New meta-analysis endorses IADT for good responders to initial CADT

A new meta-analysis of data from nine large clinical trials suggests that, “There is fair evidence to recommend use of [intermittent] instead of [continuous androgen deprivation] for the treatment of men with relapsing, locally advanced, or metastatic prostate cancer who achieve a good initial response to androgen deprivation.”

According to this article just published in the Journal of Clinical Oncology, Niraula et al. searched all literature published through August 2012 from MEDLINE, EMBASE, the Cochrane Library, and major conference proceedings. They included all randomized, controlled trials of intermittent (IADT) as compared to continuous androgen deprivation therapy (CADT) that reported either overall survival (OS) or biochemical/radiologic time to disease progression, or both.

Here are their findings:

  • Nine studies with 5,508 patients met the inclusion criteria.
  • There were no significant differences in time-to-event outcomes between the groups in any studies.
  • The pooled hazard ratio (HR) for OS was 1.02  for IADT compared with CADT
  • The pooled HR for progression-free survival was 0.96.
  • More prostate cancer–related deaths among men on IADT tended to be balanced by more deaths not related to prostate cancer among men treated with CADT.
  • Superiority of IADT with respect to sexual function, physical activity, and general well-being was observed in some trials.
  • IADT was associated with median cost savings estimated to be 48 percent of the cost of CADT.

The “New” Prostate Cancer InfoLink has not been able to ascertain (yet) exactly which nine trials were included in this meta-analysis. For example, we don’t know if it included the patients enrolled in the 17-year-long SWOG trial reported at ASCO (in June 2012) and published in the New England Journal of Medicine this April. It probably does not.

It is important, however, to note the careful statement made by Niraula et al. in their recommendation that specifies that IADT is recommendable in men “who achieve a good initial response to androgen deprivation.” The “New” Prostate Cancer InfoLink has previously suggested statements like this probably really imply men who have a stable PSA level of < 0.1 ng/ml (and, ideally, a stable serum testosterone level of < 20 ng/dl) after an initial 6-9 months of CADT.

9 Responses

  1. I am going to order a reprint of this to send to my urologist. Thank you.

  2. After being able to review the full text of this paper, we can confirm that these data do include the data from the SWOG trial abovementioned.

  3. Thanks for reporting this interesting research that again, in an overview meta-study fashion, indicates at least the non-inferiority of intermittent ADT to continuous ADT.

    I note that Dr. Ian F. Tannock is the third and last author, which I take to indicate that he is the “senior” author. He has been involved with many research papers, often involved with ADT and its management, often with prestigious members of the ADT research community.

    However, as a now savvy veteran of ADT, I’ve learned that the viewpoints and beliefs of that research community do not consistently overlap with the viewpoints and beliefs of some of the clinical physicians with large practices dedicated to prostate cancer patients, many with advanced and challenging cases. These clinicians have long experience with sophisticated ADT and countermeasures for side effects. Here are some key points likely not influencing patients in the studies included in this meta-study that would likely, as I see it, improve the experience and results under intermittent ADT as contrasted with continuous ADT.

    Use of a 5-alpha-reductase inhibitor drug as the third element of ADT3. For example, a paper published in the Journal of Urology in 2006 by Scholz et al. indicated that men taking finasteride had double the vacation period from the heavier duty drugs (such as Lupron plus Casodex), with a median of 31 months compared to a median of 15 months for men not taking finasteride. If memory serves, a friend who consulted Dr. Tannock found he was opposed to use of 5-ARI drugs for his case of relapse after surgery. My own observation from direct talks with Dr. Mario Eisenberger and some other leading academic researchers is that this attitude is not uncommon, in fact probably typical. My personal belief, based on my own continuous use of a 5-ARI drug over nearly 13 years since my first year on ADT is that a 5-ARI drug is going to make a key difference for many of us. The Scholz and colleagues team has had other papers published that are relevant, but none are randomized, controlled trials that would have been counted in the Niraula meta-analysis.

    Use of a nadir of < 0.05 while on ADT as a criterion for initiating the vacation period from the heavier duty drugs (LHRH-agonist, antiandrogen). The Scholz team has also published about this. Their finding from records in their own practice (reported in The Oncologist in 2000) included the observation that men achieving and maintaining a PSA nadir of < 0.05 for at least a year enjoyed substantially longer vacations. Subsequently, I believe that at least Dr. Scholz is comfortable initiating vacations, after a minimum time on blockade (9 to 12 months?) if the PSA drops to < 0.05 without keeping it there for a year. Another doctor I trust as an expert wants the PSA to be < 0.01, which is a newer reliable operational definition of "undetectable." The Sholz team has at times reported results with a PSA nadir of < 0.1 depending on the timeframes of treatment in their studies.

