of surgery in the levator/anal canal area below the mesorectum varies between surgeons who may operate in different surgical planes: intrasphincteric/submucosal plane, sphincteric plane, and levator plane. With an APR, there are two planes: one for the mesorectum and one for the anal canal. It is crucial to have the correct strategy when an APR is performed. The dissection from above has to be stopped from entering the levator plane. The next step is to dissect from below outside the sphincteric plane and by doing so finally divide the levators from below. With this technique, or an “apple core” just at the place of the tumor can be avoided to prevent the specimen from having positive CRM (Fig. 13.7a, b).
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Ventral view after perioperative staining of the resected specimen via A. mesenterica inferior
Dorsal view after perioperative staining of the resected specimen
a
Peritoneal fold
Mesorectum with nonviolated surface, only one punctual ink leakage (white arrow) Perineal fat tissue and partially resected M. levator ani Anus and canalis analis, yellow: intersphincteric resection line perineal tissue
b peritoneal fold
anal canal
staining via A. mesenterica inferior
TU
apple core phenomenon
Fig. 13.7 (a) Wide abdominoperineal resection (APR) for a low-lying tumor. (b) APR for a lowlying tumor with the so-called “apple core phenomenon” that should be avoided to reduce the risk of a positive circumferential resection margin
13.8.4 Partial Mesorectal Excision In rectal cancer of the upper third of the rectum (12–16 cm), a partial mesorectal excision (PME) extending 5 cm below the lower tumor margin (as measured intraoperatively) is feasible while sparing the distal part of the mesorectum. As shown in Figs. 13.8 and 13.9,
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Ventral view
Dorsal view
peritoneal fold
TU TU
TU
PME 5 cm
TME
distal resection margin
surface of distal dorsal mesorectum
Fig. 13.8 Resection margins: partial vs. total mesorectal excision (PME, TME)
uterus
lower third of the rectum with resection margin tube ovary
residual mesorectum
ureter sinister
Fig. 13.9 PME – residual mesorectum
plexus hypogastricus sinister
for TME the mesorectum is completely excised downwards to the pelvic floor, whereas for PME the mesorectum is transected at a right angle to the rectal wall at a distance of 5 cm beyond the gross distal margin of the tumor. Corresponding to this in situ situation, adequate PME requires a distal clearance to the tumor site of 3 cm when measured on fresh
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non-stretched resection specimen. It is important to avoid coning with the remaining mesorectal tissue, because this could contain cancer clusters or satellites. The transection therefore needs to be performed at the same distance from the distal tumor margin in both the outer and inner parts of the mesorectum and in the rectal muscular wall. In both TME and PME, circumferential excision needs to be performed in an anatomically defined plane (including the mesorectal fascia), and with a sharp dissection. From the oncological point of view, PME is considered sufficient for the treatment of rectal carcinomas of the upper third (distal margin of the tumor is 12 cm or more from anal verge), provided the surgeon avoids coning and the pathologist can confirm this practise (Lopez-Kostner et al. 1998). Actually the definite evidence for this procedure is investigated by the ongoing German GAST-05 trial (ISRCTN35198481).
13.8.5 Total Pelvic Exenteration T4 cancers are defined as lesions extending beyond the rectal wall with infiltration to surrounding organs or structures, and/or perforation of the visceral peritoneum (c/p T4 N0–2 M0). In these cases, the evaluation of resectability depends on the extent of the operation the surgeon is able to perform as well as the degree of morbidity the patient is willing to accept. It is mandatory for the surgeon to recognize preoperatively the extent of tumor invasion into other organs and/or the pelvic sidewall for documentation prior to preoperative chemoradiotherapy (CRT) and to establish a plan for en bloc resection (Ishiguro et al. 2009). From both the surgical as well as the oncological point of view, histologically confirmed R0 resection represents the most important parameter to achieve the best long-term outcome in T4 rectal cancer. In specialized centers there is a minimum consensus that when the trigone of the bladder or the prostate is involved by rectal cancer, a total pelvic exenteration (TPE) is recommended for all patients, irrespective of the response to preoperative multimodal treatment. The TPE involves the removal of the rectum, bladder, lower ureters, internal genital organs, and bilateral internal iliac vessels en bloc to achieve tumor-free resection margins and a complete clearance of lymphatics (Moriya et al. 2003). A TPE achieving clear resection margins (R0) is potentially curative and results in five-year overall survival rates of 52–60%, but it is accompanied by high morbidity (>50%; e.g., pelvic abscess or fistulas, sepsis, anastomotic leak, perineal wound infection, intestinal obstruction, and pulmonary disease) and impaired quality of life (Yamada et al. 2002). Furthermore, surgery extended to lateral pelvic nodes is associated with significant morbidity (Watanabe et al. 2008).
13.9 Radiotherapy and Chemotherapy The last decades have witnessed the development of a variety of preoperative and postoperative radiotherapy (RT) and CRT schedules designed to optimize the sequence of treatment modalities and the most appropriate scheduling of irradiation and 5-fluorouracil-based
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chemotherapy. On the basis of the same evidence from studies, these modalities are used differently in different parts of the world (Valentini et al. 2009).
13.9.1 Randomized Trials of Postoperative CRT Historically, the combination of postoperative RT and 5-FU-based chemotherapy has been shown in several randomized trials to reduce local recurrence rates and to improve overall survival compared with (conventional, i.e., non-TME) surgery alone or surgery plus postoperative RT (Table 13.6). In the early GITSG 7175 trial, the best local control was achieved with combined CRT (local relapse rate of 11% vs. 20% with RT alone), while no impact on local control was noted with chemotherapy as single adjuvant treatment (local relapse rate of 27% vs. 24% with surgery alone) (Gastrointestinal Tumor Study Group 1985). Although rates of distant metastases were slightly lower in the two arms that contained chemotherapy, no single arm had a significant impact on distant failure. Thus, the survival advantage achieved with combined CRT appeared to relate primarily to the marked reduction in local relapse rates. These results were later confirmed by a trial conducted by the Norwegian Adjuvant Rectal Cancer Project Group (Tveit et al. 1997). Again, the local relapse rate was significantly decreased from 30 to 12% by combined postoperative CRT compared with surgery alone, an effect which also translated into an improvement in five-year survival, though no significant impact on distant metastases was achieved. The more recent NSABP R-02 also showed that combined CRT resulted in a significantly reduced local failure rate compared with chemotherapy alone (8% vs. 13%); however, this rather small absolute reduction did no longer translate into a difference in overall survival (Wolmark et al. 2000). Evidently, in all these trials, the effect of concomitant 5-FU-chemotherapy was primarily mediated through its radiosensitization properties rather than through its own systemic efficacy. This conclusion is further strengthened by a recent Italian study that showed no significant effect on local control and survival when postoperative RT and chemotherapy was applied sequentially rather than concomitantly (Cafiero et al. 2003). The NCCTG 794751 trial was the first to integrate a course of full-dose chemotherapy before as well as after combined CRT in an attempt to exploit both the radiosensitization properties of 5-FU and its potential to reduce the incidence of distant metastases (Krook et al. 1991). Indeed, this was also the first trial in which both local relapse and distant metastasis rates were significantly reduced in the experimental arm. The NCI Consensus Conference concluded in 1990 that combined CRT was the standard adjuvant treatment for patients with TNM stages II and III rectal cancer (NIH consensus conference 1990).
13.9.2 Randomized Trials to Optimize 5-FU-Based Postoperative CRT Further trials by the GITSG (7180) and NCCTG (864751) investigated the need for methylCCNU in the chemotherapy regimen and found that it added no benefit to the 5-FU regimen (Table 13.7) (Gastrointestinal Tumor Study Group 1992; O’Connell et al. 1994).
Surgery + RT Surgery + RT + 5-FU/MeCCNU
Surgery Surgery + RT + 5-FU
Surgery + CTa Surgery + CRT
Surgery + RT Surgery + 5-FU/LEV + RT + 5-FU/LEV (RT and CT applied sequentially)
NCCTG/Mayo 794751 (Krook et al. 1991)
Norway trial (Tveit et al. 1997)
NSABP R-02 (Wolmark et al. 2000)
Italy trial (Cafiero et al. 2003)
39% 33% 29% 31%
30%; p = 0.01 12% 13%; p = 0.02 8%
a
38% 27%
46%; p = 0.01 29%
25%; p = 0.04 13.5%
20% 22%
34% 30% 27% 26%
24% 20%; p = 0.08 27% 11%
Male patients received MOF (MeCCNU, Vincristin, 5-FU) or 5-FU/LV; female patients only 5-FU/LV
Surgery Surgery + RT Surgery + 5-FU/MeCCNU Surgery + RT + 5-FU/MeCCNU
GITSG 7175 (Gastrointestinal Tumor Study Group 1985)
59% 43%
64% 64%
50%; p = 0.05 64%
48%; p = 0.025 58%
45% 52%; p < 0.05 56% 59%
Table 13.6 Randomized trials of postoperative radiation (RT), chemotherapy (CT), or combined CRT for locally advanced rectal cancer (UICC II and III) Series Treatment Local failure Distant failure Five-year-survival
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CRT bolus 5-FU + bolus 5-FU (6 cycles, escalating 5-FU) CRT bolus 5-FU + bolus 5-FU/MeCCNU (12 months treatment)
68% (3y)
75% (3y)
54% (3y); p = 0.20
66% (3y); p = 0.58
NCCTG 864751 (O’Connell et al. 1994)
2 cycles of bolus 5-FU (±MeCCNU) + CRT bolus 5-FU + 2 cycles of bolus 5-FU (±MeCCNU) 2 cycles of bolus 5-FU (±MeCCNU) + CRT PVI 5-FU + 2 cycles of bolus 5-FU (±MeCCNU)
53% (4y)
60% (4y)
63% (4y); p = 0.01
70% (4y); p = 0.005
2 cycles bolus 5-FU + CRT bolus 5-FU + 2 cycles bolus 5-FU 2 cycles bolus 5-FU/ LV + CRT bolus 5-FU/ LV + 2 cycles bolus 5-FU/LV 2 cycles bolus 5-FU/ LEV + CRT bolus 5-FU + 2 cycles bolus 5-FU/LEV 2 cycles bolus 5-FU/LV/ LEV + CRT bolus 5-FU/ LV + 2 cycles bolus 5-FU/ LV/LEV
54% (all)
64% (all)
No significant difference
No significant difference
INT 0114 (Tepper et al. 2002)
INT 0144 (Smalley et al. 2006)
2 cycles bolus 5-FU + CRT 68–69% (3y) PVI 5-FU + 2 cycles bolus 5-FU PVI 5-FU + CRT PVI No significant 5-FU + PVI 5-FU difference 2 cycles bolus 5-FU/LV/ LEV + CRT bolus 5-FU/ LV + 2 cycles bolus 5-FU/ LV/LEV
81–83% (3y) No significant difference
Thus, this compound is no longer used for adjuvant CRT in rectal cancer. NCCTG (864751) also tested the best method of administering 5-FU during radiotherapy: Bolus 5-FU (500 mg/m² for 3 days during weeks 1 and 5 of RT) was compared with continuous infusion (225 mg/m² during the whole course of RT): A 10% disease-free and overall survival advantage was achieved with continuous infusion 5-FU during RT (O’Connell et al. 1994). The INT 0144 trail tested the question whether additional continuous infusion 5-FU instead of bolus 5-FU before and after CRT (or modulation of 5-FU through addition of leucovorin
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and levamisole) may further increase tumor control (Tepper et al. 2002). There was no significant difference in local control or survival. Results of a four-arm intergroup trial, INT 0114, also showed no significant differences in local control and survival among patients receiving bolus 5-FU, bolus 5-FU + folinic acid, bolus 5-FU + levamisole, or bolus 5-FU + folinic acid + levamisole. However, gastrointestinal toxicity was higher in folinic acid–containing regimens (Smalley et al. 2006). Only one randomized phase III trial, performed by the Hellenic Cooperative Oncology Group, compared concurrent postoperative RT with combination chemotherapy including 5-FU/folinic acid plus irinotecan vs. 5-FU/ folinic acid alone (Kalofonos et al. 2008). There were no differences between the arms in three-year overall, disease-free and local relapse-free survival, whereas the incidence of severe leucopenia was significantly higher in the irinotecan containing arm. Given all these results, the standard design of postoperative CRT is to deliver 6 cycles of 5-FU chemotherapy with concurrent radiation therapy during cycles 1 and 2 or 3 and 4. During RT continuous infusion 5-FU regimens are recommended. The main advantage with the postoperative approach is the better selection of the patients based on pathologic staging. The primary disadvantages include an increased toxicity related to the amount of small bowel in the radiation field, a potentially more radio-resistant hypoxic postsurgical bed and, if the patient has undergone an APR, the radiation field has to be extended to include the perineal scar.
13.9.3 Preoperative Radiation The potential advantages of the preoperative approach include decreased tumor seeding during surgery, less acute and chronic toxicity, increased radiosensitivity due to more oxygenated cells, and according to some, a potential for sphincter preservation. The main disadvantage is related to possible overtreatment of patients with early stages (pT1–2N0) or undetected metastatic disease. This disadvantage becomes less important because imaging modalities (ERUS and high-resolution phased-array magnetic resonance imaging) allow better preoperative staging. There are more than 15 randomized trials of preoperative RT without concurrent chemotherapy for clinically resectable rectal cancer. All used low to moderate doses of RT and most showed a decrease in local recurrence. The Swedish Rectal Cancer Trial (1997) is the only one out of eight studies with more than 500 patients, which reported a survival advantage for the total treatment group. Two meta-analyses report conflicting results. While both revealed a decrease in local recurrence, the analysis by Camma et al. reported a survival advantage, whereas the Colorectal Cancer Collaborative Group did not (Colorectal Cancer Collaborative Group 2001; Camma et al. 2000). The Swedish Council of Technology Assessment in Health Care performed a systematic review of RT trials. They analyzed data from 42 randomized trials and 3 meta-analyses, 36 prospective studies, 7 retrospective studies, and 17 other articles, for a total of 25,351 patients (Glimelius et al. 2003). The main conclusion was that preoperative RT at biologically effective doses above 30 Gy decreases the relative risk of local failure by 50−70%, and by 30−40% for postoperative RT at doses that are usually higher than those used preoperatively, and that survival is
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improved by about 10% using preoperative RT. In recent years, therefore, preoperative therapy has gained a wide acceptance as the standard therapy for rectal cancer. After standardization of TME there is, however, no evidence of overall survival benefit in the so-called Dutch TME trial. This trial randomized 1,861 patients with resectable rectal cancer (stage I–III) between TME alone or TME preceded by 5 × 5 Gy. With a median follow-up of surviving patients of 6.1 years, there was a significant reduction of the five-year local recurrence risk (5.6% in the 5 × 5 arm vs. 10.9% for TME alone, p < 0.001) (Peeters et al. 2007; Kapiteijn et al. 2001). Subgroup analyses reported a significant effect of RT in reducing local recurrence risk for patients with nodal involvement, for patients with lesions 5–10 cm from the anal verge, and for patients with uninvolved CRM. Overall survival at five years was 64.2 and 63.5% (p = 0.9), respectively, indicating that the absolute reduction in local failure rates was too small to translate into a survival benefit.
13.9.4 Randomized Trials to Optimize the Sequence Until recently, the only randomized trial that directly compared preoperative to postoperative RT (both without chemotherapy) in rectal cancer has been the Uppsala trial, which was carried out between 1980 and 1985 in Sweden (Frykholm et al. 1993). In the preoperative arm, patients received intensive short-course radiation (five fractions of 5.1 Gy to a total dose of 25.5 Gy in 1 week), postoperatively conventional radiation therapy (2 Gy to a total of 60 Gy with a two-week split after 40 Gy) was applied. Preoperative radiation significantly decreased local failure rate (13% vs. 22%, p = 0.02), however, there was no significant difference in five-year survival rates (42% vs. 38%). Prospective randomized trials comparing the efficacy of preoperative with standard postoperative CRT in UICC-stage II and III rectal cancer were initiated both in the U.S.A. through the Radiation Therapy Oncology Group (RTOG 94–01) and the NSABP (R-03) as well as in Germany (Protocol CAO/ARO/AIO-94). Unfortunately, both U.S. trials suffered from lack of accrual and were closed prematurely. The NSABP R-03 trial reported results from 254 (of intended 900) patients after median follow-up for surviving patients of 8.4 years: The five-year disease-free and overall survival rates for preoperative patients were 64.7 and 74.5% vs. 53.4 and 65.6% for postoperative patients, respectively (p = 0.011, p = 0.065). The five-year cumulative incidence of locoregional recurrence was 10.7% for each arm; sphincter-saving surgery was 47.8% for preoperative patients and 39.2% for postoperative patients (p = 0.23) (Roh et al. 2009). The German study (CAO/ARO/AIO94) could be completed with more than 820 patients included (Sauer et al. 2004). The design of this trial and the treatment schedule is depicted in Fig. 13.10. Five-year results were reported in 2004 (Table 13.8): Compared with postoperative CRT, the preoperative combined modality approach was superior in terms of local control, downstaging, acute and chronic toxicity, and sphincter preservation in those patients judged by the surgeon to require an APR. Given these advantages preoperative CRT is now the preferred adjuvant treatment for patients with locally advanced rectal cancer. However, it needs to be emphasized that, with a median follow-up of 46 months, there was no difference in five-year disease-free and overall survival rates between both treatment arms.
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Arm I: 5-FU 5 x 1000 mg/m2 120h-infusion
5-FU 5 x 1000 mg/m2 120h-infusion
4 cycles of adjuvant chemotherapy with 5-FU 500 mg/m2/d i.v. bolus for 5 days 3 weeks break.
OP RT: 50.4 Gy + 5.4 Gy Boost Arm II: 5-FU 5 x 1000 mg/m2 120h-infusion
5-FU 5 x 1000 mg/m2 120h-infusion
4 cycles of adjuvant chemotherapy with 5-FU 500 mg/m2/d i.v. bolus for 5 days 3 weeks break. OP
RT: 50.4 Gy
Fig. 13.10 Design of the German CAO/ARO/AIO-94 study comparing postoperative (arm I) with preoperative radiochemotherapy (RCT) (arm II) in locally advanced rectal cancer
Table 13.8 German Rectal Cancer Study Group randomized trial of preoperative compared with postoperative CRT for rectal cancer (Sauer et al. 2004) Five-year outcome Preoperative Postoperative p Value CRT (%) CRT (%) Locoregional recurrence rate
6
13
0.006
Distant recurrence rate
36
38
0.84
Disease-free survival
68
65
0.32
Overall survival
74
76
0.80
Any grade 3/4-acute toxicity
27
40
0.001
Any grade 3/4-late toxicity
14
24
0.01
Sphincter preservation rate
39
19
0.004
a
In patients deemed to require abdominoperineal resection by the surgeon before randomization
a
The most recent UK Medical Research Council Trial MRC C07 randomized 1,350 patients with clinical stage I–III rectal cancer to preoperative 5 × 5 Gy or selective postoperative CRT (45 Gy with concurrent 5-FU), which was applied only for patients with a histologic CRM <1 mm (12% of all patients with immediate surgery). Results after a median follow-up of 4 years showed local recurrence rates at 3 years of 4.4 and 10.6% (p < 0.0001), and an absolute difference in disease-free survival at 3 years of 6.0% (77.5%
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vs. 71.5%, p = 0.013), both significantly favoring the unselected preoperative treatment approach (Sebag-Montefiore et al. 2009).
