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  • The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and PSA

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    Old 06-25-2021, 09:22 AM   #1
    IADT3since2000
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    Lightbulb The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and PSA

    Hi John, Djin, and others interested in the questions raised by Djin in post #44 of the thread entitled “How dire is this path report. Gleason 5+4” for high-risk patients of how we should keep a score for success of a treatment for prostate cancer, of the odds of going from a recurrence indicated by PSA to a clinical recurrence that will often involve symptoms or images showing progression of cancer, and whether surgery plus radiation is likely superior or inferior to going straight to radiation. Djin wrote:

    Quote:
    Originally Posted by DjinTonic View Post
    The graph at Jim's link

    https://prostatecancerfree.org/compare-prostate-cancer-treatments-high-risk/

    uses data from studies that do not look at overall survival, cancer-free survival, or even metastasis-free survival, but rather BCR (biochemical recurrence, a return of a rising PSA, over 0.2 for post-RP patients or 2.0 over the post-radiation nadir for post-RT patients. Leading radiologists are now saying that BCR is a poor outcome measure for RT studies. The problem for newer modalities like EBRT+brachy boost is that there aren't long-term survival stats....
    That is a thoughtful and seemingly common sense point about what scoring unit should be used for prostate cancer, but in this case the devil is very much in the details, and the point is not valid. The bottom line: for many kinds of prostate cancer trials, achieving superior non-recurrence rates based on PSA is the best way of keeping score. Djin, you are one of the best informed and thoughtful participants on the Board in my opinion. If you don’t see why PSA is useful and sound as a scoring unit in trials, then no doubt many others also don’t understand, and are suspicious of very impressive success rates for radiation in recent years. And it’s not just people coming to our Board: many physicians working in prostate oncology also have trouble understanding why PSA scoring is valid, including some noted researchers. The reasoning is not that complicated, but the deeply ingrained commitment to overall survival (OS) as the best scoring unit is in effect a set of blinders that prevents a sound view of prostate cancer reality. What follows is very clear to me, but I’ve been doing this for years. If any point is unclear or seems not valid to any reader, I hope the reader will raise the issue in this thread.

    The following is my take on this score-keeping issue, and I doubt that many of us board participants and newcomers are interested in this kind of “fine print” issue. If you are not, please don’t hesitate to switch back to another thread. This is a long post, and it isn’t for everybody. However, how we score success or failure in clinical trials for prostate cancer is a very important, fundamental issue, so I have tried to cover what I see as key points, with examples. It may look as if I’m posing as an authority on scoring units (“endpoints”) for clinical trials and on prostate cancer survival. I have picked up a lot of information over the years and have highly relevant education, but I am a layman without medical credentials– not an expert, and if I have missed the point somewhere, it wouldn’t be the first time. I welcome discussion of any points I’ve made here.

    My background: I’ve been involved in how we score success against prostate cancer for a very long time now, starting about this time in June 2004 in a large “workshop” of experts in prostate cancer who were focused on this issue, calling it prostate cancer study “endpoints”; I was there in the public audience. I had an advantage in my education, which featured 225 classroom/lab hours in experimental design and statistics, as well as a lot of additional math, related graduate study, plus career experience. While the experts all had far more knowledge of the disease than I did, I suspect that a majority did not have anywhere near as much or even an adequate education in experimental design and statistics. After all, would you want your surgeon or radiation oncologist to have spent many of his undergraduate hours studying statistics, or would you want him or her to have focused on biology and chemistry?

    A critical lesson I had learned is that what you use to keep score must match the reality of what you are scoring. It seems obvious, but I’ve seen many prostate cancer studies where that fundamental is violated, rendering results useless. The grossly bungled recommendations against prostate cancer screening from the US Preventive Services Task Force in 2012 are a prime example of flawed research and incompetent interpretation. (The latest USPSTF panel did much better, though still short of ideal.)

