Colorectal Cancer Prevention & Screening Rajeev Jain, M.D.
2007 Estimated US Cancer Cases* Source: American Cancer Society, 2007. Men 766,860 Women 678,060 26%Breast 15%Lung & bronchus 11%Colon & rectum 6%Uterine corpus 4%Non-Hodgkin lymphoma 4%Melanoma of skin 4% Thyroid 3%Ovary 3%Kidney 3%Leukemia 21%All Other Sites Prostate29% Lung & bronchus15% Colon & rectum10% Urinary bladder7% Non-Hodgkin4% lymphoma Melanoma of skin4% Kidney4% Leukemia 3% Oral cavity3% Pancreas2% All Other Sites19% *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
2007 Estimated US Cancer Deaths* ONS=Other nervous system. Source: American Cancer Society, 2007. Men 289,550 Women 270,100 26%Lung & bronchus 15%Breast 10%Colon & rectum 6%Pancreas 6%Ovary 4%Leukemia 3%Non-Hodgkin lymphoma 3%Uterine corpus 2%Brain/ONS 2% Liver & intrahepatic bile duct 23% All other sites Lung & bronchus31% Prostate9% Colon & rectum 9% Pancreas6% Leukemia4% Liver & intrahepatic4% bile duct Esophagus4% Urinary bladder3% Non-Hodgkin 3% lymphoma Kidney3% All other sites 24%
Colorectal Tumorogenesis Normal Early Adenoma Late Adenoma Carcinoma APC/-Catenin K-ras p53 18q LOH Fearon & Vogelstein. Cell 1990.
Age > 50 years Inflammatory Bowel Disease Familial Adenomatous Polyposis (FAP) Syndromes Hereditary Non- polyposis Colon Cancer (HNPCC) Family History Polyps Cancer Past History Polyps Colon Cancer Ovarian Cancer Uterine Cancer Breast Cancer Colorectal Cancer Risk Factors Winawer, et al. Gastro 1997.
Colorectal Cancer Risk Factors Winawer et al. J Natl Cancer Inst 1991.
Familial Adenomatous Polyposis (FAP) Autosomal dominant Mutant APC gene > 100 polyps Avg age of adenoma appearance: 16 yrs Avg age of CRC diagnosis: 39 yrs Risk of CRC ~ 100% Winawer, et al. Gastro 2003.
Hereditary Nonpolyposis Colorectal Cancer (HNPCC or Lynch Syndrome) Autosomal dominant Mutations in DNA mismatch repair genes In comparison to sporadic CRC: Earlier age of onset (mean, 44 yrs) Right-sided Synchronous or metachronous lesions Poorly differentiated histology
CRC & Ulcerative Colitis Eaden, et al. Gut 2001.
Colorectal Cancer Ulcerative colitis & Crohns colitis Risk of developing CRC increases with: Duration of disease Young age at diagnosis Extent of disease Primary sclerosing cholangitis (PSC) Familial association Munkholm P. Aliment Pharmacol Ther 2003.
Colorectal Cancer Age-Specific Incidence SEER 1973-1992.
Colorectal Cancer Incidence with Positive Family History Mecklin et al. Gastro 1986.
Colon Cancer Familial Risk Burt. Gastro 2000.
Colon Cancer Risk After Gynecologic Cancer Weinberg et al. Ann Intern Med 1999.
Distribution of Polyps & Cancer 13% 9% 11% 6% 55% 7% 13% 11% 18% 52% Adenomatous Polyps Adenocarcinoma Winawer, et al. Gastro 1997.
Colorectal Cancer Summary of Risk Factors Highest Risk Genetic syndromes (FAP & HNPCC) Inflammatory bowel disease High Risk Family history of polyps and/or CRC Average Risk
Colorectal Cancer PREVENTION Dietary Habits Medical Therapy
Western countries have 10x risk for colon cancer in comparison to Asian & other developing countries. Rapid increases in rates of colon cancer are found in: migrants from low-risk to high-risk areas. Japan since World War II. Colorectal Cancer
Colorectal Cancer Dietary Hypotheses RISK Animal Fat Fiber Excretion of bile acids Colorectal carcinogenesis Conversion to secondary bile acids deoxycholic & lithocolic acid
Colon Cancer & Animal Fat Intake Willet et al. NEJM 1990.
Colon Cancer & Dietary Fiber Possible Mechanisms of Action Increased bulk of stool Dilution of potential carcinogens Decrease in transit time Binding with potential carcinogens Lowers fecal pH Alters colonic flora Fermentation by fecal flora to SCFAs Kim. Gastro 2000.
