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Medical Forum / Diseases and Disorders / Prostate Cancer / January 2005The early adjuvant HT dilemma loooooong
THE EARLY, ADJUVANT HT DILEMMA Early screening often leads to RP or RT followed by UD (undetectable) PSA and no symptoms. We then expect a QOL graph consisting of years of high, asymptomatic QOL, followed by biochemical (PSA) failure, then clinical (symptomatic) failure, then a falling QOL curve from great to OK to bad to intolerable to blessed relief. The objective of adjuvant therapy -- HT, for this discussion -- is to prolong life by delaying recurrence/refraction. HT' s drawbacks are that its SEs lower the QOL curve right out of the gate, it may prolong heartbeat by only months if at all, and it may even exacerbate refraction. So . . . which is more important, higher QOL before recurrence or maximum delay of recurrence? That's my present dilemma, and it probably concerns a few hundred thousand others, too. OBJECTIVES FOR THIS TOME To obtain advice on this dilemma and feedback on this package (something like this goes to my medical team soon), and to provide data, philosophy, and a strawman for others facing similar decisions. My sources include the leading PC books and web sites such as Walsh, PCRI (Strum, Scholz, et.al,), Marks, Blasko, Lange, leading universities and hospitals, NCI, NEJM, JAMA, Lancet, ACS, the VA, Harrison's Internal Medicine, etc. I've researched medical web sites for many years and always wear hip boots. The good news . . . and the bad news: there's a lot of detail here. MY STATUS Athletic, energetic 61 yo w/T3c N0M0 (seminal vesicle positive, surgical margins negative), Grade 8, PSA = 8.7 and PSAV = 2.15 before 28 Oct 04 RP, PSA = 0.006 on 20 Dec., p(recurrence > 0.5. www.prostatecalculator.org from VA => 15% chance of avoiding PSA failure for a decade. ADJUVANT TREATMENTS CONSIDERED WW, ADT1,2,3 (early or @PSA or @clinical failure), IAD, antiandrogen monotherapy, immunotherapy, angiogenesis, monoclonal antibodies, voodoo. PROPOSED OPTIONS 1.. WW until biochemical, maybe clinical, failure necessitates ADT, or 2.. Early antiandrogen monotherapy, or 3.. Early immunotherapy, or 4.. New technologies such as Provenge or Aptosin. EARLY ADJUVANT HT BENEFITS . . . OR NOT. * The most promising benefit estimate I've seen, the Kattan nomogram, => ADT may increase my 5-yr-relapse-free chances from 43% to 70%, but sources differ HUGELY on such figures, down to a few % improvement. * Adjuvant HT helped N=1 patients, but trials do not demonstrate clear advantages to HT after RP w/o node involvement, even with PSA elevation. * Major meta-study found no evidence that early (pre-symptom) adjuvant HT provides any advantage, even w/rising PSA; Walsh, universities, the Mayo Clinic, Sloan-Kettering, and the ACS agree (citing SEs, QOL, failure to prolong life, and accelerated refraction). * Given that, there's little risk and much reward potential in delaying HT at least until PSADT is known. * ADT 2 or 3 (CAB) not promising, not curative, may promote refraction, no 5-yr benefit, more SEs. * IAD MAY delay refractory mutation, MAY extend heartbeat by 6-12 months, and MAY reduce side effects towards the end of each HT-off cycle . . . except after biochemical failure w/Gleason >= 8. * Young G8 T3c RP pts have unacceptably high relapse and refraction rates even with adjuvant ADT. * T3c, G > 6, and/or aneuploidy => high p(AIPC) => low p(big ADT benefit). * Antiandrogen monotherapy reduces SEs to primarily diarrhea and gynaecomastia, is as effective as LHRH agonists or castration for locally advanced PC, and is approved in 60 countries for that purpose. HT SIDE EFFECTS, DOWNSIDES, CONCERNS * HT SEs, in general, approximate decreasing order of my concern about them: fatigue/weakness/lethargy/anemia (the earliest and most obvious andropause SE), depression, osteoporosis (seriously underreported) and attendant fractures, cognitive dysfunction, hot flashes/night sweats (and the SEs of meds that reduce them), extreme irritability, emotional turmoil, poor sleep, nausea, diarrhea, lipid elevation, liver damage, psychological stress, pronounced personality alteration, upper body muscle atrophy, weight gain, breast pain, insulin resistance, and libido/ED effects. (Surprised at that last one being last? Think about it; who'd want sex with that other crap going on?) Proof low T causes this syndrome? T cures it! * HT < 12 mo => patients suffer typical ACUTE Androgen Deprivation Syndrome (ADS; see Strum) - invariably compromising healthy, active lifestyles -- but maybe not significant CHRONIC symptoms. Chronic symptoms -- some nearly inevitable in patients treated > 12 mo -- are much more prevalent with HT than is currently recognized or reported. * Probabilities of various SEs combine mathematically to virtually guarantee (p > .97) one or two SEs I'm not willing to accept for a debatable, slight, statistical lifeline benefit. * Anti-SE meds (e.g., antidepressants, anabolic steroids, NSAIDS) have their own, major, SEs. * ADT after RP can extend life . . . if given for 28 months, but * two years on ADT may permanently suppress T and thus maintain SEs, and * long-term antiandrogen use may stimulate PC. * Trial HT takes 6-12 months to reveal all its SEs - about the extent of its maximum lifeline extension. * HT => T deprivation => SEs. T > 20 => little benefit. This may mean no pain (SEs), no gain. * HT drives PSA down, hiding the REAL killer, AIPC, as it proliferates. * OHSU demonstrated that HT T deprivation alters hippocampus to sharply decrease two-minute word retention (short-term memory), resembling early Alzheimer's or stroke. * Geriatric psychologist I consulted reports most of her HT pts suffer dramatic emotional impacts, often a near absence of the emotions we want plus wide swings in the moods we don't want; she regards HT as primarily for patients who consider a heartbeat more important than QOL who fear death above all, or who are getting distant met symptoms. * Typical IAB HT on/off cycle => 9-16 months on, 6-9 off, w/lingering SEs dominating off cycle => low therapeutic index. * Antiandrogen SEs = primarily diarrhea and breast pain (pre-radiation doesn 't help the pain). * PCRI/Scholz: "The biggest difference between adjuvant treatments is QOL, not survival; choose by SEs." BOTTOM LINE The few months post-RRP HT MAY add to my life are highly likely be burdened with SEs which threaten the most important elements of my life. I'd far rather feel like an athlete, think like a student, and be a good companion to my wife for 5 years and then die than feel like road kill, think like a fencepost, and be a major