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

Colon & Rectal CancersColon & Rectal Cancers

Imran Ahmad, MD.,Imran Ahmad, MD.,Clinical Assistant Professor.Clinical Assistant Professor.

Medical Oncology,Medical Oncology,Saskatoon Cancer Centre.Saskatoon Cancer Centre.

Faculty DeclarationFaculty Declaration

Will discuss an unapproved/investigative Will discuss an unapproved/investigative use of a commercial product/deviceuse of a commercial product/device

I have/had a financial arrangement or I have/had a financial arrangement or affiliation with one or more organizationsaffiliation with one or more organizations

Research Support – Hoffman La-RocheResearch Support – Hoffman La-Roche

Colon & rectal cancersColon & rectal cancers

ObjectivesObjectives::- Colon and rectal ca statistics in Canada.- Colon and rectal ca statistics in Canada.

- Prevention and screening.- Prevention and screening.

- Medical management of localized and - Medical management of localized and advanced stage cancer.advanced stage cancer.


Statistics:Statistics:- An estimated 153,000 new cases & 70,000 - An estimated 153,000 new cases & 70,000

deaths from cancer will occur in 2006 in deaths from cancer will occur in 2006 in CanadaCanada11..

- An estimated 20,000 new cases & 8,500 - An estimated 20,000 new cases & 8,500 deaths from colorectal cancer will occur in deaths from colorectal cancer will occur in 2006 in Canada2006 in Canada11..

11Canadian cancer statistics, 2006.Canadian cancer statistics, 2006.

Percentage Distribution of Estimated New Casesfor

Selected Cancer Sites, Males, Canada, 2006.

Percentage Distribution of Estimated Deaths forSelected Cancer Sites, Males, Canada, 2006

Percentage Distribution of Estimated New Cases for

Selected Cancer Sites, Females, Canada, 2006

Percentage Distribution of Estimated Deaths forSelected Cancer Sites, Females, Canada, 2006

Age-Standardized Incidence Rates (ASIR) forSelected Cancer Sites, Males, Canada, 1977-2006

Age-Standardized Mortality Rates (ASMR) forSelected Cancer Sites, Males, Canada, 1977-2006

Age-Standardized Incidence Rates (ASIR) forSelected Cancer Sites, Females, Canada, 1977-2006

Age-Standardized Mortality Rates (ASMR) for

Selected Cancer Sites, Females, Canada, 1977-2006

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

Actual Data for New Cases for the Most Common Cancer Sites by SexAnd 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

Canadian Cancer Stats 2004


Risk factors:Risk factors: (I) Sporadic (70%):(I) Sporadic (70%):

- Age: Risk increases significantly b/w ages - Age: Risk increases significantly b/w ages of 40 and 50, & in each succeeding of 40 and 50, & in each succeeding decade thereafterdecade thereafter11..

- Lifetime incidence is about 5%.- Lifetime incidence is about 5%.

11Eddy, DM et al. Ann Intern Med 1990.Eddy, DM et al. Ann Intern Med 1990.


Risk factors (Sporadic):Risk factors (Sporadic):- Inflammatory bowel disease (Pancolitis ,5-- Inflammatory bowel disease (Pancolitis ,5-

15 fold increased risk )15 fold increased risk )11

- Alcohol- Alcohol

- Diabetes mellitus- Diabetes mellitus

- Cigarette smoking.- Cigarette smoking.

11Ekbom,A et al. NEJM 1990.Ekbom,A et al. NEJM 1990.


(II) (II) Risk factors, inherited (5-10%):Risk factors, inherited (5-10%):(a) Germ line mutations.(a) Germ line mutations.

(1) Polyposis syndromes:(1) Polyposis syndromes:

- Familial adenomatous polyposis.- Familial adenomatous polyposis.

- Less than 1% of CRC.- Less than 1% of CRC.

- Germ line mutations in APC gene on ch 5- Germ line mutations in APC gene on ch 511..

11Burt, RW et al. Ann Rev Med 1995.Burt, RW et al. Ann Rev Med 1995.


