5α-reductase inhibitors for benign prostate hypertrophy and risk of high-grade prostate cancer

[pjoshea13]

New study below.

Oh dear, it's been a few years since this issue was put to bed, & now this French study stirs things up again.

Recall that both the PCPT (Prostate Cancer Prevention Trial, using Finasteride) & the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trials led to a significant reduction in lesser PCa, but an apparent increase in high-grade disease (Gleason score [GS] 8-10).

It made sense to me. While 5alpha-reductase inhibitors (5-ARIs) reduce dihydrotestosterone [DHT], they also reduce the beneficial DHT metabolite that is the natural ligand for the protective beta estrogen receptor [ERbeta].

Time passed & there was no excess mortality in either treatment arm. Seems that the small increase (numerically) in high-grade PCa was due to detection bias caused by smaller prostate size.

The new study reports a 36% lower risk of GS<8, but a 76% higher risk of GS≥ 8.

"Patients treated for longer than 2 years with 5-alpha reductase inhibitors should be informed of increased risk for the development of high-grade disease."

The new study differs from the prevention studies. In PCPT & REDUCE, men underwent biopsies at the end of the trials. In the French study, detection was unrelated to 5-ARI use. Since 5-ARIs reduce PSA increases caused by BPH, this can have an effect on PCa screening. Perhaps some users ended up being diagnosed at a later stage?

-Patrick

ncbi.nlm.nih.gov/pubmed/300...

BJU Int. 2018 Jul 19. doi: 10.1111/bju.14495. [Epub ahead of print]

Use of 5α-reductase inhibitors for benign prostate hypertrophy and risk of high-grade prostate cancer: A French population-based study.

Scailteux LM1,2, Rioux-Leclercq N3,4, Vincendeau S5, Balusson F2, Nowak E6, Oger E1,2.

Author information

1

Pharmacovigilance, Pharmacoepidemiology and Drug Information Centre, Department of Clinical Pharmacology, Rennes University Hospital, 35033, Rennes, France.

2

Univ Rennes, EA 7449 REPERES 'Pharmacoepidemiology and Health Services Research', F 35000 Rennes, France.

3

Pathology Department, Rennes University Hospital, Rennes, France.

4

Inserm UMR 1085 - IRSET, Rennes University, France.

5

Urology Department, Rennes University Hospital, Rennes, France.

6

Université de Bretagne Loire, Université de Brest, INSERM CIC 1412, CHRU de Brest, France.

Abstract

BACKGROUND:

To assess the association between 5α-reductase inhibitor (5-ARI) use and high grade (Gleason score 8-10) prostate cancer.

METHODS:

We set up a population-based nested matched case-control study using the French Health Insurance Database linked to data from all Brittany (France) path labs. Among 74,596 men with ≥ 1 drug reimbursement for symptomatic benign prostate hypertrophy between January 1, 2010 through December 31, 2011, 767 incident prostate cancer cases between January 1, 2012 through December 31, 2013 were matched on age and delay between the first observed delivery of drug for benign prostate hypertrophy (5-ARI, alpha-blockers or phytotherapy) and diagnostic date of the case to five controls, using an incidence density sampling design.

RESULTS:

963 men (153 cases, 810 controls) had been exposed to 5-alpha reductase inhibitors. A statistically significant heterogeneity (p = 0.0048) was detected across cancer grades when estimating association between prostate cancer and 5-alpha reductase inhibitors long term use (≥ 2 years) versus no 5-alpha reductase inhibitor exposure: adjusted conditional odds ratio was 1.76 [0.97-3.21] for Gleason ≥ 8, and 0.64 [0.44-0.93] for Gleason < 8.

INTERPRETATION:

Our results supported an increased risk for high-grade and a decreased risk for low-grade prostate cancer. Patients treated for longer than 2 years with 5-alpha reductase inhibitors should be informed of increased risk for the development of high-grade disease. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS:

5 alpha reductase inhibitors; Benign prostate hypertrophy; alpha blockers; population based-study; prostate cancer

PMID: 30025199 DOI: 10.1111/bju.14495

[cesanon]

Hmmm so avodart can treat normal prostate cancer, but might help mutate normal prostate cancer into high grade aggressive small cell cancer.

Do I have that right?

[Canoehead in reply to cesanon]

The study did not look at effects on men who already have PCa. It examined risk for men with BPH. I know that many here advocate for use of Avodart once you have the disease, but I am reluctant to add it to my mix of supplements.

[Hazard in reply to Canoehead]

Avodart is not a supplement its a prescription drug.

Anyways, what is rationale for your reluctance?

I discussed adding Avodart or Proscar to my Zoldex routine (which doesn't work in any case) with my MO, he just said "oh you have read Snuffy Myers' book have you" and wouldn't give me a script. So in my case its not even an option.

[pjoshea13 in reply to cesanon]

I would look to the PCPT & REDUCE studies, since there has been long-term follow up. There has been no excess mortality, so the finding of excess high-grade PCa seems to have been an artifact of study design. Detection bias. Satisfied Dr. Myers so I'm OK with it too.

I'm sure that the 5-ARI makers already have teams looking at the French data with damage control in mind.

-Patrick

[cesanon in reply to pjoshea13]

"Satisfied Dr. Myers so I'm OK with it too."

Myers had me on low dose Avodart. When I moved to Sartor, he took me off the Avodart. Startor's explanation was that Avodart was not enough to do anything other than kill just the weak prostate cancer cells... and therefore promote continued mutation.

Myer's said that was valid thinking and didn't object to it.

So there appears to be a valid case for using Avodart (Myers) and a valid case for not using Avodart (Sartor) in a post-treatment situation.

[pjoshea13 in reply to cesanon]

With Myers, he never understood why men on ADT were not tested for DHT. Sure, the target of Lupron is testosterone, but the aim of ADT is to deny the androgen receptor DHT. Doctors assume that zero T means zero DHT, but Myers himself produced significant DHT in spite of very low levels of T while on ADT.

Only a minority of his patients needed Avodart to control DHT & a weekly dose was often enough to control it, once Avodart levels had built up. He has a vlog post on this.

The case for Avodart for everyone else on ADT is that a backdoor method of making DHT within PCa cells, independent of T, can emerge while on the way to CRPC. While Myers mentions this in another post, he seems to have believed that DHT made in the privacy of a PCa cell would show up in a blood test. I don't see why the test could be depended upon.

-Patrick