PITA for 6 or 7 and die on her anyway. Life's about quality, not just quantity, and the steeper the slide from vigor to rigor, the better. Besides, Partin says I may just beat this beast anyway. MY PROPOSED PROTOCOL 1. Measure baseline biomarkers (e.g., PSA, PAP, CEA, NSE, CGA) to estimate p(heterogeneity/AIPC) and thus likelihood ADT won't help. 2. WW, monitoring PC as closely as possible (e.g., PSA, PAP, CEA, creatinine, hypersensitive PSA plotted to distinguish trends from noise, any means of assessing androgen dependence/HT effectiveness) 3. Enjoy high QOL until PSA relapse, symptoms, or positive bone scan raises threat, then initiate HT considering options available then. 4. Or begin now with low-SE therapy (e.g., antiandrogen monotherapy such as Casodex, immunology (it may fight both PC and my colon cancer; see below), MAB. QUESTIONS REMAINING Is my PC hormone-receptive (AD)? If HT suppresses PSA, what drives IAD timing? What is my life expectancy and risk of recurrence without HT? With HT? Sketch my QOL curve with and w/o HT. Now add a time scale to QOL curve. Don't PSA @ 6 months and PSA DT <12 months vs >24 months say much about prognosis, and thus the potential value of HT, with little additional risk? COLON CANCER COMPLICATIONS MAKE MY HT DECISION EASIER My carcinoid colon tumor's size (>3 cm) and lymph nodes involvement (2 of 37) => high p(recurrence), and CC mets tend to kill much faster than PC mets. It may render PC moot. Partin tables don't reduce the CC threat; they just drown it in decimal points. Why not watch PC and CC markers very closely, see which one recurs first, and THEN define treatment? Or start now with some treatment that provides some protection from both threats. Possibilities may include Provenge, Aptosyn, oncolytic viruses . . . I'm still reading and learning, but this has deadlines. I.P. My take on HT is that it is like the "Get Out of Jail" card in Monopoly - you can use it at any time but only once. Of course, here it will only get you out for a limited amount of time and it has adverse effects on QOL, as you describe. I have seen nothing to make me want to play it early when I am asymptomatic and QOL is good and important. To my knowledge it has not even been proven definitively to prolong life due to its ineffectiveness against the hormone resistant cell population, which is what eventually is fatal. Bill Denton RP 2/12/02 Memphis > My take on HT is that it is like the "Get Out of Jail" card in Monopoly > - you can use it at any time but only once. Of course, here it will [quoted text clipped - 4 lines] > due to its ineffectiveness against the hormone resistant cell > population, which is what eventually is fatal. As with all things involving prostate cancer, it may prove to be more complicated than one would like. There has been some recent research which seems to indicate that in some cases early hormone therapy may extend life. On the other hand, waiting for symptoms may be more appropriate for many men. So, when faced with a diagnosis of metastatic prostate cancer, I think you have to do your homework, get the best advice you can as it applies to your particular case, and make a decision. > Bill Denton > RP 2/12/02 > Memphis It's my impression that even those experts who don't like early HT recommend it strongly as soon as specific mets are known to exist or met symptoms appear. I'm not sure I'd wait even that long if my post-RP PSA DT is less than a couple of years. I.P. > There has been some recent research > which seems to indicate that in some cases early hormone therapy may > extend life. On the other hand, waiting for symptoms may be more > appropriate for many men. So, when faced with a diagnosis of metastatic > prostate cancer, I think you have to do your homework, get the best > advice you can as it applies to your particular case, and make a decision. > It's my impression that even those experts who don't like early HT recommend > it strongly as soon as specific mets are known to exist or met symptoms > appear. I'm not sure I'd wait even that long if my post-RP PSA DT is less > than a couple of years. How about <6 months? "A PSADT of 6 months or less *at diagnosis or after primary treatment* by RP or RT or cryosurgery most often relates to systemic (metastatic) disease." --Strum, _A Primer on Prostate Cancer_, page F30 (emphasis added). Regards, Steve J __ "Facts are stubborn things; and whatever may be our wishes, our inclination, or the dictates of our passions, they cannot alter the state of facts and evidence." --John Adams Right. That's why I'd not feel comfortable about postponing HT until symptoms showed unless my PSA DT were >2 years, as that should give me a conservative cushion. Some say the criterion is 6 months, some say 10, some want to see two years before believing the threat of mets is significantly diminished. I think that if my post-RP PSA DT were 6 months I'd probably hop onto HT right away. Just one more example of the lack of consensus in this art, and one more reason for people to get very involved in their decisions. I.P. > > > > It's my impression that even those experts who don't like early HT recommend [quoted text clipped - 7 lines] > by RP or RT or cryosurgery most often relates to systemic (metastatic) > disease." --Strum, _A Primer on Prostate Cancer_, page F30 (emphasis added). >Subject: Re: The early adjuvant HT dilemma loooooong >From: Leonard Evens len@math.northwestern.edu [quoted text clipped - 21 lines] >> RP 2/12/02 >> Memphis The larger population becomes the deadly population first, and the hormone insensitive population is a very small fraction of the hormone sensitive population early on. As for when to get rid of it... If the hormone sensitive population converts to hormone insensitive by mutation, it is supplementing the hormone insensitive populations normal multiplication. Getting rid of the large group will retard the advance of the small group. So, if Hormone Sensitive converts to Hormone Insensitive by mutation, get early hormone therapy. Contrarywise, if the presense of Hormone Sensitive retards the multiplication of Hormone Insensitive, keep it around. Fine-tuned research is needed. And as best as I can determine, A. "they" still can't determine hormone sensitivity except by experimentation with ADT, B. they can't determine which SEs one will get from ADT for close to a year on ADT, and C. T3c and Gleason 8 tend towards high hormone insensitive population -- three reasons I'm leaning towards determining my PSA DT before deciding ADT is warranted. I'd think they could try a short burst of T or ADT, observe supersensitive T response (taking flare into account), and thus estimate hormone sensitivity to a useful degree. I.P. "Danny McCarty" <roachable@aol.comneat> wrote > > The larger population becomes the deadly population first, and the hormone > insensitive population is a very small fraction of the hormone sensitive [quoted text clipped - 6 lines] > multiplication of Hormone Insensitive, keep it around. Fine-tuned research is > needed. > My take on HT is that it is like the "Get Out of Jail" card in Monopoly > - you can use it at any time but only once. Not necessarily. Some docs use it prior to "initial" treatments, including surgery or brachy and, I imagine, EBRT or IMRT. I think I remember one case where Lupron was used before and after chemo after failed RRP. Then, of course, is internmittent HT (IHT or IADT). HT is probably the most interesting aspect of current treatment. It's been around forever and yet is proably the least known as to when and where and how it is most effeciently and effectively used.  