Finasteride and High-Grade Prostate Cancer
Finasteride and High-Grade Prostate Cancer
Background: The Prostate Cancer Prevention Trial (PCPT) reported a decreased incidence of prostate cancer overall but an increase in the incidence of high-grade prostate cancer with finasteride compared with placebo. We assessed whether the increased high-grade prostate cancer associated with finasteride in the PCPT was due to finasteride's potential effects on tumor morphology or prostate size.
Methods: Prostate biopsies with Gleason score 8-10 (n = 90, finasteride; n = 52, placebo) were examined histologically for hormonal effects, and those with Gleason score 7-10 (n = 282, finasteride; n = 244, placebo) were examined for pathologic surrogates of disease extent. Prostate volumes were measured at biopsy. Samples from radical prostatectomies (n = 222, finasteride; n = 306, placebo) were examined for tumor grade and extent, and, where possible, grades at biopsy and prostatectomy were compared between the groups. Logistic regression was used to analyze differences between treatment groups with respect to pathologic criteria. All statistical tests were two-sided.
Results: Degenerative hormonal changes in high-grade biopsies were equivalent between the finasteride and placebo groups, but prostate volumes were lower in the finasteride group (median = 25.1 versus 34.4 cm, P<.001). Pathologic surrogates for tumor extent were lower with finasteride than with placebo, including mean percentage of positive cores (34% versus 38%, P = .016), mean tumor linear extent (greatest [4.4 versus 4.8 mm, P = .19] and aggregate [7.6 versus 9.2 mm, P = .13]), bilaterality (22.8% versus 30.6%, P = .046), and perineural invasion (14.2% versus 20.3%, P = .07). Among patients who had prostatectomy, the finasteride-associated increase in high-grade disease (Gleason score ≥ 7) at biopsy (42.7% finasteride versus 25.4% placebo, P<.001) was diminished at prostatectomy (46.4% finasteride versus 38.6% placebo, P = .10). Biopsy identified a greater proportion of patients with high-grade disease present at prostatectomy in the finasteride group than in the placebo group (69.7% versus 50.5%, P = .01). The rate of upgrading (from low-grade cancer at biopsy to high-grade cancer at prostatectomy) and pathologic stage at prostatectomy were similar in both groups.
Conclusions: Effects of finasteride on prostate volume and selective inhibition of low-grade cancer, rather than effects on tumor morphology, may have contributed to the increase in high-grade cancers with finasteride in the PCPT. Although induction of high-grade cancer cannot be excluded, the results suggest that high-grade cancer was detected earlier and was less extensive in the finasteride group than in the placebo group.
The Prostate Cancer Prevention Trial (PCPT) compared the ability of the 5α-reductase inhibitor finasteride (5 mg/day) versus placebo to reduce the risk of prostate cancer. Prostate cancers were detected during the study by "for-cause" biopsy following an abnormal digital rectal examination (DRE) and/or elevated serum prostate-specific antigen (PSA) level or in end-of-study biopsies that were performed regardless of DRE/PSA status.
The PCPT found a 24.8% reduction in the 7-year period prevalence of prostate cancer, i.e., the cumulative number of prostate cancers identified during the 7-year period of the trial, including those in the end-of-study biopsies, in the finasteride group. However, the proportion and number of high-grade tumors (defined as Gleason score 7-10) were higher in the finasteride group than in the placebo group: 280 of 757 (37.0%) of the graded tumors (and 6.4% of evaluated men) in the finasteride group versus 237 of 1068 (22.2%) of the graded tumors (and 5.1% of evaluated men) in the placebo group. This finding raised concerns over the safety of finasteride for prostate cancer prevention. It has been proposed that finasteride increases the risk of high-grade cancer through changes in intraprostatic androgen and/or estrogen signaling. The increased risk of high-grade disease with finasteride in the PCPT, however, was noted in the first year, and the relative risk (RR) did not increase over time, raising the suspicion that the increase may have been due to causes other than induced aggressive disease.
Finasteride alters the levels of intraprostatic androgens, which may have morphologic effects on prostatic carcinomas and cause lower grade tumors to appear higher grade. Finasteride reduced prostate volume by an average of 24% in the PCPT (P<.001) and has recently been found to increase the sensitivity of both DRE and PSA for cancer detection, which jointly could have improved the detection of high-grade tumors in the treatment arm.
This study addresses these potential volume and pathologic biases by using a detailed pathologic analysis of biopsies with high-grade cancer and prostatectomies from the PCPT. Specifically, we report on the results from a panel of pathology experts who blindly examined high-grade biopsies to evaluate whether there was evidence of a hormonal artifact in the finasteride group compared with placebo. We compared pathologic stage and margin status in prostatectomies and measures of disease extent in high-grade biopsies between treatment groups to see whether there was evidence that high-grade cancers from the finasteride group had indications of greater disease extent. In the subset of men for whom we had both biopsy and prostatectomy specimens, we compared Gleason grading patterns to determine whether needle biopsy of the smaller volume prostates in the finasteride group led to improved detection of high-grade cancer foci compared with the placebo group, using grade at prostatectomy as the gold standard for the presence of high-grade disease.
