US FDA reviewing the safety of LHRH agonists

For many years it has been understood by specialists that hormonal treatment of prostate cancer patients with luteinizing hormone releasing hormone (LHRH) agonists — also known as gonadatropin releasing hormone or GnRH agonists — is associated with metabolic side effects that include risks for cardiovascular disease and diabetes. However, in the past couple of years the data substantiating this risk has become better characterized.

Perhaps more importantly, we are now living in a legal, political, and socioeconomic environment (at least in the USA)  in which the idea that drugs have side effects has gradually become less and less acceptable (despite the fact that this is a well understood scientific inevitability).

The consequence is that the FDA has just stated that it is “evaluating” whether LHRH agonists “may increase the risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.” The “New” Prostate Cancer InfoLink is happy to be able to inform the FDA that this is most certainly the case, in at least some patients. The question that may be worth study, however, is exactly how much LHRH agonists may increase that risk compared to non-use of these treatments or use of alternative treatments, and whether it is clinically significant in specific subsets of all prostate cancer patients.

The FDA’s statement goes on to be clear (in bold type) that:

  • “FDA’s review is ongoing. The agency has not made any conclusions about [LHRH] agonists and whether they increase the risk of diabetes and cardiovascular disease in patients receiving these medications for prostate cancer.”

It also makes a number of specific recommendations:

  • “Healthcare professionals should be aware of these potential safety issues and carefully weigh the benefits and risks of GnRH agonists when determining treatment.”
  • “Patients receiving [LHRH] agonists should be monitored for development of diabetes and cardiovascular disease.
  • “Health care professionals should manage cardiovascular risk factors for patients, such as smoking and increases in blood pressure, cholesterol, blood sugar, and weight, according to current clinical practice.”
  • “Patients should not stop their treatment with [LHRH] agonists unless told to do so by their healthcare professional.”

In March of this year the American Heart Association, the American Urology Association, and the American Cancer Society published a joint science advisory that gave exactly the same recommendations — which certainly ought to have been well understood by almost any clinician who considered him or herself competent to manage and treat patients with prostate cancer.

Hormonal therapy has been at the heart of management for advanced forms of prostate cancer for 60+ years. The idea that hormonal manipulation has metabolic side effects is hardly new. Indeed the reason that LHRH agonists become popular at all was because they were associated with significantly fewer cardiovascular side effects than diethylstilbestrol (DES), which was the form of hormone therapy most commonly used throughout the late 1970s and early 1980s.

The problem that we are really dealing with here is the use of hormone therapy in men who have relatively early stages of disease to “manage” their PSA level. This type of application of LHRH therapy is not justified by good scientific data. We barely have any data to suggest that early use of hormonal therapy in men with metastatic or node-positive prostate cancer may affect their survival. We have absolutely no good data to suggest that using hormone therapy as first-line therapy in a patient with no evident signs or symptoms of node-positive disease or metastatic disease has any long-term benefit whatsoever. So in patients of this type it is most certainly fair to ask whether the benefits of treatment are outweighed by the risks of metabolic side effects.

One Response

  1. Thanks for pointing this out. I think it’s likely the FDA will take the proper course, but it’s worth our checking to make sure.

    As an 11-year survivor of a challenging case of prostate cancer treated solely by hormonal blockade that evolved early on into triple blockade with finasteride during “off-therapy” maintenance periods, I’ve become savvy about this therapy and about the many widespread myths surrounding its use. (I’ve had no enrolled medical education.)

    The four bulleted guidance points look good to me with the following important qualification: when doctors “carefully weigh the benefits and risks,” as recommended under the first bullet, they need to consider the amount of risk AFTER likely reduction by reasonable countermeasures. For instance, the lipid risks (HDL, triglycerides) can usually be virtually eliminated if the patient can take a statin drug, as most of us can, with diet/nutrition/supplements, exercise and stress reduction also helping.

    For instance, at the 10-month point of my third full-therapy cycle of intermittent triple blockade last July, with 20 mg simvastatin in support (plus nutrition, etc.), my total cholesterol was 198, with the good HDL accounting for nearly half of that at 87 (!), LDL at 101, and trigs at just 49; my blood pressure is on the low side and pulse is fine. I believe that many if not most of us can virtually neutralize cardiovascular risk with the aid of a statin drug with supporting lifestyle tactics.

    It’s also vitally important that doctors consider intermittent versus continuous hormonal therapy. To me, the case for intermittent therapy is highly persuasive for many of us. Doctors need to be aware that side effects will disappear within months for the vast majority of us (but depending on age and length of blockade).

    That brings me to use of hormonal blockade as the prime therapy for low risk men. I agree there is no sound and convincing scientific data supporting such therapy. However, that seems more a fault of our research system than any flaw in the approach. I have been highly impressed with the informal data on one-time (or rarely intermittent) triple hormonal blockade with finasteride maintenance for men with low-risk prostate cancer, the approach informally documented by Drs. Robert Leibowitz and Stephen Tucker, including a presentation at the special ASCO/AUA conference in Orlando in 2005. Essentially, they use full triple blockade for a period of thirteen months, then have their patients cease the LHRH agonist and antiandrogen (often Lupron and Casodex) and continue maintenance with just finasteride. Their results are awesome, with almost all of their low-risk men able to continue on maintenance indefinitely with excellent control of their cancer and with virtually no lasting side effects, fully enjoying a continent, potent lifestyle.

    Of course, that low-risk population in the Leibowitz/Tucker series is the same one in which such impressive results are being achieved with active surveillance in various major programs throughout the US and internationally. However, about a third to 40% of AS patients usually require treatment, often around the two to three year point, and that result is not competitive with the far superior results of the Leibowitz/Tucker series. (On the other hand, the quality, extent, peer-review vetting and multi-institutional nature of the data for active surveillance are far superior.)

    Regarding cardio and other risks for such low-risk patients, both appropriate countermeasures and the relatively short duration of the LHRH-agonist (and antiandrogen) — just 13 months in the Leibowitz/Tucker approach — would be very likely to lower risks to very low levels. It would be interesting to have the Leibowitz/Tucker/Roundy team look at their series to see what they can glean about cardio and other risks. I’ve read some of their informally published papers, and I do not recall seeing such risks discussed in the specific patients in their clinical series, though “Dr. Bob” Leibowitz is well aware of the value of statins for prostate cancer patients.

    Again, I have had no enrolled medical education but am relaying facts that I have read and heard with a dose of logic added.

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