Malignant disease of colon and rectum Seyed vahid hosseini Professor of surgery Professor of surgery...

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Malignant disease of Malignant disease of colon and rectum colon and rectum Seyed vahid hosseini Seyed vahid hosseini Professor of surgery Professor of surgery Department of surgery Department of surgery Colo-rectal ward Colo-rectal ward

Transcript of Malignant disease of colon and rectum Seyed vahid hosseini Professor of surgery Professor of surgery...

Malignant disease of colon Malignant disease of colon and rectumand rectum

Seyed vahid hosseiniSeyed vahid hosseini Professor of surgeryProfessor of surgery

Department of surgeryDepartment of surgeryColo-rectal wardColo-rectal ward

Worldwide Statistics for Worldwide Statistics for Colorectal Cancer (CRC)Colorectal Cancer (CRC)

• Estimated 875,000 cases in 1996Estimated 875,000 cases in 1996

• 8.5% of all new cases of cancer8.5% of all new cases of cancer

• Incidence rates vary by ~20-foldIncidence rates vary by ~20-fold

• highest in North America, Western highest in North America, Western Europe, Europe,

• Australia, New Zealand, JapanAustralia, New Zealand, Japan

• lowest in India, Northern Africalowest in India, Northern Africa

• Estimated deaths for 1998: 556,000Estimated deaths for 1998: 556,000

Estimated New Cancer Estimated New Cancer Cases of 10 Leading Sites Cases of 10 Leading Sites by Gender for the US 2000by Gender for the US 2000

Colorectal Cancer Statistics Colorectal Cancer Statistics in the USin the US

• Second overall leading cause of Second overall leading cause of cancer-related deaths in the UScancer-related deaths in the US

• Estimated 130,000 new cases and Estimated 130,000 new cases and 56,300 deaths in the year 200056,300 deaths in the year 2000

• Declining trends between 1990 and Declining trends between 1990 and 19961996 Incidence reate: ~2.1% per yearIncidence reate: ~2.1% per year Mortality rates: ~1.7% per yearMortality rates: ~1.7% per year

Average Annual Age-Specific Average Annual Age-Specific US Incidence and Mortality US Incidence and Mortality Rates of CRC, 1992-1996Rates of CRC, 1992-1996

Risk Factors for Colorectal Risk Factors for Colorectal Cancer (CRC)Cancer (CRC)

• AgingAging

• Personal history of CRC or adenomasPersonal history of CRC or adenomas

• High-fat, low-fiber dietHigh-fat, low-fiber diet

• Inflammatory bowel diseaseInflammatory bowel disease

• Family history of CRCFamily history of CRC

• Hereditary colon cancer syndromesHereditary colon cancer syndromes

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

General populationGeneral population

Personal history of Personal history of colorectal neoplasiacolorectal neoplasia

Inflammatory Inflammatory bowel diseasebowel disease

HNPCC mutationHNPCC mutation

FAPFAP

5%5%

15%–15%–20%20%

15%–40%15%–40%

70%–80%70%–80%

>95%>95%

Lifetime risk (%)Lifetime risk (%)

Familial Risk for Colorectal Familial Risk for Colorectal CancerCancer

ApproximatApproximatee

lifetime lifetime CRC risk CRC risk

(%)(%)

Affected family membersAffected family members

0

20

40

60

80

100

NoneNone One 1°One 1° One 1° One 1° and two and two

2°2°

One 1° One 1° age age <45<45

Two 1°Two 1° HNPCC HNPCC mutationmutation

2%2% 6%6% 8%8% 10%10%17%17%

70%70%

Aarnio M et al. Aarnio M et al. Int J CancerInt J Cancer 64:430, 1995 64:430, 1995 Houlston RS et al. Houlston RS et al. Br Med JBr Med J 301:366, 1990 301:366, 1990 St John DJ et al. St John DJ et al. Ann Intern Med Ann Intern Med 118:785, 1993 118:785, 1993

Causes of Hereditary Causes of Hereditary Susceptibility to CRCSusceptibility to CRC

Adapted from Burt RW et al. Adapted from Burt RW et al. Prevention and Early Detection of CRCPrevention and Early Detection of CRC, 1996, 1996

Sporadic Sporadic (65(65%–%–85%)85%) Familial Familial

(10(10%–%–30%)30%)

