Although finasteride reduced the risk of prostate cancer by at least 25% in the PCPT, the observed higher risk of high-grade tumors led to a general dismissal of finasteride for preventing prostate. Since the original PCPT report in 2003, investigators have uncovered the following biases in cancer detection caused by finasteride: A ‘shift’ in the receiver operating characteristic curve of PSA, enhancing detection of overall and high-grade prostate cancer, an increased sensitivity of DRE for cancer detection, and an increased sensitivity of biopsy for high-grade cancer detection, all of which were statistically significant.6,7,8
These three biases of finasteride were accompanied by a greater likelihood of biopsy in the PCPT placebo group
The present analyses systematically controlled for these and other factors in calculating the true rate of cancer in the two study groups. Multiple factors, including baseline characteristics and characteristics of participants at their annual visits, significantly influenced whether a man underwent a biopsy, as the PCPT primary endpoint required. Older subjects and men on finasteride had a lower likelihood of biopsy, and race (white), family history of prostate cancer, and an interim prostate biopsy recommendation increased biopsy likelihood.
Our first of two major analyses incorporated all of these covariates and showed that the biopsy cancer detection rates in the entire PCPT population (15,990 men) would have been similar, albeit slightly lower, than were observed in the 10,182 men who actually had an endpoint determined. () Overall prostate cancer rates were estimated to be 14.7% (finasteride) and 21.1% (placebo) in the entire population and 16.6% (finasteride) and 22.9% (placebo) in those where the endpoint was actually evaluated. Estimates of high-grade prostate cancer rates were 4.8% (finasteride) and 4.2% (placebo) in the entire population and 5.8% (finasteride) and 4.8% (placebo) in those where the endpoint was actually evaluated. The modeled data substantiate the hypothesis that the biasing factor of an increased frequency of biopsy in the placebo group had a negligible impact on the outcome comparisons between the placebo and finasteride groups but accounting for PSA and DRE biases did result in a high grade cancer risk ratio estimate closer to 1.0 as we would expect. This conclusion is important to our second analysis, which comprehensively assessed the influence of other factors that can bias biopsy results and thus the cancer comparisons between the two study groups.
Our second analysis controlled for the increased sensitivity of biopsy in finasteride-treated men for detecting high-grade prostate cancer among men with a cancer diagnosis. We extended the prostate-cancer grade changes from biopsy to radical prostatectomy in the subset of men who had a prostatectomy to the entire PCPT population. The estimated “true” rates of high-grade disease in this analysis were 8.2% (placebo) and 6.0% (finasteride), a 27% relative risk reduction suggesting that it was highly unlikely that finasteride actually increased the risk of high-grade cancer in the PCPT ().
Limitations of these analyses include imprecision of the 27% reduction in high-grade cancer risk because of the relatively small numbers of high-grade cancers in the PCPT, assumptions that all study participants could possibly have had a prostatectomy upon cancer diagnosis, and assumptions that the weights were modeled correctly and included all the relevant information. However, it should be noted that confounding factors would need to be related to both having an endpoint and prostate cancer to have an impact. A major limitation of all estimates is inherent with the prostate biopsy itself, which is only a sampling of the prostate. The majority of PCPT men had 6-core biopsies, which would be expected to have missed many cancers that would have been detected with the current 10-12-core biopsy regimens. The advantage of the 6-core biopsy, however, was in detecting cancers that were more likely to be clinically significant (versus detection with 10-12 core biopsies).
A complex set of factors bear upon the recommendation and decision to take finasteride or virtually any other cancer preventive agent. Important factors in the finasteride recommendation/decision include the general burden of prostate cancer, clinical significance of the prevented cancers, and drug benefit-risk ratio. Consideration of each of these factors tends to throw a favorable light on finasteride prevention of prostate cancer. First, prostate cancer has a substantial medical, emotional and financial burden especially with its frequency of detection in the atmosphere of a strong emphasis on screening in the U.S. Second, the prevented cancers in the PCPT have been evaluated for, and found to have, a substantial proportion of clinically significant tumors ([Lucia, CaPR 2008]
). Even men with less-consequential, low-grade prostate cancers, however, frequently seek and receive treatments , which have the consequences of high expense, risks of sexual, urinary, and bowel side effects, and an emotional toll on patients and families from lifetime follow-up surveillance for prostate cancer recurrence.14
Last and most relevant to the debate about finasteride prevention, is the consideration of the agent’s benefit-risk ratio. Men must weigh the established benefits of an observed 25% reduction in prostate cancer (or a 30% actual risk reduction as found in this analysis) as well as a decrease in urinary symptoms and complications of an enlarged prostate against the potential side effects. Although established side effects of finasteride include reduced sexual function, the present analyses lead us to conclude that men 55 years or older can remove the perceived increased risk of high-grade prostate cancer from their consideration of the adverse effects of finasteride. We found no evidence that finasteride induced high-grade disease but that there may have been an actual reduction in risk.