Limited value of immediate, adjuvant ADT in men with pT3b prostate cancer


New data published by clinical researchers at the Mayo Clinic have suggested that there is no overall survival benefit associated with adjuvant hormone therapy after surgery in men with pathological T3b disease.

In the February issue of BJU International, Siddiqui et al. have reported data from a retrospective analysis of data from the 12,000+ patients treated surgically for prostate cancer at the Mayo Clinic between 1987 and 2002. Among this database, they were able to identify 191 men who were known to have seminal invasion at the time of surgery (pT3b disease), had negative lymph nodes, and who received immediate, adjuvant deprivation therapy (ADT).

They compared the follow-up data from these 191 men with data from a carefully matched set of patients with pT3b prostate cancer who did not receive adjuvant ADT. Clinical endpoints included biochemical progression-free survival (BPFS), local recurrence-free survival (LRFS), systemic progression-free survival (SPFS), cancer-specific survival (CSS), and overall survival.

The results of their analysis showed the following:

  • Median postoperative follow-up was 10 years.
  • Compared to the patients who receive no adjuvant ADT, patients who did receive adjuvant ADT had
    • A better 10-year BPFS (60 vs 16 percent, P < 0.001)
    • A better LRFS (87 vs 76 percent, P = 0.002)
    • A better SPFS (91 vs 78 percent, P = 0.004)
    • A better CSS (94 vs 87 percent, P = 0.037)
    • No significant improvement in overall survival (75 vs 69 percent, P = 0.12).
  • The type of ADT given to these patients (either LHRH agonist monotherapy or bilateral orchiectomy) appeared to make no difference to survival outcomes.

It is hardly surprising that immediate adjuvant hormone therapy would have a statistically significant impact on local and systemic survival after radical prostatectomy for men with pT3b prostate cancer. If you suppress hormonal expression in such men, you will inevitable affect biochemical recurrence of their disease. It is also not surprising that there is a small impact on prostate cancer-specific survival in a study of this type — but the clinical significance of the finding has to be questioned because of the retrospective, case-matched nature of the study.

And most importantly, the study clearly shows no impact of immediate adjuvant hormonal therapy on the overall survival of an otherwise wide range of men with pT3 disease.

Now it may well be the case that there is an identifiable subgroup of men with pT3 disease who would demonstrate an overall survival benefit from adjuvant ADT post-surgery. However, these might well be the same set of men who would benefit from adjuvant radiation therapy post-surgery — those with high risk disease prior to their surgery. It would take a large, complex clinical trial to evaluate this possibility, and given the other unanswered questions in the management of prostate cancer, this may not be a high priority question.

It should also be noted that hormone therapy can be given early to men with progressive disease after surgery and adjuvant radiation therapy. Giving immediate, adjuvant hormone therapy to most such men today is potentially exposing them to a higher risk for complications and side effects than giving them immediate, adjuvant radiation therapy.

30 Responses

  1. This article explains why medical castration is less than effective and why prostate cancer goes to CRPC. It has to do with bilateral varicocele and free testosterone which is 130 times serum levels in the prostate bed. BTW a lower serum testosterone level means MORE is leaking into the prostate bed and a higher chance of CRPC.

  2. Dear Bob:

    We first reported on Gat’s hypothesis back in October 2009 and again in more detail in December 2009.

    The hypothesis actually relates to the initial development of prostate cancer rather than the progression of the disease. Since publication of the original article we have heard and seen no further reports related to this hypothesis.

  3. Hi Mike.

    My oncologist at MSKCC gave me similar advice about overall survival in 2006 after I had completed radiation. He let me make the choice to go on ADT right away or defer. At the time the “prevailing wisdom” was never to let PSA (tumor burden?) rise. Triple ADT right away was their battle cry.

    The point I am trying to make here is that good doctors at top notch cancer centers will probably give patients the best choice of treatment options.

    Bill

  4. So it seems ADT is effective in controlling BPFS, but significantly less effective in controlling LRFS and SPFS. In other words, it controls better the raise of PSA, but less efficient in controlling the progression of cancer. Couple of questions: (a) Given the relatively low impact on the progress of cancer, is it worth bearing the associated side effects? (b) Does it show that the correlation between PSA level and cancer is not as strong as thought?

  5. Reuven:

    (a) The relative value of hormone therapy compared to the downsides of the side effects is a very personal decision. For a man who freaks out every time his PSA goes up by 0.1 ng/ml, it may well be that the side effects are worth putting up with to keep the PSA at near to zero. For those who can be more dispassionate about living with a chronic condition, the same may not be true. Humans have an amazing capacity to think about the same issue in very different ways.

    (b) The “correlation” between PSA levels and cancer progression is and always has been a very variable one. Again, different individuals may have PSA levels that respond differently to similar stimuli. Just as one can find men with early stage, high-risk prostate cancer and a very low PSA level (< 2.5 ng/ml), one can also find men who have extensive metastatic disease and yet a PSA under 100 ng/ml. Conversely, a while back, we referred on this site to a man who was initially diagnosed with a PSA of > 21,000 ng/ml and yet he had no apparent bone pain or other symptoms of disease at the time of diagnosis. We do know that men with progressive disease will have a rising PSA — but just how much that PSA rises can vary considerably. If we look at PSA doubling time as being a measure of risk for metastasis and death in men with progressive castration-resistant prostate cancer, then the following two individuals (with no sign of metastatic disease on Jan 1, 2011) appear to have the same risk:

    — Man 1 has a PSA of 27.6 on Jan 1, 2011; a PSA of 55.2 on July 1, 2011; a PSA of 110.4 on Jan 1, 2012; and a PSA of 220.8 on July 1, 2012.
    — Man 2 has a PSA of 11.8 on Jan 1, 2011; a PSA of 23.6 on July 1, 2011; a PSA of 47.2 on Jan 1, 2012; and a PSA of 94.4 on July 1, 2012.

