Prevention of Colon Cancer:

Does Anything Besides

Aspirin Decrease the Risk

for Colon Cancer ?

Helen Shields, M.D., FACP, AGAF

Professor of Medicine

Harvard Medical School

Division of Gastroenterology, Hepatology and Endoscopy

Brigham and Women’s Hospital

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1) Which of the following factors

has the best data to implicate it

as increasing the risk for colon

cancer?

A. Low dietary fiber

B. Obesity

C. Vitamin D deficiency

D. Exercise

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2) To decrease death from rectal

cancer, which of the following

has been recommended on the

basis of evidence?

A. Stop smoking

B. Use a statin to lower cholesterol

C. Daily dose of folate 1 mg

D. Decrease use of non-steroidal

anti-inflammatory medications

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3) Aspirin has been considered a

preventive measure for colon

cancer. Which of the following

statements is correct?A. Aspirin must be used for 10 years before a

beneficial effect on colon cancer is noted

B. The preventive effect of aspirin is only for

left sided colon cancers

C. Daily low dose aspirin use is associated

with a decline in both incidence and

mortality of colon cancer

D. Aspirin has no effect on the occurrence of

colon cancer in the Lynch Syndrome

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4) Patients who do not wish to have an

invasive procedure and liquid

preparation for colon cancer screening

may be screened by which of the

following evidence-based tests?

A. CT colonography

B. Flexible sigmoidoscopy

C. MR colonography

D. Fecal DNA Testing combined with

Fecal Immunochemical Test

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5) Patients are encouraged to have

colonoscopy so that pre-cancerous

polyps can be removed. The

mortality from colon cancer

decreases by what percentage after

removal of pre-cancerous polyps?

A. 10%

B. 50%

C. 30%

D. 20%

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Objectives:

Review Evidence for

Prevention of Colon Cancer

• Diet

• Life style modifications

• Medications

• Screening Tests

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The Bottom Line

Fiber• Background

– Colon Cancer rare in Africa

• Key Research

– Nurses Health Study: Fiber did not affect

recurrence of adenomas, precancerous polyps

(NEJM 2000)

• Implications for Prevention

– Fiber still good for overall colonic health but

appears not to affect colon cancer risk

For prevention effectiveness: Weak evidence

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The Bottom Line

Calcium Use• Background

– Calcium inhibits the mucosal injury and hyperproliferation

induced by bile acids or carcinogens.

• Key Research

– Randomized, double-blind trial supplementation with

calcium carbonate after adenoma removal by colonoscopy.

Calcium supplementation is associated with a significant –

though moderate – reduction in the risk of recurrent

colorectal adenomas. (NEJM 1999)

• Implications for Prevention

– Calcium intake of 1200-1500 mg per day

For prevention effectiveness: Very good evidence

from several lines of research

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The Bottom Line

Vitamin D and Folate

Vitamin D

• Background – Geographic epidemiology:

Decreasing gradient of mortality rates from North to South in U.S.

• Implications for Prevention– Vitamin D intake of 600 IU

daily (NEJM 2011)

For prevention effectiveness: Not recommended in doses above routine daily requirement at present

• Recent (CGH 2020)

Randomized Trial to decrease

Adenomas=No Benefit for

2000 IU daily over 5.3 years

Folate

• Background

– Folate depletion seems to enhance carcinogenesis and folate supplementation conveys a protective effect. High dose folate has been associated in some patients with an increased risk of cancer.

• Implications for Prevention:

– Folate supplementation at a dose of less than 950 µg per day

For prevention effectiveness: In patients with extensive IBD, folate supplementation appears to be protective.

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The Bottom Line

Obesity• Background

– Obesity’s importance to colon cancer risk is indicated in

men with a BMI > 30 having an increased risk. Obese men

are more likely to develop colon cancer than obese women.

• Key Research

– Obesity has consistently been associated with a higher risk

of colorectal cancer in men (RRs, about 1.5-2.0) and women

(RRs, about 1.2-1.5).

For prevention effectiveness: Very good

evidence that obesity increases the risk of

colon cancer from several lines of research

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The Bottom Line

Physical Activity

• Background

– Physical activity may be associated with a decreased colon

cancer risk.

• Key Research Findings

– Wolin and Colditz: meta-analysis of 20 studies examining the

association between physical activity and the risk of colon

adenomas. A significant inverse association was found with

an overall Relative Risk of 0.84 (CI: 0.77-0.92). The

association was similar in both men and women. Br J Cancer,

2011.

For prevention effectiveness: Physical activity may

have a role in colon cancer prevention.

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The Bottom Line

Smoking

• Background

– U.S. Surgeon General 2004: Evidence for the relationship of

smoking to colorectal cancer was suggestive

• Key Research

– Smoking has recently been shown in the Whitehall I Study from

the United Kingdom to be associated with an increased

mortality from colon or rectal cancer. Current smokers were at

50% greater risk from colon cancer and had twice the risk of

death from rectal cancer.

For prevention effectiveness: Strong support for

cessation of smoking.

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Aspirin• Key Research

– Daily use of aspirin was associated with a significant

reduction in the incidence of colorectal adenomas in

patients with previous colorectal cancer (Sandler, NEJM

2003).

