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Long-term use of 5-alpha-reductase inhibitors is safe and effective in men on active surveillance for prostate cancer

  • A. Finelli 1,
  • M. Komisarenko 1,
  • L. J. Martin 1,
  • N. Timilshina 2,
  • K. Jain 1,
  • J. Morris 1,
  • A. Zlotta 2,
  • G. Kulkarni 1,
  • N. Perlis 1,
  • T. van der Kwast 1,
  • A. Evans 1,
  • S. Ghai 1,
  • N. Fleshner 1,
  • S. M. H. Alibhai 3,
  • R. J. Hamilton 1
1 Division of Urology, Department of Surgical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada 2 Division of Urology, Department of Surgical Oncology, Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON, Canada 3 Department of Medicine, Institute of Health Policy, Management, and Evaluation, University Health Network, University of Toronto, Toronto, ON, Canada

Publication: Prostate Cancer and Prostatic Diseases, March 2020

Background

Although 5-alpha-reductase inhibitors (5ARIs) have been shown to benefit men with prostate cancer (PCa) on active surveillance (AS), their long-term safety remains controversial. Our objective is to describe the long-term association of 5ARI use with PCa progression in men on AS.

Materials/subjects and methods

The cohort of men with low-risk PCa was derived from a prospectively maintained AS database at the Princess Margaret (1995–2016). Pathologic, grade, and volume progression were the primary end points. Kaplan–Meier time-to-event analysis was performed and Cox proportional hazards regression was used to determine predictors of progression where 5ARI exposure was analyzed as a time-dependent variable. Patients who came off AS prior to any progression events were censored at that time.

Results

The cohort included 288 men with median follow-up of 82 months (interquartile range: 37–120 months). Among non-5ARI users (n = 203); 114 men (56.2%) experienced pathologic progression compared with 24 men (28.2%) in the 5ARI group (n = 85), (p < 0.001). Grade and volume progression were higher in the non-5ARI group compared with the 5ARI group (n = 82; 40.4% vs. n = 19; 22.4% respectively, p = 0.003 for grade progression; n = 87; 43.1% and n = 15; 17.7%, respectively for volume progression p < 0.001). Lack of 5ARI use was independently positively associated with pathologic progression (HR: 2.65; CI: 1.65–4.24), grade progression (HR: 2.75; CI: 1.49–5.06), and volume progression (HR: 3.15; CI: 1.78–5.56). The frequency of progression to high-grade (Grade Group 4–5) tumors was not significantly different between the groups.

Conclusions

Use of 5ARIs diminished both grade and volume progression without an increased risk of developing Grade Groups 4–5 disease.

With active surveillance, a doctor closely monitors a patient’s condition without giving any treatment unless the symptoms get worse. It is used for, among others, prostate cancer patients in whom the tumour is very small and contained within the prostate. Active surveillance may be stopped for these patients for instance when they start experiencing urinary problems. Urinary problems may occur when the enlarged prostate squeezes the urethra. Drugs out of the specific drug class called “5-alpha reductase inhibitor” may reduce these urinary problems by decreasing the size of the prostate. However, previous studies indicated that there may be a connection between this drug class and the development of advanced prostate cancer.

In this Canadian study, 288 men with prostate cancer were followed for almost seven years. The study reports that progression of prostate cancer was seen less often in men who used drugs out of the drug class “5-alpha reductase inhibitor.” No connection with advanced prostate cancer was found. As a result, drugs out of this drug class may be used during active surveillance, but it should be kept in mind that these drugs can have sexual side effects.

Commented by Dr. van den Bergh

Active surveillance is now the recommended initial treatment strategy for management of low risk prostate cancer according to different clinical guidelines. Patients who switch from expectant management to active treatment do this due to follow-up protocol violation (e.g. increase in number of positive biopsies or Gleason score, quickly rising PSA, progression on  digital rectal examination, growth of MRI lesion, or combinations), anxiety, or other reasons, such as lower urinary tract symptoms (LUTS). From a patient perspective, it is difficult to distinguish whether the LUTS are due to the benign growth component in the prostate, or due to prostate cancer, causing additional stress. 5-alpha-reductase inhibitors (5-ARIs) are one of the pharmacological options to reduce LUTS, by decreasing prostate size, by impacting metabolic transformation of testosterone. However, 5-ARIs also impact PSA levels and prostate cancer risk, so their use during active surveillance is controversial.
 
Finelli et al studied 288 Canadian men with low risk prostate cancer on active surveillance, with a median follow-up of almost 7 years. A total of 85 patients (30%) used 5-ARIs at some point during follow-up. Pathological progression was seen less frequently in the 5-ARI group (28% vs 56%, p<0.001). Grade and volume progression rates were also more favorable in the 5-ARI group. No association with higher Gleason scores at prostate biopsy was found.
 
The current results should be seen in the context of two important randomized studies. In 2012, Fleshner et al showed in the randomised, double-blind, placebo-controlled REDEEM study, that the 5-ARI dutasteride use is associated with lower risk of progression during active surveillance (38% vs 48% after 3 years).  Thompson et al presented in 2003 the impact of 5-ARI finasteride on the development of prostate cancer from the randomized, placebo-controlled PCPT. A 25% reduction in prevalence of prostate cancer was found over a 7-year period. However, a much-debated higher percentage of high Gleason score cancers was also observed in the 5-ARI group (6.4% vs 5.1%), which may be (partly) explained by a combination of volume / biopsy sampling effect, and selective inhibition of low grade cancers.
 
In conclusion, there seems no hard reason to withhold patients on active surveillance from using 5-ARIs. The progression of low risk prostate cancers seems slowed down, and the risk of developing higher risk cancer was not confirmed in the study by Finelli et al. This risk may be especially low using modern active surveillance, including MRI and targeted biopsies. It should however be noted that in this non-randomized study, men starting 5-ARIs during active surveillance follow-up are a sub selection as they have different baseline characteristics then men who don’t start this medication. Finally, 5-ARIs come at the cost of the risk of sexual side effects.