    Both men have a PSA doubling time of exactly 6 months, but we have no idea whether one is at greater risk of prostate cancer mortality any sooner than the other, and they might both show signs of metastasis by July 1, 2012.

  6. I am familiar with the studies Mayo creates from their database in other areas of prostate cancer treatment. It is important to recognize that the majority of these men were treated in the 80s and 90s, and very likely that a majority were in the period of 87-96, or so. For the 10-year survival numbers, these men, if treated today with the same surgical outcomes, would have greater survival due to improvements in drugs and knowledge of prostate cancer dynamics. The idea of treating pT3b prostate cancer with immediate orchiectomy gives significant insight into where we have come in the 25 years since the inception of this study database.

  7. I’d like to see the follow-up extended another 5 or 10 years further. There is benefit at every level in this study but the survival benefit is only about 4 in 100 men after a median of 10 years. But this is a very small retrospective view that does not seem to define those that also took on adjuvant radiation nor improvement in techniques or drugs. Thanks for the post but the most that I can take home about it is there is still hope that what I did can still be highly beneficial 15 years from now. And again — at 44 years of age 4 years ago when I had RP/adjuvant HT/adjuvant RT for my pT3b disease, the alternative to adjuvant therapies didn’t look like too much fun either.

  8. I’M FAIRLY IMPRESSED WITH THE SUCCESS OF SUCH ADT, THOUGH RESULTS QUITE TENTATIVE

    As Sitemaster has emphasized, this study has some design features that limit confidence in its results. However, I did not expect to see results this strong, after making allowance for unavoidable shortcomings in the study. Here’s why, including considerations noted by John Cochran on 2/7 11:55 AM and Tony Crispano, 2/7 3:13 PM.

    The period when the patients in the adjuvant arm received their ADT was back when ADT was primitive, at least by the standards of today’s leading clinical oncology practices. First of all, the adjuvant ADT was only aimed at testicular production of testosterone, either via an LHRH agonist drug or surgical castration, as noted by John Cochran. While that closes the barn door, to use the farming analogy, it leaves the back door and loft of the barn wide open for indirect production of testosterone, unrestricted production of DHT from that testosterone, and unrestricted docking of such androgens with the androgen receptor.

    Moreover, it is quite likely, based on the time period, that neither testosterone nor DHT levels were monitored to ensure effective hormonal blockade, That seems very significant as experts in androgen deprivation therapy have observed that about 10% of men on ADT coming to them have previously had inadequate blockade due either to flawed delivery of the shots (e.g., into fat as oppsed to muscle for Lupron; the coil working its way out for Zoladex), improper preparation of the substance (e.g., improper mixing or storage), or unusually rapid clearance of the drug due to the patient’s biology, That 10% estimate is informal, I believe, but it seems probable that some of those in the adjuvant arm had inadequate testosterone suppression.

    Moreover, the accepted standard for the drug equivalent of medical castration has been a level of 50 or lower for testosterone, while the experts are convinced that levels between 50 and 20 likely indicate inadequate (but correctable) testosterone suppression. My impression is that the latter view — a threshold of <20 — is gradually being accepted as best; I believe there have been some papers on this point.

    In short, if the study had been done with sound implementation of today's technology, I believe we would have seen even better numbers for all scored areas just due to better treatment delivery. That makes it likely, in my mind, that patients treated effectively with early adjuvant ADT these days would do better against the cancer, assuming the study’s limitations have not distorted reality, which we really do not know with high confidence.

    So far, I've tried to make the point that those in the adjuvant arm were likely not treated in a way that would have achieved the blockade that can be routinely achieved these days by sound ADT therapy. Now I want to turn to the side effect, complication, adverse event side of the equation, which would influence overall survival and perhaps prostate cancer specific survival as well.

    During the time frame in the trial, the standard of care was continuous therapy, but the abstract does not describe the duration parameters of the adjuvant ADT; it's possible that the norm was a course of ADT for months or just a few years. We now know that continuous ADT substantially raises the risks of a number of conditions that can cut life short, unless countered, and countermeasures were either unknown or likely little used during the particular years of treatment in this study.

    Even shorter term ADT with testicular testosterone suppression can cause potentially dangerous side effects unless countered. For example, decreased bone density can lead to deadly fractures, and balance and decreased muscle issues stemming from ADT can make such fractures more likely; uncountered ADT can make cholesterol and atherosclerosis issues more threatening; ADT has been associated with increased risk of metabolic syndrome.

    There are typically effective countermeasures to these and other side effects of ADT, and their use could increase overall survival. However, during the subject treatment time period, it's unlikely they would have been used much or with full effectiveness. Therefore, it is likely that death due to side effects of ADT was higher among the adjuvant ADT arm than it would be for a similar group treated today with effective implementation of countermeasures. If that were true, it would likely mean a higher overall survival for the adjuvant group than notched in this study. Depending on "cause of death" documentation, it could also mean a somewhat higher prostate cancer specific survival. Moreover, if some of the men in the adjuvant arm were not to have died as a result of uncountered ADT side effects, they would have contributed more years of successful cancer survival to the statistics.

    The third key point that strikes me is the one Tony Crispano made on 2/7 at 3:13 PM: follow-up was short by today's survival standards, and even for the period was probably too short to fully develop the true overall and prostate cancer specific survival differences between the groups. Given the figures, even with the flaws noted above, I would expect to see a larger difference favoring the ADT adjuvant group with longer follow-up.

    The abstract's conclusion (and other sections) did not mention any of these important considerations, rather focusing on a discouraging viewpoint: "… Given the lack of improvement in overall survival, continued investigation is needed to identify the cohort of pT3b patients at highest risk for cancer progression and therefore most likely to benefit from a multimodal treatment approach." Sure wish I could have rewritten that line!

