IADT: the still unanswered questions and choices that must be made


About 18 months ago, at the 2011 Genitourinary Cancer symposium in Orlando, Florida, Klotz et al. presented data from a large trial of intermittent (IADT) versus continuous androgen deprivation therapy (CADT) in the management of men with progressive prostate cancer after prior treatment with first- or second-line radiation therapy. We reported their data at the time.

The full report on the structure and results of this trial has now been published in  the New England Journal of Medicine. Unfortunately, only the abstract is available on line unless you are a subscriber to the journal. As far as we can tell, however, there is no significant difference between the published data and the data originally presented by Klotz in February 2011.

As many readers will already be aware, the results of this trial (that IADT was non-inferior to CADT in these patients) are in sharp contrast to the results of the trial reported by Hussain and her colleagues at the annual meeting of the American Society of Clinical Oncology earlier this year. It is not entirely clear at this time how to resolve these differences in outcome in the best interests of individual patients. It also needs to be realized, however, that there were some very real differences between the ways that these two trials were conducted and the eligibility criteria for participation in the two studies.

Clearly, there are men for whom IADT is not appropriate under any circumstances. Their disease is too aggressive and their PSA does not fall to a low enough nadir level during the first period on androgen deprivation, prior to any period off androgen deprivation.

The problem is whether there are men for whom IADT is entirely appropriate, how to pick these men out from the general population of men with a rising PSA who are candidates for androgen deprivation therapy, and how to then manage their intermittent protocol to optimize their outcome. There is a whole list of still unanswered questions:

  • Do these men need to exhibit a nadir PSA level of < 0.1 ng/ml after 6 or 9 months of “lead in” androgen deprivation (or is any level < 4.0 ng/ml good enough)?
  • Do these men need to exhibit a nadir serum testosterone level of < 20 ng/dl after 6 to 9 months of “lead in” androgen deprivation (or is any level < 50 ng/dl good enough)?
  • What is the most appropriate and effective type of IADT?
    • A brief period of an antiandrogen (e.g., bicalutimide) followed by an LHRH agonist alone during the “on therapy” cycles but no treatment at all during the “off therapy cycles” (IADT1)?
    • Continuous two-drug androgen deprivation with an LHRH agonist and an antiandrogen during the “on therapy” cycles but no treatment at all during the “off therapy cycles” (IADT2)?
    • Continuous three-drug androgen deprivation with an LHRH agonist, an antiandrogen, and a 5α-reductase inhibitor (e.g., dutasteride) during the “on therapy” cycles but no treatment at all during the “off therapy cycles” (IADT3)?
    • Continuous three-drug androgen deprivation with an LHRH agonist, an antiandrogen, and a 5α-reductase inhibitor (e.g., dutasteride) during the “on therapy” cycles and continued treatment with the 5α-reductase inhibitor during the “off therapy cycles” (IADT3+)?
    • Something else that we haven’t even tried yet (e.g., forms of IADT that include early use of drugs like enzalutamide)?
  • What is the most appropriate signal to restart androgen deprivation in a man with a rising PSA after a period off full androgen suppression?
  • What are acceptable nadir PSA and nadir serum testosterone levels after second, third, and subsequent “on therapy” cycles of androgen deprivation?

We know that there are men who appear to do extraordinarily well on all the different forms of IADT. We also know that there are some men who started out with “challenging” cases of progressive prostate cancer who appear to have done extraordinarily well on IADT3+ (and we fully expect at least one of those men to comment on this post). We also think that we know why the different forms of IADT fail, and it is the same reason regardless of type of IADT — because the patients’ cancers are progressing too rapidly into the realm of androgen resistance.

The problem is what we don’t know:

  • Why do the men who do well on the different types of IADT respond so well?
  • Are forms of IADT like IADT3+ truly superior to IADT1 and IADT2 — or is this a mirage because we are only really aware of the most outstanding positive responses?

And then, of course, there is the issue of whether, if we take another decade or so to conduct studies that might be able to answer these questions, we will continue to get conflicting information.

So what does an individual patient do, faced with the current challenges? He is going to have to make a very personal choice after careful discussion with his doctors.

