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Prostate Cancer Prevention with 5-alpha Reductase Inhibitors: Clinical Guideline and Recommendations

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.

MEDI-NEWS Based on 2009 ASCO/AUA Guideline

March 2009

Speaking on behalf of the joint ASCO/AUA panel, Dr. Barnett Kramer, National Institutes of Health, Bethesda, Maryland, stated panellists conducted a systematic review of the medical literature, which formed the basis for evidence-based recommendations about the use of 5-alpha reductase inhibitors (5-ARIs) to prevent prostate cancer. The review revealed 15 randomized clinical trials of sufficiently high quality to include in discussions of chemoprevention with 5-ARIs. The 15 trials included nine studies that reported prostate cancer period prevalence.

The panel’s findings and recommendations will be published in March issues of the Journal of Clinical Oncology and the Journal of Urology. The recommendations have already been posted on the organizations’ Web sites (www.asco.org and www.auanet.org).

Rather than serving as a definitive clinical guideline, the recommendations aim “to provide a useful tool for clinicians and their patients in making an informed decision about the potential harms and benefits of taking 5-ARIs for preventing prostate cancer,” the panel wrote in the introduction to the guideline. New information about the role of 5-ARIs in chemoprevention of prostate cancer will likely emerge from continued analysis of PCPT (Prostate Cancer Prevention Trial) data and from the ongoing REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial, which is evaluating chemoprevention with dutasteride.

“The principal focus of the panel was on shared decision making,” Dr. Kramer said at an ASCO press briefing.

Key ASCO/AUA Recommendations

The guideline offers three major recommendations for use of 5-ARIs to prevent prostate cancer:

• Men with a prostate-specific antigen (PSA) level of 3.0 ng/mL or lower who are screened regularly—or plan to get yearly PSA tests—and currently have no signs of prostate cancer are encouraged to talk with their doctors about the risks and benefits of taking a 5-ARI to further prevent the likelihood of prostate cancer.

• Men who are already taking a 5-ARI for other conditions should talk to their doctor about continuing the drug for prostate cancer prevention. • Chemoprevention should be an informed decision. Doctors and patients should have a thorough discussion of the trade-offs.

Dr. Kramer emphasized that the “recommendation is not that men take a 5-ARI but that the health issue is important enough that a discussion, as part of a periodic check-up, is worthwhile. Many men will choose not to take finasteride or another 5-ARI, and others will choose to take it.”

Canadian Guidelines Confirmed

The recommendations complement those from a consensus panel convened by the Canadian Urological Association (Klotz L, Saad F. Can Urol Assoc J 2007;1(1):17-21). That panel considered the larger issue of 5-ARI use in chemoprevention of prostate cancer and management of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).

With respect to chemoprevention of prostate cancer, the Canadian panel reached four principal conclusions:

• The PCPT showed that finasteride significantly reduces the risk of histologically proven prostate cancer.

• Men who have large prostates and LUTS should consider use of 5-ARIs for treatment of BPH and to reduce prostate cancer risk.

• For men who are concerned about prostate cancer, a discussion between physician and patient about chemopreventive use of a 5-ARI would be appropriate.

• Clinicians should highlight the risks and benefits associated with long-term treatment with a 5-ARI.

In the published ASCO/AUA guideline, the panel couched its findings and recommendations in nonspecific 5-ARI terms. However, the PCPT provided the bulk of the information used to develop the guideline. The trial accounted for 85% of all prostate cancers documented in the nine randomized clinical trials that were reviewed and for 57% of all patients enrolled in the trials.

Dr. Kramer noted that the literature on chemoprevention of prostate cancer is based on the PCPT, as finasteride is the only agent that has been specifically tested in this context.

PCPT Summary

Summarizing the key findings of the PCPT, Dr. Kramer reported that healthy men treated for seven years with finasteride had a 3.5% period prevalence of cause-specific prostate cancer compared with 4.9% in the placebo arm, representing a relative risk reduction of 26%. Cause-specific cancers “were the ones detected in routine practice because of abnormal digital rectal exam, elevated PSA levels, or symptoms of prostate cancer.”