SignatureProstate Cancer Survivor (so far), not a doctor PSA 16 10/17/2000 @ 46 Biopsy 11/01/2000 G7 (3+4), T2c RRP 12/15/2000 G7 (3+4), T3bN0M0 PSA .1 .1 .1 .27 .37 .75 EBRT 05-07/2002 @ 47 PSA .34 .22 .15 .21 .32 Lupron (1 mo) 07/21/2003 @ 48 PSA .07 .05 .06 Lupron (3 mo) 8/03 (48), 12/03, 4/04 (49), 09/04 (50) non Illegitimi carborundum I think you just summarized my whole "book" in one paragraph. I.P. > My take on HT is that it is like the "Get Out of Jail" card in Monopoly > - you can use it at any time but only once. Of course, here it will [quoted text clipped - 7 lines] > RP 2/12/02 > Memphis Here's another blow against ADT/HT: Eli Lilly just admitted that Prozac, an antidepressant and common "antidote" to HT SEs, has long been known (by them) to promote violence and suicide. I.P. Small correction.....there are about 30 Prozac derivatives (SSRI's). Only Effexor has show this SE so far. My daughter and sister are both on SSRI's and I can assure you they are not suicidal or violent. I believe it was Effexor that was being prescribed for HT side effects, but will double check. (OK....checked and it is that one) Heather > Here's another blow against ADT/HT: Eli Lilly just admitted that Prozac, an > antidepressant and common "antidote" to HT SEs, has long been known (by > them) to promote violence and suicide. > > I.P. The suicidal tendencies begin if the antidepressants are stopped, from what I've seen. Tapering off and withdrawal SEs can take months. I.P. > Small correction.....there are about 30 Prozac derivatives (SSRI's). Only > Effexor has show this SE so far. My daughter and sister are both on SSRI's > and I can assure you they are not suicidal or violent. > > I believe it was Effexor that was being prescribed for HT side effects, but > will double check. (OK....checked and it is that one) Yes......unfortunately doctors didn't realize that a few years back and when my daughter wanted off Luvox, the doc told her to come off them within a week......she couldn't get off the couch due to dizzy spells. A quick call to our pharmacist (who was horrified) sorted that out.....she kept cutting them smaller and smaller till she was taking crumbs. With her it was simply dizzy spells and nausea. She is now on Welbutrin and tolerates it well......it is also known as Zyban, the stop smoking drug. Cheers......Heather > The suicidal tendencies begin if the antidepressants are stopped, from what > I've seen. Tapering off and withdrawal SEs can take months. [quoted text clipped - 9 lines] > but > > will double check. (OK....checked and it is that one) I sent that loooong HT decision letter to my surgeon this week. He called Friday to discuss it, and, given the volume of studies and books and factoids and personal criteria in it, I expected a long, detailed rebuttal (he is willing to discuss issues at length). Surpriiiise! He had bounced it off several faculty members, including the urology dept head whose name and photo are on the front of the faculty's excellent joint-effort book, "P.C. for Dummies". Even collectively, they felt my whole letter was tough to refute, that virtually every point I made was valid. In fact, some of them said it introduced some new "pearls of wisdom" to the field, which made me feel my research efforts -- aided by you people -- had really paid off. In particular, it was the first time any urologist or oncologist (these guys are both) had conceded to me the number and impact of likely and serious SEs HT patients should expect. Physicians train and swear, and their trials attempt, to prolong life to the fullest extent possible (I'm tempted to have "D.N.R." tattooed on my chest when this crap gets REALLY serious) and it dominates their mindset. I plan to ask him next visit how much that might affect his preference for early, adjuvant, asymptomatic HT. His primary logic is that with a PSA of 0.006, whatever micromets may be lurking are very vulnerable to two years of HT right now. (My counter was that 24 months of HT often means permanent SEs, possibly even the whole gamut if T never comes back, which sometimes happens after 2 years of HT.) But the bottom line is that, given my criteria, he can't argue with my approach as outlined in that letter, even though the odds my PC will return are at least 0.7 to 0.8. The encouraging factor was that it's likely to take MANY years to show up, maybe even before biochemical failure. And those years give us lots of time to establish a PSA DT, vital to determining the AD/AI mix and estimating the effectiveness of HT. If PSA DT > 2 years, I may be home free. If not, we should know by the time my PSA hits even 1.0 or 2.0. A lot of new knowledge and chemistry may be available by that time. I hope this has been useful to even just a couple of you. It surely has been to me, especially considering that this is the most complex and most vital decision I've ever faced and is not likely to be trumped until my death bed. I.P. > I hope this has been useful to even just a couple of you. It surely has been > to me, especially considering that this is the most complex and most vital > decision I've ever faced and is not likely to be trumped until my death bed. It's been extremely useful to me. Not because I had to worry about asymptomatic HT. My PSA was definitely on the rise and a still feel HT was, at that time, appropriate -- as I suspect you might. However, your data re 24-month HT has given me some new insight to whether I will go IHT before July. SignatureProstate Cancer Survivor (so far), not a doctor PSA 16 10/17/2000 @ 46 Biopsy 11/01/2000 G7 (3+4), T2c RRP 12/15/2000 G7 (3+4), T3bN0M0 PSA .1 .1 .1 .27 .37 .75 EBRT 05-07/2002 @ 47 PSA .34 .22 .15 .21 .32 Lupron (1 