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Colorectal Cancer Prevention & Screening Rajeev Jain, M.D. 2007 Estimated US Cancer Cases* Men 766,860 Women 678,060 Prostate 29% 26% Breast Lung & bronchus 15% 15% Lung & bronchus Colon & rectum 10% 11%Colon & rectum Urinary bladder 7% 6% Uterine corpus Non-Hodgkin lymphoma 4% 4% Non-Hodgkin lymphoma Melanoma of skin 4% 4% Melanoma of skin Kidney 4% 4% Thyroid Leukemia 3% 3% Ovary Oral cavity 3% 3% Kidney Pancreas 2% 3% Leukemia 19% 21% All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. All Other Sites Source: American Cancer Society, 2007. 2007 Estimated US Cancer Deaths* Lung & bronchus 31% Men 289,550 Women 270,100 26% Lung & bronchus 15% Breast Colon & rectum Prostate 9% Colon & rectum 9% 10% Pancreas 6% 6% Pancreas Leukemia 4% 6% Ovary Liver & intrahepatic bile duct 4% 4% Leukemia 3% Esophagus 4% Non-Hodgkin lymphoma Urinary bladder 3% 3% Uterine corpus Non-Hodgkin lymphoma 3% 2% Brain/ONS 2% Kidney 3% Liver & intrahepatic bile duct All other sites 24% 23% All other sites ONS=Other nervous system. Source: American Cancer Society, 2007. Colorectal Tumorogenesis APC/ß-Catenin Normal Early Adenoma K-ras p53 18q LOH Late Adenoma Carcinoma Fearon & Vogelstein. Cell 1990. Colorectal Cancer Risk Factors Age > 50 years Inflammatory Bowel Disease Familial Adenomatous Polyposis (FAP) Syndromes Hereditary Nonpolyposis Colon Cancer (HNPCC) Family History – Polyps – Cancer Past History – – – – – Polyps Colon Cancer Ovarian Cancer Uterine Cancer Breast Cancer Winawer, et al. Gastro 1997. Colorectal Cancer Risk Factors IBD FAP HNPCC 1% 1% 5% FAM HX 15-20% SPORADIC 75% 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 Incidence Rate, % CRC & Ulcerative Colitis 20 18 15 10 8 5 2 0 10 20 30 Duration of colitis, years Eaden, et al. Gut 2001. Colorectal Cancer Ulcerative colitis & Crohn’s 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 Rate Per 100,000 500 400 300 200 100 0 20-24 30-34 40-44 50-54 60-64 70-74 80-84 Age (years) SEER 1973-1992. Colorectal Cancer Incidence with Positive Family History Cumulative Incidence (%) 10 <45 45-54 >55 Controls 5 0 40 50 60 70 80 Age of Relatives (years) Mecklin et al. Gastro 1986. Colon Cancer Familial Risk Risk of Colon Cancer 5 4 3 2 1 0 1 1st 1 1st <50 yrs 2 1st 1 2nd/3rd 2 2nd Familial Setting Burt. Gastro 2000. Colon Cancer Risk After Gynecologic Cancer Risk of Colon Cancer 4 3 25 - 49 yrs 50 - 64 yrs > 65 yrs 2 1 0 Cervical Endometrial Ovarian Gynecologic Cancer Weinberg et al. Ann Intern Med 1999. Distribution of Polyps & Cancer Adenomatous Polyps Adenocarcinoma 11% 11% 13% 9% 18% 7% 6% 13% 52% 55% 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 Colorectal Cancer 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 Dietary Hypotheses Excretion of bile acids Conversion to secondary bile acids deoxycholic & lithocolic acid Colorectal carcinogenesis Fiber Animal Fat RISK Colon Cancer & Animal Fat Intake 2 Relative Risk Nurses' Health Study 1.5 1 1 2 3 4 5 Intake of Animal Fat (quintile) 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 SCFA’s 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. Colon Cancer & Diet What should we tell our patients ? 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 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. Chemoprevention Folate 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 Calcium 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 Baron et al. NEJM 1999. Chemoprevention Estrogens – 422,373 patients – End point – Death 2.Nurses’ Health Study – 59,002 patients – End point - Cancer 40 Risk Reduction (%) 1.Cancer Prevention Study II 35 30 25 20 15 10 5 0 Study 1 Study 2 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, crosssectional 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 II Guaiac Hemoccult SENSA Guaiac HemeSelect Ab to H Hgb HemoQuant Heme porphyrins Rockey. NEJM 1999. Fecal Occult-Blood Tests CHARACTERISTICS GUAIACBASED HEMEPORPHYRIN IMMUNOCHEMICAL Bedside availability ++++ 0 0 to ++ Time to develop 1 min 1 hr up to 24 hrs Cost $18 $33 $18-35 Rockey. NEJM 1999. Fecal Occult-Blood Tests REASON FOR FALSE POSITIVE RESULTS GUAIACBASED HEMEPORPHYRIN IMMUNOCHEMICAL Non-human hemoglobin ++++ ++++ 0 Dietary peroxidases +++ 0 0 Rehydration +++ 0 0 Iron 0 0 0 Rockey. NEJM 1999. Fecal Occult-Blood Tests REASON FOR GUAIACHEMEFALSE NEGATIVE BASED PORPHYRIN RESULTS IMMUNOCHEMICAL Hemoglobin degradation +++ 0 +++ Storage ++ 0 ++ Vitamin C ++ 0 0 Rockey. NEJM 1999. Guaiac-based FOBT 2 slides from 3 consecutive bowel movements Dietary & medication restrictions Slides