Treatment of Advanced Stage Ovarian Cancer

Chemoprevention of Prostate Cancer Amanda Cashen, M.D. Oncology Grand Rounds September 5, 2003 Cancer chemoprevention: Definition  The use of agents to inhibit, delay, or reverse carcinogenesis Principles of Chemoprevention: Multistep Carcinogenesis From Clin Cancer Res, 2002; 8:314 Principles of Chemoprevention: Field Carcinogenesis  Patients at risk for epithelial cancer have a wide area of carcinogenic tissue change – Gross premalignant lesions (leukoplakia, polyps) – Metaplasia, dysplasia – Molecular changes (gene loss/amplification)   Multifocal, distinct premalignant lesions can progress over a ―field‖ of tissue Chemoprevention can affect the whole field Chemoprevention Trials  Populations – Primary healthy, high-risk people – Secondary patients with premalignant lesions – Tertiary patients with prior cancer Chemoprevention Trials  Phase I Trials  Phase II Trials – Short-term dose escalation trials – To determine the maximum dose that has minimal toxicity – To assess drug activity using surrogate endpoints (premalignant lesions or biomarkers) – Can lead to FDA approval (celecoxib for FAP) – May not identify important adverse effects – Can’t provide comprehensive risk-benefit information Chemoprevention Trials  Phase III Trials – – – – Gold standard of chemopreventative activity Large, long-term, randomized study Primary endpoint is invasive cancer Can address important secondary endpoints and validate surrogate endpoints – Need to select agents with strong mechanistic or experimental basis for inhibition of carcinogenesis – Recruitment and compliance can be difficult Chemoprevention Trials v. Chemotherapy Trials Chemoprevention trial Goal Outcome Reduce incidence of cancer Chemotherapy trial Improve prognosis Cancer (low frequency Death or event) progression (high frequency event) Large (thousands to tens of thousands) Relatively small Sample size Patient population Well patients (side effects not tolerated) Ill patients (side effects tolerated) Pitfalls in chemoprevention      May reduce standard screening Same agent may inhibit and promote carcinogensis in different organs (tamoxifen) Serious adverse effects of chemopreventative agents Potentially complex risk-benefit profiles Endpoint of invasive cancer is not a proven surrogate for survival Proposed chemopreventive agents Rationale for using finasteride for the chemoprevention of prostate cancer      Finasteride inhibits 5a-reductase, lowering androgen levels Growth and maintenance of the prostate gland are dependent on androgens Administration of testosterone induces prostate tumors in laboratory animals Prostate cancer regresses with antiandrogen therapy But…finasteride is not effective therapy for prostate cancer Prostate Cancer Prevention Trial NEJM 2003; 349:215  Primary objective To determine whether treatment with finasteride for 7 years can reduce the prevalence of prostate cancer Prostate Cancer Prevention Trial Methods  Eligible participants – Men > 55 years old – Normal DRE, PSA < 3 mg/ml – Adequate compliance during placebo runin period  Exclusion – Severe BPH Prostate Cancer Prevention Trial Methods  Treatment – Finasteride 5 mg qd or placebo x 7 years  Evaluation – Annual DRE and PSA (adjusted for finasteride use) prostate biopsy for abnormal DRE or reported PSA > 4.0 ng/ml – All men were offered an end-of-study biopsy (to be performed 7 years +/- 90 days from randomization) Prostate Cancer Prevention Trial Statistics  Statistical assumptions – Prevalence of prostate cancer during 7 year study will be 6% in placebo group – 25% reduction in prevalence in finasteride group is clinically significant – 60% of men will either have diagnosis of prostate cancer or undergo end-of-study biopsy – Rate of nonadherence will be 14% and ―drop-in‖ rate will be 5%  Analysis – Intention-to-treat analysis includes men with diagnosis of prostate cancer or end-of-study biopsy Prostate Cancer Prevention Trial Results   18,882 men randomized Study was terminated 15 months early – 86.3% completed the study Prostate Cancer Prevention Trial Results    Prostate cancer detected in 18.4% of finasteride group v. 24.4% of placebo group relative risk reduction of 24.8% No difference in survival (5 deaths from prostate cancer in each group) More high grade tumors (Gleason 7-10) in finasteride group (37.0% of tumors) v. placebo group (22.2% of tumors) Cumulative incidence of prostate cancer diagnosed in a biopsy performed for cause or after an interim procedure Grade of prostate cancers detected •Prevalence of high grade tumors 6.4% in finasteride group v 5.1% in placebo group (P<0.001) •Relative risk of a high-grade tumor with finasteride treatment v placebo = 1.27 [1.071.50] Prostate Cancer Prevention Trial Results  Adherence – Rate of nonadherence (percentage of days of treatment missed): 14.7% in finasteride group, 10.8% in placebo group – Drop-in rate in placebo group: 6.5% (by measurement of dihydrotestosterone level) – 36.8% in finasteride group and 28.9% in placebo group temporarily discontinued treatment during the study Prostate Cancer Prevention Trial  Conclusions – Finasteride use for 7 years decreased the prevalence of prostate cancer by 24.8% – BUT the prevalence of high grade prostate cancer was higher in the finasteride-treated group (6.4% v. 5.1%) – Prostate cancer may have been overdiagnosed in the study Prostate Cancer Prevention Trial Challenges  Why was the rate of prostate cancer detection so high? – Lifetime risk of prostate cancer diagnosis is 16.7% – Prostate cancer is found at autopsy in 30-40% of men older than 50  Were the prostate cancers found clinically significant? – The cancers found in this study were mostly low or intermediate grade and 98% were T1 or T2 Prostate Cancer Prevention Trial Challenges  Why were there more high grade tumors in the finasteride group? – Increased sampling with needle biopsy – Reduction of intraprostatic androgen levels may give competitive advantage to high grade tumors – Reduction of PSA level by finasteride may have delayed diagnosis Chemoprevention: Future Directions  Identifying and validating biomarkers and other secondary endpoints – Allows design of more efficient and cheaper chemoprevention trials   Combination chemoprevention (for example, a promoter of differentiation with an antiproliferative agent) Preventative pharmacogenomics—targeting chemoprevention to those at genetic risk