mo) 07/21/2003 @ 48 PSA .07 .05 .06 Lupron (4 mo) 8/03 (48), 12/03, 4/04 (49), 09/04 (50) non Illegitimi carborundum Speaking of which..... could you repost that letter? I thought I saved it, but I sure as hell can't find it. SignatureProstate Cancer Survivor (so far), not a doctor PSA 16 10/17/2000 @ 46 Biopsy 11/01/2000 G7 (3+4), T2c RRP 12/15/2000 G7 (3+4), T3bN0M0 PSA .1 .1 .1 .27 .37 .75 EBRT 05-07/2002 @ 47 PSA .34 .22 .15 .21 .32 Lupron (1 mo) 07/21/2003 @ 48 PSA .07 .05 .06 Lupron (4 mo) 8/03 (48), 12/03, 4/04 (49), 09/04 (50) non Illegitimi carborundum > I sent that loooong HT decision letter to my surgeon this week. He called > Friday to discuss it, and, given the volume of studies and books and [quoted text clipped - 35 lines] > > I.P. > could you repost that letter? I thought I saved it, > but I sure as hell can't find it. Here's the version that actually went to my doctor; those of you with less interest in it may wish to avert their eyes; it's still loooong >|8-( A very brief summary of his response and our plan follows this letter. LETTER TO DOCTOR EARLY, ADJUVANT ADT RATIONALE Sorry this is so long, but I hope skimming this in advance will save you more precious clinic time on Friday. This explains my tentative position against early ADT; maybe you can change or reinforce it. Post-RP w/ Gleason 8 T3c, I anticipate a QOL graph consisting of several years of high, asymptomatic QOL, followed by biochemical failure, then clinical failure, as my QOL curve falls from great to OK to bad to intolerable to blessed relief. Early adjuvant ADT MAY prolong life by delaying recurrence and/or refraction, but WILL produce SEs which lower the QOL graph right out of the gate, MAY prolong heartbeat by a few months if at all, and may even exacerbate refraction. Decisions, decisions . . . complicated by 3cm carcinoid colon tumor with 2 of 37 excised lymph nodes involved => high p(recurrence). So I've spent the last six weeks studying a dozen cancer books and dozens of web sites, including Walsh, PCRI (Strum, Scholz, et.al,), Lange, Marks, Blasko, Oersterling, leading universities and hospitals, NCI, ACS, NEJM, JAMA, Lancet, the VA, Harrison's Internal Medicine, etc. (I've researched medical issues on the web for many years and always wear hip boots.) MY STATUS With my PC numbers, www.prostatecalculator.org from VA => 15% chance of avoiding PSA failure for a decade. 5-yr survival CC prognosis in cases like mine (tumor>3 cm, lymph mets, midgut) ranges from 25%-75%. . . but most are discovered later than mine was. ADJUVANT TREATMENTS CONSIDERED WW, ADT1,2,3 (early or at biochemical or clinical failure), IAD, antiandrogen monotherapy, immunotherapy, angiogenesis, MAB, etc. MY SHORT LIST OF TREATMENT OPTIONS * WW until biochemical, maybe clinical, failure necessitates ADT, maybe plus * Early antiandrogen monotherapy or * Early immunotherapy or * New technologies such as Provenge or Aptosin. EARLY ADJUVANT ADTBENEFITS . . . OR LACK THEREOF * 5-yr-relapse-free ADT improvements run from negligible to 10-15% . . . not much benefit for the SEs. * Adjuvant ADT helped N=1 patients, but trials do not demonstrate clear advantages to ADT after RP w/N=0, even with PSA elevation. * Major meta-study found no evidence that early adjuvant ADT provides any advantage, even w/rising PSA; Walsh, the Mayo Clinic, Sloan-Kettering, the ACS, and universities agree (citing failure to prolong life, SEs, QOL, and accelerated refraction). * Pts w/asymptomatic mets MAY experience fewer serious complications with early, rather than late, ADT. * Finasteride monotherapy slightly improved prognosis, but => more, higher-grade refractory tumors. * ADT 2 or 3 (CAB) not promising, not curative, may promote refraction, no 5-yr benefit, more SEs. * IAD MAY delay refractory mutation, MAY extend heartbeat by 6-12 months, and MAY reduce side effects towards the end of each HT-off cycle . . . * Young G8 T3c RP pts have unacceptably high relapse and refraction rates even with adjuvant ADT, * But it's ineffective after biochemical failure w/Gleason >7. * T3c, G > 6, and/or aneuploidy => high p(AIPC) => low p(big ADT benefit). * All those results => little risk and much reward potential in delaying ADT at least until PSA DT is known. * (OTOH, accumulating evidence supports ADT w/locally advanced disease.) * Antiandrogen monotherapy w/Casodex reduces SEs to primarily gynecomastia, may be as effective as LHRH agonists or castration for locally advanced PC, and is approved in 60 countries for that purpose. ADT SIDE EFFECTS, DOWNSIDES, CONCERNS * ADT SEs, in approximate decreasing order of my concern about them: fatigue/weakness/lethargy/anemia (the earliest and most obvious andropause SE), depression, osteoporosis (seriously underreported) and attendant fractures, cognitive dysfunction, hot flashes/night sweats (and the SEs of meds that reduce them), extreme irritability, emotional turmoil, poor sleep, nausea, diarrhea, lipid elevation, liver damage, psychological stress, pronounced personality alteration, upper body muscle atrophy, weight gain, breast pain, insulin resistance, and libido/ED effects. (Surprised at that last one being last? Think about it; who'd want sex with all that other crap going on?) * ADT < 12 mo => patients suffer typical ACUTE Androgen Deprivation Syndrome (ADS; see Strum) - invariably compromising healthy, active lifestyles -- but maybe not significant CHRONIC symptoms. Chronic symptoms -- some nearly inevitable in patients treated > 12 mo -- are much more prevalent with ADT than is currently recognized or reported. * Probabilities of various SEs combine mathematically to virtually guarantee (p > .97) one or two SEs I'm not willing to accept just for a slight, debatable, statistical lifeline benefit. * Anti-SE meds (e.g., antidepressants, anabolic steroids, NSAIDS) have their own, major, SEs. * I have two conflicts with biphosphonates: NSAIDS give me ulcers and I'm on a PPI for GERD. * ADT after RP can extend life . . . if given for 28 months, but * Two years on ADT may permanently suppress T and thus maintain SEs, and * Trial ADT takes 6-12 months to reveal all its SEs - about the maximum extent of its lifeline extension. * ADT => T deprivation => SEs. T > 20 => little benefit. This may mean no pain (SEs), no gain. * ADT drives PSA down, hiding the REAL killer, AIPC, while it proliferates. * OHSU demonstrated that ADT T deprivation alters hippocampus to sharply decrease two-minute word retention (short-term memory), resembling early Alzheimer's or stroke. * Geriatric psychologist I consulted reports most of her ADT pts suffer dramatic to devastating emotional impacts, often a near absence of