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Medical Forum / Diseases and Disorders / Prostate Cancer / September 2007Dr. Patrick Walsh: When Should You Begin Hormonal Therapy?
I have bought recently Dr. Patrick Walsh's "Guide to Surviving Prostate Cancer", second edition (paperback, July 2007) from amazon.co.uk for £7.14 / $14.4 + shipping. What prompted me making this purchase was the fact that this was a very recent edition, with the latest views of Walsh on the treatment of pca. This is a very comprehensive book, very well organized. I had bought, a couple of years ago, the "Primer on Prostate Cancer" from Strum but now realize that Walsh's book is "mandatory" for pca patients My initial objective for reading Walsh's book was to get his view on when one should begin hormonal therapy - view that was already mentioned by IP in this forum in June. Because this is a relevant issue for many of us, I quote below a passage of the book on the subject. Just ------------------------------------------------------------------------------- What I Believe (page 479) "So far, there has been no convincing scientific evidence to prove that early hormonal therapy prolongs life. In chapter 10, we talked about the Johns Hopkins study that followed men who had an elevated PSA level after radical prostatectomy. We found that, on average, it took eight years for these men to develop metastases in the bones. We also developed a means of predicting when metastases may show up, using the Gleason score on the radical prostatectomy specimen (whether it was more or less than 8), the time after radical prostatectomy when the PSA level first increased (whether it was more or less than two years), and how long it took for the PSA level to double (whether it was more or less than ten months). Using this information, a man can quickly determine his risk of developing metastatic disease. In one of the most common scenarios, a man with Gleason 7 disease who developed a PSA level elevation more than two years after surgery who had a PSA doubling time longer than ten months had an 82 percent likelihood of being metastasis-free at seven years. On the other hand, if the PSA had gone up within the first two years and the PSA doubling time was less than ten months, then the likelihood of freedom from metastatic disease at seven years would be only 15 percent. This information can tell men how long it will be before they actually need hormones - if they ever do. Why should they subject themselves to these serious side effects if they don't have to, and if there is no convincing scientific reason to do so? Whether a man is treated with hormonal therapy immediately, as soon as the diagnosis of advanced disease is made, or his doctor waits until the man has signs of progression and then begins treatment, we believe - and study after study proves-that survival is exactly the same. There is no compelling evidence that any kind of hormonal therapy works better earlier than later, when a man begins experiencing symptoms such as urinary obstruction or has a positive bane scan. And yet, it's highly unlikely that a man who is symptom-free (also called asymptomatic) is going to feel any better once he has been deprived of his normal hormones. Again, the cancer cells that ultimately prove fatal in prostate cancer are the hormone-insensitive cells. They keep right on growing, unaffected by hormonal therapy. To these cells, whether hormonal therapy comes earlier or later does not matter. For an asymptomatic man, early hormonal therapy means going from feeling fine and normal to experiencing hot flashes; loss of libido and the ability to have an erection; weight gain; changes in muscle mass, skin, and hair growth; and the subtle changes in personality that accompany the loss of male hormones. As we discussed earlier, the long-term effects of hormonal therapy can include osteoporosis, loss of bone density, leaving bones more brittle and easy to break and decreases in mental acuity. What's the point of going through this early when, ultimately, you could achieve exactly the same benefit if you wait to start hormonal therapy until there is evidence of disease progression? The idea of early hormonal therapy appeals to many men because it's doing something rather than nothing. Many doctors, too, promote a proactive approach, telling their patients that this will delay progression of the disease. Actually, it takes a lot of time for a doctor to convince a man not to start early hormonal therapy - and unfortunately, many doctors don't have very much time to spend with their patients. If you want to attack the cancer aggressively, don't pin all your hopes on hormones. Instead, read the section below on non hormonal approaches, and consider enrolling yourself in a clinical trial - there are many - aimed at killing the cancer cells that hormonal therapy can't touch". I whole heartily agree with the article. Studies have shown for what ever positive effect hormone therapy has on PCA, the benefits are offset by the side effects and death that comes from taking the hormones. The one area I fine that is not addressed sufficiently is what should one do when he has recurrence after being undetectable for 8 years. In the case of my brother he is now monitoring his PSA's doubling time. But once he has the figures, there really isn't much information as to what if anything his course of action should be. His urologist suggests hormone therapy which is what I would expect, however, I don't think this would be in his best interest as per the article above. I don't believe there is anything effective in the pipeline and his quality of life should remain good for some time before symptoms occur. He had open RP in 1999 with Gleason 8 and PSA 6.3. Path stated everything confined but cancer had entered fatty tissue of the capsule. They gave him 36 Rad treatments immediately as a precaution. Now as you can see, the radiation was probably useless and only caused more harm. I know a lot of people believe in radiation but I believe it is overrated. And that's just my opinion. Ron S. The posts by Just and Ron S. about a urologist, I don't care how famous a surgeon he is, writing about "hormone therapy" simply reinforces my view that, by and large, uros have no business meddling in such matters. Or, as Strum puts it: "I believe it is a mistake for many urologists to be involved in the endocrine therapy of prostate cancer. Let me state why. Urologists are surgeons and many times surgeons rush to a treatment without really understanding what they are doing. The old joke in medical school was that surgeons do everything and know nothing, that internists know everything and do nothing, that psychiatrists know nothing and do nothing and finally that pathologists know everything and do everything -- but it is too late." Regards, Steve J >The posts by Just and Ron S. about a