For men who want to be sure that they have the longest possible survival, regardless of side effects of therapy, this is a no-brainer: the Hussain-reported data and the data just published in the New England Journal of Medicine both suggest strongly that CADT with an LHRH agonist alone or with an LHRH agonist + an antiandrogen has an overall survival benefit when the responses of all patients who initially respond well to androgen deprivation are assessed (even if that that overall survival benefit is very small).

However, for those men who see quality of life as being a significant factor in their decision process, the decision is going to be much more difficult, and at this point in time we do not believe that there is clinically documented evidence that can categorically be used to demonstrate that any one form of IADT is superior to any other in terms of overall survival, prostate cancer-specific survival, or long-term quality of life. Furthermore, few clinicians actually have significant experience with the more sophisticated forms of IADT, which means that persuading one’s doctors to even consider such options can be — in itself — a challenge.

In the world of prostate cancer, the importance of becoming a well-informed patient who is able and willing to make tough choices is only becoming more evident. Your doctor may be able to guide you and help you understand and interpret the available data, but in the end only you may be able to make some of the actual decisions in the most appropriate manner that suits your personal goals.

5 Responses

  1. I don’t have access to Dr. Oliver Sartor’s editorial about the study in the NEJM, but I did find a partial summary of his comments:

    ‘ “The trial represents “the most definitive study to date comparing intermittent versus continuous androgen-deprivation therapy,” Oliver Sartor, MD, of Tulane University in New Orleans, wrote in an accompanying editorial.

    ‘However, he noted, the trial left unanswered the question of which patients might not require any hormonal therapy.

    ‘ “It is still unclear which men with rising PSA levels needed treatment,” Sartor wrote. “This is a heterogeneous patient group, and only a minority of men might be expected to have clinical consequences from their rise in PSA level. Given the slow progression of prostate cancer in many men, which of these asymptomatic patients actually benefited from androgen-deprivation therapy?”

    ‘The trial also did not address the question of timing of ADT, intermittent or otherwise, for asymptomatic men, according to Sartor.

    ‘ “Does early androgen-deprivation therapy in asymptomatic men with rising PSA levels provide more benefit than treatment in symptomatic men with metastases? This question bedevils our field, and we are no closer to an answer now than we were before,” he wrote.’

  2. Hi Tom. Thanks for this link.

    The whole issue of when to start ADT of any type (or whether to start it at all in some men) is a whole different question, and, as Dr. Sartor points out, it bedevils the entire question of how to treat progressive prostate cancer.

    Our suspicion is that some men do need to start hormone therapy early and that some men could wait for years before they need hormone therapy (and have PSA levels that rise into their hundreds or even thousands before they exhibit any signs or symptoms of clinical significance). The problem is that we don’t have a clue how to differentiate between these categories of men prospectively.

  3. I don’t know if this helps, but I started DES therapy with a PSA of 98 after all kinds of alternative remedies had failed to lower the PSA. There was a real tumor on both sides of my prostate and the RH lymph node was showing metastasis. Once I started taking DES, one 2 mg capsule per day, the PSA had dropped to 0.51 in 7 weeks; and the tumors and metastasis were completely gone. The PSA is now 0.3 after 12 weeks. I am reducing the DES gradually without any doctor’s interference — one 2 mg tablet every other day for 30 days ending August 31, and one capsule every 4 days ending October 30th. I check PSA every 2 weeks. I consider PSA an excellent indicator of what the tumor is doing. As to doctor’s advice, my doctors were unanimous, “You need to cut it out right away or you will die a horrible death.” I don’t have insurance, so their expensive remedies were not an option. Insurance is a worse enemy to good health than cancer, in my opinion. It leads the patient into making bad decisions based upon bad guidance from the medical industry for purely financial and professional reasons. Cancer is not the enemy. The medical industry is the enemy. DES has been around since the 1940s, but is no longer manufactured in the US. However, it is widely known as “The poor man’s cure for prostate cancer.”

    I’ll opt for the IADT every time. I surmise that the reason it doesn’t work for some prostate patients is that they allowed the medical profession to interfere with some sort of expedient cure, such as radiation, surgery or chemo. “We are fearfully and wonderfully made”, so why screw around with it?

