Is the “flare” response to initiation of LHRH therapy “real” or not?


For all of the past 30 years, it has been the accepted wisdom that starting a patient on medically induced androgen deprivation therapy (ADT, e.g., with leuproplide acetate/Lupron) during treatment of prostate cancer placed the patient at risk for an initial “flare” response that induced a short-term stimulus to serum testosterone levels and therefore to the development of any tumor.

A new review by Vis et al. in the journal Urologic Oncology has now called this accepted wisdom into question. The full text of this paper is freely available on line until midnight on October 1, 2014.

It is impossible to tell from the review by Vis et al. whether their hypothesis is “real” or not. The point they make is that the “accepted wisdom” is not based on any objective criteria that justify a belief in the supposed “flare” reaction. It is based only on subjective opinion — as opposed to something like careful and frequent measures of PSA levels in the 2 weeks before and the 2 weeks after initiation of ADT.

There would be little difficulty involved in actually conducting objective tests to ascertain whether a “flare” reaction is real or not following the initiation of ADT. All one has to do is take PSA levels (perhaps every 3 days) on a series of patients who had received no prior treatment for prostate cancer, had M0 or M1 disease (perhaps with a PSA level of 50 or higher) and were scheduled to start LHRH therapy. The patients could be randomly assigned to LHRH agonist therapy in concert with an antiandrogen or to LHRH agonist therapy in concert with a placebo. It might need no more than 25 patients in each arm of the study.

What is important that such tests be carried out soon, because the use of oral antiandrogens in concert with the initiation of androgen deprivation therapy is entirely based on the theory that initation of medical castration with an LHRH agonist does commonly induce such a flare reaction. If there is no flare reaction, then there is (arguably) little point to treatment with an antiandrogen like bicalutamide at the time of initation of LHRH therapy.

8 Responses

  1. I am a skeptical guy, and I always wondered whether using an antiandrogen really and truly made a difference for men with minimally advanced cancer. Manufacturers of LHRH agonists do express concern about men with seriously advanced cancer — for instance, this is from the Zoladex prescription info under “Warning”:

    “Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostatic cancer, may occasionally develop during the first few weeks of ZOLADEX treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically. As with other LHRH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy considered.

    Under “Precautions/Information for Patients”:

    “The use of ZOLADEX in patients at particular risk of developing ureteral obstruction or spinal cord compression should be considered carefully and the patients monitored closely during the first month of therapy. Patients with ureteral obstruction or spinal cord compression should have appropriate treatment prior to initiation of ZOLADEX therapy.”

    Somewhere or other in a manufacturer’s prescription information I believe I have seen antiandrogens mentioned specifically as “appropriate treatment prior”.

  2. Dear Charles:

    The use of antiandrogen therapy is indeed recommended (in the prescribing information for the LHRH agonists and elsewhere) prior to initial LHRH therapy in order to prevent things like “Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostatic cancer.” The point that the authors of the current paper are making is only that those occasional “transient worsening of symptoms” appear to be based on entirely subjective opinion, and are not actually substantiated by any clear evidence that could be expected objectively (such as a transient rise in the patients’ PSA levels).

    As we have seen before in other areas of medicine, 30+ years of doing something a particular way based on what people thought 30 years earlier is not necessarily good medical practice!

  3. And I had completely forgotten about this study by Oh et al. that we had reported on in 2009, which seems to be highly supportive of the arguments of Vis et al.

  4. As often occurs, I have a somewhat different take, based on a now firmly held touchstone that all medical interventions should balance quality-of-life factors.

    My own personal experience was that the conventional wisdom is by no means widespread. Before I initiated ADT for the first time, I read everything I could, and was horriifed that my oncologist proposed to start me on leuprolide without a preliminary course of bicalutamide. The oncologist shrugged his shoulders and said, in effect, “Suit yourself.” We delayed my first Lupron shot until I had had a week of Casodex.

    Years later, when starting my third course of ADT, I was more blase, and the overhead of getting myself to a Lupron-dispensing physician was high. So I got both a Casodex prescription and a Lupron shot on a Friday afternoon.

    That weekend was extraordinary: I experienced a fantastic testosterone high that gave me a marvelous sense of drive, energy, self-confidence, and mastery in all I attempted. Fortunately, I swiftly realized that this blooming sense of superpowers was not reality-based, and I abstained from motorcycles, power tools, shouting matches, and the like. Instead, I stayed home and chronicled the trip in my journal in real time.

    My experience is probably not typical, but it might not be unusual, and it brings up a few points I’ve never seen mentioned before:

    (1) For men with no cancer symptoms whatsoever (as was true of me, and is true of most men initiating ADT in the modern prostate cancer age), there are no symptoms to manage, and hence no reason to pre-treat with Casodex.

    (2) On the contrary, for such men, allowing the testosterone flare to occur has a few boons that a physician focused on cancer-management rather than patient-wellness can easily overlook: (a) If other men are like me, it provides an excellent data set that allows the man to calibrate, to some extent, when he’s at low-T, medium-T, high-T, or castrate-level-T, on the basis of his subjective experience rather than a blood draw. This is a welcome relief from feeling completely dependent on tests and numbers, and it can prove a valuable additional tool later down the line for men whose testosterone might vary in ways unexpected or unpredicted by tests four times a year. (b) It might conceivably cause a tiny metastasis to provide a small twinge, possibly affording a clue for where to look a year or so later. (c) It feels great!

