Disclosures. GI Cancers for the Boards. Esophageal Cancer. Esophageal Cancer: Risk Factors

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1 Disclosures GI Cancers for the Boards Peter C. Enzinger, MD Dana-Farber Cancer Institute Major GI Malignancies: Esophageal Cancer Gastric Cancer Pancreatic Cancer Colorectal Cancer Less Common GI Malignancies: Hepatocellular Carcinoma Biliary Cancer/Gallbladder Pancreatic Islet Cell/Carcinoid Tumors Anal Cancer Small bowel Total Annual Cases in US 274,330 Total Deaths in US 139,580 Annual Incidence and Mortality of Gastrointestinal Malignancies United States (2010) Worldwide (2008) Jemal et al CA Cancer J Clin 2010 Jemal et al CA Cancer J Clin Cancer New Cases Deaths New Cases Death Esophageal 16,640 14, , ,800 Gastric 21,000 10, , ,000 Pancreas 43,140 36,800 Not Available 266,000 Colorectal 142,570 51,370 1,233, ,700 Liver 24,120 18, , ,900 Breast 209,060 40,230 1,383, ,400 Lung 222, ,300 1,608,800 1,378,400 Esophageal Cancer: Risk Factors Esophageal Cancer Risk Factor Squamous-Cell Carcinoma Adenocarcinoma Tobacco use Alcohol use +++ Barrett s esophagus ++++ Weekly reflux symptoms +++ Obesity ++ Poverty ++ Achalasia +++ Caustic injury to the esophagus ++++ Nonepidermolytic palmoplantar keratoderma (tylosis) ++++ Plummer Vinson syndrome ++++ History of head and neck cancer ++++ History of breast cancer treated with XRT Adapted from Enzinger and Mayer, N Engl J Med Dec 4;349(23):

2 * Per 100,000 persons 5 * ADC/Esophagus SCC Per Capita Cigarette Consumption, Major Smoking & Health Events, and Incidence of Esophageal Cancer - United States Neoplastic Progression of Barrett s Esophagus GERD 1:7 Americans Squamous 10% Metaplasia epithelium Oxidative stress Inflammation G1&G2 COX-2 BCL-2 4% /yr Low- Grade Dysplasia 0.005%/yr 0.5%/yr 1%/yr? 5% High- /yr Grade Dysplasia Early Genetic Events: 17pLOH p53; 9pLOH p16 cyclin D1 2nd Tier Genetic Events: p53 mutation; p16 mutation/methylation EGF(R), telomerase RNA Late Genetic Events: 4 N (G2) aneuploidy of 5q/13q and LOH of 5q/13q(Rb)/18q ADC 85 + % c-erbb2 E-cadherincatenin METS Local Esophageal Cancer: Treatment Options Surgery alone Resectability rates 54-69% Perioperative mortality 4-10% Perioperative complications (cardiac, infection, anastomotic leaks) 26-41% 2 year survival 35-42% 5 year survival 15-24% Local Esophageal Cancer: Treatment Options At least 3 randomized trials have shown no benefit to postoperative radiation or postoperative chemotherapy (Fok Surgery 1997, Tenier Surg Gyn Onc 1991, Ando J Thor Cardiovasc Surg 1997) 2 neoadjuvant chemotherapy trials with conflicting results (Kelson NEJM 1998; MRC Lancet 2002) Not standard practice in US postoperative therapy reserved for R1 resections Radiation Therapy vs. Chemotherapy + Radiation Therapy for Localized SCC or ADC of the Esophagus Preoperative Chemoradiation followed by Surgery versus Surgery Alone in Esophageal Cancer Herskovic. N Engl J Med 1992, Al-Sarraf. J Clin Oncol 1997 Gebski et al. Lancet Oncology. 2007; 8(3):