    FS

  4. RESULTS IN “SHARP CONTRAST” BUT ALSO COMPLETELY CONSISTENT!

    Hi Sitemaster, and thanks once again for posting this interesting and important paper. I saw your article the day you posted it, but that was the eve of the annual Conference on Prostate Cancer (in Los Angeles this year, once again), and I was preoccupied with trip preparations. I suspect that applies to others of us who may have missed this article.

    Both the Klotz and Hussain findings add confirmatory evidence to what I have learned about ADT from expert medical oncologists with practices dedicated to prostate cancer who use a lot of ADT in their practices and have tracked results for years. The bottom line, as I understand it from my layman’s viewpoint, is simple: men with metastatic disease usually are better off with continuous ADT (the Hussain finding), while those without detectable mets are better off with intermittent therapy (the Klotz finding). There is nothing inconsistent here. As with so many strategies, intermittent ADT works better when used at an earlier point in the disease.

    One of the practices has published retrospective results from several vesions of ADT/IADT in their practice records. This is the Scholz/Lam practice, formerly the Strum/Scholz practice, with all still involved with associates as a research team. They have sliced and diced their data to show different risk groups responding to variations of ADT, and, while the studies are small and from a single institution, the results are quite suggestive and encouraging. Moreover, their research has been published in several peer reviewed medical research journals. Here are some key points bearing on the issue of continuous versus intermittent ADT.

    (1) Whether the patient is able to achieve a nadir of < 0.05 is critical, at least on IADT3. While touched on in several of the team's papers, their 2007 paper published in Urology best documents the importance of achievement of a nadir < 0.05. This paper reports median 10-year follow-up on 160 men who started ADT before 2000 as primary therapy (n = 60) or for recurrence (n = 100). Seventy-six percent did not die from prostate cancer at the end of follow-up, with the remaining 24% (39 men) dying of prostate cancer. Among those who died of prostate cancer, men who did not achieve a nadir of < 0.05 were 11.6 times more likely to die of prostate cancer (per Cox multivariate regression analysis)! Put another way, only 11% of men with nadirs below 0.05 ng/ml died from prostate cancer, while 78% of those with higher nadirs died of prostate cancer. The complete paper states that cases were excluded if the baseline PSA was over 100 ng/ml (me) or there was metastatic disease, in order to present a study population more relevant to current conditions where men are typically diagnosed with earlier stage disease. This group was treated with combined ADT [an LHRH agonist plus an antiandrogen -- either flutamide or bicalutamide (Casodex), but not a 5-alpha reductase inhibitor (5-ARI)]; while the practice was also putting some men on triple blockade (adding the 5-ARI drug finasteride for maintenance or also along with combined blockade, they did not tally and compare their ADT2 versus ADT3 results, which allowed them to observe the superiority of triple blockade for many men in their practice, until 2000. (They first reported the comparison informally at the National Prostate Cancer Conference at Long Beach, CA, with striking superiority for the ADT3 group!) There was substantial risk in the total group in this 2007 study, including 65 patients diagnosed with Gleason 7 disease, plus 31 with Gleason 8-10 disease (all per expert pathologists: Bostwick, Epstein, McNeal). The doctors in this practice, and at least one other prominent doctor dedicated to prostate cancer, promptly switch tactics if a patient does not achieve a nadir below 0.05 on ADT; the switch may involve second-line ADT drugs, newly approved drugs (evolving tactics), chemotherapy, immunotherapy or other approaches to supplement or replace first line ADT. Looking at all this from another viewpoint, whether or not the patient achieves a nadir of < 0.05 is used as a critical staging indicator that is key to treatment decisions.

    (2) PSA doubling time (PSADT). While their research indicates the PSADT is also independently important in predicting both PSA progression and prostate cancer specific mortality, it is much less important, from an ADT standpoint, than whether a nadir of < 0.05 is achieved. Multivariate analysis also indicated that Gleason score was somewhat independently important in predicting prostate cancer-specific mortality.

    (3) Papers on IADT (as a one-time course, for highly successful patients, or intermittently for somewhat less successful patients) as primary therapy, from this practice. Two papers are available; one on primary intermittent androgen deprivation for men with newly diagnosed prostate cancer and the other on primary androgen deprivation followed by active surveillance — again for men with newly diagnosed prostate cancer.

