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Chemopreventive Strategies in Prostate Cancer: Resolving an Enigma

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.

42nd Annual Meeting of the American Society of Clinical Oncology

Atlanta, Georgia / June 2-5, 2006

The Prostate Cancer Prevention Trial (PCPT) demonstrated a highly statistically significant 25% reduction in the period prevalence of prostate cancer over the course of seven years in men 55 years of age and older treated with the 5-alpha reductase inhibitor finasteride 5 mg/day compared with placebo.

“This is only the second time in medical history that a medication was shown to prevent a common human cancer, the first being breast cancer prevention with tamoxifen,” Dr. Barnett Kramer, Director, Office of Disease Prevention, National Institutes of Health, Bethesda, Maryland, told delegates here. Actively treated men in the PCPT also had a significantly lower incidence of urinary symptoms, including prostatitis, urinary retention, benign prostatic hyperplasia (BPH) and transurethral resection of the prostate for BPH.

Establishing the Evidence: Corroborative Data

Having unequivocally demonstrated that men receiving finasteride are less likely to be diagnosed with prostate cancer—important in and of itself, as Dr. Kramer suggested—it may seem unnecessary for the American Society of Clinical Oncology to team up with the American Urological Association as they have recently done to carry out a systematic evidence review of the 5-alpha reductase inhibitor class. The purpose of this review will address a number of important questions, perhaps the most important being a key area of controversy that still lingers following results of the PCPT: whether or not 5-alpha reductase inhibitors potentiate the development of high-grade prostate tumours and if so, how that effect can be explained.

Dr. Scott Lucia, Associate Professor of Pathology, University of Colorado, Boulder, and lead pathologist for the PCPT, has given this issue considerable thought. As explained to delegates, there were 43 more high-grade tumours (defined as Gleason score 7 to 10) in the finasteride arm of the PCPT than in the placebo arm, translating into a 1.3% absolute increase in the number of men diagnosed with high-grade tumours in the PCPT. “The great majority of this increase was in the Gleason 8 to 10 group, the incidence of Gleason 7 tumours being very similar between the two treatment arms,” Dr. Lucia reported. (It is noteworthy that the there was a marked decrease in the prevalence of £Gleason 6 tumours in the finasteride arm in the same trial).

As Dr. Lucia observed, there are three potential reasons which might explain this development. Firstly, it is possible that the agent did potentiate the growth of high-grade tumours, at least in some men. High-grade prostate cancer is, in fact, associated with low androgen levels, which are in turn associated with a more aggressive disease course for men with prostate cancer. Thus, if finasteride were capable of potentiating high-grade tumours, prolonged exposure to the compound in a study such as the PCPT could lead to a cumulative increase in the number of men who developed high-grade cancer over the seven-year trial. This, however, was not the case. Indeed, the difference in the period prevalence of prostate cancer occurred very early on in the PCPT and the difference between the two arms did not diverge over time, suggesting that unlike a therapy such as tamoxifen, which did potentiate endometrial cancer in breast prevention cancer trials, finasteride did not.

Secondly, the agent might have altered the grading of tumours, such that low-grade tumours were somehow phenotypically altered and appeared at pathological staging as high-grade. To explore this hypothesis further, Dr. Lucia and colleagues re-reviewed key pathological features of Gleason 7-10 tumours recovered during the PCPT. For every single value they reviewed—per cent scores positive, aggregate linear extent, bilaterality and median prostate volume—the values were less, often significantly so, in the finasteride arm than in placebo controls. Values also continued to decrease during the course of the study in the active treatment arm, “suggesting that tumours in the finasteride arm were much smaller than their placebo counterparts,” Dr. Lucia observed. There was also nothing in the prostatectomy data to suggest that the 5-alpha reductase inhibitor potentiated high-grade tumour growth either, he added.

In unrelated studies, researchers have observed that androgen withdrawal causes profound changes in the morphology of prostate cancer, including changes in the glandular structure. “This is important,” Dr. Lucia stressed, “because Gleason grading is highly dependent on glandular structure for grading.” To explore the possibility that Gleason grade scoring is unreliable in the face of exposure to finasteride, PCPT trialists convened a panel of expert pathologists to review in a blinded fashion all the high-grade biopsies from PCPT. Following their review, the panel announced that they were unable to identify a single feature or even a group of criteria that could accurately distinguish a finasteride-treated tumour from its placebo counterpart. ”Thus, we do not believe a histological artefact likely explains the results of the PCPT,” Dr. Lucia said.

The third possibility that might explain the discrepancy between the number of high-grade tumours in the finasteride vs. placebo arm of the PCPT was that there was an ascertainment bias in the study. As Dr. Lucia noted, the potential for ascertainment bias in PCPT could be explained by the effect that finasteride has on both prostate volume and on prostate-specific antigen (PSA) levels. “We know that finasteride inhibits low-grade tumours, that is what the study showed,” Dr. Lucia explained. It also shrinks the prostate, so during biopsy, physicians are more apt to find a tumour if one is present, and even more likely a high-grade tumour, as it is less probable that low-grade tumours will grow in the presence of finasteride.

Finasteride also reduces PSA levels by a factor of about 2 ng/mL. Because PSA levels were lower in the active treatment arm by virtue of the compound’s effect on PSA, investigators had to keep adjusting the trigger point for biopsy to keep the number of men who underwent biopsies in each arm relatively similar. As it turned out, PSA had a better sensitivity and specificity for all prostate cancer detection, including the detection of high-grade tumours, in actively treated PCPT men than in placebo controls. An argument could also be made that the tumours biopsied in the placebo arm were undergraded and that if the data from the PCPT were modelled differently to account for undergrading, “there would have been more high-grade tumours in the placebo arm,” Dr. Lucia observed. He concluded, “There is a threshold of detection for prostate cancer based on both PSA levels and digital rectal exam and we feel that finasteride shifted the threshold of detection to the left and by doing so, we picked up more high-grade disease early on. So the observed increase in high-grade cancer in PCPT is due at least in part to increased detection rate of high-grade tumours in men receiving the drug.”

The decision to give finasteride will depend on issues such as a patient’s anxiety about developing prostate cancer, positive family history and other symptoms such as BPH which would benefit from treatment.

Even if further review shows that finasteride has no effect on survival, “you could still argue that it does have a benefit if you are reducing the number of prostate cancers that will be diagnosed and that, in turn, will reduce morbidity and the burden of treatment,” Dr. Lucia stated.

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