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Colorectal Cancer Prevention & Screening

Rajeev Jain, M.D.

2007 Estimated US Cancer Cases*

Source: American Cancer Society, 2007.

Men766,860

Women678,060

26% Breast

15% Lung & bronchus

11% Colon & rectum

6% Uterine corpus

4% Non-Hodgkin lymphoma

4% Melanoma of skin

4% Thyroid

3% Ovary

3% Kidney

3% Leukemia

21% All Other Sites

Prostate 29%

Lung & bronchus 15%

Colon & rectum 10%

Urinary bladder 7%

Non-Hodgkin4% lymphoma

Melanoma of skin 4%

Kidney 4%

Leukemia 3%

Oral cavity 3%

Pancreas 2%

All Other Sites 19%

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.

2007 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2007.

Men289,550

Women270,100

26% Lung & bronchus

15% Breast

10% Colon & rectum

6% Pancreas

6% Ovary

4% Leukemia

3% Non-Hodgkin lymphoma

3% Uterine corpus

2% Brain/ONS

2% Liver & intrahepaticbile duct

23% All other sites

Lung & bronchus 31%

Prostate 9%

Colon & rectum 9%

Pancreas 6%

Leukemia 4%

Liver & intrahepatic 4%bile duct

Esophagus 4%

Urinary bladder 3%

Non-Hodgkin 3% lymphoma

Kidney 3%

All other sites 24%

Colorectal Tumorogenesis

NormalEarly

AdenomaLate

AdenomaCarcinoma

APC/ß-Catenin K-rasp53

18q LOH

Fearon & Vogelstein. Cell 1990.

Age > 50 years Inflammatory Bowel

Disease Familial Adenomatous

Polyposis (FAP) Syndromes

Hereditary Non-polyposis Colon Cancer (HNPCC)

Family History– Polyps– Cancer

Past History– Polyps– Colon Cancer– Ovarian Cancer– Uterine Cancer– Breast Cancer

Colorectal CancerRisk Factors

Winawer, et al. Gastro 1997.

Colorectal CancerRisk Factors

IBD1%

FAP1%

HNPCC5%

SPORADIC75%

FAM HX15-20%

Winawer et al. J Natl Cancer Inst 1991.

Familial Adenomatous Polyposis(FAP)

Autosomal dominant– Mutant APC gene

> 100 polyps Avg age of adenoma

appearance: 16 yrs Avg age of CRC

diagnosis: 39 yrs Risk of CRC ~ 100%


Hereditary Nonpolyposis Colorectal Cancer

(HNPCC or Lynch Syndrome)

Autosomal dominant– Mutations in DNA mismatch repair genes

In comparison to sporadic CRC:– Earlier age of onset (mean, 44 yrs)– Right-sided– Synchronous or metachronous lesions– Poorly differentiated histology

CRC & Ulcerative Colitis

2

8

18

0

5

10

15

20

CR

C I

nci

den

ce R

ate,

%

10 20 30

Duration of colitis, years

Eaden, et al. Gut 2001.

Colorectal CancerUlcerative colitis & Crohn’s colitis

Risk of developing CRC increases with:– Duration of disease– Young age at diagnosis– Extent of disease– Primary sclerosing cholangitis (PSC)– Familial association

Munkholm P. Aliment Pharmacol Ther 2003.

Colorectal CancerAge-Specific Incidence

0

100

200

300

400

500

20-24 30-34 40-44 50-54 60-64 70-74 80-84

Age (years)

Rat

e P

er 1

00,0

00

SEER 1973-1992.

Colorectal CancerIncidence with Positive Family History

0

5

10

40 50 60 70 80

Age of Relatives (years)

Cum

ulat

ive

Inci

denc

e (%

)

<45

45-54

>55

Controls

Mecklin et al. Gastro 1986.

Colon CancerFamilial Risk

0

1

2

3

4

5

1 1st 1 1st <50 yrs 2 1st 1 2nd/3rd 2 2nd

Familial Setting

Ris

k of

Col

on C

ance

r

Burt. Gastro 2000.

Colon CancerRisk After Gynecologic Cancer

0

1

2

3

4

Cervical Endometrial Ovarian

Gynecologic Cancer

Ris

k of

Col

on C

ance

r

25 - 49 yrs50 - 64 yrs> 65 yrs

Weinberg et al. Ann Intern Med 1999.

