In August this year, Vis and Schröder published the first of two summary reviews on the key targets of hormonal treatment of prostate cancer. The second of these two key reviews has now appeared in the November issue of BJU International.
In this new mini-review, Vis and Schröder discuss the inhibition of the enzyme 5α-reductase by drugs like finasteride and dutasteride. Data on the role of 5α-reductase inhibitors (5-ARIs) in the management of prostate cancer are still evolving, and while these agents have been shown to be effective in the prevention of prostate cancer in about a quarter of the men who are treated, it is not yet clear what effect they have in the treatment of prostate cancer because there have been no large, randomized, placebo-controlled clinical trials completed to date.
Vis and Schröder clearly have an optimistic opinion about what the trials currently being carried out will show, because they state that, “Achieving more potent suppression of intracellular [dihydrotestosterone] synthesis by 5AR inhibition is expected to provide clinical benefit to patients.” However, it may still be some considerable time before the detailed results of trials like the REDUCE and the TARP trials are actually available, and the 5-ARIs can be integrated into prostate cancer treatment based on Category 1 clinical evidence.
In the meantime, this review will be a useful resource for support group leaders and other prostate cancer educators.
Filed under: Management, Treatment, Uncategorized Tagged: | 5-ARIs, 5α-reductase inhibitor
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ongoing trials on the
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And, of course, I remain a strong proponent of the inclusion of dutasteride/Avodart in androgen deprivation therapy. This report certainly leans to the same conclusion, but as noted, cannot make a conclusive comment until (and here we go again) trials provide “clinical evidence.” I’ve experienced the clinical evidence, but, obviously that doesn’t carry enough weight. The medical oncologists I know who specialize specifically in the treatment of recurring and advanced prostate cancer also advocate the importance of the 5AR inhibitor in androgen deprivation therapy as a control to inhibit testsoterone conversion to dihydrotestosterone (DHT).
I see this the way Chuck does, having personally experienced the great benefit of finasteride back in 2000 as a boost to the Lupron/Casodex regimen that had reduced my PSA from 113.6 to 0.6, where it was clearly leveling off after 9 months of combined blockade — a level far too high for comfort. Within a little over 2 months after adding finasteride, my PSA had plunged by 50% to 0.3, and it kept on falling until it reached <0.01. Of course dutasteride should be even better than finasteride for most patients.
I've seen only an abstract of the TARP study, and it's not clear whether the trialists will identify and remove patients from the dutasteride arm who have a genetic inability to use dutasteride. While it is thought there are few such patients, the trial would be cleaner if that were done. I expect the result to be so strongly favorable that such subtle problems won't matter.
It is a great shame that the medical community is so hooked on Category I evidence. Yes, such evidence is the best, but I thank God that I found intelligent, insightful, courageous physicians who were able to use their own powers of observation and conception to pioneer use of triple blockade therapy with off-label use of finasteride. Triple blockade (for me, Lupron, 50 mg Casodex, 10 mg finasteride) has enabled me to reach a nadir of <0.01 twice before going off therapy, and my PSA is now at 0.05 and falling. That kind of experience makes one a believer!
The expert cancer researcher Devra Davis lamented the fixation on Category I evidence in her book The Secret History of the War on Cancer. She portrays it as another evil consequence of the tobacco lobby's powerful and long-successful attempts to squirm away from the cancer-smoking link by setting as impossibly high a standard of evidence as they could.
Scholz, Lam, Strum study omitted from review
I read the very interesting review by Drs. Vis and Schröder, learning a lot in an area where I was already pretty well informed.
I’m glad they referenced the 2001 study of triple blockade (with finasteride) by Tucker and Leibowitz, but it is too bad their search did not pick up the impressive paper by Scholz, Jennrich, Strum, Johnson, Guess and Lam, “Intermittent use of testosterone inactivating pharmaceuticals using finasteride prolongs the time off period” in the prestigious Journal of Urology, May 2006. Basically that paper compares intermittent triple blockade with finasteride with combined blockade without finasteride, finding a marked advantage for triple blockade.
Dr. Schröder is well known to many of us for his work in active surveillance and screening, among other accomplishments. The fact that this able and dedicated physician/researcher did not know of the Scholz study is an example of the disturbingly sluggish spread of medical knowledge, in my opinion.