    Minimum time on ADT: Regarding Sitemaster's final comment, my impression is that 9 months is still the point of maximum cancer cell kill on ADT, which would suggest it is a better minimum time-on-therapy period than 6 months. Is there research now supporting maximum-cell-kill at 6 months? I'm aware of other research indicating promising outcomes after 6 months, as well as, on the other hand, research for ADT supporting radiation for Gleason 8-10 and some other patients with advanced cases that suggests that 6 months is, for such patients, clearly inferior to longer periods, with research supporting 2 years and some more recent research supporting 1 year. I realize we are mixing apples and grapefruit here (perhaps water melons), but these are the clues available.

    This morning I activated my free patient's subscription to the Journal of Clinical Oncology as suggested by Sitemaster back on February 2013. I'm looking forward to receiving the PDF for this study. Thank you for pointing out this access policy!

  4. Dear Jim:

    Until we have a meaningful, randomized, double-blind, controlled clinical trial, there is a limited amount of endorsement you will get from the academic community regarding the potential of ADT3 or intermittent ADT3. That is what academics rely on for “proof”. Without those data, it is all just speculation. Get Tony Crispino to take it up with SWOG. A small, Phase II, randomized, controlled pilot study woudn’t be that difficult, and if it showed a serious signal of clinical benefit, I’ll bet you a Phase III trial wouldn’t be far behind.

  5. To Tony Crispino (hope you will see this):

    Per Sitemaster’s suggestion, would you be interested in looking into a Phase II trial of ADT3 versus ADT2? Perhaps the primary end point would be time off therapy (the LHRH agonist and antiandrogen), and a primary exclusion criterion would be failure to achieve a PSA nadir below 0.05, the objective being to look only at patients capable of a good response to ADT.

    It seems to me it would make good sense to look at patients who were relapsing after primary surgery or radiation therapy (or both) and who were going on ADT for the first time. I would be pleased to contribute thoughts for constructing such a trial. Many of us would like to see confirmation of the Scholz/Strum/Lam and colleagues findings of a much longer vacation period following triple ADT (with the 5-ARI continued during maintenance) compared to ADT that just involved an LHRH-agonist and an antiandrogen, the findings described briefly in my response of 4/30 11:14 am above (the 2006 paper).

    Dr. Oliver Sartor was involved with a very roughly similar small trial that called for addition of a 5-ARI drug to see if it could restore effectiveness following failure of two drug blockade (PMID: 19796455). Of course, that scenario is considerably more challenging than the one I would like to see. I have been expecting results for some months now but have seen nothing, and I am not sure if this is trial NCT00470834.

  6. Jim,

    I see the post and I’m discussing it with the committee leadership. I can’t say specifically what’s in the proposal agenda but I can say there are various looks at dutasteride.

  7. Mike can you send me the Niraula paper? I’d like to see the stratifications for inclusion.

  8. Tony:

    Copyright issues mean that I cannot send you a copy of this paper directly. However, you can get it yourself with ease if you sign up for free access to JCO articles through the RightsLink system. To learn how to do this, click here.

  9. Hi Tony (responding to your 5/2 of 5:23 pm responding to me re dutasteride),

    Thank you very much!

    There are some subtleties in using these drugs that may be below the awareness of potential trialists. I hope they would consult the doctors who have long experience with these drugs. I have seen a clinical trial proposal from the then Strum/Scholz practice submitted probably in the late 1990s, but it was not funded; that’s probably why they decided to collect data from their practice in a highly disciplined manner, leading to later publication in some leading journals. Of course that proposal involved Proscar, as dutasteride was probably not even in development back then. One subtlety is that a small proportion of men have a genetic problem with dutasteride that prevents benefit, though they typically do respond to finasteride. That issue could be handled easily of course, such as by an exclusion criterion, or perhaps even protocol flexibility to try finasteride and continue in the trial if a sufficiently low level of DHT were achieved. Another not so subtle issue is the dose of the antiandrogen. Many of us without detected metastatic disease, like me, do just fine on 50 mg of bicalutamide a day, but some of us need, typically, 150 mg, with a few responding to even higher doses, something about which Dr. Charles (Snuffy) Myers has commented. I suspect a trial would need to specify one dose or perhaps the range from 50 to 150.

    I sense that I’m going into too much detail at this point, but I hope you will forgive that and see that it stems from eagerness to see triple blockade put to a long-deserved test.

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