Urologic Oncology: Seminars and Original Investigations
Original articleFinasteride does not prevent bladder cancer: A secondary analysis of the Medical Therapy for Prostatic Symptoms Study
Introduction
With the continuing high prevalence of smoking in society, the burden of bladder cancer (BC) on an individual- and societal-level remains considerable [1]. Among males, BC has the fourth highest incidence [2]. Research examining the molecular mechanisms underlying BC development and progression has outlined a potentially important role for the androgen receptor (AR) in the preclinical setting. The urothelial AR has been implicated in promoting bladder tumorigenesis and progression [3]. Several studies have demonstrated that AR expression is inversely correlated to BC grade and stage; as well as being down-regulated in neoplastic tissue compared to normal urothelium [4], [5]. Using mouse models, chemical castration or treatment with an antiandrogen was shown to decrease the incidence of carcinogen-induced tumors, whereas testosterone supplementation increased carcinogenesis [6], [7], [8]. Additionally, the AR is suggested to also be involved in disease progression [9], [10]. Subsequently, there was considerable interest in using these findings to prevent BC.
Finasteride, a common medical treatment for benign prostatic hyperplasia and androgenetic alopecia, is a potent 5α-reductase inhibitor which impedes the conversion of testosterone to dihydrotestosterone (DHT). Therefore, based on the results of the aforementioned preclinical studies it was hypothesized that finasteride could prevent the development of BC. There currently is no prospective, randomized data to support this but a recent secondary-analysis of the Prostate, Lung, Colorectal, and Ovarian cancer screening (PLCO) trial reported that finasteride use was associated with decreased incidence of BC (hazard ratio = 0.63, 95% CI: 0.49–0.86) [11]. Although this is initially encouraging there are several limitations to this study which warrant consideration when interpreting the results. As acknowledged by the authors, the analysis was based on self-reported use of finasteride with no data available regarding dose nor compliance. Furthermore, the PLCO dataset did not record DHT or testosterone levels and thus it is not possible to confirm the underlying mechanism of their observed association and establish causality.
By performing a secondary analysis of the Medical Therapy for Prostatic Symptoms (MTOPS) this study aims to characterise whether inhibiting the conversion of testosterone to DHT can prevent the development of BC. The MTOPS trial was a double-blinded, randomized study that enrolled men at least 50 years of age from 1993 to 1998 to determine whether medical therapy with an alpha-blocker (doxazosin) or 5α-reductase inhibitor (finasteride) alone, or in combination, would prevent the progression of benign prostatic hyperplasia.
Section snippets
Medical Therapy of Prostatic Symptoms trial and data
Data from all men enrolled in the MTOPS was included in this analysis. Eligible men were allocated to 1 of 4 treatment groups: placebo, doxazosin, finasteride, or combination of both active treatments. The dose of finasteride was 5 mg daily. A prostate biopsy substudy was undertaken in parallel with the MTOPS trial where randomized patients had their DHT and testosterone blood levels checked at the second screening visit and then at 12, 60, and 72 months/end of study [12]. Medication compliance
Results
Of the 3,047 men enrolled in the MTOPS trial, 338 did not meet the 95% compliance standard for finasteride and were excluded from the analysis. A further 9 patients were excluded as they did not have serum hormone results recorded. Thus, 2,700 men were included in the analysis of which 1,029 men participated in the biopsy substudy. Just under half of the participants received finasteride (45.0%, n = 1,216). Full demographic characteristics are outlined in Table 1.
The overall incidence of BC was
Discussion
Based on a cohort in a defined treatment protocol with robust data on compliance, this study demonstrates that DHT-mediated male androgen activity is unlikely to be an important factor in the development of BC up to 6 years after commencement of therapy. However, the follow-up was limited and thus it is possible that an inhibitory effect could be seen with longer term finasteride administration. Additionally, it is possible that the progression or recurrence of BC could be influenced by the
Conclusion
These results suggest that the effect of male androgens on BC is unlikely to be mediated by the DHT. Serum testosterone levels, urinary symptoms and diagnosis of prostate cancer are not associated with incidence rates of BC in men who do or do not receive a 5α-reductase inhibitor. However, these findings are limited by a lack of data on potential confounders, for example, smoking history.
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