Hereditary Hereditary nonpolyposis colorectal nonpolyposis colorectal cancer (HNPCC) (5%)cancer (HNPCC) (5%)Familial adenomatous Familial adenomatous

polyposis (FAP) (1%)polyposis (FAP) (1%)

Rare CRC Rare CRC syndromes syndromes

(<0.1%)(<0.1%)

Clinical Features of FAPClinical Features of FAP

• Estimated penetrance Estimated penetrance for adenomas >90%for adenomas >90%

• Risk of extracolonic Risk of extracolonic tumors (upper GI, tumors (upper GI, desmoid, osteoma, desmoid, osteoma, thyroid, brain, other)thyroid, brain, other)

• CHRPE may be present CHRPE may be present

• Untreated polyposis Untreated polyposis leads to 100% risk of leads to 100% risk of cancer cancer

Genetics of FAPGenetics of FAP• Autosomal dominant inheritance Autosomal dominant inheritance

• Caused by mutations in Caused by mutations in APCAPC tumor tumor suppressor gene on chromosome 5q suppressor gene on chromosome 5q

• Up to 30% of patients have Up to 30% of patients have de novo de novo germline mutationsgermline mutations

• Most families have unique mutationsMost families have unique mutations

• Most mutations are protein truncating Most mutations are protein truncating

• Genotype/phenotype relationships emergingGenotype/phenotype relationships emerging

Attenuated FAPAttenuated FAP

Later onset (CRC ~age Later onset (CRC ~age 50)50)

Few colonic adenomasFew colonic adenomas Not associated with Not associated with

CHRPECHRPE UGI lesions UGI lesions Associated with Associated with

mutations at 5mutations at 5 '' and 3 and 3'' ends of ends of APCAPC gene gene

Indications for Indications for APCAPC Gene Gene TestingTesting• Molecular diagnosis of FAP in Molecular diagnosis of FAP in

patients who present with:patients who present with:– polyposis (>100 adenomas)polyposis (>100 adenomas)– attenuated FAPattenuated FAP

• Predictive testing for FAP in blood Predictive testing for FAP in blood relatives of persons with FAP or relatives of persons with FAP or known known APCAPC mutations mutations

Giardiello FM et al.Giardiello FM et al. N Engl J Med N Engl J Med, 336:823, 1997, 336:823, 1997

Clinical Features of HNPCCClinical Features of HNPCC• Early but variable age Early but variable age

at CRC diagnosis (~45 at CRC diagnosis (~45 years)years)

• Tumor site in proximal Tumor site in proximal colon predominatescolon predominates

• Extracolonic cancers: Extracolonic cancers: endometrium, ovary, endometrium, ovary, stomach, urinary tract, stomach, urinary tract, small bowel, bile ducts, small bowel, bile ducts, sebaceous skin tumorssebaceous skin tumors

Amsterdam CriteriaAmsterdam Criteria 3 or more relatives with verified CRC in 3 or more relatives with verified CRC in

familyfamily One case a first-One case a first-degree relative of the other relative of the other

twotwo Two or more generationsTwo or more generations One CRC by age 50One CRC by age 50 FAP excludedFAP excluded

Vasen HFA et al. Vasen HFA et al. Dis Colon RectDis Colon Rect 34:424, 1991 34:424, 1991

Failure to meet these criteria Failure to meet these criteria does does notnot exclude HNPCC exclude HNPCC

Cancer Risks in HNPCCCancer Risks in HNPCC

Aarnio M et al. Aarnio M et al. Int J CancerInt J Cancer 64:430, 1995 64:430, 1995

% % with with

cancercancer

100100

8080

6060

4040

2020

002020 4040 6060 808000

Age (years)Age (years)

Colorectal Colorectal 78%78%

Endometrial Endometrial 43% 43%

Stomach Stomach 19%19%Biliary tract Biliary tract 18%18%Urinary tract Urinary tract 10%10%Ovarian Ovarian 9%9%

Microsatellite Instability Microsatellite Instability (MSI)(MSI)

• 10%–15% of sporadic tumors have MSI10%–15% of sporadic tumors have MSI• 95% of HNPCC tumors have MSI at 95% of HNPCC tumors have MSI at

multiple locimultiple loci• Routine MSI assays soon availableRoutine MSI assays soon available

