Chemoprevention of Colorectal Cancer: Design Considerations and Implications

Robert S. Sandler, M.D., M.P.H.Professor of Medicine and Epidemiology

University of North Carolina at Chapel HillChapel Hill, North Carolina

Is colorectal cancer prevention possible? How would we design a chemoprevention study? Are adenomas reasonable endpoints? How quickly might we see an effect? Is there a concern about rebound or tachyphylaxis? How long do we need to continue a study? What are the implications?

Questions

Migrants from Japan to Hawaii and the United States acquire higher rates of colorectal cancer

Japan UnitedStates

Hawaii

Is colorectal cancer prevention possible?

Patients at Risk

Eligible

Enroll Compliant

Possible Run-in

Placebo

Agent

Randomize

Endpoint

Endpoint

How would we design a chemoprevention study?

Intervention Interval

Cancer endpoint

It would be impractical to conduct a study with colorectal cancer as an endpoint.

it takes decades for colorectal cancer to develop

colorectal cancer is uncommon making the sample size for a prevention trial prohibitive

ethically complex

Vol. 8, 314-346, February 2002 Clinical Cancer Research

Special article

Treatment and Prevention of Intraepithelial Neoplasia: An Important Target for Accelerated New Agent DevelopmentRecommendations of the American Association of Cancer Research Task Force on the

Treatment and Prevention of Intraepithelial NeoplasiaJoyce A. O’Shaughnessy, Gary J. Kelloff, Gary B. Gordon, Andrew J. Dannenberg, Waun Ki Hong, Carol J. Fabian, Caroline C. Sigman, Monica M. Bertagnolli, Steven P. Stratton, Stephen Lam, William G. Nelson, Frank L. Meyskens, David S. Alberts, Michele Follen, Anil K. Rustgi, Vali Papadimitrakopoulou, Peter T. Scardino, Adi F. Gazdar, Lee W. Wattenberg, Michael B. Sporn, Wael A. Sakr, Scott M. Lippman, and Daniel D. Von Hoff

Surrogate endpoints

“Intraepithelial neoplasia is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer that predicts for a substantial likelihood of developing invasive cancer”

Colorectal adenoma is intraepithelial neoplasia

IEN (adenoma) is a disease: treatment provides clinical benefit Reducing IEN (adenoma) burden is an important and

suitable goal for a medical intervention to reduce invasive cancer risk and reduce “surgical” morbidity

Achieving prevention and regression of IEN (adenoma) confers and constitutes benefit to subjects and demonstrates the effectiveness of a new treatment agent.

American Association for Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia

Clinical Cancer Research 2002;8:314-346

Surrogate endpoints

Are adenomas reasonable endpoints?

There is compelling evidence to support adenomas as endpoints in chemoprevention trials

pathology molecular biology experience of patients with FAP National Polyp Study Telemark study Minnesota FOBT randomized trial

How quickly might we see an effect?

VOLUME 340 January 13, 1999 NUMBER 2

Number of subjects with one or more polyps – 19% decreaseMean number of polyps per subject – 24% decrease

NEJM 1999;340:101-7

Early and later effects of calcium supplements

relative risk* 95% CI

First study interval (1y) 0.78 0.63-0.96

Second study interval (1-4y) 0.81 0.67-0.99

* Adjusted relative risk of > 1 adenoma

Calcium polyp prevention study

NEJM 1999;340:101-7

0

50

100

150

200

250

treatment

Placebo

Sulindac

Time (months)3 6 9 12

Num

ber o

f Pol

yps

(% c

hang

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m b

ase

line)

NEJM 1993;328:1313

Is there a concern about rebound?

GASTROENTEROLOGY 2002;122:641-645

Long-term Treatment with Sulindac in Familial Adenomatous Polyposis: A Prospective Cohort Study

MARCIA CRUZ-CORREA, LINDA M. HYLIND, KATHRINE E. ROMANS, SUSAN V. BOOKER, and FRANCIS M. GIARDIELLO

Department of Medicine, Division of Gastroenterology, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Is there a concern about tachyphylaxis?

Number of polypsMean range % reduction p-value

Baseline 28.9 7-80 -- --

12 Months 6.8 0-28 76% 0.002

Last F-U* 8.3 0-50 74% 0.004

* Mean follow-up 63.4 months (4-98)

50% of subjects were polyp free

Duration of effect

Effect of Sulindac on Number of Rectal Polyps

Cruz-Correa et al. Gastroenterology 2002, 122:641-5

Gastroenterology 1997;112:594-642

Colorectal Cancer Screening: Clinical Guidelines and Rationale

SIDNEY J. WINAWER, ROBERT H. FLETCHER, LAURA MILLER, FIONA GODLEE, MICHAEL H. STOLAR, CYNTHIA D. MULROW, STEVEN H. WOOLF, SETH N. GLICK, THEODORE G. GANIAT, JOHN H. BOND, LESTER ROSEN, JANE G. ZAPKA, SHARON J. OLSEN, FRANCIS M. GIARDIELLO, JANE E. SISK, ROSS VAN ANTWERP, CAROLYN BROWN-DAVIS, DEBRA A. MARCINIAK, and ROBERT J. MAYER

The following organizations have endorsed the clinical practice recommendations in this report: American Cancer Society, American College of Gastroenterology, American Gastroenterological Association, American Society of Colon and Rectal Surgeons, American Society for Gastrointestinal Endoscopy, Crohn’s and Colitis Foundation of America, Oncology Nursing Society and Society of American Gastrointestinal Endoscopic Surgeons. Other endorsements are pending

How long do we need to continue a study?

“Persons in whom a large or multiple adenomatous polyps are found and removed should have an examination of the colon 3 years after the initial examination.

The interval for subsequent exams depends on the type of polyps that were detected”

3-year study Current standard of clinical practice from evidence-

based guidelines Decision point for subsequent exams Standard adopted for chemoprevention studies

How long do we need to continue a study?

Because virtually all colorectal cancers develop from adenomas, preventing adenomas prevents cancer.

Adenoma Cancer

What are the implications?

Implications

Effective chemoprevention Supplement benefit of

colonoscopy (missed polyps) Decrease the number of polyps

removed Decrease the size of polyps Prevent the development of

adenomas and cancer

CONSEQUENCES: safer exams, less frequent exams, fewer cancers

Conclusions

Colorectal cancer is a preventable disease

Adenomas are important surrogate endpoint biomarkers for chemoprevention studies

Treatment effects may be detected at one year (or sooner)

There is no evidence of rebound or tachyphylaxis

Three year duration is sensible based on opinions of experts and current clinical practice

Treatment could provide benefit by increasing the screening interval, thereby decreasing associated morbidity and lowering health care costs.