– Aspirin taken daily for several years reduced long-term

incidence of and mortality due to colon cancer (Lancet

2010).

– Regular use of aspirin

appears to reduce the risk

of colorectal cancers that

over express COX-2

(NEJM 2007)

– Low-dose aspirin use was

associated with decreased

CRC risk (OR 0.78 95%

CI 0.65 to 0.92, p=0.004)

(Gut 2010). Din FVN, et al. Gut 2010

Meta-analysis of case-control studies:

effect of low doses of aspirin on

colorectal cancer incidenceCOPYRIGHT

Alternate-Day, Low-Dose Aspirin

Decreased Colorectal Cancer:

Primarily Proximal Colon Cancer

Cook, NR et al. Ann Intern Med. 2013;159:77-85.

Placebo

Aspirin

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The Hypothesized Inter-Related

Mechanisms of Aspirin

chemoprevention.

Drew DA, Cao Y, Chan AT. Nat Rev Cancer. 2016 March ; 16(3): 173–186.

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The Bottom Line

Aspirin

• Implications for Prevention

– Chemo-prevention, as an adjunct to colonoscopy

surveillance in post-polypectomy patients may be more

cost-effective than surveillance alone.

For prevention effectiveness: Evidence is

excellent but potential side effect of bleeding

must be taken into account on an individual

basis.

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Inflammatory Bowel Disease

What are useful preventive

measures?COPYRIGHT

Declining Risk of Colon Cancer

in Ulcerative Colitis

• Meta-analysis of 89 studies, 181,923 patients

met inclusion criteria

• The risk for patients with ulcerative colitis

has decreased steadily over the last 60 years

– incidence rate in 1950 = 4.20/1000 pt yrs

– incidence rate in 2000-2010 = 1.21/1000 pt yrs

The extent and duration of ulcerative colitis

still increase the risk for colon cancer

Castaño-Milla, C. Aliment Pharmacol Ther 2014; 39:645-659

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The Bottom Line

Inflammatory Bowel Disease:

5-ASA Therapy• Key Research

– Prior studies were case-controlled, not population-based.

Case-control studies are more subject to selection bias. A

new meta-analysis of population-based studies from

Manitoba, Canada suggests that 5-ASA is not associated

with the reduced risk of colon cancer in IBD patients. These

data are in stark “contrast” to previous meta-analyses.

– For prevention effectiveness: 5-ASA should NOT be

routinely offered solely as a chemo-preventive

measure against colorectal cancer given the recent

population-based meta-analyses which do not show

a chemoprophylactic effect.

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Bernstein, C. et al. Am J Gastroenterol 2011; 106:731-736.

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Why is Colon Cancer in IBD

Difficult to Diagnose?

Beaugerie L,

Itzkowitz S.

N Engl J Med

2015;372:1441-

52.

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Example of high grade dysplasia

Normal Colon High Grade Dysplasia in a

single fold in a patient with

no current inflammation but

a long history of ulcerative

colitis

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New Worrisome Group:

Younger PatientsCOPYRIGHT

Recognize that younger age groups have

an increasing risk for colorectal cancer.

The reasons are not clear.

Therefore,

symptoms

require full

work up

Colon Cancer

Rectosigmoid

and Rectal

Cancer

Bailey CE et al.

JAMA Surg. 2015;

150(1): 17–22

*

*

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For the general population,

what is most effective for

preventing colon cancer?

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Screening for Colon Cancer:

Staging is improved by screening

Symptomatic Patient Screened Patient

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Comparison of Guaiac-Based and Quantitative

Immunochemical Fecal Occult Blood Testing in a

Population at Average Risk Undergoing Colorectal Cancer

Screening

Sensitivity Specificity

13.6

30.8

16.7

33.9

84.6

43.7

0

20

40

60

80

100

Advanced

Adenomas

Cancer ACRN

Guaiac Testing Immunochemical

Fecal Occult Blood Test

92.4 92.4 92.9

90.689.8

91.9

75

80

85

90

95

100

Advanced

Adenomas

Cancer ACRN

Percent

Park DI, et al. Am J Gastroenterol 2010;105:2017-2025.

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The Bottom Line

Accuracy of Fecal

Immunochemical Tests Update• Nineteen eligible studies were included and

meta-analyzed.

– Pooled sensitivity 0.79 (95% CI ,0.69 to 0.86)

– Specificity 0.94 (CI, 0.92 to 0.95)

– Positive likelihood ratio 13.10 (CI, 10.49 to 16.35)

– Negative likelihood ratio 0.23 (CI, 0.15 to 0.33)

– Overall diagnostic accuracy 95% (CI, 93% to 97%)

• As single sample FIT had similar sensitivity and

specificity as several samples.

Fecal immunochemical tests are moderately sensitive

and highly specific with a high overall diagnostic

accuracy for detecting colorectal cancerLee, JK, Ann Intern Med,

2014; 160:171-181þþþþþ

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Fecal Immunochemical Test

Program Performance

A Retrospective Cohort Study

• Kaiser Permanente study of 323,349 health plan

members aged 50 to 70 years on their FIT mailing date

in 2007 or 2008 who completed the first round of FIT and

were followed for up to 4 screening rounds.