  9. Jim:

    Would you seriously initiate immediate adjuvant hormone therapy in the majority of pT3b patients today unless they had VERY high risk disease (Gleason 9/10; PSA > 20), or would you want to see if they had a rising PSA after adjuvant radiation therapy?

  10. As a 70-year-old with Gleason 9, pT3b I have been researching this subject ad nauseam. My post-RP PSA readings have been 0.1 and 0.2 at 2 and 5 months post-op respectively. My next reading is in 2 weeks. My surgeon at Johns Hopkins and my local urologist both seem to think that additional therapy is not warranted due to lack of proof that it is effective for increasing survival. A Johns Hopkins oncologist thinks radiotherapy could be useful if for no other reason than if the prostate cancer is still localized I may be able to kill it and I could at least tell myself I did everything I could one way or another.

    So is it a matter of trading off the ride effects of ADT and or salvage radiation therapy against delaying the pain from metastasis? Do therapies for reducing pain associated with metastasis (ADT, chemotherapy, and targeted radiation therapy) have similar side effects to adjuvant ADT and radiation therapy?

  11. Dear Bob:

    The potential up-side of early salvage radiation therapy + ADT for a period of about 2 years is that if it works you will be able to stop the ADT again — and maybe forever. If you let your PSA rise and don’t have any treatment until it becomes necessary, then the treatment (at best) will be continuous or intermittent ADT for the rest of your life.

    A lot depends on just how fast your PSA is rising (your PSA doubling time). When you get your next PSA result, you might want to use this calculator to get an accurate estimate of the PSA doubling time.

    If your PSA doubling time is relatively short (i.e., less than 9 months), then the early treatment strategy becomes potentially wiser. If your PSA doubling time is long (i.e., 15 months or longer), then you may do just as well by defferring any form of treatment for as long as you can.

    The side effects of ADT will be the same whether you use this type of therapy earlier or later on. If you don’t have radiation thereapy, then clearly you avoid the potential side effects of radiation. However, the side effects of radiation therapy today tend to be a lot less prevalent and serious than they were 15 years ago.

  12. I don’t believe I’ve read any studies which show that early salvage radiation therapy and ADT after radical prostatectomy can actually cause prostate cancer to go into long-term remission, resulting in no further need for ADT.

    If that were the case wouldn’t it have been highly touted for high risk patients? If, as all studies seem to say , ADT + salvage radiation therapy confers no survival benefit, how does this square with the possibility of long-term remission ? Why would anyone elect to undergo these treatments for no overall survival benefit? Have these treatments been proven to delay prostate cancer-specific mortality but not delay to delay overall survival? Why is overall survival used as an endpoint instead of prostate cancer-specific mortality? What am I missing?

    Bob

  13. Dear Robert:

    I have no idea where you are getting the idea that there is no benefit from early salvage radiation therapy (with or without ADT) after radical prostatectomy. This is a well-established form of treatment for appropriately selected patients and, in such appropriately selected patients, can actually be associated with a curative outcome. Many years ago it was shown that adding 3 years of ADT to radiation therapy could significantly extend the survival of patients with node-positive prostate cancer. More recently it has been shown that only 18 months of ADT may actually have the same survival benefit for many of these patients

    However, there is a problem, which is our inability to accurately select the patients in whom salvage radiation therapy can and can not be done successfully with anything even close to 100% certainty. In other words, for a man who has had surgery, and who has a rising PSA post-surgery, we may not be able to tell, early enough, whether the recurrence is local (and therefore potentially curable) or micrometastatic (and therefore potentially incurable — even with the addition of ADT).

    There is a quite separate issue, which is the use of immediate, adjuvant radiation therapy (with or without ADT) in men with high-risk disease. This is not salvage therapy. In this subset of men, treatment is initiated as soon as the patient has recovered from his surgery, regardless of his PSA level, in order to maximize the chance that he can be cured. The use or non-use of ADT in such patients depends on a variety of factors, and there has never been any clear data from a randomized clinical trial suggesting that the addition of ADT necessarily makes a difference in a really well-defined subgroup of these patients.

    There has also never been any data from a well-designed, randomized clinical trial showing that immediate, adjuvant radiation therapy is any more effective than salvage therapy is any well-defined subgroup of patients.

    You may be confusing the data from a large and complex set of clinical trials — some of which never enrolled the numbers of patients needed to produce definitive data, and some of which had design flaws.

    The best way to think about this is as follows:

    (a) Some men with clearly high-risk disease post-surgery will increase their chances of a cure if they have immediate adjuvant radiation therapy (with or without ADT, depending on their own opinions and the guidance of their doctors). The precise definition of the most appropriate patients for such treatment is a matter of opinions and some controversy.

    (b) Some men who have a rising PSA post-surgery may still be curable if they have salvage radiation therapy (with or without ADT, depending on their own opinions and the guidance of their doctors). The appropriate selection of patients for such treatment depends on things like how soon the PSA starts to rise post-surgery; the patient’s PSA doubling time; the patient’s age and life expectancy; and other risk factors (e.g., the patient’s post-surgical Gleason score and his pre-treatment PSA at diagnosis).

    (c) The appropriateness of adjuvant and salvage RT will be best defined if there is clear evidence of exactly where a recurrence might be or is occurring — but for all too many men such accurate evidence may be impossible to obtain early enough in the process.

    It is unlikely that any really well-designed clinical trial is ever going to resolve any of these issues for any number of many issues, including the following: patients don’t like to be randomized to trials like this, so they aren’t able to enroll patients easily; such trials need a lot of patients to be followed for a long time if they are going to produce really useful data; patients would need to be “stratified” into risk groups for such trials to be meaningful because a man with a Gleason 9 tumor and one positive lymph node and positive seminal vesicles is a very different “high-risk” patient compared to a man with extracapsular extension and a Gleason score of 4 + 3 = 7 (who is also “high-risk” for progression, but not as high risk as the first man).

