Adding radiation increases survival vs. lifelong hormone therapy alone in high-risk men


Long-term follow-up of a Scandinavian randomized clinical trial has confirmed the survival benefit of adding external beam radiation to permanent ADT in high-risk prostate cancer patients.

Fossa et al. report the 15-year mortality rates on 875 mostly (90 percent) high-risk patients who were randomized to receive either lifelong anti-androgen therapy or 70 Gy of external beam radiation in addition to lifelong anti-androgen therapy.

After a median 12 years of follow-up:

  • 15-year prostate cancer-specific mortality was 17 percent in those who received radiation compared to 34 percent in those who only got the anti-androgens.
  • Median overall survival increased by 2.4 years in those receiving radiation and the anti-androgen therapy.

We’ve seen a similar benefit in another randomized clinical trial. Mason et al. last year reported the outcomes on 1,205 high-risk patients treated in the UK and Canada with either lifelong androgen deprivation therapy (ADT) or 64 to 69 Gy of external beam radiation in addition to lifelong ADT.

In that trial, after 8 years of median follow-up:

  • Overall survival was improved by 30 percent in those who also received radiation.
  • Prostate cancer-specific mortality was reduced by 54 percent in those who also received radiation.

Both of these studies used radiation levels considered too low by today’s standards. Also, the current standard of care would limit the duration of hormone therapy to 3 years or less. While there is nothing surprising in either study, it is nevertheless gratifying to get this confirmatory highest-level evidence.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

14 Responses

  1. Suspect Inadequate ADT Contributed In Part to Poor Showing for Endocrine Therapy Arm

    Thanks for reporting this study, but the devil is often in the details, and that is likely the case here.

    As a 17th year survivor of once life-threatening prostate cancer that was treated for 13 years by ADT3 (plus supporting drugs and tactics), I have paid close attention to ADT research.

    Look at the very weak form of endocrine therapy (so called because it was mainly not ADT but rather anti-androgen therapy). Here is how the authors described it: “From 1996 to 2002, 875 Scandinavian patients with high-risk (90%) or intermediate PCa were randomized to ET or ET + RAD (The Scandinavian Prostate Cancer Group-7). After 3 mo with total androgen blockade in all patients, all individuals continued lifelong antiandrogen monotherapy. Those randomized to ET + RAD started prostate radiotherapy (70Gy) at 3 mo.”

    Those of us who have depended on ADT for challenging cases cringe when we see that kind of approach, though the danger was not clear at the time of this study. Now it is clear that 3 months of “total” androgen blockade” — likely an LHRH agonist plus an antiandrogen — is not anywhere near long enough to have much of a long-term benefit. Research has also proven that depending on an antiandrogen alone (such as flutamide, bicalutamide, and nilutamide) in the era of the study (not recently approved and potent enzalutamide/Xtandi) was not that effective in controlling challenging cancer, though it might have been quite enough for men with milder cases, with the benefit of a better side-effect profile.

    The men in this study were high risk. I’m convinced they would have done better had they been on an LHRH agonist plus an antiandrogen intermittently long term as needed to achieve PSA control, and even better if a 5-alpha-reductase inhibitor drug (finasteride or dutasteride) had been added to the mix. I acknowledge that the research backing that position, though supportive and persuasive to many of us, is not top quality evidence.

    All that said, I believe that the combination of radiation plus ADT is better for high-risk men than endocrine therapy alone, especially just basically older generation antiandrogen therapy, which was the conclusion reached by the authors.

    Incidentally, today I learned that my latest PSA, at the 3-year point from an attempt at curative radiation in 2013, remained at less than 0.05! Looking good, and thanks to sophisticated ADT for giving me time for technology to give me a shot at a cure!

  2. Standard of Care for ADT

    Hi Allen,

    You wrote: “Both of these studies used radiation levels considered too low by today’s standards. Also, the current standard of care would limit the duration of hormone therapy to 3 years or less.”

    Did you mean the standard of care for using ADT in support of radiation for high-risk men?

  3. As I wrote, the Scandinavian study used lifelong anti-androgen with the radiation. The UK/Canadian study used lifelong “total androgen blockade” with any of a variety of anti-androgens plus a GnRH agonist. As you can see, mortality was cut in half in both cases by the addition of even this low level of radiation.

    Jim, I’m very happy that the therapy you used worked for you, but there is no way to sort out, based on a single case, what worked and what didn’t. That’s why we do studies and do not rely on anecdotes. I don’t know who you mean by “many of us.” Very few doctors add a 5ARi because the best data we have shows it adds nothing. There is some interest in using an adjuvant anti-androgen rather than a GnRH agonist to reduce side effects. Others are exploring novel hormonal agents for this purpose. Which medicines the doctor uses is less important than assuring that the PSA is driven down to undetectable or nearly undetectable levels. That demonstrates that the cancer is not active and is being radio-sensitized or killed.