• On first screening, the FIT positivity rate was 5.0%

and positive predictive values were 51.5% for

adenoma, and 3.4% for CRC

• Overall, over the 4-year study, programmatic FIT

screening detected 80.4% of patients with CRC

diagnosed within 1 year of testing

Jensen CD et al. Ann Intern Med. 2016;164:456-463

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Sensitivity of the Multitarget (Hemoglobin +

Stool DNA) versus the Commercial Fecal

Immunochemical Test (FIT) for Colorectal

Cancer Detection

Imperiale TF et al. N Engl J Med 2014, 370:1287-1297

DNA

FIT

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Home Testing is

Easy for the

Motivated Patient

Prince, M. et al. World J Gastroenterol 2017 January 21; 23(3): 464-471

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Early Stage Curable Colon

Cancer Discovered by Flexible

Sigmoidoscopy

http://www.sigmoidoscopeexam.com/flexible.htm

Stage 1 cancer, sigmoid colon

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Colorectal-Cancer Mortality with Screening

Flexible Sigmoidoscopy -

Overall, Distal, and Proximal Colorectal-Cancer Mortality

Schoen RE, et al. N Engl J Med 2012;366:2345-57.

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Colonoscopy:

Who Gets It in the U.S.?

Andersen SW et al. JAMA Network Open. 2019;2(12):e1917995.

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Left-Sided Colon Cancer Benefits

From Colonoscopy

• Canadian province-wide data set identified 10,292

case patients who died of colorectal cancer.

• 7% of case patients and 9.8% of controls had

colonoscopy.

• Colonoscopy was associated with fewer colorectal

cancer deaths.

• Odds ratio for death from cancer in the left colon was

0.33 and 0.99 for cancer in the right colon.

Nancy N. Baxter, MD, PhD; Meredith A. Goldwasser, ScD; Lawrence F. Paszat, MD, MS; et al.

Ann Intern Med. 2009;150:1-8

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Courtesy of Dr. Ram Chuttani, Beth Israel Deaconess Medical Center

Right Colon Polyps and Cancers May

Be Subtle and Difficult to Detect

Endoscopic mucosal resection of

sessile serrated adenoma

Right colonic lesion seen only

because of an excellent prep

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Why is colonoscopy less effective in

reducing right colon cancers compared

to left?

• Poor Preparation

• Non-Gastroenterologist

• Incomplete exams

• Rapid withdrawal

• Fast growing neoplasms

David F. Ransohoff, MD Ann Intern Med. 2009;150:50-52

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Screening for Colon Cancerwith Colonoscopy

• Background

– The effect of colonoscopy on colorectal cancer incidence and mortality has not been evaluated in a randomized, controlled trial.

• Key Research

– German population-based, case-control study estimating Odds Ratio of colon cancer associated with colonoscopy in prior 10 years

– Colonoscopy with polypectomy is associated with a decreased incidence of colon cancer of 77% (OR 0.23), particularly in left colon and rectum, but substantial reduction also in right colon (Ann Intern Med 2011).

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Cumulative Mortality from Colorectal Cancer in

the General Population, as Compared with the

Adenoma and Non-adenoma Cohorts

Zauber AG, et al. NEJM 2012; 366:687-96.

50% reduction

in expected

mortality in

patients who

had

polypectomy

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Interval Colorectal Cancer:Cumulative Hazard Rates According to the

Endoscopist’s Adenoma Detection Rate (ADR)

Kaminski MF, et al. NEJM 2010; 362(19):1795-1803. Current ADR Expected 20% Women, 30% Men

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What Colonoscopic Findings

Give a 3 Year Interval?

Adenoma > 1 cm Villous Histology High Grade Dysplasia

in an Adenoma

3 or more

Adenomas

Sessile serrated adenoma

> 1 cm

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Serration Defined

Two COMMON

entities with serrated

epithelial surface, but

differing crypt bases

AND differing

outcomesA) Hyperplastic polyp

B) Sessile serrated adenoma

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The Bottom Line

Screening for Colon Cancerwith Colonoscopy

• Implications for prevention– Colonoscopy in prior 10 years with polypectomy

very effective in reducing incidence of colon cancer

For prevention effectiveness:

Colonoscopy with polypectomy very effective in reducing incidence

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New tools for detection: CT and MRI colonography

Graser A. et al. GASTROENTEROLOGY 2013;144:743–750

Pickhardt, PJ. Dig Dis Sci. 2015 March;

60(3): 647–659.

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Summary of Evidence

• Fiber does not significantly reduce colon cancer

• Calcium, Vitamin D and Folate may be helpful

• Obesity, smoking and inactivity increase riskCOPYRIGHT

Summary of Evidence

• Aspirin decreases the risk even in low doses

• Inflammatory Bowel Disease requires careful surveillance

• Screening with FOBT, FIT, FIT + DNA, flexible sigmoidoscopy or colonoscopy with polypectomy, all significantly reduce colon cancer mortality

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