    The bottom line is that there are plenty of men who were either high risk or who had a rising PSA post-surgery and who, after radiation therapy (with or without a period on ADT), have gone into long-term remission and are either still alive today with a stable PSA or died of something other than prostate cancer. Can I tell you in advance which patients this will work for with certainty? No, I can’t, and neither can anyone else. But that doesn’t mean it doesn’t work. It just doesn’t work for everyone one would like it to work for, and we may well be giving this type of therapy to at least some men who don’t need it anyway.

    With respect to prostate cancer-specific mortality and overall survival, these are different endpoints that are profoundly impacted by the ages of the patients enrolled into specific trials. For this reason, the best trials will usually seek to assess both of these endpoints (along with such earlier endpoints as time to evident metastasis). What the value of these endpoints has depends on what the investigators are trying to prove. For example, one may be able to demonstrate that treatment X affects prostate cancer-specific survival but still has no impact on overall survival. From a population perspective, since we are now pretty good at managing pain associated with very late stage prostate cancer, is there any point in a treatment like X that actually doesn’t affect overall survival in men over 65? However, if we do the same trial with treatment X in men who are all under 65, might we get a different result, in which there is both a prostate cancer-specific and an overall survival benefit? There are certainly treatments for which that appears to be the case.

  14. Dear Sitemaster, I’m responding to your response (to my previous post) on February 9, 2011 at 5:36 pm in which asked:

    “Jim:

    “Would you seriously initiate immediate adjuvant hormone therapy in the majority of pT3b patients today unless they had very high risk disease (Gleason 9/10; PSA > 20), or would you want to see if they had a rising PSA after adjuvant radiation therapy?”

    Actually, no, I would not advocate that, though it would be worth some consideration. What I believe the experts in ADT would do would be to diligently monitor the PSA with an ultrasensitive test, preferably one capable of registering to < 0.01. Research has suggested that most men whose PSA does not fall below 0.05 ng/ml or rises to that level will recur. In this high-risk group, it makes sense to me that ADT well before PSA reaches 0.1 ng/ml is sound. That could be an independent therapy, or it could help set the patient up for adjuvant radiation. Based on my own experience with today's advanced imaging techniques, if it were me as the patient, I would want imaging to try to pinpoint any remaining cancer.

    This is a long way of saying I agree with you that immediate ADT for all (or even many) of these patients seems excessive.

  15. Hi Bob, I’m responding to your post of April 13 at 8:24 pm after seeing Sitemaster’s response that looked right on the mark to me. I have some comments about Johns Hopkins and about ADT.

    I consulted at least four times at Johns Hopkins back in 2000, including both urology, radiation oncology, and medical oncology. Hopkins is a great institution, but I have become convinced that some doctors there have some real blind spots regarding treatment that is not within their field of focus. Specifically, some of the urologists, like the one I consulted and like the great surgeon Patrick Walsh, seem to me to lack an adequate understanding of ADT. Also, Dr. Walsh’s views have influenced many there, and he does not believe in early use of ADT, a view that is in sharp contrast to the medical oncologists that seem like true experts to me. Similarly, many urologists (surgeons) have a grossly inadequate impression of modern, well-done radiation (though, of course, this is a generalization with many welcome exceptions). You need to bear in mind that trials need to be long enough to show meaningful survival results, and, as survival of prostate cancer in the US is now quite long for the vast majority of us who have advanced disease, this means that many trials are simply too short, often by several years, to show whether a treatment is effective or not. (The prostate cancer screening trials are notorious examples.)

    A key point about ADT is that it needs to be well-done ADT. Many doctors are pretty ignorant about ADT based on what I’ve seen, heard, and read over a decade and a half as a patient with a challenging case. Worse yet, many of these same doctors think they do know what they are doing. Here are some things to look for to find a doctor who understands ADT:

    (1) Does he monitor both testosterone and DHT in addition to PSA?
    (2) Does he consider ADT adequate that does not reduce testosterone to about 20 ng/dl or lower? (Higher suggests inadequate or faulty blockade.)
    (3) Can he describe what useful steps he would take if your testosterone does not fall to the desired range (such as ensuring that administration of the medications was satisfactory, including storage, mixing and delivery into muscle for Lupron, for example, and that the coil did not come out for Zoladex; such as finding out if you clear the medication unusually rapidly, before the expected 1-, 3-, 4-, 6-, or 12-month dosage period is up; such as reducing the usual interval between doses if you are clearing it unusually quickly)?
    (4) Can he describe the advantage of adding an anti-androgen drug to the surgery or drug for testicular blockade, and describe how results in many trials have indicated that two drugs are often superior to one (or surgery)?
    (5) Can he describe why adding a 5-alpha-reductase inhibitor (5-ARI: finasteride or Avodart) might be a useful step and what the mechanism of action is? (This is controversial, but followed by a number of leading medical oncologists, including mine.)
    (6) Is he looking to lower your PSA to less than 0.05 ng/ml, as measured by an ultrasensitive test, as a measure of success (should do that), recognizing that failure to achieve that calls for additional blockade or, if using three blocking agents already with a satisfactory testosterone below 20, calls for additional non-ADT therapy?
    (7) Does he favor intermittent therapy if your PSA can be driven down below 0.05 ng/ml?
    (8) Does he address the issue of highly likely lessening of bone density and explain how to counter it, not just with supplements, but with medication (such as bisphosphonate drugs, denosumab, or estradiol skin patches)?
    (9) Does he describe the likely side effects and explain how they can be blunted or eliminated through countermeasures, including exercise and diet?

    There are other points, but I think this list covers most of the main ones.

    I am not aware of doctors following these steps at Hopkins, but there may be some. I am aware that some of their researchers appreciate at least some of these points, including the use of the 5-ARI drugs.

    I am a now savvy patient, but I have had no enrolled medical education, so this is my opinion but of course it is not authoritative.