13.9.5 Concomitant Chemotherapy with Preoperative RT? The concurrent use of chemotherapy as part of the preoperative regimen is another important point. For the treatment of primarily “unresectable,” fixed T4 rectal cancer, several institutions have applied preoperative RT and CRT. The goal is to convert (“downsize”) a tumor, which is clinically not amenable to curative resection at presentation, to a resectable status. Minsky et al. (1992) compared preoperative RT (50.4 Gy) with or without 5-FU/ folinic acid and showed that initially “unresectable” tumors were converted to resectable lesions in 90% of the patients by preoperative combined therapy as compared with only 64% of those who received RT alone. Moreover, a complete pathologic response was found in 20% of patients receiving combined modality therapy as compared to 6% receiving RT alone, indicating an enhancement of radiation-induced “downstaging” by concomitant 5-FU-based CRT. In a recent randomized phase III study comparing RT (50 Gy) alone (n = 109) with combined 5-FU-based CRT (n = 98) for primarily “unresectable” T4 rectal cancer or local recurrences, Braendengen et al. (2008).could demonstrate that the addition of chemotherapy to RT significantly improved R0 resection rates, local control, time to treatment failure, and cancer-specific survival A Polish randomized trial compared preoperative short-course irradiation (5 × 5 Gy) and immediate surgery with conventionally fractionated CRT (1.8–50.4 Gy plus 5-FU/ folinic acid) and delayed surgery in 316 patients with locally advanced (T3/T4) low rectal cancer (Bujko et al. 2004). The primary endpoint of the trial was the rate of sphincter-preserving surgery. Despite a significant increase in tumor response in the CRT group (pathologic complete remission, 16% vs. 1%; mean largest tumor diameter on the operative specimen, 29 mm vs. 48 mm), the rate of sphincter preservation was 61% in the immediate surgery group and 58% in the delayed group, indicating a strong commitment of the surgeons in this trial not to change their choice whatever the tumor response was after neoadjuvant CRT. The actuarial four-year overall survival was 67% in the short-course group and 66% in the chemoradiation group; no significant differences were found in disease-free survival, incidence of local recurrence, and severe late toxicity (Bujko et al. 2006). Two other (ongoing) phase III studies (from the Berlin Cancer Society in Germany, and Trans-Tasmania group in Australia) are currently evaluating short-course RT with 5 × 5 Gy and immediate surgery vs. long-course CRT. Data from the Uppsala group in T4 rectal cancer patients have shown that short-course RT and delayed surgery also result in downsizing and possibly R0 resections (Radu et al. 2008). A three-arm ongoing study in Sweden (Stockholm III trial) is evaluating the role of short-course RT with immediate vs. delayed surgery vs. long-course RT in resectable rectal cancer patients. Two randomized trials have examined whether chemotherapy improves the results of preoperative, conventionally fractionated RT in patients with cT3/4 rectal cancer (Table 13.9). The EORTC 22921 was a four-arm randomized trial of preoperative 45 Gy
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Table 13.9 Preoperative conventionally fractionated radiotherapy with or without 5-FU/LV-based chemotherapy Five-year outcome Preoperative RT Preoperative CRT p Value EORTC 22921 (n = 1011) pCR rate ypN0 Tumor size (median) Sphincter preserved Local failure Overall survival
5.3% 60.5% 30 mm 50.5% 17% 64.8%
13.7% 71.9% 25 mm 52.8% 8% 65.6%
<0.001 <0.001 <0.0001 0.47 0.002 0.79
FFCD 9203 (n = 762) pCR rate Sphincter preserved Grade 3 + 4 toxicity Local failure Overall survival
3.6% 54.4% 2.7% 8.1% 67.9%
11.4% 52.4% 14.6% 16.5% 67.4%
<0.05 0.68 <0.0001 <0.05 0.68
Results of EORTC 22921 and FFCD 9203 randomized trials (Bosset et al. 2006; Gerard et al. 2006)
with or without concurrent bolus 5-FU/leucovorin followed by surgery with or without four cycles of postoperative 5-FU/leucovorin. A significant decrease in local recurrence was observed in three chemotherapy groups: 8.8, 9.6, 8.0%, respectively, with preoperative CRT, postoperative chemotherapy and both, vs. 17.1% without (p = 0.002) (Bosset et al. 2006). Five-year overall survival was not affected by chemotherapy at the median follow-up of 5.4 years: 65.6% vs. 64.8% (p = 0.79) for preoperative CRT vs. preoperative RT and 67% vs. 63% (p = 0.132) for postoperative chemotherapy vs. no postoperative chemotherapy. An increased rate of ypT0 (13.7% vs. 5.3%, p <0.0001) was observed, but no difference in sphincter-saving surgery (52.8% vs. 50.5%, p = 0.47); 42.9% of patients received planned adjuvant chemotherapy. The authors stated that in view of the benefit of preoperative CRT and the bad compliance of postoperative chemotherapy, preoperative CRT should be preferred. The second trial (FFCD 9203) compared preoperative 45 Gy with or without bolus 5-FU/leucovorin, and all patients received postoperative chemotherapy. An improvement in the pCR rate was observed (11.4% vs. 3.6%, p = 0.0001), and local recurrence was lower with preoperative CRT: 8.1% vs. 16.5% of preoperative RT (p = 0.004) (Gerard et al. 2006). Overall survival at 5 years was the same (67%). A recent systematic review and metaanalysis, including four relevant randomized trials, also confirmed that, compared with preoperative RT alone, preoperative 5-FU-based CRT improves local control, but does not benefit long-term survival (Ceelen et al. 2009).
13.9.6 Adjuvant Chemotherapy After Neoadjuvant RT/CRT There are no sufficient data on adjuvant postoperative chemotherapy after preoperative treatment with RT or CRT. In the EORTC 22921 trial postoperative chemotherapy had a nonsignificant influence with improvement of relapse-free and overall survival. Exploratory
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post-hoc subgroup analyses suggest that only good-prognosis patients with downstaging of cT3–4 to ypT0–2 benefit from adjuvant chemotherapy (Collette et al. 2007). In patients treated with 5 × 5 Gy preoperative radiation, postoperative chemotherapy has not been evaluated so far but is currently investigated in a randomized trial (SCRIPT, Simply Capecitabine in Rectal cancer after Irradiation Plus TME). Another randomized trial (CHRONICLE) that investigated postoperative chemotherapy with capecitabine and oxaliplatin vs. observation only after preoperative 5-FU-based CRT has unfortunately been closed due to poor accrual.
13.9.7 Integrating Combination Chemotherapy into the Combined Modality Program Given that with optimized local treatment, including preoperative RT/CRT and TME surgery, distant metastasis is by far the predominant pattern of tumor failure in rectal cancer today, the current challenge is to integrate more effective systemic therapy into the multimodal concepts for this disease. Novel chemotherapeutic agents such as capecitabine, oxaliplatin, and irinotecan, which have improved results of patients treated in the adjuvant or metastatic setting for colorectal cancer, have been incorporated into preoperative phase I/II combined modality programs for rectal cancer as well (Rodel and Sauer 2007). All suggest higher pCR rates compared with preoperative 5-FU-CRT alone. However, for some agents, with this increased pCR rate is an associated increase in acute toxicity. Clearly, phase III trials are needed to determine if these regimens offer an advantage compared with 5-FU-based combined modality regimen. These studies have now been started in Europe and the US (Table 13.10). Interestingly, early results from the ACCORD and STAR trials did not confirm a significant improvement of early endpoints (such as the pCR rate) with the addition of oxaliplatin (Aschele et al. 2009; Gerard et al. 2009). Long-term results are awaited. Given the fact that (1) in previous 5-FU-based phase III trials concomitant as well as adjuvant cycles of chemotherapy were applied and (2) the cumulative doses of the new drugs reached during RT are substantially lower than in adjuvant colon cancer trials, a multicenter phase II trial of the German Rectal Cancer Study Group has investigated the feasibility of preoperative concomitant CRT with capecitabine and oxaliplatin (XELOX) plus 4 cycles of adjuvant XELOX chemotherapy (Rodel et al. 2007). The most important result of this trial was that only 60% of the entire cohort of 103 operated patients were able to complete all 4 postoperative XELOX cycles (with or without dose reduction); 27% did not – for different reasons – receive any adjuvant chemotherapy. Thus, it is evident that preoperative CRT, surgical complications, and the fact that a substantial part of patients will have pCR or yTNM stage I and II tumors due to downstaging effects or initial clinical staging error, compromise the possibility and willingness of patients to tolerate postoperative chemotherapy. This is, however, true not only for patients treated with more active protocols, such as XELOX-RT, but also for standard 5-FU-CRT: In three recent large phase III trial of preoperative 5-FU-CRT plus postoperative 5-FU chemotherapy, the EORTC 22921, the FFCD 9293, and CAO/ARO/AIO-94 trial, a total of 25, 23, and 20%, respectively, did not start postoperative chemotherapy (Sauer et al. 2004; Bosset et al. 2006; Gerard et al. 2006).
RT 50.4 Gy + 5-FU PVI vs. RT 50.4 Gy + 5-FU + Oxaliplatin
RT 50.4 Gy + 5-FU vs. RT 50.4 Gy + 5-FU + Oxaliplatin vs. RT 50.4 Gy + Capecitabine vs. RT 50.4 Gy + Capecitabine + Oxaliplatin
RT 40–55.8 Gy + Chemotherapy according to NSABP-04 or 5-FU PVI/Capecitabin ± Oxaliplatin or 5-FU + Leucovorin
RT 50.4 Gy + 5-FU vs. RT 50.4 Gy + 5-FU + Oxaliplatin
RT ³45 Gy + 5-FU ± Leucovorin or Capecitabine
RT 45 Gy + Capecitabine vs. RT 45 Gy + Capecitabine + Oxaliplatin
RT 25 Gy/1 week
STAR
NSABP R-04
ECOG-E 5204
CAO/ARO/AIO-04
CHRONICLE
PETACC 6
SCRIPT
TME TME
TME TME
TME
Observation vs. Capecitabine
Capecitabine vs. Capecitabine + Oxaliplatin
Observation vs. Capecitabine + Oxaliplatin
5-FU vs. 5-FU + Oxaliplatin
Oxaliplatin + 5-FU/Leucovorin vs. Oxaliplatin + 5-FU/Leucovorin + Bevacizumab
TME TME TME TME
patients may enter ECOG-E5204
5-FU based CT 5-FU based CT
Postop CT free in each institution Postop CT free in each institution
Postoperative treatment
TME TME TME TME
TME TME
TME TME
Surgery
RT radiotherapy; TME total mesorectal excision; CT chemotherapy; PVI protracted venous infusion; ACCORD Actions Concertées dans les Cancers Colorectaux et Digestifs; STAR Studio nazionaleTerapia neoAdiuvante Retto; NSABP National Surgical Adjuvant Breast and Bowel Project; SCRIPT Simply Capecitabine in Rectal Cancer after Irradiation Plus TME; CAO/ARO/AIO Chirurgische Arbeitsgemeinschaft für Onkologie/Arbeitsgemeinschaft Radiologische Onkologie/ Arbeitsgemeinschaft Internistische Onkologie; CHRONICLE Chemotherapy or no chemotherapy in clear margins after neoadjuvant CRT in locally advanced rectal cancer; ECOG Eastern Cooperative Oncology Group; PETACC Pan-European Trials in Alimentary Tract Cancer
RT 45 Gy + Capecitabine vs. RT 50 Gy + Capecitabine + Oxaliplatin
ACCORD 12
Table 13.10 Ongoing phase III trials with novel agents for rectal cancer patients Preoperative treatment
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In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver neoadjuvant chemotherapy prior to preoperative CRT rather than adjuvant chemotherapy (Chau et al. 2006; Calvo et al. 2006). This strategy avoids the problems of postoperative chemotherapy, but may also be associated with its own caveats, such as selection of radio-resistance clones, possibly reduced compliance to CRT, and substantial delay of definitive surgery (Glynne-Jones et al. 2006). Thus, the strategy currently adopted by most groups that have designed phase III comparisons of standard 5-FU vs. more intense CRT protocols is to stick to the concept of preoperative CRT plus adjuvant chemotherapy and simply accept that a certain percentage of patients will not receive protocol-conformal postoperative chemotherapy (Table 13.10).
13.9.8 Integrating Targeted Agents into the Combined Modality Program The epidermal growth factor receptor (EGFR) is a promising target of antitumor treatment because it participates in cell division, inhibition of apoptosis, and angiogenesis. EGFR overexpression has been associated with a more aggressive phenotype and poor prognosis in many human cancers, including rectal cancer. Preclinical investigations have linked EGFR expression with radioresistance both in vitro and in vivo. Moreover, recent clinical studies have established EGFR expression as an independent predictor of poor tumor response and prognosis in rectal cancer patients treated with preoperative RT or CRT (Marquardt et al. 2009). Clinical studies of preoperative CRT have now been initiated to evaluate EGFR inhibitors as radiosensitizers in rectal cancer (Table 13.11). Machiels et al. (2007) have reported the safety and efficacy of combining preoperative RT with capecitabine and cetuximab in a phase I/II trial. This combination was associated with no unexpected toxicity, and full doses of RT, CT, and cetuximab could be applied. However, only two of 37 patients (5%) achieved a pCR, and a total of 25/37 patients (68%) had only moderate or minimal tumor regression. The German Rectal Cancer Study Group conducted a multicenter phase I/II study to determine the tolerability and efficacy of adding cetuximab to preoperative RT with capecitabine and oxaliplatin (Rodel et al. 2008). Again, only four of the 45 operated patients (9%) had pCR in the resected specimen, and 53% of patients had only moderate, minimal, or no tumor regression at all. As shown in Table 13.11, the disappointingly low rate of pCR rates achieved by the combination of CRT plus cetuximab has now been confirmed in several phase II studies (Horisberger et al. 2009; Bertolini et al. 2009; Debucquoy et al. 2009). Several mechanisms may contribute to the apparently subadditive interaction between CRT and cetuximab, including upregulation of cycline-dependent kinase p27 and G1 cell cycle arrest, the redundancy of EGFR pathways, K-ras mutation status, as well as sequence dependencies (Debucquoy et al. 2009). As molecular targeted therapies exert their efficacy predominantly as cytostatic rather than cytotoxic agents, it is also well conceivable that the benefit may be manifested not as an increase in early tumor regression but rather as an arrest in tumor progression. Thus, longer follow-up (and finally randomized trials) is needed to draw any firm conclusions with respect to local and distant failure rates as well as toxicity.
50
40
41
Horisberger et al. (2009)
Bertolini et al. (2009)
Debucquoy et al. (2009)
Preop. RT: 1.8–45 Gy Capecitabine 825 mg/m² during RT Cetuximab 400 mg/m² loading dose (d-7) followed by 250 mg/m² (d1, 8, 15, 22, 29)
Preop. RT: 2.0–50 Gy 5-FU: 225 mg/m² continuous infusion Cetuximab 400 mg/m² loading dose, followed by 250 mg/m² weekly, three times, followed weekly concomitantly with CRT
Preop. RT: 1.8–50.4 Gy Capecitabine 500 mg/m² bid d1–38 Irinotecan 40 mg/m² d1 ,8, 15, 22, 29 Cetuximab 400 mg/m² loading dose (d1) followed by 250 mg/m² (d8, 15, 22, 29)
Grade 3 diarrhea 15% Grade 4: myocardial infarction (1), pulmonary embolism (1), sepsis (1)
Grade 3 acneiform rash 15%, no grade 4 toxicity
Grade 3–4 leukopenia 4% Grade 3 diarrhea: 30%
5%
8%
8%
9%
Grade 3–4 diarrhea 19%
48
Rödel et al. (2008)
Preop. RT: 1.8–50.4 Gy Capecitabine 825 mg/m² bid d1–14 an d22–35 Oxaliplatin 50 mg/m² d1,8,22,29 Cetuximab 400 mg/m² loading dose (d-7) followed by 250 mg/m² (d1,10, 8, 15, 22, 29)
pCR
Table 13.11 Selected phase II studies of preoperative of CRT for rectal cancer with epidermal growth factor receptor (EGFR)-inhibition Series Concurrent CRT Toxicity N
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Angiogenesis is necessary for the survival and growth of tumors; however, tumor blood vessels are often characterized by a disorganized architecture that contributes to intratumoral regions of intermittent or chronic hypoxia. Preclinical data have suggested that proangiogenic factors, especially the vascular endothelial growth factor (VEGF), are upregulated in tumors in response to RT and may increase resistance to RT. These findings are now supported by clinical data in rectal cancer patients, such that VEGF expression has been linked to a worse prognosis (Marquardt et al. 2009). VEGF-targeted therapy may lead to a “normalization” of the tumor vasculature, thereby leading to greater tumor oxygenation and drug penetration. When combined with RT, antibodies against VEGF-induced additive to supraadditive tumor growth delay and cell death in colon cancer models. Willett et al. have reported on a phase I study of preoperative bevacizumab, 5-FU, and radiation therapy for clinical T3 or T4 rectal cancer. Preliminary data indicate safety of this regimen and significant activity (six of seven evaluable patients demonstrated only microscopic disease in the surgical specimen 7 weeks after completion of neoadjuvant treatment) (Willett et al. 2004). In a meticulous analysis of the first six patients performed 12 days after the first bevacizumab infusion, this group revealed a significant decrease in tumor blood perfusion and blood volume, and a significant decrease in tumor microvessel density. This was accompanied by an increase in pericyte coverage of tumor vessels and a decrease of the interstitial fluid pressure, indicating that a “normalization” of the tumor vasculature by anti-VEGF treatment may contribute to the high efficacy of bevacizumab in this and further trials with combined CRT and VEGF inhibition (Table 13.12) (Willett et al. 2009; DiPetrillo et al. 2008; Marijnen et al. 2008; Crane et al. 2009). Clearly the toxicity pattern (radiation-induced enteritis, perforations) and surgical complications (wound healing, fistula, bleeding) observed in at least some of the clinical studies warrants further investigations of the interaction of RT with VEGF-inhibition, both for tumor and normal tissues.