should NOT be rehydrated Slides should be stored at room temperature & developed within 7 days Fecal Occult-Blood Tests Comparison of RCTs Mandel et al Hardcastle et al Kronborg et al Kewenter et al Minnesota Nottingham Funen Gothenburg Number of patients 46,551 152,850 61,933 68,308 Follow-up 13 yrs 7.8 yrs 10 yrs 8.3 yrs FOBT frequency 1 yr 2 yr 2 yr 1.5 yr Rehydration Yes No No Yes PPV for CRC 2% 10% 18% 5% Mortality reduction 33% 14% 18% 12% Towler et al. BMJ 1998. Screening Sigmoidoscopy Mortality Reduction (%) Case-Control Studies 100 80 60 40 79 60 59 20 0 San Fransisco London VA Study Selby et al. NEJM 1993. Newcomb et al. NEJM 1993. Muller & Sonnenberg. Arch Int Med 1995. Cumulative Incidence (%) Observed and Expected CRC Incidence after Polypectomy 5 NPS SEER St. Mark's Mayo 4 3 2 1 0 0 2 4 6 7 Years Followed Winawer et al. NEJM 1993. Colonoscopy Case-Control Study Mortality Reduction (%) 100 80 60 40 20 39 52 0 Colonoscopy Polypectomy Muller & Sonnenberg. Ann Intern Med 1995. Screening Colonoscopy VA Indiana Patients 3121 1994 Age 50-75 yrs >50 yrs Men 97% ? FHx CRC 14% ? Cancer 1% 1% Lieberman et al. NEJM 2000. Imperiale et al. NEJM 2000. Major Complication Rates of Screening Tests Screening test Perforation & Hemorrhage Death Barium enema 1/10,000 1/50,000 Sigmoidoscopy 1-2/10,000 <1/10,000 Colonoscopy 1-3/1,000 1-3/10,000 Winawer, et al. Gastro 1997. Colorectal Cancer Innovative Screening Techniques Targeting exfoliated markers – Fecal • colonocytes • DNA – Immunochemical assays • p53 • CEA Colorectal Cancer Innovative Screening Techniques Virtual colonoscopy (computed tomographic colonography). – Thin-section helical CT & air insufflation generating 2-D images converted to 3-D images. Results of recent study (100 pts) – – – – Cancer: Polyps > 10 mm: Polyps 6 – 9 mm: Polyps < 5: 100% 91% 82% 55% Fenlon, et al. NEJM 1999. Colorectal Cancer Screening Guidelines American Cancer Society American College of Gastroenterology American Gastroenterological Association American Society of Colon & Rectal Surgeons American Society for Gastrointestinal Endoscopy Winawer, et al. Gastro 1997. Latest Guidelines Original panel reconvened to review latest literature Endorsed by: – – – – – – – – American Academy of Family Practice American Cancer Society American College of Gastroenterology American College of Physicians-American Society of Internal Medicine American College of Radiology American Gastroenterological Association American Society of Colon & Rectal Surgeons American Society for Gastrointestinal Endoscopy Winawer, et al. Gastro 2003. CRC Screening Guidelines Average Risk Asymptomatic Age > 50 years No other risk factors for CRC Winawer, et al. Gastro 2003. CRC Screening Guidelines Average Risk TEST FREQUENCY Fecal occult blood test* Annually Flexible sigmoidoscopy* Every 5 years Double-contrast barium enema* Every 5 years Colonoscopy Every 10 years * Positive result leads to colonoscopy Winawer, et al. Gastro 2003. CRC Screening Guidelines Familial Risk CATEGORY RECOMMENDATIONS First-degree relative with CRC or an adenomatous polyp at age >60 yrs Same as average risk but starting at age 40 yrs 2 second-degree relatives with CRC 2 or more first degree relatives with colon cancer Colonoscopy every 5 yrs beginning at the 40 yrs or 10 yrs younger than the earliest diagnosis in the family First-degree relative with CRC or adenomatous polyp < 60 yrs 1 ≥2nd degree relative with CRC Same as average risk Winawer, et al. Gastro 2003. CRC Screening Guidelines Genetic Syndromes CATEGORY RECOMMENDATION Familial adenomatous polyposis (FAP) Sigmoidoscopy beginning at age 10-12 yrs Hereditary nonpolypsosis colorectal cancer (HNPCC) Colonoscopy , every 1-2 yrs, beginning at age 20-25 yrs or 10 yrs younger than earliest case in the family Winawer, et al. Gastro 2003. Colorectal Cancer Cost-Effectiveness of Screening 5 studies: less than $50,000 per lifeyear saved. Cost-utility of one-time colonoscopic screening (50-54 yrs): $69,000 per QALYs Compares favorably to other interventions – Mammograms – Seat belts – Airbags $168,400 (40-69 yrs) $100,000 $750,000 When Not to Screen? When to Stop Screening? Patients who are to frail to tolerate – bowel preparation – sedation – colonoscopy Life expectancy less than 3 to 5 years Colonoscopy within past 5 years Colorectal Cancer Prevention & Screening Colorectal cancer is a major cause of cancer related death in the US. Dietary counseling to minimize animal fat and increase fiber intake. Chemoprevention needs further study. Colonoscopy has become the dominant screening strategy. Overall screening rates remain poor.