1Colon & Rectal Cancers Imran Ahmad, MD., Clinical Assistant Professor. Medical Oncology,Saskatoon Cancer Centre.mmmm
2Faculty DeclarationWill discuss an unapproved/investigative use of a commercial product/deviceI have/had a financial arrangement or affiliation with one or more organizationsResearch Support – Hoffman La-Roche
3Colon & rectal cancers Objectives: - Colon and rectal ca statistics in Canada.- Prevention and screening.- Medical management of localized and advanced stage cancer.
4Colon & rectal cancers Statistics: - An estimated 153,000 new cases & 70,000 deaths from cancer will occur in 2006 in Canada1.- An estimated 20,000 new cases & 8,500 deaths from colorectal cancer will occur in 2006 in Canada1.1Canadian cancer statistics, 2006.
5Percentage Distribution of Estimated New Cases for Selected Cancer Sites, Males, Canada, 2006.
6Percentage Distribution of Estimated Deaths for Selected Cancer Sites, Males, Canada, 2006
7Percentage Distribution of Estimated New Cases for Selected Cancer Sites, Females, Canada, 2006
8Percentage Distribution of Estimated Deaths for Selected Cancer Sites, Females, Canada, 2006
9Age-Standardized Incidence Rates (ASIR) for Selected Cancer Sites, Males, Canada,
10Age-Standardized Mortality Rates (ASMR) for Selected Cancer Sites, Males, Canada,
11Age-Standardized Incidence Rates (ASIR) for Selected Cancer Sites, Females, Canada,
12Age-Standardized Mortality Rates (ASMR) for Selected Cancer Sites, Females, Canada,
13Selected Causes of Potential Years of Life Lost (PYLL), Canada, 2002
14Actual Data for New Cases for the Most Common Cancer Sites by Sex And Geographic Region, Most Recent Year1, Canadafor 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
16Colon & rectal cancers Risk factors: (I) Sporadic (70%): - Age: Risk increases significantly b/w ages of 40 and 50, & in each succeeding decade thereafter1.- Lifetime incidence is about 5%.1Eddy, DM et al. Ann Intern Med 1990.
19Colon & 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 51.1Burt, RW et al. Ann Rev Med 1995.
21Colon & rectal cancers (II) Risk factors, inherited (5-10%): (a) Germ line mutations.(2) Non Polyposis syndromes- Hereditary nonpolyposis CRC.- Autosomal dominant.- More common than FAP1.1Lynch, HT et al. Gastroenterology 1993.
22Colon & rectal cancers (III) Risk factors, familial (20-25%): - Affected pts have family history, but pattern is different from inherited one.- Having an affected 10 relative increases the risk 1.7 fold.- Genetic abnormalities:? Mutated APC gene, ? loss of DNA, ?mismatch repair genes.
25Colon & rectal cancers Protective factors: - Diet high in fruits and vegetables.1(? Fiber, antioxidants, FA, Selenium)- ASA / NSAID’S2.- HMG-CoA reductase inhibitors3.1Kim et al. Nutr Rev 1996.2Giovannucci et al. NEJM 19993Sacks et al. NEJM 1996.
26Colon & 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?
27Colon & rectal cancers Screening: “Canadian Association of Gastroenterology &Canadian Digestive Foundation. Guidelines on Colon Ca Screening ”- Begin screening at age 40 if;One 10 relative >60 yrs has CRC or AP, or > one 20 relative has CRC or AP.Otherwise begin screening at age 50.
28Colon & rectal cancers Choices of screening methods include1: - 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”1Leddin et al. Can J Gastroenterol 2004.
29Colon & rectal cancersCRC Screening: Practices & opinions of primary care physicians1.< 42% of physicians were familiar with guidelines.Only 35.6% of physicians offered screening to at least 75% of their average risk pts.1McGregor et al. Preventive Medicine 2004.
30Colorectal 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)
31Colon & 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%)1Steinberg et al. Cancer 1986.
32Colon & rectal cancers Diagnosis: * Presentation of metastatic disease:% of pts have metastatic disease on presentation.- Common sites are LN, liver, lungs and peritoneum.
33Mesenteric Lymphadenopathy in a pt with colon ca
36Colon & 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?
39Colon & rectal cancers Stages of disease at presentation: “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%.
40Colon & rectal cancers Pre op staging: - Essential workup: H & P, CT scan of abd & pelvis.Chest xray, Serum CEA.- Other testsLFT’s, PET scan, EUS.
42Colon & rectal cancers Other prognostic features: - Lymphovascular invasion.- Pre op CEA Level.- Presence of microsatellite instability & loss of the Deleted in Colon Cancer (DCC) gene.
43Colon & rectal cancers Adjuvant therapy for colon cancer: * Monotherapy. 5 Fluorouracil. (no improvement in 5 yr survival)1* Combination chemo (NSABP C-01 trial)2.pts.- Arm A: Surgery, Arm B: BCG, Arm C: MOF- Result: Significant improvement in 5 yr OS with MOF.1Buyse et al, JAMA Wolmark et al, JNCI 1988
44Colon & 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?
