ADT and the Risk of Major Adverse Cardiovascular Events - Episode 1
Susan F. Slovin, MD, PhD: Cardio-oncology has become a very exciting field, particularly in the setting of patients who are found to have cardiovascular events as a result of being on androgen deprivation therapy [ADT]. The idea that cardiovascular disease can be a major adverse effect of androgen deprivation therapy is not new, but it’s really been unproven. Most of the data that we have to suggest that there’s any contribution of ADT toward the development of cardiovascular disease have really been through a variety of what we call retrospective studies. Meaning that the only evidence has come from observational studies, meta-analyses, and registry studies that all indicate that if you find or evaluate patients who have had treatment with any of the drugs that will suppress testosterone, the patients tend subsequently to develop some sort of cardiovascular problem.
Looking at the population, cardiovascular disease is actually the second-leading cause of death in men. So therefore, given the fact that we deal with a lot older men with pre-existing cardiovascular risk factors, the fact that they are at higher risk for being on androgen deprivation therapy becomes an important tool for going forward with how to treat these men if these events occur, and also to determine really how to safeguard their overall cardiovascular health. So what has been ongoing for a number of years are efforts to determine how we can actually prevent and safeguard these patients.
Going back as far as probably the 1970s, researchers have always tried to determine how to best take care of patients with prostate cancer. So we use androgen deprivation therapy or reduction in a patient’s testosterone for patients who have a variety of different clinical states, among these being patients who primarily have metastatic disease to bone or lymph nodes.
We have also used androgen deprivation therapy. And when I say androgen deprivation therapy, I’m not talking about surgical intervention such as orchiectomy but the use of a GnRH [gonadotropin-releasing hormone] agonist, and nowadays it’s GnRH antagonist.
Men who have, or who will have, a locally advanced disease and go on and have high-risk disease as defined as PSAs greater than 20, a large prostate, or a Gleason score of 8, 9, or 10 are patients who will benefit from androgen deprivation therapy up front, followed by radiation, and then with adjuvant radiation that can be given anywhere from 18 to 24 months later.
Now these men are also at risk. But again, these are primary indications for the use of hormonal therapy. Now when you look at the relationship of hormonal therapy to cardiovascular disease, there are a lot of mechanisms at play. I think the most important thing to understand really how Lupron or leuprolide—which is 1 of the earlier GnRH agonists—work, would be to tell you that, frankly, most men think with their gonads. You know women look at me when they come with their husbands or partners to a clinic visit, and when I try to discuss the mechanism, I said you have to just realize that men have a direct relationship with their gonads, and that’s why Lupron works so very, very well.
What ends up happening is that the hypothalamus in the brain produces GnRH, gonadotropin-releasing hormone, that stimulates the production of leuprolide in hormone and follicular-stimulating hormone, by the pituitary, which sends out the signals for the gonads to undergo spermatogenesis, so essentially, sexual function, including testosterone production.
What Lupron does is essentially tell the brain not to send out a signal to the gonads, and they compensate by suddenly making more testosterone, more FSH [follicle-stimulating hormone], more LH [luteinizing hormone] in order to tell the brain, “Hey, we’re here, tell me what to do. Do you want us to continue or not continue?” During that surge period, as we like to call it, you actually will see patients who happen to have a very large prostate gland, or have metastatic disease and bone or lymph node, become very symptomatic. Some men can go into urinary retention; other men may have a pain flare, and very often we use an anti-androgen, such as bicalutamide, to prevent the flare from stimulating these sites. Why? Because if you don’t, the testosterone that’s being suddenly produced is going to stimulate the growth and people become symptomatic. So very often people use an anti-androgen, anywhere from 5 to 14 days, before they give the injection. Over time the gonads no longer received that instruction from the brain, and as such a man goes into the equivalent of a chemical-induced menopause.
Transcript Edited for Clarity