    The former paper (published in 2011 paper), with a median follow-up of 12 years, focused on 73 patients of the practice who had a clinical stage less than T3, who had at least 9 months of concommitent LHRH agonist and antiandrogen treatment, who recovered testosterone levels of > 150 ng/dl within 12 months after stopping ADT, and who achieved a nadir of < 0.05 on ADT. While all were considered initially as eligible for surgery or radiation, there was substantial risk in the total group, with 15 men at low risk, 38 at intermediate risk, and 20 at high risk. Key findings included: 70 men without metastases at study end; 3 men with metastases who died (at 3.5, 7.7 and 11 years after starting ADT); 29% required no further treatment after one round of ADT; 38% underwent delayed local therapy with notable success after a median of 5.5 years; and 33% maintained a PSA level of < 5 throughout 2 to 5 cycles of intermittent ADT. To me it is amazing that nearly a third of the patients who achieved a nadir of < 0.05 and recovered testosterone after ADT to greater than 150 ng/dl were successful in controlling their cancers long-term with a single course of combined ADT, without 5-ARI maintenance drug support! Subsequent information from the practice is that ADT3 with the 5-ARI drug continued as maintenance is an even more successful protocol, but that has not been formally published yet unless it is contained in the complete details of the 2012 paper, which I have not yet read.

    The second paper (published in 2012) looks at a different grouping of 102 patients in the practice who also had ADT as primary therapy. A hallmark of this study was that all the men had biopsies to assess response to ADT. Initial risk was substantial with 22 at low risk, 30 at intermediate risk, and 50 at high risk. The researchers concluded that "Despite a high prevalence of ≥ 50% core biopsies positive at baseline, [androgen deprivation] induces durable remissions in most men with low-risk and about half with intermediate-risk PC." Again, this is an impressive result!

    (4) Finasteride (can generalize to Avodart) generally doubled the vacation time for men on intermittent blockade. This is the key paper that documents that particular finding. The main finding was that use of finasteride doubled the vacation period, specifically for these two comparison groups from 15 to 31 months, after an median of 15.8 months on ADT! Another finding, important at the time, was that the incidence of what was then called "androgen independent prostate cancer" (AIPC) was not increased among the men on finasteride through nearly 9 years of follow-up. (The prominent prostate cancer researcher/physician Eric Small, among others, was concerned at the time that use of finasteride would foster AIDP; my strong impression is that there is now a consensus that finasteride does not foster AIDP.)

    This body of research has extra credibility for me both because it is consistent with informal findings from other expert medical oncology practices dedicated to prostate cancer patients and because it is consistent with my own experience. I have not achieved the same success on intermittent ADT as the more successful patients reported in these studies who, like me, achieved nadirs below 0.05 ng/ml and recovered testosterone above 150 ng/dl, but that, as indicated in the studies, understandable in view of my very high-risk case. Even so, I am now at the end of my third vacation period, doing quite well, as I have passed the 12.5 year point of intermittent ADT3. (If I weren't in the run-up for radiation that now looks like a good bet for a cure based on advanced technology, I would be on my fourth cycle of ADT, as of July.)

  5. Dear Jim:

    I would respectfully suggest that your base summary of the results of the two randomized trials reported by Klotz et al. and by Hussain et al. ["men with metastatic disease usually are better off with continuous ADT (the Hussain finding), while those without detectable mets are better off with intermittent therapy (the Klotz finding)"] is not entirely accurate. I think one has to take into account the aggressiveness of each patient’s disease and not just whether there were or were not metastases. I do agree with you, however, that failure to be able to drive the PSA down to effectively zero (< 0.05 ng/ml) prior to stopping androgen deprivation for the first off-therapy period suggests that the patients are unlikely to respond well. In my mind this was the biggest problem of the trial conducted by Hussain et al. Most of these men were really not good candidates for IADT at all.

    I would also note that restrospective analysis of case series from carefully selected and highly motivated patients, while always interesting, offer rather less than conclusive evidence of the value of a specific type of therapy. As I was careful to note in the above, we do indeed see excellent results from IADT2 and IADT3 in some of theses types of patient … but such data have never been replicated in even a small, randomized trial. Worse still, no one has even been able to initiate such a trial (although I am aware that there have been a couple of attempts, but without the involvement of investigators of stature who might have been able to make a compelling argument).

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