Distribution of Polyps & Cancer

13%

9%

11%

6%

55%

7%

13%

11%

18%

52%

Adenomatous Polyps Adenocarcinoma


Colorectal CancerSummary of Risk Factors

Highest Risk– Genetic syndromes (FAP &

HNPCC)– Inflammatory bowel disease

High Risk– Family history of polyps and/or

CRC

Average Risk

Colorectal Cancer

PREVENTION

DietaryHabits

MedicalTherapy

Western countries have 10x risk for colon cancer in comparison to Asian & other developing countries.

Rapid increases in rates of colon cancer are found in:– migrants from low-risk to high-risk

areas.– Japan since World War II.

Colorectal Cancer

Colorectal CancerDietary Hypotheses

RISKAnimalFat

Fiber

Excretion of bile acids

Colorectal carcinogenesis

Conversion to secondary bile acids

deoxycholic & lithocolic acid

Nurses' Health Study

1

1.5

2

1 2 3 4 5

Intake of Animal Fat (quintile)

Rel

ativ

e R

isk

Colon Cancer & Animal Fat Intake

Willet et al. NEJM 1990.

Colon Cancer & Dietary FiberPossible Mechanisms of Action

Increased bulk of stool– Dilution of potential carcinogens– Decrease in transit time

Binding with potential carcinogens Lowers fecal pH Alters colonic flora Fermentation by fecal flora to

SCFA’s

Kim. Gastro 2000.

Colon Cancer & Dietary Fiber

Current evidence (epidemiological, animal, and interventional studies) is supportive of an inverse association between dietary fiber intake and CRC risk.

Protective effects seen at 30-35 gm/d (US mean 11.1 gm/d)

Intervention should begin 10-20 yrs before the peak age for CRC incidence.

Kim. Gastro 2000.

Nutritional education– Low animal fat– High fiber

Fiber supplementation (goal of 25 – 35 gm fiber/day)

Other lifestyle modifications– Weight loss– Physical activity– Avoid tobacco

Colon Cancer & DietWhat should we tell our patients ?

Colorectal CancerProtective Micronutrients ?

Calcium and Vitamin D Folic acid Vitamins A, C, and E Selenium Curcumin

Colorectal CancerChemopreventive Agents

ASA & NSAIDs Folate Calcium Estrogens

Chemoprevention with ASAU.S. Preventive Services Task Force

Colonic adenomas– RR 0.82 [95%CI, 0.70 – 0.95] RCTs– RR 0.87 [95%CI, 0.77 – 0.98] Case-control– RR 0.72 [95%CI, 0.61 – 0.85] Cohort

Colon cancer– 22% RR in cohort studies– 2 RCTs no protective benefit at low doses

Benefits seen with higher doses and for periods longer than 10 years

The USPSTF recommends against the routine use of ASA/NSAIDs to prevent CRC in average risk patients.

Dube C et al. Ann Int Med 146:365-75, 2007.

Mechanism unknown Colorectal adenomas

– Prospective cohort study (25,474 pts)– Folate 400 ug QD– 29% risk reduction

Colorectal cancer– Prospective cohort study (88,756 pts)– Folate in a multivitamin preparation– 75% risk reduction after 15 yrs

ChemopreventionFolate

Mechanism– binding of bile and fatty acids – inhibit colorectal epithelium proliferation

Case-control and cohort studies show inverse relationship between calcium intake and CRC– imprecise assessment of calcium intake– confounding factors

RCT– 930 pts with h/o adenomas– 3 gm Ca carbonate (1200 mg elemental Ca)– Serial colonoscopy 1 and 4 yrs after randomization– 15% reduction in adenoma formation

ChemopreventionCalcium

Baron et al. NEJM 1999.

1.Cancer Prevention Study II– 422,373 patients– End point – Death

2.Nurses’ Health Study– 59,002 patients– End point - Cancer

0

5

10

15

20

25

30

35

40

Study 1 Study 2

Ris

k R

educ

tion

(%)

ChemopreventionEstrogens

Calle et al. J Natl Cancer Inst 1995.Grodstein et al. Ann Intern Med 1998.

