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Chemoprevention of prostate cancer is a laudable and desirable goal. One strategy for chemoprevention is androgen deprivation therapy with 5-reductase inhibitors, such as finasteride and dutas- teride ( 1 , 2 ). The recent landmark Prostate Cancer Prevention Trial (PCPT), which used finasteride, was the first phase III clinical trial of prostate cancer prevention ( 1 ). Finasteride is the only interven- tion that has been shown to reduce the incidence of prostate cancer in a long-term prospective clinical trial ( 3 ). However, despite the impressive 24.8% relative reduction in the 7-year period prevalence of prostate cancer in the finasteride arm of the trial, finasteride has not been embraced in clinical practice ( 4 ). One reason is that there was a higher proportion and number of histologically high-grade carcinomas (defined as Gleason score 7 - 10) in the finasteride group of the PCPT compared with the placebo group. This finding raised the alarming prospect that finasteride induces, via therapeutic selec- tion pressure, the expansion or development of a higher grade, per- haps androgen-independent, tumor cell population. The investigation by Lucia et al. ( 5 ) in this issue of the Journal aimed to assess whether the increased prevalence of high-grade prostate cancer associated with fi nasteride treatment in the PCPT was a Gleason histopathologic grading artifact induced by fi naste- ride. They report important data suggesting that fi nasteride does not induce histomorphologic changes in prostatic carcinoma. The evidence, albeit somewhat indirect, is convincing because, in a blinded review, three expert urologic pathologists did not detect any histopathologic differences between carcinoma in the fi nasteride and placebo arms using nine different histomorphologic parameters that are known to be associated with androgen deprivation therapy effects. The evidence is indirect because this was not a longitudinal test in individual patients of morphologic alterations by examining carcinoma in biopsy tissue before and after fi nasteride treatment. Nevertheless, these data are important because it is well estab- lished that other types of androgen deprivation therapy can induce an apparent increase in Gleason grade due to the loss of luminal glandular spaces (luminal collapse) ( 6 ) and also to the creation of single-cell infi ltrates, which simulate high-grade cancer ( 7 ). Compared with other forms of androgen deprivation therapy, fi n- asteride ' s effects on the histologic appearance of prostatic carci- noma seem to be weaker or nonexistent, and this con clusion is consistent with previously published studies ( 8 - 9 ). As a caveat, it is possible, as the authors note, that the nine parameters may not have been the best or the only ones to defi ne fi nasteride's histo- morphologic effects. The study by Cohen et al. ( 10 ) in this issue of the Journal used two modeling methods to examine the role of detection bias (due to the effect of fi nasteride on reducing prostate volume) as a poten- tial explanation for the increased number of high-grade cancers on biopsy in the fi nasteride group. The authors fi t to the PCPT data an assumed logistic regression model for detection probability as a function of several patient characteristics, including prostate gland volume. They show that increased sampling density bias could account for the 25% increase in high-grade tumors. This explana- tion was previously proposed by Kulkarni et al. ( 11 ) based on an analysis of their patient population, in which there was a greater occurrence of high-grade cancer on biopsy among men with smaller prostates but an equivalent occurrence of high-grade dis- ease in radical prostatectomy specimens. In addition, Serfl ing et al. ( 12 ) used mathematical modeling to quantify how cancer detection probability changes with prostate gland volume when random sex- tant biopsy is performed. In that study, for 30-cm 3 prostates and 0.75-cm 3

High-Grade Prostate Cancer in the Prostate Cancer Prevention Trial: Fact or Artifact?