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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.

MEDICAL FRONTIERS - 64th Annual Meeting of the Canadian Urological Association

Toronto, Ontario / June 28-July 1, 2009

According to researchers here this week, the evidence for 5-alpha reductase inhibitors (5-ARIs) as a chemoprotective tool continues to grow. The PCPT (Prostate Cancer Prevention Trial) randomized 18,882 men aged <u>></u>55 with a prostate-specific antigen (PSA) of <u><</u>3 ng/mL to either finasteride 5 mg or placebo for seven years. The men had an annual digital rectal exam (DRE) and a prostate biopsy on completion of the study if they had not been diagnosed with prostate cancer. The study, published in 2003, found that the agent reduced the relative risk of the disease by 24.8%. However, the study raised initial concerns because of an increase in high-grade disease (Gleason scores 7 to 10) among men in the treatment arm (6.4% with finasteride vs. 5.1% with placebo).

Since then, several independent investigators have assessed the data and concluded that the vast majority of the increase in cancer grade is due to the reduction in the size of the gland. Researchers found that since men receiving finasteride have a reduced prostate size, high-grade tumours are actually more easily detectable with a biopsy.

One of the most compelling pieces of evidence was a comparison of biopsy and radical prostatectomy specimens from the PCPT that suggested that the 5-ARI facilitated detection of high-grade prostate cancer (Lucia et al. J Natl Cancer Inst 2007;99(18):1375-83). The prostatectomy specimens of treated patients were less likely to have high-grade cancer (RR 1.20) than the biopsy specimens (RR 1.68). There was also a lower risk of finding high-grade cancer in the prostatectomy specimens of actively treated men than in the biopsy specimens (70% vs. 50% with placebo, P=0.01). “That is a 40% improvement,” commented PCPT principal investigator Dr. Ian M. Thompson, Professor and Chairman, Department of Urology, University of Texas at San Antonio. “Finasteride increases the ability of PSA to detect cancer, especially aggressive high-grade cancer; it increases the fidelity of the DRE, the sensitivity of your DRE and it improves your ability to detect a cancer by doing a prostate biopsy. If you had a blood test or urine test that did this, you would make a billion dollars. It turns out that 5-ARIs do this.”

In fact, data now suggest that finasteride may be an even better chemoprotective agent than originally thought. The evidence suggests a risk reduction of 33% for low-grade cancers and 28% for high-grade cancers, Dr. Thompson told delegates. Armed with this evidence, the American Urological Association-American Society of Clinical Oncology (AUA-ASCO) consensus panel recently recommended that a man undergoing regular PSA testing should be informed of his opportunity to reduce his risk of prostate cancer with a 5-ARI.

REDUCE Study Findings

A second large trial has added even more weight to evidence backing the chemoprotective characteristics of 5-ARIs. The REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial evaluated 8000 men aged 50 to 75 years who had an elevated PSA of between 2.5 and 10 ng/mL who received 0.5 mg per day of the dual (type 1 and 2) 5-ARI dutasteride or placebo for four years. Participants had to have a negative biopsy within six months of enrolment. The study design included scheduled biopsies at years 2 and 4 and at any point in between based on the investigator’s judgment.

During the first round of biopsies (year 2), there was a 22.5% risk reduction in the occurrence of prostate cancer on biopsy. During the second round of biopsies, there was a 23.5% risk reduction in the occurrence of prostate cancer. “I think that is a very powerful piece of evidence that this drug continues to either suppress the growth or actually shrink tumour volume the longer the man takes it,” remarked Dr. Gerald L. Andriole, Chief of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri.

As also seen in the PCPT, the risk reduction in REDUCE was similar among older and younger men, those with and without a family history of prostate cancer and men with and without symptoms related to BPH, Dr. Andriole observed. As well, the agent was equally effective across all prostate sizes and PSA levels.

Sexual Side Effects

Some patients worry that the 5-ARIs will cause erectile dysfunction (ED); however, data from the two large 5-ARI studies do not support this conclusion. Dr. Andriole noted that in the REDUCE trial, the number of men who stopped treatment was very low for both arms, at about 4% for dutasteride and 2.2% for placebo. Side effects of 5-ARIs include decreased libido, changes in semen volume and gynecomastia, he added.

