5-ARIs and prostate cancer risk: one step forward; one step back


As is so often the case in medicine, data suggesting a positive finding from one study comes out at about the same time as data demonstrating exactly the opposite … and in prostate cancer this occurs all too frequently!

So the other day we reported from the Geniturinary Cancers Symposium that, at more than  10 years of follow-up,  there was no significant increase in the risk of death from prostate cancer among men who were treated with the 5α-reductase inhibitor (5-ARI) finasteride during the Prostate Cancer Prevention Trial.

By contrast, another study (by Murtola et al.), published recently in The Prostate, reports a very different set of findings.

Murtola et al. explored data on the tumor characteristics, risk of biochemical recurrence, and mortality after radical prostatectomy in 1,315 men, all of whom were diagnosed with localized prostate cancer and given a radical prostatectomy at a single, respected institution in Finland between 1995 and 2009. All of these patients had used 5-ARIs (e.g., finasteride, dutasteride) and α-blockers (e.g., terazosin, tamulosin) to manage urinary tract issues.

Among these 1,315 men, biochemical relapse after radical prostatectomy was defined by a serum PSA level ≥ 0.2 ng/ml, and information on patient mortality and medication purchases could be obtained from Finnish national registries.

Here is what the authors report:

  • The probability of a finding of high-grade tumors at surgery (Gleason score,  7 to 10) was
    • 83.3 percent among men who had used 5-ARIs for ≥ 4 years
    • 53.3 percent among non-users of 5-ARIs
    • This difference was statistically significant
  • Survival curves for biochemical relapse-free survival differed between long-term and short-term users of 5-ARI, but the hazard ratio remained statistically non-significant.
  • The risk for biochemical recurrence was also elevated among users of α-blockers (HR = 1.68).
    • This increase was only evident in men using α-blockers after prostatectomy.
    • An increased risk for mortality was not associated with α-blocker usage.

Murtola et al. conclude that (in this patient cohort) the long-term users of finasteride or dutasteride were at greater risk for high-grade prostate cancer and potentially were less likely to demonstrate progression-free survival. They also argue that the association between risk of biochemical recurrence and post-operative use of α-blockers suggests that urinary voiding or symptoms associated with urinary storage after prostatectomy may predict biochemical relapse.

Neither the study by Goodman et al. reported last week nor this study by Murtola et al. can be considered to offer definitive evidence on the risks of using 5-ARIs to prevent prostate cancer. It is clear that there are some risks. What is not clear is whether those risk levels are sufficiently low to justify the use of 5-ARIs in reduction of the risk for a diagnosis of prostate cancer (which does definitely occur) — at least in selected high-risk men.

39 Responses

  1. So very hard to know who and what to believe. Hopkins is second author and they do so so love that surgery.

  2. FINDING EXPLAINED BY SELECTION BIAS?

    While all of these patients evidently used either a 5-ARI drug or an alpha blocker or both, it is clear that not all used a 5-ARI drug. The abstract of the study does not state the numbers in the users versus non-users group for 5-ARI use. I suspect that selection bias is responsible for the main finding of a substantially higher number of Gleason 7-10 tumors among the 5-ARI users. In other words, it could be that unsuspected cancer that was aggressive enough to cause urinary symptoms is motivating a substantial portion of these Finnish men to use finasteride, in addition to those using it simply because they truly have BPH but also unsuspected cancer that is not causing urinary symptoms.

    I’m wondering if there is a way to analyze the data in this study to confirm or rule out selection bias as the likely culprit, or at least to point in either direction.

    Knowing that Dr. Patrick Walsh of Johns Hopkins has what I consider a strong bias against 5-ARI drugs, I checked Dr. Murtola’s papers in PubMed (www.pubmed.gov) to see if he had co-authored papers with Dr. Walsh, as both are from Johns Hopkins. They had not co-authored any papers.

    I am a 14-year survivor of a challenging case who has been on a 5-ARI drug continuously since September 17, 2000. I have been on finasteride most of the time, but have used dutasteride more recently and found it more effective based on DHT test results.

  3. The study addresses the use of 5-ARIs “after” radical prostatectomy, or I am wrong? What’s the way to determine a Gleason score when there is no more a prostate? Or is the title and the background information misleading and the use of the 5-ARIs was before RP?

  4. What I see as significant in both studies is there is no difference in mortality in taking 5-ARI or not. I agree with Jim about a bias potential in the Finnish study. Data show that men with BPH have a greater probability for prostate cancer later in life. I’m a fan of the pills (5-ARI) because I get severe side effects from the shots. I have the best results: low PSA, high testosterone and very low DHT.

  5. I had heard about the Goodman results at our last SWOG conference call and was encouraged but the Murtola paper takes the wind out of that sail. I think it’s quite clear to me that a 5-ARI is best used for BPH and not fighting prostate cancer.