urologist, I don't care how famous >a surgeon he is, writing about "hormone therapy" simply reinforces my >view that, by and large, uros have no business meddling in such matters. I don't understand your comments on this. Walsh was not acting as either a surgeon nor a endocrinologist or an oncologist, he was simply reviewing the statistical outcomes for a type of treatment and explaining the end results of those treatments. How would someone who specialized in one of the other specialties have come to some different conclusion then Walsh did? In this case it seems like the facts speak for themselves regardless of who is writing down what they say. >Or, as Strum puts it: > [quoted text clipped - 10 lines] > >Steve J Although he may in fact believe it, Strum has not said that all uros are incompetent when it comes to ADT: "I believe it is a mistake for many urologists to be involved in the endocrine therapy of prostate cancer." I think he means, and I agree, that the average, garden variety uro is not the guy you want when you want anything more than textbook (or what the drug co. rep taught) ADT Tx. While I think Walsh may be a little overly agnostic to ADT, he does practice w/ some of the best med-oncs in the field, has access to their Pt data, and is IMO competent to WRITE about ADT whether or not he is competent to treat w/ it. FWIW the 2 med-oncs I have seen, at Vanderbilt and Harvard/Dana Farber, agree w/ him. Strum is still the outlier. BTW has anyone compared the latest edition w/ the old one on ADT? From memory it sounds like the same text. Bill Denton RP 2/12/02 PSA 1.7 Memphis > Although he may in fact believe it, Strum has not said that all uros > are incompetent when it comes to ADT: "I believe it is a mistake for [quoted text clipped - 15 lines] > PSA 1.7 > Memphis I agree with Bill. Walsh is one of the world's leaing researchers in prostate cancer. He works with other scientists with a variety of different medical backgrounds, including oncologists. His papers usually have a list of joint authors, with these different backgrounds. Strum, on the other hand has published relatively little in the perr reviewed sciinetific literature. I am sure it true that a man who has a high likelihood of recurrence is better off be being treated by a competent oncologist than being treated by a urologist who concentrates mainly in doing surgery. But that has little bearing on the merits of different research. As to the basic question, I think, despite what Walsh says, the question is still up in the air. We just don't know whether early treatment based on hormones is merited or not. My impression is that the best evidence suggests that not much will be lost in a typical case by waiting to begin such therapy, but it is certainly not clear that this is the only conclusion that makes sense. Also, because of the complexity of prostate cancer, it may be that some men may be better off with early treatment and others not. On September 3, Bill Denton replied to me, in pertinent part: (snip) Regarding Walsh: > (he) is IMO competent to WRITE about ADT whether or not he is > competent to treat w/ it. I would ask Bill to give further thought to what he wrote. > Strum is still the outlier. Meaning what? That some don't agree with him? In this business, as I'm sure Bill knows, hardly anyone agrees with hardly anyone else. Even if Strum were entirely alone (which is very far from true) he would still IMO be a leader, a majority of one. Regards, Steve J "Do not go where the path may lead. Go instead where there is no path and leave a trail." -- Ralph Waldo Emerson "Regarding Walsh: '(he) is IMO competent to WRITE about ADT whether or not he is competent to treat w/ it.' "I would ask Bill to give further thought to what he wrote." See Leonard's succinct explanation. We thinketh alike. 'Strum is still the outlier.' "Meaning what? That some don't agree with him? In this business, as I'm sure Bill knows, hardly anyone agrees with hardly anyone else. Even if Strum were entirely alone (which is very far from true) he would still IMO be a leader, a majority of one." It simply means that his opinion/theory remains in a minority at the present time, whether it turns out to be correct or not. I.e. not some but most, if not the vast majority, of practicing med-oncs disagree w/ him (or at least will not change their Tx regimens until there is empirical proof). Most of those med-oncs indeed agree that there is no need to start ADT as soon as PSA begins to rise. Strum is a brilliant doctor; it is too bad he is not in a place (physically and mentally) where he can put that mind to better use. Bill Denton RP 2/12/02 PSA 1.7 Memphis Quoting me: > "Regarding Walsh: '(he) is IMO competent to WRITE about ADT whether > or not he is competent to treat w/ it.' > > "I would ask Bill to give further thought to what he wrote." He replied: > See Leonard's succinct explanation. We thinketh alike. So, let me see whether I understand. Although a medic is incompetent to use a certain tx, he is nevertheless competent to advise others about it. Quoting me: > 'Strum is still the outlier.' > > "Meaning what? That some don't agree with him? In this business, as > I'm sure Bill knows, hardly anyone agrees with hardly anyone else. > Even if Strum were entirely alone (which is very far from true) he > would still IMO be a leader, a majority of one." He replied: > It simply means that his opinion/theory remains in a minority at the > present time, whether it turns out to be correct or not. I.e. not [quoted text clipped - 4 lines] > a brilliant doctor; it is too bad he is not in a place (physically > and mentally) where he can put that mind to better use. Ah. Bill has taken a survey and has the stats to support his thesis. And the sneer about Strum's mental status, as to which I doubt Bill is privy, is facile and unworthy. It's interesting how a discussion of Walsh has somehow, by a couple of critics, been shifted to a discussion of Strum. Well, I won't further play the game. Regards, Steve J "We must tailor the treatment to the nature of the disease. We must listen to the biology." -- Stephen B. Strum, MD "Gracious, how outlandish!" --Me "And the sneer about Strum's mental status, as to which I doubt Bill is privy, is facile and unworthy." Sorry, that may have been a poor choice of words on the fly. I just mean that he has worked himself into the role of maverick, I think enjoys it, he doesn't have time for or interest in academic BS, and we do not get the benefit of his keen mind via peer-reviewed literature. Bill Denton RP 2/12/02 PSA 1.7 Memphis >I whole heartily agree with the article. Studies have shown for what ever >positive effect hormone therapy has on PCA, the benefits are offset by the [quoted text clipped - 18 lines] > >Ron S. Ron, I would have thought that this part from my original quote applies to the case of your brother: "Whether a man is treated