Colorectal Cancer Screening and Prevention

1. Colorectal Cancer Screening and Prevention RFUMS The Chicago Medical School 2005 David R. Rudy, MD, MPH Professor and Chairman, Family and Preventive Medicine Preventive Medicine MTD 601

2. Prevention • Primary prevention: keeping a disease process from happening (smoking cessation prevents (95% of) lung cancer • Secondary prevention: interruption of a disease process in a curable phase (Ca cervix, colon - place for screening) • Tertiary prevention: stopping or retarding a symptomatic disease (improving risk status after MI)

3. Terms of Epidemiology • Incidence - new cases over unit of time/unit of population • Prevalence - number of cases at a point in time/unit of population • Sensitivity (of a test) - proportion of cases diagnosed by a test • Specificity - proportion of population without the disease that will test negative

4. Criteria for screenability • 1. Condition has significant effect on life • 2. Significant treatment available • 3. Asymptomatic period of diagnoseability • 4. Treatment in asymptomatic phase yields result superior to delaying until symptoms appear • 5. Tests of reasonable cost- sensitivity and specificity appropriate for population risk • 6. Incidence sufficient to justify cost

5. Terms • Positive predictive value - chance of a positive test signifying disease • Negative predictive value - chance of a negative test result signifying absence of disease • None of the forgoing can be told without knowledge of prevalence of the disease

6. Colon Cancer: Causation • Combined environmental and genetic: Environmental causes include diet low in fiber and gut bile salts, higher in fat. (Harrison's Principles of Medicine; 11th Ed). Genetics to be addressed in 2. • 95% arise from adenomas; 70-90 % from adenomatous polyps (10-30 % from sessile adenomas).

7. TYPE PREVALENCE % MALIGNANT • Tubular adenoma 75% 5% • Tubulovillous 15 % 22% • Villous adenoma 10 % 40 % • Weighted chance (100 %) 10.5% • 15-30% of (US) pop. adeno- polyps/life; • Lifetime colon Ca risk 2.5-2.6% (sporadic).

8. Hyperplastic polyps Comprise up to 1/3/ of all polyps: have no malignant potential - recognized only hy histopathology

9. CRC locations: • About 1/3 of polyps arise proximal to the splenic flexure (cephalad). • (I,e,. 2/3 of polyps can be found by sigmoidoscopy • About 1/2 of colorectal carcinomas arise proximal to the splenic flexure. • (1/2 cancers found by sigmoidoscopy

10. Polyps to Carcinoma • Dwell time average 10 years, therefore five year interval between most screen methods is safe. • Odds of polyp becoming cancer in the individual case may be inferred to be about 1 in 10 within a lifetime.

11. Relative significance of Colorectal Carcinoma • Tumor Incidence Cause specific Case mortality Mort • Lung 172,570 163,510 95% M:F =55%:45% • CRC 145,290 56,290 39% • Breast 212,930 40,870 19% • Prostate 232,090 30,350 13% Jemal A, Tiwari RC, Murry T, Ward E , Samuels A, TiwariRC, Ghafoor A, Feuer EJ, Thun M: Cancer Statistics, 2005. CA: Cancer J. for Clin 2005; 55(1): 10-30

12. “BURDEN OF SUFFERING”1 • 145,290 incidence CRC/US est. for ’05; • 56,290 deaths US mortality F~M • Second leading cause of cancer death US, without sex distinction, • - albeit well below lung cancer. • Case Mortality 38.7% (Jemal A, et al: Cancer Statistics, 2005. CA: Cancer J. for Clin 2005; 55(1): 10-30

13. Case Mortality CRC 56,290 /year US mortality 2005 ÷ 145,290 incidence CRC/US = 38.7% approximate case mortality

14. Relative incidences CRC among five ethnic groups (see Table III 1B) • Ethnic group RR • Indigenous 488 1.0 • Asian/PacIsl 699 1.4 • Hispanic/Latino 731 1.5 • Whites 988 2.0 • African 1103 2.26 • Cancer Incidence and Mortality Rates by Race and Ethnicity in the US 1996-2000 (Cancer Fact and Figures 2004, American Cancer Society)

15. Relative mortality CRC among five ethnic groups (see Table III 1B) • Ethnic group RR • Asian/PacIslanders 27 1.0 • Hispanic/Latino 29 1.1 • Indigenous 30 1.1 • African 40 1.5 • Whites 42 1.6 • Cancer Incidence and Mortality Rates by Race and Ethnicity in the US 1996-2000 (Cancer Fact and Figures 2004, American Cancer Society)

