Testosterone “Flare” (Or Testosterone?) Timing to Optimize Salvage Radiation Therapy

[MateoBeach]

I have referred to the following article a few times in response to some posts about the use and timing of ADT when used in addition (adjuvant) to improve outcomes from salvage radiation therapy for BCR for failure after primary prostate treatment (surgical or radiation or other). Also for recurrences in pelvic lymph nodes and oligometastatic PC. These are attempts with “curative intent”, but many times fail.

The addition of short term ADT (sometimes 6 months but often 18-24 months) to the radiation treatments has become de facto standard of care (SOC). And often, per varying protocols from various large clinical trials, the ADT may be started a few months before starting the RT, or simultaneously. Also, some trial protocols have used bicalutamide and similar to block testosterone effects from the androgen “flare” when an ADT drug such as leuprolide or goserelin are first started. Note that the LHRH antagonists degarelix and relugolix do not have the androgen flare.

The article referenced is worth careful consideration by anyone here contemplating salvage radiation therapy to prostate, pelvic node fields and or oligometastatic SBRT. When the clinical trials are analyzed in terms of the timing of beginning ADT, simultaneously with starting RT or not, and whether bicalutamide or glutamine was used to block the testosterone flare, or not. Then it becomes clear that the weight of evidence from these multiple trials pointing to this:

It is actually the unblocked androgen flare given at the same time as starting the radiation that is actually helping to kill the most cancer cells and improving the outcomes. Not the suppression of androgens at that time. And this also appears to be the case for adding adjuvant ADT to docetaxel chemotherapy. Consider discussing the following article with your RO or MO.

ncbi.nlm.nih.gov/pmc/articl...

Androgen Flare after LHRH Initiation Is the Side Effect That Makes Most of the Beneficial Effect When It Coincides with Radiation Therapy for Prostate Cancer

Androgen Flare after LHRH Initiation Is the Side Effect That Makes Most of the Beneficial Effect When It Coincides with Radiation Therapy for Prostate Cancer

Simple Summary

Prostate cancer tumor growth is stimulated by androgens. Surgical castration or medical castration using long-acting luteinizing hormone-releasing hormone (LHRH) agonists or antagonists is the backbone of the treatments of metastatic disease. Treatment of locally advanced prostate cancer was accomplished with radiation therapy alone until multiple studies showed that combining radiation therapy with LHRH agonists results in significant survival benefit. While the goal of the use of LHRH agonists was to suppress testosterone levels during radiation, we show, through review of previous studies, that survival benefit was achieved only when LHRH was initiated during the course of radiation, and thus androgen flare during the first 1–3 weeks after the initiation of LHRH is most likely the reason for higher survival. Androgens drive tumor cells into mitosis, and mitotic death is the dominant mechanism of tumor cell kill by radiation.

Abstract

Treatment of metastatic prostate cancer was historically performed via bilateral orchiectomy to achieve castration. An alternative to surgical castration is the administration of subcutaneous recombinant luteinizing hormone-releasing hormone (LHRH). LHRH causes the pituitary gland to produce luteinizing hormone (LH), which results in synthesis and secretion of testosterone from the testicles. When LHRH levels are continuously high, the pituitary gland stops producing LH, which results in reduced testosterone production by the testicles. Long-acting formulations of LHRH were developed, and its use replaced surgical orchiectomy in the vast majority of patients. Combining LHRH and radiation therapy was shown to increase survival of prostate cancer patients with locally advanced disease. Here, we present a hypothesis, and preliminary evidence based on previous randomized controlled trials, that androgen surge during radiation, rather than its suppression, could be responsible for the enhanced prostate cancer cell kill during radiation. Starting LHRH agonist on the first day of radiation therapy, as in the EORTC 22863 study, should be the standard of care when treating locally advanced prostate cancer. We are developing formulations of short-acting LHRH agonists that induce androgen flare, without subsequent androgen deprivation, which could open the door for an era in which locally advanced prostate cancer could be cured while patients maintain .

The entire article is worthwhile and breaks down all the major clinical trials supporting this conclusion, with full references. Paul

[MateoBeach]

An additional component of this, and how I started considering this, was my recent radiation treatments including SBRT to two LNs then followed with two radioligand treatments with Lu-PSMA-J591. Since I am on cyclic high dose testosterone (modified BAT) I asked Nat Lenzo in Perth if I should stop the testosterone and go to castrate during treatments. He said No. He wanted my PC to be “maximally stimulated at the time of treatments. So that is what I did. I am now completing one month castrate level on Orgovyx post treatment. Follow up PSA will be next week.