  6. Gunterman:

    The title and background are not misleading, but you do appear to be misunderstanding the information. Most of the use of the alpha-blockers appears to have occurred after surgery; the use of the 5-ARIs appears to have occurred before and after surgery. However, since I haven’t seen the full text of the paper, I can’t tell you precisely to what degree. However, the vast majority of the use of 5-ARIs would normally occur in men who had not yet had a radical prostatectomy.

    Finally, you can only determine a Gleason score if there is cancerous tissue available to biopsy. There may still be cancerous tissue remaining after a radical prostatectomy if it was impossible to remove all of the cancer. In an ideal world, all of the cancer is removed at surgery and so the final Gleason score can only be determined based on the pathologicial examination of the tissue removed at surgery.

  7. Tony:

    My suspicion is that Dr. Thompson would have a very different “take” on the Murtola paper, but I don’t have sufficient detailed information to be able make a cogent argument about this at the present time. There is, however, some merit to Jim’s prior suggestion that if you only look at the data from men who decided to undergo a radical prostatectomy, there is inevitable selection bias built into the Murtola data. What about all the men who were diagnosed with similar-risk (and lower-risk) prostate cancers and decided not to have an RP?

  8. The information we learned from the PCPT trial told us that there was lower detection of prostate cancer but it also told us that there was higher occurrence of high-risk disease. That would seem to support the Murtola findings but as you know that’s not good science to make the connection. I will bring the Murtola paper to Nick Vogelzang when I see him later today and get the SWOG perspective. It should make for an interesting discussion. …

  9. I don’t have prostate cancer but I am probably at a high risk. My father died of prostate cancer and my PSA is in the top 5% of all men who are my age. After reading the PCPT study results, and the REDUCE study results, I consulted several very well-regarded doctors about whether I should take dutasteride or finasteride in an effort to reduce my risk of prostate cancer. I got different views. I was very tempted to do this because I would like to “do something” to reduce my risk. It always feels good to “do something” rather than “do nothing.” But ultimately I took the advice of one of the most experienced doctors at Johns Hopkins, who recommended against it. I will never know whether that was the right call, or not.

  10. Re occurrence of high-risk disease in the PCPT, mentioned by Tony at 3:04 pm

    Hi Tony,

    I have looked at that evidence of evidence of increased risk of high-grade disease in the finasteride group, and it is a shaky basis for believing that finasteride increases risk in a causal fashion (vice association). But though I have studied the key facts closely, my recollection was hazy and I have just taken another look to refresh my memory. My impression is that many of us in the community just took the ODAC advisory group finding at face value and never had or now lack a grasp of the actual facts. In short, we are now tending to exchange hazy recollections, which may have not been sound in the first place. Take a direct look at the key figures yourself. You may have ready access to the complete papers, but you can also get all key data on the FDA website under the ODAC hearing record. For a key slide, go to page 20 of 95, “Issue 1: Increased High Grade Cancer,” from the FDA background materials

    The issue centers on the 1% greater incidence of GS 7-10 cancer in the study participants who were in the finasteride arm of the study. That is in the context, as we know, of substantially reduced incidence of GS 2-6 cancer in the finasteride group. However, the increase in incidence in higher-grade disease virtually only occurred in the GS 8-10 group of the finasteride users, and there were relatively few participants in that group. (A finer grained view is that the proportion of Gleason grade 4 or higher cancer is the driver, as suggested by the split between GS 3 + 4 = 7 incidence — virtually even for GS 3 + 4 = 7 at 3.0% for finasteride [145/4775] versus 2.9% for placebo 150/5123), with GS 4 + 3 = 7 finasteride participants at 61/4775 = 1.3% versus 46/5123 = 0.9% for the placebo arm, in the context of increasingly relatively higher incidence of GS 8-10 cancers in the finasteride versus the placebo arm, though with miniscule absolute differences in incidence because the raw percentage incidences are so tiny.

    We tend to lump GS 7 disease into the high grade group, but of course GS 7 disease often has a more favorable course, and, as the numbers just cited show, GS 7 patients dominated the numbers among the GS 7 to GS 10 patients. Total GS 7 participants, 402, dwarfed the number of GS 8-10 participants at 155. (Regarding the split of GS 7 cancers, GS 3 + 4 = 7 participants at 295 for both arms outnumbered GS 4 + 3 participants at 107 by nearly three to one.) Gaining perspective on all of this from a greater distance, it is striking how small the absolute percentages are for both arms for all Gleason scores. (Mountains and mole hills?)

    There are several explanations by the leading trialists and other experts as to why there was this slightly higher absolute incidence of higher grade disease in the finasteride arm. While complementary, the explanation I find most compelling is, essentially, that by reducing the size of the prostate, finasteride created a smaller target to be covered by an equal number of biopsy probes, thereby making each probe more efficient and specifically more likely to find higher grade disease. As I recall it, one of the papers by Dr. Ian Thompson et al. makes this point about detection bias cogently.