    3. In every respect, it provides an asymptomatic man with more information and therefore more power to control his future path with prostate cancer.

    For most men starting on their first ADT, some small sense of mastery can be a very good thing.

  5. From the Vis AN et al. paper … I added all the incidence of disease flare-up for the randomized controlled trials (RCTs) reported:

    — Without AA: 332.1
    — With AA: 130.6
    — Variance: 201.5 or 60.7% less cases with the use of an AA.

    What am I missing? In most of these RCTs the flare-up was accompanied by pain. I suppose that with less incidence there is less pain. No?

  6. From my research and study, and obviously the opinion of top medical oncologists who specialize in research and treatment of recurring or advanced, high-grade prostate cancer, at least 6 to 7 days prior to administering an LHRH agonist is the number to safely avoid experiencing “flare.” The effects might be very bad if an antiandrogen is administered in less days (the 3 days you mention) prior to LHRH agonist injection. In the case of the prescribing of the LHRH antagonist Firmagon/degarelix, an antiandrogen can be administered at the same time since this “antagonist” does not cause the flare effect.

    From my paper “Flare” at http://www.theprostateadvocate.com/pdf/FLARE.pdf:

    ‘Below is the recommendation with reasonable explanation why it is important to prevent “flare” provided by Stephen B. Strum, … [in] A Primer on Prostate Cancer – The Empowered Patient’s Guide. Please note that with the suggestion to be prescribed an antiandrogen to begin at least six days prior to a first injection of an LHRH agonist, that also means if returning to an LHRH agonist after an “off-phase”.

    ‘ “Frankly, I can’t imagine the administration of an LHRH agonist like Zoladex without first pre-treating the patient with an anti-androgen to prevent flare. The LHRH product stimulates the release of LH which in turn stimulates the testicles to make testosterone. This stimulates PC growth as well as normal prostate cell growth. Such stimulation lasts for up to 2 weeks. WHAT SITUATION EXISTS IN MEDICINE WHERE WE STIMULATE CANCER GROWTH AND YET ACT SO NONCHALANTLY ABOUT DOING SO? This is utter nonsense and no man should receive an LHRH agonist without preventing flare, be it biochemical flare or clinical flare.”

    ‘Read an excellent paper regarding the effect “Flare” can cause if an LHRH agonist is not preceded by an antiandrogen at least 7 days prior to the LHRH agonist injection: http://prostate-cancer.org/clinical-flare-a-crisis-that-can-be-avoided/

  7. Sitemaster:

    In your proposed study. I am not too sure the anti-androgen is likely to have much effect on measured PSA. On the other hand, if the metric measured were side effects, as in the Oh et al. study, then yes the control should be an anti-androgen.

    My understanding is that the anti-androgen is prescribed as a prophylactic against any side effects that might occur from a testosterone flare; it provides a buffer against the possible additional testosterone. The flare will occur with or without the anti-androgen — perhaps a little less with the anti-androgen, but not much.

    We just need to measure PSA daily for 2-4 weeks after a man starts an LHRH to see if there is in fact a flare.

    Respectfully,

    RD

  8. One of the problems with the historic perception that an antiandrogen is essential for 7 days prior to any use of an LHRH agonist is that it is based in data from studies carried out in newly diagnosed and previously untreated men with (largely) symptomatic (i.e., painful), metastatic prostate cancer diagnosed in the 1970s and 1980s — long before the availability of PSA tests.

    Faced with such a man today (who would probably still have a normal serum testosterone level and a PSA level anywhere from 100 to several thousand nanograms per milliliter at the time of initiation of treatment), I would still consider that there was a real value to initiation of a non-steroidal antiandrogen several days prior to the first injection of an LHRH agonist. (Strictly speaking, there is no need to give antiandrogen therapy to a man who is started on an LHRH antagonist like degarelix.)

    However, the vast majority of men who start on an LHRH agonist today do so with a normal serum testosterone level and a PSA level that is rarely much higher than 50 ng/ml. In other words, stage shifting has affected the nature of the playing field. As Paul C. has noted, there may be good reasons to allow a small flare in serum T in such patients. But the unanswered question remains: is there any actual evidence of flare in most patents starting on LHRH agonist therapy today as opposed to those starting such therapy 25+ years ago?

    With respect to how to measure such evidence objectively (through frequent and iterative measurement of serum T and PSA levels, the reason for starting PSA testing a couple of weeks prior to the initiation of therapy (with either the antiandrogen or the LHRH agonist) is that one wants a very clear baseline prior to to treatment that is inclusive of data on the small, normal variations in the patients’ PSA levels (and serum T levels) on a day to day basis prior to actual treatment as well as after treatment starts. Precisely how long that might take I leave to experts (i.e., 4 weeks, 2 weeks, 1 week) just as I would leave the frequency of the testing (daily, every 3 days, etc.). There is no point in extending serum T or PSA testing for much more than 2 weeks after starting the LHRH agonist, because most men will demonstrate a significant drop in the serum T and PSA levels within 2 weeks of starting an LHRH agoinist, and what we are really interested in knowing is whether there is a significant rise in the PSA level after initiation of treatment with an LHRH agonist without pretreatment with an antiandrogen compared to with treatment.

    By all means one can track patients’ assessment of their pain levels (if any) over the same time period … so long as one remembers that things like pain level are highly subjective and much more difficult to interpret from a scientific perspective.

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