1. Malignant disease of colon and rectum Seyed vahid hosseini Professor of surgery Professor of surgery Department of surgery Colo-rectal ward

2. Worldwide Statistics for Colorectal Cancer (CRC) Estimated 875,000 cases in 1996 Estimated 875,000 cases in 1996  8.5% of all new cases of cancer  8.5% of all new cases of cancer Incidence rates vary by ~20-fold Incidence rates vary by ~20-fold  highest in North America, Western Europe,  highest in North America, Western Europe, Australia, New Zealand, Japan Australia, New Zealand, Japan  lowest in India, Northern Africa  lowest in India, Northern Africa Estimated deaths for 1998: 556,000 Estimated deaths for 1998: 556,000

3. Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000

4. Colorectal Cancer Statistics in the US Second overall leading cause of cancer- related deaths in the USSecond overall leading cause of cancer- related deaths in the US Estimated 130,000 new cases and 56,300 deaths in the year 2000Estimated 130,000 new cases and 56,300 deaths in the year 2000 Declining trends between 1990 and 1996Declining trends between 1990 and 1996  Incidence reate: ~2.1% per year  Mortality rates: ~1.7% per year

5. Average Annual Age-Specific US Incidence and Mortality Rates of CRC, 1992-1996

7. Risk Factors for Colorectal Cancer (CRC) Aging Aging Personal history of CRC or adenomas Personal history of CRC or adenomas High-fat, low-fiber diet High-fat, low-fiber diet Inflammatory bowel disease Inflammatory bowel disease Family history of CRC Family history of CRC Hereditary colon cancer syndromes Hereditary colon cancer syndromes

8. Risk of Colorectal Cancer (CRC) 020406080100 General population Personal history of colorectal neoplasia Inflammatory bowel disease HNPCC mutation FAP 5% 15%– 20% 15%–40% 70%–80% >95% Lifetime risk (%)

9. Familial Risk for Colorectal Cancer Approximat e lifetime CRC risk (%) Affected family members None One 1° One 1° and two 2° One 1° age <45 Two 1° HNPCC mutation 2% 6% 8% 10% 17% 70% Aarnio M et al. Int J Cancer 64:430, 1995 Houlston RS et al. Br Med J 301:366, 1990 St John DJ et al. Ann Intern Med 118:785, 1993

10. Causes of Hereditary Susceptibility to CRC Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996 Sporadic (65 %– 85%) Familial (10 %– 30%) Hereditary nonpolyposis colorectal cancer (HNPCC) (5%) Familial adenomatous polyposis (FAP) (1%) Rare CRC syndromes (<0.1%)

11. Clinical Features of FAP Estimated penetrance for adenomas >90% Estimated penetrance for adenomas >90% Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other) Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other) CHRPE may be present CHRPE may be present Untreated polyposis leads to 100% risk of cancer Untreated polyposis leads to 100% risk of cancer

12. Genetics of FAP Autosomal dominant inheritance Autosomal dominant inheritance Caused by mutations in APC tumor suppressor gene on chromosome 5q Caused by mutations in APC tumor suppressor gene on chromosome 5q Up to 30% of patients have de novo germline mutations Up to 30% of patients have de novo germline mutations Most families have unique mutations Most families have unique mutations Most mutations are protein truncating Most mutations are protein truncating Genotype/phenotype relationships emerging Genotype/phenotype relationships emerging

13. Attenuated FAP l Later onset (CRC ~age 50) l Few colonic adenomas l Not associated with CHRPE l UGI lesions l Associated with mutations at 5 ' and 3 ' ends of APC gene

14. Indications for APC Gene Testing Molecular diagnosis of FAP in patients who present with: Molecular diagnosis of FAP in patients who present with: – polyposis (>100 adenomas) – attenuated FAP Predictive testing for FAP in blood relatives of persons with FAP or known APC mutations Predictive testing for FAP in blood relatives of persons with FAP or known APC mutations Giardiello FM et al. N Engl J Med, 336:823, 1997