with hormonal therapy immediately, as soon as the diagnosis of advanced disease is made, or his doctor waits until the man has signs of progression and then begins treatment, we believe - and study after study proves-that survival is exactly the same. There is no compelling evidence that any kind of hormonal therapy works better earlier than later, when a man begins experiencing symptoms such as urinary obstruction or has a positive bone scan". It seems that Walsh recommends taking the HT route only when there are signs of progression (such as urinary obstruction or a positive bone scan). This other quote at the bottom of this message is also in those lines. However "if you want to attack the cancer aggressively, don't pin all your hopes on hormones. Instead, read the section below on non hormonal approaches, and consider enrolling yourself in a clinical trial - there are many - aimed at killing the cancer cells that hormonal therapy can't touch" - from original quote. If you do live in the USA, there are many clinical trials available. Links: http://www.emergingmed.com/ http://www.clinicaltrials.gov/ct/action/GetStudy http://www.cancer.gov/clinicaltrials/finding/treatment-trial-guide Please keep us posted on your thoughts. What are the recurrence PSAs? Just PS - It seems that adjuvant radiation was the logical next step for your brother. Unfortunately the outcome was not the best. Sorry to hear that. --------------------------------------------------------------------------------------- (page 471) "First things first: We need to get one thing straight right away: If you have metastases to bone, bone pain, or a large mass of cancer that is obstructing your kidneys or bladder, you need to start hormonal therapy now. In this situation, hormonal therapy is the right course of action - one that can make a huge, vital difference in your quality of life and can protect your body from the ravages of cancer. Also, you should select some form of treatment that will drive your blood testosterone to the lowest level-either an LHRH agonist (accompanied for the first month by an antiandrogen to block any possible flare reaction described above) or the surgical removal of both testes. This is not the time for treatment with an antiandrogen alone - you need effective, immediate action. Also, if your bone scan is positive for metastatic disease - even if you don't notice any symptoms - you should start hormonal therapy now But what if you have no cancer in your bones and no sign that anything is wrong - except a rising PSA level after surgery or radiation or the presence of cancer in your lymph nodes - and you feel fine? Many doctors would advise you to start hormonal therapy as soon as possible. The rationale here, as one oncologist puts it, is to "treat the tumour while a greater percentage of cells are responsive to hormones, and the patient should do better." Advocates of this approach also believe that it preserves quality of life, because it delays the onset of symptoms. Others - and I'm in this group - believe that there is no evidence that starting hormonal therapy now, as opposed to later, will prolong life. (This is discussed in detail below.) However, if a man adopts this philosophy, he must be followed very closely so that hormonal therapy can be started before any symptoms develop. This means a man should go back to the doctor every six months or fewer. At each visit, he should be questioned closely about any signs or symptoms that could be bone pain, undergo a physical exam to check for any increase in the size of a local tumour, have a bone scan every six or twelve months or any time a new pain develops, and have blood tests - a PSA test and a serum creatinine test to measure kidney function. (An elevated creatinine level in the blood may signal that the cancer has silently obstructed the kidneys.) Other blood chemistries such as alkaline phosphatase should be measured at least once a year". ---------------------------------------------------------------------------- >I whole heartily agree with the article. Studies have shown for what ever > positive effect hormone therapy has on PCA, the benefits are offset by the [quoted text clipped - 18 lines] > > Ron S. Interesting, Ron. Your brother's situation was very similar to mine except my post-op Gleason was 3+4. Cancer cells were found in some adipose (fat) tissue. I did *not* have radiation, and so far 5+ years out, my PSA is still less than .05. I pretty much ruled out any radiation, since I already have a mild proctitis, and we're talking about major quality of life issues if radiation makes that worse. Should my PSA start going up, I had already decided to do what Walsh is advocating here---monitoring and beginning hormone therapy when I feel it is necessary. Of course, I am 69, and the mortality issues are not as scary for me as someone younger. With heart disease in my family, likely something else will take me first. > I have bought recently Dr. Patrick Walsh's "Guide to Surviving > Prostate Cancer", second edition (paperback, July 2007) from [quoted text clipped - 80 lines] > trial - there are many - aimed at killing the cancer cells that > hormonal therapy can't touch". This information from Dr. Walsh may be true, as far as it goes. I have not read the sections preceding or succeeding the citation above from his book. I believe an important issue to be considered is risk stratification, as Walsh himself alludes to above. The Messing study of LN+ men indicated clear preference for early (neo-adjuvant) hormone initiation after surgery, and increased survival. LN spread is a clear risk factor for disease progression. The Messing results have been confirmed by Mayo Clinic studies, the most recent one just published in Journal of Urology, September, 2007. The estimable Dr. Judd Moul (Walter Reed and Duke University Hospitals) has followed a group of 1352 men with recurrence after surgery(Reviews in Urology, Supplement 8, 2004; from J of Urology, 2004;171:1141-1147) over a median time of 5.5 years (extended by statistics to 10 years or more) and found no difference in the time to bone metastasis in the entire cohort but a significant improvement in the delay of such progression in those with Gleason 8-10, or those with PSADT less than 12 months. In his words "The natural history of bone metastasis in this group of men was changed". For men in such groups this was a real advantage, and unavailable to them by any other means. This study had an end point of metastasis and not survival. After 10+ years from recurrence (0.2 psa) median survival had not ben reached. As is always the case, what is true for a group, may not be true for an individual of the group. The first step in PCa treatment always is risk stratification: GG, GS, Tumor staging, Psa, and other markers. To believe that this risk stratification is to be discarded at other decision points