    Prostate cancer is a challenge for trial design because, with the exception of patients with widespread metastases at diagnosis, we patients are blessed with remarkably long survival, often outliving the disease even when we are diagnosed with serious, challenging cases. Per widely accepted data, survival of all prostate cancer patients at the 10 year point is about 99% compared to age matched peers without prostate cancer, and survival at 15 years is in the mid-90%s. (Those with widespread mets at diagnosis pull down the survival rate and still do not usually do well on average even at the 5 year mark (though there has been recent progress), but they represent a very small percentage of patients these days and therefor have only a small impact on survival figures for all patients). The long survival of prostate cancer patients clashes with much shorter survival at 5, 10 and 15 years for most other major cancers. For pancreatic cancer, to use an example from the other end of the survival spectrum, odds of surviving at the 5 year point are less than 10%! What this means is that “overall survival” (OS) is an excellent way of scoring success of treatment for cancers that are more like pancreatic cancer because overall survival is an unambiguous, crystal clear statistic and clear results can be obtained within a few years. That makes studies for pancreatic cancer easy to score and feasible as it is not hard to hold a research team together and manage a protocol for just a few years. But we prostate cancer patients are not like the other cancer patients!

    Also, unfortunately for patients but thankfully for researchers, there has not been a lot of dramatic progress for pancreatic cancer, the pace of progress that tends to make patients reluctant to commit to clinical trials and often makes results of long trials meaningless because the findings are at least somewhat obsolete. Contrast that with research/clinical progress in radiation and supportive technologies, such as imaging, for prostate cancer. Advances continue. SBRT is the latest most prominent form of radiation treatment, but look how advances keep occurring. When I was diagnosed in 1999, conventional doses of radiation were usually delivered with “conventional” delivery systems; even then “3-D Conformal” radiation was emerging and would soon replace conventional delivery. 3-D Conformal was soon replaced by IMRT. IMRT with conventional dosing was soon replaced by what was then referred to as “escalated dosing”, in other words higher dosing that could be delivered safely because of better precision of dose delivery permitted by IMRT. By 2007 advanced imaging was rewriting what could be done with higher-dosed IMRT and was soon replacing much inferior imaging/targeting, further improving dose delivery. About this time better understanding of the role of ADT in support of radiation was being developed, as was pelvic dosing. Soon SBRT was emerging as a promising method that was even better than advanced image guided IMRT dosing at the time. All the while, other types of radiation, such as protons and brachytherapy, were also advancing. Now, systemic targeted radiation with a PSMA seeker hooked to a Lutetium isotope cancer killer is emerging – not external beam, not protons, not seeds, indeed a new way of delivering radiation. That’s a lot of progress in just two decades, and thinking about that progress spotlights the problem of obsolete-on-publication for trial score keeping units that require long follow-up, in other words overall survival, prostate cancer specific survival, and even at times metastasis free survival.

    With survival for prostate cancer patients nearly perfect at 10 years, and falling just a few percentage points by 15 years, a study using overall survival for a new treatment would have to be at least 10 years long, and unless it were quite a few years longer, would have to be very large – perhaps many thousands of patients – in order for statistical differences in overall survival to be “statistically significant”. That is so clear to me, but if it seems hard to see, consider that you are really counting on differences in the number of patients dying in the treatment versus the placebo/traditional treatment group, compared to the overall size of each group, to tell whether your new treatment gives you an advantage, and with a tiny death rate at 10 years, you have to have a huge number of patients in the study to allow statistical tests to determine meaningful differences.

    It’s hard to get funding for such large studies. It’s hard to sustain a research team, even with substitutions, over a 15 to 25 year period. And it’s extremely likely, with prostate cancer, that your results will be only useful for academic history by the time they are published, provided you can even find a peer-reviewed journal that considers them worthy enough for publication because they have been overtaken by progress.

    Moreover, for private companies that are researching new drugs or other products, keeping investors happy during a long period with no return on the investment is a very real problem; a prime example is Dendreon Corporation’s development of Provenge, with approval finally coming in 2010: with overall survival as critical endpoint at the time for approval by the FDA, investors were getting quite unhappy and restive as patients in the trial were not dying fast enough. (Those of us late-stage patients in trials do our damnedest to stay alive, while investors need to see us die so they can see a return on their investment.) Death threats were made against Dr. Howard Scher, MD, MSKCC, and Dr. Maha Hussain, MD, U. of Michigan, both prominent and highly productive prostate cancer doctors/researchers, when they called for consideration of more research that would have at the time and later did delay approval. The main hearing on Provenge was in 2007, but the FDA overruled its advisory committee which favored approval in 2007, calling for completion of more research, and that delayed approval for three years. Dendreon spent a billion dollars developing Provenge and getting it through the approval process, which wasn’t certain, and with competitors nipping at its heels for potential market share. Dendreon went into bankruptcy but later recovered. I’m not an investment expert, but I would bet that the daunting challenges of long clinical trials deter many companies from developing promising new drugs.