(II) (II) Risk factors, inherited (5-10%):Risk factors, inherited (5-10%):(a) Germ line mutations.(a) Germ line mutations.

(2) Non Polyposis syndromes(2) Non Polyposis syndromes

- Hereditary nonpolyposis CRC.- Hereditary nonpolyposis CRC.

- Autosomal dominant.- Autosomal dominant.

- More common than FAP- More common than FAP11..

11Lynch, HT et al. Gastroenterology 1993.Lynch, HT et al. Gastroenterology 1993.


(III) Risk factors, familial (20-25%):(III) Risk factors, familial (20-25%):- Affected pts have family history, but pattern - Affected pts have family history, but pattern

is different from inherited one. is different from inherited one.

- Having an affected 1- Having an affected 100 relative increases relative increases the risk 1.7 fold. the risk 1.7 fold.

- Genetic abnormalities:- Genetic abnormalities:

? Mutated APC gene, ? loss of DNA, ?? Mutated APC gene, ? loss of DNA, ?mismatch repair genes. mismatch repair genes.

Adenoma carcinoma sequence

Genetic model of CRC carcinogenesis


Protective factors:Protective factors:- Diet high in fruits and vegetables.- Diet high in fruits and vegetables.11

(? Fiber, antioxidants, FA, Selenium) (? Fiber, antioxidants, FA, Selenium)

- ASA / NSAID’S- ASA / NSAID’S22..

- HMG-CoA reductase inhibitors- HMG-CoA reductase inhibitors33..

11Kim et al. Nutr Rev 1996.Kim et al. Nutr Rev 1996.22Giovannucci et al. NEJM 1999Giovannucci et al. NEJM 199933Sacks et al. NEJM 1996.Sacks et al. NEJM 1996.


CASE #1CASE #1 63 yr old asymptomatic man with no family 63 yr old asymptomatic man with no family

h/o colorectal ca, presented for first h/o colorectal ca, presented for first annual physical exam, by family MD.annual physical exam, by family MD.

Physical exams including rectal exam was Physical exams including rectal exam was normal. Fecal occult blood testing was normal. Fecal occult blood testing was negative.negative.

What should be further recommendations What should be further recommendations for colorectal cancer screening in future?for colorectal cancer screening in future?


Screening:Screening:““Canadian Association of Gastroenterology Canadian Association of Gastroenterology

&Canadian Digestive Foundation. &Canadian Digestive Foundation. Guidelines on Colon Ca Screening. 2004.”Guidelines on Colon Ca Screening. 2004.”

- Begin screening at age 40 if;- Begin screening at age 40 if; One 1One 100 relative >60 yrs has CRC or AP, or relative >60 yrs has CRC or AP, or

> one 2> one 200 relative has CRC or AP. relative has CRC or AP.- Otherwise begin screening at age 50.Otherwise begin screening at age 50.- www.cag-acg.org/www.screencolons.cawww.cag-acg.org/www.screencolons.ca


Choices of screening methods includeChoices of screening methods include11::- FOB atleast every 2 years.- FOB atleast every 2 years.

- Flex sig (w/wo FOB) every 5 yrs.- Flex sig (w/wo FOB) every 5 yrs.

- Double contrast BE every 5 yrs.- Double contrast BE every 5 yrs.

- Colonoscopy every 10 yrs.- Colonoscopy every 10 yrs.

““Screening method should be determined by its Screening method should be determined by its availability & after discussion b/w pt & physician”availability & after discussion b/w pt & physician”

11Leddin et al. Can J Gastroenterol 2004.Leddin et al. Can J Gastroenterol 2004.


CRC Screening: Practices & opinions CRC Screening: Practices & opinions of primary care physiciansof primary care physicians11..

- < 42% of physicians were familiar with < 42% of physicians were familiar with guidelines.guidelines.

- Only 35.6% of physicians offered Only 35.6% of physicians offered screening to at least 75% of their average screening to at least 75% of their average risk pts.risk pts.

11McGregor et al. Preventive Medicine 2004.McGregor et al. Preventive Medicine 2004.