  4. Value of adding a 5-alpha reductase inhibitor drug (5-ARI) to other ADT

    The mechanism is very well understood as is the value, and there IS research documenting this impact, though I’ll agree the evidence is not of top quality, probably due to the reluctance of pharma trial sponsors to put the technology to the test during their periods of patent exclusivity.

    The main mechanism is that these drugs, finasteride/Proscar and dutasteride/Avodart, both of which are now available as much less expensive generics, sharply curtail conversion of testosterone to dihydrotestoserone (DHT). The key value achieved is that this curtailment sharply reduces the potency of fuel to the cancer, as DHT is far more potent as a fuel than is testosterone. A side benefit is that these drugs also reduce the blood supply to prostate tumors.

    Evidence from at least two large clinical trials indicates that these drugs are fairly effective at knocking out lower grade cancer – Gleason Grade 3 and lower (so most of Gleason score 6 cancers). While that, in itself, is not key to knocking down deadly prostate cancer, it can greatly reduce concern a man with low grade cancer and his loved ones may have that his cancer is a serious threat to his health and life.

    I use the term “many of us” because there is a substantial group of us patients who have followed the guidance of pioneering doctors who have advocated the use of 5-ARI drugs for about two decades. We encounter each other at patient conferences, at medical research conferences, at education and support group meetings, and on the internet. Based on that, and on knowledge of patient volumes at what I consider practices providing state-of-the-art hormonal therapy, I would be surprised if there are not thousands of men on such therapy in the US alone, with others throughout the world.

    You asserted: “Very few doctors add a 5ARi because the best data we have shows it adds nothing.” I am unaware of support in published research for such a statement and am aware of research supporting the benefit of adding 5-ARI drugs.

  5. Dear Jim:

    You should feel free to use whatever treatment you and your physicians want to believe in, but there is no meaningful clinical data whatsoever that demonstrates a beneficial effect of adding a 5-ARI to treatment with an LHRH agonist, an LHRH antagonist, an antiandrogen of any type, or any combination of the above. Just because you keep saying this does not make it true, however much you might like it to be. This type of treatemnt is an option that patients can consider with physicians who believe in it, but there are no data to justify it at all, and that — very simply — is why most clinicians do not do it. This is not a conspiracy. GlaxoSmithKline actually sponsored multiple trials to explore the effects of dutasteride in the treatment (as well as the prevention) of prostate cancer. Not one of those treatment trials produced a clinically meaningful effect.

  6. “Clinical” is the key term here

    If by “clinical” you mean a randomized, double-blind Phase III trial, then that is also the way I see the research that has been published.

    However, if “clinical” is taken to mean published results involving 5-ARI drugs added as you mention above to sets of patients, including where a 5-ARI drug was added as maintenance, whose treatments and outcomes were recorded and reported with diligence, then the statement goes too far. I hope to find time to back this up in a comprehensive fashion, but for the moment, here are two pertinent studies: the first was published in the prestigious, peer-reviewed Journal of Urology, while the second was in the more accepting journal — The Oncologist.

    A key point from a patient viewpoint is that the benefit of adding a 5-ARI drug to one’s treatment program can be easily and quickly tested. That’s what I did; within about two months my PSA went from leveling off around 0.6 on Lupron and Casodex to resuming a plunging downward pattern, dropping by about 50% a little after 2 months, and ending at < 0.01. The PSA response should occur quickly for those in the treatment phase, based on presentations I have seen, though it takes more time to see the effect in the maintenance phase.

    I do not see the lack of acceptance of using 5-ARIs in this role as a conspiracy. Rather, it strikes me as the inertia in physician cultures that we see time and again all over the world. It reminds me of the reluctance of Ignaz Semmelweis’s peers to accept his recommendations for preventing death from childbed fever.

  7. Mike,

    I must disagree when you say: “Not one of those 5-ARI treatment trials produced a clinically meaningful effect.” Aren’t you ignoring the prostate cancer incidence prevention results of some of these trials?

    I would agree that there are no RCTs to demonstrate that 5-ARI benefit when added to LHRH monotherapy or maximal androgen suppression. That said, today they have randomized trials that demonstrate that both Proscar and Avodart have activity against prostate cancer. Trials such as the PCPT, REDUCE, and REDEEM have shown benefit in reducing incidence and progression.