13.9.9 Treatment Toxicity and Quality of Life Complications of pelvic RT are a function of the volume of the radiation field, overall treatment time, fraction size, RT energy, total dose, technique and sequence of RT, and combination with concurrent chemotherapy. Acute side effects such as diarrhea, proctitis, and dysuria are common during treatment. These conditions are usually transient and resolve within a few weeks following the completion of RT or CRT. Positioning devices, such as the bellyboard, can be used to reduce small-bowel toxicity. Management usually involves the use of antispasmodic and/or anticholinergic medications. Dietary counseling is also useful in the management of diarrhea. Delayed complications occur less frequently but are substantially more serious. The initial symptoms commonly occur 6–18 months following completion of RT or CRT. Complications include: persistent diarrhea, increased bowel frequency and impairment of sphincter function, proctitis and strictures at the anastomotic site, small-bowel obstruction, perineal/scrotal tenderness, delayed perineal wound healing, urinary incontinence, and bladder atrophy/bleeding. Injury to the vascular and supporting stromal tissues as well as
23
23
32
25
Marijnen et al. (2008)
DiPetrillo et al. (2008)
Willett et al. (2009)
Crane et al. (2009)
Preop. RT: 1.8–50.4 Gy Capecitabine 900 mg/m² bid M-F Bevacizumab: 5 mg/m² d1,15,29 Surgery 6–11 weeks (median 7.3) after RT
Preop. RT: 1.8–50.4 Gy 5-Fluorouracil: 225 mg/m² continuous infusion Bevacizumab: 5 or 10 mg/m² d-14,1,15,29 Surgery: 7–9 weeks after completion of RT
Two biweekly courses of bevacizumab 5 mg/m² and modified FOLFOX6 followed by bevacizumab 5 mg/m² biweekly, oxaliplatin 50 mg/m² weekly (subsequently reduced to 40 mg/m² due to grade 3 diarrhea), 5-FU 200 mg/m² continuous infusion concurrent with 50.4 Gy pelvic irradiation Surgery 4–8 weeks after completion of RT
Preop. RT: 2.0–50 Gy Capecitabine 825 mg/m² bid Bevacizumab: 5 mg/m² d-14, 1, 15, 8 ,29 Surgery 6–10 weeks thereafter
16% (ypT0)
32% No patients had grade 3 GI or hematologic toxicity. Surgical: three wound complications that required surgical intervention
25%
Grade 3 during CRT: 75% Grade 4: neutropenia (1 patient), diarrhea (1 patient)
No acute grade 4 Grade 3 diarrhea 22% Postoperative complications: wound infection (3), delayed healing (2), presacral abscess (2), pelvic hematoma (2), ileus (2)
9%
pCR
Grade 3: skin (4), diarrhea (2), Grade 4: anal mucositis (1);Grade 5: enteritis with uncontrollable bleeding (1), Postop: 2/23 small-bowel perforations, 1 rectal wall perforation, surgical: perineal dehiscence (1), rectovaginal fistula (2), bleeding 5500 cc (1)
Table 13.12 Selected phase II studies of preoperative CRT for rectal cancer with VEGF (vascular endothelial growth factor)-inhibition Series Concurrent CRT Toxicity N
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to autonomic nerves is the presumed pathophysiology. The most common delayed severe complications are due to small-bowel damage and include small-bowel enteritis, adhesions, and small-bowel obstruction requiring surgical intervention. These complications occur more often after postoperative compared with preoperative RT/CRT (Sauer et al. 2004). The incidence of small-bowel obstruction requiring surgery following postoperative pelvic RT/CRT for rectal cancer is 4–12% in modern series, but was as low as 2% in the preoperative CRT arm of the recent German Rectal Cancer Study (CAO/ARO/AIO-94). As with surgery, RT has been shown to lead to increased sexual dysfunction, with longterm deterioration of ejaculatory and erectile function in men, and vaginal dryness and diminished sexual satisfaction in women. In the Polish randomized trial, the incidence of long-term toxicity was similar for preoperative short-course RT and 5-FU-based longcourse CRT (Bujko et al. 2006). Some evidence from long-term analysis of the Swedish trials indicate an increased risk of second cancers in organs within or adjacent to the RT volume (Birgisson et al. 2005).
13.10 Future Perspectives As depicted in Fig. 13.11, there have been two major developments in neoadjuvant treatment of rectal cancer over the past two decades. The first one has been to apply RT and CT as early as possible. Since 2004, CRT is set before surgery, and the most recent studies even incorporated neodjuvant chemotherapy prior to preoperative CRT. As a consequence, surgery has been gradually postponed. Indeed, the need for radical surgery is now challenged by series of definitive CRT that report excellent outcomes in patients with clinical complete response (Habr-Gama and Perez 2009). The second major development has been to integrate combination chemotherapy with preoperative RT (Rodel and Sauer 2007). The most recent series used triple combinations, including RT, combination chemotherapy, and targeted therapies (Marquardt et al. 2009). Phase III trials are needed to determine if these novel combination regimens offer an advantage compared with 5-FU-based combined modality. Moreover, better knowledge of microscopic lymphatic spread within the mesorectum has led to the use of TME for mid and low rectal cancer. With this “optimized” surgery, local control rates have been markedly increased and local failure rates above 10–15% are now no longer acceptable. Technical advances in RT, including tumor-optimized and radiobiologically optimized fractionation and image-guided and intensity-modulated radiation therapy will further allow application of more sophisticated treatment volume to reduce irradiation of normal tissue and increase the therapeutic index (Valentini et al. 2008). Evidently, the monolithic approaches, established by studies more than a decade ago, to either apply the same schedule of preoperative or postoperative 5-FU-based CRT to all patients with TNM stage II/III rectal cancer or to give preoperative intensive short-course RT according to the Swedish and Dutch concept for all patients with resectable rectal cancer irrespective of tumor stage and location, need to be questioned. The inclusion of different multimodal treatments into the surgical oncological concept, adapted to the tumor
416
C. Rödel et al.
GITSG 7175 and NCCTG/Mayo 794751: Superiority of combined CRT over surgery 1992 alone or adjuvant RT and CT alone. GITSG 7180: Six cycles of bolus 5-FU, RT with 3./4.cycle. Methyl-CCNU plus 5-FU not superior to 5-FU alone.
5-FU Bolus
S
5-FU continuous infusion S
NCCTG 864751: 5-FU continuous infusion during RT superior to bolus 5-FU for 1994 disease-free and overall survival (not confirmed by the more recent INT 0144). Modulation of 5-FU through addition of folinic acid, levamisol, or of both, not superior to bolus 5-FU alone (INT 0114). 2002 Korean Trial: Start of RT together with 1./2. versus 3./4. cycle of 5-FU/folinic acid improved disease-free survival.
S
German Rectal Cancer study (CAO/ARO/AIO94): Preop. superior to postop. CRT for 2004/ local control, sphincter preservation, toxicity. EORTC 22921; FFCD 9203: Preoperative 2006 RCT with 5-FU/folinic acid superior to preoperative RT alone for local control. None of the 3 trials showed improved survival.
S
Oxaliplatin or Irinotecan
Capecitabin or 5-FU
Several phase I/II-studies incorporated novel chemotherapy combinations into 2004/ preoperative RCT: 2006 pCR-rates 9-36%; increased, but manageable acute toxicity (for review: Ródel C, Sauer R 2007). The question of postoperative chemotherapy was not addressed. 2006 Multicenter phase II trial of the German Rectal Cancer Study Group: Preoperative RCT active and feasible (pCR-rate 16%, compliance 96%). Only 60% of patients received all four cycles of chemotherapy.
S
Oxaliplatin Cape
Oxaliplatin
Cape
S
Capecitabine
S
2006 Integration of neoadjuvant chemotherapy prior to RCT for MRI-defined poor risk rectal cancer.
Cetuximab or Bevacizumab Oxaliplatin or Irinotecan S Capecitabin or 5-FU
Intergration of targeted therapy (cetuximab and bevacizumab) into combined modality 2007/ programs for rectal cancer 2008
Fig. 13.11 Major developments in (neo-) adjuvant treatment of rectal cancer over the past two decades
location and stage and to individual patient’s risk factors is mandatory. Clearly, future developments will aim at identifying and selecting patients for the ideal treatment alternatives. Thus, clinicopathological and molecular features as well as accurate preoperative imaging and postoperative surgical quality control will take an important and integrative part in multimodality treatment of rectal cancer.
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References Aschele C et al (2009) Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial. J Clin Oncol (Meeting Abstracts) 27(18S):CRA4008 Barbaro B et al (2009) Locally advanced rectal cancer: MR imaging in prediction of response after preoperative chemotherapy and radiation therapy. Radiology 250(3):730–739 Beets-Tan RG, Beets GL (2008) Preoperative staging of rectal tumors: what is the most optimal staging method? Onkologie 31(5):222–223 Bertolini F et al (2009) Neoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: a phase II study in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 73(2):466–472 Bipat S et al (2004) Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging – a meta-analysis. Radiology 232(3):773–783 Birgisson H et al (2005) Occurrence of second cancers in patients treated with radiotherapy for rectal cancer. J Clin Oncol 23(25):6126–6131 Borschitz T et al (2008) Neoadjuvant chemoradiation and local excision for T2-3 rectal cancer. Ann Surg Oncol 15(3):712–720 Bosset JF et al (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355(11):1114–1123 Braendengen M et al (2008) Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol 26(22):3687–3694 Bujko K et al (2004) Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother Oncol 72(1):15–24 Bujko K et al (2006) Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 93(10):1215–1223 Cafiero F et al (2003) Randomized clinical trial of adjuvant postoperative RT vs. sequential postoperative ER plus 5-FU and levamisol in patients with stage II-III resectable rectal cancer: a final report. J Surg Oncol 83(3):140–146 Calvo FA et al (2004) 18F-FDG positron emission tomography staging and restaging in rectal cancer treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 58(2):528–535 Calvo FA et al (2006) Improved incidence of pT0 downstaged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Ann Oncol 17(7):1103–1110 Camma C et al (2000) Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA 284(8):1008–1015 Capirci C et al (2008) Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 72(1):99–107 Cavaliere F et al (1995) Coloanal anastomosis for rectal cancer. Long-term results at the Mayo and Cleveland Clinics. Dis Colon Rectum 38(8):807–812 Ceelen W et al (2009) Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: a systematic review and meta-analysis. Int J Cancer 124(12): 2966–2972 Chau I et al (2006) Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 24(4):668–674
418
C. Rödel et al.
Cho E et al (2004) Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med 140(8):603–613 Collette L et al (2007) Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 25(28):4379–4386 Colorectal Cancer Collaborative Group (2001) Adjuvant radiotherapy for rectal cancer: a systematic overview of 8507 patients from 22 randomised trials. Lancet 358(9290): 1291–1304 Crane CH et al (2010) Phase II Trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 76(3): 824–830 Debucquoy A et al (2009) Molecular response to cetuximab and efficacy of preoperative cetuximab-based chemoradiation in rectal cancer. J Clin Oncol 27(17):2751–2757 den Dulk M et al (2009) Multicentre analysis of oncological and survival outcomes following anastomotic leakage after rectal cancer surgery. Br J Surg 96(9):1066–1075 DiPetrillo TA et al (2008) Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation in clinical stage II-III rectal cancer. J Clin Oncol 26:Abstract 15041 Frykholm GJ, Glimelius B, Pahlman L (1993) Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 36(6):564–572 Gastrointestinal Tumor Study Group (1985) Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 312(23):1465–1472 Gastrointestinal Tumor Study Group (1992) Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. J Clin Oncol 10(4):549–557 Gerard JP et al (2006) Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 24(28):4620–4625 Gerard J et al (2009) Randomized multicenter phase III trial comparing two neoadjuvant chemoradiotherapy (CT-RT) regimens (RT45-Cap versus RT50-Capox) in patients (pts) with locally advanced rectal cancer (LARC): Results of the ACCORD 12/0405 PRODIGE 2. J Clin Oncol (Meeting Abstracts) 27(18S):LBA4007 Glimelius B et al (2003) A systematic overview of radiation therapy effects in rectal cancer. Acta Oncol 42(5–6):476–492 Glynne-Jones R, Anyemene N (2009) Histologic response grading after chemoradiation in locally advanced rectal cancer: a proposal for standardized reporting. Int J Radiat Oncol Biol Phys 73(4):971–973 Glynne-Jones R et al (2006) Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious? Br J Cancer 94(3):363–371 Grady WM, Carethers JM (2008) Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135(4):1079–1099 Greene FL, Stewart AK, Norton HJ (2004) New tumor-node-metastasis staging strategy for nodepositive (stage III) rectal cancer: an analysis. J Clin Oncol 22(10):1778–1784 Guerrieri M et al (2008) Transanal endoscopic microsurgery for the treatment of selected patients with distal rectal cancer: 15 years experience. Surg Endosc 22(9):2030–2035 Gunderson LL et al (2004) Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 22(10):1785–1796 Habr-Gama A, Perez RO (2009) Non-operative management of rectal cancer after neoadjuvant chemoradiation. Br J Surg 96(2):125–127 Heald RJ, Ryall RD (1986) Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1(8496):1479–1482 Hermanek P et al (2003) The pathological assessment of mesorectal excision: implications for further treatment and quality management. Int J Colorectal Dis 18(4):335–341
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Holm T et al (2007) Extended abdominoperineal resection with gluteus maximus flap reconstruction of the pelvic floor for rectal cancer. Br J Surg 94(2):232–238 Horisberger K et al (2009) Cetuximab in combination with capecitabine, irinotecan, and radiotherapy for patients with locally advanced rectal cancer: results of a Phase II MARGIT trial. Int J Radiat Oncol Biol Phys 74(5):1487–1493 Huerta S (2008) Recent advances in the molecular diagnosis and prognosis of colorectal cancer. Expert Rev Mol Diagn 8(3):277–288 Ishiguro S et al (2009) Pelvic exenteration for clinical T4 rectal cancer: oncologic outcome in 93 patients at a single institution over a 30-year period. Surgery 145(2):189–195 Jemal A et al (2009) Cancer statistics. CA Cancer J Clin 59(4):225–249 Kalofonos HP et al (2008) A randomised phase III trial of adjuvant radio-chemotherapy comparing Irinotecan, 5FU and Leucovorin to 5FU and Leucovorin in patients with rectal cancer: a Hellenic Cooperative Oncology Group Study. Eur J Cancer 44(12):1693–1700 Kapiteijn E et al (2001) Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345(9):638–646 Krook JE et al (1991) Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324(11):709–715 Lahaye MJ et al (2008) USPIO-enhanced MR imaging for nodal staging in patients with primary rectal cancer: predictive criteria. Radiology 246(3):804–811 Langer C et al (2003) Surgical cure for early rectal carcinoma and large adenoma: transanal endoscopic microsurgery (using ultrasound or electrosurgery) compared to conventional local and radical resection. Int J Colorectal Dis 18(3):222–229 Lashner BA et al (1997) The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis. Gastroenterology 112(1):29–32 Law WL et al (2007) Anastomotic leakage is associated with poor long-term outcome in patients after curative colorectal resection for malignancy. J Gastrointest Surg 11(1):8–15 Learn PA, Kahlenberg MS (2009) Hereditary colorectal cancer syndromes and the role of the surgical oncologist. Surg Oncol Clin N Am 18(1):121–144, ix Leslie A et al (2002) The colorectal adenoma-carcinoma sequence. Br J Surg 89(7):845–860 Lezoche G et al (2008) A prospective randomized study with a 5-year minimum follow-up evaluation of transanal endoscopic microsurgery versus laparoscopic total mesorectal excision after neoadjuvant therapy. Surg Endosc 22(2):352–358 Lopez-Kostner F et al (1998) Total mesorectal excision is not necessary for cancers of the upper rectum. Surgery 124(4):612–617; discussion 617–618 Machiels JP et al (2007) Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol 18(4):738–744 Marijnen CA et al (2008) Preoperative chemoradiotherapy regimen with capecitabine and bevacizumab in locally advanced rectal cancer: a feasibility study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol 26:Abstract 15040 Marquardt F et al (2009) Molecular targeted treatment and radiation therapy for rectal cancer. Strahlenther Onkol 185(6):371–378 Martling A et al (2002) The surgeon as a prognostic factor after the introduction of total mesorectal excision in the treatment of rectal cancer. Br J Surg 89(8):1008–1013 Matthiessen P et al (2007) Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer: a randomized multicenter trial. Ann Surg 246(2):207–214 MERCURY Study Group (2007) Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results of the MERCURY study. Radiology 243(1):132–139 Minsky BD et al (1992) Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy. J Clin Oncol 10(1):79–84 Moriya Y et al (2003) Aggressive surgical treatment for patients with T4 rectal cancer. Colorectal Dis 5(5):427–431
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C. Rödel et al.
Nagtegaal ID, Quirke P (2008) What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 26(2):303–312 Nagtegaal ID et al (2005) Low rectal cancer: a call for a change of approach in abdominoperineal resection. J Clin Oncol 23(36):9257–9264 NIH consensus conference (1990) Adjuvant therapy for patients with colon and rectal cancer. JAMA 264(11):1444–1450 Nivatvongs S (2000) Surgical management of early colorectal cancer. World J Surg 24:1052–1055 Norat T et al (2005) Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition. J Natl Cancer Inst 97(12):906–916 O’Connell MJ et al (1994) Improving adjuvant therapy for rectal cancer by combining protractedinfusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331(8): 502–507 Peeters KC et al (2007) The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 246(5):693–701 Puli SR et al (2009) Accuracy of endoscopic ultrasound to diagnose nodal invasion by rectal cancers: a meta-analysis and systematic review. Ann Surg Oncol 16(5):1255–1265 Quirke P et al (1986) Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision. Lancet 2(8514):996–999 Quirke P et al (2007) The future of the TNM staging system in colorectal cancer: time for a debate? Lancet Oncol 8(7):651–657 Quirke P et al (2009) Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. Lancet 373(9666):821–828 Radu C et al (2008) Short-course preoperative radiotherapy with delayed surgery in rectal cancer – a retrospective study. Radiother Oncol 87(3):343–349 Rodel C, Sauer R (2007) Integration of novel agents into combined-modality treatment for rectal cancer patients. Strahlenther Onkol 183(5):227–235 Rodel C et al (2007) Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 25(1):110–117 Rodel C et al (2008) Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys 70(4):1081–1086 Rödel C et al (2005) Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23(34):8688–8696 Roh MS et al (2009) Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 27(31):5124–5130 Rutten HJ et al (2008) Controversies of total mesorectal excision for rectal cancer in elderly patients. Lancet Oncol 9(5):494–501 Sauer R et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351(17):1731–1740 Sebag-Montefiore D et al (2009) Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 373(9666):811–820 Smalley SR et al (2006) Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 24(22):3542–3547 Sterk P et al (2000) Vascular organization in the mesorectum: angiography of rectal resection specimens. Int J Colorectal Dis 15(4):225–228 Swedish Rectal Cancer Trial (1997) Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336(14):980–987
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Tepper JE et al (2002) Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control – final report of intergroup 0114. J Clin Oncol 20(7):1744–1750 Tveit KM et al (1997) Randomized controlled trial of postoperative radiotherapy and short-term time-scheduled 5-fluorouracil against surgery alone in the treatment of Dukes B and C rectal cancer. Norwegian Adjuvant Rectal Cancer Project Group. Br J Surg 84(8):1130–1135 Valentini V et al (2008) Evidence and research in rectal cancer. Radiother Oncol 87(3):449–474 Valentini V et al (2009) Multidisciplinary Rectal Cancer Management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2). Radiother Oncol 92(2):148–163 Watanabe T et al (2008) Lateral pelvic lymph node dissection or chemoradiotherapy: which is the procedure of choice to reduce local recurrence rate in lower rectal cancer? Ann Surg 248(2): 342–343; author reply 343 West NP et al (2008) Evidence of the oncologic superiority of cylindrical abdominoperineal excision for low rectal cancer. J Clin Oncol 26(21):3517–3522 Whittemore AS et al (1990) Diet, physical activity, and colorectal cancer among Chinese in North America and China. J Natl Cancer Inst 82(11):915–926 Willett CG et al (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10(2):145–147 Willett CG et al (2009) Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 27(18):3020–3026 Williams CS, Mann M, DuBois RN (1999) The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18(55):7908–7916 Wittekind Ch, Henson DE, Hutter RVP, Sobin LH (eds) (2001) TNM supplement. A commentary on uniform use, 2nd edn. Wiley, New York Wolmark N et al (2000) Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 92(5):388–396 Yamada K et al (2002) Pelvic exenteration and sacral resection for locally advanced primary and recurrent rectal cancer. Dis Colon Rectum 45(8):1078–1084 Yee J (2009) CT colonography: techniques and applications. Radiol Clin North Am 47(1):133–145
14
Anal Cancer Rob Glynne-Jones and Suzy Mawdsley
Conflict of Interest Statement Rob Glynne-Jones has received honoraria for lectures and advisory boards and has been supported in attending international meetings by Merck, Pfizer, Sanofi-Aventis and Roche. He has also received unrestricted grants for research from Merck-Serono, Sanofi-Aventis and Roche. Suzy Mawdsley: No conflicts of interest
14.1 Incidence Squamous cell cancer (SCC) of the anus is rare and accounts for only 2–4% of all lower alimentary tract malignancies. The annual incidence is approximately 1 in 100,000 (approximately 900 cases per year in the UK, and 5,000 in the USA), and has been increasing over the past three decades (Frisch et al. 1993; Johnson et al. 2004; Bilimoria et al. 2009; Jemal et al. 2008). Anal cancers are more common in women than men (Bilimoria et al. 2009; Jemal et al. 2008) and patients are often elderly. An indolent natural history and a low rate of distant metastases (Jemal et al. 2008; Boman et al. 1984; UKCCCR Anal Cancer Working Party 1996) mean that anal cancer is usually amenable to loco-regional treatment. The relative five-year survival rate in the US for anal cancer diagnosed 1983– 1990 was 62% (Miller et al. 1973), and has changed little for patients treated in the last two decades (Bilimoria et al. 2009; Jemal et al. 2008) (Table 14.1).