    Another paper, providing corroborating evidence, looked at the patients in both groups who developed prostate cancer and went on to have an RP: 30.5% of placebo patients had their Gleason score increase from biopsy to RP pathology compared with 24.5% of finasteride patients, and 12.5% of placebo patients had a decrease in grade in post-RP pathology compared to 19.8% of the finasteride patients. (The greater the percentage with a decrease, the better.) Moreover, “high-grade tumors were detected after prostatectomy but missed by the initial biopsy half the time in the placebo group, compared to 29.7% of the time in the finasteride group.” That’s about 40% better performance for the finasteride group. These facts support the detection bias hypothesis.

    Your thoughts? I’m also curious what Dr. Vogelzang has to say.

  11. JOHNS HOPKINS VIEWS

    Hi Tracy.

    I’m responding to your initial post. Yes, there are some great surgery pioneers who report their research at Johns Hopkins, but, as you might expect, there are some strongly opposing views regarding 5-ARI drugs. I have personally talked to prominent researchers John Isaacs and Charles Drake, both of whom disagree with Dr. Walsh regarding 5-ARI drugs.

  12. These results look consistent with the PCPT (and REDEEM and REDUCE) trials, all of which show 5-ARIs significantly reducing low-risk cancer and having minimal effect on high-risk cancer. The low-risk cancers that were prevented by the 5-ARI use did not make it into the data set of 1,315 men diagnosed with prostate cancer. So a greater proportion of those cancers detected in 5-ARI users would obviously be high-risk. It says nothing about whether the 5-ARIs increased or decreased the absolute risk of getting high-risk cancer.

  13. Obviously, as an over 16-year ADT patient with PSA elevation within 18 months following my first IAD “without” a 5-ARI, but then no PSA elevation for 2 months short of “6 years” while maintaining with dutasteride/Avodart with my second IAD, I, as well as most medical oncologists we know who specialize “specifically” in research and treatment of recurring or advanced prostate cancer, are strong proponents of the value of a 5-ARI, with dutasteride/Avodart an advancement over the earlier finasteride/Proscar.

    I’m with you, Jim, as always.

  14. Dear Sitemaster,

    I gave you the information about the Murtola study (see your posting about “Dutasteride in the off therapy cycles of ADT”), because I felt, that your information about 5-ARIs were not very well balanced. As thanks you try me like an absolute beginner in medical paper reading.

    But anyway, your answer is it worth to be tried like a child, because you give me now an astonishing and simultaneously sensational information: “Finally, you can only determine a Gleason score if there is cancerous tissue available to biopsy. There may still be cancerous tissue remaining after a radical prostatectomy if it was impossible to remove all of the cancer.”

    You tell me, that after RP in the USA you can often execute biopsies to determine the shifting Gleason score after prostatectomy from residual prostate tissue.

    First point of your information is, there seem to be a lot of surgeons in the US who do not a good job. I never heard from the possibility to do often biopsies after a really successful RP in Europe.

    Second point: Now it’s a little bit clearer for me, why the percentage of RPs in contrast to RTs in prostate cancer therapy is smaller in US than in Europe. And also why in NCCN Guidelines 1-2013 in high-risk prostate cancer patients only RT + very long ADT (2-3 years) is the recommended therapy.

    In Europe it is absolutely intolerable to let prostate tissue back in high-risk patients, performing an RP.

    Can I bring in your interesting information in a discussion with a European RT specialist about the best practice in high-risk prostate cancer patients: Often biopsiable prostate tissue remains in high-risk patients after RP in US?

    If your explanation is right, so the sample of the Murtola study is a very special, from patients with unsuccessful and incomplete RP. So the question is, what is the primary reason for Gleason grade shifting, the 5-ARIs intake or the amount and aggressiveness of prostate tissue the surgeon let back in the patient.

  15. Dear Gunterman:

    Respectfully, I think we are having a communication (language) problem.

    I am absolutely not saying that prostate cancer tissue is “often” left behind after radical prostatectomies in the USA. I am, however, saying that when men have recurrence after a radical prostatectomy (or after radiation or any other form of local therapy for that matter) it may (or it may not) be possible to identify the site of recurrence if the recurrence is local and it may be possible to confirm that recurrence by a biopsy. As far as I am aware, the rates of recurrence of prostate cancer after first-line treatment of (apparently) localized prostate cancer by surgery or by radiation therapy are now very closely comparable between much of Europe and the USA. Furthermore, as far as I am aware, the rates of upgrading or downgrading of the Gleason score from initial biopsy (the initial, clinical Gleason score) to the post-surgical, pathological Gleason score in Europe and the US are also similar.