  16. Adding (10) to list for well done ADT

    Hi again Bob,

    I’m adding this number (10), though it should be (1) based on its importance in triaging doctors’ capability with ADT. I suspect I overlooked it because it became so deeply ingrained in my thinking years ago, perhaps around the time that I was outliving my original prognosis of 5 years, in early 2000, from two accomplished and well respected urologists.

    (10) What does the doctor say about how long ADT should control your cancer? For most patients, including most advanced but non-metastatic patients, the experts would say that forecast falls into two groups: men who get about 10 to 11 years on first-line intermittent ADT, and men who can stay on intermittent ADT for many, many years, perhaps indefinitely. (After that, you have second-line ADT or one of the very new therapies.) Dr. Mark Scholz, who practices in the Los Angeles area and is a co-founder of PCRI, expressed this the most clearly. Gleason 9 cancer is of course quite aggressive, so perhaps that forecast would be overoptimistic for you, but maybe not. Too many doctors will give you a forecast of 18 to 24 months, a range based on very old research using single-agent blockade for men with bone metastases. If you hear that kind of forecast, I recommend you look hard and find a better informed doctor!

    Also, I have used “he” for the doctor throughout. Of course there are excellent female medical oncologists; for example, Dr. Celestia (“Tia”) Higano in the Seattle area would be one that most of us would put in the elite group.

  17. Jim:

    I had no idea that ADT could delay prostate cancer progression for 10-11 years or indefinitely. I thought it lost its effectiveness after about 2 years. Where did you get that data?

    I’m getting a second opinion from Johns Hopkins on what treatments are indicated next for me. It will be interesting to hear what they say about ADT in light of your experience. I find it strange that an excellent hospital like Johns Hopkins, ranked as number one in total and in urology would discount a therapy which has proven to be highly effective by others.

    Bob

  18. Dear Bob:

    I do think we need to be very clear that there are men who respond extremely well to ADT (and Jim is an example of this) and then there are men who just don’t respond well to ADT at all (regardless of type). As yet, the reasons for this are (at best) unclear.

    Rightly or wrongly (and there is no really compelling data on this subject one way or another), Johns Hopkins’ position has long been that early use of ADT doesn’t offer help to men with slowly rising PSA levels (e.g., PSA doubling times of > 15 months) but is certainly advisable to prevent onset of serious pain associated with bone metastases in men with rapidly rising PSA levels (e.g., PSA doubling times of < 9 months) after first- and second-line therapies.

    There are actually almost no good data clearly demonstrating that any particular type of ADT can truly extend survival of patients with progressive forms of disease, but ADT can delay the onset of pain associated with bone mets and it may be able to delay evident appearance of those bone mets. Conversely, however, one of the problems with starting ADT early is that it may actually stimulate the onset of castration-resistant prostate cancer in some men because it may stimulate the development and growth of prostate cancer cell types that are resistant to ADT.

    This is a very complex issue, and there are a lot of “moving parts” to appropriate treatment that are still a very long way from being fully understood.

    From an historical perspective, it is important to appreciate that the original value of ADT, as shown by Huggins and his colleagues nearly 70 years ago now, was that it palliated the severe pain associated with metastatic prostate cancer. Some of Huggins’ patients were able to get back out of bed and go back to work — for years. However, the forms of ADT available well into the late 20th Century were never able to show an actual significant survival benefit in well-designed, randomized, placebo-controlled clinical trials. But there are certainly men who respond so well to ADT that they are on treatment for years and years. I know of a few who have been on ADT for about 20 years now, but I also know of patients whose disease progresses very fast — regardless of ADT, and some of those men certainly do still die within 18 months to 3 years of their initial diagnosis.

  19. So is PSADT meaningful When it goes from 0.1 to 0.2 in 3 months?

  20. Hi again Bob. I’m going to contribute what I know and believe in response to a number of important issues that you and Sitemaster have raised in separate posts, and I’ll start with the first part of what you asked on April 16, 2014 in your 11:56 am post, as follows:

    “Jim:

    “I had no idea that ADT could delay prostate cancer progression for 10-11 years or indefinitely. I thought it lost its effectiveness after about 2 years. Where did you get that data?”

    That’s what I thought too after being diagnosed and getting those two informed prognoses from the surgical community (not much experience with advanced ADT, after all, drugs are not steel, as in “Heal with steel!, and one of them from Johns Hopkins). The doctors were totally independent of each other, but they were working from the same sheet of music: 3 good years and 2 declining; that was probably based on initial ADT lasting for 2 to 3 years, then chemo for another couple of years until that failed, and then decline.

    I stumbled on another line of thinking and medical practice, and began learning a lot starting in early 2000 from Dr. Myers’ newsletter, which a friend loaned me at the outset, and from the series of nearly annual conferences sponsored by PCRI, during most years in the Long Beach area of Los Angeles, by the Foundation for Cancer Research and Education (FCRE) in 2005 and 2006 in the Washington, DC area, and Us TOO for all years. I first attended in 2000 and came away with a massive boost in hope and key information. (The next, at the Marriott very near to LAX, will be held September 5-7, with details at http://www.pcri.org.)

    The highly respected prostate cancer physician and researcher E. David Crawford, MD, spoke at the 2006 conference in Reston, VA, covering two topics including “Long-term survival in patients with bone mets on hormonal therapy”. He has been a “principal investigator” (the leader) on a number of relevant clinical trials and has been (and still is) involved in prostate cancer for decades. However, some of his key findings (not covered by this paper by Crawford et al., from 1989, in the New England Journal of Medicine) were quoted by conference presenter Dr. Charles Myers, another expert and a patient himself with advanced, metastatic cancer, on “Median [average] time to hormone resistance”:

    Median time to progression:

    — Widespread bone mets + pain [at time of diagnosis], 8 months
    — Widespread bone mets without pain, 18 months
    — Few bone mets, located in hip and spine, 4 -5 years (with 30-40% still responding to ADT at 9 years)

    In another slide, Dr. Myers highlighted the myth that hormone resistance develops in 18 months, noting that this is the case for a small minority of patients.

