Colon

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Colon Rectal Cancers

• Imran Ahmad, MD.,
• Clinical Assistant Professor.
• Medical Oncology,
• Saskatoon Cancer Centre.

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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

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Colon rectal cancers

• Objectives
• - Colon and rectal ca statistics in Canada.
• - Prevention and screening.
• - Medical management of localized and advanced
  stage cancer.

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Colon 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.

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Percentage Distribution of Estimated New Cases
for Selected Cancer Sites, Males, Canada, 2006.
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Percentage Distribution of Estimated Deaths for
Selected Cancer Sites, Males, Canada, 2006
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Percentage Distribution of Estimated New Cases for
Selected Cancer Sites, Females, Canada, 2006
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Percentage Distribution of Estimated Deaths for
Selected Cancer Sites, Females, Canada, 2006
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Age-Standardized Incidence Rates (ASIR) for
Selected Cancer Sites, Males, Canada, 1977-2006
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Age-Standardized Mortality Rates (ASMR) for
Selected Cancer Sites, Males, Canada, 1977-2006
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Age-Standardized Incidence Rates (ASIR) for
Selected Cancer Sites, Females, Canada, 1977-2006
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Age-Standardized Mortality Rates (ASMR) for
Selected Cancer Sites, Females, Canada, 1977-2006
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Selected Causes of Potential Years of Life Lost
(PYLL), Canada, 2002
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Actual 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
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Canadian Cancer Stats 2004
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Colon 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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Colon 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.

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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 51.
• 1Burt, RW et al. Ann Rev Med 1995.

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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 FAP1.
• 1Lynch, HT et al. Gastroenterology 1993.

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Colon 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.

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Adenoma carcinoma
sequence
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Genetic model of CRC carcinogenesis
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Colon 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.

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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?

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Colon 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

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Colon 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.

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Colon 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.

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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)
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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)
• 1Steinberg et al. Cancer 1986.

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Colon rectal cancers

• Diagnosis
• Presentation of metastatic disease
• - 15-20 of pts have metastatic disease on
  presentation.
• - Common sites are LN, liver, lungs and
  peritoneum.

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Mesenteric Lymphadenopathy in a pt with colon ca
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Liver mets in a pt with colon cancer
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Colon rectal cancers

• Diagnostic procedures
• - Colonoscopy.
• - Double contrast barium enema.

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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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Colon 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.

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Colon rectal cancers

• Pre op staging
• - Essential workup
• H P, CT scan of abd pelvis.
• Chest xray, Serum CEA.
• - Other tests
• LFTs, PET scan, EUS.

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Five yr survival rates for rectal cancer
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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.

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Colon 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

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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?

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Colon 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.

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Colon 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

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Colon 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.

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Colon 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.

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Colon 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.

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Colon rectal cancers

• Current options for adjuvant therapy for colon
  ca
• Oxaliplatin based regimen.
• - Oral capecitabine.

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Colon 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.

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Adjuvant therapy for rectal cancer
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Colon 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.

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Colon rectal cancers

• Adjuvant therapy for rectal ca
• Post op radiation therapy1
• - Better local control
• - no survival benefit
• 1GITSG. NEJM1985.

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Colon 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.

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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)

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Colon 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.

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Colon 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.

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Colon rectal cancers

• Management of metastatic CRC
• - Regional treatment.
• - Systemic chemotherapy.

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Colon rectal cancers

• Management of metastatic CRC
• Regional treatment.
• - Surgical resections
• - Local tumor ablation (Ethanol, RFA).
• - HIA chemo (chemoembolization)

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Colon 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.

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Colon 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.

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Colon 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.

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Colon rectal cancers

• Management of metastatic CRC
• Combination of 5 FU LV with
• - Irinotecan
• - Oxaliplatin
• - Capecitabine
• - Targeted therapies

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Colon 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.

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Colon 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.

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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
  success1.
• - Further trials underway.
• 1Kabbinavar et al. JCO 2003.

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Colon 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.

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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.

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Colon rectal cancers

• Conclusions
• 5. Treatment of metastatic colon and rectal
  cancer provides good palliation with some
  progression free survival.

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Colon rectal cancers

• ..end of beginning.