3 Esophageal Cancer: Treatment Algorithm Early stage disease (T1-2, N0) Locally advanced disease (T3, N0-1) Metastatic Disease Surgery Preoperative chemoradiation regimen followed by surgery Palliation of local symptoms Palliative chemo if appropriate Esophageal Cancer: Survival based on AJCC 6 Stage Tumor Node Mets 5 year survival 0 Tis N0 M0 > 95% 1 T1 N0 M % IIA T2-3 N0 M % III T3 N1 M % T4 Any N M0 IVA Any T Any N M1a < 5 % IVB Any T Any N M1b < 1% Adapted from Enzinger and Mayer, N Engl J Med Dec 4;349(23): Esophageal Cancer: AJCC 7 Tumor location is simplified; GE junction and proximal five cm of stomach are included. N subclassified according to the # of positive regional lymph nodes Separate stage groupings for squamous cell carcinoma and adenocarcinoma M is distant mets (no subclasses) Stage groupings are reassigned using T, N, M, and G (grade) classifications. Chemotherapy for Metastatic Esophageal and Gastric Cancer No standard therapy for metastatic disease Expectations of current treatment options Response rates 30-60% Relief of dysphagia (without XRT) up to 80% Median overall survival 7-10 months Take Home Points of Esophageal Cancer Esophageal cancer relatively uncommon in US but high rate of death from disease Localized therapy treated with surgery only or chemort followed by surgery Chemotherapy or chemort relieves local symptoms in unresectable disease Metastatic disease not curable median survival less than 1 year Gastric Cancer

4 Incidence of Gastric Cancer (Cases per 100,000 population) Men Women Risk Factors for Gastric Adenocarcinoma Nutritional Low fat or protein consumption Salted meat or fish High nitrate consumption Environmental Poor food preparation (smoked) Lack of refrigeration Poor drinking water (well water) Occupation (rubber, coal workers) Smoking (1.6x) Low social class Medical Prior gastric surgery Helicobacter pylori infection (2x) Gastric atrophy and gastritis Hereditary E cadherin mutation families Gastric Cancer Survival by Stage National Cancer Data Base Proportion of H.pylori-Positive and H.pylori-Negative Patients who Remained Free of Gastric Cancer Survival (%) Time, years IA IB II IIIA IIIB IV Uemura et al, N Engl J Med,345,2001; 345: Chemoradiotherapy After Surgery Compared with Surgery Alone for Adenocarcinoma of the Stomach or Gastroesophageal Junction CALGB 80101: Overall Survival Overall Survival by Arm Proportion Surviving Years from Study Entry ECF 5-FU P, log rank = 0.80 MacDonald et al, N Engl J Med, 2001;345: Fuchs et al ASCO 2011

5 MAGIC: Peri-operative Chemotherapy Deemed surgically resectable gastric cancer N=503 R A N D O M I Z E A B ECF Surgery only Surgery only ECF 36% v 23% at 5 years Chemotherapy for Metastatic Esophageal and Gastric Cancer No standard therapy for metastatic disease Expectations of current treatment options Response rates 30-60% Relief of dysphagia (without XRT) up to 80% Median overall survival 7-10 months Notes: 88% of patients randomized to chemotherapy arm had surgery but only 42% of patients completed all protocol treatment Cunningham N Engl J Med Jul 6;355(1):11-20 Take Home Points of Gastric Cancer Gastric cancer decreasing incidence in past few decades ~50% of patients diagnosed will pass away from gastric cancer Standard of care for localized disease is surgery and often chemort postoperatively Metastatic disease median survival < 1 yr Board Question #1 Your patient is a 72 year old carpenter who presents with several month history of difficulty swallowing, primarily just certain foods. He has lost approximately 10 pounds in the past month, but he claims that he was trying to diet. You order an EGD and there is a mass in his midesophagus. Biopsies demonstrate squamous cell carcinoma. He consults a thoracic surgeon who performs an esophagectomy and final pathology reveals invasion through the muscle to subserosa (T3) and 2 positive lymph nodes. Margins were all negative. You now recommend: A. Adjuvant chemotherapy B. Adjuvant radiation C. Combined chemotherapy and radiation D. Observation and intermittent surveillance Board Question #1 A. Adjuvant chemotherapy B. Adjuvant radiation C. Combined chemotherapy and radiation D. Observation and intermittent surveillance Pancreas Cancer Since patient has esophageal cancer, no role for adjuvant therapy based on multiple trials of either modality If tumor was GE junction, adjuvant therapy would be reasonable to offer