16. Burden of Suffering 2: by colon vs rectal (2002) • Colon Ca incidence: 105,500/US/yr • Colon Ca mortality: 48,100/US/yr (2002) implies ~ 45% colon Ca case mortality • Rectal Ca incidence: 42,000/US/yr • Rectal Ca mortality: 8,500/Us/yr (2002) implies ~ 21% rectal Ca case mortality (02) Cancer Statistics, 2003. CA - Cancer Journ Clin. 2003; 53(1): 5-26

17. Implications for increasing life expectancy • CRC assumes exponentially increasing incidence with age • The later the age onset of CRC the lesser the aggressiveness • Thus, CRC with age shows an increasing incidence and decreasing case mortality • But - secondary prevention (of progression of polyps) may neutralize that tendency

18. (COLORECTAL CANCER; BURDEN OF SUFFERING) • Incidence rate: /100,000 Pop./year, • 15/100,000 in 40-50 y.o., • >400/100,000 in > 80 y.o.[Frame, Paul S: J Fam Pract, 1986; 22(6): 511] • Fourth cancer in incidence, behind prostate, breast and lung (third in each sex). Third in cancer deaths each sex after lung, prostate (males) and lung, breast (females)

21. Characteristics of Colon Ca • Left > Rt lesions in men (earlier diagnosis); • Right > Lft in women (worse prognosis). • Patients > 70 more likely to present in Stages A or B. • Younger patients have more aggressive disease for a given stage

22. Characteristics of CRC, ethnicity(1) • African- and Hispano-Americans less likely to present in stages A or B. • Asians have presentation patterns similar to non-Hispanic whites. • Inflammatory bowel disease is a risk, may be considered premalignant.

23. Characteristics of CRC, ethnicity(2) • Askenazi Jews have lifetime risk of CRC equal to Caucasians w/ 1st degree relative with adenomatous polyp or CRC = three times the lifetime accumulative risk (2.5% -> 7.5%)

24. Characteristics of Colon Ca,( 3) • Presentation with hematochezia renders a better prognosis (only 19% die of disease) • After presentation with any other symptom 83% die of disease (e.g. BM change, obstruction).

25. GENETICS AND COLON CANCER (1): • Lifetime risk of CRC = 2.5%; • Tripled when have first degree relative w/ adenomatous colon polyp(s) or colon cancer - to 7.5 • Increasing life expectancy expected to increase cumulative incidence • Several specific genes identified

26. Five -10% of colon Ca occurs in definite hereditary patterns. • Adenomatous polyposis syndromes (APS) account for about 9-10% of CRC: • Hereditary “Non-polyposis” Colon Cancer (HNPCC, Lynch syndrome) - accounts for about 6%. Characterized by both pedunculated and sessile premalignant polyps,

27. Adenomatous Polyposis Syndromes • Familial Adenomatous Polyposis (FAP): 1-2 % of CRC • 100s -> 1000 CR polyps beginning early in life. All develop CRC by age 40. • Gardner’s syndrome: numerous polyps, risk of colon cancer, plus osteomas, epidermoid cysts and sesmoid tumors. • Turcot’s syndrome (assoc.. CNS tumors).

28. CLINICAL PRESENTATION, (BRIEFLY) • Hematochezia (distinct from melena): If first symptom, tends to indicate the descending colon - with better prognosis. • Change in bowel habit: e.g. alternating constipation and diarrhea. • Obstipation to clinical lower bowel obstruction.

29. COLORECTAL CANCER SURVIVAL (Dukes Stages, 5 y): • Stage A: limited to mucosa and submucosa 90% • Stage B: extends into muscularis or serosa 60-75% • Stage C: one positive node - 69% six or more positive nodes, 27% • Stage D: mets. to liver, bone, lung 5%

31. . COLORECTAL CANCER SURVIVAL(descriptive): • Overall 5 yr Survival About 55-75% (reciprocal of 39% case mortality = 61%) • With localized disease 80-90% • With regional metastases 36% • With distant metastasis 29% • With disseminated disease 5%

33. Screening Methods’ success, simulation model • Meth FOBT FS FS/OBT DCBE DCBE BE/FS Colnoscpy • q# yr 1 5 5 5 10 5 10 • DcrCases 2378 1975 3087 3394 2812 3875 3570 • DcrDths 1278 976 1556 1629 1418 1843 1690 • DcrMort53.5%40.1% 65.1% 68.1% 59.3% 77.1% 70.7% • Decr = decrease [cases, deaths (net after complications); mortality rate as percent] • * Based on expectation of 4988 cases CRC/100,000 pop cumulative from the ages of 50 through 85 yrs or death; and expectation of 2391 deaths due to CRC in this population, cumulatively (Winawer et al, Gastroenterology, Sept, 1997).

