EBRT + long-term ADT in treatment of men with high-risk, localized prostate cancer


A retrospective analysis has (again, somewhat predictably) shown that adding long-term androgen deprivation therapy (ADT) to dose-escalated radiation therapy improves outcomes of men initially diagnosed with high-risk prostate cancer.

The study by Feng et al. looked at data from men  with high-risk prostate cancer who were treated with dose-escalated external beam radiation therapy (EBRT), with a minimum total dose of 75 Gy, with or without ADT. All patients met National Comprehensive Cancer Network criteria for high-risk disease (clinical stage ≥ T3a and/or Gleason score 8 to 10 and/or PSA > 20 ng/ml).

Unfortunately, the abstract of the paper by Feng et al. does not provide information on the total numbers of patients included in their analysis, but we would expect that it was > 200 patients in total. With that reservation, here are the key findings of their study:

  • Average (median) follow-up time was 64 months.
  • Among men treated with radiation therapy but no adjuvant, long-term ADT
    • Metastasis was evident in 35 percent of patients at 60 months.
    • Prostate cancer-specific mortality (PCSM) occurred in 11 percent of patients at 60 months.
  • Among men treated with radiation therapy plus adjuvant, long-term ADT
    • Metastasis was evident in 13 percent of patients at 60 months.
    • Prostate cancer-specific mortality (PCSM) occurred in 6 percent of patients at 60 months.
  • Compared to men who received no adjuvant, long-term ADT
    • The hazard ratio (HR) for metastasis at 60 months among men receiving adjuvant, long-term ADT was 0.34.
    • HR for PCSM at 60 months among men receiving adjuvant, long-term ADT was 0.41.
  • On multivariate analysis,
    • Gleason score was the single, strongest, negative prognostic factor.
    • Among men with Gleason scores of 8 to 10 there was a time-on-ADT-dependent improvement in
      • Time to biochemical failure
      • Time to evident metastasis
      • Time to prostate cancer-specific death
      • Overall survival
    • Long-term ADT improved patients’
      • Metastasis-free survival (P = 0.002)
      • PCSM (P= 0.034)
      • Overall survival (P= 0.001)

Feng et al. conclude that,

For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of [long-term ADT] and [radiation therapy] provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10.

30 Responses

  1. No surprise here. We’ve already seen analyses from Harvard and Stanford confirming that, for high-risk patients post-RP, adjuvant radiation + HT has about the same improvement ratios. I looked at those data 6 years ago when I, as a high-risk case, chose the adjuvant EBRT + HT route after RP. I keep being told by patients, however, that their doctors tell them that it does not matter if you start adjuvant HT and that there is no benefit to adjuvant HT. I’m glad I didn’t listen to that gibberish. There seems to be an overwhelming benefit that is undeniable. Whether post RP or as a front-line attack to high risk disease EBRT + long-term HT helps you live longer…

  2. Tony:

    I think we need to be very clear that there are good data to support the use of radiation therapy + adjuvant ADT as front-line therapy or as post-RP therapy in carefully selected men with high-risk prostate cancer. On the other hand, there are few data supporting this strategy for most men with low- and intermediate-risk forms of prostate cancer, and the only randomized clinical trial that was designed and implemented to address this issue was unable to enroll sufficient patients. This is a complex issue (see this much earlier commentary).

  3. Tony, in your case, how long did you take adjuvant ADT and what was your treatment? I had RP 12 months ago and then 5 months later began IMRT when my PSA was 0.12. I also began degarelix at that time and have just finished 6 months of a scheduled 12 months of ADT treatment. PSA 2 months ago was zero. I am encouraged and happy that your treatment was 6 years ago. I am 76 years old.

    Dr. K

  4. Doc:

    I was 44 when diagnosed with a PSA of 20. After a RALP on 2/16/07 I had a pathologic Gleason score of 4 + 3 = 7 with positive surgical margins, extraprostatic extension, and bilateral seminal vesicle invasion. After RP my PSA dropped out to zero but I wasn’t happy waiting to see what would happen.