Electrophoresis gelElectrophoresis gel

NormalNormal MSI tumorMSI tumor

Adenomatous polypAdenomatous polyp

•Adenomatous polyp

•Can take 5-10 years for polyp to develop

•Up to 10% of polyps develop into cancer

•Size and histology are risk factors for polyp to cancer progression

SummarySummary

Risk factors for colon cancer Inherited Acquired (sporadic)-adenomatous polyp, IBD

Genetic basis for colon cancer Inherited (FAP, HNPCC, to be defined) Sporadic polyp-different pathways

Preclinical models for colon cancer

Summary (continued)Summary (continued)

Applications of chemoprevention initially in animal models and inherited forms of colon cancer, and then to general population

Determine efficacy of chemoprevention with surrogate markers

Learning ObjectivesLearning Objectives

• Discuss current recommendations regarding Discuss current recommendations regarding colon cancer screening and their evidence colon cancer screening and their evidence base.base.

• Discuss the initial management and work-up of Discuss the initial management and work-up of a patient with a biopsy showing colon cancer.a patient with a biopsy showing colon cancer.

• Discuss treatment options and follow-up for Discuss treatment options and follow-up for both advanced and local disease.both advanced and local disease.

So you want the answers?So you want the answers?

• Colonoscopy liberally: Sx, anemia, Colonoscopy liberally: Sx, anemia, over 50; (or over 40 if positive FH)over 50; (or over 40 if positive FH)

• If they have cancer refer to a If they have cancer refer to a surgeon and an oncologist.surgeon and an oncologist.

• Do what they suggest you do?Do what they suggest you do?

Can we go home now ?Can we go home now ?

GeneralGeneral

• 2002: 148,000 new cases2002: 148,000 new cases– 107,000 colonic, 41,000 rectal.107,000 colonic, 41,000 rectal.– 57,000 death57,000 death

• Mainly (90%) adenocarcinomas.Mainly (90%) adenocarcinomas.

• 90% in people over 50 years90% in people over 50 years

Risk factors for colon caRisk factors for colon ca

• 75 to 80% of colon cancer is in people with no 75 to 80% of colon cancer is in people with no risk factors (“sporadic”)risk factors (“sporadic”)

• Intermediate risk: personal history of Intermediate risk: personal history of colorectal polyps or FH of first degree relative colorectal polyps or FH of first degree relative w/ colon cancer or adenomatous polyps.w/ colon cancer or adenomatous polyps.

• High-risk: Familial hereditary cancer High-risk: Familial hereditary cancer syndromes (e.g. Familial adenomatous syndromes (e.g. Familial adenomatous polyposis, Heredity nonpolyposis colorectal polyposis, Heredity nonpolyposis colorectal cancer) or inflammatory bowel disease. cancer) or inflammatory bowel disease.

How do you “prevent” How do you “prevent” colon ca?colon ca?

PreventionPrevention

• Fecal Occult Blood testingFecal Occult Blood testing• AspirinAspirin• NSAID’s reduce adenomas in patients NSAID’s reduce adenomas in patients

w/ high risk familial syndromesw/ high risk familial syndromes• Calcium: 1200 mg/d prevents Calcium: 1200 mg/d prevents

recurrent adenomas in patients w/ recurrent adenomas in patients w/ adenoma hx (RCT)adenoma hx (RCT)

• No evidence for benefit from high-fiber No evidence for benefit from high-fiber diets.diets.

People w/ symptomsPeople w/ symptoms

• All patients (except menstruating women) All patients (except menstruating women) with iron-deficiency anemia are candidates with iron-deficiency anemia are candidates for colonoscopy. Look for a microcytic for colonoscopy. Look for a microcytic anemia and a low Ferritin.anemia and a low Ferritin.

• Symptoms of colon cancer include: Symptoms of colon cancer include: – new abdominal pain/abdominal symptomsnew abdominal pain/abdominal symptoms– change in bowel habits, change in bowel habits, – blood in the stoolblood in the stool– Weight lossWeight loss– Anemia sx: fatigueAnemia sx: fatigue

What are the screening What are the screening modalities?modalities?

