So the initial results of the AVIAS trial are not going to make a couple of our regular readers too happy — although at least a trial of the type they have been asking for has now been carried out.
The AVIAS trial was designed as a small Phase II trial, conducted by the Canadian Urology Research Consortium, to explore whether treatment with dutasteride (Avodart) during the off-treatment period could extend the length of the off-treatment period in men who were receiving treatment with intermittent androgen derivation therapy (IADT). A positive outcome in the initial Phase II study would have allowed for the trial to be extended into a randomized Phase III trial.
Klotz et al. conducted this randomized, double-blind, placebo-controlled trial in men between 45 and 80 years of age who had originally had localized prostate cancer and then had a rising PSA level after their primary treatment. The patients were randomized to either dutasteride (0.5 mg/day) or to a placebo. All patients were initially treated with androgen deprivation therapy (ADT), comprising 9 months of an LHRH agonist given as three 3-month depots and bicalutamide 50 mg once daily. ADT was stopped at month 9 if the patient’s PSA level was < 1.0 ng/ml. ADT was resumed when a patient’s PSA increased to ≥ 5.0 ng/ml. Study end points included time off treatment, PSA nadir after 9 months of ADT, serum testosterone levels, serum dihydrotestosterone levels, and time to castrate-resistant prostate cancer (a rising PSA while testosterone levels remain < 50 ng/ml).
Klotz and his colleagues report the following results in the full text of their paper:
- The study included 87 evaluable patients:
- 49/87 patients (56 percent) were randomized to treatment with dutasteride.
- 38/87 patients (44 percent) were randomized to treatment with a placebo.
- 80/87 patients completed one treatment cycle (45 on dutasteride, 35 on placebo).
- The median PSA nadir at 9 months was
- 0.1 ng/ml for the patients randomized to dutasteride
- 0.075 ng/ml for the patients randomized to a placebo
- Average (median) times off ADT for all 80 patients were
- 19.8 months for patients randomized to dutasteride
- 21.3 months for patients randomized to the placebo
- This difference was not statistically significant (p = 0.42).
- Average (median) times off ADT for the 57 patients whose PSA reached ≥ 5 ng/ml were
- 18.6 months for patients randomized to dutasteride
- 16.7 months for patients randomized to the placebo
- This difference was again not statistically significant (p = 0.76).
- There were no cases of androgen-independent prostate cancer.
The authors discuss the possible reasons for the lack of any effect on dihydrotestosterone blockade in this study (as compared to the results of the retrospective analysis of data by Scholtz et al.). They also acknowledge that one of the limitations of the current study was its short duration, with only one treatment cycle evaluated. However, they conclude that:
This small-scale Phase II randomized controlled trial showed no benefit to the addition of dutasteride to an IAD regimen.
Unfortunately, given this result from this Phase II study, the AVIAS trial was stopped, and it seems very unlikely that anyone else will be willing to invest in another large, randomized, double-blind, Phase III trial of this treatment strategy.
Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: ADT, androgen deprivation, dutasteride, IADT, IADT3, intermittent |
THE "NEW" PROSTATE CANCER INFOLINK 
Thanks for posting this. I think Klotz raises an interesting point in his discussion. He points out that a 5-ARi may exert a selective pressure on 5ARi-resistant prostate cancer cells, which may explain the earlier recovery of PSA in the treatment group. This is consonant with the “bipolar androgen therapy” hypothesis that periodic androgens may actually slow down the development of androgen resistance. The present study was too short to detect this, if it is occurring.
Allen:
Given our current knowledge that there are at least 25 subtypes of prostate cancer, my (speculative) hypothesis would be that each of these subtypes has the potential to respond slightly differently to androgen therapies of various types. In some cases, periodic androgen therapy X may well slow down development of resistance; in other cases, androgen therapy X (whether given periodically or continuously) might just as easily accelerate the development of androgen resistance. The chance that there is a common rule for all the subtypes would be very surprising to me. The truth is that using hormonal therapy to manage prostate cancer has a significant similarity to the “I have a hammer, so that must be a nail” syndrome. It works for a while a lot of the time … but that doesn’t mean its the “right” (let alone the “best”) way to be trying to treat an individual patient. All it means is that it’s the tool we are accustomed to using once prostate cancer starts to progress after first- and second-line therapies.
Bluntly, we really still know very little indeed about why individual patients (as opposed to large cohorts of patients) respond in such a diversity of ways to ADT in general — let alone specific types of ADT.
I’m so glad someone, especially Dr. Klotz, executed this trial, but yes, I’m most puzzled by the result. The slight but most surprising superiority of the placebo group is even more surprising as the same threshold — a PSA of 5.0 — was used as the vacation endpoint for both groups. Avodart/dutasteride is known to shrink the prostate, leading to lower PSA compared to no Avodart, so we would expect the Avodart group to take longer to reach the endpoint of 5.0 just from this shrinkage factor.