    You are entitled to your opinion on the Murtola study. As you will see, others have other opinions. This is very common. I appreciate you bringing the paper to my attention, but that doesn’t mean everyone is going to interpret the data the same way you do.

    Unfortunately, I am not clear what you mean by “Gleason grade shifting”. If you mean the upgrading and downgrading that occurs between biopsy and surgical treatment, I would point out that most of the time we never know whether this occurs in men who have radiation therapy or other non-surgical treatments because there is no tissue to examine after treatment (unless the patient is re-biopsied post-treatment and there is still evident cancerous tissue, which can and does occur, although I don’t have data on how frequently by treatment type).

    I would also point out that there are strong differences of opinion within Europe and even within specific European nations about the relative value of surgery and radiation therapy as first-line treatments for prostate cancer, just as there are in America. My personal view is that every patient has to be considered as an individual, and that the idea that any one form of management for localized prostate cancer is necessarily better or worse than others is unjustifiable based on the available data — which is exactly why it is so important for patients to be well-informed about their options.

  16. Yes I know I have a language problem, because I am not a native English speaker.

    I misinterpreted you and now you misinterpret me, but its my fault, because of the language, excuse me.

    Sorry, but there is nothing new for me in your statement. I am not interested in a longer discussion in this way, but I am interested in the Murtola paper. I hope there is someone who can get the original paper and give here some more substantial information.

    Some personal remarks:

    — I am not an opponent of 5 ARIs use in the prostate cancer situation. I used finasteride and dutasteride for several years and looking out do it longer or not.
    — I am very open minded in the discussion about the relative value of surgery and radiation as first-line treatments for prostate cancer, but in all risk grades.
    — I hoped it is clear, when we discussed the Murtola study, that the “Gleason grade shifting” I mentioned, is the upgrading that occurred between surgical treatment and later biopsies (if biopsies after RP may be really possible in a statistical relevant number for all Gleason scores, same prostate tissue, same volume, and so on).

  17. Dear Gunterman:

    Please let me be very clear that it is in no way “your fault” that there is a communication problem because of the language issue. It is simply a fact of life.

    I try as hard as I can to address what I think people are trying to say in languages that are not their native ones. Sometimes I just “miss” their intent, as I appear to have done in this case with you.

    I do appreciate you bringing the Murtola paper to our attention. I will see if I can get a copy. Like others, I will be interested to see whether Tony Crispino can get any feedback from Dr. Vogelzang and/or other members of the SWOG clinical trials group.

    With respect to the “Gleason grade shifting” as you describe it above, I think that one has to bear in mind that in post-surgical (and often in other post-first-line treatment biopsies too) one is not actually biopsying the prostate itself but other nearby tissues in the so-called “prostate bed” or the lymph nodes. Accurate assessment of the Gleason scores of tissues from such biopsies and comparison to Gleason scores from initial biopsies or surgical pathology specimens is of dubious value (as opposed to simply knowing that there is active cancer present in those tissues post-treatment).

  18. How depressing. Take finasteride for BPH. Don’t take. Ugh!

    Since tens of thousands of men have taken Proscar (since 1992) or Propecia (since 1997 for hair growth), shouldn’t there have been a significant and rising incidence of Gleason 8-10 cancers, more biochemical recurrences, and deaths?? Just a confused layman’s question.

  19. Dear John:

    You are not the first confused layman to ask that highly pertinent question. I think I first asked it some 10 years ago when the initial results of the PCPT trial were reported, and I asked it again to Dr. Goodman when I was looking at her poster in Orlando last week.

  20. Are low dihydrotestosterone (DHT) levels associated with better prostate cancer survival? I have seen studies that say the opposite.

    I think far more men take 5-ARIs for BPH than for prostate cancer.

    I believe that BPH is associated with lower grade prostate cancer, as opposed to men who do not have BPH.

    So now we have a group that typically gets low grade prostate cancer, getting more high grade prostate cancer.

    Something is rotten in Finland.

  21. CONSULTING ABOUT 5-ARI FOR PREVENTION

    Hi Jonathan,

    I’m responding to your post of 5:28 PM.

    As a 14th-year survivor who consulted three of Johns Hopkins doctors (urology, radiation, and medical oncology) in the first year for my challenging case, I urge you to think again about that advice you received. Whether to use a 5-ARI drug to foster prevention is something only you can decide, but I am (and others are) convinced that some of Johns Hopkins’ leading doctors, especially the surgeons, are not very familiar with finasteride or Avodart specifically (despite the assertion that Dr. Walsh has 42 years of familiarity with 5-ARI drugs) and with androgen deprivation therapy generally.

