The use of androgen deprivation therapy (ADT) is at the heart of treatment for patients with advanced forms of prostate cancer. What has been debated for years, however, is when, for how long, and in combination with what other forms of therapy ADT should be applied.
Verhagen et al. have just published a new review of the available data from randomized clinical studies of ADT (using orchiectomy or LHRH agonists) in the immediate and deferred/adjuvant treatment of locally advanced forms of prostate cancer.
According to their analysis:
- Studies of immediate versus deferred ADT without local treatment consistently showed only limited benefit for overall survival and prostate cancer-specific survival.
- Studies of ADT as an adjuvant to radiation therapy in patients with high-risk localized prostate cancer or locally advanced prostate cancer have consistently shown substantial benefit favoring overall and prostate cancer-specific survival.
- Studies of ADT as an adjuvant therapy in patients with proven systemic disease (e.g., node-positive patients after radical prostatectomy) have also consistently shown substantial benefit favoring overall and prostate cancer-specific survival.
- There appears to be a statistically significant and a clinically important survival benefit associated with adjuvant ADT when a local treatment has been applied to the primary tumor.
The full article includes a discussion of the possible mechanisms underlying this therapeutic effect. In their conclusions, the authors point out that this effect does not necessarily appear to be evident in all patients with locally advanced forms of prostate cancer. Specifically, they point out that local therapy and adjuvant ADT seems to be highly impactful for patients with T3 and/or N+ forms of prostate cancer but is not appropriate if the patient’s cancer is slowly growing or if the patient is at high risk for competing risks of mortality.
We don’t by any means expect this review to be the end of this long-running and controversial issue.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: adjuvant, ADT, androgen deprovation therapy, local therapy, locally advanced, outcome |
THE "NEW" PROSTATE CANCER INFOLINK 
The controversy is losing ground. I have many recent studies by many institutions that show combination therapy is better than any monotherapy in high-risk cases like my own. In fact, all the studies I have seen, regardless of what the local therapy is, have shown improved numbers in biochemical relapse at all stages of the study (i.e., 3-year, 5-year, 7-year, 10-year durations). My question has always been, when I see these studies, “What about mortality?”. This is why we need longer study durations. 15-year studies are at minimum needed to show the long-term results of such therapies…
I am not certain that it doesn’t matter what the local therapy is, but study data that post-RP, adding EBRT and/or ADT is having remarkable results in high-risk locally advanced cases. The same appears to be true with brachytherapy/EBRT/ADT. While the RP method is more definitive in identifying who actually might benefit from combination therapy, the brachytherapy method provides less side effects; however, some of these patients are not clearly identified as candidates who are likely to benefit from the adjuvant therapies or need them at all. The long-term race in high risk cases as to which of these methods is best still needs to be decided.
One word on your post: you say that adjuvant ADT is not appropriate if the patient has slow-growing disease, but that can’t always be determined if the patient is doing adjuvant therapy. Post-RP patients can have a PSA of < 0.1 ng/ml when deciding to do adjuvant therapies. No one knows how fast the disease is growing at the time to decide whether to add ADT or not. … Clinical data alone does not do this, either.
For now I watch on the fence, enjoying great results approaching year 4 even though I had positive bilateral seminal vesicles and a PSA at 20. Undetectable and hoping for that same results for all. …
A small point: Sitemaster does not say there is limited value in combined treatments, it is the article itself which says this — in slow-growing disease, that is.
Hi Tony, in the first response post, on August 5, 2010 at 1:48 pm, you wrote, near the end:
“… One word on your post: you say that adjuvant ADT is not appropriate if the patient has slow-growing disease, but that can’t always be determined if the patient is doing adjuvant therapy. Post-RP patients can have a PSA of < 0.1 ng/ml when deciding to do adjuvant therapies. No one knows how fast the disease is growing at the time to decide whether to add ADT or not. … Clinical data alone does not do this, either."
Actually, ultrasensitive PSA testing (a mainstay of my own management program for intermittent triple androgen deprivation therapy), can give an excellent indication of how fast the cancer is growing after an RP. Results are reliably and practically available down to <0.01, and the trend of PSA scores will give important clues about the aggressiveness of recurring cancer long before the PSA level reaches 0.1.
Hi Sitemaster,
Thanks for this article.