I have been a believer of adding a 5-alpha reductase inhibitor (5-ARI, either Proscar/finasteride or Avodart/dutasteride) as the third leg of the “on” phase of therapy (making it triple blockade, which was not done in the Klotz trial), as well as using a 5-ARI drug during the off-therapy phase of intermittent blockade with the objective of extending that vacation period. The latter approach was reported based on a clinical series by the Scholz et al. team, after two-drug blockade as was done in the Klotz trial, and the Scholz results suggested a strong benefit for the 5-ARI drug, in sharp contrast to the results here. I am now studying the complete paper, which I’m happy to see is available via the online link. It strikes me that the study was likely well done as Drs. Klotz and Higano are very well known and highly respected prostate cancer researchers. (I am not familiar with the work of the other four authors.)
Several results look odd. First, the median nadirs for both groups look rather high after 9 months of combined blockade, but I’m not as familiar as I would like to be with the expected range and median. For my own very high-risk case, my PSA was leveling out around 0.6 at about that point.
Second, the median nadir for the placebo group is 25% lower than for the intervention group despite the fact that both groups had had the same treatment up to that point, suggesting that individual differences among patients were prominent enough to noticeably influence results in this relatively small trial.
Third, Figure 2 of the complete paper shows that in the vacation months — the months when the intervention group was getting the 5-ARI that suppresses DHT, DHT was generally higher in the placebo group than in the intervention group, or at least equal, the exact reverse of what we would expect! Really strange!
Fourth, in line with the overall negative results of the study, a substantially higher percentage of men in the control group succeeded in not reaching the end-of-vacation trigger PSA of 5.0. The figures were 24.4% success in the intervention group (11/45) and 34.3% in the control group (12/35).
Fifth, the vacation time off ADT is very likely less than twice as long as the ADT period for the intervention group as at least half, based on the median of 1.0 at 9 months, had not reached the trigger of 21.3/9 = 2.3, more than double the ADT period. Again, this is in sharp contrast to what was found in the Scholz team’s clinical series.
One likely difference in management tactics, which may or may not be significant to the difference in results between the Klotz and Scholz studies, is that the Scholz, Strum and others team may have been managing its patients by requiring a nadir of ≤ 0.05 at that time, perhaps even requiring them to maintain that for a year before taking a vacation from the LHRH agonist and antiandrogen drugs. I clearly recall that was the advice I was following prior to my first vacation in 2002. This was back in the days when intermittent therapy was highly controversial, and the pioneers of that therapy — Scholz and Strum among them (as well as Dr. Klotz) — were taking extra care as they moved patients into their vacations.
I'm thinking another possibility is that an unluckily disproportionate number of patients may have had difficulty achieving androgen deprivation, either because of unusually rapid personal clearance of the LHRH agonist or problems with its delivery (improper injection or coil implantation, faulty storage prior to treatment, faulty mixing, etc. — all infrequent but known issues). That's easy to determine based on monitoring T and ADT levels, as was done here, so the complete paper likely will have the answer. One likely difference in tactics is that the Klotz group use a T of < 50 to indicate adequate T suppression while the Scholz group very likely was using a T of < 20 to indicate adequacy. My strong impression is that most oncologists still use the < 50 threshold, while the doctors I've followed most closely, including the Scholz team, are convinced the threshold should be < 20, with a higher level usually signaling a need to adjust the therapy (such as a shorter dosing interval) to achieve "adequate" suppression of testosterone. (Similarly, my gurus like DHT to be < 5.0.)
It's possible that an unfortunate confluence of factors such as these distorted the result. Of course, it's also possible that we are seeing a true result — that the addition of the 5-ARI drug does not make a difference.
All this said, my bottom line is that I'm most puzzled! I hope that Drs. Scholz, Strum, Leibowitz, Myers and other experts will weigh in on this new study.
I am admittedly quite ignorant about the mechanism of a 5-ARI, That said, I read two statements made in the Klotz report which are confusing and on which I hope Sitemaster may shed some light.
Klotz states that: “Consequently, a 5ARI that raises testosterone and reduces levels of nuclear DHT could provide a useful adjunct to IAD.”
I had thought that a 5-ARI only inhibits conversion of T to DHT. How does it also simultaneously increase T? And I didn’t think it can be reasonably concluded yet that increasing T is definitely beneficial in controlling prostate cancer in the off period.
Second, Klotz concludes that:
“Patients treated with dutasteride had a higher increase of PSA and testosterone during the off-treatment interval. There was no difference in serum DHT levels.”
Is a 5-ARI in fact completely ineffective in inhibiting the conversion of T to DHT? That combined with the increase of T by a 5-ARI would reasonably explain why the 5-ARI had no significant effect (and perhaps adverse effect) on the length of time of the off period (or, following Klotz’ statement that T is beneficial, the 5-ARI should have resulted in a longer off period)?
If the answer to these questions is “See above answer to Allen’s question”, please just say so! :-)
Thank you.
Richard
More evidence that the intervention and control groups may not have been equivalent at outset, despite apparent balance of patient characteristics
Figure 2 shows graphs of median values of PSA, testosterone, and dihydrotestosterone recovery during the off-therapy period for the intervention (dutasteride during the vacation) and control (no dutasteride) groups. The red line for the dutasteride group tracks through month 56 or 57, while the blue line for the control group tracks through month 66, which is 9 or 10 months longer.
