- Email: [email protected]
Re: Effect of Dutasteride on the Risk of Prostate Cancer
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EUROPEAN UROLOGY 58 (2010) 311–316
Re: Effect of Dutasteride on the Risk of Prostate Cancer Andriole G, Bostwick D, Brawley O, et al N Engl J Med 2010;362:1192–202 Expert’s summary: This is the first published report of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial, a 4-yr, multicenter, randomized, double-blind, placebo-controlled study involving 6729 men and comparing dutasteride 0.5 mg daily to placebo. The study was similar to the Prostate Cancer Prevention Trial (PCPT) [1] with some key differences. To be eligible, men had to have a prostate-specific antigen (PSA) level between 2.5 and 10 ng/ml, and a prior negative prostate biopsy (6–12 cores) within 6 mo before enrollment (vs a PSA <3.0 in PCPT); and the biopsies were at 2 and 4 yr (vs 7 yr). The primary end point was the presence of cancer on 10-core biopsy at 2 and 4 yr. Eighty-three percent of participants were biopsied (vs <50% in PCPT). Less than 7% of cancers were diagnosed on protocol-independent biopsies (vs 52% of cancers diagnosed on for-cause biopsies in PCPT). Of the 3305 men in the dutasteride group and the 3424 men in the placebo group, 659 (20%) and 858 (25%), respectively, had cancer on the follow-up biopsies—an absolute reduction of 5.1% and a relative risk reduction of 23% ( p < 0.001). There was no difference between the groups in Gleason 7–10 cancers overall. Twenty-nine patients on dutasteride had Gleason 8–10, compared with 19 on placebo ( p = 0.15). The most likely explanation for this difference was the removal of 141 more men from the trial with Gleason 5–7 cancers. Based on surveillance studies, about 7% would be upgraded to Gleason 8–10 on rebiopsy [2]. Dutasteride also decreased the rate of urinary retention (1.6% vs 6.7%: a 77.3% relative reduction).
difference in the cancer diagnosis rate when biopsies were being done ‘‘for cause’’; that there was no decrease in higher grade cancers; and that 5a-reductase inhibitors (5-ARIs) do not prevent cancer and may cause a false sense of security by lowering PSA. The for-cause biopsy rate in the REDUCE study was only 6%. Stratification analysis based on this group lacks power. The distinction between a patient having a forcause biopsy for a mild elevation of PSA (in most cases, due to benign prostate hyperplasia) and the patient having a mandated biopsy is moot. In both cases, the results of the prostate biopsy are not predicted by the PSA. Thus the interpretation of these studies should be based on the overall risk reduction and not restricted to the impact on patients having for-cause biopsies. Moreover, diagnosis of a non-lifethreatening cancer is avoided in the sense that the patient is spared the effects of this diagnosis on his life. In the current context of widespread diagnosis and treatment of prostate cancer, a prevention strategy is enormously attractive to patients and physicians. The REDUCE trial provides very strong support for the incorporation of prostate cancer prevention with 5-ARIs into widespread clinical practice.
Conflicts of interest: The author has nothing to disclose.
References [1] Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215–24. [2] Choo R, Danjoux C, Morton G, et al. How much does Gleason grade of follow-up biopsy differ from that of initial biopsy in untreated,
Expert’s comments: The results of this trial complement those of the PCPT trial by demonstrating the efficacy of dutasteride in a group of men most problematic for urologists: those with an elevated PSA and negative biopsy. Whether or not the prevented cancers are clinically significant by pathologic criteria is moot. More than 90% of newly diagnosed favorable-risk cancers are treated radically in the United States; thus, they are clinically significant (even if, by treating aggressively, we make them so). Moreover, a negative biopsy means the patient avoids the cancer diagnosis, an outcome that has significant quality-oflife benefits. Finally, modeling of the PCPT data with correction for the ascertainment bias associated with cytoreduced glands predicted a reduction of Gleason 7–10 cancers of 12–27% [3–6]. The bias-adjusted risk reduction for Gleason 7–10 in the REDUCE study was 38%. In an accompanying editorial, Dr Patrick Walsh looks askance at these data. He argues that there was no significant
Gleason score 4-7, clinically localized prostate cancer? Prostate 2007;67:1614–20. [3] Pinsky P, Parnes H, Ford L. Estimating rates of true high grade disease in PCPT. Cancer Prev Res 2008;1:182–6. [4] Redman M, Tangen C, Goodman P, Lucia S, Coltman C, Thompson I. Finasteride does not increase the risk of high grade prostate cancer: A bias adjusted modeling approach. Cancer Prev Res 2008;1:174–81. [5] Cohen YC, Liu KS, Heyden NL, et al. Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2007;99: 1366–74. [6] Lucia S, Darke A, Goodman P, et al. Pathologic characteristics of cancers detected in the PCPT. Cancer Prev Res 2008;1:167–73. Laurence Klotz Sunnybrook Medical Center, Toronto, Canada E-mail address: [email protected]
