Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

21st Annual Congress of the European Association of Urology

Paris, France / April 5-8, 2006

As discussed by Dr. Michael Marberger, Chairman, Department of Urology, University of Vienna, Austria, prostate cancer affects basically the same population as patients affected by lower urinary tract symptoms and benign prostatic hyperplasia (BPH). Therefore, the Prostate Cancer Prevention Trial (PCPT) message that the 5-alpha reductase inhibitor finasteride reduces overall prostate cancer risk by 24.8% over seven years compared to placebo is very relevant to urologic patients with those conditions.

He enumerated the most common questions posed by individuals with BPH: “‘Do I have prostate cancer? Will I develop prostate cancer? What can I do to prevent prostate cancer?’ Therefore, the possibility of chemoprevention with finasteride appears to be appropriate, given the wide coverage this topic is receiving. An important message from the seven-year, 18,882-man PCPT was that about 50% of cancers are now detected in patients with prostate-specific antigen [PSA] <3 ng/mL. While these tend to be low-risk cancers in younger men, cancer-specific mortality usually increases suddenly after a few years among those patients who remain untreated.”

The question remains whether or not finasteride should be recommended for chemoprevention of prostate cancer, as reduced mortality has not yet been proven. Dr. Marberger suggested that on balance, the risk:benefit ratio among patients at high risk for prostate cancer is efficacious, and even more so in those with symptomatic BPH.

PCPT Revisited

The PCPT trial reported that men taking finasteride achieved a nearly 25% reduction in prostate cancer compared to placebo, regardless of patient age, race, family history or PSA status over seven years. The confounding factor was an absolute increase in high-grade disease (Gleason score 7-10) found in biopsies from the actively-treated cohort of 6.4% vs. 5.1% with placebo.

However, Dr. Scott Lippman, M.D. Anderson Cancer Center, Houston, Texas, reported that major new findings from the latest analyses of new PCPT data on PSA and high-grade disease have indicated that the finding was most likely an ascertainment artefact, due to increased detection of high-grade disease because of a significant 25% reduction in gland volume resulting from finasteride treatment. He also noted that Gleason staging is unreliable in patients given hormonal therapy. Pathologists have also stated that the agent is known to shift Gleason grades to higher values.

“There is also a biologic possibility for this finding,” Dr. Lippman indicated. “If a drug causes an effect, one would normally expect that its effect would be greater the longer a patient is taking the drug. However, that was not the pattern in PCPT, in which the finasteride and placebo curves separated early but remained parallel as the study progressed. This was not consistent with the drug causing the effect. All subjects were biopsied at the end of the study, and there was essentially no difference in high-grade disease in the men who had been taking the drug for seven years. An expert panel reported that the types of histologic changes were not different between finasteride- and placebo-treated subjects. They concluded that although a grade effect may have occurred, there was no compelling evidence that finasteride affected tumour grade or that a grading artefact explained the results of the PCPT.”

Other factors also suggest that the compound was not responsible for high-grade disease, he continued. Many men underwent prostatectomy during the trial and upon analysis, no significant difference in pathologic stage was detected between the placebo and active treatment populations, nor was there any difference in margin status.

According to Dr. Lippman, finasteride does not induce more high-grade tumours; it just makes them easier to detect. The 5-alpha reductase inhibitor decreased gland size by about 27% compared with placebo, which resulted in an increased ratio of tumour:prostate volume. If the shrinkage is primarily in the normal part of the gland, which is believed to be the case, and tumour size is unchanged, there is a much greater chance the biopsy needle will strike the sector with high-grade disease simply because it is relatively larger than the rest of the gland, he explained. “The strongest evidence of such an ascertainment artefact is that among men with high-grade disease before surgery, pre-prostatectomy biopsies detected high-grade disease in 70% of finasteride-treated patients, compared to 50% in the placebo population. So among patients receiving placebo, you simply missed finding high-grade disease 50% of the time, whereas you missed it only 30% of the time among patients on finasteride. Clearly, grading was much more accurate on the 5-alpha reductase inhibitor because it clearly increased the specificity of biopsies for high-grade disease,” he concluded.

Dr. Ian Thompson, University of Texas, San Antonio, added that his group reviewed every core from all high-grade biopsies taken in PCPT and actually found fewer positive cores in the active treatment cohort than in placebo patients. Both linear and aggregate extent were diminished and there was less, not more, high-grade cancer in finasteride-treated individuals. Moreover, it was more often bilateral in placebo-treated patients. Prostatectomy data suggested high-grade disease is found more effectively in biopsy samples since PSA works better with finasteride. High-grade disease was most often detected by elevated PSA in the “for-cause” period.

Chemoprevention in Clinical Practice

“In the practice of chemoprevention, it is my belief that we should focus on potentially clinically significant prostate cancers, ones that, had they not been prevented, would lead to treatment-related morbidity/mortality,” stated Dr. Neil Fleshner, Princess Margaret Hospital, Toronto, Ontario. “The question is what level of risk warrants intervention with a drug to prevent cancer.”

Dr. Fleshner presented a case study: A 44-year-old otherwise healthy black male with a father who died of prostate cancer and a brother who had a recent prostatectomy presents with obvious concerns about prostate cancer. His International Prostate Symptom Score (IPSS) is 12, with a normal digital rectal examination (DRE), an estimated 30 cc gland and PSA 1.2 ng/mL. Should he get a 5-alpha reductase inhibitor? “I believe when we define a man at risk for prostate cancer, we should think not only about his PSA, biopsy status or age, but we should also consider his lifestyle, race and family history. We may see men like this one who have no clinical indication for biopsy or intervention, but have risk factors for prostate cancer that may require chemoprevention,” he told delegates.

Rather than perform a biopsy in this case, Dr. Fleshner started the man on finasteride. After 12 months, he tolerated the treatment well, had an IPSS of 8, the DRE remained benign and his PSA fell from 1.2 to 0.9 ng/mL. So, what happens next? Taking into account that the PCPT trial demonstrated cancer and high-grade disease detection to be better in actively-treated individuals, this patient was biopsied. One core (of 12) showed high-grade prostatic neoplasia. That presented the options of consultation or repeat biopsy at six to 12 months, radical prostatectomy or discontinuing the 5-alpha reductase inhibitor. Since there is good evidence that the compound should depress PSA in prostate cancer for nine to 12 months, the decision was made to repeat the biopsy after a year since the patient had a first-degree family history of the disease. It has been shown that the risk of developing prostate cancer after high-grade diagnosis is only slightly above the risk of benign biopsy. The biopsy was negative and he currently remains on finasteride after more than two years.

Summary

According to Dr. Thompson, urologists may now be able to prevent prostate cancer in some men, and they must understand this opportunity and provide it to patients. Urologists can offer an annual PSA with a 40% to 50% risk for prostate biopsy and about a one in five chance of a positive diagnosis, or they can offer a pill taken once daily which reduces the risk by at least 25%. “My take-home message is crystal clear: you must offer prevention opportunities.”