    This makes overall survival (OS), and for similar reasons prostate cancer specific survival (PCSS), poor and impractical main scoring units for prostate cancer research except for men with late state disease with widespread metastases, a very important group where many advanced treatments are usually tried first (and where sufficient survival results unfortunately accumulate in just a few years), with later migration to less advanced patients, where they typically are much more effective. However, studies for less advanced prostate cancer patients, often with follow-up well under 10 years, at times state ‘There was no significant difference in overall survival” as if that finding indicated lack of impact, when in fact, because of the long survival for less advanced patients, that statement is absolutely worthless except to indicate that the treatment itself was not lethal in the short term.

    The FDA had a real problem for years in accepting as evidence anything other than overall survival, or disease specific survival results to support applications for approval of prostate cancer drugs and treatments. The FDA was so used to short average survival for other cancers and even for prostate cancer a couple of decades earlier that their experts would not consider other evidence. It was just extremely difficult and often impossible to get a drug, device, etc. approved unless you could demonstrate an advantage with those units (OS or PCSS), or an improvement in quality of life. That inertia is kind of understandable when we keep in mind that such data is not hard to get for many other major cancers and deadly diseases. However, with a lot of advocacy work by savvy physicians, researchers, prostate cancer organizations and survivors, the FDA has loosened up somewhat in recent years. That brings us to metastasis free survival (MFS) as a scoring unit.

    Metastases that end with the patient’s death (not all do, especially in this modern era and when they are not widespread), occur typically several years before mortality. A now old article observed that patients with metastases in the skeleton whose ADT began to fail to control the cancer survived for an average of 40 more months – 3 1/3 years, measured from the date that ADT began to fail, and metastases often are present for some time before that point. (https://pubmed.ncbi.nlm.nih.gov/15017212/) That makes metastasis free survival (MFS) a more practical endpoint than overall or prostate cancer specific survival because MFS occurs years earlier. For some trials, the predicted time to metastasis is a reasonable primary scoring unit because it means the trial will likely complete at a sufficiently timely date to be meaningful and practical. For other trials, that is not the case. For instance, for intermediate-risk prostate cancer patients having radiation therapy, where detectable metastases, if any, are very unlikely to occur for many years, and in view of the rapid progress in radiation and associated technologies, MFS is often likely to be a poor primary endpoint, though it may be somewhat useful in a secondary supporting role. That may change if more trials begin to use the highly sensitive and specific scans, such as the Axumin and two PSMA PET scans, as those advanced scans are able to spot micro-metastases years before a conventional (technetium) bone scan and CT scan combo would reveal them. However, the advanced scans are a lot more expensive, and as scanning all patients in a trial at least once and likely more than once would require a lot of additional funding. As obtaining funding for a trial is a big deal, and as patients with fairly early stage prostate cancer are very unlikely to have any metastases, there is a large cost-effectiveness obstacle in the way of wide use of such scans in trials. Unfortunately, the older less expensive scans are just not that sensitive or specific – in short not that accurate and reliable, to give high confidence in their results.

    So where does that leave us regarding “overall survival” (OS), “prostate cancer specific survival” (PCSS), and “metastasis free survival” (MFS) as primary scoring units for studies of treatments, especially for earlier stage patients (particularly non-metastatic or minimally metastatic), such as for radiation, where technology for the treatment itself as well as supportive technology is developing at a quick pace? Basically, none of them are going to be of much use to answer questions in a timely way so that treatments can move from the research lab to the clinic where they benefit you and me. Those doctors and researchers who won’t accept the validity of a new treatment unless it is based on those endpoints are, in effect, like the young child who tries to force a square object into a round opening in one of those box type puzzles that teach kids about shape. It just won’t work. So what can you do to address the challenge of an emerging new technology, such as the awkwardly named Stereotactic Body Radiotherapy, known as SBRT? (As most of us here know, SBRT basically means giving higher doses to the patient but fewer of them, such as giving a full course of treatment in just 4 or 5 sessions instead of around 39 or 40 sessions.)