R. Glynne-Jones (*) Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, UK and Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex HA6 2RN, UK e-mail:
[email protected] S. Mawdsley Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex HA6 2RN, UK C.D. Blanke et al. (eds.), Gastrointestinal Oncology, DOI: 10.1007/978-3-642-13306-0_14, © Springer-Verlag Berlin Heidelberg 2011
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72
283
Newman et al. 1992)
Friberg et al. 1998) Anal canal
60–64
50 Gy/20f
45–62
222
Not stated
3
3
55
55/72 T1=100
T1/T2 = 84
T1/T2 = 77
Papillon and Montbarbon (1987)
6 20% late complications
63.95
35
Doggett et al. 1988)
12
T1/T2 = 91 T1/T2 = 90
65–69
14
T1/T2 = 56
33
60–65
9
67
San Francisco, Cantril et al. (1983)
64
Institut Gustave Roussy
65–67
8
Local control (%)
T3 = 76
21
Cutuli et al. 1988) (margin)
65–75
Complications needing surgery %
Eschwege et al. 1985)
158
Institut Curie Salmon et al. 1984)
Table 14.1 Results of historical studies with radiotherapy alone Series Number Dose Gy
60
66
65
92
79
46
55
59 (70% for<4 cm)
5-Year survival (%)
58
74
Not stated
77 Surgical definition
78
74
45
73 for <4 cm
Functioning anus (%)
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This chapter will limit its discussion to SCC arising in the anal canal and margin, and ignore other biologically distinct anal tumours such as melanoma, neuroendocrine tumours, adenocarcinomas, lymphomas and GIST tumours.
14.2 Aetiology and Risk Factors Human papilloma virus (HPV) infection is closely correlated with squamous cell anal carcinoma (Williams et al. 1996). Using polymerase chain reaction (PCR), the presence of the HPV genome has been identified in 80–85% of cases (Frisch et al. 1997; Crook et al. 1991). This parallels the prevalence seen in cervical and vulval carcinoma in women (Bosch et al. 1995). In one study 331 patients were examined and 84% demonstrated HPV in the malignant tissue. HPV 16 made up 87% of these (Frisch et al. 1999a). The role of HPV has therapeutic implications, as patients with HPV positive tumours in some tumour sites appear to be more radiosensitive (Licitra et al. 2006). Immuno-suppression is a further important risk factor, particularly in renal and cardiac transplant recipients (Penn 1986). Even before the current HIV epidemic an excess risk of 40–50 times was observed in the homosexual population for anal cancer (Daling et al. 1982; Daling and Weiss 1987). Currently HIV is a recognised risk factor (Melbye et al. 1994), but the precise relationship is difficult to separate from the prevalence of HPV. Anal cancer is strongly associated with cigarette smoking (Holly et al. 1989; Daling et al. 1992; Tseng et al. 2003; Frisch et al. 1999b). In a case–control study current cigarette smoking was a major risk factor in both sexes, with relative risk 7.7 in women and 9.4 in men (Daling et al. 1992). There is no clear association with dietary habits and chronic inflammatory diseases and the presence of haemorrhoids do not appear to predispose to anal cancer development (Frisch et al. 1994; Frisch and Johansen 2000).
14.3 Pathology and Biology The neoplastic process in the anus can be divided into intra-epithelial neoplasia (AIN) and invasive disease.
14.4 Intra-Epithelial Neoplasia AIN can be graded from one to three in severity. The incidence of AIN in homosexual men is >36% (Clark et al. 1986; Daling et al. 2004). The natural history of progression from AIN3 to invasive malignancy in anal cancer is generally poorly documented. It appears
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low in immuno-competent patients (Schofield et al. 2005). In contrast, progression is more likely in systemically immuno-suppressed patients (Lacey et al. 1999), and is influenced by HIV seropositivity, low CD4 count and serotype of HPV infection (Zbar et al. 2002; Abbasakoor and Boulos 2005).
14.5 Histological Types In terms of histological appearances, colorectal type mucosa is found about 1 cm above the dentate line. Between this level and the dentate line is a transitional zone with epithelial variants of columnar and cuboidal cells and areas of colorectal crypts above and squamous epithelium below. Terms such as basaloid transitional or spheroidal and cloacogenic have a similar natural history and patterns of spread, and have been replaced by SCC.
14.6 Tumour Grade Tumours of the anal canal are often poorly differentiated SCC, but grading is subject to considerable inter-observer variability, and considerable heterogeneity in larger tumours. Hence, although high-grade tumours are generally accepted to have a worse prognosis, this has not been confirmed in multivariate analysis (Shepherd et al. 1990).
14.7 Anatomy The anal canal measures approximately 4 cm in length. The anatomical definition and terminology used to describe the anal canal are often confused and imprecise. We would define the anal canal as that part of the large intestine beginning at the anorectal junction, passing through the anorectal ring and ending where true skin is found at the anal margin. Because the dentate line is the most easily identified landmark in the mucosa of the anal canal, many have suggested that the canal is divided into infra dentate and supra dentate regions (Wendell-Smith 2000). The anal margin reflects that region of pigmented skin with skin folds surrounding the anus. Although the lateral border of the anal margin has not been defined, tumours of the perianal skin within a radius of approximately 5 cm from the anal orifice are usually considered as anal margin cancer.
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14.8 Lymphatic Drainage The most proximal portion of the anal canal drains to perirectal nodes and nodes along the superior rectal vessels to the inferior mesenteric system, and then to the para-aortic nodes. There is also drainage to the internal iliac and obturator nodes (Hill et al. 2003). The canal above the dentate line drains to internal pudendal nodes and to the internal iliac system. Venous drainage of the upper half of the canal is mainly by the superior rectal vein to inferior mesenteric vein, while drainage of the lower half is by the inferior rectal vein, to the internal pudendal vein and internal iliac vein. Hence, metastases may occur to either liver via the portal system or lung via the systemic circulation, depending on tumour position. The canal below the dentate line drains to the medial group of superficial inguinal nodes with some communication with femoral nodes and to external iliac nodes. Involved nodes are often palpable, but historical pathology studies, using a ‘clearing’ technique, demonstrated that almost half of all involved lymph nodes were smaller than 5 mm in diameter (Wade et al. 1986). The inguinal, femoral and iliac lymph nodes are the most frequent sites for nodal metastases (Greenall et al. 1985; Beahrs and Wilson 1976; Stearns et al. 1980; Greene et al. 2002).
14.9 Presentation The initial and most common symptom is bleeding and occurs in approximately 50% of patients, and 25% present with an obvious mass and discomfort (Stearns et al. 1980). Pruritus and discharge are found in 25% (Stearns et al. 1980) and less commonly, patients may present with faecal incontinence or a rectovaginal fistula. Diagnosis can be made on rectal examination. Small, early cancers often cause few symptoms, and are sometimes diagnosed serendipitously with the removal of anal tags. Suspicious lesions should always be biopsied.
14.10 Staging and Risk Assessment The American Joint Committee on Cancer (AJCC) in 2002, tumour node metastases staging system (Greene et al. 2002) is based on size (T stage), regional lymph node involvement (N) and spread to different sites (M). Data from surgical studies prior to the use of chemoradiation suggest that small tumours <2 cm were associated with five-year survival in the range of 60–80%, but this figure fell to 24–55% when tumours were >5 cm (Boman et al. 1984; Greenall et al. 1985; Sato et al. 2005). A cut off of 4 cm has been proposed as
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the size, which distinguishes good and poor prognosis (Touboul et al. 1994). Because currently few cancers are surgically resected, this classification is now based on clinical examination and imaging studies. Nodal status is based on distance from the primary site rather than the number of nodes involved, as this has more prognostic significance, and the definition is different for cancers in the anal canal and margin.
14.11 Pre-Treatment Assessment Patients should be assessed for performance status, renal function and medical co-morbidity. Patients should also be tested for relevant infections and other malignancies. Clinical examination and digital rectal examination (DRE) remain a valuable method for assessing TNM staging. Imaging can provide information such as tumour length, degree of circumferential extent, involvement of adjacent structures and extension above the dentate line and below the anal margin. Direct proctoscopy is often difficult in more advanced lesions because of pain. Hence, examination under anaesthetic (EUA) may be required for biopsy. Vaginal examination is essential in female patients to assess extension into the post vaginal wall or even breaching of the vaginal mucosa. Currently, a cervical smear is also recommended for younger patients in whom the cervix can be accessed. The assessment of inguino-femoral lymph nodes remains controversial. In a retrospective surgical series 30% of patients had involvement of their inguinal nodes; however, in the early T1/T2 tumours the incidence was only 12% (Stearns et al. 1980; Pyper and Parks 1985; Clark et al. 1986). Involvement is usually unilateral and occasionally bilateral but not usually contralateral to the tumour. Involved nodes can be imaged on MRI (Roach et al. 2005), but clinically suspicious nodes should be assessed by biopsy where possible, as only 50% will contain tumour; the remainder are enlarged due to secondary infection.
14.12 Radiological Staging Given that definitive chemoradiation is currently the standard of care, there are few data to confirm the accuracy of staging, as there can be no histopathological correlation. MRI is favoured for assessing loco-regional disease extent (Salerno et al. 2006) as this provides good contrast resolution and multiplanar anatomical detail. The intermediate to high signal intensity tumour is well delineated on T2 and STIR-weighted sequences and primary tumour extent into surrounding structures (Koh et al. 2008). Endo-anal ultrasound (Magdeburg et al. 1999; Giovannini et al. 2001; Berton et al. 2008; Otto et al. 2009) and computed tomography (CT) may also provide useful information. Endoscopic ultrasound may be superior to MRI for detecting small superficial tumours. However, magnetic resonance imaging appears more effective for N staging.
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Carcinoma of the anus has a low rate of distant metastasis (Boman et al. 1984; Kuehn et al. 1968). Haematogenous spread at presentation is noted in less than 5% of cases and predominantly involves lung or liver. CT of the thorax and abdomen is therefore preferred to a chest radiograph and liver ultrasound for assessing metastatic disease due to its higher sensitivity. Prediction of lymph node involvement by size alone is inaccurate, as 44% of all involved lymph nodes are smaller than 5 mm in diameter (Wade et al. 1986). More recently, staging by virtue of positron emission tomography/CT with 18-F fluorodeoxyglucose (FDG-PET/ CT) has been advocated, because positive lymph nodes may be more easily identified than with other imaging modalities (Trautmann and Zuger 2005; Cotter et al. 2006). FDG-PET/ CT is recommended in the current National Comprehensive Cancer Network treatment guidelines (Engstrom et al. 2008). More accurate staging of lymph nodes is important as treatment is potentially influenced in terms of the radiation fields and the need for a boost to these sites. The use of MR lymphangiography with ultra-small superparamagnetic iron oxide particles (USPIO) to improve specificity and sensitivity of the nodes remains investigational (Koh et al. 2004).
14.13 Other Investigations/Procedures HIV testing is recommended in any patient with an at-risk lifestyle. HIV status has major implications both in terms of excess treatment toxicity and the development of infection. Optimisation of anti-retroviral treatment is therefore essential. Sperm banking should be discussed prior to the commencement of treatment with male patients, who wish to preserve fertility. It is assumed that scattered doses of radiation to the testes will invariably induce permanent sterility. A defunctioning colostomy should be considered prior to treatment in patients with significant faecal incontinence or in female patients with transmural vaginal involvement at risk of development of an anorectal-vaginal fistula, due to marked tumour regression following chemoradiation (CRT). Smoking may worsen acute toxicity during treatment and lead to a poorer outcome in terms of disease-free and colostomy-free survival (Mai et al. 2007). Every effort should be made to ensure that patients quit smoking prior to therapy.
14.14 Predictive Factors The association of response with tumour T stage has been noted previously in anal carcinomas (Gerard et al. 1998). In a study of chemoradiation (Doci et al. 1996), a 100% complete response rate was reported in T1/2 tumours and 60% in T3 tumours. The Intergroup and EORTC trials (Bartelink et al. 1997; Flam et al. 1996) also reported a higher complete response rate on univariate analysis by tumour size.
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14.15 Prognostic Factors Analysis of prognostic factors in anal cancer has only been reported from the smallest of the four published randomised studies (Bartelink et al. 1997), which suggested that skin ulceration as well as gender and nodal status were important, but not tumour size. Retrospective analyses with all their inherent limitations have highlighted gender, nodal status and tumour size (Greenall et al. 1985; Sato et al. 2005; Touboul et al. 1994; Longo et al. 1994; Peiffert et al. 1997; Das et al. 2007; Myerson et al. 2001) as prognostic factors. Tumour size has also been supported in multivariate analyses (Constantinou et al. 1997; Papillon and Montbaron 1987; Schlienger et al. 1989). In a series of 118 patients treated by external beam and brachytherapy there was an increase in local failure with increasing T stage (T1, 11%; T2, 24%; T3, 45% and T4, 43%) and a corresponding decrease in fiveyear survival Peiffert et al. 1997). The level of tumour regression (>80%) after primary chemoradiation may be predictive of colostomy-free and disease-free survival Chapet et al. 2005). A basaloid rather than squamous histological subtype has also been shown to have a higher risk of developing metastatic disease (Das et al. 2007). The impact of treatment factors has also been analysed. External beam (rather than iridium implant) to deliver boost radiotherapy and overall treatment time greater than or equal to 75 days, have been associated with poorer local control, but these factors did not remain significant in multivariate analysis (Allal et al. 1998). Others have not found any relationship between local control rates and total radiation dose, overall treatment time or irradiation technique in 270 patients treated with radiotherapy (Touboul et al. 1994).
14.16 Biological Markers Anal carcinomas appear to have a high proliferative index (Allal et al. 1998; Noffsinger et al. 1995). However, only two studies have shown prognostic significance. Nilsson demonstrated that a high cyclin A expression was prognostic for an improved tumour-specific survival, overall survival (OS), and loco-regional failure rate (Nilsson et al. 2006). In a very small study of just 30 patients, Ki67 expression correlated significantly with diseasefree survival (DFS) (Ajani et al. 2008). In contrast, the family of cyclin-dependent kinases (cyclin E and D1), which regulate transition through the cell cycle appear to have no significant prognostic effect (Allal et al. 2004). A high proliferative index may also be predictive of treatment response and in the ACT I series, of 240 patients, a higher expression of cyclin A predicted for an improved response to irradiation (Mawdsley et al. 2004). Over-expression of p53 is common in anal carcinomas (Ogunbiyi et al. 1993; Jakate and Saclarides 1993). Alterations in p53 protein function may result from either mutations in its gene or sequestration by other cellular proteins such as the E6 viral oncoprotein of the HPV virus (Gangopadhyay et al. 1997). HPV E6 protein has a direct effect on p53 in the basal layers of the anal epithelium, allowing the continuous proliferation of the host
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cells and increasing their risk of mutation (Zwerschke and Jansen-Durr 2000). Several studies have looked at the association of p53 and HPV. P53 nuclear accumulation has been found to be associated with the presence of HPV without an effect on clinical outcome. However, in other studies p53 was not found to be associated with HPV and coexpression of p53 and the HPV E6 oncoprotein was uncommon (Ogunbiyi et al. 1993; Jakate and Saclarides 1993; Tanum et al. 1993). In a recent analysis of 240 patients in the UKCCR ACT I anal cancer trial, p53 predicted for a poorer cause-specific survival (Mawdsley et al. 2004). In a smaller study of (Wong et al. 1999) 49 patients, p53 expression predicted for a poorer DFS. Other studies however, have been contradictory (Tanum et al. 1993). The RTOG study (Bonin et al. 1999) of 64 patients found there was a trend for patients whose tumours over-expressed p53 to have an inferior outcome. In a further small study of 18 patients, p53 had no prognostic impact and the authors concluded that p53 gene over-expression may simply confer a more aggressive growth pattern (Indinnimeo et al. 1998). The apoptotic marker Bcl-2 has been analysed extensively. In a study of 98 anal carcinoma patients, 51 of whom received combined modality treatment, lack of bcl-2 expression was associated with lower local control and OS. This association remained significant on multivariate analysis (Allal et al. 2003). Patients with a positive bcl-2 and negative p53 tumour had a significantly higher five-year local control compared to patients with negative bcl-2 and positive p53 (93 vs. 53%). There is little data on the potential role of angiogenic markers. A study of CD31 (Indinnimeo et al. 2001), a platelet endothelial cell adhesion molecule, showed no correlation with neoplastic relapse but there was a significant correlation with the depth of tumour invasion, supporting the concept that tumour growth is angiogenesis-dependent. Increasing micro-vessel density has also been demonstrated to correlate with increasing grade of intraepithelial anal neoplasia (Litle et al. 2000), suggesting that angiogenesis is a pre-malignant event. In the ACT I analysis (Mawdsley et al. 2004), decreasing CD34 was significantly associated with a poorer relapse-free survival (RFS), in multivariate analysis. This may reflect that those tumours with low vessel counts are more hypoxic and will therefore respond less well to treatment. In the ACT I series (Mawdsley et al. 2004) the markers of 5-fluorouracil (5-FU) metabolism, i.e. dihydropyrimidine dehydrogenase and thymidylate synthase expression, failed to correlate with survival. Thymidine phosphorylase expression did however correlate with a poorer RFS, although this observation could reflect the dual role of its direct involvement in angiogenesis.
14.17 Tumour Markers Squamous cell carcinoma antigen (SCCAg) is expressed by several epidermoid tumours, including carcinoma of the anal canal. In small historical studies, SCCAg levels have not been demonstrated to be of prognostic value in anal carcinoma (Petrelli et al. 1988), or useful in follow-up (Petrelli et al. 1992). In a series of 66 patients, the SCCAg correlated
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with nodal invasion (p < 0.05), but did not offer any prognostic value (Fontana et al. 1991). In another study with 60 patients, actuarial survival analyses for patients with normal vs. elevated SCCAg concentrations showed that the projected five-year OS was 81% for those with a normal level and 43% for those with an elevated level (p = 0.004), and for tumourspecific survival the figures were 83 vs. 45% respectively (p = 0.004) (Goldman et al. 1993). More recently a larger retrospective study from the UK suggests that the initial SCCAg level prior to treatment appears to be related to tumour stage and/or nodal status, and may assist in guiding planning target volumes (Swampillai et al. 2009).
14.18 Surgery as Primary Treatment for Anal Cancer Up until the mid 1980s surgery was the cornerstone of treatment for this disease (Boman et al. 1984; Stearns et al. 1980; O’Brien et al. 1982). Local resection was usually performed for cancer of the anal margin, which behaves in a similar fashion to skin cancer, and rarely it was used for smaller lesions of the anal canal. Abdomino-perineal resection was recommended as the best method of achieving adequate resection margins for most cancers in the anal canal. Inguinal node dissection was originally performed electively, but fell out of fashion because of concerns regarding morbidity (Golden and Hosley 1976). Some authors also advocated full pelvic node dissection; however, this aggressive surgical strategy failed to show any improvement in survival. Surgical treatment was associated with local failure in up to half of cases (Boman et al. 1984; Stearns et al. 1980), and fiveyear survival rates in the region of 50–70%. Local excision may be appropriate for small well-differentiated carcinomas of the anal margin (T1 N0), i.e. <2 cm in diameter, if there is no evidence of disease within the anal canal, there is no evidence of nodal spread clinically or on imaging and if clear lateral and deep margins are likely to be obtained. Further excision can be undertaken if the margins are not satisfactory (<3 mm). In contrast, local excision of a lesion in the anal canal may compromise sphincter function and an incomplete excision can severely impair long-term sphincter function from both the surgical procedure and from the additional CRT. Hence, there is no evidence to support a “debulking” approach prior to chemoradiation.
