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CADT and IADT in the management of progressive and advanced prostate cancer

8 Responses

1. jimwaldenfels, on October 27, 2015 at 7:59 pm said:

   Interesting, but Really Inferior Versions of ADT and IADT!

   As a 14-year veteran of IADT3 at nearly the 15-year point as a survivor of a challenging case, I was a bit stunned by the kinds of ADT offered to these patients who had challenging cases — all metastatic to some degree. Right up front, despite that these patients were treated recently (2006 to 2015), more than half had monotherapy (just about 55% in both the IADT and CADT groups)! I am really surprised that less than half were given an antiandrogen in combination with the LHRH agonist, not to mention that they were not also given a 5-alpha reductase inhibitor (finasteride/Proscar or dutasteride/Avodart).

   It is also surprising that in the past 10 or so years during which these patients were treated a PSA low point of 1.0 was used as the trigger to stop ADT. It should be clear that a much lower nadir, at least less than 0.05 but arguably less than 0.01, is beneficial, with higher nadirs indicating a need to change tactics, especially with metastatic patients!

   I have had time to scan the paper and have so far noticed no indication that these patients were monitored for dihydrotestosterone, though thankfully at least testosterone was monitored.

   I expect to post more comments.
2. Jerry, on October 27, 2015 at 8:59 pm said:

   Is 20 months to CRPC what we’ve seen in other studies? Just my personal observation, but I’ve seen a lot of guys (both IHT and CHT) that go years before CRPC. Very seldom do I see HT only be effective for 20 months or less.

   All other stats aside, IHT allows a guy to feel normal while on a HT vacation (I have been able to go 3 years). While on therapy it gives a guy something to possibly look forward to. In this crazy world of advanced prostate cancer, one needs a break from drugs and hope.
3. Sitemaster, on October 28, 2015 at 7:53 am said:

   Dear Jim:

   (1) The fact that these patients were treated on “monotherapy” does not mean that they didn’t (a) receive an antiandrogen for a short period prior to initiation of the LHRH agonist or (b) that they didn’t receive second-line antiandrogen therapy after their PSA started to rise on LHRH agonist monotherapy.

   (2) Despite your personal fervor about IADT3, I would (yet again) point out that there are absolutely no data from any well conducted, long-term, randomized study to prove that IADT3 works better than any other form of IADT for the majority of patients. We don’t even know for sure that it has been beneficial in the long term for you. As I have said before, it may well be appropriate for a subset of patients — but we have no way to identify them.

   (3) The fact that all these patients had to have their PSA level drop to at least < 1 ng/ml was better than we have seen in any other large, long-term study of IADT vs. CADT.

   (4) Many of these patients, today, would presumably be most appropriately treated with initial ADT + chemotherapy if they had a significant level of metastasis at time of initial treatment. No one has any data whatsoever about whether such patients could later be switched to IADT — regardless of what their PSA level fell to after initial ADT + chemotherapy.
4. Sitemaster, on October 28, 2015 at 8:23 am said:

   Dear Jerry:

   The 20 months (600 days) reported in this study is an average (median) time from initiation of IADT or CADT to initiation of CRPC. If you look at Figure 1 in the actual paper, you will see that the range of times to onset of CRPC was from something like 90 days (3 months) to 2,500 days (nearly 7 years). That range would correlate very closely to the ranges seen in other studies. And yes, there are small numbers of patients who do seem to live for as much as 30 years after initiation of ADT … but they are certainly the exceptions as opposed to the rule.
5. jimwaldenfels, on October 28, 2015 at 3:36 pm said:

   Regarding the average time from initiation of ADT to onset of CRPC (castration-resistant prostate cancer), and impressed with success of IADT in metastatic patients

   Dear Jerry and Sitemaster,

   Here’s an expansion of the point in Sitemaster’s post of 8:23 am: those “other studies” are for men with identified metastases, and the figures in the subject study look similar to those in prior studies to me too.

   Jerry: I’m thinking the guys you are observing who do very well with IADT for many years are those who did not have identified mets at the onset of ADT. I’ve also seen such patients do very well for many years, especially with more sophisticated forms of ADT. That was true in my own case, which was a challenging, high-risk case at the outset but with arguably no detectable mets; I was still responding well to IADT when I stopped it at the 14-year point, though that final response (PSA 0.02) was no doubt aided by radiation the year before. One expert medical oncologist, Dr. Mark Scholz, MD (author of Invasion of the Prostate Snatchers), used to say that (non-metastatic) patients on ADT/IADT typically achieved excellent control of prostate cancer for either about 10 years or indefinitely; in other words, patients tended to fall in one group or the other. I believe those figures were based on his own experience in a practice dedicated to prostate cancer and research published by Memorial Sloan Kettering oncologists. (Note that these figures were from the era prior to the exciting new ADT drugs.)