This is consistent with a later start of the vacation for the dutasteride group, as indicated by the fact that more than half had not reached the vacation threshold of a PSA of < 0.1 by the 9-month point, in contrast with the control group (median PSA of 0.75 at that point), despite equal treatment up to that point for both arms and what looked to the researchers (and me) to be a reasonably equivalent balance of key patient characteristics. My first impression is that it took 9 or 10 months longer for the intervention group to achieve a median eligible for the vacation from ADT.
This set of facts and impressions suggests notably higher risk in the intervention group in this relatively small Phase II trial.
Yet I still find the overall result most puzzling.
Confusing!
Why does the DHT level not fall under dutasteride therapy, but is even still rising (Fig.2)? This then causes directly a PSA increase, which is not surprising.
(Please have a look at the ARTS study done by Schröder et al., published in May 2013.)
Much as I would like to be able to provide accurate and meaningful explanations of the issues raised by Richard, Jim, and LowRoad above, frankly:
(a) I can’t. I am by no means a specialist in the biochemistry and molecular biology of prostate cancer (and neither is Dr. Klotz for that matter). Speculation is the way one creates hypotheses that then need to be tested through experiment. Speculation for its own sake can be fun but tends to lead nowhere.
(b) I strongly suspect that my prior answer to the issue raised by Allen is indeed relevant. Prostate cancer is not “one disease”; it is a spectrum of malignant disorders.
(c) Whether we like it or not, when Klotz and his colleagues actually did the trial that people like Jim have been asking to be done for years, they got a negative result. What this means is that the theory behind IADT3 doesn’t work for everyone. On the other hand, this trial result also doesn’t mean that IADT3 doesn’t work well for some men. What we don’t know now is whether some of the men who seem to have done really well on IADT3 might not have done just as well on standard IADT. Remember that there has always been vast variation in how individual patients do or don’t respond to IADT.
Well, Sitemaster, you “knew” I would be responding.
First, the study is not telling us at which time each patient’s PSA level dropped to < 0.05 ng/ml and testosterone level to near or below 20 ng/dl — the prerequisite espoused by, for example, Stephen Strum (and I), and the time at which one only then begins to measure the "beginning" of timing ADT3 effectiveness to maintain those same low levels over the next "12 months," not 9 months. Then, if "maintained" for at least 12 full months to only then go off the LHRH agonist or GnRH antagonist and antiandrogen but continue dutasteride/Avodart.
The study appears to indicate the patients simply began ADT3 and from that point began the timing of 9 months of use. … It does not indicate that the timing of 9 months began only after PSA dropped to < 0.05 ng/ml and testosterone to near or below 20 ng/dl. In fact, from what you provide from the study, we are not even provided the levels of PSA or T from which time the timing of ADT effectiveness began. Would that make a difference? Well, we don't know, do we? Thus, in my personal opinion, the study was flawed if not following those prerequisites of first attaining PSA of < 0.05 ng/ml and T of near or below 20 ng/dl before beginning their 9 month of effectiveness as well as not continued on the ADT3 for the additional months. Yes, there are "subsets" of prostate cancer and apparently I experienced the "better subsets" with my own experience of only 18 months on IAD without "maintaining" with dutasteride/Avodart following earlier 12 continuous months of steady < 0.01 ng/ml PSA and 23 ng/dl. Yet, after then returning to ADT and adding dutasteride/Avodart to what had earlier been ADT2 with only Lupron and Casodex, then continuing a steady total 12 months with those low PSA and T levels, my subsequent IAD while then "maintaining" with dutasteride/Avodart lasted for 2 months short of 6 years! Thus, when not prescribed Avodart my IAD time only lasted 18 months, but when prescribed Avodart my IAD lasted 70 months. Therefore, this trial does not change my opinion of the importance of dutasteride/Avodart during ADT as well as the continued "maintenance" with this medication when moving to IAD to help inhibit returning testosterone from converting to the more powerful stimulant to prostate cancer cell growth, dihydrotestosterone/DHT.
Dear Chuck:
As I just wrote above, this trial does not prove that IADT3 is ineffective in all men. It shows us that IADT3 was ineffective in this trial based on this trial design. Since the full text of the paper is available on line (and I provided a link to it), you can read that full paper to get all the published details.
I think we can all agree that Drs. Klotz and Higano are experienced investigators who know what they are doing. Since the trial was funded by GlaxoSmithKline (GSK), the manufacturer of dutasteride, I think we can also reasonably assume that they did whatever they thought they could do to be sure that a positive trial result would be likely. I am in no position to tell you why they chose the data points that they did choose … but it could well have had something to do with the time it would take to enroll enough patients if those patients’ PSA levels were all required to drop to < 0.05 ng/ml and their serum T levels to ≤ 20 ng/dl. Even I am unsure just how common that is … but I know it doesn't happen for an awful lot of patients.
Whatever you and others may believe, the one thing that I am quite sure about is that we won't see another trial like this (unless people like you and Jim want to design it and pay for it!)
Hello again Sitemaster (and you know that both Jim and I respect the depth of work you provide us). I have reviewed the Klotz et al. paper and like Jim am perplexed by various results. One thing that caught my eye were the graphs in Figure 2. The graph on the right indicates that this is a graphing of the median testosterone level in ng/dl but only indicates levels up to 20 ng/dl. Then the lower graph indicates this is a graphing of the median dihydrotestosterone level in ng/dl, but goes as high as levels up to 2000 ng/dl. Have these two graphs been incorrectly identified. The up to 20 ng/dl would appear more appropriate for DHT, while the graph up to 2000 ng/dl would appear more appropriate for T.
