Short- and medium-term ADT and risk for cardiovascular mortality: an update

The degree to which modern forms of androgen deprivation therapy (ADT) increase risk for serious cardiovascular side effects (and death from heart attacks in particular) is a complex and controversial subject, and there are few really good prospective data on which to base sound clinical decision-making.

Historically, it was very clear from the Veterans Administration Cooperative Urologic Research Group (VACURG) trials of ADT in men with metastatic prostate cancer, that high doses of diethylstilbestrol at 5 mg/day and even 3 mg/day were indeed associated with a significant increase in risk for cardiovascular events. These trials were conducted in men with very advanced forms of prostate cancer, using continuous, long-term therapy with estrogenic agents like diethystilbestrol (before the availability of drugs like the LHRH agonists and antiandrogens). Since the introduction of the LHRH agonists in the mid 1980s, it has become a lot less clear how serious these side effects really are, especially when ADT is used earlier in the development of prostate cancer (e.g., in men with localized and locally advanced disease in combination with radiation therapy).

In an analysis of data from the TROG 96.01 trial earlier this year, Wilcox et al. have demonstrated that, at 10 years of follow-up:

  • Fatal cardiac events occurred with a cumulative incidence of
    • 7.54 percent in men with localized prostate cancer who were randomized to treatment with radiation therapy alone
    • 6.44 percent in men with localized prostate cancer who were randomized to treatment with radiation therapy and 6 months of neoadjuvant ADT
  • This difference was not statistically significant.
  • Men of 65 or more years of age were at no increased risk by comparison with younger men.

In other words, at least for men with no prior history of heart disease who received no more than 6 months of hormone therapy, there was no increase in risk of cardiovascular mortality from short-term use of ADT.

Denham (the lead investigator for the TROG 96.01 trial) has also noted that the ongoing RADAR trial (a successor to the TROG 96.01 trial) will, in the relatively near future, report data collected from a prospective study with a minimum follow-up of 5 years. In the RADAR trial, 1,071 men have been randomized to receive radiation therapy with either 6 months or 18 months of ADT for treatment of intermediate- or high-risk, localized or locally advanced prostate cancer. A wide range of cardiovascular data has been collected in this trial, alongside the data on the incidence of myocardial infactions (heart attacks), so we may be able to gain greater clarity on the risk for cardiovascular deaths and other cardiovascular side effects of modern forms of ADT — at least in men on short- and medium-term courses of ADT.

As these data continue to evolve, we do need to be clear, however, that (although there are strong opinions on both sides of the question) the risk for cardiovascular side effects associated with ADT is still very real for men with prostate cancer and a clear history of cardiovascular problems. In such men, any form of ADT needs to be applied with a great deal or care and attention to cardiovascular risk.

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