1. COLORECTAL CANCER Ozlem Uysal-Sonmez, MD Yeditepe University Hospital Department of Medical Oncology

2. Anatomy of the Colon and Rectum The colon + rectum = the large intestine Colon makes upto first 150-180 cm of large intestine Rectum makes up the last 12-15cm ending at the anus

3. The Colorectum

6. Epidemiology Third most common cancer Second most common cause of cancer death Male = Female Lifetime probability of 6% (1 in 17) Very curable if detected in early stages

7. Epidemiology Males=Females Risk increases with age –Average age at diagnosis is 67-70 yrs Highest in industrialized nations: –Canada, US, N/W Europe Most cancers start as polyps - precancerous growths that develop on the inner wall of the colon and rectum

8. Most of the colon and Rectum cancers are diagnosed at: 1)Routine physical to evaluate anemia 2)Screening colonoscopy recommended for age 50 and over

9. How Does Colorectal Cancer Develop? Janne PA, Mayer RJ. N Engl J Med 2000;342:1960. 10 years

10. Etiology Polyps (adenomatous) Diet High-calorie, high-fat Western diet Inflammatory bowel disease Ulcerative collitis –Risk varies directly with extent of colonic involvement and duration of active disease –Cumulative risk: 2% at 10 years, 8% at 20 years, 18% at 30 years –Screening: Annual or semiannual colonoscopy in disease >8 years duration Crohn’s disease –Risk increased 1.5-2 folds

11. Etiology Genetic factors –Family history: depends on age of onset and number of relatives One 1st degree relative with CRC - 2 to 3 x risk Two 1st degree relative with CRC -3 to 4 x risk 1st degree relative < 50 years - 4 to 6 x risk One 2nd degree relative with CRC- 1.5 x risk One 1st degree relative with polyp - 2 x risk –Hereditary syndromes (gene changes) Familial adenomatosis poli HNPCC (Hereditary nonpoliposis colorectal cancer)

12. Etiology Smoking Other factors Personal or family history of other cancers (breast, endometrium, ovary) Exposure to asbestos (risk 1-2x)

13. Risk factors for Colorectal Cancer Sporadic/ Sporadic/ Average Risk 75% 75% Family History 15-20% HNPCC 5% FAP-1% IBD-1%

14. Risk groups for screening Average risk –Age ≥ 50 y –No inflammatoy bowel disease –No history of adenoma or colorectal cancer –Negative family history Increased risk –Personal history of Adenoma/sessile serrated polyp Inflammatoy bowel disease Colorectal cancer –Positive family history High risk syndromes –Lynch syndrome/Hereditary nonpolyposis colorectal cancer (HNPCC) –Polyposis syndromes (familial adenomatous polyposis, Peutz- Jeggers syndrome, Juvenile polyposis syndrome, hyperplastic polyposis syndrome)

15. Screening tests for colorectal cancer Average risk Starts at age 50 1. Colonoscopy every 10 years preferred if available For every 1% increase in complete colonoscopy rate, the hazard of death decreased by 3%. 2. Annual FOBT+Flexible sigmoidoscopy every 5 years Annual Fecal occult blood test (FOBT) Testing of stool for occult blood to detect colorectal cancer at an early stage Variation is observed in estimates of the sensitivity but its lower cost and increased specificity to detect right-isded colonic lesions make it a good screening test Flexible sigmoidoscopy every 5 years In contrast to FOBT, has a high sensitivity and specificity Involves the use of a 60 cm flexible sigmoidoscope Detects left sided lesions

16. Screening Average risk –Colonoscopy every 10 yrs –Annual fecal occult blood test (FOBT) + Flex sigmoidoscopy every 5 years –Double contrast barium every 5-10 yrs High-Risk –Depends on risk

17. Who is High Risk? Familial Polyposis (APC Mutation) –Sigmoidoscopy in teenage years –Colectomy HNPCC (Mismatch Repair Genes) –Colonoscopy in 20’s Family History: –Colonoscopy 10 years younger than index family case

18. Screening Strategies Colonoscopy FOBT+ Flex Sig. Virtual Colonoscopy One-Stage ScreeningTwo-Stage Screening Colonoscopy