   What I find discouraging is the number of patients without detectable metastases who are still, in 2015, told by their doctors that ADT is likely to work for only a year or two. Their doctors do not realize that the short time frame they are reciting is for men with detectable mets at the time of beginning ADT, not for men without detectable mets at that time. (Fortunately, that number of mis-advised men seems seems smaller now than some years ago, though I wish there had been a study of the proportion of patients getting such misleading and discouraging advice.)

   While I have serious concerns about the form of ADT used for the patients in the subject study, I accept that the doctor involved was doing a good job, in fact pioneering, within the prevailing medical culture, and this study is evidence that IADT can work well even with metastatic patients, a result which helps advance knowledge in an important area. My impression as someone pretty savvy about ADT/IADT is that even doctors I follow as experts in ADT were reluctant to put their metastatic patients on intermittent ADT and normally used continuous therapy, at least based on the older drugs (not Zytiga, Xtandi, Firmagon).
6. jimwaldenfels, on October 28, 2015 at 7:54 pm said:

   Issues Raised by Sitemaster

   Dear Sitemaster,

   I have now read the whole study and can comment on the important issues you raised. I’ll quote your words for each issue from your comment today at 7:53 am and then respond to each in order to advance the discussion.

   You wrote:

   “Dear Jim:

   (1) The fact that these patients were treated on “monotherapy” does not mean that they didn’t (a) receive an antiandrogen for a short period prior to initiation of the LHRH agonist or (b) that they didn’t receive second-line antiandrogen therapy after their PSA started to rise on LHRH agonist monotherapy.”

   My response: The figures for monotherapy and “maximal androgen blockade” (study authors’ term, and also frequently used by others, though in fact short of real maximal blockade), meaning to them the use of an LHRH agonist combined with an antiandrogen) are provided in Table 1. That table shows 55.9% of the continuous patients had monotherapy versus 54.4% who had “maximal” ADT therapy in the intermittent group. The use of the term “maximal”, with a referenced study involving constant use of an antiandrogen in the continuous arm, suggest that those on “maximal” blockade were on both drugs throughout their blockade.

   You wrote: “(2) Despite your personal fervor about IADT3, I would (yet again) point out that there are absolutely no data from any well conducted, long-term, randomized study to prove that IADT3 works better than any other form of IADT for the majority of patients. We don’t even know for sure that it has been beneficial in the long term for you. As I have said before, it may well be appropriate for a subset of patients — but we have no way to identify them.”

   My response: I certainly agree (again) with your first statement: no well conducted, long-term randomized study exists. However, in view of the strong likelihood that no such study will ever be performed, the question is whether there are other data that can help us make decisions as patients and doctors. I am convinced there are such helpful data, of the form that led to many of the great advances against microbial disease and other illness. I’ve just finished rereading Paul DeKruif’s 1926 classic Microbe Hunters, which relates the great breakthroughs of Pasteur, Koch, Theobald Smith, Bruce, Ross and Grassi, Reed, Ehrlich and others, none of whom conducted large-scale, long-term, placebo-controlled Phase III clinical trials in humans. We have some highly relevant evidence regarding ADT that is clearly superior in quality to the evidence leading to their breakthroughs. While we would all love to have definitive Phase III studies, I, as a patient, am delighted with this other evidence because Phase III evidence on these issues is virtually impossible to obtain. The kind of evidence that has been meaningful to me is well done retrospective (chart review) data from scientifically astute doctors, mainly from practices devoted to prostate cancer patients, many of whom have patients with advanced cases, who are monitored closely with a variety of tests related to the hormonal axis, particularly testosterone and DHT (as needed, meaning at key points).

