IAD vs. CAD all over again: are you confused yet?

New data from the randomized FinnProstate Study VII trial comparing outcomes of men randomized to treatment with either intermittent (IAD) or continuous (CAD) androgen deprivation therapy are going to further confuse physicians and patients about the relative merits of these two types of androgen deprivation therapy.

Regular readers will remember that, earlier in the year, at the ASCO annual meeting, Hussain et al. presented data suggesting that IAD was significantly less clinically effective than CAD for the initial treatment of most men with metastatic prostate cancer. This finding set off something of a firestorm in the professional and the lay prostate cancer communities because other trials had suggested that the relative efficacies of the two forms of therapy were very similar.

The FinnProstate Study VII has now provided published data in two recent articles: the first deals with relative efficacy and the second with side effects and quality of life.

Salonen et al. initiated the FinnProstate Study VII by enrolling 852 men with locally advanced or metastatic prostate cancer who all received therapy with 12.5 days of antiandrogen therapy (using cyproterone acetate) to prevent a flare reaction and 24 weeks (6 months) of androgen deprivation with the LHRH agonist goserelin acetate (Zoladex). These 852 men were enrolled into the study between 1997 and 2003.

To be specific, the men initially enrolled into the trial had to meet at least one of the following criteria:

  • M1 disease and any PSA level
  • M0 disease and a PSA level ≥ 60 ng/ml
  • T3-4M0 disease and a PSA level ≥ 20 ng/ml

In theory it was also possible to enroll patients who had received  prior treatment with surgery or radiation therapy for localized prostate cancer and a recurrent PSA level ≥ 20 ng/ml (with no prior hormonal or other medical treatment). However, no such patients weere, in fact, enrolled into this trial.

After the initial 24 weeks of therapy,

  • 554/852 men (65 percent) had a PSA than had declined to < 10 ng/ml or by ≥ 50 percent if their original PSA was < 20 ng/ml at baseline.
  • 298/852 men (35 percent) did not meet the above eligibility criteria for a sufficient decline in their PSA and were excluded from randomization.

The 554 men who did have a sufficient initial decline in their PSA levels at 24 weeks were randomized to either CAD (n = 280) or IAD (n = 274) and followed until January 2010. The results of the study  with respect to effectiveness are as follows:

  • Average (median) follow-up was 65 months (5.4 years).
  • Average (mean) age of patients was 71.5 years and there was no difference in the ages of patients in the two arms of the study.
  • No patients were lost to follow-up, and one patient was followed for a total of 11.4 years.
  • 79 percent of patients randomized had PSA levels of ≤ 4.0 ng/ml at the time of randomization.
  • For the men treated with IAD
    • The average number of cycles of IAD was 3 (range, 0 to 14 cycles).
  • 392/554 patients (71 percent) died of all causes during follow-up.
    • 186/274 patients who died (68 percent) had been treated with IAD.
    • 206/280 patients who died (74 percent) had been treated with CAD.
    • This difference was not statistically significant.
  • 248/554 patients (54 percent) died of prostate cancer during follow-up.
    • 117/274 patients who had been treated with IAD (43 percent) died of prostate cancer .
    • 131/280 patients who had been treated with CAD (47 percent) died of prostate cancer.
    • Again, this difference was not statistically significant
  • The average (median) times from randomization to progression or death were as follows:
    • 34.5 months from randomization to disease progression for the men on IAD
    • 30.2 months from randomization to progression for the men on CAD
    • 45.2 months from randomization to death from all causes for the men on IAD
    • 45.7 months from randomization to death from all causes for the men on CAD
    • 45.2 months from randomization to prostate cancer-specific death for the men on IAD
    • 44.3 months from randomization to prostate cancer-specific death for the men on CAD
    • 22.9 months from randomization to treatment failure for the men on IAD
    • 30.5 months from randomization to treatment failure for the men on CAD

Note that the definitions of treatment failure and disease progression are complex but are listed in full in Appendix 2 of the full text of the paper in the Journal of Urology.

Now let’s look at the adverse effect and quality of life results from the second of the two papers. Salonen et al. report that:

  • There were no significant differences in the prevalence of serious adverse effects between the two groups of patients.
    • 87/274 men treated with IAD (32 percent) had adverse cardiovascular effects.
    • 95/280 men treated with CAD (34 percent) had adverse cardiovascular effects.
    • 24/274 men treated with IAD (9 percent) withdrew from the trial after adverse cardiovascular effects.
    • 29/280 men treated with CAD (10 percent) withdrew from the trial after adverse cardiovascular effects.
    • 19/274 men treated with IAD (7 percent) had bone fractures.
    • 15/280 men treated with CAD (5 percent) had bone fractures.
    • Hot flashes and/or night sweats were reported by 47.1 percent of patients treated with IAD.
    • Hot flashes and/or night sweats were reported by 50.4 percent of patients treated with CAD.
  • Interestingly, however:
    • Erectile dysfunction was reported by 15.7 percent of men treated with IAD.
    • Erectile dysfunction was reported by 7.9 percent of men treated with CAD.
    • Depressed mood was reported by 2.2 percent of men treated with IAD.
    • Depressed mood was reported by no men treated with CAD.
    • These differences are statistically significant.
  • Significant differences favoring men treated with IAD as opposed to CAD were evident with regard to
    • Limitations on activity
    • Physical capacity
    • Sexual function