6 Pancreatic Cancer: Survival Data from National Cancer Database Relative % at each time point Risk Factors for Pancreatic Adenocarcinoma Hereditary Hereditary chronic pancreatitis Peutz-Jeghers syndrome Ataxia-telangiectasia Chronic pancreatitis mixed data Diabetes (relative risk 2) Smoking Obesity History of partial gastrectomy Niederhuber et al. (2006) Cancer. 76 (9): Pancreatic Cancer: Treatments Local disease: Surgery + adjuvant therapy Locally advanced: Chemoradiotherapy Metastatic: Chemotherapy Pancreatic Cancer: Local Disease Curative resection possible in only 15% of all patients with pancreatic cancer 15% of resected patients survive 5 years Adjuvant Therapy trials ChemoRT after surgery beneficial in 1 trial of 43 patients in US; not beneficial in 2 European trials Chemotherapy beneficial in 2 trials in European Nonetheless improvements are modest Yang et al. CA Cancer J Clin (6): Pancreatic Cancer: Locally Advanced Pancreatic Cancer: Metastatic Disease Locally advanced pancreatic cancer n = R A N D O M I Z E Survival (Weeks) 4000 RADS XRT + 5-FU 6000 RADS XRT + 5-FU 6000 RADS XRT only 4000r+5FU 6000r+5FU 6000r alone Moertel CG, et al. Cancer 1981;48: Response rate 5% 0% Burris HA, et al J Clin Oncol 1997;15:

7 Metastatic Pancreatic Cancer: Erlotinib Metastatic Pancreatic Cancer: FOLFIRINOX R A N D Gemcitabine + Erlotinib Response rate 8.6% Median overall survival 6.24 m 1 year survival 23% R A N D Gemcitabine O M I Z E Gemcitabine Response rate 8.0% Median overall survival 5.91 m 1 year survival 17% O M I Z E FOLFIRINOX (5-FU, LV, Irinotecan, Oxaliplatin) Progression-Free Survival Overall Survival Response Median Rate PFS Median OS 1 year OS Grade 3/4 WBC Grade 3/4 Emesis Gemcitabine 9 % 3.3 m 6.8 m 21 % 19 % 5 % FOLFIRINOX 31 % 6.4 m 11.1 m 48 % 46 % 15 % P value < < < Moore et al Journal of Clinical Oncology, Vol 25, No 15 (May 20), 2007: pp Thierry Conroy et al ASCO 2010 New Targets May Have Hope Take Home Points of Pancreatic Cancer IGF-1 Hedgehog Inhibitor Stephenson et al ASCO 2011 Kindler et al ASCO 2010 Only 15% of patients diagnosed are eligible for surgery and only 15% of those patients will be cured (cure rate 2-3%) Locally advanced disease chemort Metastatic disease treated with chemotherapy and median survival 6-8 months (recent trial up to 11 months but toxicity needs to be weighed) Risk Factors for Developing Colorectal Cancer Colorectal Cancer Decrease Risk Increase Risk Uncertain Impact Screening Family history Statins Exercise IBD Fiber Vitamin D Diabetes Glycemic index Aspirin / NSAIDs Obesity Fruits/Vegetables Post-menopausal estrogen Calcium Red meat Western diet Alcohol Smoking Folic Acid