    The first thing to do is recognize that although the existing evidence is not supported by randomized clinical trials, there is enough evidence that 5-ARIs are useful in the treatment of prostate cancer. There is evidence that 5-ARIs (Proscar, Avodart) reduce the incidence of prostate cancer by some 25%. Why ignore this? Why ignore the reduction in progression?

    What is that evidence?:

    1. The PCPT trial demonstrated a 25% prostate cancer prevention benefit. The implication is that inhibiting DHT is men older than 50 can have a protective effect. Also that these inhibitors are active compounds in prostate cancer. The supposed increase in aggressive cancers, by their use has been a red herring, but several explanations seem to agree that it was an artifact finding. After 18 years those trial participants with more “aggressive disease” have not experienced a higher mortality rate.

    2. In the Dominican Republic there are several families of men born with a genetic disorder by which they do not convert testosterone to dihydrotestosterone (DHT). These men all have prostate atrophy, do not experience either BPH or prostate cancer and are capable of procreation. It is a medical fact that DHT is recognized as the androgen involved in the development of the prostate gland.

    3. Finasteride was developed by Merck to treat BPH. Since BPH and prostate cancer are two diseases that could cause a PSA elevation and those prostate conditions can and do coexist in many males, Merck promoted studies known as The Finasteride Group Study to ensure that men treated with finasteride for BPH would not be at increased risk of prostate cancer by having reduced levels of PSA. In those studies, men treated with Proscar for prostate enlargement experienced a blood serum PSA reduction of approximately 50%. There is ample evidence that this PSA reduction is related to a reduction in gland volume (maximized by 1 year of treatment) caused by cell death and reduced cell proliferation. In other words, the PSA reduction is not an artifact causing a masking effect on the measuring test, but simply an effect caused by definitive biological factors (gland volume reduction)induced by the inhibition of DHT.

    4. The use of Proscar to treat prostate cancer is not a recognized label use for this product. In spite of this, Proscar is used in hormone suppression protocols when maximal suppression is intended. It is used in intermittent androgen suppression during the off-cycle period to extend the time off medications. Drs. Leibowitz, Strum/Scholz and Bruchovsky have successfully used Proscar to effectively extend the off-cycle period.

    5. Dr. William Fair studied the use of Proscar in treating stage D prostate cancer and concluded that a decrease in serum PSA in the finasteride treatment group suggests that finasteride exerts a minor effect in patients with prostate cancer. This effect does not approach that seen with medical or surgical castration, but it is important because finasteride’s lack of toxicity.

    6. Damber and coworkers in Sweden showed that finasteride treatment decreases VEGF expression in the human prostate. Vascular endothelial growth factor (VEGF) is a potent regulatory factor of angiogenesis in human prostate tissue. Also Wang and coworkers at New York University demonstrated that the level of androgen receptor was dramatically decreased in the cells treated with finasteride.

    7. In hematuria cases caused by TURP procedures, finasteride has been proven effective in reducing or preventing the event by reducing the flow of blood to the prostate. Also in bleeding caused by radiation treatment, finasteride is effective in managing this complication. Finasteride’s action in reducing blood flow to prostate tissues indicates that the action mechanism is antiangiogenic and explains its value in promoting longer off-cycle periods in an intermittent hormonal suppression protocol.

    In summary, Proscar and Avodart have a place in the treatment of prostate cancer. These drugs are a milder form of hormone suppression and yet have an important place in this treatment. Many men on active surveillance use 5-AR inhibitors to slow down disease progression. In men with more advanced disease the major benefit is the prolongation of hormone suppression off-cycles that is an improvement in patient’s quality of life.

    In patients diagnosed with prostate cancer there is no need to double PSA when using these inhibitors. This is because these inhibitors have an effect on prostate cancer tumor cells by inducing cell death and the PSA level is a true measurement of their disease.

    References:
    1: Hagerty JA, Ginsberg PC, Harmon JD, Harkaway RC. Pretreatment with finasteride decreases perioperative bleeding associated with transurethral resection of the prostate. Urology. 2000 May;55(5):684-9. PMID: 10792079

    2: Foley SJ, Soloman LZ, Wedderburn AW, Kashif KM, Summerton D, Basketter V, Holmes SA. A prospective study of the natural history of hematuria associated with benign prostatic hyperplasia and the effect of finasteride. J Urol. 2000 Feb;163(2):496-8. PMID: 10647664

    3: Lekas E, Bergh A, Damber JE. Effects of finasteride and bicalutamide on prostatic blood flow in the rat. BJU Int. 2000 May;85(7):962-5. PMID: 10792183