    Citing data from another series from the highly respected M. D. Anderson, Dr. Myers showed us that men with with lymphadenectomy-proven pelvic nodal metastases who underwent immediate androgen ablation as the only initial treatment had a median time to progression of 67 months.

    The myth about short progression-free survival, according to several experts I’ve heard analyze this, probably came about because back in the late 1980s/early 1990s — basically prior to PSA — most men were diagnosed with well advanced disease, often with at least some metastases if not widespresd mets, so such short survival times were typical. Perhaps loose thinking caused doctors to think of average progression-free survival on ADT as being short. Considering all patients at the time, where the center of gravity was in the well advanced with mets zone, average progression free survival, not separating by stage of disease but rather lumping all together, was short.

    Also, the Crawford paper is one of the earliest papers on two-drug blockade, in this case Lupron + placebo vs Lupron + flutamide (incidentally, a drug I was taking until a week ago Tuesday in conjunction with Lupron and Avodart). The paper clearly showed superiority of two-drug blockade even in these advanced patients. It is possible that most doctors attended mostly to the single drug trials, where survival would not have been as good as it was, even then, with two drugs, and those one drug trials would have reflected shorter survival.

    Referring to data from a Mayo Clinic series, Dr. Myers noted that 64% of men with lymph node-positive disease after radical prostatectomy were still responding to ADT at 10 years, and, if only one lymph node were found, 94% (!) were still responding at 10 years.

    Keep in mind that these patients were treated with technology that was really old by today’s standards, so results today should be better, probably far better. Also keep in mind that that 2006 conference is now nearly 8 years in the past, and a great deal of progress has happened since then.

    Dr. Crawford went into detail in his talk, including mention of a subset of patients still responding at 20 years (!) but the foregoing is enough evidence to make the point that short progression-free survival on ADT is a myth. In your case, while your Gleason is high, you have no detected mets at this point, so I hope you will find this encouraging.

    In his book The Invasion of the Prostate Snatchers, Dr. Mark Scholz, an expert on ADT, writes that,

    “Now, however, we know that men who start TIP [Testosterone Inactivating Pharmaceuticals — meaning ADT] before the onset of bone metastasis respond well for more than ten years before developing resistance to TIP.1” That reference 1 is to a paper by Judd Moul (a very well known doctor specializing in prostate cancer; a leader at the Army’s famed Walter Reed hospital at the time), entitled “Early versus delayed hormonal therapy for prostate-specific antigen only recurrence of prostate cancer after radical prostatectomy“. The abstract does not mention the 10 years figure — you need the complete paper for that, but I think the results and conclusion may be of considerable interest to you regarding early versus delayed ADT for patients with high Gleason scores:

    “RESULTS:

    “Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p > 0.05).

    “CONCLUSIONS:

    “The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue.”

    That hazards ratio indicates that the likelihood of delayed metastasis was more than doubled by early ADT, and the p value indicates that this was a true result with a very small likelihood due to chance.

    On the other hand, you can disregard all this and similar research and trust in Dr. Patrick Walsh, who does virtually no early ADT but considers himself expert on the subject, who believes in waiting to use ADT until very late, such as when the patient has metastases. (Might his vehement defense of late ADT just stem from a budding sense of guilt that he has misled many patients for many years?)

    Me? I went with the guys who use ADT a lot and have tracked results in many, many patients; these are the doctors who believe in early use of ADT.

  21. Robert:

    Yes … A PSA that goes from 0.1 to 0.2 in 3 months has a PSADT of 3 months. However, such a PSADT would be more meaingful if it went from 0.1 to 0.2 in 3 months and then from 0.2 to 0.4 in the next 3 months. If your PSA was to go from 0.1 to 0.2 in 3 months and then stayed at 0.2 three months later, then it is much harder to interpret.

  22. Dear Jim:

    I don’t think that anyone is arguing over the very clear fact that the value of ADT is directly associated with the appropriate selection of patients who have a high likelihood of benefit from its use. However, none of these data can be used to prove that early use of ADT actually affects overall or prostate cancer-specific survival in any of the subcategories of patient you refer to (although it may well defer the onset of symptoms and evidence of metastasis).

    Furthermore, despite the original 1989 trial of Lupron + flutamide vs. Lupron + placebo (a trial in which all the patients were still being treated with daily injection of Lupron), many data published since then have failed to reproduce the evidence that the addition of an antiandrogen to an LHRH agonist in such two-drug combinations extends survival in any subgroup of patients — with the single exception of the combination of an LHRH agonist + an antiandrogen + radiation therapy as first-line therapy in men with locally advanced prostate cancer (as first reported by Bolla et al. over the years and then most recently by Warde et al.).

    With the single exception of the data from the Bolla et al. and Warde et al. studies, clear Level 1 evidence from large, randomized, double-blind trials that any form of ADT can extend survival in well-defined subgroups of patients is missing. The MRC trial carried out in the early to mid-1990s did suggest a benefit to the early use of ADT in men initially diagnosed with micrometastatic (M0) disease, but there were a number of problems with this trial that have always left its results open to question. The only other randomized trial to suggest a benefit from early as opposed to delayed use of ADT (the Messing et al. study) has always been considered to be too small to offer Level 1 evidence since it was based on only about 90 patients.

  23. Sitemaster:

    Thanks. I hope it stays at 0.2 but I’ll be surprised if it doesn’t increase!

    Bob

  24. I thought a recurrence was indicated by a PSA of 0.2 twice in a row. I’ve read a recent paper that says it should be 0.4. Why is it necessary to have PSA measured to three decimal places? Is it really necessary and doesn’t it cause unnecessary anxiety?

