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Colon & Rectal Cancers Imran Ahmad, MD., Clinical Assistant Professor. Medical Oncology, Saskatoon Cancer Centre.

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Presentation on theme: "Colon & Rectal Cancers Imran Ahmad, MD., Clinical Assistant Professor. Medical Oncology, Saskatoon Cancer Centre."— Presentation transcript:

1 Colon & Rectal Cancers Imran Ahmad, MD., Clinical Assistant Professor. Medical Oncology, Saskatoon Cancer Centre.

2 Faculty Declaration  Will discuss an unapproved/investigative use of a commercial product/device  I have/had a financial arrangement or affiliation with one or more organizations Research Support – Hoffman La-Roche

3 Colon & rectal cancers Objectives: - Colon and rectal ca statistics in Canada. - Prevention and screening. - Medical management of localized and advanced stage cancer.

4 Colon & rectal cancers Statistics: - An estimated 153,000 new cases & 70,000 deaths from cancer will occur in 2006 in Canada 1. - An estimated 20,000 new cases & 8,500 deaths from colorectal cancer will occur in 2006 in Canada 1. 1 Canadian cancer statistics, Canadian cancer statistics, 2006.

5 Percentage Distribution of Estimated New Cases for Selected Cancer Sites, Males, Canada, 2006.

6 Percentage Distribution of Estimated Deaths for Selected Cancer Sites, Males, Canada, 2006

7 Percentage Distribution of Estimated New Cases for Selected Cancer Sites, Females, Canada, 2006

8 Percentage Distribution of Estimated Deaths for Selected Cancer Sites, Females, Canada, 2006

9 Age-Standardized Incidence Rates (ASIR) for Selected Cancer Sites, Males, Canada,

10 Age-Standardized Mortality Rates (ASMR) for Selected Cancer Sites, Males, Canada,

11 Age-Standardized Incidence Rates (ASIR) for Selected Cancer Sites, Females, Canada,

12 Age-Standardized Mortality Rates (ASMR) for Selected Cancer Sites, Females, Canada,

13 Selected Causes of Potential Years of Life Lost (PYLL), Canada, 2002

14 Actual Data for New Cases for the Most Common Cancer Sites by Sex And Geographic Region, Most Recent Year 1, Canada for Canada, Quebec; 2002 for Ontario; 2003 for Newfoundland, Prince Edward Island, Nova Scotia, New Brunswick, Manitoba, Saskatchewan, Alberta, British Columbia; average for Yukon, Northwest Territories, Nunavut

15 Canadian Cancer Stats 2004

16 Colon & rectal cancers Risk factors: Risk factors: (I) Sporadic (70%): (I) Sporadic (70%): - Age: Risk increases significantly b/w ages of 40 and 50, & in each succeeding decade thereafter 1. - Lifetime incidence is about 5%. 1 Eddy, DM et al. Ann Intern Med 1990.

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18 Colon & rectal cancers Risk factors (Sporadic): - Inflammatory bowel disease (Pancolitis,5- 15 fold increased risk ) 1 - Alcohol - Diabetes mellitus - Cigarette smoking. 1 Ekbom,A et al. NEJM 1990.

19 Colon & rectal cancers (II) Risk factors, inherited (5-10%): (a) Germ line mutations. (1) Polyposis syndromes: - Familial adenomatous polyposis. - Less than 1% of CRC. - Germ line mutations in APC gene on ch Burt, RW et al. Ann Rev Med 1995.

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21 Colon & rectal cancers (II) Risk factors, inherited (5-10%): (a) Germ line mutations. (2) Non Polyposis syndromes - Hereditary nonpolyposis CRC. - Autosomal dominant. - More common than FAP 1. 1 Lynch, HT et al. Gastroenterology 1993.

22 Colon & rectal cancers (III) Risk factors, familial (20-25%): - Affected pts have family history, but pattern is different from inherited one. - Having an affected 1 0 relative increases the risk 1.7 fold. - Genetic abnormalities: ? Mutated APC gene, ? loss of DNA, ?mismatch repair genes. ? Mutated APC gene, ? loss of DNA, ?mismatch repair genes.