    I looked at a couple clinical trials I was qualified for but my research hit a gem of studies by Stanford and Harvard that were specifically defining patients like myself and using EBRT and HT as adjuvant therapies showing — at THAT time — that patients were living longer after 6 years of follow-up. I decided to forego the trials because both of the trials I looked at would not allow the EBRT.

    Within 90 days of my RALP I started adjuvant HT with Lupron and Casodex. 30 days later I underwent 39 fractions of EBRT that were designed to hit not just the prostate bed but also the regional iliac and inguinal lymph nodes (WPRT). I remained on HT for 28 months, but it took an additional 9 months before my serum T levels were back to pre-surgery levels. I have never had a rise in PSA since the RALP.

  5. Mike:

    Absolutely understood. High risk ONLY. Either before or after RP.

    This isn’t a scientific observation, but among the guys at the support groups I’m involved in there seems to be an equal trend. Guys that took the adjuvant route seem to have fared better. The guys that didn’t had some successes but they trended to quite a bit of reactive therapies ~ either salvage radiation or HT or both. There even seems to be a trend that men with AJCC IIIb disease benefit more than those with AJCC IIIA disease, as observed in the Harvard study (using AJCC2002). Even guys with a couple of positive dissected nodes seem to be able to benefit. Regardless, my advice is always talk to a radiation oncologist with experience with WPRT.

    I have also seen a growing trend of radiation oncologists becoming more familiar with WPRT or EBRT with a plan to radiate the regional lymph nodes. And I have observed that adding EBRT can lead to some nasty side effects too. So the decision is going to be an individual decision that has to weigh the benefits and risks. This isn’t for everybody in the cohort and I’d be interested in Dr. Feng’s observations on the side effects.

  6. Tony:

    I see no sign in the abstract of the paper by Feng et al. of any reference to the side effects of therapy.

  7. If you have Gleason 9 cancer with seminal vesicle invasion, radical prostatectomy, adjuvant radiation, and androgen deprivation (AD), it might be very difficult to maintain an active working life, overall health, a marital relationship, and mental stability while the side effects of AD are around. I quit the Trelstar after a year. I just couldn’t stand it any more. In fact, I get angry thinking about it. Oncologists seem to be in love with androgen deprivation the same way urologists love the PSA. They can tout survival all they want, but their treatment is not benign. Quality of life is an important factor to consider. I hope something better than androgen deprivation is found.

  8. Dear Dr. Hanline:

    I think everyone would agree that we would just love to find treatments that had the clinical benefits of androgen deprivation therapy (ADT) without the side effects. Anyone who is under the illusion that ADT is a “benign” treatment clearly needs to try it for a year or so!

    Having said that, there does appear to be a considerable range of responses to ADT. You appear to have been on the “bad” end of the side effect profile. Others seem to be able to tolerate this type of treatment without too much difficulty at all.

  9. “LONG-TERM” ADT IN SUPPORT OF EBRT

    This topic caught my eye immediately as this is my current situation. Fortunately, I tolerate ADT fairly well — not a cake walk, but certainly quite tolerable. I’m now at the start of my seventh month of my fourth round of intermittent triple ADT, this time in support of a planned 39 session course (78 Gy + 46 Gy to pelvis) of TomoTherapy. I completed my 28th session this morning.

    I’m trying to get a fix on the best length of ADT for me. I’ve seen one good study that indicates 24 months is better than 6 months. I’ve seen another suggesting that 18 months is as good as 24 months. My radiation oncologist and I have discussed this, and he noted that some of the older studies from the 90s might be more relevant to my high-risk case (high risk at least initially) than the more modern study that favored 18 months. The earlier work involved 28 months, and I suspect it is one of the studies Tony was citing.