    Consider one of Dr. Walsh’s classic books on prostate cancer; while he is a legitimate standout hero for surgery, his treatment of DHT (dihydrotestosterone) is all over the map in his 2001 Guide to Surviving Prostate Cancer. While that book is very old now, I doubt he has changed his opinion regarding DHT, based on the consistency of his statements over the years and at the FDA hearing on dutasteride for prevention on December 1, 2010, at which he denigrated the role of DHT in prostate cancer, in sharp contrast to the view of many expert medical oncologists as well as prominent researchers right at Johns Hopkins. Consider page 95: “… there is no evidence that DHT is the hormone responsible for the growth of prostate cancer.” Consider page 356: “… Testosterone is transformed, by an enzyme called 5-alpha reductase, into a hormone called DHT (dihydrotestosterone) — which is more than twice as powerful as testosterone. [My comment here: That’s true, though now experts believe that DHT is 5 to 10 times more potent than testosterone as a fuel for prostate cancer.] Several studies have shown that the prostate contains less 5-alpha reductase when it is cancerous; therefore, DHT is not believed to be as important in prostate cancer as it is in the normal prostate or in BPH.” He goes on to note that DHT binds far more securely to the cancer cell fuel docking sites, and that when docked, testosterone and DHT both attach to DNA, which activates certain genes. On pages 363-364 he states: “… But in prostate cancer, testosterone is more of a villain than DHT, and finasteride does little to stop it.” These passages show an inconsistent view of DHT’s role in prostate cancer. The Winter 2012 edition, volume 8, of Prostate Cancer Discovery, a newsletter closely associated with Dr. Walsh, continues to reflect his earlier view that DHT is not as big a player as testosterone. The article goes even further, quoting Dr. Walsh’s statement that “If you are worried about dying from prostate cancer, taking a 5-alpha reductase inhibitor is the last thing you should do. These drugs do not prevent the disease, but give a false feeling of security because they lower PSA.”

    While the statement is true that 5-ARI drugs lower PSA, experts are well aware that that fact actually enhances the benefits of PSA testing. It does so because the PSA eliminated is mostly “noise” PSA (as far as cancer is concerned), stemming mainly from BPH, and elimination of that “noise” makes it much easier to observe a PSA trend line that is substantially more closely related to prostate cancer. Of course, the new baseline for observing the trend is re-established at a lower level, and old benchmarks about PSA thresholds are not very useful. But neither are they necessary, as experts grow quite concerned about the likelihood of prostate cancer if the PSA shows a substantial upward trend for patients on 5-ARI drugs. Similarly, 5-ARI drugs have been found to increase the usefulness of DRE exams. All this is supported by research. Dr. Eric Klein, a prominent urologist from the Cleveland Clinic, has provided clear explanations of these facts. (He is far from alone in sharing a conviction opposed to Dr. Walsh’s view.)

    Leading medical oncologists I have followed for years, who use 5-ARI drugs extensively as part of their programs to help prevent and to treat prostate cancer, are fully convinced that DHT is by far more dangerous than testosterone for prostate cancer. The Prostate Cancer Research Institute has some good information about this that is readily available. Dr. Laurence Klotz, arguably the leading physician/researcher expert on active surveillance, is very interested in using 5-ARI drugs for active surveillance patients.

    All this said, it appears that nutrition, exercise, and stress reduction also help reduce the risk of incurring serious prostate cancer. They should also be part of a prevention program.

  22. CONCURRING WITH RICHARD’S COMMENT OF 2/21/13 8:21 PM, AND POSSIBILITY OF 5-ARIs REDUCING RISK OF HIGH GRADE DISEASE

    Hi Richard,

    I concur with the important point you make in your post, a point that was ably made though not well appreciated at the FDA ODAC hearing of December 1, 2010. However, while the basic study results say “nothing about whether the 5-ARIs increased or decrease the absolute risk of getting high-risk cancer,” as you stated, there is at least one follow-up analysis that the data, carefully interpreted with an additional 3 months of data and follow-up for 500 PCPT patients getting prostatectomies, which suggests that 5-ARIs actually reduce (by 27%) the risk of high grade disease!

    Here’s one citation with an abstract indicating this. There may be others.

    Redman MW, Tangen CM, Goodman PJ, Lucia MS, Coltman CA Jr, Thompson IM. Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach. Cancer Prev Res (Phila). 2008 Aug;1(3):174-81. doi: 10.1158/1940-6207.CAPR-08-0092. Epub 2008 May 18. PMID: 19138953

    My impression is that the prostatectomy analysis was complex enough, including assumptions, that the resulting suggestion of lower-risk of high grade disease in the finasteride arm is far from conclusive. However, the conclusion makes good sense to me, and I would bet that further study (if only) would support the tentative conclusion. We should all ponder this: if this Redman et al study is right, then 5-ARI drugs, one of which is already generic and fairly inexpensive, deserve very serious consideration for prevention of prostate cancer. Unfortunately, I have a sinking feeling that this line of thought too was broached at the FDA meeting but stiff-armed by opponents.

  23. Jim,

    Good response.