[MateoBeach]

An additional component of this, and how I started considering this, was my recent radiation treatments including SBRT to two LNs then followed with two radioligand treatments with Lu-PSMA-J591. Since I am on cyclic high dose testosterone (modified BAT) I asked Nat Lenzo in Perth if I should stop the testosterone and go to castrate during treatments. He said No. He wanted my PC to be “maximally stimulated at the time of treatments. So that is what I did. I am now completing one month castrate level on Orgovyx post treatment. Follow up PSA will be next week.

[Scout4answers]

Nine months into Lupron starting radiation on Monday, this research suggests a supra high T boost during radiation might be beneficial.

[MateoBeach]

Agree Scout. It is a natural conclusion that if this mechanism is correct, then those starting salvage RT who are already on ADT could just do one shot of Testosterone-cypionate or Enanthate a few days before the RT starts and achieve the same (possible) benefit. However that would be much more controversial than simply adjusting the timing of starting ADT. “Pouring gasoline on the fire” and all of that thinking will die hard with much outrage and criticism. So they propose a more acceptable path, probably wisely.

[Scout4answers in reply to MateoBeach]

I proposed a T spike to both my MO and RO based on this study. Will see what happens...thanks for the idea Paul

[MateoBeach]

Exactly so smurtaw! Very perceptive. See my reply to Scout above.

[MateoBeach]

Yes! Great add on article regarding ADT initiation with docetaxel chemo from the same author and emphasizing the same principle of short term pulse of testosterone potentiating cytotoxicity of actively dividing cancer cells by a cytotoxic agent targeting cellular replication. Thanks for finding this. paul

[Graham49 in reply to MateoBeach]

Great find. I hope this stuff works. I don't think big pharma will like it though. It might be difficult to get a clinical trial. I don't know about the US but I don't think many hospitals in the UK will use it without a clinical trial.

[maley2711]

From the mdpi text....... " The current standard of care of hormonal therapy in the United States and Canada resulted erroneously from skipping one clinical trial. Instead of taking the winning arm of the RTOG 8531 trial that showed significant survival benefit when LHRH agonist was given during the last week of radiation, compared to radiation alone [47,57], the researchers chose the winning arm of RTOG 8610, which provided neoadjuvant, concomitant and adjuvant hormonal therapy and radiation, and did not show significant survival benefit compared to radiation alone [60]. RTOG 9413 chose the winning arm of RTOG 8610, which did not show survival benefit, and compared it to fully adjuvant hormonal therapy, rather than providing LHRH during the last week of radiation. No trial compared the winning arms RTOG 8531 and RTOG 8610.

Giving the first dose of LHRH agonist on the first day [46] or last week [57] of radiation showed a clear survival benefit compared to radiation alone. This may be due to testosterone flare or because of other hormones or effects that LHRH agonists induce and we do not know about them yet. The standard of care for prostate cancer patients should be one of the trial arms that showed significant survival benefit when hormonal therapy was combined with radiation as in RTOG 85–31 and EORTC 22863. Because of the similar survival in the control arms of these studies (Table 1), and the higher overall survival in EORTC 22863, starting LHRH agonist on the first day of radiation for patients with high-risk prostate cancer should be the standard of care, until a better standard evolves. "

Is this researcher's conclusion contradicting what many of us have been told re the timing of ADT with radiation for local high risk PCa? Or am I misinterpreting what I am reading? If not, should we disagree with our ROs?

[dhccpa in reply to maley2711]

Good catch!

[maley2711 in reply to dhccpa]

I don't know...a whole bunch of brainy MDs bought into a bogus SOC??? Really?? Looking for TA to chime in on this !! Pertinent for so many making decsions now and future!! But, don't trials of ADT + radiation prove the benefit of 24 months of ADT versus 12 months or less for initial treatment of local high risk cancer. At Kaiser , 1-2 months of ADT prior to radiation, and a total of 18 months of ADT. Thus, the "flare" would occur prior to radiation. Something not adding up?

[dhccpa in reply to maley2711]

Yes, it's curious.

[MateoBeach in reply to maley2711]

Yes that is exactly the point. Those planning SRT should take this to their MO/ROs IMO.

[dhccpa]

Hasn't TA cautioned against doing chemo when ADT is working properly and things are suppressed? Am I recalling that correctly, TA? And isn't this find in a similar vein?