in the battle seems misguided. I also believe that a doctor who counsels his patient to delay treatment while ignoring the risk stratification information is doing his patient no good. I do agree that clinical trials for men in lower risk strata can be hopeful and productive. Delaying hormone therapy for them can provide QOL, potential successful therapies, at the risk of mental anguish. As one who has made his choice based on membership in a high risk stratum from above, I am comfortable with that choice. tarhoosier >This information from Dr. Walsh may be true, as far as it goes. I have >not read the sections preceding or succeeding the citation above from [quoted text clipped - 33 lines] > >tarhoosier Below please find an additional quote from Walsh book where he comments on the ECOG study (which I believe is the same you mention as Messing study). Just --------------------------------------------------------------------------- (page 476) "A study from the Eastern Cooperative Oncology Group (ECOG), published in the New England Journal of Medicine, has received a lot of attention. This study looked at radical prostatectomy patients who turned out to have cancer in the lymph nodes. These men were randomly assigned either to receive hormonal therapy right away or to delayed treatment - hormonal therapy given only when these men developed signs or symptoms of metastatic disease. After a relatively short follow-up interval of seven years, the authors found that the men who received early hormonal therapy lived longer. However, these findings have proven somewhat surprising - at least to scientists heading similar studies. One of these is a European study in which 304 men with cancer in the lymph nodes who did not undergo radical prostatectomy were randomly assigned to early or delayed hormone therapy. In this much larger study, in which patients have been followed for an equal length of time, no significant difference in survival has been reported yet. Another study led by the Mayo Clinic retrospectively reviewed data from a large group of men with cancer in the lymph nodes, many of whom were treated with hormonal therapy. At seven years after treatment, the Mayo scientists found no overall survival benefit for men receiving early hormonal therapy. Beyond ten years, however, they identified a small subset of men (12 out of 790) with diploid tumours (which have the normal number of chromosomes-an indication that they are slower-growing) whom they felt did benefit from early hormonal treatment. Why haven't other scientists been able to achieve the same success? One possible reason is that there weren't enough men in the ECOG study. When scientists carry out a randomized study, they need to have comparable patients in each group. This study was designed to evaluate 240 patients; however, the scientists had trouble recruiting men for the study and ended up with only 98 men. This left a smaller number in each group, and it's possible that unintentional bias might have been introduced. More recently, there have been two informative studies conducted in Europe. One study from Switzerland involved 197 men treated with either immediate or deferred surgical castration for locally advanced prostate cancer. The Swiss scientists found that there was no significant difference in these two groups in overall survival or in the time it took for metastases to reach bane and cause painful symptoms. Another important point is that many men in this study required no treatment at all; it took so long for their cancer to progress that they died of other causes. The second study, carried out by the European Organization for Research in the Treatment of Cancer, was larger - involving 985 men with locally advanced cancer. Once again, there was no evidence that early hormonal therapy reduced a man's likelihood of dying from prostate cancer. Thus, of alI the trials in which early hormonal therapy was used alone, without radiation therapy, there is only one that showed a survival benefit - the small ECOG study, in which hormonal therapy was started early in men who were found to have positive lymph nodes at the time of surgery". I appreciate all of your comebacks and agree with the studies that little benefit can be shown for hormone therapy for recurrent pca. My brother's first rise in psa was this last June with a 1.3. A month later it was 1.5 and the last was 1.7 taken at Kennedy Krieger Institute in Baltimore, Maryland. He has no symptoms as of yet and hasn't had any bone scans or other test. he's waiting to find out what his doubling time is before he proceeds any further. Ron S. >I appreciate all of your comebacks and agree with the studies that little > benefit can be shown for hormone therapy for recurrent pca. My brother's [quoted text clipped - 5 lines] > > Ron S. Hi, Ron. Forgive me if I missed something. Is this your brother's first experience with rising PSAs or has he had PCa, been treated, and is now having a rise?  SignaturePSA 16 10/17/2000 @ 46 Biopsy 11/01/2000 G7 (3+4), T2c RRP 12/15/2000 G7 (3+4), T3cN0M0 Neg margins PSA <.1 <.1 <.1 .27 .37 .75 PSAD 0.19 years EBRT 05-07/2002 @ 47 PSA .34 .22 .15 .21 .32 PSAD .056 years Lupron 07/03 (1 mo) 8/03 and every 4 months there after PSA .07 .05 .06 .09 .08 .132 .145 PSAD 1.4 years Casodex added daily 07/06 PSA <0.04, <0.05, <0.04 (06/12/2007) Non Illegitimi Carborundum > I appreciate all of your comebacks and agree with the studies that little > benefit can be shown for hormone therapy for recurrent pca. My brother's [quoted text clipped - 5 lines] > > Ron S. Ron: The Moul study (above) identified psa cut points of less than 5.0, 5-10, and above ten as the early, intermediate, and delayed (late) intervention points for ADT. For the risk groups of Gleason 8-10 and PSADT less than a year, institution at psa of less than 5 was better than 5-10 which was better than above ten. This allows for a third stratification of risk. All the better. I appreciate all of your comebacks and agree with the studies that little benefit can be shown for hormone therapy for recurrent pca. My brother's first rise in psa was this last June with a 1.3. A month later it was 1.5 and the last was 1.7 taken at Kennedy Krieger Institute in Baltimore, Maryland. He has no symptoms as of yet and hasn't had any bone scans or other test. he's waiting to find out what his doubling time is before he proceeds any further. Ron S. Steve, In an earlier post I stated that he had Open RP in 1999 with 36 Rad treatments. After about 7 1/2 years of <0.1 this June he got his first 1.3 psa. Ron S. Sorry, Ron. If it was during the ADT discussion, I just glossed over it. Having been on ADT for four years, reading that it's not working just doesn't to much for me. SignaturePSA 16 10/17/2000 @ 46 Biopsy 11/01/2000 G7 (3+4), T2c RRP 12/15/2000 G7 (3+4), T3cN0M0 Neg margins PSA <.1 <.1 <.1 .27 .37 .75 PSAD 0.19 years