    I’m hoping the full text of the current paper mentions the time frame for “long term” ADT. I’m a bit frustrated that key element was not spelled out in the abstract.

    I’m hoping research will be published to clarify whether I need to continue ADT beyond 18 months, but I suspect that I and my doctors will once again be making a call based on our best judgement.

    I’m also a believer in triple ADT, so that is what I’m on once again. My impression is that the studies of adjuvant ADT for EBRT involve just single-agent ADT and that the issues of the use of combined and triple ADT have not been addressed. Have I missed something?

    By the way, I’ve had an interesting experience regarding hot flashes, the side effect that typically is the one that is most bothersome for those of us that have a really hard time on ADT. During this fourth round, instead of using a bisphosphonate (or denosumab) for bone density protection, I’m on Vivelle estradiol patches, with one 0.025 mg patch replaced every 3.5 days. I delayed starting the estradiol for 37 days, and at the 15-day point after my first Lupron shot I started again experiencing hot flashes (though quite mild, as they were during my third round of ADT). They continued to be mild and infrequent during the month after I started the patches, but by January they had virtually disappeared. I understand this is typical when the patches are used. On the other hand, gynecomastia is associated with use of the patches, as well as mild soreness and tenderness.

  10. I had EBRT + HDR brachytherapy + ADT (Zoladex) for 3 years. Tough, but bearable. Unless I am mistaken, recent studies have shown that such trimodal combinations are effective (I have not yet looked at the statistics in the latest paper). The most recent I’ve seen though, used 2 years ADT, not 3. I was the first patient where I now live who got the 3-year ADT. The treatment was completed in May 2012, and the Zoladex left my body 12 weeks later. So far the PSA value is undetectably low and the testosterone value is increasing. The brachytherapy PSA “bounce” is now possible. We’ll see what happens.

  11. Dear Jim:

    The original study by Bolla et al. that showed an overall survival benefit for radiation therapy + 3 years of ADT at 5 and 10 years of follow-up used goserelin acetate + 1 initial month of cyproterone acetate. However, you need to remember that this study was sponsored by the developer of goserelin acetate and that the company had input into the study design. It was in their interests to have long-term use.

  12. Well, as I was told last Wednesday, the optimal duration of ADT for high-risk localised or locally advanced prostate cancer is an open question. I’ve heard 6 months, 18 months, 28, and 36. Perhaps others. I knew what I was getting into: mainly an increased risk of cardiovascular problems. Under these conditions, and with this knowledge, I figured, why not try 3 years? I was told I could stop whenever I felt like it, so why pre-judge this before starting?

  13. There is no mention in the abstract as to the definition of long-term ADT. This, for me is the key issue. … How long should a man remain on ADT?

    There have been several studies ranging from 18 months to 3 years; I think there may have been a recent study featured here (Sitemaster??) , that was the first to compare duration and found no benefit to remaining on ADT beyond 24 (18?) months.

    Anecdotally, I have seen men who had difficulty staying on ADT beyond 12 months have less success in controlling their disease.

  14. PELVIC RADIATION NOT ADDRESSED IN THIS STUDY

    Tony’s posts already mentioned that he received radiation to the pelvis as well as to the prostate, and I mentioned that I have also received pelvic radiation. However, three other fellow patients now undergoing TomoTherapy at about the same time as I am in the morning at my center are not having pelvic radiation; it is my understanding that all have lower risk cases, in contrast to my own case.

    In addition to the dose of EBRT, which in this paper seems reasonably high at a minimum of 75 Gy (though perhaps somewhat below what I believe is today’s norm of 78 – 81 Gy), it seems to me that, for men with high-risk cases, pelvic radiation is a very important variable determining success in addition to the duration of ADT.

    (By the way, I have requested my helpful local medical library to provide me with a copy of this paper.)

