Title: Colon
1Colon Rectal Cancers
- Imran Ahmad, MD.,
- Clinical Assistant Professor.
- Medical Oncology,
- Saskatoon Cancer Centre.
2Faculty 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
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, 1977-2006
10Age-Standardized Mortality Rates (ASMR) for
Selected Cancer Sites, Males, Canada, 1977-2006
11Age-Standardized Incidence Rates (ASIR) for
Selected Cancer Sites, Females, Canada, 1977-2006
12Age-Standardized Mortality Rates (ASMR) for
Selected Cancer Sites, Females, Canada, 1977-2006
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, Canada
1 2001 for Canada, Quebec 2002 for Ontario
2003 for Newfoundland, Prince Edward Island, Nova
Scotia, New Brunswick, Manitoba, Saskatchewan,
Alberta, British Columbia 199-2003 average for
Yukon, Northwest Territories, Nunavut
15Canadian Cancer Stats 2004
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.
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18Colon rectal cancers
- Risk factors (Sporadic)
- - Inflammatory bowel disease (Pancolitis ,5-15
fold increased risk )1 - - Alcohol
- - Diabetes mellitus
- - Cigarette smoking.
- 1Ekbom,A et al. NEJM 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.
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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.
23 Adenoma carcinoma
sequence
24 Genetic model of CRC carcinogenesis
25Colon rectal cancers
- Protective factors
- - Diet high in fruits and vegetables.1
- (? Fiber, antioxidants, FA, Selenium)
- - ASA / NSAIDS2.
- - HMG-CoA reductase inhibitors3.
- 1Kim et al. Nutr Rev 1996.
- 2Giovannucci et al. NEJM 1999
- 3Sacks 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. 2004. - - Begin screening at age 40 if
- One 10 relative gt60 yrs has CRC or AP, or gt
one 20 relative has CRC or AP. - Otherwise begin screening at age 50.
- www.cag-acg.org/www.screencolons.ca
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 cancers
- CRC Screening Practices opinions of primary
care physicians1. - lt 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
- - 15-20 of pts have metastatic disease on
presentation. - - Common sites are LN, liver, lungs and
peritoneum.
33Mesenteric Lymphadenopathy in a pt with colon ca
34 Liver mets in a pt with colon cancer
35Colon rectal cancers
- Diagnostic procedures
- - Colonoscopy.
- - Double contrast barium enema.
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?
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39Colon rectal cancers
- Stages of disease at presentation
- Dukes 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 tests
- LFTs, PET scan, EUS.
41Five yr survival rates for rectal cancer
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.
- - 1166 pts.
- - Arm A Surgery, Arm B BCG, Arm C MOF
- - Result Significant improvement in 5 yr OS with
MOF. - 1Buyse et al, JAMA 1988. 2Wolmark 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 1995.
2OConnell 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)1
- - 2246 pts.
- - 5FU and Leucovorin /- Oxaliplatin.
- - 3 yr DFS 78 vs 73 (plt 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)1
- - 1987 pts.
- - 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 cancers
- Current options for adjuvant therapy for colon
ca - Oxaliplatin based regimen.
-
- - Oral capecitabine.
51Colon rectal cancers
- Adjuvant 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
- lt6 LN in surgical specimen, T4 lesions,
perforation, poorly differentiated histology.
52 Adjuvant therapy for rectal cancer
53Colon rectal cancers
- Adjuvant therapy for rectal ca
- Pattern of relapse (local)1
- - T1-2 lt10.
- - T3N0 15-35
- - 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 benefit
- 1GITSG. NEJM1985.
-
55Colon rectal cancers
- Adjuvant therapy for rectal ca
- Post op chemo and radiation
- (GITSG TRIAL)1
- - 227 Pts.
- - 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 SCC
- 5FU bolus?5FU cont inf xrt? 5FU bolus
- (2 mo) (6 wks) (2
mo)
57Colon rectal cancers
- Pre op vs post op chemoxrt for rectal ca1
- Pts T3, T4 or Node , (n823)
- Pre op Post op
- 5 yr OS 76 74 p0.80
- Local relapse 6 13 p0.006
- Toxicity 27 40
p0.001 - 1Sauer et al NEJM, Oct 2004.
58Colon rectal cancers
- Pre op vs post op chemoxrt 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.
59Colon rectal cancers
- Management of metastatic CRC
- - Regional treatment.
- - Systemic chemotherapy.
60Colon rectal cancers
- Management of metastatic CRC
- Regional treatment.
- - Surgical resections
- - Local tumor ablation (Ethanol, RFA).
- - HIA chemo (chemoembolization)
61Colon rectal cancers
- Management of metastatic CRC
- Surgical resections
- - 5 yr RFS ranges from 24-581.
- - Only potentially curative option for isolated
liver mets. - - lt10 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 866
- 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
reported2 - 1Simmonds, 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 pattern
- 1Meta-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/Oxaliplatin1,2
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
- 1Douillard et al. Lancet 2000. 2Saltz 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.
- - 80 -90 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.
71Colon rectal cancers