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Lalan S. Wilfong GI malignancies September 26, 2005 Colon Cancer 800,000 new cases per year globably 11% of cancer mortality in the US Lifetime risk of 0.5-2.0% of developing colon cancer Risk factors Age, Western countries, high-fat diets Obesity, Genetics, Inflammatory Bowel Disease Genetic Causes Familial Adenomatous Polyposis Hereditary Nonpolyposis Colorectal Cancer Hamartomatous Polyposis Syndromes Familial Colorectal Cancer Familial Adenomatous Polyposis 1% of all colorectal cancer Hallmark is hundreds to thousands of colon polyps 100% develop colon cancer Extracolonic features: Hypertrophy of retinal epithelium Mandibular osteomas Epidermal cysts Desmoid tumors Adrenal cortical adenomas Gene is APC on 5q21 HNPCC 3% of colorectal cancer Usually occurs in right colon Accelerated progression of polyps to cancer Can have extracolonic tumors Risk: 80% for colon cancer 40% for endometrial With skin tumors called Muir-Torre syndrome Autosomal dominant with 80% penetrance Defect in mismatch repair genes Can test for Microsatellite instability in tumors Diagnosis of HNPCC Diagnosis of HNPCC What Happens? Mismatch Repair genetic defect Encode enzymes that repair errors during DNA replication Main genes MLH1, MSH2, MSH6 and PMS2 Microsatellite instability Microsatellites are repetitive DNA sequences found throughout the genome Loss of MMR results in repetitive coding and noncoding regions of genes including genes involved in tumor initiation and progression Putative Role of Mutations in Mismatch-Repair Genes Lynch, H. T. et al. N Engl J Med 2003;348:919-932 Strategy for Risk Reduction Colonoscopy every 1-3 years beginning age 2025 or 10 years before earliest relative Prophylactic colectomy Chemoprevention? Transvaginal ultrasound or endometrial aspiration annually Prophylactic hysterectomy If stomach cancer in family, EGD every 1-2 years If urinary tract cancer, sono or urine cytology every 1-2 years Screening for Population Slow progression from adenoma to cancer make screening appropriate Best approach is unknown DRE Fecal occult blood Sigmoidoscopy Barium enema Colonoscopy Average Risk FOBT Flex sig every 5 yrs Colon every 10 yrs Increased Risk Colon starting 10 years before youngest affected member 3 or more polyps, colon in 3 years 1-2 polyps (<1cm) colon in 5 yrs Chemoprevention Medications to prevent cancer before cancer begins Since colon cancer has stepwise progression from adenoma to invasive disease, if we can block one of the steps we can stop cancer Colon Carcinogenesis and the Effects of Chemopreventive Agents Janne, P. A. et al. N Engl J Med 2000;342:1960-1968 Stage I II N III IV 1: invades submucosa 2: invades muscularis propria 3: through muscularis propria 4: invades other organs 0: no lymph nodes 1: 1-3 lymph nodes 2: 4 or more lymph nodes M: 0: no mets 1: with mets 100 90 80 70 60 50 40 30 20 10 0 5 year survival II II I IV T I Treatment Stage I – surgery Stage II – surgery unclear role of chemotherapy Stage III – surgery followed by adjuvant chemotherapy Stage IV – palliative chemotherapy Rectal Cancer – surgery, radiation and chemotherapy Disease-free survival after adjuvant chemotherapy for colorectal cancer using Fluorouracil and Leucovorin (FL) or FL + Oxaliplatin Andre, T. et al. NEJM 2004; 350:2343-2351 Trends in the Median Survival of Patients with Advanced Colorectal Cancer Meyerhardt, J. A. et al. NEJM 2005; 352:476-487 Adapted from Grothey et al Targeted Therapies Avastin VEGF inhibitor Blocks blood vessel formation All cells need O2 and therefore blood Erbitux EGFR inhibitor Overexpression in many cancer cell lines Important ligand for growth factors Angiogenesis Cells cannot survive if they lack oxygen and nutrients Oxygen can diffuse from capillaries to a distance of only 150 to 200 µm when cells are farther away from a blood supplythey die. Thus, to become clinically relevant, a tumor requires neovascularization or angiogenesis to survive Epidermal Growth Factor Receptor Inhibitor EGFR overexpressed on many epithelial cancers Correlates with poor outcome Acts as a tyrosine kinase Blocking this receptor can lead to cell cycle arrest and apoptosis EGFR blockade can improve survival in many cancers Fig 1. Mechanisms of receptor activation Mendelsohn, J. J Clin Oncol; 20:1s-13s 2002 Copyright © American Society of Clinical Oncology Esophageal Cancer 12,000 cases in US per year More common in Asia, blacks, males, age >50 Two Cell Types Squamous – • associated with smoking, etoh, nitrities, pickled vegetaqble, lye, achalasia, esophageal web, diet • Incidence decreasing Adenocarcinoma – • associated with reflux, Barrett’s, obesity • Incidence increasing esp in white males Clinical Features Location 15% upper 1/3 40% middle 1/3 45% lower third Symptoms Dysphagia Weight loss Pain vomiting Spread Adjacent lymph nodes Lung Liver Pleura Diagnosis Endoscopy CT scans PET Treatment Most patients present with advanced disease and prognosis is <5% 5 year survival Resection for early stage disease Chemoradiation for locally advanced disease Chemotherapy for advanced disease PEG tube or stents for nutrition Gastric Cancer Incidence decreasing 21,500 new cases per year More common in Asia 85% adenocarcinomas Diffuse – infiltrate and thicken the stomach wall causing linitis plastica Intestinal type – glandlike structures Features Etiology Ingestion of nitrates H pylori Loss of gastric acidity Presentation Upper abdominal pain Anorexia +/- nausea Weight loss dysphagia Spread Directly to perigasatric tissues Peritoneal seeding Intra-abdominal and supraclavicular lymph nodes Ovary (Krukenberg) Periumbilical (sister Mary Joseph) Peritoneal cul-de-sac (Blummers shelf) Liver Treatment Resection for early stage Lymph node dissection 20% 5 year survival Palliative even in advanced disease Chemotherapy for advanced disease Palliative benefit ? Prolongs survival Radiation only for palliation Pancreatic Cancer Incidence increasing – 28,299 cases in 2000 Risk factors Smoking Age Male Blacks Chronic pancreatitis Diabetes obesity Treatment Resection Only 15% have resectable lesions 5 year survival 10% Maybe improved with chemoradiation Unresectable or metastatic Survival 6 months Chemo offers palliation Clincal Features 90% adenocarcinomas 70% in head, 30% in body and tail Onset insidious Jaundice Pain Weight loss Diagnosis Ct scan MRI EGD, ERCP, EUS Ca 19-9