Based on the data from these two papers, Salonen et al. conclude that, compared to CAD:

  • IAD is “a feasible, efficient and safe method to treat advanced prostate cancer.”
  • IAD “showed benefits” with respect to quality of life.
  • IAD was associated with a similar prevalence of adverse effects.

Now it does have to be clearly pointed out that the FinnProstate Study VII was based on a significantly smaller study population than the data reported by Hussain at ASCO. Furthermore, in the trial reported by Hussain, men’s PSA levels had to drop to < 4.0 ng/ml before they were eligible for randomization, whereas in the Finnish trial men’s PSA levels only had to drop to < 10 ng/ml (although, as noted earlier, 79 percent of the men in the Finnish trial did have PSA levels of ≤ 4.0 ng/ml at the time of randomization). It is not really possible to make an accurate comparison of the “meaningfulness” of the results of the two trials, as a consequence.

What is clear is that — depending on people’s perspectives — they are going to use one or other of these sets of data to argue that CAD or IAD may be a “better” option for specific patients. It is going to be difficult for most men to really appreciate the distinctions between these two sets of data, let alone use them to make clinically appropriate decisions for themselves as individuals.

It should be noted that Salonen et al. do state in their conclusions that:

[P]atients with the most advanced and the most aggressive prostate cancer with a high pre-treatment PSA do not show an adequate biochemical PSA response to androgen deprivation therapy, and are not candidates for IAD.

7 Responses

  1. It’s very interesting. In 2007 researchers from Johns Hopkins identified that a prostate cancer treatment called androgen deprivation therapy may encourage prostate cancer cells to produce a protein that makes them more likely to spread throughout the body (metastasize):

    “David Berman, an assistant professor of pathology, urology and oncology at The Johns Hopkins University School of Medicine, and his colleagues identified the unsuspected potential problem with treatments that suppress testosterone after discovering that the gene that codes for the protein, called nestin, was active in lab-grown human prostate cancer cells.

    “What all this suggests is that nestin levels increased when prostate cancer cells are deprived of androgens and may encourage the cells
    to metastasize,” says Berman.”

    For sources please click here and here.

  2. Dear John:

    The potential for overly early use of androgen deprivation therapy (ADT) to stimulate the early growth of androgen-resistant prostate cancer cells is well known. The researchers and clinicians at Johns Hopkins have long been resistant to the overly early use of ADT for this reason. However, there has never been any clear proof of whether this actually happens or whether it happens in a definable subset of men. (The “New” Prostate Cancer InfoLink suspects that the latter is a likely scenario.)

    The report you refer to is just one in a whole stream of articles over the years addressing this issue — which still needs resolution. The “New” Prostate Cancer InfoLink is of the opinion that: (a) ADT is commonly initiated far too early in many men who will gain no well-defined benefit from such therapy until later in the progression of their disease and (b) ADT is often not initiated soon enough in a much smaller group of men who really do need early and aggressive therapy. There have been published reports that support this opinion.

    The fact that excessive overuse of ADT may actually stimulate the early growth of androgen-resistant prostate cancer is one of the arguments used by advocates for the use of IAD as opposed to CAD. However, again, there is no actual proof of this hypothesis.

  3. Confused … Yes.

    One observation from someone on IAD. The on and off aspect at least for me creates more depression since when I come off I know (quickly rising PSA) that I will need to go back on and, since it takes several months for me to recover, then just when I am feeling better … bang … back on. I am not sure if I would feel less depression on CAD.

  4. John R. was not referring to the potential for ADT to lead to castration resistance. Rather, the study he referred to suggested that ADT increased the motility of the cancer, making it more likely to spread, regardless of resistance status. This would be another separate argument against premature application of ADT.

  5. Dear Cherub:

    Yes. I appreciate that, but the data he is referring to needs to be seen in the context of the 20-year-long resistance of some individuals at Johns Hopkins to the use of hormone therapy in prostate cancer for any reason except palliative care. As far as I am aware, since the article in 2007, there has been no further data suggesting (let alone confirming) that increasing nestin levels actually have any meaningful impact on the risk for prostate cancer metastasis, let alone that this is stimulated by androgen deprivation therapy.

