Reports

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.

2nd CSSAM / ISSAM North American Congress on the Aging Male

Montreal, Quebec / February 8-10, 2007

Prostate cancer is the most common histologic cancer in men and the third most common cause of cancer death in North America. Because it is ubiquitous but typically slow growing, prostate cancer is considered an appropriate target for chemoprevention. The PCPT (Prostate Cancer Prevention Trial) confirmed the efficacy of the 5-alpha reductase inhibitor finasteride as preventive therapy in men at risk (Thompson et al. N Engl J Med 2003;349(3):215-24). In this study, seven years of active treatment vs. placebo produced a 24.8% reduction in prostate tumour development. The REDUCE (Reduction by Dutasteride in Prostate Cancer Events) trial, a similar evaluation of the 5-alpha reductase inhibitor dutasteride, is underway. The cancer-preventive effects of vitamin E and selenium are also currently undergoing investigation in the 32,000-patient SELECT (Selenium and Vitamin E Cancer Prevention Trial); results are expected by 2013. Some evidence suggests NSAIDs may help protect against prostate cancer, although the hypothesis is unlikely to be tested in a prospective trial, remarked Dr. Armen Aprikian, Chief, Division of Urology, McGill University Health Centre, Montreal, Quebec.

Epidemiologic Implications of the PCPT

Further evaluation of the PCPT data continues to provide highly relevant information on prostate cancer epidemiology, diagnosis, and monitoring of patients with prostate-specific antigen (PSA) testing.

It was an unexpected development to the trial’s investigators that the rate of prostate cancer development in the PCPT placebo group was 24.8% over seven years, observed Dr. Aprikian. Although these tumours were detected through compulsory biopsy and might have remained clinically insignificant, he noted, “This was quite alarming.... What the PCPT did in my mind is change a little all the previous studies that looked at the risk for prostate cancer. Now the denominator is quite different. So we may have to rethink the epidemiology, taking into account this fact that the control group had such a high rate of prostate cancer.” For example, he elaborated, the finding may have an impact on interpretation of case-control studies, where it has been assumed controls are free of disease.

The PCPT and the PSA

The rate of cancer detected in the PCPT placebo group provoked some doubt about the value of PSA measurement. In fact, the finding does suggest a need to revise PSA interpretation, Dr. Aprikian indicated. “We need to adjust the level at which we decide there is a risk for prostate cancer or not. I think we are moving away from using the PSA test as a plus/minus—that if the PSA score is 4, we should do a biopsy [but] if the PSA is under 4, we can observe. That is no longer valid.” Assessment of a patient’s risk must take into account such factors as age, race, family history, prostate volume and the results of a rectal examination.

Data from the PCPT have been used to develop a tool that predicts not only the patient’s overall risk, but also the likelihood of a high-grade tumour, Dr. Aprikian remarked (Thompson et al. J Natl Cancer Inst 2006; 98(8):529-34). “If [the risk] is 50%, probably that person deserves a biopsy. If the risk is really low, less than 10%, perhaps you can avoid the biopsy. But what is important is the risk is never zero,” he stressed.

An interesting finding from the PCPT is that PSA testing was more accurate in men taking finasteride than in those receiving placebo, because the agent dampens PSA fluctuations, Dr. Aprikian explained. As a result, follow-up and determination of a patient’s need for a biopsy may be enhanced. Typically, he noted, PSA levels decrease by about half within a year after therapy is initiated. Subsequently, any rise in PSA must be taken seriously. “A rising PSA while on finasteride or another 5-alpha reductase inhibitor is a stronger predictor of cancer than rising PSA without the agent,” he stated.

Still unclear is whether PSA screening or finasteride treatment reduces prostate cancer mortality, noted Dr. Aprikian. “There has been a decrease in mortality seen in several areas around the world where the PSA test is being used. This is indirect but strong evidence.” Ongoing follow-up of PCPT participants will establish if treatment vs. placebo translated into a reduction in mortality.

Treatment with an alpha blocker and a 5-alpha reductase inhibitor may reduce symptoms in men with benign prostatic hypertrophy or lower urinary tract symptoms. That a 5-alpha reductase inhibitor may also reduce or delay prostate cancer will likely increase the use of this type of agent, Dr. Aprikian suggested. Moreover, chemoprevention with a 5-alpha reductase inhibitor may be considered in asymptomatic men at risk for prostate cancer—for example, those with a strong family history of the disease, those in whom biopsy detected premalignant lesions or those with negative biopsies but elevated PSA.

Androgens and the Cardiovascular System

A second area of active investigation widely discussed here was the potential benefit of testosterone supplementation in aging men.

Androgens have traditionally been believed to be detrimental to the cardiovascular (CV) system, due in part to the earlier development of CV disease (CVD) in men vs. women. However, “the endogenous effects of testosterone are not sufficient to explain the sex differences in CV morbidity and mortality,” observed Dr. Juan Carlos Monge, Division of Cardiology, St. Michael’s Hospital and Associate Professor of Medicine, University of Toronto, Ontario. The difference is more likely a consequence of the protection associated with female sex hormones than to a higher risk conferred by androgens. Another longstanding misconception, he noted, was that the CV system has no androgen receptors. In fact, receptors have been identified in smooth muscle and endothelial cells as well as atrial and ventricular myocytes. Through its activity on these receptors, conversion to estradiol by aromatization, and through direct, nongenomic mechanisms, testosterone has several beneficial effects on the CV system. These include vasodilation and antiplatelet, anti-atherogenic and antiproliferative effects. In addition, at physiologic levels, testosterone has a positive impact on certain lipids and lipoproteins, lean vs. fat body mass, insulin resistance and other features of the metabolic syndrome, Dr. Monge told the audience.

Some epidemiologic and clinical studies have highlighted an association between decreasing testosterone levels and increasing incidence of CVD or risk factors such as dyslipidemia. In the Massachusetts Male Aging Study, for example, patients whose androgen levels were in the highest quartile had the lowest incidence of ischemic heart disease, while those with the lowest testosterone had the highest incidence. “This is age-adjusted, so it was not just the fact that people were getting older, but there was a correlation with androgen levels,” Dr. Monge noted. A recent study has also detected a correlation between androgen deficiency and severity of heart failure as well as heart failure-related mortality, he stated.

A Possible Therapeutic Role

Numerous experiments and clinical studies conducted over the last few years have allowed investigators to begin to assess whether administration of physiologic levels of testosterone might be of CV benefit in aging men. Studies of men with documented coronary artery disease have found that acute administration of testosterone increases treadmill walking time to a similar extent as anti-ischemic agents such as beta blockers and calcium channel blockers. Another found symptomatic and silent ischemia decreased significantly and nitroglycerine consumption was reduced among men receiving testosterone undecanoate.

To date, most investigations of the CV impact of testosterone replacement have been small and included only short- or intermediate-term outcomes, such as hemodynamic effects and exercise tolerance, Dr. Monge emphasized. Longer-term studies with established clinical end points have not been conducted, so it is difficult to predict what role testosterone might play in patients with CVD. Current data suggest, however, that physiologic levels of testosterone are at worst neutral and at best beneficial in the presence of CVD or risk factors, he concluded.