    How do you explain the fact that the majority of studies show that low testosterone and DHT are associated with worse survival in prostate cancer?

    Also, the studies are pretty consistent that the users of 5-ARIs get more aggressive cancers than non-users.

    Doug

  24. I’m getting frustrated. I posted here yesterday with supportive remarks to Jim Waldenfels. He and I have a similar history (I’m over 20 years out and still dealing with PC), and he and I have met and discussed prostate cancer and ADT issues at length. I’ve come to recognize that Jim has extensively studied our insidious disease as have I, and I continue to back anything Jim may comment. I have a hard time understanding how much patients (and too many physicians) do not understand about treating recurring or advanced prostate cancer, and in this case, the importance of 5-ARIs when ADT becomes the treatment requirement. My opinions with loads of supporting references can be viewed here, >here, and here.

  25. 5-ARIs supresses 5α-androstane-3β,17β-diol (3ß-Adiol), which might have a protective effect on prostate cancer cell migration. For this effect see, for example, the following papers:

    Mak P, et al. ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading: “We report that a key function of ERβ and its specific ligand 5α-androstane-3β,17β-diol (3β-adiol) is to maintain an epithelial phenotype and repress mesenchymal characteristics in prostate carcinoma.”

    >Dondi D, et al. Estrogen receptor beta and the progression of prostate cancer: role of 5alpha-androstane-3beta,17beta-diol: “Here, by combining in vitro assays and in vivo imaging approaches, we analyzed the effects of 3β-Adiol on PC proliferation, migration, invasiveness, and metastasis in cultured cells and in xenografts using luciferase-labeled PC3 (PC3-Luc) cells. We found that 3β-Adiol not only inhibits PC3-Luc cell migratory properties, but also induces a broader anti-tumor phenotype by decreasing the proliferation rate, increasing cell adhesion, and reducing invasive capabilities in vitro.”

    My question is, why are these papers and conclusions unimportant in weighing out the benefits and risks of 5-ARIs?

    Could the supression of 3ß-Adiol through 5-ARIs not be an explanation for the statements of Doug?

  26. Gentlepersons:

    (1) Can we please differentiate between the effects of 5-ARIs in the potentiual prevention of prostate cancer and its use in the treatment of advanced protate cancer as one part of a 3ADT regimen? These are two very different animals.

    (2) The biological effects that can be demonstrated in vitro and in animal models (as I have said multiple times before) may or may not be relevant to what actually occurs when drugs are given to men or women. Basing one arguments for or against the use of 5-ARIs on such data is simply not compelling one way or the other bu comparison with actual clinical data.

    (3) If a few of you want to continue this discussion, can you please do it by e-mail because it is going to be of limited interest to the vast majority of readers.

  27. Doug,

    Per Sitemaster’s suggestion, I would like to respond to your questions of 2/22 4:12 PM by e-mail but do not have a way to contact you. Would you care to post your e-mail address here?

  28. I agree with Jim on the minuscule number of so-,high-risk Gleason numbers not warranting the condemnation of 5-ARI. What has not been mentioned is the good news in the study, the 25% difference in prostate cancer occurrence in comparison to the placebo group. Furthermore, Jim, I recall another factor in the study that may have caused the “high risk” tag. In the first phase (2 years), men in the placebo group that developed cancer were removed from the continuing study for treatment. This upset the statistical balance in the 5-year program. In essence, the higher risk comparisons are flawed against 5-ARI. Are you aware of this follow-up review?

  29. Hi George,

    Wishing to comply with Sitemaster’s suggestion, I’ll only say yes. That too is a good point.

  30. Pergunta-se: Qual é mais eficaz: ADT OU IADT?
    Pela hipótese que formulei: os câncros da próstata quando produzem PSA < 0,05 ng/ml enquistam. Se esta hipótese for verdadeira e que tudo indica que sim, então ADT apresenta maior longevidade que IADT. Qual a razão: Se o cãncro enquista as células não se devem multiplicar e portanto não sofrem mutações e não adquirem células independentes

  31. Dear António:

    There is no “right” answer to whether ADT is “better” that IADT or vice versa. It all depends on the individual characteristics of the patient and how he personally values quality of life as opposed to quantity of life.

    What I do think is clear today, however, is that IADT is really only as effective as it can be in those men whose PSA level drops to < 0.1 ng/ml within 6-9 months after initial treatment with androgen deprivation. Indeed, it may only be optimally effective in men whose PSA drops to < 0.1 ng/ml and whose serum testosterone level also drops to < 20 ng/dl in that first 6-9 months of ADT.

  32. Hi Antonio (and Sitemaster),

    IADT VS. ADT

    I have followed this issue fairly closely as a 14th year veteran of IADT3, now on my fourth round of ADT. I cannot read your post, but it appears you are asking about your case with a PSA now less than 0.05.

