Salvage ADT after failure of radiation therapy — the art of good timing


The art of good timing and good patient selection is important to the appropriate use of salvage hormone therapy in all men who are in biochemical failure after first- or second-line radiation therapy. A study published in “the Red Journal” helps to make this point.

Myrdin et al. carried out a secondary (retrospective) assessment of data from the Irish Clinical Oncology Research Group 97-01 trial. The original study was a randomized clinical trial designed to compare the benefits of 4 months as opposed to 8 months of neoadjuvant androgen deprivation therapy (ADT) + radiation therapy (RT) in men with intermediate- and high-risk prostate cancer. Myrdin et al. wanted to use data from this study to evaluate the survival benefit of early vs late salvage ADT in the men who progressed after initial neoadjuvant ADT + RT.

The authors identified 102 participants in the original trial who had a clinically significant recurrence of their disease at an average (median) follow-up of 8.5 years. These 102 participants were then classified into one of three groups:

  • 57 patients had PSA levels of ≤ 10 ng/ml and no distant metastases at initiation of salvage ADT (Group A).
  • 21 patients had PSA levels > 10 ng/ml and no distant metastases at initiation of salvage ADT (Group B).
  • 24 patients had distant metastases at initiation of salvage ADT (Group C).

The authors then set out to assess overall survival of the men in each of these groups from two different time points:

  • Time point 1 was the date of enrollment in the original trial.
  • Time point 2 was the date of initiation of salvage ADT.

The analysis of overall survival based on the three pre-specified groups and the two time points showed the following:

  • Overall survival from time point 1 at a median follow-up of 10 years was
    • 78% for patients in Group A
    • 42% for patients in Group B
    • 20% for patients in Group C
  • Overall survival from time point 2 at a median follow-up of 6 years was
    • 70% for patients in Group A
    • 47% for patients in Group B
    • 22% for patients in Group C
  • The average (median) time from end of RT to biochemical failure was
    • 3.3 years for patients in Group A
    • 0.9 years for patients in Group B
    • 1.7 years for patients in Group C
  • The average (median) PSA doubling time also varied by group, as follows
    • 9.9 month for patients in Group A
    • 3.6 months for patients in Group B
    • 2.4 months for patients in Group C
  • On multivariate analysis, timing of salvage ADT, time from end of RT to biochemical failure, and PSA nadir on salvage HT were all significant predictors of survival.

It is apparent from this study that, at least in men with intermediate- and high-risk prostate cancer, early use of salvage ADT (i.e., in men with a PSA level  ≤ 10 ng/ml and the absence of distant metastases) is likely to be associated with longer survival after failure of initial treatment with neoadjuvant HT + RT.

It is also reasonable to hypothesize that (with the same condition that PSA levels are ≤ 10 ng/ml and there is no evidence of distant metastases), men with less aggressive cancer and longer PSA doubling times after first-line radiation therapy may well be able to defer initiation of hormone therapy for a while as opposed to initiating hormone therapy at the very first signs of a rising PSA.

11 Responses

  1. Mike:

    What are your thoughts on whether this study can be extrapolated to salvage hormone therapy after first-line radical prostatectomy and salvage radiation therapy? Thanks.

    Richard

  2. Richard:

    I think you can probably apply the principle, but I would be cautious about applying the numbers. The principle then needs to get tested.

  3. Coincidentally, I received the Summer 2012 Johns Hopkins Prostate Disorders Bulletin today, and in discussing advanced prostate cancer and when to start salvage hormone therapy after first-line radiation therapy or radical prostatectomy, it states (at page 13): “If there is no sign, other than a rising PSA, that cancer has spread, you should know that no evidence shows that starting hormonal therapy early (standard treatment for the past 50 years) will prolong your life compared to starting hormone therapy later, so there may be no advantage to beginning this therapy immediately”. The author cites the VA Cooperative Urological Research Group study as authority. I assume the Red Journal report was not available to the author when the Johns Hopkins article was prepared, but the Red Journal study results seem to contradict the findings of the VA study results (at least to the extent the Johns Hopkins author has interpreted them). Thanks for your insight.

    Richard

  4. Richard:

    Johns Hopkins has long taken the position you describe. Others would dispute this, and there are some limited data to support the position that early hormone therapy actually does extend survival (at least in some men). The problem is that:

    (1) There are no really good data from appropriately randomized and structured prospective trials that prove either hypothesis.

    (2) The VA studies conducted back in the 1960s and early 1970s were carried out on men who in no way reflect the health status of men being treated with early hormone therapy today AND they used a form of hormone therapy that is very rarely used today.

    (3) The VA studies never categorized patients into risk groups in a way that was designed to answer the question being posed by the article in the Red Journal (which has been asked over and over again over the past 20 years).

