Controversies of 5 alpha reductase Inhibitors on Prostate Cancer

Controversies of 5 alpha reductase Inhibitors (Finasteride, Dudasteride) on Prostate Cancer

A review of an article: “Prostate Cancers Detected during 5-aplha Reductase Inhibitor (5aRI) Use are Smaller, De-differentiated, but Confined when Compare to Controls” by Drs. Lee, Badalament, et al.
Journal of cancer, 2012; 3: 122-128

Duke K. Bahn, M.D.
Director, Prostate Institute of America
Ventura, CA

The editor of “Choices” published by PAACT asked me to review the article above due to ongoing controversy in 5aRI and prostate cancer prevention and in the management of localized prostate cancer.

Summary of the paper:

This is a comparison study of cancers detected during the use of 5aRI with cancers detected in untreated controls. All patients have had prostate biopsy “for cause”, as indicated by a rising PSA, positive digital rectal examination, or positive ultrasound finding. Cancer was diagnosed in 76% of patients treated with 5aRI and in 58% of the control group. Much larger tumor diameters were found in the controls (14.3 mm average) than in the 5aRI subjects (9.4 mm). For small volume tumors less than 1.0 Cm, the proportion of high grade cancers (Gleason 7 (4+3) or more) was higher in 5aRI subject than in the control. Even though the Gleason grade was higher, there were fewer incidences of an extracapsular extension of the tumor and abnormal DNA ploidy.

Therefore, besides the Gleason score, the other surrogate markers of tumor aggressiveness suggest that small tumors may still be low risk if detected when small. The authors recommended an aggressive screening strategy for patients who are expected to remain on 5aRI drugs for long time period. It might be also applicable to patients who are undergoing active surveillance management.

5 alpha Reductase Inhibitors (5aRI):

The reason for the use of 5aRI as chemopreventive agents (cancer preventing chemical) is due to the prostate cancer being androgenic in nature and almost no prostate cancer among men with a congenital deficiency of 5aRI. The enzyme 5 alpha reductase is found in prostate tissue and converts testosterone (androgen) to dihydrotestosterone, a more potent agonist of androgen receptors in prostate cells. There are two isoforms; type I predominates in prostate cancer and type II in benign prostate tissue. Finasteride (Proscar) inhibits type II enzyme and dudasteride (Avodart) inhibits both type I and type II enzymes.

The controversy:

Prostate cancer prevention trial (PCPT)

The PCPT evaluated the daily use of finasteride 5 mg vs a placebo for 7 years. The incidence of prostate cancer was reduced by 25% in the finasteride group. The reduction of prostate cancer risk was limited to prostate cancers with low Gleason scores (6 or under). However, there was an increased risk of high grade cancer (Gleasen 8-10) in those taking finasteride. It was also noted that the use of finasteride improved the diagnostic accuracy of PSA and DRE, and more likely diagnose the cancer and high-grade cancer. In addition, finasteride reduced the risk of having HGPIN (probably a precursor to cancer) on rebiopsy by 21.4% relative to the placebo.

Reduction by dudasteride of Prostate Cancer Events (REDUCE)

This study was compared the daily use of dudasteride 0.5 mg over the placebo for 4 years. The analysis showed a 22.8% reduction of cancer risk in the group. The overall risk reduction was limited to a decrease in prostate cancers with a Gleason 6 or lower. It also showed an increased incidence of higher Gleason cancers as in the PCPT study.

Two theories have been postulated as to why a higher grade tumor is seen in 5aRI arms. The first theory is a down sized prostate with 5aRI that make detection easy. The second theory is the increased sensitivity of the PSA and DRE due to downsized prostate volume.

Regardless of the explanation, both trials observed a concerning trend towards increased high-grade disease. However, it should be noted that the absolute risk increase is small.

REDEEM trial

The patients were randomized to receive either dudasteride or a placebo for 3 years. All have low-risk prostate cancer and chose to follow-up with active surveillance. The study showed a significant delay in cancer progression, a more negative follow-up biopsy, and reduced cancer-related anxiety in the dudasteride group. More importantly, there was no evidence of the Gleason score upgrading over time

ASCO/AUA/FDA

The American Society of Clinical Oncology (ASCO) and the American Urology Association (AUA) presented “Clinical Guidelines” for the use of 5aRIs for chemoprevention of prostate cancer in 2008. However, ASCO/AUA have eliminated these from the main “Clinical Guidelines” in 2012, due to the US Food and Drug Administration denying the use of dudasteride for prostate cancer chemoprevention.

What now?

This article reports similar findings as observed in the PCPT and REDUCE trials. Definitely, using 5aRI for the cancer prevention remains controversial due to the questionable clinical significance of the prevented tumors (usually Gleason 6 or under tumors are no treat to life) and an excess of high grade disease in the treated group. It is still unknown whether it is a result of detection bias or a true biological change with the medication.

One can argue that not detecting low grade disease (most of cancers are low grade in PSA era) will eliminate unnecessary treatment and avoiding treatment related morbidity and cost.

For selected patients, chemoprevention with 5aRI could be a reasonable approach after a discussion of the benefits and risks. These include: men at high risk of getting cancer, such as a strong family history, a high base line PSA, a persistent high PSA with negative biopsy. Also included are men who have benign prostate hyperplasia (BPH) with significant lower urinary tract symptoms with high risk factors for cancer.Based on the REDEEM trial results, men diagnosed with a low risk prostate cancer may benefit from 5aRI, as it may result in a significant delay in cancer progression.

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