Colorectal Cancer Screening: Percentage of Men and Women Aged50 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)


Diagnosis:Diagnosis:*Presenting symptoms *Presenting symptoms 11(resectable cancer):(resectable cancer):

- Abdominal pain (44%)- Abdominal pain (44%)- Change in bowel habit (43%)- Change in bowel habit (43%)- Haematochezia or melena (40%)- Haematochezia or melena (40%)- Fe def anemia, w/o other GI symp (11%)- Fe def anemia, w/o other GI symp (11%)- Weight loss (6%)- Weight loss (6%)

11Steinberg et al. Cancer 1986.Steinberg et al. Cancer 1986.


Diagnosis:Diagnosis:* Presentation of metastatic disease:* Presentation of metastatic disease:

- 15-20% of pts have metastatic disease on - 15-20% of pts have metastatic disease on presentation.presentation.

- Common sites are LN, liver, lungs and - Common sites are LN, liver, lungs and peritoneum.peritoneum.

Mesenteric Lymphadenopathy in a pt with colon ca

Liver mets in a pt with colon cancer


Diagnostic procedures:Diagnostic procedures:

- Colonoscopy.- Colonoscopy.

- Double contrast barium enema.- Double contrast barium enema.


CASE #2CASE #2 65 yr old woman, with no significant 65 yr old woman, with no significant

medical history presented to family doctor medical history presented to family doctor with h/o tiredness and easy fatigue. with h/o tiredness and easy fatigue.

Blood studies showed evidence of Blood studies showed evidence of hypochrmic microcytic anemia secondary hypochrmic microcytic anemia secondary to iron deficiency.to iron deficiency.

What inv will be needed to r/o colorectal What inv will be needed to r/o colorectal ca as the cause of problem?ca as the cause of problem?


Stages of disease at presentation:Stages of disease at presentation: “ “Duke’s classification & AJCC staging” Duke’s classification & AJCC staging”

- Localized to mucosa and submucosa (Dukes A - Localized to mucosa and submucosa (Dukes A or TNM stage I) 23%.or TNM stage I) 23%.

- Extending through muscle layer without LN - Extending through muscle layer without LN involvement (Dukes B or TNM stage II) 31%.involvement (Dukes B or TNM stage II) 31%.

- LN involvement (Dukes C or TNM stage III) 26%.- LN involvement (Dukes C or TNM stage III) 26%.

- Distant mets (Dukes D or TNM stage IV) 20%.- Distant mets (Dukes D or TNM stage IV) 20%.


Pre op staging:Pre op staging:- Essential workup:- 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- Other tests

LFT’s, PET scan, EUS.LFT’s, PET scan, EUS.

Five yr survival rates for rectal cancer


Other prognostic features:Other prognostic features:- Lymphovascular invasion.- Lymphovascular invasion.

- Pre op CEA Level.- Pre op CEA Level.

- Presence of microsatellite instability & loss - Presence of microsatellite instability & loss of the Deleted in Colon Cancer (DCC) of the Deleted in Colon Cancer (DCC) gene.gene.


Adjuvant therapy for colon cancer:Adjuvant therapy for colon cancer:* Monotherapy. 5 Fluorouracil. (no * Monotherapy. 5 Fluorouracil. (no

improvement in 5 yr survival)improvement in 5 yr survival)11

* Combination chemo (NSABP C-01 trial* Combination chemo (NSABP C-01 trial)2.)2. - 1166 pts.- 1166 pts.- Arm A: Surgery, Arm B: BCG, Arm C: MOF - Arm A: Surgery, Arm B: BCG, Arm C: MOF - Result: Significant improvement in 5 yr OS - Result: Significant improvement in 5 yr OS

with MOF.with MOF.11Buyse et al, JAMA 1988. Buyse et al, JAMA 1988. 22Wolmark et al, JNCI 1988 Wolmark et al, JNCI 1988


CASE #3:CASE #3: Lady in case #2 underwent colonoscopy Lady in case #2 underwent colonoscopy

followed by laparotomy for cecal cancer.followed by laparotomy for cecal cancer. She was found out to have a 5 cm mod She was found out to have a 5 cm mod

differentiated adenocarcinoma, with one differentiated adenocarcinoma, with one out of 11 lymph node positive.out of 11 lymph node positive.

