Gastrointestinal Oncology: A Practical Guide

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

1  Imaging in Gastrointestinal Cancer

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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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M. Choi and A.F. Shields

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

1  Imaging in Gastrointestinal Cancer

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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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1  Imaging in Gastrointestinal Cancer

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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M. Choi and A.F. Shields

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

1  Imaging in Gastrointestinal Cancer

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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 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.

1  Imaging in Gastrointestinal Cancer

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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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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/

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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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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

90

110

130

150

170

190

110

130

150

170

190

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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K. Washington and C.L. Corless

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

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