14.19 Non-Surgical Treatment The initial studies of Nigro (Nigro 1974, Nigro et al. 1983; Vaitkevicius et al. 1974) demonstrated high rates of local control with the use of approximately 30 Gy of irradiation with concurrent mitomycin C (MMC) and 5-FU. Cummings (1991) reported a series of 190 patients treated with radiotherapy (RT) or CRT using seven sequential regimens and concluded retrospectively that CRT and the addition of MMC to 5-FU improved local control.
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Subsequently, randomised controlled studies in Europe have confirmed that synchronous chemoradiation (SCRT), as the primary modality, is superior to radiotherapy alone in the treatment of anal cancer (UKCCCR Anal Cancer Working Party 1996; Doci et al. 1996). The RTOG phase III study (Flam et al. 1996; Bartelink et al. 1997) has also helped to confirm the value of adding MMC to 5-FU-based CRT (Table 14.2). Together with sequential phase II studies Cummings et al. 1991; Cummings 1993; Rich et al. 1993; Martenson and Lipsitz 1995; John et al. 1996; Friberg et al. 1998), these randomised trials have helped to refine techniques of radiotherapy and the efficacy of relatively low total radiation doses. However, the optimal schedules, radiation dose, technique, duration of gap and chemotherapy choice have been repeatedly questioned and remain in some cases the subject of ongoing clinical trials. The established European philosophy of treatment has usually relied on split-course radiotherapy with high total doses, and the use of interstitial implants based on the tradition of Papillon and Montbaron (1987). Anal cancers regress slowly and the perineal skin reactions take about four weeks to heal. Several authors suggested that it was impossible to deliver either an immediate perineal boost with external beam radiotherapy (EBRT) or an I-192 wire implant (Schlienger et al. 1989; Eschwege et al. 1985) and studies of continuous CRT in anal cancer confirmed that unscheduled breaks in treatment for up to two weeks were commonly required to allow severe skin and anorectal reactions to settle (Flam et al. 1996; Tanum et al. 1991). Therefore the rationale of this gap has been to allow the acute toxicity of skin and mucosal surfaces to resolve, to allow sufficient time for the bulk of the tumour to shrink and hence facilitate both an effective assessment of tumour response and the delivery of high doses of radiation using an interstitial implant to the smallest possible volume. This practice also minimises the risk of necrosis in the high-dose area. In addition, the long gap allows the selection of patients who fail to respond after the initial phase of treatment to proceed to surgical resection. The early randomised European trials advocated a six-week gap in treatment following wide-field pelvic chemoradiotherapy to a dose of 45 Gy prior to embarking on a more localised boost (UKCCCR Anal Cancer Working Party 1996; Bartelink et al. 1997). In contrast, the American view has opted for large shrinking field techniques with higher initial total doses in the region of 48–50 Gy in conjunction with synchronous chemotherapy, which avoid interruptions in the radiotherapy (Flam et al. 1996). However, evidence from the two cohorts in the RTOG 92-08 anal trial implies that even a short gap is detrimental to outcome. When the cohort with a two-week mandated gap is compared to those with similar initial characteristics in the RTOG-04 trial, where a median initial dose of 45 Gy was prescribed (Flam et al. 1996), OS, DFS and Colostomy free survival (CFS) all fared worse (Konski et al. 2008). In contrast, patients with no mandated break had similar outcomes to those in the RTOG 87-04 study. Small patient numbers and non-randomised comparisons make the study difficult to interpret. More recent sequential EORTC trials have integrated infusional 5-FU and reduced the gap to 2 weeks (Bosset et al. 2003; Crehange et al. 2006), allowing the overall treatment time to be within 65 days. This practice also allows two doses of mitomycin to be delivered. However, the use of any planned gap defies standard radiotherapy principles regarding overall treatment time, breaks in treatment and the concept of repopulation.
42 months
110
291
644
EORTC 22861 (Bartelink et al. 1997)
RTOG 87-04/ ECOG (Flam et al. 1996)
RTOG 98-11 (Ajani et al. 2008)
2.51 years
42 months
585
ACT 1 (UKCCCR Anal Cancer Working Party 1996)
CRT with MMC vs. NACT and CRT with cisplatin
CRT ± MMC 9 Gy salvage CRT for biopsy proven residual post CRT
RT vs. CRT
RT vs. CRT
Table 14.2 Designs of randomised phase III trials in anal cancer Trial No. Median FU Randomisation
5-FU 1,000 mg/m2 D1–4, 29–32 Cisplatin 75 mg/ m2 D1 and 29
No
No
No
NACT No
M Chemo
2
45–59 Gy 5-FU 1,000 mg/m2 D1–4, 29–32 MMC 10 mg/m2 D1 and 29 Or 5-FU 1,000 mg/m2 D57–60, 85–88 Cisplatin 75 mg/m2 D57and 85
5-FU 1,000 mg/m D1–4, 29–32 ± MMC 10 mg/m2 D1 and 29 If residual disease 9 Gy boost/5-FU/cisplatin 100 mg/m2
45–50.4 Gy
No
No
45 Gy/25F No 5-FU 750 mg/m2 D1–5, 29–33 MMC 15 mg/m2 D1 6 week gap 15 Gy (CR) or 20 Gy boost (PR)
45 Gy/20–25F ± 5-FU 1,000 mg/m2 D1–4, 29–32 MMC 10 mg/m2 D1
CRT schedule
OS
DFS
DFS
Local control Colostomy free survival
Local failure (disease or complications of treatment)
Primary endpoint
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940
ACT II (James et al. 2009)
36 months
43 months
2 × 2 factorial CRT cisplatin and maintenance CT cisplatin
No
50.4 Gy/28F 5-FU 1,000 mg/m2 D1–4, 29–32 MMC 12 mg/m2 D1 Or 5-FU 1,000 mg/m2 D1–4, 29–32 Cisplatin 60 mg/m2 D1 and 29
5-FU 800 mg/m2/ 45 Gy/25F day 5-FU 800 mg/m2 D1–4, 29–32 Cisplatin 80 mg/m2 D1 and 29 NACT and CRT D1–4, 29–32 Or (5-FU/Cisplatin) 5-FU 800 mg/m2 D57–60, 85–88 ±HDRT Cisplatin 80 mg/m2 D57 and85 Cisplatin 80 mg/m2 D1 and 29 ± 15 Gy boost
2 × 2 Factorial
DFS OS
5-FU 1,000 mg/m2 D1–4 Cisplatin 60 mg/m2 D1 Every 3 weeks
Colostomyfree survival
OS
DFS
Two cycles
No
Anal cancer phase III trials. CRT chemoradiation; RT radiotherapy; NACT neoadjuvant chemotherapy; MMC mitomycin C; HDRT high dose radiotherapy; NR not reported; M Chemo maintenance chemotherapy
307
ACCORD 03 (Conroy et al. 2009)
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14.20 T1/T2 Tumours
14.21 The Use of Radiation Alone For small tumours, some investigators have used high dose EBRT alone, followed by a small volume boost with either photons or electrons, or interstitial implantation. In addition, interstitial implantation has been advocated as a sole modality (Papillon and Montbaron 1987; Newman et al. 1992). Scandinavian retrospective series (Glimelius and Pahlman 1987) have also described the use of high doses in the region of 60 Gy EBRT with results that compare favourably in terms of local control with the randomised trials of chemoradiotherapy. High rates of local control after radiotherapy alone have been observed in a retrospective series from the Institut Gustave Roussy (91% for T1/T2 tumours). Salmon and colleagues (Salmon et al. 1984) found that tumour size was significantly related to survival, in which radiation therapy alone was the primary treatment. In addition, in a study from San Francisco, node-negative patients with T1/T2 tumours had a five-year survival rate of 92%. For this reason, it has been suggested that small volume T1 and early T2 tumours (<4 cm) can be treated with radiation alone to achieve a high cure rate. Nevertheless, the 20% long-term complication rate in the series treated with radiotherapy alone from San Francisco (Doggett et al. 1988) raises a note of caution. Although EBRT alone without chemotherapy is an acceptable alternative (Martenson and Lipsitz 1995), randomised trials have shown that chemoradiation is more effective even for T1 cancers (UKCCCR Anal Cancer Working Party, 1996; Northover et al. 1997). Initial data from Nigro (Nigro et al. 1983; Vaitkevicius et al. 1974) prompted Papillon (1990) to use chemoradiation rather than radiation alone, and local control for T3 tumours improved from 70% with radiotherapy alone to 90% with chemoradiation. Nigro showed that tumours under 5 cm in size could usually be controlled with 30 Gy in combination with chemotherapy. It is entirely possible that 45–50 Gy in combination with 5-FU/mitomycin is sufficient for local control of a large proportion of anal cancers, particularly those with stage T1 and T2. However, it remains unclear whether, in such early tumours, the optimal dose for RT alone is 45–50 Gy or 60–65 Gy. Most of the studies using RT alone used a tolerance dose of 60–65 Gy. It might be expected that late morbidity would be more common and more pronounced with a higher radiation dose. Cummings also noted an improvement in local control for T2–T4 tumours but not for T1 cancers (Cummings et al. 1991). In contrast, the UKCCR Anal Cancer Trial (ACT 1) demonstrates that even T1/T2 lesions appear to obtain the benefit from the addition of chemotherapy (UKCCCR Anal Cancer Working Party, 1996; Northover et al. 1997). The randomised trials confirm that more than 75% of patients will suffer at least one grade 3 or higher toxicity during modern chemoradiotherapy regimens. There is an exacerbation of acute toxicity with chemoradiation compared to radiation alone, but there is no clear increase in late effects, although accurate information on quality of life (QOL) and
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late morbidity from these studies is sparse. In the Accord-03 study, assessment two months after completion of treatment did not show that induction chemotherapy and high-dose radiotherapy either alone or in combination had any negative impact on QOL (TournierRangeard et al. 2008). Approximately 10% of patients suffer severe long-term toxicity after chemoradiation, and 5% require a subsequent colostomy for treatment-related problems (chronic diarrhoea, incontinence of faeces, pain on defecation and anorectal stenosis) rather than tumour recurrence (Ajani et al. 2008). Therefore it would seem logical to use chemoradiation even if there is only a small benefit in local control for small tumours by the addition of chemotherapy. Some studies have demonstrated a low risk of relapse in the inguinal region even for higher-stage lesions (Newman et al. 1992; Ferrigno et al. 2005), and many Europeans have a conservative approach to treating the inguinal region. The inguinal lymph node region is included in the fields only when the primary tumour is located in the canal <1 cm from the anal orifice, or if there is actual invasion of the anal orifice, or in case of clinical involvement of pelvic lymph nodes (on CT or MRI criteria). Some suggest that a conservative approach, avoiding elective groin irradiation, might be possible for all T1 and T2 tumours, but most authors still advocate formal groin irradiation for more advanced tumours (Das et al. 2007). A recent study (TROG 99-02) closed early because of an unacceptable rate of inguinal node relapse (Matthews 2005).
14.22 The Boost If required, a radiotherapy boost can be delivered by interstitial Iridium-192 implant to a dose of 20 Gy at a dose rate of 10 Gy per day according to the techniques of Papillon and Montbarbon (1987), delivering a dose to the 85 % reference isodose of the Paris system. A crescent-shaped template can ensure regular spacing of the radioactive sources, and is advocated in many centres. However, the experience and skills required for performing interstitial implants are not widespread, and the risks of necrosis are not insubstantial.
14.23 Treatment for Late Stage (T3/T4) Studies have demonstrated that the higher the stage of tumour, the lower the response to treatment and likelihood of achieving a complete response (Salmon et al. 1984; Touboul et al. 1994; Gerard et al. 1998; Bartelink et al. 1997; Flam et al. 1996; Constantinou et al.; 1997; Schlienger et al. 1989). Response rates for T3 and T4 tumours have been reported to be between 45 and 60% (Doci et al. 1996; Peiffert et al. 1997). For patients with locally advanced disease (stages T2N1, T3 and T4 (which is over 50% of cases), there is a high risk of recurrence. Patients with >5-cm tumour and N1 status have only 30% chance of being disease-free at three years (Ajani et al. 2009). The most
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favourable prognostic subgroup in the RTOG is patients with <5-cm diameter, clinically node-negative tumours with three- and five-year DFS of 74 and 66%, respectively, and three and five-year OS of 86 and 80%. The worst prognoses for DFS are for patients with tumour >5-cm diameter and clinically positive nodal status (approximately 25% of all patients) with three-year DFS of only 30% and four-year OS of 48%. A recent retrospective study suggested that doses >50 Gy are associated with improved local control (Ferrigno et al. 2005). Although higher radiation dose appears to improve outcome in some studies (Constantinou et al. 1997; Rich et al. 1993; Hughes et al. 1989), it remains unclear if increasing the radiation dose in patients with locally advanced anal cancer receiving combined modality therapy, will improve the results compared with doses of 45–50 Gy (John et al. 1996). Radiotherapy dose escalation to improve local control may not be the most appropriate strategy with standard planning techniques, because the risk of late adverse effects is related to the total radiotherapy dose (Allal et al. 1997). However, intensity modulated radiotherapy (IMRT) may be more practical. Most current radiation protocols for T3/T4 tumours use techniques that employ an initial wide field of radiotherapy, treating the whole of the lower pelvis and including the inguinal lymph nodes and the posterior pelvic lymph nodes in continuity with the primary cancer. Subsequent field reductions aim to encompass the primary treatment plus a margin.
14.24 Neoadjuvant Chemotherapy Neoadjuvant chemotherapy (NACT) has been associated with high response rates in chemotherapy naïve anal cancer (Gerard et al. 1998). However, despite this very high response rate, the addition of NACT prior to chemoradiation has not improved either local regional or distant control (Ajani et al. 2008; Conroy et al. 2009). The Intergroup RTOG 98-11 accrued a total of 682 patients between 1998 and 2005. Randomisation was between the standard arm of concurrent chemoradiation with 5-FU and mitomycin, and the novel arm of neoadjuvant 5-FU and cisplatin for two cycles prior to chemoradiation with concurrent 5-FU and cisplatin. NACT with cisplatin followed by 5-FU/cisplatin-based chemoradiation failed to improve OS, DFS, loco-regional control and distant relapse when compared to the standard of concurrent 5-FU with mitomycin chemoradiation. In fact, trends favoured the control arm of mitomycin. The cumulative rate of the requirement for a colostomy was significantly higher for the cisplatin arm compared to the standard of mitomycin (19 vs. 10%; p = 0.02). In a further recent phase 3 study, the Intergroup/ACCORD 03 trial, patients were randomised in a 2 × 2 factorial manner to moderate dose vs. high dose RT, and induction chemotherapy with 5-FU/cisplatin prior to CRT (Conroy et al. 2009). The aim of the study was to assess the benefit on the colostomy-free survival of two cycles of induction chemotherapy and an increase of the dose of irradiation delivered to the primary, from 60 to 65–70 Gy. Interim analysis suggested that this study would be underpowered to show a significant difference for NACT. More recent updated results after a mean follow-up of three years showed an 88% local control rate but did not show any benefit of the RT dose intensification group or NACT compared to standard treatment (Conroy et al. 2009). In fact,
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three-year actuarial local control was equivalent in the NACT and the standard arm – 88 and 90% respectively.
14.25 Consolidation Chemotherapy It has been argued that OS will only improve if there are both improvements in local regional control from chemoradiation and more effective systemic chemotherapy, which can decrease the risk of distant metastases. To date neither cisplatin in the chemoradiotherapy phase nor 5-FU and cisplatin in the maintenance or consolidation phase has been shown to improve outcome (James et al. 2009). The co-operation of additional effective drugs should be investigated in both the chemoradiotherapy and consolidation settings. Various groups are attempting to integrate capecitabine (Glynne-Jones et al. 2008), oxaliplatin (Eng et al. 2009) or cetuximab (RTOG). We have also not yet begun to identify molecular predictive and prognostic factors, and the new targeted therapies have yet to be integrated.
14.26 Biological Agents Biological therapy could be integrated into the chemoradiation component, or as a consolidation manoeuvre following the completion of chemoradiation, at a point when the cancer appears to express high levels of both vascular endothelial growth factor and epidermal growth factor. There are no data on the efficacy of biologicals combined with chemoradiation although several trials are currently in progress (RTOG Trials). A phase I study from Brazil reported efficacy and safety at ASCO 2008 in 10 patients with cetuximab added to CRT (Olivatto et al. 2008). Anal cancers commonly over-express epidermal growth factor receptor (EGFR) (Le et al. 2005; Van Damme et al. 2008). In addition, radiation itself induces EGFR activation, which contributes, at least in part, to the mechanism of accelerated proliferation, and which can be expected to increase the capacity for DNA damage repair. Over-expression of EGFR has been linked to radio-resistance (Miyaguchi et al. 1991); hence, one of the most promising recent additional avenues of treatment has been to target the EGFR pathway.
14.27 Radiotherapy Technique and Treatment Fields There are significant differences in approach to radiotherapy fields and techniques within Europe, but in general, treatment should aim to encompass the primary tumour and any sites of nodal involvement within the high-dose volume.
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The inguinal nodes are usually included in the radiation fields in the majority of cases, even in the absence of clearly demonstrable involvement. The incidence of nodal involvement increases with increasing primary tumour size and is at least 20% in patients with T3 disease. Some clinicians may decide to treat clinically uninvolved inguinal nodes only in certain circumstances (e.g. T3–4 primary disease, location of primary tumour within the canal, £1 cm from the anal orifice, or if there is involvement of pelvic lymph nodes (on CT or MRI criteria). The results of the ACT II trial should clarify the optimum strategy.
14.28 Post-Operative Adjuvant Treatment Post-operative chemoradiation should be considered in patients in whom completeness of excision cannot be guaranteed, when the resection margin is involved or in the case of narrow margins. Some authors argue that smaller fields can be treated, and the total dose can be lowered to 30 Gy for microscopic disease (Hu et al. 1999; Hatfield et al. 2008). Some patients may undergo initial abdominoperineal excision as definitive treatment of their anal cancer. This sometimes results from a small poorly differentiated biopsy, which is not recognised as squamous histology, and treated as a low rectal cancer. Post-operative chemoradiation should be considered when there is evidence of involvement of the circumferential resection margin (deep or lateral resection margins £1 mm), or numerous involved mesorectal lymph nodes.
14.29 Toxicity and Supportive Care During Radiotherapy CRT (particularly if Mitomycin C is used) is associated with high risks of G3 and G4 haematological toxicity (Ajani et al. 2008). The EORTC trial had no toxic deaths. In the UKCCR ACT I trial there were six treatment-related deaths in the first 116 patients; after amending the protocol to provide antibiotic cover during treatment, there were no more septicaemic deaths. In the RTOG study 20% of patients experienced G4/G5 toxicity with 5-FU MMC vs. 7% of those on 5-FU alone. There were four (3%) treatment-related deaths in the MMC arm. In the recent ACT II trial all patients were given prophylactic antibiotic cover during CRT. Tolerance to treatment can be maximised with the use of simple anti-emetics, analgesia, skin care, advice regarding nutrition and psychological support. Expected acute side effects include diarrhoea, proctitis, urinary frequency and dysuria, loss of pubic hair and erythema, lymphoedema and moist desquamation of the skin in the groins and perineum. Skin effects rapidly disappear within 2–3 weeks after treatment is completed. The use of vaginal dilators in sexually active females is recommended.