    I don’t know that we are ever going to be able to answer this question. The problem now is that (at least in America) I can’t see men agreeing to being randomized to early vs. deferred hormone therapy if they have a rising PSA after radiation therapy. Furthermore, because this trial would need to stratify men into at least three or more risk groups, it is a trial that would require thousands of patients (unless it was a trial which we only carried out in men with, say, intermediate-risk disease).

  5. Mike

    I agree with you that we are most likely not going to get this answer from a clinical trial.

    Hopefully there will be a better management agent or a cure in the semi-near future.

    For me personally it is, “Pick your poision (or not) and roll the dice.” I have very seriously considered stopping my hormone therapy and continue to contemplate it. The risk as explained to me by the MSKCC doctors is that once you lose control of the disease and it invades the bones and demonstrates skelatal events it is almost impossible to expect a cure. So their advice is to keep trying to manage the disease and hope for the future. The flip side (as I understand it) is, once you go castrate resistant on treatment, you lose the palliative benefits of ADT.

    For me personally the side effects of ADT are significant and severely impact my quality of life … but it is a really tough call for me to stop and potentially give up a shot at a cure or at least better disease management.

    Who knows … but I do think about it every day.

    Bill

  6. As you appropriately state in your article title, good timing seems to be the key. The problem is, as you recognize, the time of evident metastasis can only be determined in hindsight. That makes it impossible for the person who wishes to delay salvage hormone therapy (until just before evident metastasis) to know when to start.

    Thanks Sitemaster.

  7. UNFORTUNATE THAT KIND OF ADT WAS NOT IN ABSTRACT

    As a veteran of a challenging case of prostate cancer in my 13th year since diagnosis with intermittent androgen deprivation therapy (plus supportive program) as my sole therapy, doing well, I am again frustrated that the authors do not report on the kind of ADT in the abstract. That happens frequently in such studies. Perhaps the authors addressed the nature of the ADT in the study itself. I see failure to address this point as a key deficiency in many such studies, greatly undermining their value for patients and doctors looking for research that will help guide therapy decisions.

    I am personally convinced that single blockade (either medically or surgically) is frequently ineffective in achieving significant long-term effective control of the cancer. My view is there is persuasive evidence that combined blockade (blocking testicular testosterone plus restricting access to androgen receptor (cancer fuel docking ports) with drugs like bicalutamide is far more effective. I am personally convinced, based on quite limited formal evidence but experience of hundreds of fellow ADT veterans and doctors treating them with triple ADT that triple ADT is often the best approach. The third drug is finasteride or dutasteride (Avodart).

    Frankly, bluntly, the overall survival times from point 2 at six years are pretty sorry compared to what should be achievable with well-done ADT3.

    If anyone has seen this paper, would you share with us any details provided about the kind of blockade?

  8. Jim:

    Are you aware of any documentation at all regarding the proportion of men on ADT who are actually using triple androgen deprivation (intermittent or continuous)?

    I have to tell you that I am not, and the number of physicians who I am aware of who prescribe this form of ADT on a regular basis is tiny.

    I am not arguing with your belief that ADT3 may be highly beneficial for at least some men. On the other hand, I think we can safely guarantee that most specialists are not using ADT3 on a regular basis, and that the vast majority of published literature is not referring to this type of ADT. Since the clinical literature supporting its use is minimal, this is not exactly surprising, and I continue to be disappointed that those who use this type of ADT on a regular basis have completely failed to publish meaningful data that would support such therapy.

  9. Jim (jimwaldenfels):

    The report mentions a conflict of interest: “J. G. Armstrong received research funding from Ipsen Pharmaceuticals and has provided expert testimony on behalf of Amgen Inc.” So it may be reasonable to assume that one of the drugs could have been triptorelin? It is probable that an anti-androgen was used alongside this. I don’t fancy paying $30 just to confirm this. ;-)

    I’m a relative newcomer to this subject (diagnosed in early June 2012, cT3NxM0, Gleason 10). I have been reading a lot about Snuffy Myers’ ADT3 regime with the inclusion of Avodart. I was interested in this approach until I saw that Avodart may not be a great thing to take if you want to avoid/survive prostate cancer. See this press release.

    Anyway best of luck,

    Jim

  10. Dear Jim McAree:

    The risks associated with use of Avodart in the prevention and management of prostate cancer are actually extremely small and poorly defined. I think you need to look carefully at who distributed the media release you refer to … a lawyer who is clearly trolling for cases in the hope that he can develop a class action lawsuit.

    The FDA issued it’s caution about the risks associated with Avodart based on two trials of 5-alpha-reductase inhibitors in the prevention (not the treatment) of prostate cancer, and even then the caution was considered controversial by many. Hundreds of thousands of men have been treated with Avodart for benign prostatic hyperplasia, and (as far as I am aware) there is no actual evidence that such treatment has had any effect on the risk for prostate cancer in these men over the past 10 or more years.

  11. Dear Sitemaster:

    Thanks for the heads up on Avodart. I’ll have another look into it. Great site by the way.

    Jim

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