The Prostate Cancer Prevention Trial (PCPT), sponsored by the National Cancer Institute and coordinated by the Southwest Oncology Group, was the first large-scale phase III chemoprevention trial for prostate cancer. The study randomized over 18,000 men to receive either finasteride (5 mg/day) or placebo and followed them with annual examinations and prostate-specific antigen (PSA) measurements. Biopsies of the prostate were obtained during the study if clinically indicated and also at the end of the study regardless of exam or PSA findings. The PCPT was designed to answer a single question: could finasteride, a selective type 1 5α-reductase inhibitor (5ARI), prevent the diagnosis of prostate cancer in men taking the drug versus placebo over a seven year period. In this aspect, the PCPT was a success. The study found a 24.8% reduction in the seven-year period-prevalence of prostate cancer in the finasteride group compared with placebo.1 However, the secondary findings of the study raised two critical concerns that reduced enthusiasm for the use of 5ARI’s for prostate cancer prevention.
The first concern revolved around the nature of the cancers that were “ prevented” in the trial. A unique aspect in the design of the PCPT was the end-of-study biopsy, performed regardless of digital rectal exam (DRE) findings or PSA level. Since almost half of the cancers diagnosed in the PCPT were in men with PSA values ≤4.0 ng/ml and a normal DRE, the concern was that finasteride may have only prevented clinically “insignificant” tumors that would otherwise have not been diagnosed and thus would have little value for impacting prostate cancer as a whole. Pathological criteria have been proposed to identify potentially insignificant tumors on prostate needle biopsy.2,3 When applied to biopsies from the PCPT, it was revealed that 75% of the cancers diagnosed in the PCPT including those at end-of-study met the most commonly used criteria for defining clinically significant tumor.4 This figure is similar to observed rates of insignificant disease of up to 31% in men undergoing radical prostatectomy in previously published studies.3,5
The second and more serious concern was the possibility that finasteride might selectively induce high-grade tumors: the number of men diagnosed with high-grade (Gleason score 7-10) tumors was increased in the finasteride group compared with placebo (6.4% vs. 5.1%, respectively, p<0.005). Subsequent analyses of the data collected during the PCPT do not support this contention but point to an alternative explanation for this apparent increase in high-grade cancer: improved cancer detection. The findings can be summarized as follows: 1) the cumulative proportional incidence of high-grade disease did not exhibit a time-dependent increase in the hazard ratio with prolonged exposure to the drug. 2) pathological analysis of the tumors in the PCPT did not find that high-grade tumors were larger or more advanced in the finasteride arm compared with placebo as would be expected if finasteride potentiated their growth.6 3) finasteride improved the sensitivity and specificity for PSA for detection of cancer overall and high-grade cancer specifically.7 4) finasteride improved the sensitivity of DRE for detection of cancer.8 5) finasteride significantly reduced prostate volume and improved the sensitivity and negative predictive values for prostate biopsy for detecting high-grade cancer.6 Statistical modeling adjusted for biases in prostate cancer detection have estimated that finasteride may actually reduce the risk of high grade disease in addition to its overall reduction in risk of prostate cancer.9,10 These new analyses demonstrate a more favorable risk:benefit ratio for the use of finasteride as a chemopreventive agent for prostate cancer.
The interpretation issues exemplified by the PCPT emphasize an important problem regarding the design of chemoprevention trials that target the androgen axis: how to optimally detect and grade prostate cancer when the agents employed effect our current means of diagnosis. In order for an individual to be diagnosed with cancer on biopsy, two things must happen: 1) there must be an indication for biopsy (ie. an elevated PSA or abnormal DRE) and 2) the needle must strike the tumor when inserted into the prostate. The effects of finasteride on PSA performance (possibly due to the ability of finasteride to suppress PSA being produced by the benign prostate to a greater degree than that produced by cancer) and biopsy performance (due to shrinkage of the prostate) have impacts on both of these factors. Finasteride apparently inhibited low-grade cancer to a greater degree than high-grade cancer in the PCPT leaving high-grade foci to be impacted more by increased detection. This may or may not be due to increased expression of Type 1 5α-reductase in high-grade cancer.11 Whether dutasteride, a dual type 1 and 2 5ARI, has similar effects in the REDUCE trial remains to be seen.12
Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN01-02.
Seventh AACR International Conference on Frontiers in Cancer Prevention Research-- Nov 16-19, 2008; Washington, DC