Use of 5α-reductase inhibitors for lower urinary tract symptoms and risk of prostate cancer in Swedish men: nationwide, population based case-control study.


Abstract

Objective To assess the association between 5α-reductase inhibitor (5-ARI) use in men with lower urinary tract symptoms and prostate cancer risk.

Design Nationwide, population based case-control study for men diagnosed with prostate cancer in 2007-09 within the Prostate Cancer data Base Sweden 2.0.

Setting The National Prostate Cancer Register, National Patient Register, census, and Prescribed Drug Register in Sweden, from which we obtained data on 5-ARI use before date of prostate cancer diagnosis.

Participants 26 735 cases and 133 671 matched controls; five controls per case were randomly selected from matched men in the background population. 7815 men (1499 cases and 6316 controls) had been exposed to 5-ARI. 412 men had been exposed to 5-ARI before the diagnosis of a cancer with Gleason score 8-10.

Main outcome measures Risk of prostate cancer calculated as odds ratios and 95% confidence intervals by conditional logistic regression analyses.

Results Risk of prostate cancer overall decreased with an increasing duration of exposure; men on 5-ARI treatment for more than three years had an odds ratio of 0.72 (95% confidence interval 0.59 to 0.89; P<0.001 for trend). The same pattern was seen for cancers with Gleason scores 2-6 and score 7 (both P<0.001 for trend). By contrast, the risk of tumours with Gleason scores 8-10 did not decrease with increasing exposure time to 5-ARI (for 0-1 year of exposure, odds ratio 0.96 (95% confidence interval 0.83 to 1.11); for 1-2 years, 1.07 (0.88 to 1.31); for 2-3 years, 0.96 (0.72 to 1.27); for >3 years, 1.23 (0.90 to 1.68); P=0.46 for trend).

Conclusions Men treated with 5-ARI for lower urinary tract symptoms had a decreased risk of cancer with Gleason scores 2-7, and showed no evidence of an increased risk of cancer with Gleason scores 8-10 after up to four years’ treatment.

Introduction

Chemoprevention by use of 5α-reductase inhibitors (5-ARI) to decrease risk of prostate cancer has been investigated in two large randomised clinical trials. Both these trials showed a decreased risk of prostate cancer overall in men on 5-ARI—finasteride in the Prostate Cancer Prevention trial (PCPT) and dutasteride in Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.1 2 These 5-ARIs inhibit the conversion of testosterone to dihydrotestosterone, the most potent androgen in the prostate, and thereby decrease androgen receptor activity.3 There was a 23-25% reduction in risk of prostate cancer at biopsy for men receiving 5-ARI, compared with men receiving placebo, in both trials. However, in both trials, there was also an increased risk of cancer with Gleason scores 8-10. Based on these findings, The US Food and Drug Administration (FDA) issued a safety announcement in 2011, stating that “5 alpha reductase inhibitors may increase the risk of a more serious form of prostate cancer.”4

The reason for the observed increase in risk in these trials has not been conclusively elucidated, with different explanations for these associations put forward.5 6 7 8 910 11 One theory is that the increase is real and that 5-ARI promotes prostate cancer with Gleason scores 8-10, possibly mediated through lower concentrations of 3β-Adiol and resulting in a decreased stimulation of the oestrogen β receptor.12 Another theory is that the association is spurious and caused by detection bias, because 5-ARI facilitates the detection of small foci of tumours with Gleason scores 8-10.4 To what degree these Gleason 8-10 cancers are associated with progression and prostate cancer death has not been studied. However, because 5-ARIs are widely used in men with lower urinary tract symptoms due to benign prostatic hyperplasia, there is a need to further elucidate the association between 5-ARI use and high grade prostate cancer.

The aim of this study was to investigate the association between the use of 5-ARI for treating lower urinary tract symptoms due to prostatic enlargement in a clinical setting and prostate cancer risk, in particular cancer with Gleason scores 8-10.

Source: BMJ

Use of 5α-reductase inhibitors for lower urinary tract symptoms and risk of prostate cancer in Swedish men: nationwide, population based case-control study.


Abstract

Objective To assess the association between 5α-reductase inhibitor (5-ARI) use in men with lower urinary tract symptoms and prostate cancer risk.

Design Nationwide, population based case-control study for men diagnosed with prostate cancer in 2007-09 within the Prostate Cancer data Base Sweden 2.0.

Setting The National Prostate Cancer Register, National Patient Register, census, and Prescribed Drug Register in Sweden, from which we obtained data on 5-ARI use before date of prostate cancer diagnosis.

Participants 26 735 cases and 133 671 matched controls; five controls per case were randomly selected from matched men in the background population. 7815 men (1499 cases and 6316 controls) had been exposed to 5-ARI. 412 men had been exposed to 5-ARI before the diagnosis of a cancer with Gleason score 8-10.

Main outcome measures Risk of prostate cancer calculated as odds ratios and 95% confidence intervals by conditional logistic regression analyses.

Results Risk of prostate cancer overall decreased with an increasing duration of exposure; men on 5-ARI treatment for more than three years had an odds ratio of 0.72 (95% confidence interval 0.59 to 0.89; P<0.001 for trend). The same pattern was seen for cancers with Gleason scores 2-6 and score 7 (both P<0.001 for trend). By contrast, the risk of tumours with Gleason scores 8-10 did not decrease with increasing exposure time to 5-ARI (for 0-1 year of exposure, odds ratio 0.96 (95% confidence interval 0.83 to 1.11); for 1-2 years, 1.07 (0.88 to 1.31); for 2-3 years, 0.96 (0.72 to 1.27); for >3 years, 1.23 (0.90 to 1.68); P=0.46 for trend).

Conclusions Men treated with 5-ARI for lower urinary tract symptoms had a decreased risk of cancer with Gleason scores 2-7, and showed no evidence of an increased risk of cancer with Gleason scores 8-10 after up to four years’ treatment.

Discussion

In this nationwide, population based, case-control study, increasing duration of exposure to 5-ARI was associated with a decreased risk of prostate cancer overall, and this decrease was restricted to cancers with Gleason scores 2-6 and 7. There was no significant association in risk of cancers with Gleason scores 8-10. Our data, together with previous studies, suggest that the net balance between benefit and harm for 5-ARI use is favourable in men with lower urinary tract symptoms based on prostatic enlargement.

What is known on this topic

  • Several studies have shown that 5α-reductase inhibitors decrease the risk of prostate cancer with Gleason scores 2-7
  • However, the effect of 5α-reductase inhibitors on the risk of cancers with Gleason scores 8-10 is uncertain
  • Men receiving up to four years’ treatment of 5α-reductase inhibitors for lower urinary tract symptoms showed no evidence of an increased risk of prostate cancer with Gleason scores 8-10

What this study adds

Source: BMJ