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14.30 Patterns of Relapse Recognition of the patterns of loco-regional failure after definitive chemoradiation is a crucial aspect in the management of anal cancer. Cancer can recur either at the primary tumour site, in the regional lymph nodes or very occasionally, at distant sites such as liver and lung (Boman et al. 1984; Kuehn et al. 1968). Patients tend to relapse in the local region rather than at distant sites, although loco-regional failure is quite commonly followed by distant failure. In the UKCCCR ACT I trial only 21 of 285 patients (7%) treated with chemoradiation developed metastatic disease outside the pelvis in the absence of evidence of pelvic recurrence (UKCCCR Anal Cancer Working Party 1996). Long-term follow-up of this study, with a median follow-up of 11.5 and 13.5 years in the RT and CMT groups respectively, shows that 239 of 560 patients had a local relapse (153 radiotherapy, 86 CMT). Only four of these patients had a distant relapse before their first recorded local relapse (James et al. 2009).
14.31 Chemoradiotherapy Salvage Salvage chemoradiotherapy using cisplatin and radiation to a dose of 9 Gy has been reported to salvage up to 50% of patients not responding to the first phase of chemoradiation (Flam et al. 1996), although others have not proved this strategy so successful (Longo et al. 1994). Slow or late response could also play a part in these favourable results.
14.32 Surgical Salvage Patients who have persistent or progressive disease following chemoradiation or local recurrence should be considered for surgical salvage with an abdomino-perineal resection. However, biopsy and restaging for metastatic disease is recommended first. Outcomes from surgical salvage are variable with five-year survival rates ranging from 24 to 64% (Longo et al. 1994; Zelnick et al. 1992; Pocard et al. 1998; Smith et al. 2001; Renehan et al. 2005). Close follow-up of patients after completion of chemoradiation and a proactive approach to salvage surgery appears more successful (Renehan et al. 2005). Achievement of negative resection margins appears crucial to subsequent outcome (Sunesen et al. 2009). Persistent or progressive disease in the inguinal lymph nodes should be considered for radical groin dissection.
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14.33 Treatment of Recurrent and/or Metastatic Anal Cancer Fit patients with metastatic or recurrent disease not amenable to surgery should receive chemotherapy – usually with a combination of cisplatin and 5-FU, which offers approximately a 50% response rate. Responses are rarely complete and usually of short duration. In these circumstances, therapy is aimed at palliation.
14.34 Late Sequelae Long-term morbidity includes ulceration of the anal/rectal area, necrosis, small bowel obstruction, uretheral obstruction and fistula formation. Pelvic and hip fractures are also more common (Baxter et al. 2005). All such late effects should be carefully documented. No differences in late toxicity were observed between radiotherapy and chemoradiation in the EORTC and UKCCR trials. However, no formal assessments of QOL have been performed on patients within the randomised trials.
14.35 Follow-Up and Surveillance Follow-up relies on DRE and palpation of the inguinal lymph nodes. MRI can complement clinical assessment. Patients should be evaluated clinically between 8 and 12 weeks following the completion of chemoradiation. Evidence of major residual tumour or progression should be considered for biopsy. Patients in complete remission at eight weeks should be evaluated every 3–6 months for a period of two years, and 6–12 monthly until five years. Patients tend to relapse loco-regionally rather than at distant sites, and given that distant relapse are uncommon without relapse at the primary site, the scheduling of regular CT scans for metastatic surveillance outside trials remains controversial. The level of tumour regression (>80%) after primary chemoradiation may be predictive of colostomy-free and disease-free survival Chapet et al. 2005). Early studies assessed with biopsy at 6–8 weeks, and positive biopsy findings led to an APER (Martenson and Lipsitz 1995). Some prospective studies have examined clinical response at four weeks (Glynne-Jones et al. 2008) and six weeks following completion of CRT (UKCCCR Anal Cancer Working Party 1996). Complete clinical response at two months predicted DFS (Gerard et al. 1998; Derniaud-Alexandre et al. 2003). Hence response by RECIST criteria at 6–8 weeks has been suggested to be a highly relevant endpoint, which allows phase II trials to explore novel treatments and chemoradiation combinations.
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The recent national UK trial (ACT II) has collected additional data on clinical response at 18 and 26 weeks. Other authors suggest that cell death from radiotherapy can continue up to 12 weeks following the completion of CRT (Cummings et al. 1991), suggesting that salvage surgery should present an option only after 12 weeks. Hence, most authors recommend that patients should be evaluated clinically between 8 and 12 weeks following the completion of chemoradiation. The skin reaction should have settled by this time, and failure to achieve complete response, major residual tumour or progression on digital rectal examination, should be considered for biopsy (Tanum et al. 1993). It may take 3–6 months for complete resolution to occur, and during this period ulceration can cause concerns (Schlienger et al. 1989; Borzomati et al. 2005).
14.36 Conclusions In anal cancer, a multidisciplinary approach is essential with close co-operation and communication required between surgeon, radiologist, medical oncologist, radiation oncologist, pathologist and nursing specialists. The results of five randomised phase III trials in anal cancer confirm that the paradigm of external beam radiation therapy with concurrent 5-FU and mitomycin remains the standard of care. The endpoint of colostomy-free survival is probably the best measure of the success of chemoradiation in preserving the anal sphincter in anal cancer. However, we need much more data regarding severe complication rates and proportion of patients who maintain a functioning anus. As anal cancer is a rare tumour, it is in the interest of all patients to be offered participation in a clinical trial. National and international trials in this disease site are ongoing throughout Europe.
14.37 Guidelines • Engstrom PF, Amoletti JP, Benson AB, et al., NCCN Practice Guidelines: Anal Cancer Version 2. 2009 (08/19/09). Available at www.nccn.org/professionals/physician (last accessed September 27 2009) • Guidelines for the management of Colorectal cancer issued by the Association of Colopro ctology of Great Britain and Ireland; 3rd Edition 2007. • Fleshner PR, Chalasani S, Chang GJ et al., Practice parameters for anal squamous neoplasms. Dis Colon Rectum 2008;51:2–9. • Glynne-Jones R, Northover J, Oliveira J. ESMO Guidelines Working Group. Anal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009; 20(4):57–60.
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14.38 Reviews Poggi MM, Suh WW, Saltz L et al (2007) ACR Appropriateness Criteria on treatment of anal cancer. J Am Coll Radiol 4:448–456 Uronis HE, Bendell JC (2007) Anal cancer: an overview. The Oncologist 12(5):524–534 Das P, Crane C, Ajani J (2007) Current treatment of localized anal carcinoma. Curr Opin Oncol 19:396–400 Fleshner PR, Chalasani S, Chang GJ et al (2008) Practice parameters for anal squamous neoplasms. Dis Colon Rectum 51:2–9 Czito BG, Willett CG (2009) Current management of anal canal cancer. Curr Oncol Rep 11(3):186–192 Buchs NC, Allal AS, Morel P, Gervaz P (2009) Prevention, chemoradiation and surgery for anal cancer. Expert Rev Anticancer Ther 9(4):483–489 Eng C, Pathak P (2008) Treatment options in metatstatic squamous cell carcinoma of the anal canal. Curr treat Options Oncol 9 (4–6):400–407
References Frisch M, Melbye M, Moller H (1993) Trends in incidence of anal cancer in Denmark. BMJ 306:419–422 Johnson LG, Madeleine MM, Newcomer LM et al (2004) Anal cancer incidence and survival: the surveillance, epidemiology and end results experience, 1973–2000. Cancer 101:281–288 Bilimoria KY, Bentrem DJ, Rock CE et al (2009) Outcomes and prognostic factors for squamouscell carcinoma of the anal canal: analysis of patients from the National Cancer Data Base. Dis Colon Rectum 52(4):624–631 Jemal A, Siegel R, Ward E et al (2008) Cancer statistics. CA. Cancer J Clin 58:71–96 Boman BM, Moertel CG, O’Connell MJ, Scott M, Weiland LH, Beart RW, Gunderson LL, Spencer RJ (1984) Carcinoma of the anal canal. A clinical and pathologic study of 188 cases. Cancer 54:114–125 UKCCCR Anal Cancer Working Party (1996) Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil and Mitomycin C. Lancet 348:1049–1054 Miller BA, Ries LAG, Hankey BF et al (1992) SEER cancer statistics review 1973–1989. NIH pub No 94-2789. National Cancer Institute, Bethesda Williams GR, Lu QL, Love SB et al (1996) Properties of HPV-positive and HPV-negative anal carcinomas. J Pathol 180(4):378–382 Frisch M, Glimelius B, Van Den Brule AJ et al (1997) Sexually transmitted infection as a cause of anal cancer. N Engl J Med 337(19):1350–1358 Crook T, Wrede D, Tody J et al (1991) Status of c-myc, p53 and retinoblastoma genes in human papillomavirus positive and negative squamous cell carcinomas of the anus. Oncogene 6(7):1251–1257 Bosch FX, Manos MM, Munoz N et al (1995) Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 87(11):796–802 Frisch M, Fender C, Vandenbruller AJC et al (1999a) Varieties of squamous cell carcinoma of the anal canal and peri-anal skin and their relation to human papilloma viruses. Cancer Res 59:753–757
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Licitra L, Perrone F, Bossi P et al (2006) High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 24:5630–5636 Penn I (1986) Cancers of the anogenital region in renal transplant recipients: analysis of 65 cases. Cancer 58:611–616 Daling JR, Weiss NS, Klopfenstein LL et al (1982) Correlates of homosexual behaviour and the incidence of anal cancer. JAMA 247:1988–1990 Daling JR, Weiss NS, Hislop TJ et al (1987) Sexual practices, sexually transmitted diseases and the incidence of anal cancer. N Eng J Med 317:973–978 Melbye M, Cote TR, Kessler L et al (1994) High incidence of anal cancer among AIDS patients. The AIDS/Cancer Working Group. Lancet 343:636–639 Holly EA, Whittemore AS, Aston DA et al (1989) Anal cancer incidence: genital warts, anal fissure or fistula, hemorrhoids, and smoking. J Natl Cancer Inst 81:1726–1731 Daling JR, Sherman KJ, Hislop TG et al (1992) Cigarette smoking and the risk of anogenital cancer. Am J Epidemiol 135:180–189 Tseng HF, Morgenstern H, Mack TM, Peters RK (2003) Risk factors for anal cancer: results of a population-based case-control study. Cancer Causes Control 14:837–846 Frisch M, Glimelius B, Wohlfahrt J et al (1999b) Tobacco smoking as a risk factor in anal carcinoma: an antiestrogenic mechanism? J Natl Cancer Inst 91:708–715 Frisch M, Olsen JH, Bautz A et al (1994) Benign anal lesions and the risk of anal cancer. N Engl J Med 331:300–302 Frisch M, Johansen C (2000) Anal carcinoma in inflammatory bowel disease. Br J Cancer 83:89–90 Daling JR, Madeleine MM, Johnson LG et al (2004) Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer 101(2):270–280 Schofield JH, Castle MT, Watson NFS (2005) Malignant transformation of high-grade anal intraepithelial neoplasia. Br J Surg 92:1133–1136 Lacey HB, Wilson GE, Tilston P et al (1999) Anal squamous intraepithelial lesions in HIV-positive and HIV – negative homosexual and bisexual men. Sex Transm Infect 75:172–177 Zbar AP, Fenger C, Efron J et al (2002) The pathology and molecular biology of anal intraepithelial neoplasia: comparisons with cervical and vulvar intraepithelial neoplasia. Int J Colorectal Dis 17:203–215 Abbasakoor F, Boulos PB (2005) Anal intraepithelial neoplasia. Br J Surg 92:277–290 Shepherd NA, Scoffield JH, Love SB et al (1990) Prognostic factors in anal squamous carcinoma: a multi variant analysis of clinical, pathological and flow cytometric perimeters in 235 cases. Histopathology 16:545–555 Wendell-Smith CP (2000) Anorectal nomenclature. Fundamental terminology. Dis Colon Rectum 43:1349–1358 Hill JH, Meadows H, Haboubi N et al (2003) Pathological staging of epidermoid anal cancer for the new era. Colorect Dis 5(3):206–213 Wade DS, Herrera L, Castillo NB et al (1986) Metastases to the lymph nodes in epidermoid carcinoma of the anal canal studied by a clearing technique. Cancer 57:400–406 Beahrs OH, Wilson SM (1976) Carcinoma of the anus. Ann Surg 184:422–428 Stearns MW, Urmacher C, Sternberg SS (1980) Cancer of the anal canal. Curr Probl Cancer 4:1–44 Greene FL, Page DL, Fleming ID et al (eds) (2002) AJCC Staging Manual, 6th edn. Springer, New York, pp 125–130 Greenall MJ, Quan SH, Urmacher C, DeCosse JJ (1985) Treatment of epidermoid carcinoma of the anal canal. Surg Gynecol Obstet 161(6):509–517 Sato H, Koh PK, Bartolo DC (2005) Management of anal canal cancer. Dis Colon Rectum 48(6):1301–1315
446
R. Glynne-Jones and S. Mawdsley
Touboul E, Schlienger M, Buffat L, Lefkopoulos D, Pene F, Parc R et al (1994) Epidermoid carcinoma of the anal canal. Results of curative-intent radiation therapy in a series of 270 patients. Cancer 73:1569–1579 Pyper PC, Parks TG (1985) The results of surgery for epidermoid carcinoma of the anus. Br J Surg 72(9):712–714 Clark J, Petrelli N, Herrera L, Mittelman A (1986) Epidermoid carcinoma of the anal canal. Cancer 57(2):400–406 Roach SC, Hulse PA, Moulding FJ et al (2005) Magnetic resonance imaging of anal cancer. Clin Radiol 60(10):1111–1119 Salerno G, Daniels IR, Brown G (2006) Magnetic resonance imaging of the low rectum: defining the radiological anatomy. Colorectal Dis 8(suppl 3):10–13 Koh DM, Dzik Jurasz A, O’Neill B et al (2008) Pelvic phased array MR imaging of anal carcinoma before and after chemoradiation. Br J Radiol 81:91–98 Magdeburg B, Fried M, Meyenberger C (1999) Endoscopic ultrasonography in the diagnosis, staging, and follow-up of anal carcinomas. Endoscopy 31(5):359–364 Giovannini M, Bardou VJ, Barclay R et al (2001) Anal carcinoma: prognostic value of endorectal ultrasound (ERUS). Results of a prospective multicenter study. Endoscopy 33:231–236 Berton F, Gola G, Wilson SR (2008) Perspective on the role of transrectal and transvaginal sonography of tumors of the rectum and anal canal. AJR Am J Roentgenol 190(6):1495–1504, Review Otto SD, Lee L, Buhr HJ et al (2009) Staging anal cancer: prospective comparison of transanal endoscopic ultrasound and magnetic resonance imaging. J Gastrointest Surg 13(7):1292–1298 Kuehn PG, Eisenberg H, Reed JF (1968) Epidermoid carcinoma of the perianal skin and anal canal. Cancer 22(5):932–938 Trautmann TG, Zuger JH (2005) Positron emission tography for pre-treatment staging and postreatment evaluation in cancer of the anal canal. Mol Imaging Biol 7:309–313 Cotter SE, Grigsby PW, Siegel BA et al (2006) FDG-PET/CT in the evaluation of anal carcinoma. Int J Radiat Oncol Biol Phys 65:720–725 Engstrom PF, Amoletti JP, Benson AB et al www.nccn.org/professionals/physicianls/PDF/anal. pdf. Accessed 13 March 2008 Koh DM, Brown G, Temple L et al (2004) Rectal cancer: mesorectal lymph nodes at MR imaging with USPIO versus histopathologic findings – initial observations. Radiology 231:91–99 Mai SK, Welzel G, Haegele V, Wenz F (2007) The influence of smoking and other risk factors on the outcome after chemoradiotherapy for anal cancer. Radat Oncol 2:30 Gerard JP, Ayzac L, Hun D et al (1998) Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum: long term results in 95 patients. Radiother Oncol 46:249–256 Doci R, Zucali R, La Monica G, Meroni E, Kenda R, Eboli M, Lozza L (1996) Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients. J Clin Oncol 14:3121–3125 Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG et al (1997) Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 15:2040–2049 Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S et al (1996) Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 14:2527–2539 Longo WE, Vernava AM III, Wade TP, Coplin MA, Virgo KS, Johnson FE (1994) Recurrent squamous cell carcinoma of the anal canal. Predictors of initial treatment failure and results of salvage therapy. Ann Surg 220(1):40–49
14 Anal Cancer
447
