Colorectal cancer

1. Colorectal cancer R.ALShalfan,K.AlKhayal

2. Objectives: • Epidemiology, Risk Factors • Molecular Biology & Pathology 3) Diagnosis , Stages, Screening • Therapy

3. EPIDEMIOLOGY • one of the most common cancers in the world • US: 4th most common cancer (after lung, prostate, and breast cancers) • 2nd most common cause of cancer death (after lung cancer) Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al. Cancer statistics,2004. CA Cancer J Clin 2004;54:8–29.

6. Our statistics • Accounting for 11.3% of all newly diagnosed cases in year 2009. • Ranked first among male population and third among female population. • Male to female ratio of 125:100. • The median age at diagnosis was 60 years among males 56 years among females. Cancer Incidence Report Saudi Arabia 2009

7. Cancer Incidence Report Saudi Arabia 2009

8. Cancer Incidence Report Saudi Arabia 2009

9. Risk Factors • Age • Adenomas, Polyps • lifestyle, Diet, Obesity • Family History of CRC • Inflammatory Bowel Disease (IBD) • Hereditary Syndromes

10. The incidence of colon cancer rises sharply with age,beginning at age 50 years. • The incidence is slightly higher in American men than women

11. Colorectal polyps • Neoplastic (adenomas). • Nonneoplastic (hyperplastic, inflammatory, juvenile,andhamartomatous polyps). • The incidence of colorectal malignancy is two to five times higher in patients with adenomatous polyps than in those without them.

12. Modifiable Risk Factors consumption of red meat saturated fat refined carbohydrates alcohol increased risk dietary fiber vegetables fruits antioxidant vitamins calcium folate (B Vitamin) decreased risk

13. Red meat and fat intake have the most consistently direct association, and fiber intake has the most consistently inverse association with colorectal cancer. • Several mutagenic compounds in cooked meat have been identified. • The role of fiber was originally seen simply as the provision of bulk to dilute potential carcinogens and speed their transit through the colon. • Micronutrients such as folate, methionine, vitamin D, and calcium may provide protection against oxidative stress at the cellular level.

14. Alcohol Consumption, Acetaldehyde may contribute to free radical formation and proliferative growth of mucosal polyps. • Smoking,18% higher odds of developing colorectal cancers. • higher for cancers in the rectum compared with those in the colon • Risk was significant among persons who smoked more than 30 years and was dose dependent. • Exercise and Obesity, • reduce inflammation and potentially contribute to reduced free radicals • averaged more than 4 hours per week of moderate exercise demonstrate a 22% and 29% reduction in CRC incidence, respectively Marshall T, et al. A meta-analysis of the association of physical activity with reduced risk of colorectal Cancer Colorectal Dis 2005;7(3):204–213.

15. Familial cancer • familial colorectal cancer syndromes are • familial adenomatous polyposis (FAP) • hereditary nonpolyposis colon cancer(HNPCC). Bishop DT, et al. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med 1988;319(9):533–537.

16. Hereditary Colorectal Cancer • Familial adenomatous polyposis • FAP account for <1% of all colorectal cancers • Due to mutation of the adenomatosis polyposis coli (APC) gene • Numerous adenomas appear as early as childhood and virtually 100% have colorectal cancer by age 50 if untreated • Hereditary non-polyposis colorectal cancer / Lynch syndrome • More common than FAP and account for ~1-5% of all colonic adenocarcinomas • Due to a mutation in one of the mismatch repair genes • Earlier age onset (39-46) of colorectal cancer and predominantly involve the right colon • HNPCC also increases the risk of • Endometrial, ovarian, breast ca • Stomach, small bowel, hepatobiliary ca • Renal pelvis or ureter ca

17. Lynch syndrome • Lynch I • Lynch II

18. Inflammatory Bowel Disease • The duration of inflammatory bowel disease is a critical factor in predicting the likelihood of adenocarcinoma. • Cancer develops in about 3% of patients during the first 10 years after the onset of colitis and in an additional 20% during each of the next two decades. • In chronically inflamed or colitic patients, dysplasia is believed to progress from inflammation, to low-grade, to indefinite, to high-grade dysplasia.