8 Colorectal Cancer: Risk Factors Hereditary Familial syndromes (~5% of CRC) Familial adenomatous polyposis Hereditary nonpolyposis cancer syndrome Colorectal Cancer: Screening Why screen? Family history (or personal history) (~10-15%) ~ 2 x risk of developing CRC Depending on age of relative at dx and # of relatives Winawer, S. J. et al. N Engl J Med 1993;329: Colorectal Cancer: Screening American Cancer Society recommendations for average risk patients (updated 2008) Tests that find polyps and cancer Flexible sigmoidoscopy every 5 years * Colonoscopy every 10 years Double contrast barium enema every 5 years * CT colonography (virtual colonoscopy) every 5 years * Tests that mainly find cancer Fecal occult blood test (FOBT) every year * Fecal immunochemical test (FIT) every year * Stool DNA test (sdna), interval uncertain * *Colonoscopy should be done if test results are positive. Levin et al CA Cancer J Clin 2008; 58: Colorectal Cancer: Screening Despite evidence, screening rates still low National Health Interview Surveys of subjects 50 and older and no history of colorectal cancer 32% of men and 30% of women reported having a colonoscopy 16% of men and 15% of women reported FOBT 8% men and 6% of women had sigmoidoscopy Age dependence Age greater than 65 - ~ 50% had any screening Age % had any screening Increased use since 2000 due to colonoscopy Meissner, CEBP 2006; 15: Colorectal Cancer: AJCC 7 Primary tumor (T) Tx Primary tumor cannot be assessed Tis Carcinoma in situ T1 Tumor invades submucosa T2 Tumor invades muscularis propia T3 Tumor invades through the muscularis propia into the subserosa T4 Tumor directly invades other organs or structures, and/or perforates Nodal status (N) Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastases in 1 to 3 regional lymph nodes N2 Metastases in 4 or more regional lymph nodes Distance Metastases (M) N1a = 1 node N1b = 2-3 nodes N1c = tumor deposits in subserosa or mesentery N2a = 4-6 nodes N2b = 7+ nodes Colorectal Cancer: Staging Stage 5 year survival Stage I > 90% Stage II 70-85% Stage III 30-70% Stage IV 8-10 % Mx M0 M1 Distant metastases cannot assessed No distant metastases detected Presence of distant metastases M1a = single organ M1b = more than 1 organ or peritoneum

9 Colorectal Cancer: Surgery Surgical resection cures a large number of patients with early disease 80% of patients present without detectable mets Colorectal Cancer: Therapy Schema Stage Colon Rectal I (T 1 -T 2, N 0, M 0 ) Surgery only Surgery only Colon cancer At least nodes should be included in sample Increasing evidence for equivalent outcomes with laparoscopic colectomy Rectal cancer Low anterior resection maintains sphincter Abdominoperineal resection low tumors permanent colostomy II (T 3 -T 4, N 0, M 0 ) Surgery +/- chemo III (T any, N 1-2, M 0 ) Surgery Chemo IV (T any, N any, M 1 ) Chemo +/- surgery ChemoRT Surgery Chemo OR Surgery ChemoRT and Chemo Chemo +/- surgery Colorectal Cancer: Radiation Why beneficial in rectal and not colon? Related to risk of local recurrence (radiation is a local treatment) In colon cancer <2% risk of local recurrence In rectal cancer up to 30% local recurrence rate with surgery alone Colorectal Cancer: Chemotherapy Stage III colon cancer Adjuvant 5-FU/LV reduces the risk of disease recurrence by 40% and overall mortality by 33% consensus statement from NCI committee recommended adjuvant 5-FU and leucovorin for stage III patients 2 trials demonstrated improvements with adding oxaliplatin to 5-FU/leucovorin Downside: Neurotoxicity Sun W, Haller DG. Seminars in Oncology. 2005;32(1): Andre T, et al. N Engl J Med 2004;350(23): Colorectal Cancer: Chemotherapy 5 yr overall survival for stage III colon cancer surgery surgery w/chemo Stage IIIA 52% 71% Stage IIIB 37% 51% Stage IIIC 21% 32% using AJCC 6 Surgery only Surgery + Adjuvant 5-FU Greene FL, et al. Ann Surg. 2002;236:416 Colorectal Cancer: Chemotherapy Stage II colon cancer No randomized trials with enough stage II patients to draw definitive recommendations. 2 meta-analyses (IMPACT and NSABP) give conflicting results ASCO Consensus panel concluded that based on available evidence, benefit would not exceed 5% - a benefit between 0-5% possible (JCO 2004) High risk patients may be appropriate T4 lesions, obstruction or perforation, few lymph nodes in sample. Further work on molecular markers needed (18q, MSI)