EBRT 05-07/2002 @ 47 PSA .34 .22 .15 .21 .32 PSAD .056 years Lupron 07/03 (1 mo) 8/03 and every 4 months there after PSA .07 .05 .06 .09 .08 .132 .145 PSAD 1.4 years Casodex added daily 07/06 PSA <0.04, <0.05, <0.04 (06/12/2007) Non Illegitimi Carborundum > Steve, > In an earlier post I stated that he had Open RP in 1999 with 36 Rad > treatments. After about 7 1/2 years of <0.1 this June he got his first 1.3 > psa. > > Ron S. No problem Steve. I guess what well all will have to face someday is when recurrence happens is should we try one of the various treatment regimes or just say no. It's really difficult guessing what might happen if we say no to furthur treatment. It's scares us about not knowing so if we try something then we feel we have done all we can feeling if we didn't then we might miss out on an opportunity to delay the inevitable. The big question is when will the recurrence progress to Mets without treatment and does treatment really slow the progress. Studies haven't show much success in that it does. Ron S. > I guess what well all will have to face someday is when recurrence happens > is should we try one of the various treatment regimes or just say no. It's [quoted text clipped - 5 lines] > recurrence progress to Mets without treatment and does treatment really > slow the progress. Studies haven't show much success in that it does. Please keep us advised. Hi Steve, Not to worry! In his "new and improved" updated version Dr. Walsh used most of the old text fron the original version plus he added a couple of comments about studies (not referenced) supporting his views. Left intact are his comments about the randomized, control study done by Dr. Messing. He conveniently ignored the latest results of the study's update published before his book was updated (maybe because it showed the flaws of his views). Here are those results: Patients were accrued onto this trial from 1988-1993, and the median follow-up of the population entered into this study is currently 11.9 years (range, 9.7-14.5 years). Table 1. Immediate (n = 47) vs delayed (n = 51) androgen deprivation following radical prostatectomy Total number of deaths Immediate therapy: 17 (36.2%) Total number of deaths Delayed Therapy: 28 (54.9%) Deaths from prostate cancer Immediate therapy: 7 (14.9%) Deaths from prostate cancer Delayed Therapy: 25 (49.0%) Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006;7:472-479. Now, which group would you prefer to be in? Why would he ignore these results? Why does he go out of his way to say that these results have never been duplicated when there is ample evidence, including the VACOUR data to support a survival benefit of early versus delayed suppression. How is the data cited in his book (Pound C et al) that surgery alone is all is needed to control disease progression when so many men have biochemical progression after surgery? He mentions that on average it takes 8 years for men to develop metastasis after surgery(actually the study said the median was 8 years, which is a different thing). How do surgically treated men compare to those treated with other therapies? It is well supported by clinical studies that RT with adjuvant HT provides a survival benefit. The Messing study as well as Mayo studies support the survival benefit to early HT. Still Dr. Walsh continues to ignore the potential benefit of early systemic treatment with hormone suppression to fit his views... Not to worry Steve! "Non Illegitimi Carborundum" RalphV www.pcainaz.org/phpvv > Sorry, Ron. If it was during the ADT discussion, I just glossed over it. > Having been on ADT for four years, reading that it's not working just [quoted text clipped - 12 lines] > PSA <0.04, <0.05, <0.04 (06/12/2007) > Non Illegitimi Carborundum"ronju99" <jlsp...@nospam.verizon.net> wrote in message -- > Hi Steve, > Not to worry! In his "new and improved" updated version Dr. Walsh used [quoted text clipped - 4 lines] > update published before his book was updated (maybe because it showed > the flaws of his views). Here are those results: > [ Study data redacted] > Not to worry Steve! "Non Illegitimi Carborundum" > > RalphV Thanks, Ralph! On September 5, Ron S replied to (presumably) Steve K: > Steve, In an earlier post I stated that he had Open RP in 1999 with > 36 Rad treatments. After about 7 1/2 years of <0.1 this June he got > his first 1.3 psa. I recommend that the very first thing he should do is simply to have the test redone. Lab mistakes happen, as I -- and others -- know from experience. Regards, Steve the J "What are the facts? Again and again and again -- what are the facts? Shun wishful thinking, ignore divine revelation, forget 'what the stars foretell,' avoid opinion, care not what the neighbors think, never mind the unguessable 'verdict of history' -- what are the facts, and to how many decimal places? You pilot always into an unknown future; facts are your single clue. Get the facts!" --Lazarus Long I just wrote: > On September 5, Ron S replied to (presumably) Steve K: (ka-snip) Oops. It was September 3. Regards, Steve the J ;-) > I appreciate all of your comebacks and agree with the studies that little > benefit can be shown for hormone therapy for recurrent pca. My brother's [quoted text clipped - 5 lines] > > Ron S. That's too bad, Ron. For your brother's sake -- as well as for all of us -- I wish there was more clarity about this portion of the treatment protocol. --charlie Signature6/2006 PSA 5.2, DRE suspicious 7/2006 Biopsy: 2 of 10 positive, Gleason 7(3+4) 11/2006 LRP: Clear margins PSA < 0.01 on 1/2007, 3/2007, 6/2007 so far, so good ... > >This information from Dr. Walsh may be true, as far as it goes. I have > >not read the sections preceding or succeeding the citation above from [quoted text clipped - 91 lines] > men who were found to have positive lymph nodes at the time of > surgery". The studies that Walsh mentions, as you have quoted from his text, were those in which the prostate was intact and untreated, except hormonally. It has been apparent for many years that in such situations that the cancer cells in the intact prostate harbor the largest number of androgen insensitive cells and are the source of the greatest risk to health of the patient. In Europe, and in the U. S. in the past, locally advanced patients were treated with hormones only. This is less common today. These studies are not comparable to those with men treated surgically for prostate removal with potentially curative effect. Also, though I agree with Walsh in the larger sense, I note that no comment about risk stratification was mentioned in any of his quoted studies. This is the key point. Dr. Walsh wrote: > ... Again, the cancer cells that ultimately prove fatal in > prostate cancer are the hormone-insensitive cells. They keep > right on growing, unaffected by hormonal therapy. To these > cells, whether hormonal therapy comes earlier