  15. HIGH-RISK CASES, ADVANCED BONE AND NODE IMAGING, AND SUCCESS FOR RADIATION

    In addition to other variables affecting the success of radiation for high-risk situations (the dose to the prostate, the dose to the pelvis [if any], and the length [and type?] of ADT), the use of advanced imaging is now practical and probably will modify success outcomes for prostate cancer radiation.

    Imaging for bone metastases now appears to be superb, but my layman’s impression, with no awareness of pertinent research, is that it is not yet in common use for high-risk cases. I’m thinking specifically of sodium [18F]fluoride PET/CT with a 3-T MRI. I had this scan in December 2011, and it showed no metastases. I understand that this scan is much more sensitive and specific than the technetium scans that have been the workhorse for detection of bone metastases detection over the years.

    These scans are relevant in at least two ways to the success of radiation. They can with high confidence, which was not possible in the past using technetium scans, stratify patients for success results into groups of men with high-risk cases who do not have bone metastases, who have some bone metastases, or who have a heavy burden of bone metastases. These scans can also identify men with a few (five or fewer) bone metasztases that are targetable with radiation with curative intent. (At least we think so at this point; this is the “oligometastatic” prostate cancer concept.)

    Similarly, highly accurate and precise imaging for lymph node metastasis has now emerged. The [11C]choline PET, [11C]acetate PET, and feraheme USPIO 3-T MRI scans all appear to be able to detect very small metastases in lymph nodes with very high reliability. The feraheme scan I had is considered to be able to detect metasases as small as 2 mm, or even perhaps 1 mm, though research is now in process and not yet published. While even smaller metastases could exist and contain millions of cells, it seems unlikely that many such micrometastases would occur without growing large enough to be detected. In other words, it is reasonable that scan results would identify all of the existing mets in most cases.

    As with bone metastases, these lymph node scans can stratify patients and can also be used to target metastases with curative intent in many patients, we think.

  16. Dear Jim:

    While we are certainly getting better at using innovative imaging technology, I would just note that: (a) all of the tests you describe still come with significant risk for false negatives and false positives; (b) the number of centers that have access to and can use such technology with reasonable accuracy is still tiny; (c) the number of uro-radiologists who have the skill to readc these scans is minute; and (d) if we are to be able to afford to use this technology for those who would really benefit, we’d better find a way to stop wasting millions of dollars a year over-treating all the men who have low-risk disease (unless you think everyone should pay for these scans themselves).

  17. Sitemaster:

    Thank you for your response to my post. I apologize for my emotional outburst directed against androgen deprivation therapy. For the record, I would not wish the side effects on anyone, friend or foe. I agree that some men might benefit from ADT. However, some might not. I do not do research, and I do not always believe statistics. However, I do think it is irrational, if not unethical, to impose dogmatically on an individual patient a treatment like ADT which is controversial and has significant adverse effects .

  18. Jim,

    Just so it’s clear to our listening audience here, my primary therapy was RP. EBRT using the WPRT method was adjuvant as was my 2+ year stint on HT. WPRT in my case is defined as IMRT to the prostate bed and the surrounding lymph nodes.

    Just a side note for the estradiol patches. Some of the guys I know that went that route had “minor” doses of radiation applied to the breast area. This stopped development of gynecomastia and also, according to the guys, they had limited breast soreness.

  19. @mmhj:

    You appear to miss the fact that no one is forcing you or anyone else to undergo ADT. The decision is totally up to each man. There is no dogmatic enforcement — a man can say no!!!! Moreover, he can accept the alternative and enjoy QoL until the side effects of prostate cancer triumph.

    Having said that, I agree that many physicians do a poor job of explaining the potential side effects of HT. … There again, every man responds differently.

    My own response at UCSF was to initiate a pamphlet endorsed by nationally reknowned doctors Peter Carroll and Mack Roach. They both acknowledged that many doctors are deficient when placing men on HT. The pamphlet may be helpful and can be found if you click here.