45Colon & rectal cancers Adjuvant therapy for colon cancer: (NCCTG trial)1- 5 FU & levamisole vs surgery alone.- 40 % reduction in risk of recurrence.- OS benefit only in lymph nodes positive disease.1Laurie et al; JCO 1989.
46Colon & rectal cancers Adjuvant therapy for colon cancer: * Trials using combination of 5FU & leucovorin.(NSABP C-03, IMPACT report1, NCCTG trial2)- 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.1Impact investigators; Lancet O’Connell et al; JCO 1997
47Colon & rectal cancers Adjuvant therapy for colon cancer: 1990 NIH consensus conference1,“Adjuvant 5 FU containing chemotherapy is the standard of care for resected node positive (stage III) colon cancer”.1NIH consensus conf; JAMA 1990.
48Colon & rectal cancers New developments in adjuvant therapy: Oxaliplatin containing regimens.(MOSAIC trial)1pts.- 5FU and Leucovorin +/- Oxaliplatin.- 3 yr DFS 78% vs 73 % (p< 0.05).- OS was similar.1Andre T et al. NEJM 2004.
49Colon & rectal cancers New developments in adjuvant therapy: Use of oral Capecitabine(X-ACT study)1pts.- 5FU and LV vs oral Capecitabine- Capecitabine was at least as effective as 5FU and LV, but better tolerable.1Scheithauer W et al. Ann Oncol 2003.
50Colon & rectal cancersCurrent options for adjuvant therapy for colon ca:Oxaliplatin based regimen.- Oral capecitabine.
51Colon & rectal cancersAdjuvant therapy for Stage II (Duke B) colon cancer:“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.
53Colon & rectal cancers Adjuvant therapy for rectal ca: Pattern of relapse (local)1:- T1-2: <10%.- T3N0: %- T3-4,N1-2: 45-65%.1Willett et al. Cancer 1992.
54Colon & rectal cancers Adjuvant therapy for rectal ca: * Post op radiation therapy1:- Better local control- no survival benefit1GITSG. NEJM1985.
55Colon & rectal cancers Adjuvant therapy for rectal ca: Post op chemo and radiation(GITSG TRIAL)1Pts.- Obs vs chemo vs xrt vs xrt & chemo.- Significant lower local recurrence.- Improvement in OS.1NEJM 1985.
56Colon & rectal cancers Adjuvant therapy for rectal ca: Our Practice at SCC5FU bolus→5FU cont inf & xrt→ 5FU bolus(2 mo) (6 wks) (2 mo)
57Colon & rectal cancers Pre op vs post op chemo+xrt for rectal ca:1 Pts: T3, T4 or Node +, (n=823)Pre op Post op5 yr OS: % % p=0.80Local relapse: 6% % p=0.006Toxicity: % % p=0.0011Sauer et al; NEJM, Oct 2004.
58Colon & rectal cancers Pre op vs post op chemo+xrt for rectal ca: Critiques:Primary end point (OS) was not statistically different.Similar rates of sphincter preservation.Possibility of over treating early stage tumors.EUS neither perfectly accurate nor universally available.
61Colon & rectal cancers Management of metastatic CRC: * Surgical resections:- 5 yr RFS ranges from 24-58%1.- Only potentially curative option for isolated liver mets.- <10% of pts are surgical candidates.1Fong et al. Ann Surg 1999.
62Colon & rectal cancers Management of metastatic CRC: Systemic chemotherapy.(Meta-analysis of seven randomized trials1)Palliative chemo vs BSC- N= 866Median 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 reported21Simmonds, PC et al. BMJ 2000.2H. Hurwitz et al. NEJM 2004.
63Colon & rectal cancers Management of metastatic CRC: Infusional vs bolus 5 FU meta- analysis1- RR 22% vs 14%- Median OS 12 vs 11mo- Different Toxicity pattern1Meta-analysis. JCO 1998.
64Colon & rectal cancers Management of metastatic CRC: *Combination of 5 FU & LV with- Irinotecan- Oxaliplatin- Capecitabine- Targeted therapies
65Colon & rectal cancers Management of metastatic CRC: 5 FU + LV+ Irinotecan/Oxaliplatin1, vs 5 FU + LVRR % vs %TTP mo vs moMedian OS 17.4 mo vs mo1Douillard et al. Lancet Saltz et al. NEJM 2000.
66Colon & 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 study1 RR 9% in chemo refractory pts.- With or without chemotherapies (Trials open).1Saltz et al. JCO 2004.
67Colon & 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 success1.- Further trials underway.1Kabbinavar et al. JCO 2003.
68Colon & rectal cancers Conclusions: Colorectal ca is the second common cause of ca deaths in males and third common cause of ca deaths in females.Risk increases significantly b/w ages of 40 and 50, & in each succeeding decade thereafter.
69Colon & 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.
70Colon & rectal cancers Conclusions: 5. Treatment of metastatic colon and rectal cancer provides good palliation with some progression free survival.