23 Adenoma carcinoma sequence

24 Genetic model of CRC carcinogenesis

25 Colon & rectal cancers Protective factors: - Diet high in fruits and vegetables. 1 (? Fiber, antioxidants, FA, Selenium) (? Fiber, antioxidants, FA, Selenium) - ASA / NSAID’S 2. - HMG-CoA reductase inhibitors 3. 1 Kim et al. Nutr Rev Giovannucci et al. NEJM Sacks et al. NEJM 1996.

26 Colon & rectal cancers  CASE #1  63 yr old asymptomatic man with no family h/o colorectal ca, presented for first annual physical exam, by family MD.  Physical exams including rectal exam was normal. Fecal occult blood testing was negative.  What should be further recommendations for colorectal cancer screening in future?

27 Colon & rectal cancers Screening: “Canadian Association of Gastroenterology &Canadian Digestive Foundation. Guidelines on Colon Ca Screening ” - Begin screening at age 40 if; One 1 0 relative >60 yrs has CRC or AP, or > one 2 0 relative has CRC or AP. One 1 0 relative >60 yrs has CRC or AP, or > one 2 0 relative has CRC or AP. - Otherwise begin screening at age

28 Colon & rectal cancers Choices of screening methods include 1 : - FOB atleast every 2 years. - Flex sig (w/wo FOB) every 5 yrs. - Double contrast BE every 5 yrs. - Colonoscopy every 10 yrs. “Screening method should be determined by its availability & after discussion b/w pt & physician” 1 Leddin et al. Can J Gastroenterol 2004.

29 Colon & rectal cancers CRC Screening: Practices & opinions of primary care physicians 1. - < 42% of physicians were familiar with guidelines. - Only 35.6% of physicians offered screening to at least 75% of their average risk pts. 1 McGregor et al. Preventive Medicine 2004.

30 Colorectal Cancer Screening: Percentage of Men and Women Aged 50 Years and Over Reporting a Screening Fecal Occult Blood Test (FOBT Within the Last 2 Years, by Province. Regions (Within SK, ON)*, 2003 * Based on selected sampling units (regions) where relevant data were collected: 7 of 11 units in Saskatchewan (63% of SK population) and 14 of 37 units in Ontario (27% of ON population; Toronto not included)

31 Colon & rectal cancers Diagnosis: *Presenting symptoms 1 (resectable cancer): - Abdominal pain (44%) - Change in bowel habit (43%) - Haematochezia or melena (40%) - Fe def anemia, w/o other GI symp (11%) - Weight loss (6%) 1 Steinberg et al. Cancer Steinberg et al. Cancer 1986.

32 Colon & rectal cancers Diagnosis: * Presentation of metastatic disease: % of pts have metastatic disease on presentation. - Common sites are LN, liver, lungs and peritoneum.

33 Mesenteric Lymphadenopathy in a pt with colon ca

34 Liver mets in a pt with colon cancer

35 Colon & rectal cancers Diagnostic procedures: - Colonoscopy. - Double contrast barium enema.

36 Colon & rectal cancers  CASE #2  65 yr old woman, with no significant medical history presented to family doctor with h/o tiredness and easy fatigue.  Blood studies showed evidence of hypochrmic microcytic anemia secondary to iron deficiency.  What inv will be needed to r/o colorectal ca as the cause of problem?

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39 Colon & rectal cancers Stages of disease at presentation: “Duke’s classification & AJCC staging” “Duke’s classification & AJCC staging” - Localized to mucosa and submucosa (Dukes A or TNM stage I) 23%. - Extending through muscle layer without LN involvement (Dukes B or TNM stage II) 31%. - LN involvement (Dukes C or TNM stage III) 26%. - Distant mets (Dukes D or TNM stage IV) 20%.

40 Colon & rectal cancers Pre op staging: - Essential workup: H & P, CT scan of abd & pelvis. H & P, CT scan of abd & pelvis. Chest xray, Serum CEA. Chest xray, Serum CEA. - Other tests LFT’s, PET scan, EUS. LFT’s, PET scan, EUS.

41 Five yr survival rates for rectal cancer

42 Colon & rectal cancers Other prognostic features: - Lymphovascular invasion. - Pre op CEA Level. - Presence of microsatellite instability & loss of the Deleted in Colon Cancer (DCC) gene.