Screening ModalitiesScreening Modalities

• Guaic-cardsGuaic-cards

• SigmoidoscopySigmoidoscopy

• ColonoscopyColonoscopy

• Double-contrast barium enemaDouble-contrast barium enema

• Virtual colonoscopy using CT/MRIVirtual colonoscopy using CT/MRI

• DNA stool testsDNA stool tests

FOBTFOBT• 3 consecutive stool samples. Rehydration 3 consecutive stool samples. Rehydration

increases sensitivity, decreases specificity. increases sensitivity, decreases specificity. Pts should follow special diet.Pts should follow special diet.

• 1993 Minnesota RCT showed that “about a 1993 Minnesota RCT showed that “about a 1000 people would need to be screened 1000 people would need to be screened annually over 10 years to prevent one annually over 10 years to prevent one death from colorectal cancer.” 38% will end death from colorectal cancer.” 38% will end up getting colonoscoped over 13 yrs.up getting colonoscoped over 13 yrs.

• Am Fam Physician 2002;66:297-302Am Fam Physician 2002;66:297-302

• No evidence for benefit from a sample No evidence for benefit from a sample collected during PE.collected during PE.

Double contrast BEDouble contrast BE

• Winawer et. al. compared DCBE w/ Winawer et. al. compared DCBE w/ colonoscopy in patients w/ a history of colonoscopy in patients w/ a history of adenoma. Compared to colonoscopy, adenoma. Compared to colonoscopy, DCBE has a sensitivity of:DCBE has a sensitivity of:– 32% for adenomas less than ½ cm32% for adenomas less than ½ cm– 53% for adenomas between 0.6 and 1 cm53% for adenomas between 0.6 and 1 cm– 48% for adenomas over 1 cm.48% for adenomas over 1 cm.

• Specificity was 85% (i.e. 15% false Specificity was 85% (i.e. 15% false pos)pos)

•N Engl J Med 2000:342:1766-72.N Engl J Med 2000:342:1766-72.

SigmoidoscopySigmoidoscopy

• Images about ½ of the colon & requires Images about ½ of the colon & requires no anesthesia.no anesthesia.

• Obviously less sensitive than Obviously less sensitive than colonoscopy, but perforation rate is colonoscopy, but perforation rate is 1/10,000 as compared with 2/1000 with 1/10,000 as compared with 2/1000 with the colonoscope.the colonoscope.

• Typically polyps are not biopsied so that Typically polyps are not biopsied so that about ¼ of pts will need a colonoscopy.about ¼ of pts will need a colonoscopy.

Evidence BasisEvidence Basis

• FOBT: 3 large RCT’sFOBT: 3 large RCT’s

• DCBE: not even controlled trialsDCBE: not even controlled trials

• Flex sig: controlled studiesFlex sig: controlled studies

• Colonoscopy: “indirect evidence” Colonoscopy: “indirect evidence” from the FOBT & flex sig trials.from the FOBT & flex sig trials.

• JAMA 2003:289:1288-1296JAMA 2003:289:1288-1296

SurgerySurgery

• Resect tumor, mesentery and regional Resect tumor, mesentery and regional mesentery (best 12 lymph nodes).mesentery (best 12 lymph nodes).

• Thoroughly explore abdomen for Thoroughly explore abdomen for metastatic disease.metastatic disease.

• There does not seem to be good evidence There does not seem to be good evidence concerning primary vs secondary closure concerning primary vs secondary closure of the colon.of the colon.

SurgerySurgery

• Resect tumor, mesentery and regional Resect tumor, mesentery and regional mesentery (best 12 lymph nodes).mesentery (best 12 lymph nodes).

• Thoroughly explore abdomen for Thoroughly explore abdomen for metastatic disease.metastatic disease.

• There does not seem to be good evidence There does not seem to be good evidence concerning primary vs secondary closure concerning primary vs secondary closure of the colon.of the colon.

ChemotherapyChemotherapy

• No demonstrated benefit for patients w/ No demonstrated benefit for patients w/ stage I or II disease.stage I or II disease.

• Stage III: 5-FU and leucovorin; typically 5 Stage III: 5-FU and leucovorin; typically 5 days every 4 weeks for six cycles.days every 4 weeks for six cycles.

• Radiotherapy is used for rectal cancers.Radiotherapy is used for rectal cancers.

ChemotherapyChemotherapy

• No demonstrated benefit for patients w/ No demonstrated benefit for patients w/ stage I or II disease.stage I or II disease.