Colorectal Cancer Prevention

Dietary habits– Increase fiber intake– Decrease animal fat intake

Chemoprevention– Not enough data to firmly

recommend

Definitions

Screening: search for neoplasia in asymptomatic population with no prior neoplasia

Surveillance: evaluation of patients with prior colorectal adenomas or cancer, or with IBD

Diagnosis: evaluation of symptomatic patients and patients with positive screening tests

CRC Screening

Only 26% of eligible population has had FOBT within 3 yrs; 33% have never had FOBT

Most common reason given: test was never recommended Of those offered screening, only 4% decline Cancer Prevention Study (CPS) II Nutrition Cohort, cross-

sectional data from 1997– Men 86,404; women 97,786– 42% men & 31% women underwent screening FS or colonoscopy

In pts > 50 yrs, 33% had undergone FS/C in 1999. By 2004, 52% had undergone screening FS/C.

Vernon, J Natl Cancer Inst 1997.Leard et al, J Fam Prac 1997.

Chao, Am J Public Health 2004.Smith,CA Cancer J Clin 2006.

CRC Screening

Women who underwent screening mammography and Pap smear– 52% underwent CRC screening

Men who underwent prostate cancer screening with PSA– 65% underwent CRC screening

Carlos, Acad Radiol 2005.Carlos, J Am Coll Surg 2005.

Medicolegal Issues

Delay in diagnosis of CRC accounts for >50% of all litigation against PCPs for GI disease– Attributing rectal bleeding to hemorrhoids– Inadequate evaluation of positive FOBT– Failure to screen

Gerstenberger & Plumeri. Gastrointest Endosc 1993.

Risk Stratification

Has the patient had colorectal cancer or an adenomatous polyp?

Does the patient have an illness that predisposes him or her to colorectal cancer?

Has a family member had colorectal cancer or an adenomatous polyp?

Winawer et al. Gastroenterology 2003.

Screening Tests for Colorectal Cancer

Fecal occult blood test Flexible sigmoidoscopy Double-contrast barium enema Colonoscopy

Fecal Occult Blood Tests

Rationale: colorectal cancers bleed Guaiac-based

– pseudoperoxidase activity of hemoglobin

Immunochemical– antibodies to human globin epitopes

Heme-porphyrin– hemoglobin derived porphyrin

Fecal Occult-Blood Tests

TestBasis of

Reaction

Hemoccult II Guaiac

Hemoccult

SENSAGuaiac

HemeSelect Ab to H Hgb

HemoQuant Heme porphyrins

Rockey. NEJM 1999.


CHARACTERISTICSGUAIAC-

BASED

HEME-

PORPHYRIN

IMMUNO-

CHEMICAL

Bedside availability ++++ 0 0 to ++

Time to develop 1 min 1 hr up to 24 hrs

Cost $18 $33 $18-35

Rockey. NEJM 1999.

Fecal Occult-Blood TestsREASON FOR FALSE POSITIVE RESULTS

GUAIAC-

BASED

HEME-

PORPHYRIN

IMMUNO-

CHEMICAL

Non-human hemoglobin

++++ ++++ 0

Dietary peroxidases +++ 0 0

Rehydration +++ 0 0

Iron 0 0 0

Rockey. NEJM 1999.


REASON FOR FALSE NEGATIVE RESULTS

GUAIAC-

BASED

HEME-

PORPHYRIN

IMMUNO-

CHEMICAL

Hemoglobin degradation

+++ 0 +++

Storage ++ 0 ++

Vitamin C ++ 0 0

Rockey. NEJM 1999.

Guaiac-based FOBT

2 slides from 3 consecutive bowel movements

Dietary & medication restrictions Slides should NOT be rehydrated Slides should be stored at room

temperature & developed within 7 days

Fecal Occult-Blood TestsComparison of RCTs

Mandel et al Minnesota

Hardcastle et al Nottingham

Kronborg et al Funen

Kewenter et al Gothenburg

Number of patients

46,551 152,850 61,933 68,308

Follow-up 13 yrs 7.8 yrs 10 yrs 8.3 yrs

FOBT frequency 1 yr 2 yr 2 yr 1.5 yr

Rehydration Yes No No Yes

PPV for CRC 2% 10% 18% 5%

Mortality reduction

33% 14% 18% 12%

Towler et al. BMJ 1998.

5979

60

0

20

40

60

80

100

San Fransisco London VA

Study

Mor

talit

y R

edu

ctio

n (%

)Screening Sigmoidoscopy

Case-Control Studies

Selby et al. NEJM 1993.Newcomb et al. NEJM 1993.