or later does not > matter.... If I understand his position, he is implying that a man with prostate cancer has some number of androgen independent cells at the time of failure of primary treatment. This number will grow at a predetermined rate, regardless of whether ADT is applied or not. The other, androgen dependent cells, also grow, but they are irrelevant because their growth can be stopped at any time that they might cause, or be about to cause, symptoms. Once we apply androgen deprivation therapy, the androgen dependent cells cease to be a factor in the disease. In the passage quoted by Just, Walsh makes no biological argument for this view, but he does support it with some empirical research that appears to show that time of death is the same for most men receiving early or late ADT, thus implying that they must have had the same rate of growth of androgen independent cells. Does anyone know what the current molecular biological theory is regarding this view? Do our androgen independent cancer cells only come from other androgen independent cells? Or is it possible that cells with androgen dependence will sometimes give rise to daughter cells that are independent, or less dependent, on androgens? Is there any scientific consensus regarding this? If Dr. Walsh is right, a man with 1000n dependent cells and 1n independent cells will have the same life expectancy as a man with 0n dependent cells and 1n independent cells - assuming the characteristics of those independent cells are the same in the two men, and assuming that ADT is eventually used to keep the dependent cells from killing the man who has them. There is another issue that also clouds this. I had thought that androgen dependence was not a "yes" or "no" characteristic of cancer cells, but rather a "more" or "less" characteristic. I had thought that some cells are highly dependent and die without androgens; some are highly independent and are completely unaffected by the presence or absence of androgens; and some are in between. If that were true, then wouldn't early application of ADT slow the growth of cancer cells that will become dangerous? But of course, whatever the theory, if Dr. Walsh is right about the facts of survival - an issue which appears to be in dispute - then there wouldn't be much point to early ADT. Alan Alan, You hit the nail in the head! If androgen-dependent cells in time turn androgen- independent, why not kill them before they do? It seems that this process happens with accumulated cell mutations even before diagnosis and is one of the reasons why advanced PCa is more resistant to treatments. The presence of androgen-independent stem cells in the prostate gland at birth is the main reason androgen deprivation is not considered curative for prostate cancer. In simple words, prostate epithelium is made up of three different types of cells. The largest portion is made of secretory epithelial cells. There are also basal epithelial cells and endocrine-paracrine cells. Not much is known about the endocrine- paracrine cells, their function and androgen sensitivity. The normal secretory epithelial cells are sensitive to androgens while the basal cells do not require androgens to grow and can survive without it. Basal cells are believed to be the stem cells of the prostate or cells that generate secretory epithelial cells. Bruchovsky and others believes that androgen independence is related to a shift in the ratio of androgen-dependent cells to androgen- independent cells in the tumor load. This, happens as cell mutations accumulate and dedifferentiation proceeds to an endpoint. This would explain why very advanced PCa is already androgen-independent at diagnosis and does not respond to hormonal suppression. Arnold and Issacs describe the relationship between cell of origin for prostate cancer and androgen responsiveness. "Based on stem cell organization, it is possible for prostate cancer to have three distinct cells of origin. The first alternative is that the prostate cancer is monoclonally derived from an androgen-independent stem cell. Even if the cell of origin is an androgen-independent stem cell, it is still possible for the resulting cancer to be responsive to androgen ablation. The malignant stem cell could retain the ability to progress down the hierarchical pathway, giving rise to larger subsets of androgen- sensitive amplifying and even larger numbers of androgen-dependent transit malignant cells. Such a heterogeneous cancer composed of these three cell types would respond to androgen ablation with the elimination of the largest subset of cancer cells (i.e. the androgen dependent malignant transit cells) and a reduction in the growth rate of the next largest subset of cancer cells (i.e. the androgen- sensitive malignant amplifying cells). Such a response would not be curative because neither the malignant androgen-independent stem cell nor the androgen-sensitive malignant amplifying cells would be eliminated." "A second alternative is that the original prostate cancer is monoclonally derived from an androgen-sensitive amplifying basal cell. If this occurs, the cancer would again be androgen responsive because it is composed of androgen-sensitive malignant amplifying cells that retain the ability of differentiating into androgen-dependent transit cell progeny. Again, owing to clonal expansion, the major type of cancer cells present would be the androgen-dependent malignant transit cells. Such a heterogeneous cancer would be responsive to androgen ablation because of the elimination of the major subset of malignant transit cells; however, the cancer would not be cured by such therapy because the androgen-sensitive amplifying cells would not be eliminated." A third alternative is that the original cancer is monoclonally derived from an androgen-dependent transit (glandular) cell. If this occurs, the cancer would initially be highly androgen responsive to androgen ablation. If no further malignant progression occurred, the cancer theoretically could be cured by such therapy; however, even if this third possibility occurs and the initial prostate cancer is homogeneously composed of androgen-dependent cancer cells, as these cells undergo sufficient cellular proliferation to produce clinically detectable prostate cancer (i.e. more than 39 population doublings), a series of mechanisms would eventually lead to the heterogeneous development of malignant clones of androgen-sensitive or androgen- insensitive prostate cancer cells, or both." Then they further say: "Development of androgen-independent prostate cancer cells As subpopulations of malignant prostate epithelial cells begin to grow independent of androgen, basic genetic changes likely occur in the cancer cell genome. The tumor cells become increasingly genetically unstable, developing clones that can proliferate without the requirement for androgenic stimulation (Isaacs et al. 1982, Wake et al. 1982). Once these androgen-independent clones develop, they have a growth advantage following androgen ablation over all other newly developed tumor clones that retain androgen dependence. Other genetic changes may contribute to the progression to androgen independence. The frequency of expression of the apoptosis inhibitor, bcl-2, has been correlated with the progression from androgen dependence to the androgen independent metastatic phenotype (Furuya et al. 1996). If cells over-express bcl-2 and are thereby protected from apoptotic stimuli, their resistance to androgen depletion is augmented, along with their ability to progress towards hormone- refractory tumors (Raffo et al. 1995)." I really believe that Dr. Walsh ignores much of the existing evidence because it doesn't fit the Hopkins mold where reliance is on surgery. RalphV www.pcainaz.org/phpbb Source: J T Arnold1 and J T Isaacs Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault. Endocrine-Related Cancer (2002) 9 61-73 <SNIP> > There is another issue that also clouds this. I had thought that > androgen dependence was not a "yes" or "no" characteristic of [quoted text clipped - 11 lines] > > Alan Ralph, Thanks for the explanation. I have studied enough molecular biology that I could follow it to some degree. It appears that the bottom line for patients, if the theory is correct, is that early ADT might or might not be of significant help, depending on the specific characteristics of their cancer. For some patients it could be of great help, for others no help at all, and for others it might be of some help. Judging from the nature of the issues involved, it also sounds like a typical pathology lab would not be able to distinguish these cases and even a research institution would probably not be able to. It sounds like it would be necessary not only to biopsy the patient's cancer cells, but also to culture them and then subject them to various tests for androgen independence, and even then a patient couldn't know how representative the cells were of his total cancer. I would guess that a conclusion from that is that, like so much in prostate cancer, the patient must make choices based on insufficient information. The patient who wants the best chance of survival regardless of the side effects of ADT should request ADT. It might not increase his lifespan. But then again it might. On the other hand the patient who hates ADT and is willing to take his chances might choose to wait until symptoms are very close to developing. He might reduce his lifespan by doing that, but then again he might not. Life is full of tough choices isn't it? Alan > ... > I would guess that a conclusion from that is that, like so > much in prostate cancer, the patient must make choices > based on insufficient information. ... One more note about this. There might be ways to look at secondary effects as a guide to the success of ADT. If I remember correctly, Strum claimed that there was a correlation between the PSA on ADT and the likely success of ADT as a treatment. IIRC, he said that some patients will have a rapid reduction of PSA to a very, very low level and others will not. That, he thought, was an indicator of how successful ADT would be. Assuming that's so, a patient might try ADT for, say, 3 months. If his response to it was good, he might stay on it. If his response was poor, i.e., not a big drop in PSA, then he might consider going off again and restarting further down the road. But this is speculation on my part. Men facing failure of primary treatment would have to get more expert opinion than this layman's speculation before making decisions. Though of course if the two experts he consults are Walsh and Strum, he still won't know exactly what to do. Alan snip.... >I really believe that Dr. Walsh ignores much of the existing evidence >because it doesn't fit the Hopkins mold where reliance is on surgery. > >RalphV Hi Ralph! This seems to be a serious accusation: that Dr. Walsh deliberately ignores valid data so that his analysis can lead into a pre-defined direction. If this were so for one of the most well known doctors in the Pca area, who can we trust? And why? And... how can he get away with it, I wonder. Just Hi Just, It really is not that serious. He has certainly the right to have an opinion. He mentioned studies for which he doesn't provide references. For example, yesterday I spent more than an hour searching for a Swiss study in which 197 men were hormonally treated with no benefit. Guess what? If it is in PubMed it is well hidden. Mind you, in these discussions anyone can have opinions, theories or whatever, but is very important to provide references so that things can be verified. There is no doubt that Dr. Walsh is an authority in prostate cancer and well qualified in the endocrinology of the disease. At the same time it is well known that Johns Hopkins is a super duper surgical establishment with a bias against most other treatments as a primary therapy. Hormonal therapy is one of them when used with early recurrence. In his original guide the prostatectomy chapter is prominent while the chapter on radiotherapy and cryosurgery are less supported. He is a surgeon and as such he believes surgery is best, even in some T3 cases. Best regards, RalphV www.pcainaz.org/phpbb > snip.... > [quoted text clipped - 15 lines] > > Just snip... > He mentioned studies for which he doesn't provide references. >For example, yesterday I spent more than an hour searching for a Swiss >study in which 197 men were hormonally treated with no benefit. Guess >what? If it is in PubMed it is well hidden. Mind you, in these >discussions anyone can have opinions, theories or whatever, but is >very important to provide references so that things can be verified. snip.... Hi Ralph! I guess this is the study you were looking for: http://jco.ascopubs.org/cgi/content/full/22/20/4109 Just This article from PubMed kind of sums it up for early or deferred ADT for recurrent or advanced PCA. http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&dopt=AbstractPlu s&list_uids=17404365. Ron S. RalphV wrote: > I really believe that Dr. Walsh ignores much of the existing evidence > because it doesn't fit the Hopkins mold where reliance is on surgery. That ... or we've relied so hard on the pro-ADT steamroller that we place too much faith in pro-ADT literature and ignore what Walsh feels are the core facts of the issue. After all, Walsh isn't the only authoritative source to advise choosing our secondary treatment based on SE priorities rather than (debatable) benefit. Is it too big a stretch that just as the non-scientific world has been deceived by the man-made global warming steamroller, maybe we've been deceived by an overly optimistic ADT steamroller driven by the pharmaceutical industry (imagine that!), some favorable but far-from-unanimous