15. Clinical Features of HNPCC Early but variable age at CRC diagnosis (~45 years) Early but variable age at CRC diagnosis (~45 years) Tumor site in proximal colon predominates Tumor site in proximal colon predominates Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors

16. Amsterdam Criteria l 3 or more relatives with verified CRC in family l One case a first- relative of the other two l One case a first-degree relative of the other two l Two or more generations l One CRC by age 50 l FAP excluded Vasen HFA et al. Dis Colon Rect 34:424, 1991 Failure to meet these criteria does not exclude HNPCC

17. Cancer Risks in HNPCC Aarnio M et al. Int J Cancer 64:430, 1995 % with cancer 100 80 60 40 20 0 204060800 Age (years) Colorectal 78% Endometrial 43% Stomach 19% Biliary tract 18% Urinary tract 10% Ovarian 9%

18. Microsatellite Instability (MSI) 10%–15% of sporadic tumors have MSI 10%–15% of sporadic tumors have MSI 95% of HNPCC tumors have MSI at multiple loci 95% of HNPCC tumors have MSI at multiple loci Routine MSI assays soon available Routine MSI assays soon available Electrophoresis gel Normal MSI tumor

19. Adenomatous polyp Can take 5-10 years for polyp to develop Up to 10% of polyps develop into cancer Size and histology are risk factors for polyp to cancer progression

20. Summary Risk factors for colon cancer l Inherited l Acquired (sporadic)-adenomatous polyp, IBD Genetic basis for colon cancer l Inherited (FAP, HNPCC, to be defined) l Sporadic polyp-different pathways Preclinical models for colon cancer

21. Summary (continued) Applications of chemoprevention initially in animal models and inherited forms of colon cancer, and then to general population Determine efficacy of chemoprevention with surrogate markers

23. Learning Objectives Discuss current recommendations regarding colon cancer screening and their evidence base. Discuss current recommendations regarding colon cancer screening and their evidence base. Discuss the initial management and work-up of a patient with a biopsy showing colon cancer. Discuss the initial management and work-up of a patient with a biopsy showing colon cancer. Discuss treatment options and follow-up for both advanced and local disease. Discuss treatment options and follow-up for both advanced and local disease.

24. So you want the answers? Colonoscopy liberally: Sx, anemia, over 50; (or over 40 if positive FH) Colonoscopy liberally: Sx, anemia, over 50; (or over 40 if positive FH) If they have cancer refer to a surgeon and an oncologist. If they have cancer refer to a surgeon and an oncologist. Do what they suggest you do? Do what they suggest you do?

25. Can we go home now ?

26. General 2002: 148,000 new cases 2002: 148,000 new cases –107,000 colonic, 41,000 rectal. –57,000 death Mainly (90%) adenocarcinomas. Mainly (90%) adenocarcinomas. 90% in people over 50 years 90% in people over 50 years

27. Risk factors for colon ca 75 to 80% of colon cancer is in people with no risk factors (“sporadic”) 75 to 80% of colon cancer is in people with no risk factors (“sporadic”) Intermediate risk: personal history of colorectal polyps or FH of first degree relative w/ colon cancer or adenomatous polyps. Intermediate risk: personal history of colorectal polyps or FH of first degree relative w/ colon cancer or adenomatous polyps. High-risk: Familial hereditary cancer syndromes (e.g. Familial adenomatous polyposis, Heredity nonpolyposis colorectal cancer) or inflammatory bowel disease. High-risk: Familial hereditary cancer syndromes (e.g. Familial adenomatous polyposis, Heredity nonpolyposis colorectal cancer) or inflammatory bowel disease.

28. How do you “prevent” colon ca?

29. Prevention Fecal Occult Blood testing Fecal Occult Blood testing Aspirin Aspirin NSAID’s reduce adenomas in patients w/ high risk familial syndromes NSAID’s reduce adenomas in patients w/ high risk familial syndromes Calcium: 1200 mg/d prevents recurrent adenomas in patients w/ adenoma hx (RCT) Calcium: 1200 mg/d prevents recurrent adenomas in patients w/ adenoma hx (RCT) No evidence for benefit from high-fiber diets. No evidence for benefit from high-fiber diets.