I would like to call attention to one area where the data available were insufficient to adequately illuminate the issue whether immediate or deferred primary ADT have much benefit as sole therapy. Here’s the line from the analysis: “Studies of immediate versus deferred ADT without local treatment consistently showed only limited benefit for overall survival and prostate cancer-specific survival. ”
As you note, ADT in the study was monotherapy, either orchiectomy or an LHRH agonist. Many of us are convinced that two-drug and triple-drug ADT therapies are essential for many men to achieve excellent results under ADT. For instance, one problem with monotherapy is that the body will often sense a shortage of testosterone from the testes and will compensate by substantially boosting testosterone produced via the adrenal glands. Also, reducing testosterone in a substantial portion of men does little to reduce dihydrotestosterone (DHT), which is a far more potent fuel for prostate cancer. As a final thought, experts in ADT have stated repeatedly that about 10% of ADT patients do not have ADT delivered adequately due to faulty delivery practices or to unusually rapid personal clearance of the LHRH agonist medication. These are both issues that can be spotlit with tests for testosterone and DHT, and then favorably resolved. However, if these issues are not noted and resolved, as was likely for patients in this study, I think, they would dilute the results regarding impact.
This study does add to the growing mound of evidence for ADT in certain settings as adjuvant therapy.
Jim:
(1) Unless I am badly mistaken, the levels of testosterone are actually irrelevant to the growth of prostate cancer. It is the conversion of T to DHT, and therefore the levels of available DHT, that drive the growth of prostate cancer cells. A man with low T levels but a high efficiency for conversion of T to DHT may in fact be at higher risk for progression than a man with high T levels but a low efficiency of conversion of T to DHT. The levels of DHT in the tissue of prostate and prostate cancer cells are actually driven by sophisticated biochemical feedback loops, so we shouldn’t make the assumption that the absolute level of T is necessarily the issue. On the other hand, there is an uncontradicted hypothesis still out there suggesting that one potential driver for the initial development of prostate cancer is flooding of the prostate with T because of an age-associated malfunction of the testicular and the prostatic venous drainage systems. To date, I am unaware of any paper that has either confirmed or been able to deny the validity of this hypothesis.
(2) The data from any study are the data from the study. One of the problems with this entire therapy area is all of the “opinion-based” forms of treatment (including triple-drug ADT) which people believe in but which are not substantiated by sound, evidence-based, randomized studies. While I might agree with you in theory (some of the time), it disturbs me personally that “belief” is not supported by evidence in all too many situations.
(3) One of the most important studies in this particular area was the one by Widmark et al., published just a couple of years ago in The Lancet, which finally showed that hormone therapy + radiation was better than hormone therapy alone. For years that had been taken on faith based on the Bolla data showing that the addition of hormone therapy to radiation was better than radiation alone, but it was very gratifying to me to see the reverse actually confirmed in a large, randomized study.
Hi Sitemaster,
I’m responding to your post of August 6, 2:45 PM, the latest post as of this moment, in which you advanced the thought that the levels of testosterone were irrelevant to the growth of prostate cancer, with the level of DHT being the real culprit.
Intermittent ADT has been my sole therapy for over 10 years, and I have tried to follow developments closely. I fully agree that DHT is far more potent as a fuel for prostate cancer, but all the expert oncologists I follow closely believe that testosterone is very important. For one thing, it is the source for DHT by conversion, so the more testosterone available to convert, without restriction (by finasteride or Avodart), the greater the amount of DHT. Also, testosterone does link with androgen receptor, fueling the cancer, even if it does so less effectively than DHT.
THE ISSUE OF RANDOMIZED TRIAL EVIDENCE FOR ADT
Hi once again Sitemaster,
I’m responding to your post of August 6, 2:45 PM, particularly to your second point regarding evidence in the area of androgen deprivation therapy. You raise a very important point, but I’ve come to a different position over the years from the one you have expressed. (I have no convincing proof of course, but I wanted to explain what I’m thinking.)
You wrote: “(2) The data from any study are the data from the study. One of the problems with this entire therapy area is all of the “opinion-based” forms of treatment (including triple-drug ADT) which people believe in but which are not substantiated by sound, evidence-based, randomized studies. While I might agree with you in theory (some of the time), it disturbs me personally that “belief” is not supported by evidence in all too many situations.”
The key problem, among several daunting problems, with such randomized trial evidence, is simply that we survivors with challenging cases involving hormonal therapy survive too long! (Tongue firmly in cheek here!) But actually, that’s so: we survive too long for the strongly preferred clinical trial endpoints to be practically achievable, especially overall survival, but also prostate cancer-specific survival. There are two major obstacles here: first, our length of survival, and second, the capacity of researchers to stick with very long clinical trials in the fast-moving world of modern research and tight budgets.
Regarding long survival, consider that experts in hormonal therapy, such as Dr. Mark Scholz, say that their patients on first-line intermittent triple androgen deprivation therapy, with finasteride or Avodart as maintenance, are now responding well to the regimen in a bimodal fashion: either about 10 to 11 years or indefinitely long. (I’m in my eleventh year, starting with a baseline PSA of 113.6, Gleason 4 + 3 = 7, Stage 3, perineural invasion, now on my third vacation from Lupron and Casodex.)
