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6th World Congress on the Aging Male

Tampa, Florida / February 21-24, 2008

According to Dr. Ian Thompson, Professor and Chair, Department of Urology, University of Texas Health Science Center, San Antonio, the prevailing lesson from the PCPT (Prostate Cancer Prevention Trial), as well as from clinical experience with androgen deprivation, is that a reduction in androgen stimulus to the prostate can result in significant reduction in the risk of adenocarcinoma of the prostate. Addressing delegates here this week, Dr. Thompson, principal investigator for the landmark study, shared his insights into the interplay between androgens, prostate cancer and other diseases of the prostate.

The PCPT was a randomized, double-blind, placebo-controlled study involving 18,882 healthy men aged ³55. The trial ended in June 2003, after an interim analysis showed a clear reduction of prostate cancer risk in men assigned to the 5-alpha reductase inhibitor (5ARI) finasteride. The risk reduction was nearly 25% for men on treatment compared with placebo, even after controlling for patient age, race, family history or prostate-specific antigen (PSA) status.

At the same time, however, investigators detected a significant absolute increase in the proportion of high-grade lesions (Gleason scores of 7-10) among patients treated with the 5ARI at 6.4% vs. 5.1% for those on placebo. This led to an editorial by Dr. Peter T. Scardino, Memorial Sloan-Kettering Cancer Center, New York, New York, who wrote, “The study results suggest that finasteride may accelerate the growth of high-grade cancers, which may pose a threat to life and health if they are not treated successfully” (N Engl J Med 2003; 349(3):297-9). However, Dr. Thompson stated, “We now know that is not true.”

Ascertainment Bias

“We now understand that the reason for the increased risk of high-grade disease was simply ascertainment bias,” Dr. Thompson reported. He cited a study he co-authored that examined whether the increased high-grade prostate cancer associated with finasteride in the trial was due either to the agent’s potential effects on tumour morphology or on prostate size (Lucia et al. J Natl Cancer Inst 2007;99(18):1375-83).

Investigators found that while there were comparable degenerative hormonal changes in high-grade biopsies between the active treatment and placebo groups, treated prostates had significantly smaller volumes (P<0.001). In addition, when pathologic surrogates for tumour extent in core biopsy samples were examined, researchers found that the mean percentage of positive cores, mean tumour linear extent (greatest and aggregate), bilaterality and perineural invasion were all lower among treated patients compared with the placebo cohort. Additionally, investigators found that among patients who underwent radical prostatectomy, the significantly higher treatment-associated increase in tumours with a Gleason score of ³7 (P<0.001) was no longer significant in post-surgical pathology (P=0.10).

“It turns out that if you were on placebo and if you were not on a 5ARI, there is a 50-50 chance that if you have high-grade cancer in the prostate, the biopsy will miss it,” Dr. Thompson explained. “If you are on finasteride, there is a 70% chance you will find it, a highly significant improvement in the likelihood of ascertainment.”

To determine whether the tumours identified among men treated with finasteride were clinically significant, researchers examined biopsy samples obtained from 737 patients in the PCPT treatment arm and 1047 in the placebo arm. They defined an insignificant tumour as one with a PSA/cancer volume £0.15, Gleason score of £6 and <3 mm of tumour in not more than one biopsy core.

Among all assessable biopsies (1648 treated patients and 1784 from the placebo arm), only 33% of tumours overall were deemed to be insignificant. Among men on the 5ARI, 28% of tumours were judged to be insignificant compared with 36% of those found in men on placebo. Additionally, of the 97 presumably insignificant tumours removed by radical prostatectomy, 13% were found on pathology studies to be stage T3 lesions, with positive margins or a Gleason score of ³7, “suggesting that the majority of the cancers that were prevented by the use of a 5ARI were clinically significant,” Dr. Thompson commented.

The PCPT investigators concluded that the observed increase in high-grade cancers among treated patients may have been due to finasteride-associated shrinkage of tumour volume and inhibition of low-grade cancer, rather than an unexplained effect of the compound on tumour morphology.

Improved Sensitivity of PSA, DRE and Biopsy

According to Dr. Thompson, 5-alpha reductase inhibition improves the sensitivity of PSA and digital rectal examination for prostate cancer detection and, in the case of biopsy, improves both sensitivity for detection of prostate cancer and high-grade disease. “Finasteride significantly shifts the receiver-operating characteristic [ROC] curve for PSA,” he stated. “There are very few clinical tests that shift an ROC curve for any biomarker in any biologic disorder, and it is a significant shift in the ROC. If we use a cutpoint of 4 [ng/mL] to recommend a biopsy, the adjusted finasteride-treated cutpoint would be 1.6 to obtain the same specificity.”

At that level of specificity, the sensitivity of PSA for prostate cancer among patients on placebo was 24% compared with 37.8% for patients on finasteride, he noted. Similarly, at a PSA cutpoint of 4.1 ng/mL for patients on placebo or 1.6 ng/mL for those on the 5ARI, the specificity of the test for high-grade disease was 90.5% and the sensitivity was 39.2% for those on placebo, compared with 53% for treated patients.

Treating BPH with 5ARIs

The use of the 5ARIs dutasteride and finasteride for the treatment of lower urinary tract symptoms associated with BPH was addressed by Dr. Timothy D. Moon, Professor of Urology, University of Wisconsin, Madison. Dutasteride is an inhibitor of both type I and type II 5-alpha reductase, whereas finasteride is selective for type I. Both agents produce significant lowering of serum and intraprostatic dihydrotestosterone. Dr. Moon reported that both agents significantly decrease prostate volume, reduce urinary symptom scores and the risk of urinary retention, and decrease the need for surgical interventions for BPH by acting on receptors in the prostate and genitourinary tract.

Sexual side effects of finasteride include decrease in libido, ejaculate volume and potency, although the incidence of these is low, Dr. Moon noted. In an efficacy study of dutasteride, the incidence of erectile dysfunction, decreased libido, gynecomastia and ejaculatory disorders were all significantly higher among treated patients during the first year of the two-year placebo-controlled trial, but by the second year, only the gynecomastia remained significantly elevated. Both agents also are associated with an increase in serum testosterone from 10% to 20%, but the increase is within the normal physiologic range and not considered to be clinically significant, Dr. Moon added.

Because the 5ARIs take about six months to reach their maximal effect on BPH reduction, there is some concern among physicians that their patients might be unwilling to wait that long for symptomatic relief. “I think there is a general sense from physicians of all types that immediate gratification is required,” Dr. Moon observed, “but surveys of patients suggest that is not the case. They are happy to go for the long term rather than the short term, in which case having to wait six months is not going to be a problem for them.” Combination therapy with an alpha-adrenergic blocking agent, such as alfuzosin or tamsulosin, and a 5ARI may be required for optimal symptomatic relief in patients with larger prostates, he added.