Peiffert D, Bey P, Pernot M et al (1997) Conservative treatment by irradiation of epidermoid cancers of the anal canal: prognostic factors of tumoral control and complications. Int J Radiation Oncol Biol Phys 37:313–324 Das P, Bhatia S, Eng C et al (2007) Predictors and patterns of recurrence after definitive chemoradiation for anal cancer. Int J Radiat Oncol Biol Phys 68(3):794–800 Myerson RJ, Kong F, Birnbaum EH, Fleshman JW, Kodner IJ, Picus J, Ratkin GA, Read TE, Walz BJ (2001) Radiation therapy for epidermoid carcinoma of the anal canal, clinical and treatment factors associated with outcome. Radiother Oncol 61:15–22 Constantinou EC, Daly W, Fung CY, Willett CG, Kaufman DS, DeLaney TF (1997) Time-dose considerations in the treatment of anal cancer. Int J Radiat Oncol Biol Phys 39:651–657 Papillon J, Montbaron JF (1987) Epidermoid carcinoma of the anal canal. Dis Colon Rectum 30:324–333 Schlienger M, Krzisch C, Pene F et al (1989) Epidermoid carcinoma of the anal canal: treatment results and prognostic variables in a series of 242 cases. Int J Radiat Oncol Biol Phys 17:1141–1151 Chapet O, Gerard JP, Riche B et al (2005) Prognostic value of tumour regression evaluated after first course of radiotherapy for anal canal cancer. Int J Radiat Oncol Biol Phys 63: 1316–1324 Allal AS, Alonso-Pentzke L, Remadi S (1998) Apparent lack of prognostic value of MIB-1 index in anal carcinomas treated by radiotherapy. Br J Cancer 77((8):1333–1336 Noffsinger AE et al (1995) The relationship of human papillomavirus to proliferation and ploidy in carcinoma of the anus. Cancer 75(4):958–967 Nilsson PJ, Lenander C, Rubio C et al (2006) Prognostic significance of cyclin A in epidermoid anal cancer. Oncol Rep 16(3):443–449 Ajani JA, Winter KA, Gunderson LL et al (2008) Fluorouracil, mitomycin and radiotherapy vs fluorouracil, cisplatin and radiotherapy for carcinoma of the anal canal: a randomised controlled trial. JAMA 199:1914–1921 Allal AS, Gervaz P, Brundler MA (2004) Cyclin D1, cyclin E, and p21 have no apparent prognostic value in anal carcinomas treated by radiotherapy with or without chemotherapy. Br J Cancer 91:1239–1244 Mawdsley S, Meadows H, James R et al (2004) The role of biological molecular markers in predicting both response to treatment and clinical outcome in squamous cell carcinoma of the anus. ASCO GI (Abstr 183) Ogunbiyi OA, Scholefield JH, Smith JH et al (1993) Immunohistochemical analysis of p53 expression in anal squamous neoplasia. J Clin Pathol 46(6):507–512 Jakate SM, Saclarides TJ (1993) Immunohistochemical detection of mutant P53 protein and human papillomavirus-related E6 protein in anal cancers. Dis Colon Rectum 36(11):1026–1029 Gangopadhyay S, Abraham J, Lin Y et al (1997) The tumour suppressor gene p53. In: Peters K (ed) Frontiers in molecular biology. Oxford University Press, New York Zwerschke W, Jansen-Durr P (2000) Cell transformation by the E7 oncoprotein of human papillomavirus type 16: interactions with nuclear and cytoplasmic target proteins. Adv Cancer Res 78:1–29 Tanum G, Tveit KM, Karlsen KO (1993) Chemoradiotherapy of anal carcinoma tumour response and acute toxicity. Oncology 50:14–17 Wong CS et al (1999) Prognostic role of p53 protein expression in epidermoid carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 45(2):309–314 Bonin SR, Pajak TF, Russell AH et al (1999) Overexpression of p53 protein and outcome of patients treated with chemoradiation for carcinoma of the anal canal: a report of randomized trial RTOG 87-04. Radiation Therapy Oncology Group. Cancer 85(6):1226–1233 Indinnimeo M, Cicchini C, Stazi A et al (1998) The prevalence of p53 immunoreactivity in anal canal carcinoma. Oncol Rep 5(6):1455–1457
448
R. Glynne-Jones and S. Mawdsley
Allal AS, Waelchli L, Brundler MA et al (2003) Prognostic value of apoptosis-regulating protein expression in anal squamous cell carcinoma. Clin Cancer Res 9(17):6489–6496 Indinnimeo M, Cicchini C, Stazi A et al (2001) Prognostic impact of CD31 antigen expression in anal canal carcinoma. Hepatogastroenterology 48(41):1355–1358 Litle VR, Leavenworth JD, Darragh TM et al (2000) Angiogenesis, proliferation, and apoptosis in anal high-grade squamous intraepithelial lesions. Dis Colon Rectum 43(3):346–352 Petrelli NJ, Shaw N, Bhargava A et al (1988) Squamous cell carcinoma antigen as a marker for squamous cell carcinoma of the anal canal. J Clin Oncol 6(5):782–785 Petrelli NJ et al (1992) The utility of squamous cell carcinoma antigen for the follow-up of patients with squamous cell carcinoma of the anal canal. Cancer 70(1):35–39 Fontana X, Lagrange JL, Francois E et al (1991) Assessment of “squamous cell carcinoma antigen” (SCC) as a marker of epidermoid carcinoma of the anal canal. Dis Colon Rectum 34(2):126–131 Goldman S, Svensson C, Bronnergard M et al (1993) Prognostic significance of serum concentration of squamous cell carcinoma antigen in anal epidermoid carcinoma. Int J Colorectal Dis 8(2):98–102 Swampillai A, Williams M, Osborne M et al (2009) A single-center study of the utility of squamous cell carcinoma antigen (SCCAg) levels in epidermoid carcinoma of the anal canal and margin (ECACM) treated with chemoradiation (CRT). J Clin Oncol 27:15s (suppl; Abstr 4117) O’Brien PH, Jenrette JM, Wallace KM et al (1982) Epidermoid carcinoma of the anus. Surg Gynecol Obstet 155:745–751 Golden GT, Hosley JS (1976) Surgical managemenet of epidermoid carcinoma of the anus. Ann J Surgery 131:275–280 Nigro ND, Vaitkevicius VK, Considine B Jr (1974) Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 17:354–356 Nigro ND, Seydel HG, Considine B Jr et al (1983) Combined radiotherapy and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 51:1826–1829 Cummings BJ, Keane TJ, O’Sullivan B, Wong CS, Catton CN (1991) Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. Int J Radiat Oncol Biol Phys 21:1115–1125 Cummings BJ (1993) Anal cancer – radiation alone or with cytotoxic drugs? Int J Radiat Oncol Biol Phys 27(1):173–175 Rich TA, Ajani JA, Morrison WH et al (1993) Chemoradiation therapy for anal cancer: radiation plus continuous infusion of 5-fluorouracil with or without cisplatin. Radiother Oncol 27:209–215 Martenson JA, Lipsitz SR, Lefkopoulou M et al (1995) Results of combined modality therapy for patients with anal cancer (E7283) An Eastern Cooperative Oncology Group study. Cancer 76:1731–1736 John M, Pajak T, Flam M et al (1996) Dose escalation in chemoradiation for anal cancer: preliminary results of RTOG 92-08. Cancer J Sci Am 2:205–210 Friberg B, Svensson C, Goldman S, Glimelius B (1998) The Swedish National Care Programme for Anal Carcinoma – implementation and overall results. Acta Oncol 37:25–33 Eschwege F, Lasser P, Chavy A et al (1985) Squamous cell carcinoma of the anal canal treatment by external beam radiation. Radiother Oncol 4:145–150 Tanum G, Tveit K, Karlsen KO, Hauer-Jensen M (1991) Chemotherapy and radiation therapy for anal carcinoma. Survival and late morbidity. Cancer 67:2462–2466 Konski A, Garcia M, John M et al (2008) Evaluation of planned treatment breaks during radiation therapy for anal cancer: update of RTOG 92-08. Int J Radiat Oncol Biol Phys 72((1):114–118 Bosset JF, Roelefsen F, Morgan D et al (2003) Shortened irradiation scheme, continuous infusion of fluorouracil in locally advanced anal carcinomas: results of a phase II study of the of the European Organization for Research and Treatment of Cancer. Eur J Cancer 39:45–51
14 Anal Cancer
449
Crehange G, Bosset M, Lorchel F et al (2006) Combining cisplatin and mitomycin with radiotherapy in anal carcinoma. Dis Colon Rectum 50:43–49 Newman G, Calverley DC, Acker BD et al (1992) The management of carcinoma of the anal canal by external beam radiotherapy, experience in Vancouver 1971–1988. Radiother Oncol 21:196–202 Glimelius B, Pahlman L (1987) Radiation therapy of anal epidermoid carcinoma. Int J Radiat Oncol Biol Phys 13(3):305–312 Salmon RJ, Fenton J, Asselain B et al (1984) Treatment of epidermoid anal cancer. Am J Surg 147:43–48 Doggett SW, Green JP, Cantril ST (1988) Efficacy of radiation therapy alone for limited squamous cell carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 15:1069–1072 Northover J, Meadows H, Ryan C et al (1997) Combined radiotherapy and chemotherapy for anal cancer. Lancet 349:205–206 Papillon J (1990) Effectiveness of combined radiochemotherapy in the management of epidermoid cancer of the anal canal. Int J Radiat Oncol Biol Phys 19:1217–1218 Tournier-Rangeard L, Mercier M, Peiffert D et al (2008) Radiochemotherapy of locally advanced anal canal carcinoma: prospective assessment of early impact on the quality of life (randomised trial ACCORD 03). Radiother Oncol 87(3):391–397 Ferrigno R, Nakamura RA, Dos Santos Novaes PE et al (2005) Radiochemotherapy in the conservative treatment of anal carcinoma: retrospective analysis of results and radiation dose effectiveness. Int J Radiat Oncol Biol Phys 61:1136–1142 Matthews J; on behalf of TROG 99.02 participants (2005) Early anal canal carcinoma – the TransTasman Radiation Onocology Group (TROG) experience in TROG 99.02 study. Australas Radiol 49(2)A3 Ajani JA, Wang X, Izzo JG et al (2009) Molecular biomarkers correlate with disease free survival in patients with anal canal carcinoma treated with chemoradiation. Dig Dis Sci 55(4): 1098–1105 Hughes LL, Rich TA, Delclos L et al (1989) Radiotherapy for anal cancer: experience from 1979– 1987. Int J Radiat Oncol Biol Phys 17(6):1153–1160 Allal AS, Mermillod B, Roth AD, Marti MC, Kurtz JM (1997) The impact of treatment factors on local control in T2-T3 anal carcinomas treated by radiotherapy with or without chemotherapy. Cancer 79:2329–2335 Conroy T, Ducreux M, Lemanski C et al (2009) Treatment intensification by induction chemotherapy (ICT) and radiation dose escalation in locally advanced squamous cell anal canal carcinoma (LAAC): definitive analysis of the intergroup ACCORD 03 trial. J Clin Oncol 27:15s (suppl; Abstr 4033) James R, Wan S, Glynne-Jones R et al (2009) A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5-FU in squamous cell carcinoma of the anus (ACT II). J Clin Oncol 27:18s (suppl; Abstr LBA4009) Glynne-Jones R, Meadows H, Wan S et al; National Cancer Research Institute Anal Subgroup and Colorectal Clinical Oncology Group (2008) EXTRA – a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. Int J Radiat Oncol Biol Phys 72(1):119–126 Eng C, Chang GJ, Das P et al (2009) Phase II study of capecitabine and oxaliplatin with concurrent radiation therapy (XELOX-XRT) for squamous cell carcinoma of the anal canal. J Clin Oncol 27:15s (suppl; Abstr 4116) Olivatto LO, Meton F, Bezerra M et al (2008) Phase I study of cetuximab (CET) in combination with 5-flurouracil (5-FU), cisplatin (CP) and radiotherapy (RT) in patients with locally advanced squamous cell anal carcinoma (LAAC). J Clin Oncol 26(15S):240s (Abstr 4609) Le LH, Chetty R, Moore MJ (2005) Epidermal growth factor receptor expression in anal canal carcinoma. Am J Clin Pathol 124:20–23
450
R. Glynne-Jones and S. Mawdsley
Van Damme N et al (2008) EGFR and Kras status in anal canal cancer. ASCO 660s (Abstr 15569) Miyaguchi M, Olofsson J, Hellquist HB (1991) Expression of epidermal growth factor receptor in glottic carcinoma and its relation to recurrence after radiotherapy. Clin Otolaryngol Allied Sci 16(5):466–469 Hu K, Minsky BD, Cohen AM et al (1999) 30 Gy may be an adequate dose in patients with anal cancer treated with excisional biopsy followed by combined-modality therapy. J Surg Oncol 70:71–77 Hatfield P, Cooper R, Sebag-Montifiore D (2008) Involved field low dose chemoradiotherapy for early stage anal carcinoma. Int J Radiat Oncol Biol Phys 70(2):419–424 Zelnick RS, Haas PA, Ajlouni M et al (1992) Results of abdominoperineal resections for failures after combination chemotherapy and radiation therapy for anal canal cancers. Dis Colon Rectum 35:574–577 Pocard M, Tiret E, Nugent K et al (1998) Results of salvage abdominoperineal resection for anal cancer after radiotherapy. Dis Colon Rectum 41:1488–1493 Smith AJ, Whelan P, Cummings B, Stern HS (2001) Management of persistent or locally recurrent epidermoid cancer of the anal canal. With abdominoperineal resection. Acta Oncol 40:34–36 Renehan AG, Saunders MP, Schofield PF, O’Dwyer ST (2005) Patterns of local disease failure and outcome after salvage surgery in patients with anal cancer. Br J Surg 92:605–614 Sunesen KG, Buntzen S, Tei T et al (2009) Perineal healing and survival after anal canal cancer salvage surgery: 10-year experience with primary perineal reconstruction using the vertical rectus abdominis myocutaneous (VRAM) flap. Ann Surg Oncol 16:68–77 Baxter NN, Habermann EB, Tepper JE et al (2005) Risk of pelvic fractures in older women following pelvic irradiation. JAMA 294:2587–2593 Derniaud-Alexandre E, Touboul E, Tiret E et al (2003) Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal. Int J Radiat Oncol Biol Phys 56:1259–1273 Borzomati D, Valeri S, Ripetti V et al (2005) Persisting anal ulcer after radiotherapy for anal cancer: recurrence of disease or lat radiation-related complication? Hepatogastroenterology 52:780–784 Cutuli B, Fenton J, Labib A et al (1988) Anal margin carcinoma: 21 cases treated at the Institut Curie by exclusive conservative radiotherapy. Radiother Oncol 11(1):1–6 Cantril ST, Green JP, Schall GL, Schaupp WC (1983) Primary radiation therapy in the treatment of anal carcinoma. Int J Radiat Oncol Biol Phys 9(9):1271–1278 Papillon J, Montbarbon JF (1987) Epidermoid cancer of the anal canal. A series of 276 cases. Dis Colon Rectum 30:324–333
Index
A Abdominoperineal resection (APR), 396 Abdominothoracic esophagectomy, 76 Adenocarcinoma classification and pathology, 71 etiologic factors, 69–70 glandular dysplasia, 71 Siewert’s classification, 73 Adenomatous polyposis coli (APC), 329 Adjuvant therapy borderline resectable pancreatic adenocarcinoma CONKO-001, 189 EORTC, 188 ESPAC-3 trial, 189 multi-institutional phase II study, 191 prospective and retrospective series, 185–187 RTOG 97-04, 189–190 colon cancer, 348–349 gastrointestinal stromal tumors, 162–163 Alpha-fetoprotein (AFP) CT, 229 liver biopsy, 229 MRI, 229 ultrasound, 228 American Joint Committee on Cancer (AJCC) colorectal cancer, 390–391 gallbladder cancer, 255, 256 gastric cancer, 106–108 American Society of Clinical Oncology (ASCO), 209 Anal cancer aetiology and risk factors, 425 anatomy, 426 biological agents, 439 markers, 430–431 boost response, 437
chemoradiation, 443 clinical presentation, 427 consolidation chemotherapy, 439 histological types, 426 history, 423–424 HIV testing, 429 lymphatic drainage, 427 non-surgical treatment mitomycin C (MMC), 432 phase III trials, 433–435 radiotherapy, 433 pathology, 425 predictive factors, 429 pre-treatment, 428 prognostic factors, 430 radiation therapy, 436–437 radiological staging, 428–429 recurrent/metastatic, 442 relapse, patterns, 441 salvage chemoradiotherapy, 441 sequelae, 442 staging and risk assessment, 427–428 surgery, 432 surgical salvage, 441 surveillance, 442–443 toxicity and supportive care, 440 treatment late stage (T3/T4), 437–438 post-operative adjuvant, 440 radiotherapy, 439–440 tumour grade, 426 markers, 431–432 APC. See Adenomatous polyposis coli B Barium enema, 332 Barrett’s esophagus, 21, 22 Best supportive care (BSC), 126–128 451
452 Biliary tract carcinoma extrahepatic bile duct cancer diagnosis, 263–264 epidemiology, 262 pathology, 263 radiation therapy, 268–271 risk factors, 262 staging, 264–266 surgical resection, 265–268 gallbladder cancer diagnosis, 254–255 epidemiology, 252 pathology, 253–254 radiation therapy, 260–262 risk factors, 252 staging, 255, 256 surgical resection, 255–260 intrahepatic cholangiocarcinoma diagnosis, 273–274 epidemiology, 272 pathology, 272–273 radiation therapy, 277 risk factors, 272 staging, 274–276 surgical resection, 276–277 systemic therapy adjuvant, 283–284 metastatic disease, 277–283 Borderline resectable pancreatic adenocarcinoma adjuvant therapy CONKO-001, 189 EORTC, 188 ESPAC-3 trial, 189 multi-institutional phase II study, 191 prospective and retrospective series, 185–187 RTOG 97-04, 189–190 clinical staging and preoperative management CA 19-9, 177 coronal image, 176 cross-sectional and sagittal images, 175 endoluminal ultrasonography, 177 positron emission tomography, 176–177 surgery and neoadjuvant strategies, 175 neoadjuvant therapy MD Anderson Cancer Center, 192, 193 median survival, 192 radiation schema, 193 resectable strategies, 194–196 surgical management pancreatic reconstruction, 182–183
Index regional lymphadenectomy, 179, 180 standard gastrectomy vs. pyloricpreserving Whipple operation, 181–182 surgical morbidity and mortality, 183–184 vascular resection, 179–181 C Cancer and leukemia group B (CALGB), 346 Carcinoid heart disease (CHD), 313 Celiac plexus neurolysis (CPN), 32 CGH. See Comparative genomic hybridization Chemoradiotherapy esophageal cancer perioperative treatment, 85–86 treatment protocols, 87–88 locally advanced pancreatic cancer vs. chemotherapy, 209 Eastern Cooperative Oncology Group, 208 radiotherapy protocols, 207 Chemotherapy adjuvant, 408–409 biliary cancers ABC-001 survival curve, 282 ABC-02 trial, 281 GEMOX, 282 National Cancer Institute of Canada, 280 nucleoside analog gemcitabine, 280 randomized trials, 279 EORTC 22921, 407–408 esophageal cancer chemoradiation vs. surgery, 90 metastatic disease treatment, 90–92 perioperative treatment, 85 randomized studies, 89 treatment protocols, 87 gastric cancer vs. best supportive care, 126–128 single-agent, 121 GTX, 195 locally advanced pancreatic cancer American Society of Clinical Oncology, 209 vs. chemoradiotherapy, 209 gastrointestinal tumor study group, 208 radiation, 206 metastatic pancreatic cancer, 212–214 modality program, 409–411 Cholangiocarcinoma hilar malignant biliary obstruction, 37
453
Index intrahepatic (see Intrahepatic cholangiocarcinoma) Chromogranin A (CGA), 306 Chromosomal instability (CIN), 45, 326 Circumferential resection margin (CRM), 392 Colon cancer adjuvant therapy, 348–349 chemotherapy-refractory disease, 362–364 5-FU monotherapy, 345–346 oxaliplatin, 346 laparoscopic surgery, 343 liver-limited metastatic chemotherapy, 354 clinical risk, 351, 352 diagnosis, 351 incidence, 352, 353 outcome, 353, 354 prognostic factor, 355 propensity, 350 radiofrequency ablation, 353 lymphadenectomy biology, 341 mesenteric excision, 342 stage migration, 340 surgical technique, 343 lymphatic drainage, 339, 340 malignant polyps classification, 338 definition, 337 endoscopic removal, 338 invasive adenocarcinoma, 336, 338 metastasis, 349–350 negative trials, 346–347 pathology biomarkers, 327 classification, 326 prognosis, 326–327 suppressor, mutator pathway, 326 radiotherapy considerations, 343–344 risk factors acquired, 329–330 inflammatory bowel disease, 329 inherited predisposition, 327–329 screening barium enema, 332 colonoscopy, 334 conventional principles, 331 CT colonography, 332–333 current guidelines, 334–336 fecal immunochemistry tests, 332 fecal occult blood test, 331 flexible sigmoidoscopy, 333