    That brings us to the old standby for many trials but not so much for approval by the FDA, though with hopeful signs of loosening up: PSA, where the researchers look for a change in PSA as the primary indicator whether the drug, device, treatment, etc. is working or not. The beauty of PSA is that it reflects changes in the cancer quickly and fairly reliably. We know it isn’t perfect; there are some fairly rare types of prostate cancer that do not produce much PSA, and PSA won’t work as a primary scoring unit for those types. We also know that other factors can influence PSA, though researchers can make pretty good adjustments for such factors. We know that PSA is not that great for a substantial proportion of late-stage patients (where OS, PCSS or MFS are effective and should be used with PSA often in a secondary role). We also have learned that the success of some therapies is not going to be reflected in PSA changes, or at least not be reflected in a timely manner (e.g, some immune system therapies). On the other hand, we know that PSA as a primary scoring unit is a very good indicator of success or failure for many circumstances, especially with the vast majority of patients as they are “early stage”, and that is why PSA is such a popular research score-keeping tool. If the PSA is rising significantly after treatment, adjusting for temporary “bounces” after radiation, that is a strong indicator of recurrence as well as an early indicator of risk of subsequent metastases and shortened survival (unless countered, if needed, with other treatment). PSA is not a perfect indicator, but it is timely and has sufficient reliability based on hundreds if not thousands of clinical trials. To me, it makes abundant sense to put that PSA tool to use. While there are some PSA skeptics among doctors/researchers, there is an abundance of PSA believers.

    CONTINUED IN THE FIRST RESPONSE DUE TO SPACE LIMITATIONS

     
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    Old 06-25-2021, 09:27 AM   #2
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    CONTINUED FROM FIRST POST

    Getting back to SBRT, as an example for using PSA as the primary score unit in research, established knowledge of physics, biology and chemistry enabled pioneers to predict that giving fewer but higher doses for a lower total cumulative dose than in traditional IMRT (Intensity Modulated Radiation/Radio Therapy) would actually deliver a higher, more desirable and effective “biological dose”, in theory meaning that the rate of recurrent cancer after treatment should be even lower than traditional IMRT dosing, which was already notching impressive research results. Advances in targeting and imaging enabled them to predict success in achieving tolerable side effects. The pioneering doctors/researchers put that to the test using PSA as the primary end point of success, with awareness that a follow-up of patients in trials for at least five years, as had been proven in many other trials, would be a reliable period for gauging both effectiveness against prostate cancer and success in holding down the impact of long-term side effects. The researchers were able to demonstrate both effectiveness and an acceptably low impact from side effects, with the consequence that SBRT has become very popular.

    If anyone knows of any researchers/doctors, any “radiologists” as Djin put it above, who disagree that these OS and PCSS are poor primary scoring units for early stage patients, I would like to know who they are. I will likely contact them. (I’m not shy: I ask questions from the audience regularly at prostate cancer conferences; I have delivered oral statements at FDA Advisory Committee hearings; and I’ve communicated strong objections to the US Preventive Services Task Force to encourage them to a sound understanding of PSA screening for prostate cancer.) Through the years I’ve become aware of some physicians with excellent reputations, certainly very fine doctors, who trip-up over fundamentals of experimental design and statistics, areas where many doctors have little education or experience; being a coauthor for published clinical trials is no assurance that the doctor has played an important role in trial design, execution management or statistics; for instance, the doctor/co-author may have simply enrolled patients in the trial and given them the trials treatment. (If the MD co-author is also a PhD, a fairly rare combination, there is a substantial likelihood that he or she is versed in statistics and trial design/management, and there are other exceptions, with some docs becoming savvy in these skills through The School of Hard Knocks.) Also, overall survival or prostate cancer specific survival are meaningful as secondary scoring units as you want to make sure your treatment itself is not causing deaths directly or indirectly, and treatment-caused death is not affected by the long typical survival of prostate cancer patients, so OS and PCSS are useful for assessing treatment caused deat. (As an example, years ago, estrogen taken orally, specifically diethylstilbestrol (DES), proved to work great against prostate cancer; however, it also proved to significantly increase cardiovascular risks, such as for strokes, and that resulted in its discontinuance for prostate cancer treatment. Note that these risks are not significant for transdermal estrogen (through the skin, such as patches or gels), which has several roles in prostate cancer management.)