10 Colorectal Cancer: Chemotherapy Metastatic disease In general, not curable Few cases of isolated metastases that can be surgically resected can have a long term survival. Chemotherapy known to prolong life and improves symptoms Median survival without therapy ~ 6 months Colorectal Cancer: Chemotherapy 1998 FDA approved chemotherapy option for metastatic colorectal cancer 5-FU Median survival with therapy months Colorectal Cancer: Chemotherapy 2011 Colorectal Cancer: Progress Current FDA approved chemotherapy options for metastatic colorectal cancer First line 5-FU Capecitabine FOLFIRI or IFL FOLFOX IV 5-FU with bevacizumab Second-line Irinotecan (5-FU progression) FOLFOX (Irinotecan progression) Previously treated with irinotecan Cetuximab Cetuximab + Irinotecan Panitumumab Prior to any active chemotherapy Fluoropyrimidine only Fluoropyrimidine + 1 other active cytotoxic chemotherapy (irinotecan or oxaliplatin) Fluoropyrimidine + irinotecan + oxaliplatin (at some point in course of treatment) All three cytotoxic chemotherapy during course of treatment with exposure to bevacizumab and/or cetuximab 6 months months months months 2+ years Adapted from Meyerhardt and Mayer, NEJM 2005 Take Home Points of Colorectal Cancer Disease common various risk factors that are reversible 80% patients without detectable mets at diagnosis Treatment depends on stage of disease surgery is considered in all patients Stage III colon cancer adjuvant chemo Stage II and III rectal neoadj chemort or post op chemort and chemo adjuvant either way Stage II colon? Chemo adjuvant? Board Question #2 Your patient is a 56 year old school teacher who presented with about 2 months of intermittent blood in the toilet bowl with bowel movements. A colonoscopy is performed which demonstrates a mass in the mid sigmoid and biopsy confirm adenocarcinoma. He undergoes laparoscopic hemicolectomy and final pathology reveals a 3 cm, moderately differentiated adenocarcinoma through the muscle layer into the serosa with 2 of 9 lymph nodes positive. The next step would be: A. Re-operate for more complete lymph node dissection B. Referral to medical oncologist for consideration of chemotherapy C. Followup colonoscopy in one year D. Referral to radiation oncologist for postoperative radiation

11 Board Question #2 A. Re-operate for more complete lymph node dissection B. Referral to medical oncologist for consideration of chemotherapy C. Followup colonoscopy in one year D. Referral to radiation oncologist for postoperative radiation Patient has stage III colon cancer Lymph node sampling is not ideal (12 is preferred #) can request pathologist to further search Patient should be considered / offered chemotherapy Colonoscopy in 1 yr is appropriate surveillance but not next step Radiation reserved for rectal and rarely colon (T4) Selected References Enzinger and Mayer. Esophageal cancer. N Engl J Med. 2003;349: Alberts et al. Gastric cancer: epidemiology, pathology and treatment. Ann Oncol. 2003;14 Suppl 2: ii31-6. Lim et al. Adjuvant therapy in gastric cancer. J Clin Oncol. 2005;23(25): Chari. Detecting early pancreatic cancer: problems and prospects. Semin Oncol. 2007; 34: Ko and Tempero. Systemic therapy for pancreatic cancer. Semin Radiat Oncol. 2005; 15: Benson. Epidemiology, disease progression, and economic burden of colorectal cancer. J Manag Care Pharm. 2008;13(6 Suppl C):S5-18. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Levin B, Lieberman DA, McFarland B, Andrews KS, Brooks D, Bond J, Dash C, Giardiello FM, Glick S, Johnson D, Johnson CD, Levin TR, Pickhardt PJ, Rex DK, Smith RA, Thorson A, Winawer SJ. Gastroenterology. 2008; 134: Meyerhardt and Mayer. Systemic therapy for colorectal cancer. N Engl J Med. 2005; 352:

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