staging classification, 336, 337 diagnostic evaluation, 334 stage II considerations, 347–348 stereotactic body radiotherapy, 356–357 surgical procedures arterial blood supply, 339, 341 proctocolectomy, 340 segment resection, 339 standard surgical resection, 339, 342 Colorectal carcinoma molecular pathways chromosomal instability, 45 microsatellite instability, 45–49 potential molecular markers, 44 Combined modality program adjuvant chemotherapy, 411 angiogenesis, 413 CRT and VEGF inhibition, 413, 414 EGFR, 411 phase III trials, 409, 410 preoperative CRT, 411, 412 Comparative genomic hybridization (CGH), 304 Computed tomography colonography (CTC), 2–3, 331 CpG Island methylator phenotype (CIMP), 327 D Digital rectal examination (DRE), 428 Discovered On GIST-1 (DOG-1), 145–146 Disease free survival (DFS), 430 Distal esophagectomy, 79 Double contrast barium enema (DCBE), 331 Doxorubicin, 124 Dynamic contrast-enhanced Doppler ultrasound (DCE-US), 160 E Eastern Cooperative Oncology Group (ECOG), 208 Electron microscopy, 146–147 EMR. See Endoscopic mucosal resection Endoluminal ultrasonography (EUS), 177 Endorectal ultrasound (ERUS), 383 Endoscopic mucosal resection (EMR) Barrett’s esophagus, 21, 22 colorectum, 24 duodenal adenoma, 23 gastric cancer, 108–109 HGD/IMC, 21 histological staging, 22
454 indications, 78 neoplastic duodenal lesion, 23 tubulo-villous adenoma, rectum, 23–24 Endoscopic retrograde cholangiopancre atography (ERCP), 177 Endoscopic submucosal dissection (ESD) endoscopic resection margins, 24, 25 endoscopy, surveillance, 24, 26 intramucosal gastric cancer, pylorus, 24, 25 pylorus preservation, 24, 25 Endoscopic therapy, 78–79 Endoscopic ultrasound (EUS) celiac plexus blockade, 32 colorectal carcinoma, 31 esophageal neoplasms, 30–31 EUS-guided fine-needle injection, 33 gastric cancer, 30 hepatobiliary neoplasms, 29 lung malignancy, 31 pancreatic adenocarcinoma, 26–27 pancreatic cystic lesions, 27–28 pancreatico-biliary access/drainage, 32, 33 submucosal gastrointestinal lesions, 29, 30 Epidermal growth factor receptor (EGFR), 411 ERCP. See Endoscopic retrograde cholangiopancreatography ESD. See Endoscopic submucosal dissection Esophageal cancer chemoradiotherapy chemoradiation vs. surgery, 90 randomized studies, 89 classification and pathology adenocarcinoma, 71 differential pathologic diagnosis, 71 distant metastases, 72 lymphatic spread, 72 precancerous lesions, 71 Siewert’s classification, 73 specific histotypes, 71–72 squamous cell carcinoma, 70 UICC TNM classification system, 73, 74 clinical diagnostics, 75–76 endoscopic therapy, 78–79 epidemiology, 67–68 etiologic factors adenocarcinoma, 69–70 squamous cell cancer, 68–69 indications and selection, 78 metastatic disease chemotherapy, 90–92 local treatment, 92–93 monitoring, FDG-PET, 9–11 perioperative treatment
Index neoadjuvant chemoradiation, 85–86 neoadjuvant chemotherapy, 85 neoadjuvant radiation, 84 protocols, 87–88 quality of life, 86–87 response evaluation and response prediction, 88–89 preoperative risk assessment, 76–77 staging GI cancers, 5 surgical therapy cervical esophagus, 79, 81 distal esophagectomy, 79, 80 high intrathoracic anastomosis, 82 long-term surgical outcome, 83–84 perioperative morbidity and mortality, 82–83 transhiatal/cervical esophagectomy, 79 transthoracic en-bloc esophagectomy, 79, 80 symptoms, 73, 75 European Organization for Research and Treatment of Cancer (EORTC), 188, 268 European Study Group for Pancreatic Cancer (ESPAC-1), 188 EUS. See Endoluminal ultrasonography EUS-guided fine-needle injection (EUS-FNI), 33 Examination under anaesthetic (EUA), 428 External beam radiotherapy (EBRT), 343, 433 Extrahepatic bile duct cancer diagnosis, 263–264 epidemiology, 262 pathology, 263 radiation therapy adjuvant, 268–269 neoadjuvant, 269–270 unresectable cholangiocarcinoma, 270–271 risk factors, 262 staging AJCC 6th edition, 265 Bismuth-Corlette classification system, 264 clinical T-stage criteria, 266 surgical resection future remnant liver, 267 percutaneous transhepatic cholangiography, 267 F Familial adenomatous polyposis (FAP), 328, 380 Fecal immunochemistry tests (FIT), 331
Index Fecal occult blood testing (FOBT), 331 Flexible sigmoidoscopy, 333 Fluordeoxyglucose-positron emission tomography (FDG-PET), 88, 89 Future remnant liver (FRL), 267 G Gallbladder cancer diagnosis, 254–255 epidemiology, 252 pathology, 253–254 radiation therapy adjuvant, 260–261 unresectable, 261–262 risk factors, 252 staging, 255, 256 surgical resection incidental management, 259–260 laparoscopic cholecystectomy, 259 T1 and T2 lesions, 258 Gastric cancer diagnosis and workup, 105–106 environmental risks and prevention, 103–105 epidemiology, 101–102 etiology, 102–103 radiotherapy local unresectable/postoperative residual local disease, 116–117 neoadjuvant chemotherapy, 117–118 palliative, 113–114 patterns of failure, 114–115 postoperative adjuvant radiation, 115–116 preoperative, 119–120 radiochemotherapy, 117 staging, 106–108 surgical treatment D-level trials, 109–111 endoscopic mucosal resection, 108–109 low Maruyama Index, 111–113 lymphadenectomy, 109–111 subtotal vs. total gastrectomy and margins, 108 systemic therapy best supportive care, 126–128 cisplatin-based combinations, 124–125 combination chemotherapy, 121–123 doxorubicin, 124 epirubicin-based combinations, 126 5-fluorouracil, 124 INT0116 study, 130 irinotecan-based therapy, 125–126
455 leucovorin, 124 MAGIC study, 130 methotrexate, 124 mitomycin regimens, 124 monoclonal antibodies, 128 nitrosourea combinations, 122–123 single-agent chemotherapy, 121 symptom management, 130 targeted therapy, 128 taxane-based regimen, 125 tyrosine kinase inhibitors, 128 Gastroesophageal reflux disease (GERD), 102–103 Gastrointestinal (GI) cancer allelic imbalance, 18q, 51 doublet therapy, 8 KRAS, 49–51 molecular abnormalities, 51 molecular bases, 43–44 molecular testing, 51–52 monitoring, FDG-PET colorectal cancer, 10, 12 esophageal cancer, 9–11 GISTs (see Gastrointestinal stromal tumor) RECIST (see Response evaluation criteria in solid tumors) screening colon cancer, 2–3 diagnosis and staging, 3 endoscopic procedure, 1 PET imaging, 3–5 PET, staging, 5–8 surveillance, curative resection, 13–14 Gastrointestinal stromal tumor (GIST) adjuvant therapy, 162–163 behavior and prognosis patterns of metastasis, 149 prediction of behavior, 149–150 clinical management borderline resectable disease, 153 recurrence, 153–154 resectable primary, 152–153 diagnosis and staging clinical presentation, 151 investigations, 151–152 electron microscopy, 146–147 epidemiology demographics, 139–140 familial, 141 pediatric, 140 syndromic, 141 everolimus, 165–166 FDG-PET/CT imaging, 160, 161
456 gross pathology, 142 imatinib resistance sunitinib, 57 tyrosine kinase inhibitors, 57–58 kinase genotype and imatinib mesylate, 56–57 light microscopy immunohistochemistry, 143–146 markers, 146 morphology, 142–145 medical management chemotherapy, 154 imatinib mesylate, 154–159 sunitinib, 159–160 metabolic activity, 12 molecular biology and mutational analysis BRaf V600E, 148 IGF-1, 148 KIT, 147 PDGFR, 148 molecular classification biological and clinical implications, 54, 55 familial, 55 pediatric, 55–56 type I neurofibromatosis, 56 motesanib diphosphate, 166 neoadjuvant therapy, 163–164 nilotinib, 164 oncogenic kinase mutations, 53–54 pathology, 52–53 radiotherapy, 161–162 recommendations, 58 retaspimycin hydrochloride, 165 sorafenib, 165 submucosal gastrointestinal lesions, 29, 30 GIST. See Gastrointestinal stromal tumor Glandular dysplasia, 71 Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR), 210 H Health-related quality of life (HRQL), 86–87 Hepatic artery chemoembolization (HACE), 317–318 Hepatic artery infusion (HAI), 355 Hepatocellular carcinoma (HCC) clinical presentation, 226–227 CYP3A4, 227 diagnosis, 228 FDG-PET, 7–8 growth factors, 242–243 incidence, 225–226 staging and prognostic systems, 230–234
Index surgical resection, 234–238 treatment, 234, 235 Hereditary diffuse gastric cancer (HDGC), 104 Hereditary nonpolyposis colorectal cancer (HNPCC), 380 High-grade dysplasia (HGD), 21 Human papilloma virus (HPV), 425 5-Hydroxyindoleacetic acid (5-HIAA), 306 I Ileocolonic stent placemen, 35, 36 Imatinib resistance, 57–58 Inflammatory bowel disease, 329 Intensity modulated radiotherapy (IMRT), 438 International Union Against Cancer (UICC), 255, 256 Intraductal papillary mucinous neoplasm (IPMN), 28 Intra-epithelial neoplasia (AIN), 425–426 Intrahepatic cholangiocarcinoma (ICC) diagnosis Ca19-9, 273 PET-based imaging, 274 staging, 274–276 epidemiology, 272 pathology, 272–273 radiation therapy, 277 risk factors, 272 surgical resection, 276–277 Intramucosal cancer (IMC), 21 Intraoperative electron beam radiotherapy (IOERT), 343 Intraoperative radiation therapy (IORT), 260 Irinotecan-based therapy, 125–126 Islet cell tumors gastrinomas, 310–311 glucagonomas, 311 insulinomas, 310 pancreatic polypeptidomas, 312 somatostatinoma, 311 VIPoma, 311–312 K KRAS mutational analysis, 50–51 L Leucovorin, 124 Light microscopy immunohistochemistry CD34, 144–145 CD117, 143–144 DOG-1, 145–146
457
Index PDGFR, 145 protein kinase C theta, 145 markers, 146 morphology, 142–143 Liver cancer alpha fetoprotein CT, 229 liver biopsy, 229 MRI, 229 ultrasound, 228 clinical presentation, 226–227 diagnosis and staging, 228 epidemiology, 225–226 HCC CYP3A4, 227 growth factors, 242–243 staging and prognostic systems, 230–234 treatment, 234, 235 liver transplantation, 238–239 nonresectional locoregional therapies percutaneous ethanol injection, 239 radiofrequency ablation, 239–240 transarterial chemoembolization, 240 risk factors, 225–226 surgical resection hepatic resection, 237 model for end-stage liver disease, 236 portal vein embolization, 236 systemic therapy MAPK, 241 PI3K/Akt/mTOR pathway, 242 SHARP, 241 Locally advanced pancreatic cancer (LAPC) American Society of Clinical Oncology, 209 chemoradiotherapy vs. chemotherapy, 209 Eastern Cooperative Oncology Group, 208 5-FU, 208 gastrointestinal tumor study group, 208 gemcitabine, 207 Groupe Cooperateur Multidisciplinaire en Oncologie, 210 radiation, 206 Radiation Therapy Oncology Group, 208 radiotherapy protocols, 207 targeted therapy, 210–211 Locally advanced rectal cancer apple core, 397, 398 neoplasm, 396 pathology, 397 TME procedure, 396 Loss of heterozygosity (LOH), 326
Lymphadenectomy biology, 341 colon cancer biology, 341 mesenteric excision, 342 stage migration, 340 surgical technique, 343 and D-level trials, 109–111 low Maruyama Index, 111–113 mesenteric excision, 342 regional, 179, 180 stage migration, 340 surgical technique, 343 Lynch syndrome, 328 M Magnetic resonance imaging (MRI), 307 Malignant gastrointestinal obstruction biliary obstructions, 36, 37 colorectal obstruction, 35, 36 gastro-duodenal obstruction, 35 malignant esophageal obstruction, 33–35 Metaidobenzyguanidine (MIBG), 308 Metastatic pancreatic cancer chemotherapy, 212–214 second-line therapy, 217–218 targeted therapy anti-EGFR agents, 214–215 AVITA study, 217 CALGB, 217 fluorescent in situ hybridization, 215 smoking status, 216 Methotrexate, 124 Microsatellite instability (MSI) genetic alterations, 46 guidelines, 47 IHC testing, 49 immunohistochemistry, 48 PCR-based techniques, 47–48 pre-symptomatic detection, 47 Mitogen-activated protein kinase (MAPK), 241 Mitomycin C (MMC), 432 Model for end-stage liver disease (MELD), 236 Multimodality management adjuvant therapy, 184–191 clinical staging, 174–178 neoadjuvant therapy, 191–196 preoperative management, 174–178 surgical management, 178–184 Multiple endocrine neoplasia type 1 (MEN1), 303
458 N National Cancer Institute of Canada (NCIC), 280 National Comprehensive Cancer Network (NCCN), 313, 363 Neoadjuvant chemotherapy (NACT), 438–439 Neuroendocrine tumor (NET) advanced treatment biochemotherapy, 319 biotherapy, 317 chemotherapy, 319 control methods, 319 hepatic artery embolization, 317–318 hepatic metastases, 316 peptide receptor radionuclide therapy, 319 radiofrequency ablation, 318 somatostatin analog, 316–317 targeted therapy, 320 carcinoid appendiceal, 309 crisis, 313 gastric, 308–309 heart disease, 313 rectal, 309–310 small intestine, 309 syndrome, 312–313 clinical symptom, diagnosis CT and MRI, 307–308 endoscopy, 307 nuclear scintigraphy techniques, 308 octreoscan, 308 PET, 308 test and markers, 306–307 epidemiology, 302–303 islet cell tumors gastrinomas, 310–311 glucagonomas, 311 insulinomas, 310 pancreatic polypeptidomas, 312 somatostatinoma, 311 VIPoma, 311–312 medical oncologist, 321 pathogenesis and molecular biology, 303–305 pathologic classification, 305–306 prognosis, 303 surgical interventions, 314 therapy, 314, 315 Nonresectional locoregional therapies percutaneous ethanol injection, 239 radiofrequency ablation, 239–240 transarterial chemoembolization, 240
Index Nonsteroidal anti-inflammatory drugs (NSAIDs), 331, 381 O Orthotopic liver transplantation (OLT), 238 Oxaliplatin, 346 P Palliative radiotherapy, 113–114 Pancreatic adenocarcinoma, 26–27 Partial mesorectal excision (PME), 398 Percutaneous ethanol injection (PEI), 239 Percutaneous transhepatic cholangiography (PTC), 267 Perioperative treatment, esophageal cancer evaluation and prediction, 88–89 neoadjuvant chemoradiation, 85–86 chemotherapy, 85 radiation, 84 protocols, 87–88 quality of life, 86–87 Platelet-derived growth factor receptor alpha (PDGFRA), 53–54 Portal vein embolization (PVE), 236 Positron emission tomography (PET) advantage, 386 gastric cancer, 105–106 imaging accuracy, PET-CT, 5 FDG phosphorylation, hexokinase, 3, 4 18 F-FDG uptake, 3–5 malignant tumors, metabolic measurements, 4 Warburg phenomenon, 3 NETs evaluation, 308 staging GI cancers colorectal cancer, 6 esophageal cancer, 5 gastric carcinoma, 6 HCC (see Hepatocellular carcinoma) pancreatic cancer, 7 recurrent rectal cancer, liver lesions, 6–7 sensitivity and specificity, 6, 7 therapeutic management, 7 Practical correlative science colorectal carcinoma chromosomal instability pathway, 45 microsatellite instability pathway, 45–49 gastrointestinal cancer
Index allelic imbalance, 18q, 51 KRAS, 49–51 molecular abnormalities, 51 molecular bases, 43–44 molecular testing, 51–52 GIST imatinib resistance, 57–58 kinase genotype, 56–57 molecular classification, 54–56 oncogenic kinase mutations, 53–54 pathology, 52–53 recommendations, 58 Primary sclerosing cholangitis (PSC), 262 Progression-free survival (PFS), 317 Protein kinase C (PKC), 145 Q Quality of life (QoL), 86–87, 436 R Radiation therapy (RT) extrahepatic bile duct cancer adjuvant, 268–269 neoadjuvant, 269–270 unresectable cholangiocarcinoma, 270–271 gallbladder cancer adjuvant, 260–261 unresectable, 261–262 gastric cancer local unresectable/postoperative residual local disease, 116–117 neoadjuvant chemotherapy, 117–118 palliative, 113–114 patterns of failure, 114–115 postoperative adjuvant radiation, 115–116 preoperative, 119–120 radiochemotherapy, 117 intrahepatic cholangiocarcinoma, 277 Radiation Therapy Oncology Group (RTOG) trial 97-04, 189–190 Radiochemotherapy (RCT), 117 Radiofrequency ablation (RFA), 239 Rectal cancer anatomy, 387–389 apple core, 397, 398 chemotherapy adjuvant, 408–409 combination, 409–411 concomitant, 407–408 clinical manifestations, 382 CRM, 392 epidemiology, 380
459 etiology, 380–381 5-FU-based postoperative CRT, 401–404 histopathology, 388 neoadjuvant treatment, 415, 416 neoplasm, 396 optimized surgery, 415 partial mesorectal excision, 398–400 partial vs. total mesorectal excision, 399 pathology, 397 PET, 386 postoperative CRT, 401 preoperative radiation, 404–405 pretreatment staging anal manometry, 383 ERUS, 384 MRI scan, 385–386 sensitivity and specificity, 384 standard workup, 382, 383 primary prevention, 381 radiotherapy, 386–387 screening, 382 sequence optimization, 405–407 surgery local excision, 394–396 standard resection, 396 surgical quality, 393–394 targeted agents, 411–413 TEM, 394 TME procedure, 396 TNM classification, 389–392 total pelvic exenteration, 400 toxicity side effects, 413 small-bowel obstruction, 415 tumor regression, 394 Relapse-free survival (RFS), 431 Resectable neuroendocrine tumor, 314–315 Response evaluation criteria in solid tumors (RECIST), 8 S Self-expanding metallic covered/uncovered stents (SEMS), 33–35 Single-agent chemotherapy, 121, 123 Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP), 241 Squamous cell carcinoma (SCC) classification and pathology, 70 etiologic factors, 68–69 Standardized uptake value (SUV), 3–4 Stereotactic body radiotherapy (SBRT), 356–357 Superior mesenteric vein (SMV), 174–176
460 Surveillance epidemiology and end results (SEER), 303 Systemic therapy biliary cancer adjuvant, 283–284 metastatic disease, 277–283 targeted therapies, 282–283 gastric cancer chemotherapy vs. best supportive care, 126–128 cisplatin-based combinations, 124–125 combination chemotherapy, 121–123 doxorubicin, 124 epirubicin-based combinations, 126 5-fluorouracil, 124 INT0116 study, 130 irinotecan-based therapy, 125–126 leucovorin, 124 MAGIC study, 130 methotrexate, 124 mitomycin regimens, 124 monoclonal antibodies, 128 nitrosourea combinations, 122–123 single-agent chemotherapy, 121 symptom management, 130 targeted therapy, 128 taxane-based regimen, 125 tyrosine kinase inhibitors, 128 T Time to progression (TTP), 358 Total mesorectal excision (TME), 379, 389 Total pelvic exenteration (TPE), 400 Transanal endoscopic microsurgery (TEM), 394
Index Transarterial chemoembolization (TACE), 240 Transhiatal/cervical esophagectomy, 79 Transthoracic en-bloc esophagectomy, 79 Tumor node metastasis (TNM), 336 Tumor regression grading (TRG), 394 U Unresectable metastatic disease radiotherapy considerations, 357 systemic therapy bevacizumab, 360–362 cetuximab and panitumumab, 362 description, 358, 359 first and second-line, 358–360 phase 3 study, 360, 361 Unresectable pancreatic cancer locally advanced pancreatic cancer American Society of Clinical Oncology, 209 chemoradiotherapy protocols, 207–208 gastrointestinal tumor study group, 208 meta-analysis, 209 radiation and chemoradiotherapy, 206 systemic review, 210 targeted therapy, 210–211 metastatic pancreatic cancer chemotherapy, 212–214 second-line therapy, 217–218 targeted therapy, 214–217 V Vascular endothelial growth factor (VEGF), 347, 413