She is 3 wks out of surgery, and asking for She is 3 wks out of surgery, and asking for further recommendations?further recommendations?


Adjuvant therapy for colon cancer:Adjuvant therapy for colon cancer: (NCCTG trial)(NCCTG trial)11

- 5 FU & levamisole vs surgery alone.- 5 FU & levamisole vs surgery alone.

- 40 % reduction in risk of recurrence.- 40 % reduction in risk of recurrence.

- OS benefit only in lymph nodes positive - OS benefit only in lymph nodes positive disease.disease.

11Laurie et al; JCO 1989.Laurie et al; JCO 1989.


Adjuvant therapy for colon cancer:Adjuvant therapy for colon cancer:* Trials using combination of 5FU & * Trials using combination of 5FU &

leucovorin.leucovorin. (NSABP C-03, IMPACT report(NSABP C-03, IMPACT report11, NCCTG , NCCTG

trialtrial22))- 5 FU & leucovorin for at least 6 mo.- 5 FU & leucovorin for at least 6 mo.- Approx 20% reduction in death, 5% benefit - Approx 20% reduction in death, 5% benefit

in 3 yr OS.in 3 yr OS.- Benefit limited to node positive disease.- Benefit limited to node positive disease. 11Impact investigators; Lancet 1995. Impact investigators; Lancet 1995. 22O’Connell et al; JCO 1997O’Connell et al; JCO 1997


Adjuvant therapy for colon cancer:Adjuvant therapy for colon cancer:

1990 NIH consensus conference1990 NIH consensus conference11,,

““Adjuvant 5 FU containing chemotherapy is Adjuvant 5 FU containing chemotherapy is the standard of care for resected node the standard of care for resected node positive (stage III) colon cancer”.positive (stage III) colon cancer”.

11NIH consensus conf; JAMA 1990.NIH consensus conf; JAMA 1990.


New developments in adjuvant therapy:New developments in adjuvant therapy:Oxaliplatin containing regimens. Oxaliplatin containing regimens.

(MOSAIC trial)(MOSAIC trial)11

- 2246 pts.- 2246 pts.

- 5FU and Leucovorin +/- Oxaliplatin.- 5FU and Leucovorin +/- Oxaliplatin.

- 3 yr DFS 78% vs 73 % (p< 0.05).- 3 yr DFS 78% vs 73 % (p< 0.05).

- OS was similar.- OS was similar.11Andre T et al. NEJM 2004.Andre T et al. NEJM 2004.


New developments in adjuvant therapy:New developments in adjuvant therapy: Use of oral CapecitabineUse of oral Capecitabine (X-ACT study)(X-ACT study)11

- 1987 pts.- 1987 pts.- 5FU and LV vs oral Capecitabine- 5FU and LV vs oral Capecitabine- Capecitabine was at least as effective as - Capecitabine was at least as effective as

5FU and LV, but better tolerable.5FU and LV, but better tolerable. 11Scheithauer W et al. Ann Oncol 2003.Scheithauer W et al. Ann Oncol 2003.


Current options for adjuvant therapy for Current options for adjuvant therapy for colon ca:colon ca:

- Oxaliplatin based regimen.Oxaliplatin based regimen.

- Oral capecitabine.- Oral capecitabine.


Adjuvant therapy for Stage II (Duke B) Adjuvant therapy for Stage II (Duke B) colon cancer:colon cancer:

“ “ASCO 2004 recommendation”ASCO 2004 recommendation”

- Recommend against routine administration - Recommend against routine administration of chemo in stage II colon ca.of chemo in stage II colon ca.

- Adjuvant chemo can be considered for- Adjuvant chemo can be considered for

<6 LN in surgical specimen, T4 lesions, <6 LN in surgical specimen, T4 lesions, perforation, poorly differentiated histology.perforation, poorly differentiated histology.

Adjuvant therapy for rectal cancer


Adjuvant therapy for rectal caAdjuvant therapy for rectal ca:: Pattern of relapse (localPattern of relapse (local)1:)1:

- T1-2: <10%.- T1-2: <10%.