    Bob

  25. Hi again Sitemaster, I’m responding to your post of 8:19 am. Thank you for your thoughts, which I will try to work into later responses on some of the other issues, which I hope to get to. Here are a few observations.

    DIFFERENT PURPOSES. I believe that you and I are looking at the evidence with different purposes in mind, though those purposes overlap somewhat. I believe you are looking at evidence to see whether there is reasonably conclusive proof that has validity for use as a firm guideline to practice. I too see that Level 1 evidence as highly desirable for such proof. In contrast, I am looking at the evidence from the perspective of patients (and clinicians on the front line) who must make decisions based on incomplete and far from perfect data. The evidence that is meaningful is of varying degrees of quality and credibility, but it is the grist for reason and judgment to guide decisions for choices of therapies. I would love to have had nice Level 1 evidence for all my decisions, but it simply was not there. I support striving for that evidence, but I also support making decisions on the balance of available evidence, each piece weighted for relevance and credibility. Both purposes seem valid to me; perhaps you see this the same way.

    Sitemaster’s response: Jim: This is all true … but I would feel a lot more comfortable if you pointed out more clearly on a regular basis that there is no Level 1 evidence for many of the strategies that you argue for. I’m not saying that they are wrong, but I am saying there is no evidence. There was no evidence for all the problems associated with antibiotics either — until we discovered what happens when we overuse them!

    SURVIVAL OR PROXY. Survival of prostate cancer is so long today, even for many patients with advanced disease, that in my layman patient’s view a proxy, usually biochemical-recurrence free survival (PSA behaving nicely), seems essential to me in judging what seems to be working well and what seems to be working poorly. Based on that kind of evidence, I believe combined and triple blockade extend survival, but I too doubt that can be proven, as you have pointed out. I do believe combined and triple blockade look good based on proxy evidence.

    Sitemaster’s response: Jim: Proxy data are incredibly dangerous. This is exactly why the FDA is so resistant to proxy endpoints being used in clinical trials unless there is a very clearly established relationship between a specific proxy endpoint and a really meaningful endpoint. We already know that, for example, there is no necessary association between progression-free survival and overall or disease-specific survival for the majority of cancers. That doesn’t mean that progression-free survival is a useless endpoint, but a progression-free survival benefit of a month or so is pretty meaningless if it doesn’t predict a true survival benefit — especially if it costs the patient and society $50,000 or more.

    SHORT USEFULNESS OF ADT (18-24 MONTHS) IS A MYTH, FOR MOST. A third point is that patients need to know is that the short prognosis of effectiveness of ADT is a myth, and I believe you agree with that. I’m surprised that so many doctors and their patients have not caught on, but myths are hard to rub out. Clearly Bob, and probably his doctor, subscribed to the myth.

    Sitemaster’s response: Jim: I think that starting ADT early is a good idea for some men and a lousy idea for others. I just wish we knew how to select the patients appropriately, becuase we don’t. We have to guess. What I will tell you is that, like Terry Herbert, from an entirely personal point of view, I believe in avoiding ADT to the greatest extent possible, and I certainly wouldn’t start ADT early if my own PSA was rising slowly, because in such cases I think that most of the time it will work just as well when your PSA gets to something like 50 or 100 ng/ml as it does when your PSA is 2 or 3. (Indeed, you are arguably living proof of that hypothesis.)

    CANNOT FIND DATA CONTRADICTING THE CRAWFORD STUDY
    I searched http://www.pubmed.gov using ““(leuprolide OR Zoladex) AND (flutamide OR bicalutamide) AND prostate cancer NOT (radiotherapy OR radiation)” and filters set to “Clinical Trial, Phase III, Abstract available” to narrow 361 hits down to 22. One Italian study (Bono 1998) used almost the words you did: “However, many controlled studies have failed to demonstrate a benefit for CAB in comparison with simple surgical or chemical castration.” But I did not see much evidence of that in my search results, or the result was explainable. Perhaps the studies the authors had in mind were controlled but not Phase III trials. I would like to take a look at the more prominent papers to see if they stand up for me as sound evidence or not. After the botched roll out of the PLCO and ERSPC screening trials in the NEJM in 1999, I’m not taking much medical research on faith these days. if anyone could steer me to a few prominent studies I would appreciate it.

    Sitemaster’s response: Jim: You need to look at all the meta-analysis data, and include the trials of all the other antiandrogens. No one ever studied whether adding bicalutamide to an LHRH agonist had a survival benefit. They only had to show that it was comparable to an LHRH agonist + flutamide.

    YOUR EMPHASIS ON “DAILY” LEUPROLIDE DOSES. I’m doubtful that daily dosing would be any more effective than well done delivery of the bolus of leuprolide by injection. Is there research suggesting an issue? I am aware that some patients clear the bolus significantly earlier than the norm and that some patients/doctors are casual about the 28 day (and multiples) dosing schedule. Perhaps that is what you were suggesting?

    Sitemaster’s response: Jim: What I am suggesting is that the original leuprolide + flutamide trial (which is the only randomized trial of an antiandrogen + an LHRH agonist to show a survival benefit in men with M+ prostate cancer, ever) potentially had factors inherent to it that made it very unusual. One of the most unusual ones was that this was actually a trial done (by most of the physicians involved) to try and prove that adding an antiandrogen to an LHRH agonist would not have any survival benefit. I have to tell you that I think that if we re-did that trial today, using 2 weeks of an anti-androgen (to prevent flare) + an LHRH agonist and then a placebo + an LHRH agonist, and we compared that to an anti-androgen + an LHRH agonist, in men diagnosed with M+ disease, I don’t think we’d see any survival benefit in the combined therapy arm of the trial. (And yes, I understand that you’d want to see a third arm of the trial that included dutasteride too. Of course such a trial would arguably be unethical, so it ain’t gonna happen!

    Thank you again for your time and thoughts.