the emotions we want plus wide swings in the moods we don't want; she regards ADT as primarily for patients who consider a heartbeat more important than QOL, who fear death above all, or who are encountering clinical failure. * "PC for Dummies" says ADT converts Mr. Nice to Mr. Extremely Irritable. I' m Mr. Irritable awreddy. * My survey of adjuvant ADT pts on alt.support.cancer.prostate => 14 respondents => 3 w/light SEs, 5 w/serious SEs, 6 w/devastating SEs; some of the latter - and their wives -- considered ADT worse than the alternative. * Typical IAD on/off cycle => 9-16 months on, 6-9 off, w/lingering SEs dominating off cycle => little SE break => low therapeutic index. * Antiandrogen SEs = primarily diarrhea (less w/Casodex) and breast pain . . . + maybe long term PC stimulation. * PCRI/Scholz: "The biggest difference between adjuvant treatments is QOL, not survival; choose by SEs." BOTTOM LINE The few months adjuvant ADT MAY add to my life are highly likely be burdened with SEs which threaten the most important elements of my life. I'd far rather feel like an athlete, think like a student, and be a good companion to my wife for 5 years and then die than feel like road kill, think like a fencepost, and be a major PITA for 6 or 7 and die on her anyway. Life's about quality, not just quantity, and the steeper the slide from vigor to rigor, the better. Besides, Partin says my glass is 1/6 to 2/5 full; I don't want to poison it, especially with CC waiting to render my PC -- and ADT -- moot. MY PROPOSED PROTOCOL 1. Measure baseline biomarkers (e.g., PAP, CEA, NSE, CGA) to get some idea of heterogeneity/AIPC and thus likelihood ADT might help, then 2. WW, monitoring PC and CC as closely as is useful (e.g., biomarkers, creatinine, hypersensitive PSA plotted to distinguish trends from noise, bone scans (if informative), Octreoscans, any other CC markers.) for reliable indication of PSA DT, mets, and/or degree of heterogeneity, and 3. Enjoy high QOL until lab or symptoms indicate PC or CC recurrence, then initiate treatment based on which cancer recurs and the treatment options available then. 4. In the meantime, consider A or B: A. Begin now with a low-SE PC therapy such as Casodex monotherapy, or B. Begin now with a low-SE protocol which fights both PC and CC, such as immunotherapy. Possibilities may include Provenge, Aptosyn, oncolytic viruses . . . I don't usually chase unproven medical treatments, but doesn't my colon cancer present a threat we can't ignore just because the carcinoid colon cancer statistical basis is weaker than Partin's? Partin tables don't reduce the CC threat; they just outshout it with decimal points. CC concerns include: * Midgut carcinoid tumor > 2 cm (wasn't mine > 3 cm?) => p(recurrence) > 0.5. * Lymph node met raises those odds (fortunately, my 2 nodes were below the ominous four-nodes threshold). * Carcinoid recurrence kills fast. * Mine was not observable via colonocopy just three years ago, thus seems especially aggressive. (What did its pathology reveal?) QUESTIONS REMAINING Is my PC hormone-receptive (AD)? If ADTsuppresses PSA, what drives IAD timing? What is my life expectancy and risk of recurrence without HT? With HT? Sketch my QOL curve with and w/o HT. Now add a time scale to QOL curve. Don't PSA @ 6 months and PSA DT <12 months vs >24 months say much about prognosis, and thus the potential value of ADT, with little additional risk? Does all this alter your collective advice for immediate ADT? Feel free to bounce this off any of your colleagues, and to pass on their prognosis and comments to me, no matter how gloomy. Caca pasa. When it does, we deal with it. And the more we know about a threat, the better we deal with it. END OF LETTER TO DOCTOR HIS FEEDBACK, paraphrased and culled from a 20-30-minute phone call: "You pretty much nailed everything. The SEs are heavy, indeed, and very likely to have a huge impact on your active lifestyle. I hope you'll reconsider, though, because your odds of PC recurrence due to micromets run at least 70-80%, and a PSA of .006 gives us our best shot at eradicating them for good. I don't recommend RT for you because you already have some urinary incontinence and bowel incontinence is a far worse burden. You should see many years before PC recurrence, but if and when it appears, ADT will be less effective than right now. An increasing number of PC specialists disagree with the thesis that delaying ADT until biochemical or clinical failure does no harm." Our plan is very WW, including frequent testing, with consideration given to trying ADT next Fall, when it will have less impact on my spring/summer/fall lifestyle. The problem is that he advises 24 months of ADT, which tests show that testosterone, and thus SEs, may not fully recover from. More trials are under way to determine how effectiveness and recovery behave with ADT periods < 24 months (actually 28, the IAD period of one substantive trial). I'm strongly inclined to wait longer for ADT treatment unless recurrence changes my mind, but then I have a second sword hanging over my head with its own implications. Frankly, I think that second sword just reinforces, not drives, my ADT decision. I.P. >>could you repost that letter? I thought I saved it, >>but I sure as hell can't find it. [quoted text clipped - 31 lines] > mine (tumor>3 cm, lymph mets, midgut) ranges from 25%-75%. . . but most are > discovered later than mine was. This may not be terribly relevant, but this calculator is much more pessimistic than that at the Sloan Kettering website or the results that Walsh gives. For example, in my case, it predicts a 68 percent chance of being recurrence free while the Sloan Kettering nomogram predicts over a 95 percent chance. The two predictions are not even within each other's error estimates. So either one of them is way off or the populations studied are very different for some unknown reason. Perhaps the results at the Josephine Ford Cancer Center are poor for one reason or another. The Sloan Kettering nomogram has been tested at other major treatment centers, and verified. Walsh's results lie somewhere between these, but because different criteria are used, it is a bit hard to compare. Also, sometimes these guys just get the statistical analysis wrong. The prostate calculator does seem to say it is using a neural networks approach. I've seen other such approaches which also come up with pessimistic estimates. Personally, I don't see why neural networks, aside from being fashionable, should give any better results than standard well recognized statistical methods. You might try to Sloan Kettering calculator. I don't know if it will give