    It often baffles me that men complain bitterly about HT without acknowledging they are here to do so. In my own case, I spent 2+ years on HT, and suffered from and still endure side effects 3 years later. But, … I much prefer these co-morbidities to the alternative. Prostate cancer is an unpleasant and very painful death. So if we can stave off the ultimate solution with HT while there is no other easily available alternative, I propose we quit bitching about hormone therapy and be grateful we are still alive.

  20. Dear Rick (and Dr. H):

    In Dr. H’s defense, I do think one of the problems is that many physicians start a lot of patients on androgen deprivation therapy in a relatively thoughtless manner, without doing things like checking PSA doubling times or really considering how long the patients may actually need to be on this type of therapy (let alone helping the patients to understand the potential consequences or making sure that they know there are things that can be done to minimize side effects).

    Many patients have no idea what they are getting into when they are started on ADT, and so when they become more educated they become (understandably) upset and even angry that they weren’t given the appropriate information at the time that the potential need for ADT was first brought up.

    Over-treatment with ADT is arguably as prevalent as the over-treatment of low-risk prostate cancer (in relative terms). When seen from that perspective. Dr. H does, I think, have a point.

  21. I certainly agree with you, Mike, that all too frequently doctors place men on ADT without fully explaining the consequences; I am a huge advocate of that position and made that very point originally. I am not so certain about over-treatment, if we exclude short-term ADT pre-radiation.

    Notwithstanding, there is some degree of responsibility on the part of the patient to inform himself as to consequences of treatment. One of the reasons UCSF came up with the pamphlet was to make that task easier.

    But the bottom line for me is that ADT does extend life — we know this from a multitude of clinical tests. While it usually compromises quality of life, that has to be better than death from prostate cancer for the vast majority of men.

  22. Dear Rick:

    I am curious as to the data that you think show clearly that ADT extends overall survival in any situation except when combined with radiation therapy for management of locally advanced disease.

    The only large, randomized clinical trial to show that early use of ADT offers a survival benefit when compared to a delayed ADT when not combined with radiation therapy that I am aware of is the MRC trial conducted in the 1990s, and there is still a great deal of controversy about whether any form of ADT really increases overall survival (although there is no question at all that it improves quality of life for men with metastatic disease by palliating bone pain). The fundamental question today — as I understand it — is which patients really benefit from the early use of ADT. A lot of specialists consider that benefit is limited to those with PSA doubling times of under 12 months.

    There is most certainly a strong argument that early initiation of ADT (i.e., on biochemical progression of men with a rising PSA only) may well be highly inappropriate for patients with a PSA doubling time of > 18 months because it offers minimal or no survival benefit and it most certainly will come with significant quality of life problems and with the potential risk for accelerated onset of castration resistance.

  23. Thank you, Sitemaster for your kind words. In fact, my radiation oncologist insisted dogmatically that I have two years of ADT. We parted company. As Rick D. says, a man can say no. Fortunately, my urologist was more compassionate, and we agreed that I could come off the stuff after a year. My PSA was 0.01 a year later. If it goes up again (and it certainly may), then we will have a discussion.

    Rick D. reminds me of the Army Sergeants when I did a little training with them: we volunteered to be there, so quit complaining! Or the cardiologists who insist that patients have an LDL of less than 70 even if the statins make their legs so weak they can no longer do moderate exercise (yes, that does happen). But I will stick to my guns in believing that I did the right thing for myself.

    I relied heavily on the ACR Appropriateness Criteria in making my decision. I am not sure I can accept the assumption that the alternative to long-term ADT is certain death from prostate cancer. I don’t feel like I am on the brink of my demise. And, like Rick D., I enjoy my life and appreciate it much more after my experiences with prostate cancer.

    Rick D. did what he believed was best for himself. So did I. Each of us is convinced he did the right thing. And, indeed, each of us did.

    Now, if someone can come up with cure for being old and grumpy and opinionated, I might risk the side effects to try it.