    For anyone who has read all of this, thanks for your attention. You deserve an award of some kind!

    As I said at the outset, I welcome questions and different points of view.

    I hope this has been helpful.

    ….Jim

    - - - - - - - - - - - - - - - - - - - - - - - -
    21 years as a survivor. Doing well. Diagnosis Dec 1999 PSA 113.6 (first ever), age 56
    Gleason 4+3=7 (J. Epstein, JHU), all cores +, most 100%; "rock hard" prostate with ECE - stage 3, PNI, PSADT determined later 3-4 months; technetium bone scan and CT scan negative; prognosis 5 years.
    Later ProstaScint scan negative except for one suspicious small area in an unlikely location. ADT Lupron as first therapy, in Dec 1999, then + Casodex in March 2000, then + Proscar and Fosamax in Sep 2000. Rejected for surgery January 2000; offered radiation but told success odds were low; switched to ADT only vice radiation in May 2000, betting on holding the fort for improved technology; PSA gradual decline to <0.01 May 2002. Commenced intermittent ADT3 (IADT3) with first vacation from Lupron & Casodex. Negative advanced scans in 2011 (NaF18 PET/CT for bone) and 2012 (Feraheme USPIO for nodes and soft tissue). With improved technology, tried TomoTherapy RT, 39 sessions, in early 2013, plus ADT 3 in support for 18 months (fourth round of IADT3), ended April 2014. Continuing with Avodart as anti-recurrence shield. Current PSA remarkably low and stable at <0.01; apparently cured (Current PSA as of 12/2/2020). (Current T 93 12/2/2020.) Supportive diet/nutrition, exercise, supportive medications during this journey, as well as switches in antiandrogen, 5-ARI, and bone drugs. Barely noticeable side effects from radiation; continuing low T, likely do to long use of ADT, but good energy and adequate strength. I have a lot of School of Hard Knocks knowledge, and have followed research, which has made me an empowered and savvy patient, but I have had no enrolled medical education. What I experienced is not a guarantee for all but shows what is possible.

     
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    Old 06-25-2021, 09:58 AM   #3
    DjinTonic
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    Long-term biopsy outcomes in prostate cancer patients treated with external beam radiotherapy: a systematic review and meta-analysis (2021, Review, Full Text)

    https://www.nature.com/articles/s41391-021-00323-6

    "Biochemical failure (BCF) after EBRT is the most established predictor of PCa recurrence. BCF is currently assessed using the Phoenix criteria, defined as a rise by 2 ng/ml or more above nadir prostate specific antigen (PSA) levels [5]. Despite its obvious benefits, the primary drawback of BCF is that it does not discriminate between locally recurrent disease and metastasis. Increasingly for the assessment of local tumour control, imaging and biopsy are used [4]. Both multiparametric magnetic resonance imaging (mpMRI) and prostate specific membrane antigen-positron emission tomography (PSMA-PET) have shown promise in detecting residual or recurrent cancer after EBRT but can be difficult to interpret due to treatment related changes in the prostate and spatial resolution [6,7,8]. Therefore, to confirm recurrence or residual disease, biopsy is usually performed."

    This is just one point.

    That long-term OS and PCa-Free survival stats are hard to collect doesn't address any problems with BCR stats.