I would certainly take nothing away from the expertise of both Klotz and Higano, but that does not mean that they did not gather their figures in a manner quite different from that of Scholz, Strum, et al. And, quite notably, Scholz, Strum, Meyers, Leibowitz, Lam, and others specialize only in research and treatment of recurring or advanced prostate cancer, and in my opinion that gives them an edge in the understanding and prescribing of ADT. Please note again — my opinion.
P.S.: I meant to add that if I, and I expect Jim, were to win a lottery of several hundred million dollars, we would be inclined to support a more thorough such study. Unfortunately, since the likelihood of that occurring in our lifetime is about nil, you are correct that another such study is not going to happen. Thus we continue with what we each have come to our conclusions about from our own, personal research and study of this insidious men’s disease.
Klotz addresses the difference between his prospective randomized clinical trial, and Scholz’s retrospective analysis:
“In contrast, a retrospective analysis of 101 patients on IAD reported by Scholz and colleagues showed that finasteride increased the time off treatment from 15 to 31 months.This study involved a different drug (finasteride), and different criteria for initiating and discontinuing treatment. Finasteride was administered in the off-treatment interval only, in contrast to this present study. The PSA threshold for re-treatment was reduced to 2.5 ng/mL in the finasteride group and 5.0 in the historic control group. In the current study, the time off treatment was defined as the time from stopping ADT until the PSA level increased to ≥5.0 ng/ mL; no distinction was made between patients treated with dutasteride or placebo.”
If nothing else, the fact that the Klotz study is a randomized clinical trial, while the Scholz study had all the selection biases that characterize a retrospective study with a historical control means that the Klotz study carries much greater weight.
Jim, I’d caution you to be careful about looking for a difference in numbers that may not be statistically significantly different.
Richard, dutasteride increases T levels because it inhibits conversion of T into DHT (one of two major metabolic pathways). Thus, T accumulates. Scholz, and others, considered that to be a good trade-off because DHT is a much more powerful androgen receptor stimulant than T.
Remember that DHT has been continuously suppressed in all the men in this study since they began ADT. One can only speculate about the reasons why serum DHT does not significantly relatively recover in the control group during the off-cycle.
Klotz is raising the caution that overuse of 5ARis may be driving resistance, while providing no discernable benefit on average.The Sitemaster is right to caution about heterogeneity. Studies like this predict for the average; you might be the exception, but chances are you aren’t. Considering this and the B.A.T. hypothesis I mentioned above, the strategy of continuous DHT suppression has been called into question and should be carefully considered by patients.
CORRECTION TO MY EARLIER STATEMENT RE FIGURE 2
This is what I wrote that is not what I intended: “Third, Figure 2 of the complete paper shows that in the vacation months — the months when the intervention group was getting the 5-ARI that suppresses DHT, DHT was generally higher in the placebo group than in the intervention group, or at least equal, the exact reverse of what we would expect! Really strange!”
What is really strange is that the group getting the DHT suppressor drug (the dutasteride, aka intervention group) had a higher DHT (or about equal) for most months during the vacation period of the study than the group not getting the DHT suppressor (the placebo group). I think I made the mistake because what I originally, incorrectly, stated was what we would expect, which was contrary to the “Really strange!” result from the trial. At least I got the “Really strange!” part right.
THIS WAS NOT A STUDY OF ADT3
Hi Chuck and Sitemaster,
Thanks to both of you for the good points you are raising.
However, regarding your respective comments of 2/18 8:28 am and 2/18 8:42 am respectively, this Klotz study was not a study of ADT3 or IADT3, at least in the typical sense of these acronyms. Of course you are thoroughly familiar with this Chuck, but note that the study is based on IADT2, with two drug blockade in the intervention period followed by the third, 5-ARI, drug only in the maintenance period. That is actually the same situation as the situation in the Scholz et al. study. I think there is confusion because Drs. Scholz, Strum, and teammates are so closely associated with IADT3.
CLARIFYING MY UNCLEAR AND FAULTY STATEMENT (“FIFTH”) IN ORIGINAL POST OF 2/17 4:55 pm (not to be confused with my “faulty” statement addressed earlier, LOL)
My original statement was “Fifth, the vacation time off ADT is very likely less than twice as long as the ADT period for the intervention group as at least half, based on the median of 1.0 at 9 months, had not reached the trigger of 21.3/9 = 2.3, more than double the ADT period. Again, this is in sharp contrast to what was found in the Scholz team’s clinical series.”
Here’s what that statement should have looked like: Fifth, the median vacation time off ADT for the intervention group (19.8 months for all 45 patients in that group) is glaringly less than twice as long as the median vacation period for the control group (21.3 months for all 35 patients in the control group), in contrast to the Scholz study where the vacation period for the intervention (Proscar/finasteride) group was 31 months as contrasted with just 15 months for the non-intervention (no 5-ARI drug) group. In fact, the median vacation period for the intervention group was not even as long as in the group not taking dutasteride during the vacation.