  24. SOME ADDITIONAL DETAILS OF STUDY FROM COMPLETE PAPER (FIRST CUT AT THIS)

    I now have the complete paper, which has many interesting and relevant details that are not included in the abstract. I’ve had time to study part of this 8=page paper, and here are some of these details.

    GLEASON SCORE DISTRIBUTION: The detail I find most interesting is the far heavier proportion of men with high Gleason scores of 8-10 in the long-term ADT group (LTAD). The other two groups are None (no ADT) and STAD (short-term ADT). In the None group, 40% of the patients had Gleason 8-10 cancer; in the STAD group, 51% had Gleason 8-10 cancer; and in the LTAD group 81% had Gleason 8-10 cancer. Moreover, for each group, the proportion with Gleason 9-10 cancer was similarly distributed: 19% for None; 26% for STAD; and 45% for LTAD. Yet the LTAD (long-term ADT) group consistently did better than the other two groups over the various success measures.

    PELVIC RADIATION: The abstract did not cover this, but substantial “elective” pelvic radiation was typical in all three groups. Virtually all the LTAD patients had pelvic RT (99%), while 77% of the None group and 89% of the STAD group had pelvic RT. Therefore, it appears that a somewhat disproportionately heavier use of pelvic RT in the STAD group, and especially the LTAD group, somewhat confounds the results. In other words, some of the success of the LTAD group is likely due to pelvic radiation independent of ADT. The dose of pelvic radiation routinely used ranged from 45 to 50.4 Gy. (I got 46 Gy, so I’m thinking this is a modern dosing range.)

    STUDY POPULATION: 234 patients with high-risk (NCCN criteria) prostate cancer were treated between 1998 and 2008 at the University of Michigan, either with 3D-CRT or IMRT. The None group was comprised of 48 patients, the STAD group of 84 patients, and the LTAD group of 102 patients. Follow-up was 78 months for the None group, 74 months for the STAD group, and 47 months for the LTAD group, with interquartile ranges of 49-118, 36-113, and 32-77 respectively.

    BIOCHEMICAL FAILURE: The Phoenix definition was used.

    TYPE OF ADT: The paper states that ADT consisted of either an “LHRH-analog”, which would have been an LHRH receptor agonist at that time, or combined blockade with the addition of an antiandrogen. However, as far as I’ve read, including the Treatment section, there is no breakout of how many patients got which treatment.

    LENGTH OF ADT: The duration of ADT was 6.1 months for the STAD group with an inter-quartile range of 4.3-6.4 months. The duration of ADT was 25.6 months for the LTAD group with an inter-quartile range of 24.0-28.8 months.

    TYPE OF RADIATION: Image guidance was emerging during this period. It was used for 6% of the None group, 19% of the STAD group, and 38% of the LTAD group. In my view, the disproportionate use of IGRT likely accounts for some of the superior success experienced by the LTAD group.

    IMRT, as contrasted with 3D-CRT, was used for 4% of the None group, 15% of the STAD group, and 41% of the LTAD group. In my view, the disproportionate use of IMRT likely accounts for some of the superior success experienced by the LTAD group.

    COMBINATION OF CONFOUNDING ADVANTAGES FAVORING THE LTAD GROUP: It seems reasonable that some of the superior success enjoyed by the LTAD group is based on the combination of what are considered advances in RT: pelvic radiation, use of IGRT, and use of IMRT.

    I have not mentioned other details that some of us will find of interest, such as a full breakdown of staging characteristics as well as co-morbididy (~ equal among the groups).

    MY TENTATIVE TAKE: Whatever caused the superior performance of the LTAD group, I’m still quite impressed that this group, with its much higher proportions of patients with Gleason 8-10 and Gleason 9-10 disease, did markedly better than the None and STAD groups!

  25. We could drive a London bus through your exception, Mike … I was thinking of several trials showing that ADT in conjunction with radiation shows improved survival, since this is the circumstance under which most men are introduced to HT, either as primary treatment for high-risk disease, or adjuvant or salvage reasons after surgery.