Dear Jim:
I suspect that the reason the paper by Scholz et al. was not included in this review is simply that it was a selective, retrospective analysis as opposed to a prospective (pre-planned) clinical trial. I would be very surprised if Dr. Schröder “did not know of” this paper. This does not invalidate the findings of the paper by Scholz and his colleagues, but this type of retrospective analysis is “hypothesis-generating” rather than “practice-changing.”
I think there are a whole bunch of ways we can “do better” in generating clinical data to support clinical use of specific therapies, but even registry trials need to be pre-planned to collect specific categories of data from pre-defined groups of patients if they are to be used to “prove” the value of a specific type of treatment. Unplanned, retrospective data analysis is always fraught with problems because of the assumptions that get made and the “cherry-picking” of what to include or not include. Scholz and his colleagues chose to exclude from their analysis all men with M+ disease, all men whose PSA failed to reach a nadir of < 0.1 ng/ml and stay there, and all men whose testosterone level did not recover to > 150 ng/dl during the first 12 months off therapy. That's a pretty significant degree of selectivity, because what the data are then showing is that finasteride therapy was associated with an increase in time off full androgen deprivation only in men who were doing really well anyway. This raises the question of whether one is really managing their disease or just managing their PSA level, which is what trials like REDUCE and TARP will need to help us to answer.
Dear Sitemaster,
In the previous post you thought about a possible reason the Scholz study was not included in the review: “I suspect that the reason the paper by Scholz et al. was not included in this review is simply that it was a selective, retrospective analysis as opposed to a prospective (pre-planned) clinical trial.” A couple of things lead me to doubt that reason. First, the methodology was a very simple broad search. (I’m looking at the complete paper.) Here’s the entire “methods” section, which is described only in the abstract: “METHODS We searched Pubmed for data obtained from pharmacological, preclinical and clinical studies.” Technically, those boundaries do not include a selective clinical series like the Leibowitz/Tucker paper on intermittent triple blockade, which is included and described in a paragraph in the text (reference 56), but a related interview-based article says that Drs. Vis and Schröder were after both clinical and experimental studies. That Leibowitz paper is the second basis for doubt: the patients selected themselves by refusing major treatment for their generally low-risk cases; also, it was not a prospective clinical trial, yet it was included.
But your post hightened my curiosity, and I just thought, “Why not contact the authors?” I just sent an email to Dr. Vis and will post any reply. He is listed as the correspondence author, and his email is: a.vis@vumc.nl . If he does not respond to me, perhaps your credentials would do the trick.
You also raised a concern that cherrypicking accounted for the results in the Scholz paper: “… Scholz and his colleagues chose to exclude from their analysis all men with M+ disease, all men whose PSA failed to reach a nadir of 150 ng/dl during the first 12 months off therapy. That’s a pretty significant degree of selectivity, because what the data are then showing is that finasteride therapy was associated with an increase in time off full androgen deprivation only in men who were doing really well anyway. This raises the question of whether one is really managing their disease or just managing their PSA level.”
I agree up front that the impact of their research is hypothesis generating rather than proof, but I suggest their results go far beyond just covering men who “were doing really well anyway.” Here are the reasons for their selectivity, as I understand them; perhaps Chuck will also chime in. They exclude M+ men and those who fail to reach a nadir of 0.1 and stay ther because those characteristics are highly suggestive of the kind of very high risk cases that do not respond well to hormonal therapy. (Actually, this team now uses the ability to achieve a nadir of 0.05, or achieve it or better for a year, as a diagnostic indicator of patients very likely to do well on intermittent therapy.)That still leaves a huge pool of patients, and many in that pool are not going to automatically do well – this is not an active surveillance cohort! Actually, about half of each group has a Gleason of 7 or higher, and about half had a clinical stage of T2b or higher or had experienced a PSA relapse. (I think the 0.1 was chosen to include men in the early years before reliable ultrasensitive PSA tests became available; not sure though.) Similarly, men who have prostate cancer despite low testosterone tend not to do well on hormonal blockade, and the failure to achieve a recovery testosterone of 150 or more suggests that. Again, a huge pool of patients in the prostate cancer universe is left. Beside all this, these exclusions applied to BOTH the ADT2 group and the ADT3 group, so it’s an apples-to-apples comparison with the ADT3 group winning hands down! Isn’t that a powerful indication that finasteride worked superbly overall, not just for those who were going to do well anyway? I can’t help feeling these guys were like me, only with lower risk; no one was predicting I would do well on this therapy, but I have.