studies, and a buncha dudes who credit ADT without proof for their survival to date? Is the PC patient and professional world letting the ADT noise level overrule substance in the debate? I sure don't know the answer, and I recognize the *potential* for Walsh's surgery bias, but it's not like he gets to suppress strong objections from the whole J-H oncology staff, and I did tell my uro/onc/surgeon yet again just weeks ago that until my cancer returns and we can prove that adjuvant ADT would have cured it and let me live to 90, I thank him from the bottom of my torso for allowing me many great years of physical, mental, and emotional vitality I would not have had if he had somehow "forced" ADT on me. I don't see how any current patient can know how much early or late or no ADT affected his survival, but every ADT pt has a pretty good idea how it affected his overall QOL, for better and/or worse. Maybe that implies that pessimists should opt for early adjuvant ADT and optimists should wait for recurrence. I.P. snip...... >My initial objective for reading Walsh's book was to get his view on >when one should begin hormonal therapy - view that was already [quoted text clipped - 4 lines] > >Just Maybe I should add that Walsh defends short-term hormonal therapy in conjunction with radiation therapy in some circumstances (see below). Just ------------------------------------------------ Big Difference (page 477) "Now, hormonal therapy by itself is one thing, and beginning it early (and staying on it for years) is highly overrated. But hormonal therapy in conjunction with radiation therapy is something else altogether. In chapter 9, we reported that in some men, hormones plus radiation therapy can be better than radiation therapy alone. Why is this? Because hormonal therapy makes the radiation work better. This was most dramatically demonstrated in a study conducted at Harvard, which looked at the use of short-term (six months) hormonal therapy plus radiation in men with Gleason scores of 7 or higher and PSA levels greater than 10 ng/ml. The investigators found that after five years, there was not only an improvement in disease control but also a 10 percent improvement in overall survival. There's a big difference between these two kinds of hormonal therapy, and if your doctor is talking to you about early hormonal therapy, you need to know exactly what's being proposed: hormonal therapy alone for an indefinite time period or hormonal therapy for a finite period along with radiation therapy. But doesn't receiving early hormonal therapy delay the progression of cancer? The answer is yes and no. It delays your knowledge of progression, but it doesn't stop the clock. Another way to look at it is "pay me now, or par me later." Eventually, the result is the same. Hormonal therapy does two things: it stops cells from making PSA and shrinks the hormone-sensitive cell population. Say a man begins hormonal therapy when his PSA level is elevated, but his bone scan is negative. His PSA level will drop dramatically and he may feel that his cancer is gone. But it's not; it has just slipped below the radar screen. Those hormone-insensitive cells continue to grow silently. There is a euphemism for this called a delay in progression. What it really is, unfortunately, is a silent progression. Over time (and this may take years), these hormone-insensitive cells will reappear on the medical radar - the PSA level will begin to rise again, the bone scan will become positive, and the tumour will begin to attack bone, producing the signs and symptoms of advanced, hormone-refractory disease. Actually, this delay is just a time shift. Say the man waited to start hormonal therapy until his bone scan was positive. Right away, his tumour would shrink, his PSA level would fall, and the man would experience a remission of indefinite duration - until, just as in the first scenario, his hormone-insensitive cells reached a critical mass. Eventually - whether the man started hormonal therapy early or late - the result would be the same. If the man had begun hormonal therapy early, his cancer would have progressed, but he wouldn't have been aware of it. The trade-off is that he would have endured the side effects of hormonal therapy for a much longer time. If the man had begun hormonal treatment later, he would have had fewer side effects. What about peace of mind? Well, in both cases, the cancer is growing. The man who begins treatment early has a false peace of mind based on the idea that what he can't see won't hurt him. Unfortunately, as we've discussed at length, hormones are not the long-term answer to controlling prostate cancer. The best hope is in the non hormonal approaches, which we're going to discuss a bit later". >I have bought recently Dr. Patrick Walsh's "Guide to Surviving >Prostate Cancer", second edition (paperback, July 2007) from [quoted text clipped - 16 lines] > >Just <snip> Thanks for posting this, and what a cracking thread! The now/later dilemma flashed me back a vivid memory from over 30 years ago when I shared a flat with a physics post-grad student. He was a bit of an idler and I was in no hurry so we always took our time over breakfast which for him was a carefully choreographed though quite unscientific ritual where the coffee/tea was prepared before the eggs went into the pan but drunk after the eggs had been fried and eaten. Yet, in spite of this tactical blunder, he liked his drink to be as hot as possible so he insisted on making what he thought was the best of a bad job by adding the milk at the last moment, just before drinking rather than immediately after brewing, arguing that such a temperature curve ensured a hotter bevvy when it came time to drink. I'd done relatively lowly physics - far too simple for him - and remembered Newton's law of cooling (totally intuitive - rate of cooling is proportional to excess temperature over surroundings - IOW, hotter things cool faster, no surprise there!!) so I tried hard to persuade him that in fact he'd get a better result by adding the milk at the beginning even if this meant a sudden and shocking dip in temperature - more to the point, Newton's law points to a benefit in this immediate temperature fall. Even now, I'm not sure the two methods would have resulted in as much as a 1 deg difference. Of course, a thermometer in each cup would have settled it once and for all but leaving it unresolved left a bit of vital research on the books or, more likely, perhaps neither of us had the courage of our convictions. In any case, it wasn't important, though Phileas Fogg would surely have disagreed. I've enjoyed all the posts on this and like everyone else, keenly interested in anything that illuminates it. Any similarity in my milk anectode to survival strategies current or anticipated is entirely coincidental. |
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