Abstract and Introduction
Abstract
Background: The Prostate Cancer Prevention Trial (PCPT) reported a decreased incidence of prostate cancer overall but an increase in the incidence of high-grade prostate cancer with finasteride compared with placebo. We assessed whether the increased high-grade prostate cancer associated with finasteride in the PCPT was due to finasteride's potential effects on tumor morphology or prostate size.
Methods: Prostate biopsies with Gleason score 8-10 (n = 90, finasteride; n = 52, placebo) were examined histologically for hormonal effects, and those with Gleason score 7-10 (n = 282, finasteride; n = 244, placebo) were examined for pathologic surrogates of disease extent. Prostate volumes were measured at biopsy. Samples from radical prostatectomies (n = 222, finasteride; n = 306, placebo) were examined for tumor grade and extent, and, where possible, grades at biopsy and prostatectomy were compared between the groups. Logistic regression was used to analyze differences between treatment groups with respect to pathologic criteria. All statistical tests were two-sided.
Results: Degenerative hormonal changes in high-grade biopsies were equivalent between the finasteride and placebo groups, but prostate volumes were lower in the finasteride group (median = 25.1 versus 34.4 cm, P<.001). Pathologic surrogates for tumor extent were lower with finasteride than with placebo, including mean percentage of positive cores (34% versus 38%, P = .016), mean tumor linear extent (greatest [4.4 versus 4.8 mm, P = .19] and aggregate [7.6 versus 9.2 mm, P = .13]), bilaterality (22.8% versus 30.6%, P = .046), and perineural invasion (14.2% versus 20.3%, P = .07). Among patients who had prostatectomy, the finasteride-associated increase in high-grade disease (Gleason score ≥ 7) at biopsy (42.7% finasteride versus 25.4% placebo, P<.001) was diminished at prostatectomy (46.4% finasteride versus 38.6% placebo, P = .10). Biopsy identified a greater proportion of patients with high-grade disease present at prostatectomy in the finasteride group than in the placebo group (69.7% versus 50.5%, P = .01). The rate of upgrading (from low-grade cancer at biopsy to high-grade cancer at prostatectomy) and pathologic stage at prostatectomy were similar in both groups.
Conclusions: Effects of finasteride on prostate volume and selective inhibition of low-grade cancer, rather than effects on tumor morphology, may have contributed to the increase in high-grade cancers with finasteride in the PCPT. Although induction of high-grade cancer cannot be excluded, the results suggest that high-grade cancer was detected earlier and was less extensive in the finasteride group than in the placebo group.
Introduction
The Prostate Cancer Prevention Trial (PCPT) compared the ability of the 5α-reductase inhibitor finasteride (5 mg/day) versus placebo to reduce the risk of prostate cancer. Prostate cancers were detected during the study by "for-cause" biopsy following an abnormal digital rectal examination (DRE) and/or elevated serum prostate-specific antigen (PSA) level or in end-of-study biopsies that were performed regardless of DRE/PSA status.
The PCPT found a 24.8% reduction in the 7-year period prevalence of prostate cancer, i.e., the cumulative number of prostate cancers identified during the 7-year period of the trial, including those in the end-of-study biopsies, in the finasteride group. However, the proportion and number of high-grade tumors (defined as Gleason score 7-10) were higher in the finasteride group than in the placebo group: 280 of 757 (37.0%) of the graded tumors (and 6.4% of evaluated men) in the finasteride group versus 237 of 1068 (22.2%) of the graded tumors (and 5.1% of evaluated men) in the placebo group. This finding raised concerns over the safety of finasteride for prostate cancer prevention. It has been proposed that finasteride increases the risk of high-grade cancer through changes in intraprostatic androgen and/or estrogen signaling. The increased risk of high-grade disease with finasteride in the PCPT, however, was noted in the first year, and the relative risk (RR) did not increase over time, raising the suspicion that the increase may have been due to causes other than induced aggressive disease.
Finasteride alters the levels of intraprostatic androgens, which may have morphologic effects on prostatic carcinomas and cause lower grade tumors to appear higher grade. Finasteride reduced prostate volume by an average of 24% in the PCPT (P<.001) and has recently been found to increase the sensitivity of both DRE and PSA for cancer detection, which jointly could have improved the detection of high-grade tumors in the treatment arm.
This study addresses these potential volume and pathologic biases by using a detailed pathologic analysis of biopsies with high-grade cancer and prostatectomies from the PCPT. Specifically, we report on the results from a panel of pathology experts who blindly examined high-grade biopsies to evaluate whether there was evidence of a hormonal artifact in the finasteride group compared with placebo. We compared pathologic stage and margin status in prostatectomies and measures of disease extent in high-grade biopsies between treatment groups to see whether there was evidence that high-grade cancers from the finasteride group had indications of greater disease extent. In the subset of men for whom we had both biopsy and prostatectomy specimens, we compared Gleason grading patterns to determine whether needle biopsy of the smaller volume prostates in the finasteride group led to improved detection of high-grade cancer foci compared with the placebo group, using grade at prostatectomy as the gold standard for the presence of high-grade disease.
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