you any more reliable information, but it may make you feel better. At least you sho9uld take an average of different predictions, and that might give you a more realistic idea of where you are. One has to view all these results with some suspicion, but if you are going to try to base decisions on the numbers, it might helpt to look at a variety of different numbers. > ADJUVANT TREATMENTS CONSIDERED > WW, ADT1,2,3 (early or at biochemical or clinical failure), IAD, [quoted text clipped - 166 lines] > > I.P. "Leonard Evens" <len@math.northwestern.edu> wrote SNIP > This may not be terribly relevant, but [the VA prostate calculator] is much more > pessimistic than that at the Sloan Kettering website or the results that > Walsh gives. SNIP > Personally, I don't see why neural > networks, aside from being fashionable, should give any better results [quoted text clipped - 7 lines] > to base decisions on the numbers, it might helpt to look at a variety > of different numbers. The VA prostate calculator has been described as the most comprehensive predictor available as recently as last Spring, and gives me a 15% chance of UD PSA @ 10 years with my specific case, Gleason 8-10 and T3cN0M0. Walsh says 41%, with less specific criteria. The Kaplan-Meier nomogram you refer to is comparatively optimistic because it addresses 5-year prognosis, not 10-year, and because it lumps T1-T2-T3 together, obscuring the dramatic prognosis variations between those stages. My surgeon was a Fellow in oncologic urology at S-K when their nomogram was developed, and his prognosis for me agrees with the VA prostate calculator. My doc specifically pins my 15% PSA-free chances on my Gleason 8, my seminal vesicle involvement (both HUGE factors in recurrence), and my bilateral tumor -- none of which is addressed by Kaplan-Meier. And since my decision is to pass on ADT for now, I'd RATHER use the most pessimistic predictor. If I were relying on the optimistic predictors, I could have saved myself weeks of research into the nuances. The Kattan nomogram at http://www.prostate-cancer.org/education/riskases/scholz_newlydiagnosed.html gives me 50% without ADT, 65% w/ADT, at 5 years -- a mere 15% improvement as payoff for all that SE misery. In addition, young men (in the eyes of PC docs) with my numbers have unacceptably high relapse rates even WITH local therapy + ADT. Actually, I don't think I'd change my decision even if my PSA-free chances were even lower. My PSA may well stay very low for 6-8-10 years, with symptoms holding off several years past that. The choice between a dozen years of high QOL vs 13 years, starting now, of feeling like road kill is an easy choice for me, especially since I may get PC again even if I DID start ADT, chemo, accupuncture, voodoo, hypnosis, and a blow torch tomorrow. The only "numbers" that might -- MIGHT -- lead me to rethink my choice would be: 1. A HUGE statistical advantage to adjuvant ADT. (I'm seeing almost no ADT or IAD advantage for T3c.) 2. A detectable PSA in 6 months or PSA DT < 24 months. Numbers, schmumbers; I'm just not willing to screw up my remaining years with any of half a dozen of the common worst ADT SEs. They rob us of half of the area beneath the QOL curve, at least until PC symptoms appear and I get actually SCARED and maybe even disabled. These freaking diapers have already interfered enough in my life, as I couldn't accompany my wife across the country to the funeral of her mother a couple of days after Christmas. Neural networks, as you know, are the latest incarnation of pattern recognition. I worked full time in that field in the late '60s and early '70s at RADC, where ARPA and the Air Force developed and applied pattern recognition theory, math, and software to achieve practical military and civilian objectives. I've also taken several graduate courses in Bayesian statistics, so I have a feel for both sides of the issue and in their overlaps. It's been too long now to remember the details, but as good as pattern recognition was 40 years ago, I've got to believe it has only improved as math and computing power have advanced. I.P. > "Leonard Evens" <len@math.northwestern.edu> wrote > SNIP [quoted text clipped - 27 lines] > 10-year, and because it lumps T1-T2-T3 together, obscuring the dramatic > prognosis variations between those stages. I don't mean to dispute what you say. I've been interested in these different predictors because they produce such different results, and that means that some of them are wrong or else they are using very different patient populations. In my case, it does make a difference to me whether my likelihood of recurrence is roughly 60 percent or 95 percent, but after 4 years without recurrence, it doesn't have any immediate effect on my life. So it is more the scientific question that puzzles me. It is clearly a much more serious matter for you. I must say that I find your rational approach to the whole thing quite admirable, and I doubt if I could think so clearly under the same circumstances. You raise very important considerations which will help some of the rest of us when and if we face similar prospects. Actually, I was referring to the nomogram at the Sloan Kettering website, which predicts 2, 5, and 7 year recurrence free rates. It doesn't refer to stage for post surgical recurrence, but lists different statuses for prostate capsule invasion. It also uses presurgical PSA and pathological Gleason score as well as margin status, etc. Kattan is one of the lead authors listed in the references. I tried putting in some figures for your case, but I wasn't sure what to include. The result is quite sensitive to which choice of invasiveness one chooses: none, InvCapsule, Focal, or Established. I'm not familiar with the Kaplan-Meier nomogram. Can you provide a reference? > My surgeon was a Fellow in > oncologic urology at S-K when their nomogram was developed, and his [quoted text clipped - 12 lines] > docs) with my numbers have unacceptably high relapse rates even WITH local > therapy + ADT. I looked at that website, and it seems to use a modified form of an earlier Kattan nomogram. It isn't what is at the Sloan Kettering website. > Actually, I don't think I'd change my decision even if my PSA-free chances > were even lower. My PSA may well stay very low for 6-8-10 years, with [quoted text clipped - 23 lines] > pattern recognition was 40 years ago, I've got to believe it has only > improved as math and computing power have advanced. Pattern recognition is the general field, but neural networks are a specific way which is supposed to help detect patterns. I found a historical discussion at