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© Oxford University Press 2006.
NEWS |
New Finasteride Trial Results Aim To Curb Controversy
Three years after publication of the history-making Prostate Cancer Prevention Trial (PCPT), the controversy that often overshadowed the positive results appears headed toward resolution.
The PCPT demonstrated that 7 years of prophylactic treatment with finasteride reduced the risk of prostate cancer by 6% (from 24.4% in the placebo group to 18.4% in the finasteride group). However, the results also revealed a statistically significant 1.3% absolute increase in the incidence of high-grade cancer (Gleason sum 
7) in the finasteride patients.
The high-grade disease "issue" assumed a front-and-center position and dampened enthusiasm for the use of finasteride to prevent prostate cancer, acknowledged PCPT principal investigator Ian M. Thompson, M.D., professor and chair of urology at the University of Texas Health Sciences Center in San Antonio. Little evidence exists to indicate that physicians are prescribing a 5
-reductase inhibitor like finasteride for chemoprevention, even in high-risk patients, he said.
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Over the past 3 years, investigators inside and outside the PCPT have tried to figure out whether the increase in high-grade disease was a spurious finding or a true biological effect of finasteride, examining prostate-specific antigen (PSA) levels, risk of high-grade tumors, and prostate size. This issue of the Journal (see p. 1128) includes the first published evidence that finasteride may not increase the rate of high-grade prostate cancer.
Thompson and his coauthors describe the results of an analysis of finasteride's effect on the sensitivity and specificity of PSA's ability to detect prostate cancer. The study shows that finasteride did affect the performance characteristics of PSA in a way that enhanced the chances of detecting prostate cancer. The sensitivity of PSA for prostate cancer was greater in the finasteride group at all levels of detection. Notably, finasteride would therefore increase the chance of detecting high-grade prostate cancer by using PSA, as well as prostate cancer in general.
"For any level of specificity, sensitivity for detecting cancer is improved [with finasteride], and sensitivity for detection of high-grade disease is improved. The implication is that some of the increased detection of high-grade disease [in the PCPT] may have been related to improved PSA performance," Thompson said at the American Urological Association meeting in Atlanta.
The improved performance characteristics of PSA with finasteride results in a stronger signal for a prostate biopsy, he added. Finasteride effectively removes "some of the noise and chatter" caused by benign prostatic hyperplasia (BPH).
"If man undergoes PSA screening for prostate cancer and is on finasteride, the [PSA] screening will work better," Thompson concluded.
That is, during treatment with finasteride, the PSA produced by BPH "goes away, and any elevation in the new baseline PSA is representative of prostate cancer," said Eric Klein, M.D., head of urologic oncology at the Cleveland Clinic. "Since we've lost the background PSA from the BPH, we're more likely to find cancer."
These PSA data represent just one piece of evidence that the increase in high-grade disease with finasteride was not a true change in the underlying aggressiveness of the cancer. One of the first signals that the finding might not have been real came when the researchers realized that prostate cancer risk did not increase over time in PCPT patients treated with finasteride. Among men treated for the full 7 years, the number of high-grade cancers was almost identical: 92 in the finasteride group and 89 in the placebo group. The incidence of high-grade cancer in the finasteride group was double that of the placebo group during the first year of the PCPT, but thereafter the incidence was similar in the two treatment groups.
If finasteride induced high-grade cancer, "one would expect the number of cases to continue to increase [relative to the placebo arm] with increased length of exposure to the drug," Thompson said during the AUA meeting. In the Breast Cancer Prevention Trial, by contrast, the number of endometrial cancer cases due to tamoxifen continued to increase throughout the study (J Natl Cancer Inst 1998;90:1371–8).
Another line of speculation about the increase in high-grade disease centered on finasteride's potential to change the histologic features of prostate cancer in such a way as to increase detection of high-grade cancer. A panel of genitourinary pathologists reviewed specimens of high-grade cancers from the PCPT, specifically looking at nine features typical of prostate cancer. The pathologists found no evidence to support the speculation that finasteride altered the appearance of prostate cancer in any way that affected tumor grade.
Considerable attention has focused on finasteride's effect on prostate volume. When used to treat BPH, the drug relieves symptoms, in part, by shrinking the prostate. In the PCPT, finasteride-treated men had prostates that were about 25% smaller than those of men in the placebo group. Some researchers said a smaller prostate might increase the likelihood of detecting cancer upon biopsy, including high-grade cancer. A recent article in the Journal of Urology supported that concept. Investigators at the University of Toronto reviewed data on 369 radical prostatectomy specimens and found that the risk of missing high-grade cancer increases as prostate volume increases.
Also, Thompson and his colleagues examined the relationship between gland size and detection of high-grade cancer in two ways. First, investigators studied features of biopsy specimens of high-grade cancers from the finasteride and placebo groups, including the number of positive cores, percent positive cores, greatest linear extent, aggregate linear extent, percent bilateral, and percent perineural invasion. If finasteride had caused high-grade cancer, those parameters should be greater in the finasteride group. Instead, the opposite was true: They were increased in the placebo group.
A second analysis focused on the grade differences between a patient's biopsy and his radical prostatectomy. If a detection bias in favor of finasteride existed because of prostate shrinkage, fewer tumors would be expected but they would increase in grade from biopsy to radical prostatectomy, Thompson noted. The analysis showed that 30.5% of placebo patients had their tumor's grade increased after their biopsy, compared with 24.5% of finasteride patients. Moreover, 12.5% of the placebo patients had a decrease in tumor grade at radical prostatectomy, compared with 19.8% in the finasteride group. Perhaps most telling, high-grade tumors were detected after prostatectomy but missed by the initial biopsy half the time in the placebo group, compared to 29.7% of the time in the finasteride group.
Whether this accumulation of evidence over the past 3 years has resolved the controversy over finasteride's role in high-grade cancer remains to be seen, but some opinion leaders in urologic oncology have been swayed. Speaking at an instructional course during the American Urological Association meeting, Klein said the PCPT results have affected his clinical practice. In selected patients with mildly elevated PSA, an enlarged prostate, and a negative biopsy, he prescribes finasteride or a similar drug, which would be expected to reduce the patient's PSA level by 50% after 6 months. If the PSA level does fall by 50%, he continues to monitor the patient. If the PSA level doesn't decrease by 50% after 6 months, he performs another prostate biopsy.
In 2003, Peter Scardino, M.D., head of urologic oncology at Memorial Sloan-Kettering Cancer Center, wrote that finasteride was not a good choice to prevent prostate cancer. By 2005, he had changed his mind. He wrote: "Data presented at recent scientific meetings support the concept that [finasteride and similar drugs] may be safe and effective in preventing prostate cancer."
The PCPT results, combined with emerging evidence on other approaches to prostate cancer prevention, indicate to Scardino that "chemoprevention of prostate cancer is at hand. The implications for management are as profound as are those for the medical therapy of BPH."
In the current clinical practice environment in the United States, 95% of men with newly diagnosed prostate cancer grade 6 or above undergo some type of treatment, Klein noted. For radical prostatectomy, only 60% of patients achieve what Scardino has dubbed the clinical "trifecta": negative surgical margins, potency, and continence.
"There is a clear advantage [for chemoprevention] that I think is obvious," said Klein. "If you have an agent that makes a man 25% less likely to be diagnosed with a cancer that is 95% likely to be treated but only 60% likely to achieve an optimal outcome, preventing it in the first place would be preferable."
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