There are differences in treatment, particularly for hormone therapy between the United States and France. In France, the use of ADT3 is quite rare (usually using the agonist alone), and the use of dutasteride in the off periods for IADT is rare too. I am often asking questions about these differences, but urologists generally viewed here tell me that it is useless, but without giving an answer scientifically substantiated.
Personally, for years I took both IADT3 and dutasteride without stopping it, both during on and off periods. From several years now, I have no longer used either dutasteride or bicalutamide and therefore nothing in the off periods.
This was not statistically significant, but I must say that my results are quite better.
Jean
Jean:
Actually the use of IADT3 is really rather unusual here in the USA as well. Most men on hormone therapy will only get an LHRH agonist (either continuously or intermittently) following a short course of bicalutamide to suppress the possibility of a testosteroine flare. So the differences between the USA and France when it comes to the use of ADT may not be as big as you think.
Jean:
Actually the use of IADT3 is really rather unusual here in the USA as well. Most men on hormone therapy will only get an LHRH agonist (either continuously or intermittently) following a short course of bicalutamide to suppress the possibility of a testosteroine flare. So the differences between the USA and France when it comes to the use of ADT may not be as big as you think.
Thank you Mike. Are you also using antagonist like Firmagon?
Jean:
Some urologists and urologic oncologists will start patients on and LHRH antagonist, i.e., degarelix (Firmagon), and then switch them over to an LHRH agonist after 1 or 3 months.
The number of men who are managed long-term on an LHRH antagonist appears to be really very small (perhaps because of cost but perhaps also because there appear to be more problems with the injection site reactions).
This is a great discussion! This discussion will be very beneficial to those unfortunate readers that have recently been advised of a rising PSA after first-line treatment.
I think the main point being made, at least to those of us not that well versed in the science of our disease, is that really no one knows what is really going on with our individual disease. The site master, a wise site master at that, is making a statement of paramount importance and wisdom: “Bluntly, we really still know very little indeed about why individual patients (as opposed to large cohorts of patients) respond in such a diversity of ways to ADT in general — let alone specific types of ADT.”
I, as Jim, have been the beneficiary of IADT3, with dutasteride in the off periods. I have also met the criteria for the < 0.01 PSA level for at least 6 months prior to the off period. As a Gleason 9 this is quite unexpected, if not gratifying, and only achieved after visiting with four different oncologists. However, from what I have been exposed to this form of treatment, as many other forms, does not necessarily work for every one of us.
What I do find odd is that many oncologists totally disregard the possibility that IADT3 with dutasteride in the off periods can work in a subset of their patients, and fail to even try it, citing anecdotal evidence, and not as evidence based medicine. Some going directly to more invasive treatments like IMRT after surgery where the side effects can be more pronounced, and which also only works on a selective group of patients. I believe that a number of around 30% effectiveness for that treatment form was cited to me after recurrence.
These are exciting times for prostate cancer patients, with all types of new drug treatments coming on line. However, we do need to keep our options, if not our minds, open until typing of our individual disease can be achieved.
Allen,
You said, “Remember that DHT has been continuously suppressed in all the men in this study since they began ADT. One can only speculate about the reasons why serum DHT does not significantly relatively recover in the control group during the off-cycle.”
Just so I am clear — were all the patients taking dutasteride during the on cycle? If not, how was DHT suppressed?
Thanks,
Jerry
Jerry,
Sorry, I misstated that — DHT was continuously suppressed only in the men in the treatment group in this study. The control group did not have any dutasteride at all throughout the study. Klotz et al. wrote, “Patients were randomized to dutasteride 0.5 mg daily or placebo, administered throughout the course of the study.”
DHT was suppressed as much as it was for everyone during the “on-cycle” by a combination of an LHRH agonist (given along with daily bicalutamide.) With no testosterone, very little DHT can be formed.
I still wonder why DHT did not recover more for the control group as their T levels rose during the “off-cycle.” For the control group, the rising T should have been converted into DHT. For the treatment group, conversion of T into DHT should be suppressed by the dutasteride. So, I would have expected the control group’s DHT level to be higher than the treatment group’s during the off-cycle.
Allen
I have been on the “off-cycle” for close to 30 months. I take Avodart and blood work is done every month to make sure that DHT is less than 5. If you look at the Figure 2 (DHT) it looks like neither group comes close to being less than 5.
The whole point of taking Avodart is to reduce DHT isn’t it? Well, it looks like those taking dutasteride didn’t get their DHT levels down to where it even played a role.
So, yes my question would be the same as Allen’s. … Why didn’t the control group’s DHT level return to higher than the treatment group’s. But also, why didn’t the treatment group’s DHT level get below 5. (Many of the red dots are above 10 … or perhaps I’m not reading it correctly.)