43 Colon & rectal cancers Adjuvant therapy for colon cancer: * Monotherapy. 5 Fluorouracil. (no improvement in 5 yr survival) 1 * Combination chemo (NSABP C-01 trial ) pts. - Arm A: Surgery, Arm B: BCG, Arm C: MOF - Result: Significant improvement in 5 yr OS with MOF. 1 Buyse et al, JAMA Wolmark et al, JNCI 1988

44 Colon & rectal cancers  CASE #3:  Lady in case #2 underwent colonoscopy followed by laparotomy for cecal cancer.  She was found out to have a 5 cm mod differentiated adenocarcinoma, with one out of 11 lymph node positive.  She is 3 wks out of surgery, and asking for further recommendations?

45 Colon & rectal cancers Adjuvant therapy for colon cancer: (NCCTG trial) 1 (NCCTG trial) FU & levamisole vs surgery alone % reduction in risk of recurrence. - OS benefit only in lymph nodes positive disease. 1 Laurie et al; JCO 1989.

46 Colon & rectal cancers Adjuvant therapy for colon cancer: * Trials using combination of 5FU & leucovorin. (NSABP C-03, IMPACT report 1, NCCTG trial 2 ) (NSABP C-03, IMPACT report 1, NCCTG trial 2 ) - 5 FU & leucovorin for at least 6 mo. - Approx 20% reduction in death, 5% benefit in 3 yr OS. - Benefit limited to node positive disease. 1 Impact investigators; Lancet O’Connell et al; JCO Impact investigators; Lancet O’Connell et al; JCO 1997

47 Colon & rectal cancers Adjuvant therapy for colon cancer: 1990 NIH consensus conference 1, 1990 NIH consensus conference 1, “Adjuvant 5 FU containing chemotherapy is the standard of care for resected node positive (stage III) colon cancer”. 1 NIH consensus conf; JAMA 1990.

48 Colon & rectal cancers New developments in adjuvant therapy: Oxaliplatin containing regimens. (MOSAIC trial) 1 (MOSAIC trial) pts. - 5FU and Leucovorin +/- Oxaliplatin. - 3 yr DFS 78% vs 73 % (p< 0.05). - OS was similar. 1 Andre T et al. NEJM 2004.

49 Colon & rectal cancers New developments in adjuvant therapy: Use of oral Capecitabine Use of oral Capecitabine (X-ACT study) 1 (X-ACT study) pts. - 5FU and LV vs oral Capecitabine - Capecitabine was at least as effective as 5FU and LV, but better tolerable. 1 Scheithauer W et al. Ann Oncol Scheithauer W et al. Ann Oncol 2003.

50 Colon & rectal cancers Current options for adjuvant therapy for colon ca: - Oxaliplatin based regimen. - Oral capecitabine.

51 Colon & rectal cancers Adjuvant therapy for Stage II (Duke B) colon cancer: Adjuvant therapy for Stage II (Duke B) colon cancer: “ASCO 2004 recommendation” “ASCO 2004 recommendation” - Recommend against routine administration of chemo in stage II colon ca. - Adjuvant chemo can be considered for <6 LN in surgical specimen, T4 lesions, perforation, poorly differentiated histology. <6 LN in surgical specimen, T4 lesions, perforation, poorly differentiated histology.

52 Adjuvant therapy for rectal cancer

53 Colon & rectal cancers Adjuvant therapy for rectal ca: Pattern of relapse (local )1: Pattern of relapse (local )1: - T1-2: <10%. - T3N0: 15-35% - T3-4,N1-2: 45-65%. 1 Willett et al. Cancer 1992.

54 Adjuvant therapy for rectal ca: * Post op radiation therapy 1 : - Better local control - Better local control - no survival benefit - no survival benefit 1 GITSG. NEJM1985. Colon & rectal cancers

55 Adjuvant therapy for rectal ca: Post op chemo and radiation Post op chemo and radiation (GITSG TRIAL) 1 (GITSG TRIAL) Pts. - Obs vs chemo vs xrt vs xrt & chemo. - Significant lower local recurrence. - Improvement in OS. 1 NEJM NEJM 1985.

