Getting to the HEART on Hormone Therapy!
AnCan has an ongoing interest in issues around heart health for men on hormone therapy – especially if it involves androgen deprivation with an LHRH drug. We speak about this often in our High Risk/Recuirrent/Advanced meetings where many men are impacted, including our Moderators.
Last year AnCan produced a great webinar addressing this issue – yup, we know it says Active Surveillance, but Dr. Darryl Leong did a great job addressing LHRH implciations too. Watch it here. We are now particpating with Drs. Leong and Narayan at Penn who were just awarded a research grant to address heart health. We followed this up by nominating Dr. John Antonucci to appear on a CureTalk Panel addressing cardio-oncology issues. Listen to Dr. John talking with UCSF’s Dr. Javid Moslehi here. And recently Professor Herb Geller PhD spotted a good ASCO journal article reviewing the state of play. Herb and Dr. John, who himself has cardio considerations, worked together to summarize this piece, that follows. (rd)
The first line of treatment for recurrent and advanced prostate cancer is Androgen Deprivation Therapy (ADT). ADT is known to promote metabolic syndrome that has adverse cardio results. One controversial issue is whether an agonist Leutinizing Hormone Releasing Hormone (LHRH) like Lupron (and its sisters) or an antagonist LHRH like Firmagon (and its brothers) is safer for our hearts? Most of us with high-risk/recurrent disease are on one or the other and we generally hate them, though they keep our PSAs very low, sometimes for years.
So how do they work? Well, we want to keep our testosterone (T) as low as possible to “starve” out our prostate cancer that feeds on it. The drugs to do this are those that interfere with the brain’s signals to the testes to make T; that signal comes from the pituitary gland. There are two ways to do this:
- Goose the pituitary gland in the brain with an “agonist” LHRH that overstimulates it producing excess testosterone. That explains the T. flare we often speak about. The over-signal shuts down this response in the pituitary by flooding and desensitizing receptors over time. The testes may also be complaining to the hypothalmus they are overworked in a separate feedback loop to the pituitary. The whole production of testosterone eventually stops. This LHRH drug is leuprolide; brand names include Lupron, Eligard, Zoladex, and Trelstar (we capitalize brand names and not generic names).
- Block LHRH with an “antagonist”. No signal deactivates the pituitary signal to the testes and voila … no testosterone. Antagonists are Firmagon (degarelix) and Orgovix (relugovix).
Both work well, albeit differently, to do the job
No testosterone in your body can result in cardiac implications. There is a vigorous, ongoing debate whether the type of LHRH used mitigates your heart risk. This is of intense interest to us prostate cancer men with heart disease that can take us under.
As our Blog Editor remarked above, AnCan closely follows this debate. Some studies seem to clearly say the agonists are toxic to the heart, and others don’t demonstrate this. Every study has been faulted by the community of scientists, which by this time includes many in the new specialty of cardio-oncology. As a result, researchers are making painstaking efforts to remove all possible flaws from their study designs—a difficult task outside the lab. As these studies are better designed, they have shown decreasing cardiotoxicity for the medications and less and less difference between the two types of medications.
A recent paper, Should Prostate Cancer Patients With History of Cardiovascular Events Be Preferentially Treated With Luteinizing Hormone-Releasing Hormone Antagonists? Tisseverasinghe, et al.McGill University, Montreal, Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), reviews significant studies addressing cardio implications that may be associated with using LHRH drugs.
The most reliable study in this review, PRONOUNCE, was a randomized controlled study (the best kind of experiment) that compared an agonist, leuprolide/Lupron, against an antagonist, degarelix/Firmagon. All the men in the study had cardiovascular disease. The outcome measure was major adverse cardiovascular events, and the raters scored these events without knowing what medications the subjects were on. Tisseverasinghe said PRONOUNCE “was ideally conceived to isolate results from confounders and biases”. Results of PRONOUNCE? No significant difference between the two medications in terms of the heart, and very low cardiovascular events overall. So, do we finally have an answer?
Well even PRONOUNCE can be criticized. It tried for 900 subjects to make its statistics valid; it only got 545 – that’s still a pretty good number. Bad outcomes were very low: about 5% – some 3% died in the 1st year, 1.5 % from heart attack, 1% from stroke. It’s very hard to meaningfully compare groups with such small numbers. But the authors of the Tisseverasinghe article argue that even if PRONOUNCE was fully completed the outcome would still be the same. Our takeaway: it was the excellent and modern cardiological and cardio-oncological care that made those numbers of adverse cardiovascular effects in PRONOUNCE so low.
And so what can we conclude? It’s not proven, but it does not look like your doctor has to worry about using antagonists over agonists out of concern for your heart. And given modern cardio-oncological care, it does not look like we have to be terribly frightened for our heart IF we take care of it ….. HOW??
- be aware of angina symptoms,
- ask about aspirin,
- monitor blood pressure,
- monitor cholesterol and lipids,
- stop smoking tobacco in any form
- maintain a good diet (i.e. Mediterranean),
- exercise regularly, and
- practice weight control.
If there is risk, have a good cardiologist, and if risk is very high or you’re on immune therapy, find a cardio-oncologist.
John Antonucci & Herb Geller (follow up directly at dr.john@ancan.org; herb@ancan.org)
Work cited:
Tisseverasinghe S, Tolba M, Saad F, Gravis G, Bahoric B, Niazi T. Should Prostate Cancer Patients With History of Cardiovascular Events Be Preferentially Treated With Luteinizing Hormone- Releasing Hormone Antagonists? J Clin Oncol. 2022 Jul 21:JCO2200883. doi: 10.1200/JCO.22.00883 https://ascopubs.org/doi/full/10.1200/JCO.22.00883?bid=187952004&cid=DM11125