Colon Cancer & Dietary Fiber Current evidence (epidemiological, animal, and interventional studies) is supportive of an inverse association between dietary fiber intake and CRC risk. Protective effects seen at 30-35 gm/d (US mean 11.1 gm/d) Intervention should begin 10-20 yrs before the peak age for CRC incidence. Kim. Gastro 2000.
Nutritional education Low animal fat High fiber Fiber supplementation (goal of 25 35 gm fiber/day) Other lifestyle modifications Weight loss Physical activity Avoid tobacco Colon Cancer & Diet What should we tell our patients ?
Colorectal Cancer Protective Micronutrients ? Calcium and Vitamin D Folic acid Vitamins A, C, and E Selenium Curcumin
Colorectal Cancer Chemopreventive Agents ASA & NSAIDs Folate Calcium Estrogens
Chemoprevention with ASA U.S. Preventive Services Task Force Colonic adenomas RR 0.82 [95%CI, 0.70 0.95] RCTs RR 0.87 [95%CI, 0.77 0.98] Case-control RR 0.72 [95%CI, 0.61 0.85] Cohort Colon cancer 22% RR in cohort studies 2 RCTs no protective benefit at low doses Benefits seen with higher doses and for periods longer than 10 years The USPSTF recommends against the routine use of ASA/NSAIDs to prevent CRC in average risk patients. Dube C et al. Ann Int Med 146:365-75, 2007.
Mechanism unknown Colorectal adenomas Prospective cohort study (25,474 pts) Folate 400 ug QD 29% risk reduction Colorectal cancer Prospective cohort study (88,756 pts) Folate in a multivitamin preparation 75% risk reduction after 15 yrs Chemoprevention Folate
Mechanism binding of bile and fatty acids inhibit colorectal epithelium proliferation Case-control and cohort studies show inverse relationship between calcium intake and CRC imprecise assessment of calcium intake confounding factors RCT 930 pts with h/o adenomas 3 gm Ca carbonate (1200 mg elemental Ca) Serial colonoscopy 1 and 4 yrs after randomization 15% reduction in adenoma formation Chemoprevention Calcium Baron et al. NEJM 1999.
1.Cancer Prevention Study II 422,373 patients End point Death 2.Nurses Health Study 59,002 patients End point - Cancer Chemoprevention Estrogens Calle et al. J Natl Cancer Inst 1995. Grodstein et al. Ann Intern Med 1998.
Colorectal Cancer Prevention Dietary habits Increase fiber intake Decrease animal fat intake Chemoprevention Not enough data to firmly recommend
Definitions Screening: search for neoplasia in asymptomatic population with no prior neoplasia Surveillance: evaluation of patients with prior colorectal adenomas or cancer, or with IBD Diagnosis: evaluation of symptomatic patients and patients with positive screening tests
CRC Screening Only 26% of eligible population has had FOBT within 3 yrs; 33% have never had FOBT Most common reason given: test was never recommended Of those offered screening, only 4% decline Cancer Prevention Study (CPS) II Nutrition Cohort, cross- sectional data from 1997 Men 86,404; women 97,786 42% men & 31% women underwent screening FS or colonoscopy In pts > 50 yrs, 33% had undergone FS/C in 1999. By 2004, 52% had undergone screening FS/C. Vernon, J Natl Cancer Inst 1997. Leard et al, J Fam Prac 1997. Chao, Am J Public Health 2004. Smith,CA Cancer J Clin 2006.
CRC Screening Women who underwent screening mammography and Pap smear 52% underwent CRC screening Men who underwent prostate cancer screening with PSA 65% underwent CRC screening Carlos, Acad Radiol 2005. Carlos, J Am Coll Surg 2005.
Medicolegal Issues Delay in diagnosis of CRC accounts for >50% of all litigation against PCPs for GI disease Attributing rectal bleeding to hemorrhoids Inadequate evaluation of positive FOBT Failure to screen Gerstenberger & Plumeri. Gastrointest Endosc 1993.
Risk Stratification Has the patient had colorectal cancer or an adenomatous polyp? Does the patient have an illness that predisposes him or her to colorectal cancer? Has a family member had colorectal cancer or an adenomatous polyp? Winawer et al. Gastroenterology 2003.
Screening Tests for Colorectal Cancer Fecal occult blood test Flexible sigmoidoscopy Double-contrast barium enema Colonoscopy
Fecal Occult Blood Tests Rationale: colorectal cancers bleed Guaiac-based pseudoperoxidase activity of hemoglobin Immunochemical antibodies to human globin epitopes Heme-porphyrin hemoglobin derived porphyrin
Fecal Occult-Blood Tests Test Basis of Reaction Hemoccult IIGuaiac Hemoccult SENSA Guaiac HemeSelectAb to H Hgb HemoQuantHeme porphyrins Rockey. NEJM 1999.