    The truth is that we are still almost completely clueless about exactly why cancer starts to metastasize from the prostate, and there is no clinical evidence at all (that I am aware of) to support the idea that early use of hormone therapy actually stimulates the motility of prostate cancer cells in man, thus leading to increased risk for metastatic disease. What one can show in Petri dishes and laboratory animals and what actually happens in the real world of clinical medicine are commonly very, very different from each other.

  6. STILL AMAZED BY VAST GULF IN UNDERSTANDING OF IAD (now at 12 1/2 year point, third off therapy cycle, intermittent triple IAD)

    Reading abstracts of such studies makes me so grateful I stumbled upon very different advice for ADT/IADT, advice that has served me so well with a case that was considered aggressive and locally advanced back in December 1999 (less than 3 years after enrollment commenced for this study). Here are just a few comments (instead of a book). I’m just stating a viewpoint — not trying to build a case, though there is substantial evidence available.

    I am convinced that combined (two drug) or triple blockade are far more effective than single blockade. These patients were all essentially on single blockade except for a short period of less than two weeks during which they were on cyproterone acetate — a drug not approved in the US due to its risks, as preparation to prevent flare for Zoladex treatment. It makes me sad that a likely substantial proportion of the 298 men (35% of initial pool) who had an inadequate response to single-drug ADT would have had a better response to combined or triple ADT. I am saddened that the times from randomization to progression were relatively short (34.5 months IAD group, 30.2 months, CAD group). My own first full treatment phase was 31 months, and my first IAD vacation lasted 34 months, that vacation alone virtually as long as the median time to progression for the IAD group. Granted, the men in this study were at a fairly advanced disease point, but so were I and others with challenging cases who have enjoyed much longer-term success.

    Doctors whose views I follow suspect that at least 9 months of ADT is needed, a duration much longer than the 6 months of Zoladex (alone) in this study.

    There is no indication in the abstract that the men in this study were monitored with testosterone, DHT, and some other tests where appropriate, For some men (I’ve heard about 10%), such tests indicate the need to adjust or correct the treatment regimen so that the desired blockade is achieved.

    Regarding Johns Hopkins, as mentioned by Sitemaster, one prominent doctor there is especially known for his outspoken opposition to early initiation of blockade. It is worth noting that he is not in a position to have observed the effectiveness of early and well-done blockade because he does not believe in it or use it. However, some prominent prostate cancer researchers at Johns Hopkins have far different, favorable views of the usefulness of ADT.

    IADT3 has created one problem for me: I have done so well that I now need to think hard to select a therapy for a good shot at a cure! My once “rock hard”, enlarged prostate (PSA 113.6 initially, all cores positive with most 100% cancer) is now small and normal, with advanced, sensitive lymph node and bone scans recently negative. I’m mentioning this just to indicate that the doom and gloom scenarios about ADT use are arguably overblown, at least for some of us.

    I can appreciate that short on-therapy cycles would tend to be followed by short off-therapy vacations. That’s one reason I believe in on-therapy cycles of at least 9 months. My own full-therapy cycles have been 31 months, 19 months, and 19 months. (It took about 10 months of that first cycle to build up to triple blockade.)

  7. Dear Jim:

    While I appreciate that IAD3 (and IAD2) have appeared to work well for some men, one of the very real problems is what we don’t know — which is whether you and some of those other men might have just been among the men who do extremely well on single-agent IAD (which is a far from unknown experience) or even on single-agent CAD. We also know nothing at all about the men who try IAD2 and IAD3 and progress rapidly. No one ever reports data on those patients.

    While there is an enormous amount of “expert opinion” expressed on this issue, I find it saddening that the experts in question (several of whom expressed strong opinions about the data presented by Hussain at the ASCO meeting earlier this year) seem to have been less than willing to really argue fiercely for the execution of sound, randomized trials of IAD2 and IAD3 compared to single-agent IAD and CAD in the treatment of progressive prostate cancer in well-defined patient populations. All we have from these experts are data from (relatively small) patient series among highly selected and highly motivated patients. Such data are notoriously unreliable and can really only be considered to be hypothesis-generating. The hypothesis needs to be actually proven in the real world of clinical practice.

    We know that individual responses to ADT of any type are enormously varied — in terms of therapeutic effect and in terms of adverse events to therapy. If we had any compelling data from even a single, half-decent, randomized Phase II study of IAD3 vs CAD or single agent IAD, it would make it a great deal easier to support the position that you (and others such as Chuck Maack) have expressed over the past decade … but we don’t have such data, and until we do your expression of belief is personally justified but scientifically and clinically unsubstantiated. This is not a matter of a “gulf in understanding”; it is a gulf of evidence that is the problem.

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