   I have been especially impressed by publications involving Dr. Mark Scholz (as well as his mentor Dr. Strum, and colleagues) from one of the practices that have pioneered advanced ADT. Some of their research has been directly on point regarding which patients will benefit from ADT long term; specifically, their records indicate that patients failing to achieve a nadir of < 0.05 are unlikely to do well on ADT long-term and need to add additional therapy (81% progression among those with a nadir above 0.05 versus 8% with a nadir of 0.05 or lower –- pretty sharp distinction!). The title of their paper involves the awkward term “testosterone inactivating pharmaceuticals, which means ADT, but which was influenced by a rival pioneer’s copyrighting a more appropriate term. The kind of ADT in this (Scholz and colleagues) study involved an LHRH agonist and an oral antiandrogen for all patients; this was the same combination as in the subject Korean study.) The findings by Scholz and colleagues have also suggested that an extended time to nadir suggests an unfavorable course, though there are exceptions, including me. (Actually, I would have been excluded from the Scholz study as they were aiming at a cohort like those diagnosed in modern times, so they excluded men with PSAs over 100 ng/ml, such as me, or with bone mets.) I do see that their findings are somewhat tentative rather than definitive, but such findings can do the job until, if ever, definitive Phase III results are available.)

   Regarding the likelihood that I have benefited from ADT long term, here is my take. While I believe lifestyle tactics and supporting medications (bisphosphonates and estradiol patches for bone density, Celebrex, thalidomide, simvastatin, come to mind) have clearly slowed the disease temporarily or otherwise benefited me, my many tests over 14 years clearly show that ADT is what has mainly controlled my cancer, based primarily on PSA results and physical exams, with scans and special blood tests at key points. ADT (with supporting medications and lifestyle tactics) was my sole therapy for more than 13 years. With a doubling time of 3 to 4 months and a PSA starting at 113, within 1 year, unchecked, my PSA would have been over 1,000, would have been over several thousand in 2 years, and would have been climbing into ranges rarely survived for more than months in the third year. Yet here I am, doing well. I agree that is not conclusive evidence that ADT has played a key role for me, but you can appreciate why I am persuaded. I have talked or communicated with a number of other patients with similar stories. Moreover, the Scholz practice is in the Los Angeles area, perhaps the epicenter of savvy survivors of prostate cancer in the world, and the practice is extremely well regarded. That’s not exactly peer review, but it is the kind of review that is highly meaningful to a survivor.

   You wrote: "(3) The fact that all these patients had to have their PSA level drop to at least < 1 ng/ml was better than we have seen in any other large, long-term study of IADT vs. CADT."

   My response: Thanks. An important point!

   You wrote: "(4) Many of these patients, today, would presumably be most appropriately treated with initial ADT + chemotherapy if they had a significant level of metastasis at time of initial treatment. No one has any data whatsoever about whether such patients could later be switched to IADT — regardless of what their PSA level fell to after initial ADT + chemotherapy."

   My response: Another key point! Also, such patients would also be put on Zytiga, Xtandi, or both, off-label, in some practices. After demonstrating resistance to ADT, many could be on those drugs in accordance with current FDA approvals.
7. jimwaldenfels, on October 28, 2015 at 8:00 pm said:

   Looks Like a Mislabeling Point in the Study, But Meaning Still Clear

   The vertical axis of Figure 1 y axis is labelled “Probability of Progression to CRPC”. It should be labeled “Freedom from Progression to CRPC” as is clear from the figure itself.
8. jimwaldenfels, on October 29, 2015 at 7:56 pm said:

   The Proportion of Metastatic Cancer In Both Arms of this Study, and the Effect of Imbalance of Aggressiveness on the Study Findings

   I would like to correct an impression I gave in my first comment that all men in this study were metastatic to some degree. That is not the case. (Sitemaster’s characterization, which I misinterpreted, was accurate.)

   Instead of all men being metastatic, 75% of the men in the continuous arm had either bone and/or lymph node metastases, and 61% of men in the intermittent group had either or both kinds of metastases (study, Table 1). This documents that substantial proportions of men in each arm were not metastatic, and it also indicates a substantial imbalance in cancer aggressiveness in the two groups. Moreover, 67% of the men in the continuous arm had a Gleason greater than 7, while only 48% of men in the intermittent arm had such a high Gleason (Table 1) – again a substantial imbalance in seriousness of the cases between the two groups.

   These imbalances, especially the lack of metastatic cancer in 39% of the men in the intermittent group, would be expected to be associated with longer time to disease progression in the form of castration-resistant prostate cancer (CRPC) in the intermittent group. It would be interesting to see figures showing time to CRPC for just metastatic patients in both groups, also for just Gleason 8 – 10 patients in both groups, and also for patients with either characteristic in both groups, but those figures are not presented in the study. However, the reported advantages for intermittent treatment are so marked that I suspect that intermittent treatment itself is accounting for some real improvement in time to CRPC.

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