If first-line therapy fails, we now have several second- and third-line approaches that further extend survival. If those fail, we have drugs like Leukine, and now Provenge, that extend survival.
Even before the modern pharmaceutical arsenal was developed, an eye catching study by Oefelein, Agarwal and Resnick found in a retrospective study that survival after true refractory disease developed was 40 months for men with bone mets at the time of going refractory and 68 months (!) for men without bone mets at that time. (2004; This study was based on counting from the date the PSA rose while the men had castrate levels of testosterone, unlike the clinical trial realities where the refractory date is often, by convention, the date of trial enrollment. The Halabi nomogram is based on trials that used the convention, thereby underestimating true refractory survival, but that’s another story.)
You can see that if you add about 10 to 11 years for first-line success (conservative — ignores those successful indefinitely), plus say 2 to 3 years for second line blockade (just guessing, think it’s at least that typically), plus 5 more years for post-refractory survival, plus a bonus of say 2 years (guessing again, probably conservative) for modern improvements, you can easily get to typical survival for patients who would be in ADT trials of more than 20 years! As corroborating evidence, we already have data that men with high-risk prostate cancer overwhelmingly are alive at the 10-year point (95% per “Long Term Survival Rates …”, J Clin Onc, v23, page 441, January 2003, based on treatment technology that is obviously quite dated.)
Then consider the poor researcher looking to make a name by publishing a lot of weighty studies, especially as first or last (senior) author, particularly in today’s very tight research budget environment. It’s clearly hard to get researchers to stick with that kind of commitment. The grossly premature screening studies published in the New England Journal of Medicine last year are likely symptoms of the difficulty of sustaining long trials.
Here’s another problem: keeping the study subjects free from major contaminants. For example, if such a study were now ongoing (survival endpoints), what if the promising research regarding pomegranate juice and extract panned out during the study? You would then have many of the men consuming pomegranate, and that would have to mess with the interpretation of the findings. A recent example comes from the SELECT trial, where a research finding from a completely different study, well after SELECT had launched, that the trial dose of 400 IU of vitamin E could be dangerous, was probably enough, by itself, to derail the trial. For long-haul studies, there must be ways of providing such flexibility while maintaining integrity of the protocol, but that’s difficult.
A further problem is the reluctance of pharmaceutical companies to fund trials that probably will not help their ledger sheets. Many years ago (around 2000 I think) Drs. Strum and Scholz submitted a protocol of a trial of intermittent triple blockade to a major LHRH-A source, but you can understand the company’s reluctance to back a trial that might have proved intermittent blockade superior to continuous blockade, thereby reducing the company’s sales.
My bottom line is that I’m convinced we need alternatives to the classic, gold standard type, large, long, expensive and probably impractical clinical trials using survival endpoints when it comes to studing intermittent ADT in men who are still responsive to ADT.
An alternative is shorter studies using end point surrogates like PSA velocity. I’m hoping that Dr. Sartor’s trial of triple ADT, now in progress, will provide some of the needed evidence.
Your thoughts?
Jim:
I have been arguing for years that we need a prospective, structured, national prostate cancer registry that would allow for long-term monitoring of patients based on highly defined criteria.
Clearly it is time to rethink the research model — for the simple reason that to a large extent we have already “succeeded” (at least to some extent) in extending prostate cancer survival for select groups of patients. (Although I think you may be overly optimistic about the mean survival of a man with metastatic disease. I don’t know of too many 20-year survivors.)Littleof what we are doing today is helping to give decisions about what is “best” for patients. We cannot operate a research program that focuses on on what is “best” for the research community.
Hi again Sitemaster:
I’m responding to your post of 4:40 pm, regarding the evidence for ADT.
The national cancer registry you describe is a great idea! Do you see a path to implementing the concept? Are advocates becoming involved in this yet?
Regarding survival of 20 years or more, that would be for men who are on hormonal therapy but who start out without metastases, hopefully avoiding them for many years. The metastatic aspect of my earlier post of 8/13 11:36 AM had to do with that sole study that analyzed survival for men in its database after they became hormone refractory. That refractory period, often involving metastases, would perhaps account for about roughly four to six years of the total contemplated survival of twenty years or more, though perhaps that refractory survival could be extended with modern approaches. Some men are certainly now doing better than that despite refractory disease. (The whole area of refractory disease bears scrutiny – is a PSA of 50 or below 20 essential for determining successful hormonal blockade; what about DHT; what about second line ADT; etc.)