Dear Jim:
Respectfully, I think you are missing my point, which has nothing to do with this specific study and everything to do with retrospective analysis in general. That was why I was so careful to say that nothing invalidated the Scholz study per se. However, it can only be interpreted for what it is — hypothesis-generating — as we seem to agree. I just don’t want anyone to get the idea that (as yet) we have documented proof that adding a 5-ARI will definitively improve outcomes for all patients on hormone therapy (intermittent or otherwise). It may well do that for some patients, but we still need a prospective trial to provide that proof — and my guess is that that proof is most likely to be establishable in men like you and Chuck who appear to have a subtype of prostate cancer that responds particularly well to hormone therapy over long periods of time.
I’ve provided my input, and I fully support the conclusions of Jim Waldenfels. I know Jim from some years back and have learned that he and I have come to similar conclusions regarding appropriate androgen deprivation therapy. And these conclusions were developed from deep research and study, not just off-the-cuff assertions. Interesting is that those medical oncologists who “specialize specifically” in research and treatment of recurring and advanced prostate cancer have drawn these same conclusions earlier that advocates like Jim and I have only confirmed. And through that confirmation and insuring that our treatment fell in line with those conclusions, we have survived much longer than may have been anticipated.
I believe the three of us are in fundamental agreement. I know Chuck and I have both been frustrated that the medical community had not put this therapy to the kind of prospective trial that you are highlighting. I’m delighted that is finally happening with the TARP trial, and I’m glad that the eminent medical oncologist Dr. Oliver Sartor is involved.
You mentioned that we appear to have a subtype of prostate cancer: “my guess is that that proof is most likely to be establishable in men like you and Chuck who appear to have a subtype of prostate cancer that responds particularly well to hormone therapy over long periods of time.” I believe that is so, but I’m also persuaded the subtype is widely spread, more common than not. Of course that too needs to be tested.
Dr. Scholz has said most men respond to hormonal blockade for either about 10-11 years or indefinitely; his statement may be primarily about triple blockade, especially intermittent triple blockade. Several of the experts in hormonal blockade believe the early work by Dr. David Crawford and others in 1989 led to the myth that blockade only works for a short time, such as a few years, before resistance develops. They think the Crawford work (NEJM 321:419, 1989) was misinterpreted to mean that blockade only worked for a short time, around a year and a half, an approximate duration that unfortunately pops up rather frequently. That research, which did not involve triple blockade, actually showed such short response times, but in men with very late stage disease characterized by widespread bone mets (with pain, 8 months median to resistance, without pain 18 months median). The same paper documented a response time of 4-5 years for men with just a few bone mets in the hip and spine, with 30-40% still responding at 9 years (the latter may have been in a follow-up paper). We survivors during this current decade find it commonplace that our fellow survivors without detectable mets are making it to at least around the 10-year point on first-line hormonal blockade, especially in its advanced forms like triple blockade.
Please note also the article by Sartor et al. just published (on combination of dutasteride + ketoconazole) — with additional comment on this site, just published today.
Interestingly, regarding this subject and reported yesterday on UroToday, see “Activity of dutasteride plus ketoconazole in castration-refractory prostate cancer after progression on ketoconazole alone,” which states: “We conclude that dutasteride added to ketoconazole at the time progression might prolong time to PSA progression in patients with CRPC.” And I would add –- would also apply to earlier triple hormonal blockade.
Follow-up on omission of the Scholz et al study of triple (with finasteride) vs. combined blockade
Our posts 3 – 5 on this topic, dated 11/4 8:54, 11/5 8:47, and 11/5 1:42 speculated on the specific question why the study was omitted from the review.
Dr. Vis did kindly reply. Here is what he said:
“Dear Jim,
“Thank you very much for your e-mail.
“With interest I read your e-mail conversion.
“There’s no clear explanation for leaving out the [above]mentioned paper of Scholtz et al in the Journal of Urology. The message of the paper is evident. Probably, it should have been referenced by the authors of the review papers indeed. On the other [hand], it has not been referenced much by other authors. I do not have a clear explanation for this [either].
“As you might have noticed, Professor Schröder and I have high hopes in treating patients with metastatic prostate cancer with 5-alpha reductase inhibitors, preferably dutasteride (besides LHRH agonists). A large phase III trial has been planned.
“Kind regards, and very good luck with the fight against (your) prostate cancer,
“André N. Vis, Urologist, MD, PhD, VUMC, Amsterdam”
[Editor's note: Certain minor m odifications have been made to Dr. Vis's e-mail for clarity. English is not his first language, but his intention was clear.]