The threshold for physicians to accept worthiness of chemoprevention with 5-α reductase inhibitors remains high.
Conventional wisdom would have it that when results of a major trial are released, and those results strongly encourage a change in the standard of care, then physicians will ultimately make the switch in their treatment approaches. Seven years ago, data from the 8,000-man Prostate Cancer Prevention Trial showed that finasteride (Propecia) was effective in reducing the incidence of prostate cancer. Unfortunately, primary care physicians and urologists in the veterans' healthcare system have not yet gotten the message about the value of finasteride as chemoprevention.
Robert J. Hamilton, MD, Linda S. Kinsinger, MD, MPH, and colleagues looked at trends on monthly new and total prescriptions for finasteride within the Veterans Affairs (VA) system from 2000 to 2005. They wanted to determine how these prescription trends correlated with the 2003 publication of PCPT results (see Table 1).
Prostate cancer chemoprevention trials
Prostate Cancer Prevention Trial (PCPT)
• Study objective: 5 mg finasteride vs placebo
• Result: 25% relative reduction in the incidence of prostate cancer with finasteride
• Extra finding: Proportion of high-grade tumors (Gleason grade =7) was 27% higher with finasteride
N Engl J Med
J Natl Cancer Inst
Reduction by Dutasteride of Prostate Cancer Events (REDUCE)
• Study objective: 0.5 mg dutasteride vs placebo
• Result: 23% reduction in the risk of prostate cancer with dutasteride
• Extra finding: Nonsignificant trend toward increased risk for high-grade disease with dutasteride
N Engl J Med
Dr. Kinsinger is the chief consultant for preventive medicine at the Veterans Health Administration National Center for Health Promotion and Disease Prevention in Durham, N.C. Her coauthors are from the same institution and the department of surgery at the University of Toronto.
The study was conducted in two parts. First, the researchers analyzed prescriptions for 5 mg finasteride or 0.5 mg dutasteride (Avodart) from the VA pharmacy benefits database. Because dutasteride prescriptions made up less than 1% of all 5-a reductase inhibitors (5-ARI), the term "finasteride" was used to refer to both drugs in this study, the authors explained (Cancer Epidemiol Biomarkers Prev online, August 10, 2010).
The second part consisted of a Webbased survey sent to 1,072 primary care physicians (PCPs) and urologists in the VA system. The survey included questions on practice patterns for the diagnosis and treatment of benign prostate hyperplasia (BPH), knowledge of issues surrounding finasteride use in BPH or for cancer prevention, and the use of finasteride as a preventive medication.
The primary outcome for the study was changes in new finasteride prescriptions over time. The authors found that 237,286 patients had new prescriptions for the drug in the study time period. The use of finasteride increased, although the number of new users per month after publication of the PCPT results was less than expected and not statistically significant (P = .45). Also, the number of finasteride prescriptions given as chemoprevention did not change significantly post-PCPT results publication (P = .76).
For the survey, 43.3% of the invited PCPs and 44.7% of the invited urologists responded. Urologists reported prescribing finasteride more often than PCPs, although 64% of those urologists said they never considered it as a chemopreventive, citing the induction of high-grade tumors as the main reason. Among the PCPs, 80% said they never prescribed finasteride as chemoprevention and 52% reported that they did not know the drug could be used in this manner.
One reason for this lack of interest or awareness among the surveyed physicians could be the format in which trial results were presented, the authors suggested. Both the benefits and the harms of finasteride for chemoprevention were discussed in PCPT results, and the effect was different on PCPs and urologists: "PCPs did not seem to hear the message at all, and the urologists heard mostly the potential harms," they wrote.
Of the physicians who did prescribe finasteride, the majority reserved it for those patients they perceived as being at high risk for prostate cancer. Dr. Kinsinger's group noted that the respondents rated moderate to severe BPH as having the greatest influence in their prescription decision. But "BPH is not a risk factor for prostate cancer," the authors pointed out. "Physicians indicated this as a more influential factor than known prostate cancer risk factors such as family history, African-American race, and elevated prostate-specific antigen [PSA]."
The authors outlined some of the data they did not assess with this study: They did not explore whether physicians understood the difference between finasteride and the relative risk for high-grade tumors (27%) vs the much lower absolute risk (1.3%). Also, at the time of the study, physicians may have been reluctant to prescribe chemoprevention because of a lack of clinical guidelines. The American Society of Clinical Oncology (ASCO) and the American Urological Association have recently developed such guidelines (see Table 2).
Guidelines for 5-ARI chemoprevention
"Use of 5-alpha reductase inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology-American Urological Association 2008 Clinical Practice Guideline," J Clin Oncol 27:1502-1516, 2009.
The authors noted that the recent Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial of 6,729 men found a 23% reduction in the risk of prostate cancer with dutasteride, but these results were published after the current study was conducted.
An interesting study during the evolution of chemoprevention
BY JUDD MOUL, MD
Dr. Hamilton and colleagues took a novel look at finasteride prescriptions and physician preferences for prostate cancer chemoprevention in the VA health system. As a busy urologic clinician, I am not surprised by the findings.
Soon after the publication of the PCPT results, there was much controversy and concern over the induction of high-grade cancer by finasteride, and this dampened the enthusiasm for prostate chemoprevention. I took the "kill-two-birds-with-one-stone" approach: I would use finasteride in men who had multiple indications (BPH, lower urinary tract symptoms, desire for hair growth, elevated PSA) and then discussed the possible added benefit of chemoprevention with my patients. I rarely prescribed the drug solely for prostate cancer prevention.
In their paper, Dr. Hamilton's group showed that most of the VA physicians followed the same prescribing patterns as I did: Moderate to severe BPH was the most common indication for finasteride.
The prostate chemoprevention landscape has changed with the release of results from the REDUCE trial, in which Gerald Andriole, MD, and colleagues showed that dutasteride also was effective for prostate cancer chemoprevention (see Table 1). Based on these findings, manufacturer GlaxoSmithKline has resubmitted an FDA application for approval of dutasteride as a chemopreventive agent.
Questions remain about prostate chemoprevention with 5-α reductase inhibitors Are there meaningful differences between finasteride and dutasteride? Both have a similar risk reduction of 23%-25%, but only finasteride was initially associated with a higher grade cancer. Will the FDA approve dutasteride for chemoprevention and would that approval increase the use of this agent for pure chemoprevention among physicians and the public? Will chemoprevention eventually result in a decline in mortality rates for prostate cancer? The study by Dr Hamilton's group comes at an interesting time in the evolution of this field.
Dr. Moul is the James H. Semans, MD, professor of surgery and chief of the division of urologic surgery at Duke University in Durham, N.C. He serves on the Oncology News International editorial advisory board.