Hi Allen,
Here are two thoughts in response to your comment of February 18, 2015 at 12:49 pm, in which you said in part:
“… Jim, I’d caution you to be careful about looking for a difference in numbers that may not be statistically significantly different.”
and
“Klotz is raising the caution that overuse of 5ARis may be driving resistance, while providing no discernable benefit on average …”
Regarding the first sentence, it’s not the insignificant differences in the Klotz study that are so striking. Rather it is the striking difference between these results and the results in the Scholz study. In essence, the Scholz study found that the use of a 5-ARI drug, finasteride, doubled the time off therapy, and did that with a marked handicap: the trigger to restart therapy was a PSA of just 2.5, compared to 5.0 in the non-finasteride group. In other words, if the higher trigger of 5.0 had been used for the finasteride group as well, the difference would almost certainly have been substantially greater than double the time off therapy! In contrast, as we have seen, the vacation period was actually somewhat longer in the control (non-5-ARI drug, Avodart/dutasteride) group in the Klotz study.
Regarding the second sentence, after reading the study a couple of weeks ago, and after searching for the word “resistance” just to double check, I don’t see that Dr. Klotz is raising the caution you mention. Have I missed something?
COMBINED THERAPY USE IN THE US
Hi Sitemaster, I’m responding to your statement on February 19, 2015 at 6:38 pm in which you wrote in part:
“Jean:
Actually the use of IADT3 is really rather unusual here in the USA as well. Most men on hormone therapy will only get an LHRH agonist (either continuously or intermittently) following a short course of bicalutamide to suppress the possibility of a testosteroine flare. So the differences between the USA and France when it comes to the use of ADT may not be as big as you think.”
My impression matches yours regarding IADT3 being rather unusual in the US, but while “most” men probably get only an LHRH agonist after a short course of bicalutamide to suppress flare as you stated, I have a hunch that there is a very substantial minority who are put on combined therapy — the LHRH agonist plus an antiandrogen, most likely bicalutamide. I wish I could present some numbers but do not have them. A Japanese study showed that in Japan — where ADT is typically used earlier and more commonly — combined therapy (testicular suppression by drug or surgery plus accompanying long-term use of an antiandrogen) is the most common course (nearly 60%). Figure 1 of the study shows that 53.8% of men getting initial ADT therapy got an LHRH-long-term antiandrogen combo while an additional 5.2% had surgical castration plus an antiandrogen drug over a long term. (Current status of endocrine therapy for prostate cancer in Japan analysis of primary androgen deprivation therapy on the basis of data collected by J-CaP. (Hinotsu S, Akaza H, Usami M, Ogawa O, Kagawa S, Kitamura T, Tsukamoto T, Naito S, Namiki M, Hirao Y, Murai M, Yamanaka H; Japan Study Group of Prostate Cancer (J-CaP). Jpn J Clin Oncol. 2007 Oct;37(10):775-81. Epub 2007 Oct 26. PMID: 17965423 The entire paper is available free online at http://www.pubmed.gov.)
BOTH GROUPS ACHIEVED DHT <5 AFTER CONVERSION TO UNITS COMMONLY USED IN THE US
Hi Jerry, you raised this concern, which others have also raised, in your earlier comment as follows:
"Jerry, on February 27, 2015 at 8:06 pm said:
"I have been on the “off-cycle” for close to 30 months. I take Avodart and blood work is done every month to make sure that DHT is less than 5. If you look at the Figure 2 (DHT) it looks like neither group comes close to being less than 5."
The results are in the third graph, for median DHT, reported in Figure 2 (of this free online complete paper), as you have noted. Notice that the units are ng/dL – nanograms per deciliter. In the US, the units used are ng/mL – nanograms per milliliter. What that means is that you have to multiply the denominator by ten to get from deciliters to centiliters, and then by 10 again to get from centiliters to deciliters – in other words, you have to multiply the denominator by 100. That makes the denominator 100 times larger, so, when you divide into the numerator, the result becomes 100 times smaller.
As the graph shows, both the Avodart/dutasteride and the control group had DHT levels falling below 500 ng/dL when the patients stopped the main ADT drugs and started their vacations. Therefore, dividing 500 by 100, it is clear that both groups had achieved DHT levels below 5 ng/mL.
I hope this helps.
By the way, for my challenging case, I was on ADT3 (mostly) with Lupron, Casodex, and finasteride (plus Fosamax for bone density protection, a statin, and various supplements/lifestyle tactics) for 31 months (starting in December 1999 with the first 9 to 10 months on just Lupron and Casodex) for my first cycle, achieving my goal of a PSA of < 0.05 and holding that for a year (now an obsolete tactic) before starting my vacation, using finasteride (and Fosamax, the statin, plus the supplements, etc.). My vacation lasted 34 months, but I had to use low-dose thalidomide/vitamin B6 to eke out the last half year or so. (For later cycles I switched at some point to generic bicalutamide instead of brand-name Casodex, and then to flutamide in response to a possible androgen receptor mutation; to get better DHT numbers I switched from finasteride to Avodart/dutasteride. It worked.)
Jim,
Thanks for the reply and explaining the difference between ng/ml and ng/dl.
I see where both groups got under 5 ng/ml when they started the HT vacation and kept it around 5 for about a year. But then, it rises and by month 20 it’s well above 10 ng/ml. I realize this is still quite low since the normal range is 30-85 ng/mL for the adult male, but isn’t the goal while on Avodart/dutasteride to keep it as low as possible?
I have always been able to keep it under 5 with a normal testosterone. Is it a challenge for some guys to remain under 5 while on Avodart/dutasteride? And if not, why weren’t these guys under 5 throughout the time off HT?
