Chemoprevention of Colorectal Cancer: Design Considerations and Implications

1. 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 Hill Chapel Hill, North Carolina

2. Questions • 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?

3. Is colorectal cancer prevention possible? UnitedStates Japan Hawaii Migrants from Japan to Hawaii and the United States acquire higher rates of colorectal cancer

4. How would we design a chemoprevention study? Endpoint Placebo Compliant Enroll Randomize Possible Run-in Endpoint Agent Intervention Interval Eligible Patients at Risk

5. 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

6. Surrogate endpoints Vol. 8, 314-346, February 2002 Clinical Cancer Research Special article Treatment and Prevention of Intraepithelial Neoplasia: An Important Target for Accelerated New Agent Development Recommendations of the American Association of Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia Joyce 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 “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

7. Surrogate endpoints • 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

8. 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

9. 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

10. Calcium polyp prevention study 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 NEJM 1999;340:101-7

11. Is there a concern about rebound? Placebo Number of Polyps (% change from base line) Sulindac treatment 3 6 9 12 Time (months) NEJM 1993;328:1313

12. Is there a concern about tachyphylaxis? 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

13. Duration of effect Effect of Sulindac on Number of Rectal Polyps Number of polyps Mean 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 Cruz-Correa et al. Gastroenterology 2002, 122:641-5

14. How long do we need to continue a study? 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

15. 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

16. What are the implications? Adenoma Cancer Because virtually all colorectal cancers develop from adenomas, preventing adenomas prevents cancer.

17. 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

18. 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.