www.doc.ic.ac.uk/~nd/surprise_96/journal/vol4/cs11/report.html The idea would be to have the neural network decide which factors were important in predicting recurrence by picking out a pattern. Standard statistical methods start with some known factors and then try to see how relevant they are to prediction. But since they all end up using more or less the same factors in the end anyway, I'm not sure what the pattern recognition part does. The nomograms or calculators make predictions about something that is supposed to happen to a large population of men given certain characteristics. They should produce results that are relatively similar. They also give error estimates which are supposed to specify the numbers to within 95 percent certainty. So when one prediction isn't even in the error bar of another, there is clearly something wrong with one prediction or the other. Either the statistical analysis is wrong or the two populations being studed are very different. > I.P. "Leonard Evens" <len@math.northwestern.edu> wrote > > I'm not familiar with the Kaplan-Meier nomogram. Can you provide a > reference? > > I looked at that website, and it seems to use a modified form of an > earlier Kattan nomogram. It isn't what is at the Sloan Kettering website. Sorry, but I can't find the plot I referred to, and it wasn't sufficiently impressive to look any longer. It was a simple plot of 5-year prognosis for T1-T2-T3 lumped together. While looking, I ran across this interesting collection of PC graphs and discussions I'd not seen before: http://www.baylorcme.org/prostate/presentations/morton/presentation_text.cfm I can't access the Sloan-Kettering calculator their site refers us to. My firewalls and some computer bugs inhibit some websites, and I haven't the time to work around them. My standalone home computer, for example, does not accept me as its Adminstrator, and Dell can't solve the problem. If they can't resolve that in several LONG phone sessions, I sure as heck can't solve it with a few keystrokes or a magazine chapter. I.P. > ... The prostate calculator does seem to say it is using a neural > networks approach. I've seen other such approaches which also come up > with pessimistic estimates. Personally, I don't see why neural > networks, aside from being fashionable, should give any better results > than standard well recognized statistical methods. Neural networks may give better results for a variety of reasons. Whether they actually do is a question best left to appropriate testing. I assume by "pessimistic", you mean that estimated probabilities of undesireable outcomes are biased high. If this is the case, it should show up in the testing. Regardless, it would seem that the most accurate method is the "best", without regard to being either "standard" and "well recognized" on the one hand, or "fashionable" on the other. -Will Dwinnell http://will.dwinnell.com > > ... The prostate calculator does seem to say it is using a neural > > networks approach. I've seen other such approaches which also come [quoted text clipped - 12 lines] > "standard" and "well recognized" on the one hand, or "fashionable" on > the other. I'm a programmer and I have no idea why they even mention neural nets. Seems that there are only a few variables and the internal logic of the calculator could be expressed by a couple case statements, maybe a table lookup. There isn't a pile of subtle data to "tease" out of your vitals, T, Gleason, PSA, whatever. I'm afraid that they are hyping the "magic" in their calculators and it's not much better than saying, "Oh, we're not sure but here's a guess." My understanding is that it's almost binary. If the cancer has spread, that's a big problem but there are treatments. If the cancer hasn't spread AND if it's been torched through radiation or been surgically removed, then the issue remaining are the side effects. Well, except for those cases where the cancer has metasticized but the number of cells is so low that it'll take years to build up to a problem, unless it's unusually aggressive. The PSA trends tell this story. So we look for a low or falling PSA and hope for the best. >>>... The prostate calculator does seem to say it is using a neural >>>networks approach. I've seen other such approaches which also come [quoted text clipped - 24 lines] > There isn't a pile of subtle data to "tease" out of your vitals, T, > Gleason, PSA, whatever. That was my feeling, but I don't claim to be an expert in either neural networks or biostatistics. > I'm afraid that they are hyping the "magic" in their calculators and > it's not much better than saying, "Oh, we're not sure but here's a > guess." > > My understanding is that it's almost binary. If the cancer has > spread, that's a big problem but there are treatments. It is more like three alternatives. (1) The cancer metastasized before the treatment begins. Then the treatment ultimately will prove ineffective, although treatment could slow it down because the primary source is removed. (2) the treatment doesn't remove all the cancer but what remains is still confined to the local area. In that case, it could still be removed by follow-up treatment, or, if not caught in time, it could metastasize. (3) The cancer has been removed entirely. Then it can't recur. If some prostate tissue remains behind, though, it is possible a new cancer could develop later. Unfortunately, that's really a model we have in our minds of what is happening, and although it makes a lot of sense, the biology in our bodies may be more subtle than is captured by the model. In the end, there is only the observed data. > If the cancer hasn't spread AND if it's been torched through > radiation or been surgically removed, then the issue remaining are [quoted text clipped - 4 lines] > problem, unless it's unusually aggressive. The PSA trends tell this > story. It does appar that there are a whole range of possibilities even after metastasis. > So we look for a low or falling PSA and hope for the best. > >>>... The prostate calculator does seem to say it is using a neural > >>>networks approach. I've seen other such approaches which also come [quoted text clipped - 27 lines] > That was my feeling, but I don't claim to be an expert in either neural > networks or biostatistics. I should add that I am not an expert either. I have no understanding of neural nets other than glancing at a couple lay descriptions. My knowledge of cancer dynamics is limited to reading a few popular books (PC for dummies, Grimm-Blasko-Sylvester, the out-of-date Hopkins book, etc.) after my own diagnosis. I took one AI class in graduate school but I did not gain any insight. I did play with the