- T3N0: 15-35%- T3N0: 15-35%

- T3-4,N1-2: 45-65%.- T3-4,N1-2: 45-65%.

11Willett et al. Cancer 1992.Willett et al. Cancer 1992.

Adjuvant therapy for rectal ca:Adjuvant therapy for rectal ca:* Post op radiation therapy* Post op radiation therapy11::

- Better local control- Better local control - no survival benefit- no survival benefit

11GITSG. NEJM1985.GITSG. NEJM1985.



Adjuvant therapy for rectal ca:Adjuvant therapy for rectal ca: Post op chemo and radiationPost op chemo and radiation (GITSG TRIAL)(GITSG TRIAL)11

- 227 Pts.- 227 Pts.- Obs vs chemo vs xrt vs xrt & chemo.- Obs vs chemo vs xrt vs xrt & chemo.- Significant lower local recurrence.- Significant lower local recurrence.- Improvement in OS.- Improvement in OS. 11NEJM 1985.NEJM 1985.


Adjuvant therapy for rectal ca:Adjuvant therapy for rectal ca:

Our Practice at SCCOur Practice at SCC

5FU bolus5FU bolus→→5FU cont inf & xrt5FU cont inf & xrt→→ 5FU bolus 5FU bolus

(2 mo) (6 wks) (2 mo)(2 mo) (6 wks) (2 mo)


Pre op vs post op chemo+xrt for rectal Pre op vs post op chemo+xrt for rectal ca:ca:11

Pts: T3, T4 or Node +, (n=823)Pts: T3, T4 or Node +, (n=823)

Pre op Post opPre op Post op

5 yr OS: 76% 74% p=0.805 yr OS: 76% 74% p=0.80

Local relapse: 6% 13% p=0.006Local relapse: 6% 13% p=0.006

Toxicity: 27% 40% p=0.001Toxicity: 27% 40% p=0.001 11Sauer et al; NEJM, Oct 2004.Sauer et al; NEJM, Oct 2004.


Pre op vs post op chemo+xrt for rectal ca:Pre op vs post op chemo+xrt for rectal ca:Critiques:Critiques:• Primary end point (OS) was not Primary end point (OS) was not

statistically different.statistically different.• Similar rates of sphincter preservation.Similar rates of sphincter preservation.• Possibility of over treating early stage Possibility of over treating early stage

tumors.tumors.• EUS neither perfectly accurate nor EUS neither perfectly accurate nor

universally available.universally available.


Management of metastatic CRC:Management of metastatic CRC:

- Regional treatment.- Regional treatment.

- Systemic chemotherapy.- Systemic chemotherapy.


Management of metastatic CRCManagement of metastatic CRC::

* Regional treatment.* Regional treatment.

- Surgical resections- Surgical resections

- Local tumor ablation (Ethanol, RFA).- Local tumor ablation (Ethanol, RFA).

- HIA chemo (chemoembolization)- HIA chemo (chemoembolization)


Management of metastatic CRC:Management of metastatic CRC: * Surgical resections:* Surgical resections:

- 5 yr RFS ranges from 24-58- 5 yr RFS ranges from 24-58%1.%1.

- Only potentially curative option for isolated - Only potentially curative option for isolated liver mets.liver mets.

- <10% of pts are surgical candidates.- <10% of pts are surgical candidates.

11Fong et al. Ann Surg 1999.Fong et al. Ann Surg 1999.


Management of metastatic CRC:Management of metastatic CRC:• Systemic chemotherapy.Systemic chemotherapy. (Meta-analysis of seven randomized trials(Meta-analysis of seven randomized trials11)) Palliative chemo vs BSCPalliative chemo vs BSC- N= 866- N= 866- Median OS; 3.7 mo longer for palliative chemo.Median OS; 3.7 mo longer for palliative chemo.- With use of newer drugs (like avastin) along with chemo median With use of newer drugs (like avastin) along with chemo median

overall surv of 20 months has been reportedoverall surv of 20 months has been reported22

11Simmonds, PC et al. BMJ 2000.Simmonds, PC et al. BMJ 2000.22H. Hurwitz et al. NEJM 2004.H. Hurwitz et al. NEJM 2004.