19. Molecular Biology & Pathology • CRCs arise from a series of histopathological and molecular changes that transform normal epithelial cells • Intermediate step is the adenomatous polyp • Adenoma-Carcinoma-Sequence (Vogelstein & Kinzler) • In colon cancer, the most important genetic alteration is a mutation of the K-ras protooncogene, which is associated with poorer prognosis.

20. Pathways • The chromosomal instability (CIN) pathway • characterized by mutations of the APC, p53, and K-ras genes • 80% of tumors develop along this pathway. • The microsatellite instability (MIN) pathway • These tumors have aberrant DNA mismatch repair • is responsible for approximately 20% of carcinomas. • Better prognosis

22. Diagnostic approach • Colorectal cancer is diagnosed during the evaluation of a symptomatic patient or during screening or surveillance of asymptomatic patients. • The symptoms of colorectal cancer tend to be nonspecific. • Symptoms depend on cancer location, cancer size, and presence of metastases.

23. Symptoms associated with CRC weight loss loss of appetite night sweats fever rectal bleeding change in bowel habits obstruction abdominal pain & mass iron-deficiency anemia

24. Examination • Signs of primary cancer • Abdominal tenderness and distension – large bowel obstruction • Intra-abdominal mass • Digital rectal examination –can be reached by examining finger • Rigid sigmoidoscope • Signs of metastasis and complications • Cachexia,loss of weight ,loss of appetite • Hepatomegaly (mets) • Bone pain

25. Site

27. Investigations • Faecal occult blood • Guaiac test (Hemoccult) – based on pseudoperoxidase activity of haematin • 50% sensitivity for colorectal cancers and about 98% specificity. • Dietary restrictions – avoid red meat, melons, horse-radish, vitamin C and NSAIDs for 3 days before test • Immunochemical test (HemeSelect, Hemolex) – based on antibodies to human haemoglobins • Used for screening and NOT diagnosis • Stool DNA • PCR-analysis of sloughed mucosal cells in stool, • seeking genetic alterations associated with colorectal cancer Gastroenterologist. 1998 Mar;6(1):66-78. Fecal occult blood testing: clinical value and limitations.

28. Double contrast barium enema • Does not require sedation • More limited in detecting small lesions • (82.9% sensitivity) • All lesions need to be confirmed by colonoscopy and biopsy • Performed with sigmoidoscopy • Second line in patients who failed / cannot undergo colonoscopy. • Rectal lesions may be missed because of interference by the intrarectal occluding balloon. Gastroenterology. 1997 Jan;112(1):17-23. Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice. Rex DK, Rahmani EY, Haseman JH, Lemmel GT, Kaster S, Buckley JS.

29. Colonoscopy/sigmoidoscopy • Can visualize lesions ~ 5mm • Colonoscopy is highly sensitive at detecting large (>1 cm) colonic polyps, with a miss rate of only 6%, and is moderately sensitive at detecting (0.6 cm) polyps with a miss rate of about 27%. • Performed under sedation • The overall complication rate is 0.4% • bleeding, infection, perforation (1 in 3000), missed diagnosis, failed procedure, anaesthetic/medical risks • bowel prep, abdominal bloating/discomfort afterwards Rex DK, Cutler CS, Lemmel GT, Rahmani EY, Clark DW, Helper DJ, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997;112:24–8. SurgEndosc. 1994 Jun;8(6):672-6. Complications in endoscopy of the lower gastrointestinal tract. Therapy and prognosis.

30. CT colonography • CT colonography is not diagnostic; that is, patients with positive findings must undergo a traditional colonoscopy for biopsy or polypectomy • sensitivity and specificity as high as 92% and 94%, respectively, for patients with polyps or lesions greater than 6 mm have been reported. A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. N Engl J Med 1999;341(20):1496–1503.