    4: Stewart RJ, Panigrahy D, Flynn E, Folkman J. Vascular endothelial growth factor expression and tumor angiogenesis are regulated by androgens in hormone responsive human prostate carcinoma: evidence for androgen dependent destabilization of vascular endothelial growth factor transcripts. J Urol. 2001 Feb;165(2):688-93. PMID: 11176459

    5: Haggstrom S, Bergh A, Damber JE. Vascular endothelial growth factor content in metastasizing and nonmetastasizing Dunning prostatic adenocarcinoma. Prostate. 2000 Sep 15;45(1):42-50. PMID: 10960841

    6: Levine AC, Liu XH, Greenberg PD, Eliashvili M, Schiff JD, Aaronson SA, Holland JF, Kirschenbaum A. Androgens induce the expression of vascular endothelial growth factor in human fetal prostatic fibroblasts. Endocrinology. 1998 Nov;139(11):4672-8. PMID: 9794479

    7: Sokoloff MH, Chung LW. Targeting angiogenic pathways involving tumor-stromal interaction to treat advanced human prostate cancer. Cancer Metastasis Rev. 1998-99;17(4):307-15. Review. PMID: 10453273

    8: Matsushima H, Goto T, Hosaka Y, Kitamura T, Kawabe K. Correlation between proliferation, apoptosis, and angiogenesis in prostate carcinoma and their relation to androgen ablation. Cancer. 1999 Apr 15;85(:1822-7. PMID: 10223578

    9: Mukherjee P, Sotnikov AV, Mangian HJ, Zhou JR, Visek WJ, Clinton SK. Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor expression. J Natl Cancer Inst. 1999 Mar 17;91(6):512-23. PMID: 10088621

    10: Joseph IB, Nelson JB, Denmeade SR, Isaacs JT. Androgens regulate vascular endothelial growth factor content in normal and malignant prostatic tissue. Clin Cancer Res. 1997 Dec;3(12 Pt 1):2507-11. PMID: 9815654

    11: Rittmaster RS, Norman RW, Thomas LN, Rowden G. Evidence for atrophy and apoptosis in the prostates of men given finasteride. J Clin Endocrinol Metab. 1996 Feb;81(2):814-9. PMID: 8636309

  8. Dear Jim:

    We have had this conversation 40 times before already. I would settle for any clearly positive data from any well-conducted, randomized trial. There are no such data. And just to be clear, one of the two papers you reference below excluded any patients who were receiving a 5-ARI. You keep pointing to the same paper over and over again. The data in that paper are from a retrospective analysis of a very highly selected group of patients, treated by a physician group who were convinced that such treatment is beneficial. And let me be very clear all over again. I am not saying that no patients would benefit from this type of treatment. I am saying that there is no indication that most patients would benefit from this type of treatment, and (as far as I can tell) we have no way to identify the one’s who would with accuracy.

    Please don’t try to “back this up in a comprehensive fashion” all over again. You can’t because there are no good data to support your premise, which is why most clinicians don’t use the treatment strategy you are advocating for.

  9. Dear Ralph:

    I was extremely careful in what I wrote, which was, “there is no meaningful clinical data whatsoever that demonstrates a beneficial effect of adding a 5-ARI to treatment with an LHRH agonist, an LHRH antagonist, an antiandrogen of any type, or any combination of the above. The use of 5-ARIs in monotherapy as preventive agents is an entirely separate issue. And I feel obliged to point out that “managing PSA levels” with a 5-ARI and proving some form of beneficial therapeutic effect are radically different issues.

    I know of no data as yet showing that men on active surveillance who take a 5-ARI are any more or less likely to have disease progression and need treatment over the next 10 or 20 years than men who don’t take a 5-ARI. That was a trial that GlaxoSnmithKline actually carried out many years ago. They have never reported any results, which suggests to me that there were no positive results.

  10. Ralph,

    Thanks for your outstanding post with so much good information and references. Bravo!

    One minor issue: you had a sentence that read in part — “… to ensure that men treated with finasteride for BPH would not be at increased risk of prostate cancer by having reduced levels of PSA.” Did you mean to put DHT instead of PSA?

  11. Thanks Sitemaster.

    You wrote in reply at 5:31 on May 14 to my post:

    “And just to be clear, one of the two papers you reference below excluded any patients who were receiving a 5-ARI.” I’m sorry for including that reference, which excluded such patients, as you stated, in order to include them in another study. I appreciate your effort to check it.

    Here is the citation for that other study, which, while small and of a hypothesis-generating nature, showed a doubling of the time off therapy in the group that used finasteride as maintenance during the off-therapy period (31 months versus 15.8 months).