    We should also consider men who are considered unsuitable or ineligible for primary radiation or surgery because their cancer is too advanced at diagnosis; they receive ADT off the bat; I doubt whether there could ever be a trial in such cases — it would be unethical since right now there are really no other alternatives for these men … although I suppose they could get some form of immunotherapy alone.

    I suspect there are very few men with low- or intermediate-risk disease who receive HT alone as primary treatment; also very few with low- or intermediate-risk disease who have surgery plus adjuvant HT without radiation. I don’t have statistics — maybe you do in your records.

    The studies suggest that if radiation is prescribed, then men with intermediate- and high-risk disease initially, or adjuvant/salvage cases will benefit from receiving HT for some term — from 4 months upto 3 years — in conjunction with radiation, without regard to their PSA doubling times or level.

    I am not sure which study you have in mind that suggests that HT is redundant for men with doubling times > 18 months, and under what treatment circumstances this was conducted?

  26. Dear Rick:

    First, the issue of who should or should not get long-term, short-term or indeed any ADT in combination with radiation therapy unless they have high-risk disease is still an open question. There isn’t even any agreement within the specialist radiation ocnology community. There have been multiple trials based around this question and to date there are still questions. Please remember that the men in the original Bolla et al. trial that showed a survival benefit all had very definitive high-risk, locally advanced disease. They are the only group for whom there is a definitive survival benefit. The other unresolved question is whether immediate adjunct radiation + ADT for patients at risk after first-line surgery is any better or worse than the use of salvage radiation + ADT.

    Second, I suspect you would be amazed how many older men who get first-line radiation therapy and then have a rising PSA get immediate ADT regardless of their PSA doubling time despite extensive data from Antonarakis et al. that clearly demonstrate that most men like this with a PSA doubling time of > 15 months (after any form of first-line therapy) never go on to have metastasis within a 12-year follow-up period. My suspicion has long been that many men with PSA bounces after first-line radiation therapy often end up on unnecessary ADT before it is clear whether they are just having a PSA bounce.

    Go have a chat with Peter Caroll. I believe he will confirm for you that there is a growing realization that overly early use of ADT in men with a long PSA doubling time is associated with all sorts of avoidable problems — from osteoporesis and fractures to cardiovascular events — and with minimal (if any) benefical impact on prostate cancer-specific survival.

  27. Thanks Mike. I was not aware that many older men receive ADT indiscriminately after first-line radiation,

    Clearly the bounce should be taken into account, especially for those men with a 4 in their Gleason score numbers who may have received neo-adjuvant HT.

    I would be interested to learn how many men receive ADT before unequivocally indicated.

  28. Rick:

    I don’t think anyone has a clue how many men get treated this way, but it is a lot. This is the classic issue of a “managing” a patient’s PSA as opposed to managing his clinical condition. And the patients are often complicit because they worry about tiny changes in their PSA level as opposed to the long-trem implications.

  29. SOME CLUES IN PAPER ABOUT RADIATION PLUS ADT FOR MEN AT LOWER RISK (BENEFIT NOT APPARENT HERE)

    (additional details of complete 2013 paper by Feng et al. — my second cut at details)

    Sitemaster has made the key point here at least twice that, while there is some good evidence for using ADT in support of radiation for men at high risk, evidence for ADT for men at intermediate- and low-risk is sketchy, and this has resonated (response of 4/11 8:59 am to Tony Crispino; George Berger response of 4/12 7:00 am re ADT for locally advanced being an open question; Sitemaster of 4/13 8:50 pm to Rick).