56 Colon & rectal cancers Adjuvant therapy for rectal ca: Our Practice at SCC 5FU bolus→5FU cont inf & xrt→ 5FU bolus (2 mo) (6 wks) (2 mo)

57 Colon & rectal cancers Pre op vs post op chemo+xrt for rectal ca: 1 Pts: T3, T4 or Node +, (n=823) Pre op Post op Pre op Post op 5 yr OS: 76% 74% p=0.80 Local relapse: 6% 13% p=0.006 Toxicity: 27% 40% p= Sauer et al; NEJM, Oct Sauer et al; NEJM, Oct 2004.

58 Colon & rectal cancers Pre op vs post op chemo+xrt for rectal ca: Critiques: Primary end point (OS) was not statistically different. Primary end point (OS) was not statistically different. Similar rates of sphincter preservation. Similar rates of sphincter preservation. Possibility of over treating early stage tumors. Possibility of over treating early stage tumors. EUS neither perfectly accurate nor universally available. EUS neither perfectly accurate nor universally available.

59 Colon & rectal cancers Management of metastatic CRC: - Regional treatment. - Systemic chemotherapy.

60 Colon & rectal cancers Management of metastatic CRC : * Regional treatment. - Surgical resections - Local tumor ablation (Ethanol, RFA). - HIA chemo (chemoembolization)

61 Colon & rectal cancers Management of metastatic CRC: * Surgical resections: * Surgical resections: - 5 yr RFS ranges from %1. - Only potentially curative option for isolated liver mets. - <10% of pts are surgical candidates. 1 Fong et al. Ann Surg 1999.

62 Colon & rectal cancers Management of metastatic CRC: Systemic chemotherapy. Systemic chemotherapy. (Meta-analysis of seven randomized trials 1 ) (Meta-analysis of seven randomized trials 1 ) Palliative chemo vs BSC Palliative chemo vs BSC - N= Median OS; 3.7 mo longer for palliative chemo. - With use of newer drugs (like avastin) along with chemo median overall surv of 20 months has been reported 2 1 Simmonds, PC et al. BMJ H. Hurwitz et al. NEJM 2004.

63 Colon & rectal cancers Management of metastatic CRC: Infusional vs bolus 5 FU meta- analysis 1 - RR 22% vs 14% - Median OS 12 vs 11mo - Different Toxicity pattern 1 Meta-analysis. JCO 1998.

64 Colon & rectal cancers Management of metastatic CRC : *Combination of 5 FU & LV with - Irinotecan - Irinotecan - Oxaliplatin - Oxaliplatin - Capecitabine - Capecitabine - Targeted therapies - Targeted therapies

65 Colon & rectal cancers Management of metastatic CRC: 5 FU + LV+ Irinotecan/Oxaliplatin 1,2 vs 5 FU + LV 5 FU + LV+ Irinotecan/Oxaliplatin 1,2 vs 5 FU + LV RR 40-50% vs 20-30% TTP 6.7 mo vs 4.4 mo Median OS 17.4 mo vs 14.1mo 1 Douillard et al. Lancet Saltz et al. NEJM 2000.

66 Colon & rectal cancers Management of metastatic CRC: * Targeted therapies: Cetuximab (Erbitux) - Human/mouse chimeric monoclonal antibody. - Binds to EGFR expressed on cells % of CRC expresses EGFR. - In an open label study 1 RR 9% in chemo refractory pts. - With or without chemotherapies (Trials open). 1 Saltz et al. JCO Saltz et al. JCO 2004.

67 Colon & rectal cancers Management of metastatic CRC: *Targeted therapies: Bevacizumab (Avastin) - Anti-VEGF MoAb. - No molecular markers predict efficacy. - Studied in combination with chemo with some success 1. - Further trials underway. 1 Kabbinavar et al. JCO 2003.

68 Colon & rectal cancers Conclusions: 1. Colorectal ca is the second common cause of ca deaths in males and third common cause of ca deaths in females. 2. Risk increases significantly b/w ages of 40 and 50, & in each succeeding decade thereafter.

69 Colon & rectal cancers Conclusions: 3.Adjuvant 5 FU containing chemotherapy is the standard of care for resected node positive (stage III) colon cancer. 4. For rectal cancer chemo should be combined with XRT in adjuvant setting.

70 Colon & rectal cancers Conclusions: 5. Treatment of metastatic colon and rectal cancer provides good palliation with some progression free survival.

71 Colon & rectal cancers ………..end of beginning. ………..end of beginning.


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