    My other concern is that PSA takes a fairly long time to drop post-RT in the best of oncological outcomes. Does one really know what's going on with PCa-survival/metastases during this period? You have to wait for any PCa-induced PSA rise overtakes the PSA downward curve after RT (I assume the 2 years of SOC ADT for high-grade men opting for RT is for this purpose.) And YES, PSA can be an exquisite measure of cancer control in post-RP men. However, most men who have BCR do not go on to clinical recurrence. John's Hopkins originally proposed 0.4 as an "official" mark of BCR because many of their patients had post-op PSA that rose, but then plateaued.
    ________________________________________ _______________
    Prognostic Value of Biochemical Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic Review (2018, Review, Full Text)

    https://www.sciencedirect.com/science/article/pii/S0302283818307528?casa_token=42-Ts_wa-fQAAAAA:5U-Wg3h9vno6JOiyTgc3aGL5-CzdakBdpc9op6MYT6K80H6bITZxHQx9Qjc9Rg-pBUC9tQ6Q

    "Conclusions
    BCR has an impact on survival, but this effect appears to be limited to a subgroup of patients with specific clinical risk factors. Short PSA-DT and a high final Gleason score after RP, and a short IBF after RT and a high biopsy Gleason score are the main factors that have a negative impact on survival. These factors may form the basis of new BCR risk stratification (European Association of Urology BCR Risk Groups), which needs to be validated formally."
    ________________________________________ _____________

    Event-Free Survival, a Prostate-Specific Antigen-Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation

    https://opus.cloud.lib.uts.***.au/handle/10453/145849

    "Purpose
    Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion.

    ...

    Conclusion
    EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials."

    Djin
    __________________
    69 yr at Dx, BPH x 20 yr, 9 (!) neg. Bx, PCA3-
    7-05-13 TURP for BPH (90→30 g) path neg. for PCa, then 6-mo. checks
    6-06-17 Nodule on R + PSA rise on finasteride: 3.6→4.3
    6-28-17 Bx #10: 2/14 cores: G10 (5+5) 50% RB, G9 (4+5) 3% RLM
    Nodule negative for PCa. Bone scan, CTs, X-rays: neg.
    8-7-17 Open RP, negative frozen sections, Duke Regional Hosp.
    SM EPE BNI LVI SVI LNI(5L, 11R): negative, PNI+, nerves spared
    pT2c pN0 pMX, G9 (4+5) 5% of prostate (4.5x5x4 cm, 64 g)
    Dry; ED OK with sildenafil
    Decipher 0.37 (Low Risk), uPSA: 0.010 (3 mo.)...0.023 (4 yr. 6 mo.)

     
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    Old 06-26-2021, 05:33 AM   #4
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    Whether Prostate Cancer Is Still Aggressive In the Early Years After Radiation

    Hi Djin, and thanks for raising concerns about the original topic. I've been looking at that first study and will have comments later. Right here is a good place to consider one of your concerns that is not on the topic of how we score clinical trial results for prostate cancer but is likely on the minds of many patients considering radiation for intermediate and advanced prostate cancer (with low-risk patients better handled with active surveillance, in most cases). You wrote:

    Quote:
    Originally Posted by DjinTonic View Post
    ...My other concern is that PSA takes a fairly long time to drop post-RT in the best of oncological outcomes. Does one really know what's going on with PCa-survival/metastases during this period? You have to wait for any PCa-induced PSA rise overtakes the PSA downward curve after RT (I assume the 2 years of SOC ADT for high-grade men opting for RT is for this purpose.)...
    I think you have identified both a problem - remaining aggressiveness of cancer after radiation, and a solution: ADT.

    To me there is clear, convincing evidence that for many men radiation by itself is not able to cure cancer in a substantial portion of intermediate- and high-risk men. The key evidence is in trial results showing that radiated patients in higher risk groups who are not on ADT, though some are cured, have their cancer recur substantially more often than men who are on ADT. Moreover, trials have demonstrated that the length of ADT matters: for high-risk men, shorter ADT, 6 months as I remember it but not certain, was substantially inferior to two years of ADT, but two years was as good as three years, and it appears that 18 months may be as good as two years. (Trials have also demonstrated that a short course of ADT for just 4 months is sufficient for intermediate-risk patients, with favorable intermediate-risk patients (Gleason Group 2, the GS 3+4=7 guys), not needing ADT in some circumstances.

    I'm impressed with how major medical advances can occur when two or more therapies that cannot do the job of curing patients on their own are combined with stunning success. Drug combinations that now routinely cure testicular cancer, which often strikes young men (remember Chicago Bears player Brian Piccolo as memorialized with Gayle Sayers in the movie classic "Brian's Song") were ineffective when given as individual, stand-alone medications. Another example that we know well is surgery for high-risk prostate cancer; you have been fortunate, but as we all know, many men need follow-up radiation to achieve a decent chance of a cure. The combo works! Now we are having the debate about which is the best combo overall and which patients may be better suited for one approach versus others.