Muller & Sonnenberg. Arch Int Med 1995.

Observed and Expected CRC Incidence after Polypectomy

0

1

2

3

4

5

0 2 4 6 7

Years Followed

Cum

ulat

ive

Inci

denc

e (%

) NPSSEERSt. Mark'sMayo

Winawer et al. NEJM 1993.

3952

0

20

40

60

80

100

Colonoscopy Polypectomy

Mor

talit

y R

edu

ctio

n (%

)Colonoscopy

Case-Control Study

Muller & Sonnenberg. Ann Intern Med 1995.

Screening Colonoscopy

VA Indiana

Patients 3121 1994

Age 50-75 yrs >50 yrs

Men 97% ?

FHx CRC 14% ?

Cancer 1% 1%

Lieberman et al. NEJM 2000.Imperiale et al. NEJM 2000.

Major Complication Rates of Screening Tests

Screening testPerforation & Hemorrhage

Death

Barium enema 1/10,000 1/50,000

Sigmoidoscopy 1-2/10,000 <1/10,000

Colonoscopy 1-3/1,000 1-3/10,000


Colorectal CancerInnovative Screening Techniques

Targeting exfoliated markers– Fecal

• colonocytes• DNA

– Immunochemical assays• p53• CEA

Virtual colonoscopy (computed tomographic colonography).– Thin-section helical CT & air insufflation

generating 2-D images converted to 3-D images.

Results of recent study (100 pts)– Cancer: 100%– Polyps > 10 mm: 91%– Polyps 6 – 9 mm: 82%– Polyps < 5: 55%

Colorectal CancerInnovative Screening Techniques

Fenlon, et al. NEJM 1999.

Colorectal Cancer Screening Guidelines

American Cancer Society American College of Gastroenterology American Gastroenterological Association American Society of Colon & Rectal

Surgeons American Society for Gastrointestinal

Endoscopy


Latest Guidelines

Original panel reconvened to review latest literature Endorsed by:

– American Academy of Family Practice– American Cancer Society– American College of Gastroenterology– American College of Physicians-American Society of

Internal Medicine– American College of Radiology– American Gastroenterological Association– American Society of Colon & Rectal Surgeons– American Society for Gastrointestinal Endoscopy


CRC Screening GuidelinesAverage Risk

Asymptomatic Age > 50 years No other risk factors for

CRC


TEST FREQUENCY

Fecal occult blood test* Annually

Flexible sigmoidoscopy* Every 5 years

Double-contrast barium enema* Every 5 years

Colonoscopy Every 10 years

CRC Screening GuidelinesAverage Risk


* Positive result leads to colonoscopy

CRC Screening GuidelinesFamilial Risk

CATEGORY RECOMMENDATIONS

First-degree relative with CRC or an adenomatous polyp at age >60 yrs

Same as average risk but

starting at age 40 yrs

2 second-degree relatives with CRC

2 or more first degree relatives with colon cancer

Colonoscopy every 5 yrs beginning at the 40 yrs or 10 yrs younger than the earliest diagnosis in the family

First-degree relative with CRC or adenomatous polyp < 60 yrs

1 ≥2nd degree relative with CRC Same as average risk


CRC Screening Guidelines Genetic Syndromes

CATEGORY RECOMMENDATION

Familial adenomatous polyposis (FAP)

Sigmoidoscopy beginning at age 10-12 yrs

Hereditary nonpolypsosis colorectal cancer (HNPCC)

Colonoscopy , every 1-2 yrs, beginning at age 20-25 yrs or 10 yrs younger than earliest case in the family


5 studies: less than $50,000 per life-year saved.

Cost-utility of one-time colonoscopic screening (50-54 yrs): $69,000 per QALYs

Compares favorably to other interventions– Mammograms $168,400 (40-69 yrs)– Seat belts $100,000– Airbags $750,000

Colorectal CancerCost-Effectiveness of Screening

When Not to Screen?When to Stop Screening?

Patients who are to frail to tolerate– bowel preparation– sedation– colonoscopy

Life expectancy less than 3 to 5 years

Colonoscopy within past 5 years

Colorectal CancerPrevention & Screening

Colorectal cancer is a major cause of cancer related death in the US.

Dietary counseling to minimize animal fat and increase fiber intake.

Chemoprevention needs further study. Colonoscopy has become the dominant

screening strategy. Overall screening rates remain poor.