aaps talk 1996
Transcript of aaps talk 1996
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
of P
olyp
s(%
cha
nge
from
bas
e lin
e)
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.