  12. Jim,

    In men treated for BPH with Proscar, Merck wanted to ensure that a lower PSA measurement would not mask occult prostate cancer in these men. That is why they recommended to double PSA results in such men. This has caused years of confusion when applied to men with a positive prostate cancer diagnosis when treated with Proscar (or Avodart). No need to double PSA results in such men.

    Mike,

    I know that your statement was extremely accurate. I just wanted to add information for those that might be contemplating maximal androgen suppression. Some out-of-the-box thinking doctors reported a benefit.

  13. Trying to Understand Anti-5-ARI Mindset

    In the context of the preceding discussion, I have been and continue to try to understand the viewpoint, the mindset of researchers and physicians who oppose the use of finasteride and dutasteride to counter prostate cancer. There are several key points.

    Importance of DHT: I am convinced that the vast majority of informed physicians and researchers involved with prostate cancer recognize that dihydrotestosterone (DHT) is a far more potent fuel for the cancer than is testosterone. Is there any serious challenge to that these days? (I know that Dr. Patrick Walsh’s viewpoint was ambiguous, at least in the past and perhaps today, but he is, of course, a surgeon, and not an oncologist, the field that is generally a lot more savvy about drug issues.)

    Role of finasteride and dutasteride in reducing DHT: I am equally convinced there is no dispute that these 5-alpha-reductase inhibitor drugs sharply reduce DHT by sharply reducing the conversion of testosterone to DHT. Any disagreement there?

    Therefore, does it not follow that 5-ARI drugs might reduce the danger from at least that major form of dangerous prostate cancer that is fueled by androgens? I see no reason for disputing this hypothetical statement.

    Awareness of enthusiasm for 5-ARI drugs in some practices. There should be awareness among oncologists treating prostate cancer that a number of prominent medical practices in the US dedicated to treating prostate cancer, known for working with a large proportion of advanced cases, have been enthusiastic about the success of including 5-ARI drugs in their hormonal therapy approaches. My contacts with researchers at various medical researcher meetings (as a survivor representative), with researchers and physicians at FDA hearings, with physician presenters at Us Too meetings, and at patient oriented conferences suggest that physicians and researchers involved with prostate cancer are mostly aware of that enthusiasm, though most of them seem not to use 5-ARI drugs themselves for prostate cancer because of the absence of top quality evidence and the limited amount of other published evidence, which is a reasonable position.

    So why has there been no push to research the effectiveness of 5-ARI drugs as part of an anti-prostate cancer treatment program? This is what amazes me. I can understand a pharmaceutical manufacturer of an LHRH agonist or an antiandrogen being reluctant to sponsor a trial for a drug that looked like it could cut product demand by substantially increasing the vacation period from LHRH agonist and/or anti-androgen use as part of intermittent ADT therapy. But why haven’t research oriented physicians and PhDs seen value in putting 5-ARI drugs to the test? It is clear that they have not. I am aware of a proposal to do so from the Strum, Scholz, and colleagues team that was rejected about two decades ago. I am aware of some research on a combination of an antiandrogen with a 5-ARI drug. I am aware of Dr. Oliver Sartor’s attempted trial of a very disadvantageous use of 5-ARI drugs that fell far short of its recruitment requirement and essentially failed as a trial.

    I am unaware of any other attempt. Ralph, Sitemaster, fellow participants here, I would appreciate your input in understanding the failure to put 5-ARI drugs to the test as part of an ADT program.

  14. Dear Jim:

    The way you frame the question betrays your misunderstanding of the problem you think you are seeing.

    The problem is not an “Anti-5ARI Mindset” at all. The problem is that every time any real researchers have tried to study the possibilities that you think you see, they have got a negative result, and no one has given any potential funder a compelling reason to study this issue (except when it was of interest to the drug companies).

    I will also tell you that some of your enthusiastic, “prominent medical practices” are not exactly viewed by the medical research community with a high degree of favor for a range of historical reasons.

    The bottom line is very simple. Most basic researchers and most high status clinical researchers aren’t going to put in the time to develop grant requests for grants to study something that is highly unlikely to get funded. Getting an research grants today is hard enough. Getting a grant to study an “offbeat” idea is near to impossible. And the patients like you who have been sitting on panels at meetings such as the DoD Prostate Cancer Research Program clearly haven’t been able to put forward a sufficiently compelling reason to study this either.

    Quite simply, without a truly compelling argument to justify this research, no one is going to pursue it. This is a fact of life. The best possible chance was probably nearly 20 years ago, when Dr. Strum first started to propose this hypothesis. … For whatever reason (and I can think of quite a few) he wasn’t able to convince anyone to back his idea.

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