Thanks,
Jerry
Jim,
The Scholz study was only a retrospective analysis, while the Klotz study was a randomized clinical trial. Where the two conflict, there is no doubt that we put our faith in the randomized clinical trial. Its prospective nature and its randomization process eliminates biases inherent in retrospective analyses. It’s actually very common for retrospective studies to be disproven by randomized clinical trials.
You seem to have missed the part where Klotz wrote about resistance:
“This uncertainty may be due to the “unmasking” of PSA secretion by 5ARI-resistant prostate cancer cells in the setting of IAD, in contrast to BPH. The PSA kinetics might be accelerated by the presence of 5ARI-resistant prostate cancer cells. It is also possible that 5ARIs exert a deleterious effect on prostate cancer in this situation, promoting more rapid recovery of PSA than expected.”
IMPORTANT CORRECTION TO MY COMMENT OF March 1, 2015 at 8:28 pm – “BOTH GROUPS ACHIEVED DHT <5 AFTER CONVERSION TO UNITS COMMONLY USED IN THE US" -Correcting to: Neither Group Achieved "<5"
Hi Jerry and other interested participants in this thread.
Yesterday the unwelcome thought popped into mind that I had mis-analyzed the relationship of the units. I also thought it best to confirm the units used in the US, which I had stated were ng/mL (milliliter). I checked, and I had missed on both counts. Here is the reality:
In the US, at least for my own DHT results, the units are the SAME as in the Klotz trial: ng/dL. Therefore, no conversion was needed (and I'll drop the issue of misstating the direction of the conversion to avoid further confusion). Thinking back, I believe I made the mistake because (1) there are some tests expressed in different units in different countries, and (2) because I thoroughly expected that men in at least the Avodart intervention group would have achieved a DHT of < 5. Sometimes believing is seeing, and fully expecting that at least the Avodart/testosterone group would have an initial DHT value of 5 or lower, this time I was the victim. I'm humbled by this mistake.
All this said, I now join Jerry and others in wondering how in the world DHT — a far more potent fuel of prostate cancer than testosterone — could be so high (> 250 per Figure 2!) either at the start of the vacation from ADT (the placebo group) or about 3 months later (the Avodart/dutasteride maintenance group). My own values of DHT on Avodart along with Lupron and an antiandrogen have nadired at < 3 ng/dL — that's < 3.0, not 30, or 300. While that was achieved on triple ADT (Lupron, the antiandrogen, plus Avodart/dutasteride), giving me a testosterone of about 20 or below, both groups in this study also achieved a testosterone in that neighborhood for the early vacation months judging from the testosterone graph in Figure 2. Since DHT is metabolized from testosterone, one would think that there was no reason for initial levels of DHT to be so high.
Really, really puzzled!!!!!
CRITICAL DIFFERENCE BETWEEN KLOTZ AND SCHOLZ STUDIES, AND SURPRISINGLY (AMAZINGLY) LOW RECOVERY OF T IN KLOTZ GROUP
There are likely a number of important differences that might help explain the stark difference in results between the Scholz and Klotz studies, but here is one that strikes me as absolutely critical: it is almost a certainty that very few if any of the patients in the Klotz study would have qualified for inclusion in the Scholtz study!
I have been rereading the complete Scholz paper, and one of the inclusion criteria was that men in this retrospective chart review had to have recovered greater than 150 ng/dL of testosterone within the first 12 months of the vacation period (criterion 6 under the “Patient Selection and Treatment Paragraph). In other words, all patients in the Scholz study had recovered more than 150 ng/dL of testosterone within the first year of vacation; my impression is that that achievement is routinely anticipated in the practices involving Dr. Scholz and team members (and matches my own experience). Their thinking was that there’s not much enjoyment in the vacation if you suffer from very low T.
In sharp and surprising contrast, Figure 2 of the Klotz study shows that median testosterone recovery through month 12 of the vacation period was in the range of 8 to 12 ng/dL, and in fact rose to a high point of just 20 ng/dL throughout the 66 months of follow-up. If the median was that low (meaning half lower/half higher), it is very unlikely that more than a few if any patients would have recovered to greater than 150 ng/dL. None of the median figures for any month indicates any where near to normal testosterone.
I am having great difficulty grasping that testosterone recovery could be so extremely low in the Klotz study. How can this be possible? Especially how can it be possible with relatively short ADT of 9 months or a few months longer and a median age of 71 — not that old? I have known of individuals who suffered from slow and low recovery, but my strong impression — backed by my own experience (ADT of 31 months, 19 months, 19 months, and 18 months) and that of friends, as well as numerous presented and published reports by doctors I follow — is that such profoundly low recovery is infrequent to rare. What gives here? Am I missing something? I keep looking at the graphs, triple and quadruple checking, but seeing the same thing. It’s like there are two different medical communities, with one routinely achieving successful testosterone recovery in its patient community and the other not, yet both communities highly respected and accomplished.
Extremely puzzling!
Dear Jim:
I don’t mean to be unkind, but you really are beating a dead horse.
First, it is important to understand how little we actually know about why ADT does and doesn’t work. Just because there is a nicely packaged theory about suppressing androgen receptors in the prostate and the consequent suppression of serum T and serum DHT by differing drugs does not mean we understand what is really going on in individual patients at a biochemical level.