30. People w/ symptoms All patients (except menstruating women) with iron-deficiency anemia are candidates for colonoscopy. Look for a microcytic anemia and a low Ferritin. All patients (except menstruating women) with iron-deficiency anemia are candidates for colonoscopy. Look for a microcytic anemia and a low Ferritin. Symptoms of colon cancer include: Symptoms of colon cancer include: –new abdominal pain/abdominal symptoms –change in bowel habits, –blood in the stool –Weight loss –Anemia sx: fatigue

31. What are the screening modalities?

32. Screening Modalities Guaic-cards Guaic-cards Sigmoidoscopy Sigmoidoscopy Colonoscopy Colonoscopy Double-contrast barium enema Double-contrast barium enema Virtual colonoscopy using CT/MRI Virtual colonoscopy using CT/MRI DNA stool tests DNA stool tests

33. FOBT 3 consecutive stool samples. Rehydration increases sensitivity, decreases specificity. Pts should follow special diet. 3 consecutive stool samples. Rehydration increases sensitivity, decreases specificity. Pts should follow special diet. 1993 Minnesota RCT showed that “about a 1000 people would need to be screened annually over 10 years to prevent one death from colorectal cancer.” 38% will end up getting colonoscoped over 13 yrs. 1993 Minnesota RCT showed that “about a 1000 people would need to be screened annually over 10 years to prevent one death from colorectal cancer.” 38% will end up getting colonoscoped over 13 yrs. Am Fam Physician 2002;66:297-302 Am Fam Physician 2002;66:297-302 No evidence for benefit from a sample collected during PE. No evidence for benefit from a sample collected during PE.

34. Double contrast BE Winawer et. al. compared DCBE w/ colonoscopy in patients w/ a history of adenoma. Compared to colonoscopy, DCBE has a sensitivity of: Winawer et. al. compared DCBE w/ colonoscopy in patients w/ a history of adenoma. Compared to colonoscopy, DCBE has a sensitivity of: –32% for adenomas less than ½ cm –53% for adenomas between 0.6 and 1 cm –48% for adenomas over 1 cm. Specificity was 85% (i.e. 15% false pos) Specificity was 85% (i.e. 15% false pos) N Engl J Med 2000:342:1766-72. N Engl J Med 2000:342:1766-72.

35. Sigmoidoscopy Images about ½ of the colon & requires no anesthesia. Images about ½ of the colon & requires no anesthesia. Obviously less sensitive than colonoscopy, but perforation rate is 1/10,000 as compared with 2/1000 with the colonoscope. Obviously less sensitive than colonoscopy, but perforation rate is 1/10,000 as compared with 2/1000 with the colonoscope. Typically polyps are not biopsied so that about ¼ of pts will need a colonoscopy. Typically polyps are not biopsied so that about ¼ of pts will need a colonoscopy.

36. Evidence Basis FOBT: 3 large RCT’s FOBT: 3 large RCT’s DCBE: not even controlled trials DCBE: not even controlled trials Flex sig: controlled studies Flex sig: controlled studies Colonoscopy: “indirect evidence” from the FOBT & flex sig trials. Colonoscopy: “indirect evidence” from the FOBT & flex sig trials. JAMA 2003:289:1288-1296 JAMA 2003:289:1288-1296

37. Surgery Resect tumor, mesentery and regional mesentery (best 12 lymph nodes). Resect tumor, mesentery and regional mesentery (best 12 lymph nodes). Thoroughly explore abdomen for metastatic disease. Thoroughly explore abdomen for metastatic disease. There does not seem to be good evidence concerning primary vs secondary closure of the colon. There does not seem to be good evidence concerning primary vs secondary closure of the colon.

38. Surgery Resect tumor, mesentery and regional mesentery (best 12 lymph nodes). Resect tumor, mesentery and regional mesentery (best 12 lymph nodes). Thoroughly explore abdomen for metastatic disease. Thoroughly explore abdomen for metastatic disease. There does not seem to be good evidence concerning primary vs secondary closure of the colon. There does not seem to be good evidence concerning primary vs secondary closure of the colon.