34. CRC Screening Guidelines according to AGA:Average Risk - Option 1 • Digital rectal examination/fecal occult blood (DRE/FOBT) start @ 50 years every yr (AGA): predicts 50% (or less) reduced mortality

35. CRC Screening Guidelines:Average Risk - option 2 • Flexible sigmoidoscopy every 5 years (60 cm): Predicts only 40% reduction of CRC mortality

37. CRC Screening Guidelines:Average Risk option • 3. FOBT + Flexible Sigmoidoscopy q 5 yr predicts 65% reduction CRC mortality

38. CRC Screening Guidelines:Average Risk - options (AGA) • 4. Dual Contrast BE every five yr.; Predicts 68% reduction in mortality from CRC

39. CRC Screening Guidelines:Average Risk - options (AGA) • 5. DCBE every 10 yr. Predicts 59% reduction in mortality due to CRC

40. CRC Screening Guidelines:Average Risk - options (AGA) • 6. FS + DCBE every 5 yr predicts 77% reduction in mortality due to CRC.

41. CRC Screening Guidelines:Average Risk - options (AGA) • 7. Colonoscopy every 10 yr predicts 71% reduction in mortality from CRC

42. Does CRC meet Criteria for screenability! • 1. Condition has significant effect on life (Yes) • 2. Significant Treatment available in curative phase (Yes) • 3. Asymptomatic period of diagnose-ability (Yes) • 4. Tx in the asymptomatic phase yields result superior to delaying until symptoms appear (Yes) • 5. Tests of reasonable cost- sensitivity and specificity appropriate for population risk (Yes, with some argument) • 6. Incidence sufficient to justify cost (Yes)

43. CRC Screening Guidelines:Normal Risk (ACS) • For average risk status start @ 50 years of age • or start @ 40 years q 1 yr (AGA) if 1st degree relative w/ adenomatous polyp or CRC

44. CRC Screening Guidelines:Higher Risk (ACS) • Presence of Familial Adenomatous Polyposis: • Starting @ 10 y.o., DRE + colonoscopy; if polyps present repeat in 1 year, otherwise repeat in 3 years (ACS per Jessup et al: CA Cancer J Clin 1997; 47:70-92)

45. CRC Screening Guidelines:Higher Risk (ACS) • Presence of HNPCC: • Starting in the teen years, proceed as with FAP [DRE + colonoscopy]; if polyps, repeat in 1 year, otherwise repeat in 3 years (ACS per Jessup et al: CA Cancer J Clin 1997; 47:70-92)]

46. CRC Screening Guidelines:Higher Risk (ACS) • Symptoms present: • Starting at 25 years age, same as for 50 without symptoms, average risk (DRE + FOBT + colonoscopy; if neg repeat in 3-5 years)

47. Clinical terms used in CRC • Carcinoembryonic antigen (CEA): tumor marker - sensitive but not specific. Best used for follow-up after definitive surgery • Synchronous: (as in polyps or cancers) existing at the same time as index cancer in a single patient • Metachronous: cancers or polyps occurring subsequent to the index cancer or polyp

48. Pre-operative Workup : Colonoscopy • Synchronous cancer in 2%-7.2% • Synchronous polyps: 12%-62% • Most surgeons favor colonoscopy > DCBE

49. Pre-op carcinoembryonic antigen (CEA) • Described by Gold and Freedman 1965 • Usually returns to normal within one month after (successful) excision • If post-op fall to normal is f/b persistent steady rise signals recurrent cancer in 95%

50. Primary Prevention CRC: • ASPIRIN and other NSAIDs: 662,424 adults tracked 1982 through 1988 for occurrence of CRC and whether or using aspirin (observational study): RR for CRC in those who used ASA > 15 times/month was 0.60 in men, 0.58 in women (Thun MJ et al: N Engl J Med 1991; 325:1593-96)