According to Dr. Neil E. Fleshner, Head, Division of Urology, Department of Surgical Oncology, Princess Margaret Hospital, Toronto, Ontario, previous large benign prostatic hyperplasia (BPH) trials comparing placebo and 5-ARIs showed an ED rate of only about 5% but a placebo effect that could reach 30%. “When a man comes back complaining of ED, there is a six of seven chance that it has nothing to do with the drug,” he told delegates.

Characteristics of Different 5-ARIs

During a presentation on medical therapy for BPH, Dr. Steven Kaplan, Chief, Institute for Bladder and Prostate Health, and Professor of Urology, Weill Cornell Medical College, New York, New York, discussed research comparing 5-ARIs. He referred to the EPIC (Enlarged Prostate International Comparator) trial that demonstrated similarities between finasteride and dutasteride. That study showed an almost identical mean prostate volume reduction (-26.7 for finasteride vs. -26.3 for dutasteride at 12 months; P=0.65).

The differences were also similar for changes in the AUA symptom index (adjusted mean change from baseline at 12 months, -5.5 for finasteride and -5.8 for dutasteride) and for sexual function (impotence, 9% vs. 8%; decreased libido, 6% vs. 5%; and ejaculation disorders, 2% vs. 2% for finasteride and dutasteride, respectively.)

However, Dr. Kaplan stressed that this and other studies included men with a prostate volume of at least 30 cc, which excludes virtually half of the male population. “So in half the patients, we do not know if it really works and in the other half of patients in the comparative trial, there is no difference.”

Dietary and Lifestyle Interventions

While early animal and epidemiological studies provided promising evidence that vitamin E and selenium might prevent prostate cancer, a more recent study has revealed that this is not the case.

The SELECT (Selenium and Vitamin E Cancer Prevention Trial) was a large, randomized study in over 35,000 men who received either placebo, vitamin E or selenium, or vitamin E/selenium. Eligible patients were >55 years of age (or >50 if of African-American descent) and had a PSA of <4 ng/mL.

After a median follow up of 5.46 years, hazard ratios (99% confidence intervals [CIs] for prostate cancer were 1.13 (99% CI, 0.95-1.35; n=473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n=432) for selenium and 1.05 (99% CI, 0.88-1.25; n=437) for selenium/vitamin E vs. 1.00 (n=416) for placebo (Lippman et al. JAMA 2009; 301(1):39-51). “So largely, this is a negative trial and it suggests that these compounds have no beneficial effect,” commented Dr. Fleshner.

Another randomized, placebo-controlled trial investigated the benefits of a 40-g soy protein product enriched with 800 IUs of vitamin E and 200 µg of selenium in men with high-grade prostatic intraepithelial neoplasia (PIN). The men had biopsies at 6, 12, 24 and 36 months. According to the as-yet unpublished study results, there was a 26.4% rate of progression to invasive prostate cancer. “The hazard ratio for the nutritional supplement was 1.03, indicating no effect,” reported Dr. Fleshner.

Despite these negative results, Dr. Fleshner suggested that lifestyle approaches are still important. “Although the chemoprevention aspect is obviously looking like the winner at this point, I think we still need to look at lifestyle and how that affects the prostate cancer continuum.”

There is growing interest in lycopene, a nutrient with strong antioxidant properties found in tomatoes and other red fruits and vegetables, as another potential cancer prevention agent. In one study presented here during the scientific sessions, researchers administered combinations of micronutrients to mice that were genetically engineered to form prostate tumours at about 24 to 30 weeks. The combination of vitamin E, selenium and lycopene resulted in a “dramatic effect” on the cancer while the effect of a combination that did not contain lycopene was much less dramatic, Dr. Fleshner reported. “At least in the laboratory, lycopene appears to have significant impact on the development and progression of prostate cancer.” As well, human studies are beginning to show a dramatic inhibition of tumour proliferation among men taking various supplements containing lycopene, he noted.

As the obesity epidemic continues to grow across North America, there is growing concern about the link between excess body fat and increased risk of prostate cancer. Diagnosing such cancers is more challenging in an overweight patient because, among other things, performing a DRE on such a patient is more difficult and the PSA levels tend to be lower. “Almost everyone in the field believes that obesity is a risk factor, particularly for more aggressive types of prostate cancer,” confirmed Dr. Laurence H. Klotz, Chief, Division of Urology, Sunnybrook Health Sciences Centre, Toronto. “If your weight goes down, insulin levels go down, IGF-1 levels go down and oxidative stress goes down, but proving that this reduces cancer risk is another story.”