39. Chemotherapy No demonstrated benefit for patients w/ stage I or II disease. No demonstrated benefit for patients w/ stage I or II disease. Stage III: 5-FU and leucovorin; typically 5 days every 4 weeks for six cycles. Stage III: 5-FU and leucovorin; typically 5 days every 4 weeks for six cycles. Radiotherapy is used for rectal cancers. Radiotherapy is used for rectal cancers.

40. Chemotherapy No demonstrated benefit for patients w/ stage I or II disease. No demonstrated benefit for patients w/ stage I or II disease. Stage III: 5-FU and leucovorin; typically 5 days every 4 weeks for six cycles. Stage III: 5-FU and leucovorin; typically 5 days every 4 weeks for six cycles. Radiotherapy is used for rectal cancers. Radiotherapy is used for rectal cancers.

41. Metastatic disease Resection of up to 3 liver lesions improves survival. Resection of up to 3 liver lesions improves survival. Mainstay of therapy is usually chemotherapy: 5-FU +/- leucovorin. Mainstay of therapy is usually chemotherapy: 5-FU +/- leucovorin. Newer drugs include irinotetin. Newer drugs include irinotetin.

42. Chemotherapeutic agents: older 5-FU: 5-FU: –Pyrimidine antagonist; interferes w/ thymidlyate synthesis –Mucositis, alopecia, myelosuppression, diarrhea/vomiting. Irinotecan (Camptosar): Irinotecan (Camptosar): –Inhibits topoisomerase I which is needed for DNA synthesis. –Diarrhea, often serious, is major side effect.

43. Newer agents Oxaliplatin (Eloxatin): Oxaliplatin (Eloxatin): –inhibits DNA sythesis by causing cross- linkages. –Significant neurotoxicity. –May show promise for both initial and rescue therapy.

44. Newer agents Cetuximab (Erbitux): Cetuximab (Erbitux): –Monoclonal Antibody to EGFR (epithelial growth factor receptor) –Most common side effect: acne-like rash Bevacizumab (Avastin) Bevacizumab (Avastin) –Monoclonal ab to Vascular endothelial growth factor –2% risk of GI bleed. –Can prolong survival

45. Recurrence Usually within 3 to 5 years of surgery. Usually within 3 to 5 years of surgery. Typically in liver, site of original tumor, abdomen & lung. Typically in liver, site of original tumor, abdomen & lung. Evidence on surveillance strategies not great. Evidence on surveillance strategies not great. Meta-analysis found that “intensive surveillance strategies” reduced RR of death by 20% (absolute risk reduction 7%). Meta-analysis found that “intensive surveillance strategies” reduced RR of death by 20% (absolute risk reduction 7%). –NEJM 2004:350:2375-82

46. Surveillance strategies History/PE/routine lab tests: Risk of recurrence greatest in those w/FH & those diagnosed at age 50 or younger. History/PE/routine lab tests: Risk of recurrence greatest in those w/FH & those diagnosed at age 50 or younger. Chest X-ray Chest X-ray CEA CEA CT abdomen (or) US of the liver CT abdomen (or) US of the liver Colonoscopy currently preferred method Colonoscopy currently preferred method

47. How often colonoscopy? ESMO: Colonoscopy q5 yrs. ESMO: Colonoscopy q5 yrs. NCCN: 1 yr after primary (6 mo if obstructing); q1yr if abnormal, q3yr if neg. NCCN: 1 yr after primary (6 mo if obstructing); q1yr if abnormal, q3yr if neg. ASCO: Colonoscopy q 3-5 yrs. ASCO: Colonoscopy q 3-5 yrs. Figueroa: Yearly if polyps or high risk, q 3- 5 yrs if normal. Figueroa: Yearly if polyps or high risk, q 3- 5 yrs if normal. Berman: q 3-5 yrs. Berman: q 3-5 yrs. –NEJM 2004:350:2375-82

48. Have a nice weekend!