Treatment for four years with a 5-alpha reductase inhibitor (5-ARI) for lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement was not associated with the development of prostate cancer, a case control study has found.

A total of 26,735 cases of prostate cancer were identified on the Swedish prostate cancer database and matched with 133,671 controls. Of these, 1,499 cases and 6,316 controls had been treated with 5-ARIs, with 412 men exposed to 5-ARI therapy before diagnosis of a Gleason 8-10 tumour.

Increased length of exposure to 5-ARI treatment was associated with an overall decrease in the risk of prostate cancer. Treatment for more than three years was associated with an odds ratio (OR) of 0.72 (95% CI:0.59-0.89, P < 0.001).

This pattern was also seen for low- and intermediate-grade tumours, i.e. those up to and including Gleason 7.

Risk of high-grade prostate cancer (Gleason ≥ 8) was as follows:

• OR 0.96 (95% CI:0.83-1.1) for up to one year of exposure to 5-ARIs

• OR 1.07 (95% CI:0.88-1.31) for 1-2 years

• OR 0.96 (95% CI:0.72-1.27) for 2-3 years

• OR 1.23 (95% CI:0.90-1.68) > 3 years, P = 0.46 for trend

The 5-ARIs have long been thought of as potential chemopreventive agents in prostate cancer i.e. that long-term use, through inhibiting testosterone conversion to dihydrotestosterone, would decrease the long-term risk of development of prostate cancer. However, previous large long-term studies i.e. the PCPT using finasteride and the REDUCE study using dutasteride, while showing a decrease in overall risk of prostate cancer, have shown a small increase in the risk of more aggressive prostate cancers, with a Gleason grade ≥ 8.

This resulted in a warning from the FDA in the US in 2011, stating that 5-ARIs may increase the risk of a more serious form of prostate cancer. Numerous explanations for these findings have been offered, with many experts feeling that the increase is caused by detection bias and is not a true increase in risk.

This study, which showed no increase in risk of Gleason ≥ 8 tumours, has certain strengths compared with the PCPT and REDUCE studies. First, in terms of numbers of men exposed to 5-ARIs and subsequently diagnosed with prostate cancer — 412 men in this study compared with 90 and 29 in PCPT and REDUCE respectively. Second, this study looked at men treated with 5-ARIs for LUTS and only receiving biopsies for prostate cancer based on abnormal digital rectal examination or rising PSA i.e. in the same way as in real life clinical practice. The PCPT and REDUCE studies biopsied men routinely as per the study protocol.

What should we tell men in primary care before commencing treatment with 5-ARIs? First, the evidence for use solely as a chemopreventive agent is not sufficient, given the concerns previously raised over increased risk of high-risk cancer.

However, for men with significant bothersome LUTS requiring optimal medical treatment with a 5-ARI with or without an alpha-blocker, this study strengthens the argument that any increase in risk of development of higher-grade tumours in the long term is not proven and that the long-term benefits to quality of life are likely to outweigh any risk.

Dr Jonathan Rees

• Robinson D, Garmo H, Bill-Alexson A et al. Use of 5α-reductase inhibitors for lower urinary tract symptoms and risk of prostate cancer in Swedish men: nationwide, population based case-control study. BMJ 2013;346:f3406 doi:10.1136/bmj.f3406