    Now there were no low- or even intermediate-risk patients in this study — all met the NCCN criteria for high-risk disease. However, the complete paper has some very interesting facts that bear on the issue. The key fact is that Gleason score dwarfed other features of advanced disease. Indeed, it overshadowed those features like a high rise building set in a neighborhood of two- and three-story homes. Table 2, which displays data from “Fine and Gray’s” multivariate models, shows this clearly (though some of the fine points are over my head). What I see clearly is that Gleason score 9-10 has a hazard ratio of 12.1 for metastasis, with Gleason 8 limping behind at 2.3, but no other factor even coming remotely close except PSA at 2.7 for biochemical failure.

    The same point is evident in Figures 1 (left column) and 2 (right column), which show failure curves to 10 years for all high-risk men and then separately for the subset of high-risk men with Gleason 8-10. The columns contain separate graphs for biochemical failure, metastasis, prostate cancer death, non-prostate cancer death, and all-cause death. It is quite clear that, for the Gleason 8-10 column, the ADT group (really a proxy for ADT, pelvic radiation, IGRT for a substantial portion, and IMRT for a substantial portion, as described in one of my previous posts) does substantially, even strikingly better than the “No ADT” group. It was evident that the Gleason 8-10 patients were accounting for most of the differences that appeared in the left column, the one that included all high-risk men regardless of a Gleason of 8-10.

    Therefore, I took a look at what the left-hand column would look like with the Gleason 8-10 patients pulled out. This should give us a glimpse of how truly low- and intermediate-risk men would fare; naturally, we would expect them to do better than the men in the left-hand column after exclusion of men with Gleasons 8-10. All these men were still “high-risk,” but not because of Gleason 8-10 disease.

    What I did was this: Knowing there were 234 men in the left column (all), and 143 of these men in the right column (GS 8-10), I took the failure percentages at 5 years, stated in the paper except for non-prostate death for the high Gleason group (but reasonably clear from the graph), and multiplied by the group count to get the numbers of failures. I then subtracted the failures in the high Gleason column from the failures in the all high-risk column, which produced the number of failures for men who did not have Gleason scores of 8-10, and I divided these numbers of failures by the total of 89 men in the all-risk column, the total for men who did not have high Gleason disease.

    The bottom line: for men without Gleason 8-10 disease, success across all criteria is substantially greater than for men with Gleason 8-10 disease whether the latter got ADT or not. Moreover, failures using all five criteria (PSA, metastases, prostate cancer-specific death, non-prostate cancer-specific death, and all-cause death) are few, and the differences in the percentages of failures for those using ADT or not are small. (That said, the numbers of failures are very small also, so, while this look provides some interesting evidence, it is very weak evidence.)

    Specifics:

    PSA failure: 11% failure (n = 10) for the No ADT group (versus 56% for high Gleason No-ADT), compared with 20% failure (n = 18) for the ADT group (versus 36% failure for high Gleason). (By this small, weak piece of evidence, No ADT looks better for men without Gleason 8-10 disease.)

    Metastases: 10% failure (n = 9) for the ADT group (versus 50% for high Gleason No-ADT), compared with 4% failure (n = 4) for the ADT group (versus 18% failure for the high Gleason group).

    Prostate cancer mortality: 4% failure for both the No ADT and the ADT groups (n = 4 for each) (versus 23% for the No ADT high Gleason group and 10% for the ADT high Gleason group).

    Non-prostate cancer mortality: 3% for the No ADT group (n = 3) (versus 11% for the high Gleason No ADT group), compared with 7% failure for the ADT group (n = 6) (versus 14% failure for the high Gleason ADT group).

    All-cause mortality: 6% for the No ADT group (n = 5) (versus 27% for the high Gleason No ADT group), compared with 11% failure for the ADT group (n = 11) (versus 21% failure for the high Gleason ADT group.

    I suspect there is some “selection bias” at work in the non-prostate cancer and the all-cause mortality figures, with sicker men tending to get the combo of ADT and other features.

  30. Ummm … Jim, I think that you are hunting for worms in what was already a retrospective analysis. I doubt if any of these data have any statistical significance at all.

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