Management of metastatic CRC:Management of metastatic CRC:Infusional vs bolus 5 FU meta- analysisInfusional vs bolus 5 FU meta- analysis11

- RR 22% vs 14%- RR 22% vs 14%

- Median OS 12 vs 11mo- Median OS 12 vs 11mo

- Different Toxicity pattern- Different Toxicity pattern

11Meta-analysis. JCO 1998.Meta-analysis. JCO 1998.


Management of metastatic CRCManagement of metastatic CRC::

*Combination of 5 FU & LV with *Combination of 5 FU & LV with

- Irinotecan- Irinotecan

- Oxaliplatin- Oxaliplatin

- Capecitabine- Capecitabine

- Targeted therapies- Targeted therapies


Management of metastatic CRC:Management of metastatic CRC: 5 FU + LV+ Irinotecan/Oxaliplatin5 FU + LV+ Irinotecan/Oxaliplatin1,21,2

vs 5 FU + LV vs 5 FU + LV

RR 40-50% vs 20-30%RR 40-50% vs 20-30%

TTP 6.7 mo vs 4.4 moTTP 6.7 mo vs 4.4 mo

Median OS 17.4 mo vs 14.1moMedian OS 17.4 mo vs 14.1mo

11Douillard et al. Lancet 2000. Douillard et al. Lancet 2000. 22Saltz et al. NEJM 2000.Saltz et al. NEJM 2000.


Management of metastatic CRC:Management of metastatic CRC:* Targeted therapies: Cetuximab (Erbitux)* Targeted therapies: Cetuximab (Erbitux)- Human/mouse chimeric monoclonal antibody.- Human/mouse chimeric monoclonal antibody.- Binds to EGFR expressed on cells.- Binds to EGFR expressed on cells.- 80 -90% of CRC expresses EGFR.- 80 -90% of CRC expresses EGFR.- In an open label study- In an open label study11 RR 9% in chemo RR 9% in chemo

refractory pts. refractory pts. - With or without chemotherapies (Trials open).- With or without chemotherapies (Trials open).

11Saltz et al. JCO 2004.Saltz et al. JCO 2004.


Management of metastatic CRC:Management of metastatic CRC:*Targeted therapies: Bevacizumab (Avastin)*Targeted therapies: Bevacizumab (Avastin)

- Anti-VEGF MoAb.- Anti-VEGF MoAb.

- No molecular markers predict efficacy.- No molecular markers predict efficacy.

- Studied in combination with chemo with - Studied in combination with chemo with some successsome success11..

- Further trials underway.- Further trials underway.11Kabbinavar et al. JCO 2003.Kabbinavar et al. JCO 2003.


Conclusions:Conclusions:

1.1. Colorectal ca is the second common Colorectal ca is the second common cause of ca deaths in males and third cause of ca deaths in males and third common cause of ca deaths in females.common cause of ca deaths in females.

2.2. Risk increases significantly b/w ages of Risk increases significantly b/w ages of 40 and 50, & in each succeeding decade 40 and 50, & in each succeeding decade thereafterthereafter..


Conclusions:Conclusions:3.Adjuvant 5 FU containing chemotherapy is 3.Adjuvant 5 FU containing chemotherapy is

the standard of care for resected node the standard of care for resected node positive (stage III) colon cancer.positive (stage III) colon cancer.

4. For rectal cancer chemo should be 4. For rectal cancer chemo should be combined with XRT in adjuvant setting.combined with XRT in adjuvant setting.


Conclusions:Conclusions:5. Treatment of metastatic colon and rectal 5. Treatment of metastatic colon and rectal

cancer provides good palliation with some cancer provides good palliation with some progression free survival. progression free survival.


……… ………..end of beginning...end of beginning.

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

Documents

Transcript of Colon & Rectal Cancers Imran Ahmad, MD., Clinical Assistant Professor. Medical Oncology, Saskatoon...