DOI: 10.1016/j.eururo.2010.05.017
EUROPEAN UROLOGY 58 (2010) 311–316
Re: Effect of Dutasteride on the Risk of Prostate Cancer Andriole G, Bostwick D, Brawley O, et al N Engl J Med 2010;362:1192–202 Expert’s summary: This is the first published report of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial, a 4-yr, multicenter, randomized, double-blind, placebo-controlled study involving 6729 men and comparing dutasteride 0.5 mg daily to placebo. The study was similar to the Prostate Cancer Prevention Trial (PCPT) [1] with some key differences. To be eligible, men had to have a prostate-specific antigen (PSA) level between 2.5 and 10 ng/ml, and a prior negative prostate biopsy (6–12 cores) within 6 mo before enrollment (vs a PSA <3.0 in PCPT); and the biopsies were at 2 and 4 yr (vs 7 yr). The primary end point was the presence of cancer on 10-core biopsy at 2 and 4 yr. Eighty-three percent of participants were biopsied (vs <50% in PCPT). Less than 7% of cancers were diagnosed on protocol-independent biopsies (vs 52% of cancers diagnosed on for-cause biopsies in PCPT). Of the 3305 men in the dutasteride group and the 3424 men in the placebo group, 659 (20%) and 858 (25%), respectively, had cancer on the follow-up biopsies—an absolute reduction of 5.1% and a relative risk reduction of 23% ( p < 0.001). There was no difference between the groups in Gleason 7–10 cancers overall. Twenty-nine patients on dutasteride had Gleason 8–10, compared with 19 on placebo ( p = 0.15). The most likely explanation for this difference was the removal of 141 more men from the trial with Gleason 5–7 cancers. Based on surveillance studies, about 7% would be upgraded to Gleason 8–10 on rebiopsy [2]. Dutasteride also decreased the rate of urinary retention (1.6% vs 6.7%: a 77.3% relative reduction).
difference in the cancer diagnosis rate when biopsies were being done ‘‘for cause’’; that there was no decrease in higher grade cancers; and that 5a-reductase inhibitors (5-ARIs) do not prevent cancer and may cause a false sense of security by lowering PSA. The for-cause biopsy rate in the REDUCE study was only 6%. Stratification analysis based on this group lacks power. The distinction between a patient having a forcause biopsy for a mild elevation of PSA (in most cases, due to benign prostate hyperplasia) and the patient having a mandated biopsy is moot. In both cases, the results of the prostate biopsy are not predicted by the PSA. Thus the interpretation of these studies should be based on the overall risk reduction and not restricted to the impact on patients having for-cause biopsies. Moreover, diagnosis of a non-lifethreatening cancer is avoided in the sense that the patient is spared the effects of this diagnosis on his life. In the current context of widespread diagnosis and treatment of prostate cancer, a prevention strategy is enormously attractive to patients and physicians. The REDUCE trial provides very strong support for the incorporation of prostate cancer prevention with 5-ARIs into widespread clinical practice.
Conflicts of interest: The author has nothing to disclose.
References [1] Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215–24. [2] Choo R, Danjoux C, Morton G, et al. How much does Gleason grade of follow-up biopsy differ from that of initial biopsy in untreated,
Expert’s comments: The results of this trial complement those of the PCPT trial by demonstrating the efficacy of dutasteride in a group of men most problematic for urologists: those with an elevated PSA and negative biopsy. Whether or not the prevented cancers are clinically significant by pathologic criteria is moot. More than 90% of newly diagnosed favorable-risk cancers are treated radically in the United States; thus, they are clinically significant (even if, by treating aggressively, we make them so). Moreover, a negative biopsy means the patient avoids the cancer diagnosis, an outcome that has significant quality-oflife benefits. Finally, modeling of the PCPT data with correction for the ascertainment bias associated with cytoreduced glands predicted a reduction of Gleason 7–10 cancers of 12–27% [3–6]. The bias-adjusted risk reduction for Gleason 7–10 in the REDUCE study was 38%. In an accompanying editorial, Dr Patrick Walsh looks askance at these data. He argues that there was no significant
Gleason score 4-7, clinically localized prostate cancer? Prostate 2007;67:1614–20. [3] Pinsky P, Parnes H, Ford L. Estimating rates of true high grade disease in PCPT. Cancer Prev Res 2008;1:182–6. [4] Redman M, Tangen C, Goodman P, Lucia S, Coltman C, Thompson I. Finasteride does not increase the risk of high grade prostate cancer: A bias adjusted modeling approach. Cancer Prev Res 2008;1:174–81. [5] Cohen YC, Liu KS, Heyden NL, et al. Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2007;99: 1366–74. [6] Lucia S, Darke A, Goodman P, et al. Pathologic characteristics of cancers detected in the PCPT. Cancer Prev Res 2008;1:167–73. Laurence Klotz Sunnybrook Medical Center, Toronto, Canada E-mail address: [email protected]
DOI: 10.1016/j.eururo.2010.05.017