    My strong impression is that many oncologists, including some important medical societies, now favor IADT for non-metastatic patients, but with many doctors still not certain which is better, as Sitemaster indicated. My strong impression is also that there is a firm consensus among medical oncologists who specialize in prostate cancer and use a lot of ADT that well done IADT is clearly superior to ADT, but with the clear understanding that that is not so for men with metastatic prostate cancer, where the reverse is almost surely true (continuous ADT better than intermittent ADT).

    I also have a strong impression, generally along the lines that Sitemaster mentioned, that IADT is likely optimally effective when the PSA drops fairly rapidly to a low point, with either <0.05 or <0.01 being the target for two experts I follow. Moreover, the doctors who specialize in prostate cancer and use ADT a lot monitor testosterone and DHT, and they want the testosterone to be below 20 and the DHT to be 5 or below. If they cannot get the PSA below 0.05 despite low T and DHT, they typically move rapidly to other supplementary or substitute tactics.

    However, patients differ. It took me 14 months to drop from 113.6 to 1.5, and I did not get to below 0.05 until 19 months after starting, reaching 0.02 about 25 months after starting, and < 0.01 sometime within the next 4 months. Despite that slow drop, I have done very well, and have just had a course of hopefully curative TomoTherapy, a type of IMRT radiation. On my second round of ADT3, starting at 10.46, my PSA again dropped slowly compared to what most of us achieve, but I got it to < 0.1 within about 9 months. Where the PSA is at the start of ADT makes a difference.

    I hope this helps you.

  33. Sitemaster and Jim:

    I agree with you both, but with one exception (for me) … testosterone level or low T as being a key indicator vs. DHT. I have had fast response to both ADT and IADT but my PSA tracks DHT and not T.
    .
    My cancer came back 10 years after radiation therapy with a bang of Gleason 8 in the capsule, positive seminal vesicles, and a PSA of 14. I went on ADT, had a bad reaction to Lupron, and switched to Avodart and Casodex. You might call this ADT2. After a year my PSA dropped to 0.01, my testosterone rose to 500, and DHT went down to 2.3. Great results.

    I then went on IADT, no Casodex for 14 months until my PSA went to 7.0. On January 1 of this year I went back to Casodex and my PSA dropped to 0.7 in 2 months and now is at 0.07. Great results again. My testosterone is still above 500 and my DHT after a rise is down to 2.8.

    Clearly, in my case, my PSA tracks DHT and not testosterone. I would like to hear from those who are hybrids like me (IADT2). I feel great and I am now wondering when I should go back on IADT. For me the suggestion of low T as an effectiveness measure is not appropriate.

  34. Dear George:

    Of course serum T is not relevant as a measure of the effectiveness of ADT in your case. You are not doing anything that would lower serum T levels. Neither bicalutamide (Casodex) nor dutasteride (Avodart) act directly to lower testosterone levels. There is a strong argument that more men should be treated the way you are before being placed on LHRH agonists when their disease progresses … but we need larger clinical trials of this strategy to know just what percentage of patients respond to this form of therapy as well as you have.

  35. I agree. Testosterone is not a factor in my case, but DHT is the key for me and potentially a lot of others. The typical urologist, and the AUA Best Practices, start ADT with LHRH agonists and in turn introduce all those upsetting side effects. This all is based upon the unproven theory that testosterone is the cause of prostate cancer.

    As you know, Casodex was approved in FDA trials when combined with LHRH agonists. To my knowledge, FDA has yet to approve Casodex as a “monotherapy.” It is not expected that since Casodex is now a generic that there is money in conducting new clinical trials as you have suggested.

    What also amazes me is if serum T is so important, why don’t urologists’ test for it during their PSA tests before starting ADT. I have to beg to get the more critical DHT test. ADT is an important treatment path for those of us that have recurrence, we need more effective clinical trials that resolve these continuing controversies over the current group of flawed studies.

  36. Hi George,

    You lucky devil! Seriously, thanks for sharing your experience of that dramatic impact. I’m really envious!

    I’m hoping more guys on a 5-ARI and an antiandrogen will respond, but I thought I would add this just to make sure it is covered in this thread with so many responses.

    As Sitemaster noted at 5:14 am, there is a strong argument for such an approach. I do hope we will have confirming trials, as, without them, so many physicians will be reluctant to accept this approach, especially as long-reported trials have indicated that involving an LHRH agonist is typically (but that means not always) superior. However, long ago convinced that timely trials are quite challenging in view of the long survival times typical for the vast majority of us, even for those of us with challenging cases, I’m also convinced that the evidence observed by medical oncologists with large practices dedicated to prostate cancer should play an important role, until sound trials are completed that yield a superior quality of evidence. To me, information from these doctors is often the “best available information.”