Case Studies

Delegates here were asked to choose a treatment for a 57-year-old slightly obese Caucasian male with mild lower urinary tract symptoms (LUTS), no family history of prostate cancer, a palpably benign 35 cc prostate and a PSA of 2.1 ng/mL. The treatment options were no intervention; a 5-ARI; micronutrients; dietary and weight loss advice; both a 5-ARI and micronutrients; or all of the options.

Among the delegates, 26% said they would opt for a 5-ARI, 33% for dietary advice and 30% for all strategies. In short, two-thirds of the audience would advise this relatively healthy male with no risk factors to go on a 5-ARI.

After further discussion about 5-ARIs, the delegates were given a second case scenario: a patient with the same characteristics as the first but with a brother and father who were diagnosed with prostate cancer in their 60s and the father already dead of the disease at age 75.

For this patient who is at increased risk for prostate cancer, the number of delegates who would opt for a 5-ARI increased to 40%, with another 10% choosing a 5-ARI with micronutrients and 45% selecting all strategies, resulting in 95% who would recommend treating this patient with a 5-ARI. “For the first time ever, there was a really clear consensus by everyone at this meeting that, after looking hard at this data, they would use 5-ARIs in patients to reduce risk of prostate cancer,” commented Dr. Klotz.

Prostate Cancer Risk Calculator

The Cancer Risk Calculator for Prostate Cancer, developed from the PCPT trial, calculates the risk of biopsy-detectable prostate cancer based on the patient’s race, age, PSA level, family history of prostate cancer, DRE, prior prostate biopsy and whether or not he is taking finasteride. To access the calculator, visit: http://deb.uthscsa.edu/URORiskCalc/Pages/uroriskcalc.jsp.

Questions and Answers

The following question-and-answer session includes material from a panel discussion during the scientific sessions and subsequent interviews. The panel was moderated by Dr. Laurence H. Klotz and its members included Dr. Ian M. Thompson, Dr. Gerald L. Andriole, Dr. Neil E. Fleshner and Dr. Yves Fradet, Professor of Surgery, Université Laval, Quebec City, Quebec.

Q: Are prevention interventions warranted for healthy men who are concerned about their prostate cancer risk, and if so, which strategies?

Dr. Fradet: There is good reason to believe that dietary intervention and adopting better health habits will have an effect, but certainly 5-ARIs to me are at the forefront. This type of drug is the only intervention that has been proven in two very big trials to prevent a diagnosis of prostate cancer and also in men with mild LUTS and PSA of 2.1, which already probably means a slightly enlarged prostate and a higher risk of having complications from BPH. This strategy is going to reduce that risk.

Dr. Thompson: A high-risk man starts at a low risk and so the better time to prevent it is before he achieves high risk. If that man achieves a sufficient high risk and then you find it and you start prevention then, it is too late.

Q: For a patient taking a 5-ARI whose PSA level starts to rise, at what point do you consider a biopsy?

Dr. Andriole: We are still looking at the positive predictive value of a 0.1, 0.2, 0.3 etc. rise-off of your post-dutasteride meter; we just do not have that analyzed fully at this point. If you take a 5-ARI, it stabilizes the production of PSA from that BPH so much that almost any tiny confirmed rise in your post-5-ARI PSA is almost certainly coming from cancer.

Q: How powerful is a 5-ARI in preventing high-grade cancers?

Dr. Andriole: A 5-ARI can control a high-grade tumour for a certain length of time but it cannot control it forever—nothing controls a high-grade tumour forever. I do not think we are ever going to prevent those [Gleason scores of] 8, 9 and 10 from reaching the clinical horizon because we do not have anything that can treat them. All we can hope to do is improve the ability of PSA to cause me to do a biopsy sooner so that I find it when the biopsy volume is smaller.

Q: Where do we stand now in terms of micronutrients in risk reduction?

Dr. Fleshner: At least currently, there would basically be no role for vitamin E and selenium both in combination or alone in terms of preventing prostate cancer. I think that soy as well would not be indicated for patients with high-grade PIN. I think that lycopene experimental systems look good but we need to do some more work and we need to continue to do well-conducted phase III trials for men in this condition.

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