• Stage III: 5-FU and leucovorin; typically 5 Stage III: 5-FU and leucovorin; typically 5 days every 4 weeks for six cycles.days every 4 weeks for six cycles.

• Radiotherapy is used for rectal cancers.Radiotherapy is used for rectal cancers.

Metastatic diseaseMetastatic disease

• Resection of up to 3 liver lesions Resection of up to 3 liver lesions improves survival.improves survival.

• Mainstay of therapy is usually Mainstay of therapy is usually chemotherapy: 5-FU +/- leucovorin.chemotherapy: 5-FU +/- leucovorin.

• Newer drugs include irinotetin.Newer drugs include irinotetin.

Chemotherapeutic agents: Chemotherapeutic agents: olderolder• 5-FU: 5-FU:

– Pyrimidine antagonist; interferes w/ Pyrimidine antagonist; interferes w/ thymidlyate synthesisthymidlyate synthesis

– Mucositis, alopecia, myelosuppression, Mucositis, alopecia, myelosuppression, diarrhea/vomiting.diarrhea/vomiting.

• Irinotecan (Camptosar): Irinotecan (Camptosar): – Inhibits topoisomerase I which is needed Inhibits topoisomerase I which is needed

for DNA synthesis.for DNA synthesis.– Diarrhea, often serious, is major side Diarrhea, often serious, is major side

effect.effect.

Newer agentsNewer agents

• Oxaliplatin (Eloxatin): Oxaliplatin (Eloxatin): – inhibits DNA sythesis by causing cross-inhibits DNA sythesis by causing cross-

linkages. linkages. – Significant neurotoxicity. Significant neurotoxicity. – May show promise for both initial and May show promise for both initial and

rescue therapy.rescue therapy.

Newer agentsNewer agents

• Cetuximab (Erbitux): Cetuximab (Erbitux): – Monoclonal Antibody to EGFR (epithelial growth Monoclonal Antibody to EGFR (epithelial growth

factor receptor)factor receptor)– Most common side effect: acne-like rashMost common side effect: acne-like rash

• Bevacizumab (Avastin)Bevacizumab (Avastin)– Monoclonal ab to Vascular endothelial growth Monoclonal ab to Vascular endothelial growth

factorfactor– 2% risk of GI bleed.2% risk of GI bleed.– Can prolong survivalCan prolong survival

RecurrenceRecurrence

• Usually within 3 to 5 years of surgery.Usually within 3 to 5 years of surgery.

• Typically in liver, site of original Typically in liver, site of original tumor, abdomen & lung.tumor, abdomen & lung.

• Evidence on surveillance strategies Evidence on surveillance strategies not great.not great.

• Meta-analysis found that “intensive Meta-analysis found that “intensive surveillance strategies” reduced RR surveillance strategies” reduced RR of death by 20% (absolute risk of death by 20% (absolute risk reduction 7%).reduction 7%).

– NEJM 2004:350:2375-82NEJM 2004:350:2375-82

Surveillance strategiesSurveillance strategies

• History/PE/routine lab tests: Risk of History/PE/routine lab tests: Risk of recurrence greatest in those w/FH & recurrence greatest in those w/FH & those diagnosed at age 50 or younger.those diagnosed at age 50 or younger.

• Chest X-rayChest X-ray

• CEACEA

• CT abdomen (or) US of the liverCT abdomen (or) US of the liver

• Colonoscopy currently preferred methodColonoscopy currently preferred method

How often colonoscopy?How often colonoscopy?

• ESMO: Colonoscopy q5 yrs.ESMO: Colonoscopy q5 yrs.• NCCN: 1 yr after primary (6 mo if NCCN: 1 yr after primary (6 mo if

obstructing); q1yr if abnormal, q3yr if obstructing); q1yr if abnormal, q3yr if neg.neg.

• ASCO: Colonoscopy q 3-5 yrs.ASCO: Colonoscopy q 3-5 yrs.• Figueroa: Yearly if polyps or high risk, Figueroa: Yearly if polyps or high risk,

q 3-5 yrs if normal.q 3-5 yrs if normal.• Berman: q 3-5 yrs.Berman: q 3-5 yrs.

– NEJM 2004:350:2375-82NEJM 2004:350:2375-82

Have a nice weekend!