Second, the Scholz/Strum patient cohort was very highly selected. (It was based initially on self-selecting patients who chose to go to this practice — for whatever reason; then, the physicians at the practice selected some of those patients for treatment with their form of IADT3.) When you do a randomized, multi-center clinical trial, you are dealing with a much more diverse set of patients. And the whole point of this trial was to see if this form of IADT3 worked in a relatively diverse group of patients — as opposed to a highly pre-defined subset who were identified retrospectively from a single practice.
Third, as I pointed out in my very first comment above (in response to Allen’s initial comment), we know there are at least 25 genetically different subtypes of adenocarcinoma of the prostate.
It makes perfectly good sense to me that Scholz et al. could get the result that they got from a retrospective analysis of a pre-selected cohort while Klotz et al. were unable to show any evidence of benefit in their randomized study (albeit small, as they freely acknowledge). And it will make perfectly good sense to me if at some point in time we find that there is, for some reason, a small subset of definable patients who really do do rather well on some form of IADT3. We do know that such patients exist. But we don’t know — prospectively — how to identify them!
It also seems highly unlikely to me that the characteristics that might allow us to pre-identify such patients are based only on how they respond to ADT at first and how fast they recover their testosterone level during the off-cycle period. Men like you and Chuck Maack and a relatively small number of others who have 10+ years of survival after actual or potential evidence of metastatic or at least micrometastatic disease appear to be rare to begin with. Your long-term survival after identification of metastasis may have far less to do with how you are treated and far more to do with the biology of your cancer, the inherent capacities of your immune system, and a whole bunch of unknowns.
What the two studies tell me has to be seen in that context. If some patient wants to follow some type of IADT3 protocol to treat his progressive prostate cancer, there are data from Scholz et al. that tell us that this does work in some men, and that there are certain criteria a man must meet to have a decent shot if they want to try this. On the other hand, what Klotz’s study appears rather strongly to suggest is that we would be delusional to think it is likely to work well in the majority of men — even if they meet the entry criteria used by Scholz et al. These are not “conflicting” ideas. It is perfectly possible for them both to be correct. The problem is that it may take us a very long time to work out why.
I would point out that no one has ever able to replicate the results for combined androgen deprivation with flutamide and Lupron that were initially claimed by Ferdinand Labrie either! And all his data were based on a cohort of largely self-selecting patients too. Indeed, since the original double-blind, randomized trial by Crawford et al. in the late 1980s that showed a 7-month median overall survival benefit from adding flutamide to Lupron, no one has ever again been able to re-demonstate that survival benefit either!
Sorry to beat this dead horse again … but can someone just answer me this one question?
If the whole purpose of the study was to see if adding Avodart to the off-period of hormone therapy (and reduce DHT to near non-detectable levels) would provide more time on HT vacation, then why wouldn’t the guys taking the Avodart show near 0 DHT throughout the time off HT and not the numbers we are seeing in Figure 2?
The State of Research on Combined ADT
Hi Sitemaster,
Thanks for your reply. I do hope that this important thread will remain active so we may all gain the benefit of mutual insights.
Some doctors whom appear extraordinarily expert to me regarding ADT have a different view of our understanding of ADT and the biology of the disease. It seems to me they feel we have achieved a lot of knowledge about how ADT affects the disease, to the point that they confidently navigate even challenging cases with success. However, if the criterion for recognized knowledge is classic randomized Phase III trials, the state of knowledge can be judged more tentative, and I think that is where you are coming from.
That 1989 Crawford trial was for men with metastatic disease, accounting for a modest survival advantage of the type typical of trials that support FDA approvals. Results in the trial suggested that the difference between combined blockade and single blockade would be even greater for men with minimal stage D2 disease. As with a number of treatments initially tested with late-stage patients, the combined treatment appeared even more effective with non-metastatic patients, as stated in the abstract. Dr. Crawford has presented details from this study as has at least one other presenter at the series of National Conferences on Prostate Cancer.
A more recent study from Japan, using a Japanese dose of 80 mg of bicalutamide, is a current Phase III, double-blind randomized affirmation of the effectiveness of combined blockade over monotherapy, despite very short follow-up that limits the maturation of mortality results. Here is the citation: Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Cancer. 2009 Aug 1;115(15):3437-45. doi: 10.1002/cncr.24395. PMID: 19536889 A complete copy of the paper is available free online. While results are still in a fairly early stage, with “just” a 22% (just statistically significant) reduction in mortality, a more currently meaningful indicator is the number achieving a PSA nadir of <= 0.2: 73% for the combined group versus just 14% for the monotherapy group. The paper has a nice, fairly current discussion of the literature regarding combined blockade.
Little has been published in peer-reviewed journals on true ADT3/IADT3. Drs. Leibowitz and Tucker published tentative early data many years ago, but they have not followed up with long-term results, partly due to a lengthy illness that led Dr. Leibowitz to send many of his patients to other doctors, resulting in issues with records. The Scholz/Strum/Lam and colleagues team has published informally, but the closest formal publication is limited to combined blockade with 5-ARI use for maintenance, as in the Klotz study. I believe I heard they had something in the works on IADT3.