    Along that line, Dr. Mark Scholz, MD, has often observed that the approach using an antiandrogen paired with a 5-ARI drug gives “80% of the benefit with just 20% of the side effects,” and is especially useful for many elderly men who would have a tough time with the side effects of an LHRH agonist like Lupron or Zoladex. For a lot of men, the cancer is well controlled by this approach, and side effects are minimized. For others of us, that approach is not going to give us adequate control, and I suspect I am in that group. Fortunately, I tolerate ADT3 well.

    Also, Dr. Charles “Snuffy” Myers has been emphatic on the need to track DHT (as well as testosterone and other markers), observing that DHT is a key driver of the cancer in a significant portion of patients even when testosterone has been adequately suppressed. For a lot of us, DHT is going to drop profoundly when testosterone is suppressed, but Dr. Myers, who monitors patients carefully, has noted that response is often not the case. In other words, for a lot of men, single element androgen deprivation therapy without addressing DHT is not going to work!

    As has probably been noted on this thread, Dr. Patrick Walsh, the brilliant surgeon and researcher at Johns Hopkins, is not impressed with the role of DHT or 5-ARI drugs. Unfortunately, he considers himself an expert in this area, so testifying at an important FDA advisory group meeting. We would be well advised to remember that, not believing in the role of DHT or 5-ARI drugs, he lacks experience from regularly and often (or at all!) prescribing 5-ARI drugs or in observing how patients do who have been on these drugs after recurrence. Dr. Walsh is deservedly “the emperor” in certain areas of prostate cancer technology, but in this area, he is without clothes, as the proverbial story has it.

  37. Dear George:

    (1) The manufacturer sought approval of Casodex as monotherapy for prostate cancer at a dose of 150 mg/day. The FDA refused to approve this dose because there was an increased risk for serious side effects in the clinical trials. Maybe the menaufacturer should have tried a lower dose of bicalutamide — but they didn’t.

    (2) I would respectfully suggest to you that there is a lot of evidence that controlling testosterone with LHRH agonists does, in fact, control growth of prostate cancer tumors (for years). This may not be the best approach for some men, but it works extremely well for many.

    (3) There is little point to measuring serum testosterone or DHT levels until a patient has been on some form of ADT for a while (unless one wants to establish a baseline).

    (4) There is an argument that urologists should regularly measure serum T and DHT levels as well as PSA levels in men receiving ADT. However, the available data on the benefits of doing this are few, which is why most urologists don’t do it.

    Please understand that I am not trying to justify any of these facts, just to give some perspective.

  38. Dear Sitemaster,

    I’m responding to your 4:05 pm post on this revived thread.

    The oncologists who have treated me and whom I follow believe in measuring both testosterone and DHT as, ideally, a pre-treatment baseline and to check response early. They also check other markers, such as LH and LHRH, as needed. The ones with high volume practices dedicated to prostate cancer have formed a consensus that about 10% of patients will not have the desired response to ADT because of either their personal biology, particularly abnormally rapid clearance of the drug, or drug administration issues. Patients come to them after not having success with urologists, typically, who are treating with ADT. Rapid clearance can apparently be effectively handled by reducing the dosing interval, with monitoring androgens to assess the interval needed. Administration problems involve flaws including injection of the bolus into fat instead of muscle, the Zoladex coil actually coming out, insufficient mixing of the drug prior to administration, ineffective storing of the drug, and other issues. These problems are addressed, naturally, by competent delivery of the drug. Apparently most of the patients who previously did not respond well do respond well after this superior attention.

    I’m under the impression that the labels for the LHRH agonists call for monitoring at least testosterone and possibly DHT, but I’m not certain. I have heard that from a doctor I consider an expert, who is frustrated with the practice of his medical colleagues. If no one else is able to check, I’ll try to do that. Based on what you have said, I’m now interested in finding data on the number of patients who need this extra attention.

  39. Dear Jim:

    I do not believe that the labeling of LHRH agonists actually advises physicians to monitor serum T levels. Monitoring DHT levels is certainly not recommended.

    As far as I am aware, the only item specified in the labeling for the LHRH agonists is the definition of “castrate” as being a serum T level of less than 50 ng/dl (which many specialists now consider to be too high, as you well know). However, it is impossible for the FDA to go back and change this because it would require trials to be done all over again. The onus is on the urology and oncology community to endorse a new guideline that specifies appropriate clinical recommendations.

    I do think we need to be careful about “over-endorsement” of the views of the very small group of oncologists that you frequently refer to. Some of their clinical practices (which I am not necessarily disagreeing with) are not supported by any really robust clinical data, and so there is no compelling message that can be delivered to the medical oncologist or urologist “in the street” (so to speak). I would be a lot more supportive of some of the physicians you refer to if they actually got together with some leading academics and put together a set of research protocols for discussion with someone like the Prostate Cancer Foundation. In the end it is good data that changes physician behavior.

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