website that offered the neural net based calculator and it seemed simplistic. > > I'm afraid that they are hyping the "magic" in their calculators and > > it's not much better than saying, "Oh, we're not sure but here's a [quoted text clipped - 12 lines] > Then it can't recur. If some prostate tissue remains behind, though, > it is possible a new cancer could develop later. Yes, it's something like that. > Unfortunately, that's really a model we have in our minds of what is > happening, and although it makes a lot of sense, the biology in our > bodies may be more subtle than is captured by the model. In the end, > there is only the observed data. I think there is a long-lived shower of sparks model, groups of ten, fifty, a hundred cells are floating around. Too small a colony to be detected by PSA tests. Perhaps in most cases, they wink out of existance. Maybe they are pre-cancerous and won't cause a problem. But then, in a few cases, one cell in a small colony shifts to full cancer mode and after years, the cancer starts up again. The books say that a biopsy, surgery, or seeding won't spread the cancer but I don't see why breaching the capsule doesn't lead to that, at least in a few cases. > > If the cancer hasn't spread AND if it's been torched through > > radiation or been surgically removed, then the issue remaining are [quoted text clipped - 7 lines] > It does appar that there are a whole range of possibilities even after > metastasis. Yes, it seems more complex than the docs present to us. I clocked a 0.0 PSA after the IMRT and a couple weeks after the Palladium-103 seeding. One of my docs recommends 2 years on Lupron as a general rule and advises at least a year for me. I'm at month 8 on Lupron with a zero PSA. Why does he recommend a 3rd four month shot? It's because this is more complex than it appears and he's trying to tilt the odds with the only tools at his disposal. I think that even post-treatment, it makes sense to use the preventative guidelines, tofu, flaxseed, and other herbal remedies. It's not a guarentee but maybe it will tilt the odds slightly. > > So we look for a low or falling PSA and hope for the best. > The books say that a biopsy, surgery, or seeding won't spread the > cancer but I don't see why breaching the capsule doesn't lead to > that, at least in a few cases. The theory, which appears in Walsh's Guide to Surviving Prostate cancer, is that cells escape the prostate all the time, including cancer cells if present. That is not what is supposed to lead to metastasis. Instead, the cancer cells have to develop the ability to live outside the prostate, which is their normal environment. That is what leads to metastasis. This theory seems to be supported by clinical evidence. For example, if surgery itself led to significant risk of metastasis, then you might expect external radiation to yield signficantly lower rates of recurrence than surgery for similar cases. According to Walsh there is no evidence for major cancers that biopsies or surgery lead increase the risk of metastasis. And he refers on p. 165 to a paper in the Journal of Urology (by Partin, it appears) that confirms the theory described above. Of course, it is possible that it does happen in a small number of cases but at such a low level that it is hidden in the observational noise. > Yes, it seems more complex than the docs present to us. > [quoted text clipped - 3 lines] > One of my docs recommends 2 years on Lupron as a general rule and > advises at least a year for me. I know that HT is often used in conjuction with radiation. It appears that the radiation makes the cells more susceptible to damage by radiation. But I don't really understand the basis for continuing the HT for an extended period of time afterwards. Perhaps it was just one more thing to try and initial studies showed it was helpful in some cases. > I'm at month 8 on Lupron with a zero PSA. Why does he recommend a > 3rd four month shot? [quoted text clipped - 4 lines] > I think that even post-treatment, it makes sense to use the > preventative guidelines, tofu, flaxseed, and other herbal remedies. As long as they don't cause other problems. Unfortunately, virtually anything you do can have both beneficial and detrimental side effects. For example, including lots of calcium in your diet may be helpful in a variety of ways, including controlling blood pressure. On the other hand, it may increase the risk of prostate cancer in the first place and presumably its development after treatment if any is left in your body. To make it more complicated, it is possible that lots of fruit in your diet can protect you from increased calcium. Some herbal remedies have proven to be highly detrimental. I learned from a Frontline presentation that a bipartisan combination of a conservative Republican and moderate Democrat had protected the dietary supplement industry from the same regulation that prescription drugs must abide by. As things now stand, the FDA has to wait until there is evidence of significant undesirable side effects before they can act. For prescription medications, studies have to show a medication is safe and effective before release, though as we've seen with the Cox-2 inhibitors that large scale studies can sometimes reveal problems afterwards. > It's not a guarentee but maybe it will tilt the odds slightly. > > > >>>So we look for a low or falling PSA and hope for the best. On January 11, Leonard Evens wrote, in pertinent part: (su-nip) > I know that HT is often used in conjuction with radiation. It appears > that the radiation (sic: HT, properly called ADT) makes the cells more > susceptible to damage by > radiation. But I don't really understand the basis for continuing the > HT for an extended period of time afterwards. Perhaps it was just one > more thing to try and initial studies showed it was helpful in some cases. It is used in cases such as mine, a high Gleason (8-9) with low PSA (baseline 5.7). The substantial danger that such a cancer has a high aneuploid cell population, coupled with its highly-aggressive tendency to shed cells into the bloodstream, make it prudent to "starve" those cells of the testeosterone and DHT upon which they are (we hope) dependent. The means of doing so is suppression of testosterone production by means of ADT. (su-nip) Regards, Steve Jordan __ "Never give in--never, never, never, never, in nothing great or small, large or petty, never give in except to convictions of honour and good sense. Never yield to force; never yield to the apparently overwhelming might of the enemy.'' --Sir Winston L. S. Churchill |
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