19. Prevention Periodic sigmoidoscopy+FOB or colonoscopy Diet NSAID: Sulindac, aspirin

20. Pathology and natural history Pathology –Adenocarcinoma is most common type –Cancers of anal verge: Most often squamous cell or basaloid carcinomas Most arise from adenomatous polyps

21. Site Distribution

22. Pathology and natural history Proximal tumors –More genetically unstable –May arise through same mechanisms underlying HNPCC Distal tumors –greater genetic stability –May develop through same mechanisms underlying polyposis-associated colorectal cancer

23. Natural history Tumors spread through the walls of the intestine and into the lymphatic system Metastases to lymph nodes in 40%-70% Tumors most commonly spread to the liver because venous blood flow from the colorectal tumor is through the portal vein Most common: Liver, peritoneal cavity, lung Rectum cancers are 3 times more likely to recur locally, because most of rectum lacks serosal layer Because of venous and lymphatic drainage of rectum to inferior vena cava, rectum cancers often recur first in lung

24. Clinical Manifestations Many colorectal cancers cause no symptoms in the early stages. Goal of screening is to detect cancers in the early stages, before symptoms develop. Symptoms in the later stages include: –Change in bowel habits –Blood in stool –Fatigue –Loss of appetite –Abdominal pain –Nausea –Weight loss –Anemia.

25. Clinical Manifestations Cancer on the right side gives rise to manifestations that are different from those on the left side of the colon Left-sided lesions Rectal bleeding Alternating constipation and diarrhea Narrow, ribbonlike stools Right-sided lesions Usually asymptomatic Vague abdominal discomfort Iron deficiency anemia Occult bleeding

26. Diagnosis & Staging General evaluation –History, Physical examination with digital rectal examination –CBC, liver function tests –Chest x-ray Carcinoembryonic antigen (CEA) screening Colonoscopy or sigmoidoscopy or barium enema Imaging tests –CT scan or MRI –Ultrasound, Endorectal ultrasonography

29. Colon Polyp

30. Colon Cancer

31. Staging Stage I- Invades into muscle layer, but not into subserosa Stage II- Invades into subserosa, other organs, or associated with perforation, no nodal involvement Stage III- Lymph Node involvement Stage IV- Distant spread to other organs (liver, lungs)

32. Layers of the Colon Wall

34. Prognostic factors Stage Histological grade Clinical presentation Perforation, obstruction worse High serum CEA level prior to surgery

35. Prognosis Stage is the most powerful predictor of prognosis. Five-year relative survival by stage Stage I >90% Stage IIA 70-85% Stage IIB 55-65% Stage IIIA 45-55% Stage IIIB 35-45% Stage IIIC 25-35% Stage IV 8%

36. Treatment Treatment of colorectal cancer is one of the most rapidly changing and advancing areas in cancer research. Surgery is the mainstay of therapy Adjuvant chemotherapy –Large cancers or cancer that has spread to lymph nodes may have left behind few scattered cancer cells in the body, even though no remaining cancer is detectable. –Chemotherapy, 5-FU-based, may be recommended. –Stage III patients benefit most from chemotherapy after surgery. –Some Stage II patients may also benefit. –Usually given for 6 months. Radiation: –Has a major role in rectal cancer –Given either before surgery, or after surgery

37. Treatment Stage I-III: Goal is cure –Surgery –Adjuvant chemotehrapy: Stage III, some stage II 5-Fluorouracil based Oxaliplatin –Adjuvant radiotherapy: Rectal cancers

38. Treatment Stage IV: –Goals of therapy: palliation To improve cancer-related symptoms To control cancers by delaying further growth and spread To shrink cancers To improve survival (ie. to live longer with cancer) –Chemotherapy: not curative –Palliative surgery and radiotherapy

39. Chemotherapy 5-Fluorouracil based Chemotherapeutics: Irinotecan, oxaliplatin Targetted agents –Anti VEGF antibody: Bevacizumab –Anti-EGFR antibody: Cetuximab

40. Summary Early detection is crucial The development of new drugs and new drug combinations will continue to improve the outcome for cancer patients.