31. Other Imaging • Endorectal ultrasound • Determine: depth, mesorectal lymph node involvements • No bowel prep or sedation required • Help choose between abdominoperineal resection or ultra-low anterior resection • CT and MRI – staging prior to treatment • Blood tests • FBE – anaemia • Coagulation studies – for surgery • UECr - ?take contrast. • Tumour marker CEA • Useful for monitoring progress but not specific for diagnosis

32. SCREENING • AVERAGE-RISK SCREENING • HIGH-RISK SCREENING

36. staging

37. staging Table 1 -- TNM Classification for Colorectal Cancer Staging From the American Joint Committee on Cancer TNM staging system, ed 6

38. staging

39. TREATMENT OF PRIMARY COLON CARCINOMA • The mainstay of therapy for locoregional colon and rectal carcinoma is surgery. • In colon cancer, adjuvant chemotherapy is administered to reduce the risk of recurrence.

41. Recommendation: When approaching colon resection laparoscopically, every effort should be made to localize the tumor preoperatively. Small lesions should be marked endoscopically with permanent tattoos before surgery to maximize the surgeon’s ability to identify the lesion. Surgeons should be prepared to use colonoscopy intraoperatively if lesion localization is uncertain. (++OO, strong). • Recommendation: We recommend that laparoscopic resection follow standard oncologic principles: proximal ligation of the primary arterial supply to the segment harboring the cancer, appropriate proximal and distal margins, and adequate lymphadenectomy. (++++, strong). • Recommendation: We recommend that laparoscopic resection for rectal cancer follow standard oncologic principles: Adequate distal margin, ligation at the origin of the arterial supply for the involved rectal segment, and mesorectal excision. (+++O, strong)

45. Resection • Caecum or ascending colon • Right hemicolectomy • Vessels divided – ileocaecal and right colic • Anastamosis between terminal ileum and transverse colon • Transverse colon • Close to hepatic flexure  right hemicolectomy • Mid-transverse  extended right hemicolectomy (up to descending) + omentum removed en-bloc with tumour • Splenic flexure  subtotal colectomy (up to sigmoid) • Descending colon • Left hemicolectomy • Vessels divided – inferior mesenteric, left colic, sigmoid

46. Sigmoid colon • High anterior resection • Vessels ligated – inferior mesenteric, left colic and sigmoid • Anastomoses of mid-descending colon to upper rectum • Obstructing colon carcinoma • Right and transverse colon – resection and primary anastomosis • Left sided obstruction • Hartmann’s procedure – proximal end colostomy (LIF) + oversewing distal bowel + reversal in 4-6 months • Primary anastamosis – subtotal colectomy (ileosigmoid or ileorectal anastomosis) • Intraoperative bowel prep with primary anastomosis (5% bowel leak) • Proximal diverting stoma then resection 2 weeks later • Palliative stent

47. Rectal Cancer • Options • Low anterior resection • Transanal local excision • Abdomino-perineal resection • Palliative procedure • Factors influencing choice • Level of lesion – distance from dentate line, <2 cm requires abdomino-perineal resection to obtain adequate margin • Note: only 3% of tumours spread beyond 2cm • Grade – poorly differentiated  larger margin • Patient factors – incotinence • Mesorectal node status – resect if LN mets

48. Adjuvant Chemotherapy • Stage 1 (T1N0 or T2N0): No adjuvant therapy is recommended. • Stage 2: T3N0 with MSI-H: Adjuvant therapy can be omitted. • Stage 2 colon cancer with MSS or MSI-low and with any one of poor prognostic features: Consider 6 months of adjuvant therapy with 5-FU/Leucovorin or Capecitabine. FOLFOX or CapeOx may be considered.

50. Stage 3 (T1-4,N+): 6 months of FOLFOX or CapeOx. Consider using a single agent (5-FU/Leucovorin or Capecitabine) in patients who are not candidate of Oxaliplatin-based combination therapy.