The overall prostate cancer incidence in the PCPT was 6.3% in the finasteride arm and 9.2% in the placebo arm, also a 26% difference in relative risk. The PCPT results translated into a number-needed-to-treat of 71, i.e. 71 men would have to be treated with finasteride for seven years to prevent the occurrence of one case of prostate cancer. For comparison, the panel noted that the Breast Cancer Prevention Trial showed that 100 women with a 2% baseline risk of breast cancer would have to be treated with tamoxifen for six years to prevent one case of breast cancer (Fisher et al. J Natl Cancer Inst 1998;90(18):1371-88). “I think this is a legitimate intervention, just as tamoxifen has been proven to decrease the risk of breast cancer in women at high risk of breast cancer,” remarked Dr. Kramer. “However, the decision remains a personal one. People make personal decisions not only on evidence but what their own concerns are and personal trade-offs.”

In contrast to the Breast Cancer Prevention Trial, discussions about using finasteride to prevent prostate cancer involve healthy men with a normal risk of prostate cancer. However, Dr. Kramer pointed out that American men have about a one in six lifetime risk of developing prostate cancer, one of the highest rates in the world.

Treatment had additional benefits beyond cancer prevention in the PCPT. Men assigned to finasteride had a lower incidence of acute urinary retention and need for surgical intervention to treat urinary retention. Men in the 5-ARI arm did have more sexual dysfunction, reduced ejaculate volume, a slight decrease in libido and a slight increase in the frequency of breast tenderness.

The PCPT data included the controversial finding of an increased incidence of high-grade prostate cancer (Gleason score <u>></u>7) in the finasteride arm. After carefully reviewing available data, the panel concluded that plausible factors could have led to a spurious increase in high-grade cancers.

“The panel came to that conclusion because careful pathologic analysis of prostate specimens from prostatectomy showed smaller tumours and less dangerous-appearing tumours with less invasion among men treated with finasteride,” said Dr. Kramer. “Subsequent statistical analyses have confirmed that finasteride is unlikely to have caused an increase in high-grade cancer.”

Data have yet to demonstrate that finasteride reduces prostate cancer mortality, noted Dr. Paul Schellhammer, Eastern Virginia Medical School, Norfolk, and co-chair of the ASCO/AUA panel with Dr. Kramer. “However, the demonstrated effect of 5-ARIs in reducing prostate cancer incidence makes it reasonable to recommend them for use to prevent the disease.”

To help physicians interpret the guideline and recommendations and discuss them with patients, ASCO has developed a Decision Aid Tool that includes multiple charts and diagrams to explain the risks and benefits of 5-ARIs. Additionally, ASCO has developed a patient guide designed to prepare patients to discuss chemoprevention with 5-ARIs with their physicians and to make more informed decisions.

Questions and Answers

The following section is based on interviews with Dr. Laurence Klotz, Chief, Division of Urology, Sunnybrook Health Sciences Centre and Professor of Surgery, University of Toronto, Ontario, and Dr. Martin E. Gleave, Director, Prostate Centre, Vancouver General Hospital, and Distinguished Professor of Urologic Sciences, University of British Columbia.

Q: How do the ASCO/AUA guidelines compare with those published in Canada?

Dr. Klotz: The two sets of guidelines are actually quite similar. The conclusions of the two documents are the same, namely, that use of a 5-ARI to reduce the risk of prostate cancer is something that physicians should discuss with men who have an increased risk or who are concerned about it. The ASCO/AUA guideline is a pretty good vindication of the Canadian perspective on this.

Q: What is the level of physician awareness about the PCPT results?

Dr. Klotz: I think Canadian physicians are very familiar with the original PCPT data and know that treatment with finasteride reduced the risk of prostate cancer by about 25%. I think physicians are less aware of last year’s series of publications that addressed the rate of high-grade cancer in the finasteride group. When the Canadian guidelines were published in 2007, we believed that the increase of high-grade cancer was artifactual and now we can say that with a greater level of confidence.

Q: Who should be taking a 5-ARI for prostate cancer prevention?

Dr. Gleave: The most obvious group is men who have a positive family history of prostate cancer. Secondly, men who have an enlarged prostate and symptoms of bladder outlet obstruction could get an additional benefit from treatment with a 5-ARI. Men with male-pattern baldness might lower their risk of prostate cancer and possibly have new hair growth. Finally, someone who has an elevated PSA level but who has had a negative prostate biopsy. That group of men is being studied in an ongoing clinical trial, and a positive result from that trial would reinforce the recommendation for such men.

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