  26. I am stage pT3b (Gleason 9, EPE, SVI, margin +ve at base with Gleason 7) after RP, but I had 10 lymph nodes removed, all found to be negative for prostate cancer. The referenced studies seem to deal with benefit of ADT for lymph node metastasis. Did the guys in the study have negative lymph nodes after RP, but prostate cancer had later spread to lymph nodes or did they all have prostate cancer in lymph nodes at pathology? In other words, is ADT best suited for prostate cancer in lymph nodes? Or is prostate cancer in the seminal vesicles just as bad as in the lymph nodes?

    Bob

  27. Bob:

    Re your comment from 7:24 pm on April 17 …

    The formal definition of a biochemical recurrence post surgery is a PSA level of 0.2 ng/ml or higher. However, the argument that a PSA of 0.4 ng/ml may be appropriate is certainly reasonable for some (but not all) patients … see below. It depends on the patient’s PSA doubling time (and other factors, like his Gleason score).

    The formal definition of a biochemical recurrence after radiation therapy is a PSA level that is 0.2 ng/ml higher than the nadir level (i.e. the lowest level the patient’s PSA reaches post=surgery) and that is continuing to rise for at least one more PSA test.

    However, in a patient who was of relatively high risk prior to treatment, a steadily rising PSA level post-surgery that goes from 0.003 to 0.010 to 0.050 ng/ml over 9 months is a pretty clear indication of a problem.

    The reason that ultrasensitive PSA tests are valuable has a lot to do with the initial assessment of PSA levels post-treatment. In other words, both doctor and patient really do want to know if the patient’s PSA falls to just 0.090 (which is OK) as opposed to 0.009 ng/ml (which is much better). However, both ultrasensitive and standard PSA tests can be used to evaluate the speed at which PSA levels are rising if they start to rise, and decisions need to be made on an individual, patient-specific basis. It is certainly true that all too many patients will over-react to a PSA level going from (say) 0.009 to 0.010 ng/ml over a 3-month or a 6-month period. Doctors should be explaining to their patients that that degree of variation is well within the limits of variation of the accuracy of the test, and one can’t base good clinical decisions on that sort of variation. But the case described in the immediately presecing paragraph is one where there may well be a benefit associated with monitoring the PSA using the ultrasensitive test.

  28. Dear Bob:

    Re your comment at 11:56 am on April 18 …

    As far as I am aware, no one has ever done a randomized trial in which they set out to accurately subcategorize (“stratify”) the patients in advance based on whether they had “only” positive seminal vesicles or they definitively had positive lymph nodes. Your question is therefore unanswerable in any practical sense. However, I think it is reasonable to argue that a man with Gleason 8-10 disease and positive seminal vesicles but no evidence of positive lymph nodes is probably at a similarly high risk level as a man with Gleason 4 + 3 = 7 disease and psoitive lymph nodes. In other words, it’s not as simple as just whether the lymph nodes are positive or negative.

  29. Hi Bob, I’m responding to part of your April 17, 2014 at 7:24 pm post after reading Sitemaster’s apt response. I’m just adding a bit of what I’ve learned regarding ultrasensitive tests.

    You wrote in part: “… Why is it necessary to have PSA measured to three decimal places? Is it really necessary and doesn’t it cause unnecessary anxiety?”

    There are actually quite a few papers on ultrasensitive testing. Dr. Stephen Strum, MD, a co-founder of the Prostate Cancer Research Institute and the original driving force behind the conference series covered ten of them in a talk at The National Conference on Prostate Cancer in 2000, and more have been published since then.

    They can be used to estimate whether a recurrence is likely after a radical prostatectomy (RP), as research papers have provided odds estimates for values including less than 0.01, 0.01, 0.02, 0.03, 0.04, 0.05, and perhaps higher. My recollection is that a level of 0.05 or higher with an increasing trend is a strong indication that the accepted recurrence threshold of 0.2 will be passed at some time. If a patient’s first post-RP value is very low, such as 0.02 or lower, he would probably just want to get follow-up tests as scheduled. But if the value is, say, 0.03 or 0.04, some of us would want to switch to monthly or bimonthly PSA testing to see if there were an early trend.

    Values showing three places — thousandths of a unit — are now possible with reliable results, but as of a few years ago (the last time I got an update), there was no clinical utility differentiating the value of these lower values to the third decimal place from less than 0.01.

    Knowing your value within months of the surgery can give you wonderful peace of mind if you have a great value, as many men do. On the other hand, while delivered with a dose of disappointment and some anxiety, as you mentioned, a value at, say, 0.05 or higher with an upward trend can give you early warning of a recurrence, and that allows time for empowerment, consultation, planning, decisions, and perhaps early treatment or commitment to a program to slow or halt regrowth of the cancer. As I believe Sitemaster noted recently, many recurrences are too mild to require aggressive (or any) treatment, and ultrasensitive testing can sometimes give us an early estimate of the PSA doubling time, which can help in gauging the mildness or aggressiveness of the suspected recurrence.

  30. RELEVANCE OF PAPERS INVOLVING LYMPH NODE CASES FOR MEN AT EARLIER STAGE

    Hi again Bob,

    I’m responding to your question, on April 18, 2014 at 11:56 am. I have read Sitemaster’s response but am looking at a different aspect of your question. You said, in part,:

    “… The referenced studies seem to deal with benefit of ADT for lymph node metastasis. Did the guys in the study have negative lymph nodes after RP, but prostate cancer had later spread to lymph nodes or did they all have prostate cancer in lymph nodes at pathology? In other words, is ADT best suited for prostate cancer in lymph nodes? Or is prostate cancer in the seminal vesicles just as bad as in the lymph nodes?”

    The value of studies focused on patients with lymph node-positive disease is that men at earlier stages should have even better results, on average, than these men. Sitemaster already addressed the degree of risk of seminal invasion versus positive nodes.

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