    ….Jim

    - - - - - - - - - - - - - - - - - - - - - - - -
    21 years as a survivor. Doing well. Diagnosis Dec 1999 PSA 113.6 (first ever), age 56
    Gleason 4+3=7 (J. Epstein, JHU), all cores +, most 100%; "rock hard" prostate with ECE - stage 3, PNI, PSADT determined later 3-4 months; technetium bone scan and CT scan negative; prognosis 5 years.
    Later ProstaScint scan negative except for one suspicious small area in an unlikely location. ADT Lupron as first therapy, in Dec 1999, then + Casodex in March 2000, then + Proscar and Fosamax in Sep 2000. Rejected for surgery January 2000; offered radiation but told success odds were low; switched to ADT only vice radiation in May 2000, betting on holding the fort for improved technology; PSA gradual decline to <0.01 May 2002. Commenced intermittent ADT3 (IADT3) with first vacation from Lupron & Casodex. Negative advanced scans in 2011 (NaF18 PET/CT for bone) and 2012 (Feraheme USPIO for nodes and soft tissue). With improved technology, tried TomoTherapy RT, 39 sessions, in early 2013, plus ADT 3 in support for 18 months (fourth round of IADT3), ended April 2014. Continuing with Avodart as anti-recurrence shield. Current PSA remarkably low and stable at <0.01; apparently cured (Current PSA as of 12/2/2020). (Current T 93 12/2/2020.) Supportive diet/nutrition, exercise, supportive medications during this journey, as well as switches in antiandrogen, 5-ARI, and bone drugs. Barely noticeable side effects from radiation; continuing low T, likely do to long use of ADT, but good energy and adequate strength. I have a lot of School of Hard Knocks knowledge, and have followed research, which has made me an empowered and savvy patient, but I have had no enrolled medical education. What I experienced is not a guarantee for all but shows what is possible.

     
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    Old 06-26-2021, 06:23 AM   #5
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    ADT is a treatment, not a solution.

     
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    Old 06-26-2021, 06:55 AM   #6
    DjinTonic
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    Quote:
    Originally Posted by Prostatefree View Post
    ADT is a treatment, not a solution.
    And it's a treatment with unknown duration of effectiveness. Regarding the time to become castrate-resistant, my Decipher report fortunately placed me at low-risk for mets, but accompanying GRID report scored the theoretical duration of effectiveness of ADT for my tumor at 0 on a 0 to 100 scale (based on my tumor's RNA)!

    My uro was taught that about 20% of men have PCa that will not respond to ADT, but he said that in all his years of practice he has never had a patient that did not respond at least initially. And the GRID report has not been clinically validated and the report says it's not for clinical decision making.

    All well and good. STILL, where might that have left me if I had gone the RT route with 2 years of ADT planned? What kind met protection would I have had if the ADT stopped working? My PSA might have (eventually) risen and I would have had metastatic PCa to deal with,

    Djin
    __________________
    69 yr at Dx, BPH x 20 yr, 9 (!) neg. Bx, PCA3-
    7-05-13 TURP for BPH (90→30 g) path neg. for PCa, then 6-mo. checks
    6-06-17 Nodule on R + PSA rise on finasteride: 3.6→4.3
    6-28-17 Bx #10: 2/14 cores: G10 (5+5) 50% RB, G9 (4+5) 3% RLM
    Nodule negative for PCa. Bone scan, CTs, X-rays: neg.
    8-7-17 Open RP, negative frozen sections, Duke Regional Hosp.
    SM EPE BNI LVI SVI LNI(5L, 11R): negative, PNI+, nerves spared
    pT2c pN0 pMX, G9 (4+5) 5% of prostate (4.5x5x4 cm, 64 g)
    Dry; ED OK with sildenafil
    Decipher 0.37 (Low Risk), uPSA: 0.010 (3 mo.)...0.023 (4 yr. 6 mo.)

     
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    Old 06-26-2021, 07:17 AM   #7
    IADT3since2000
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    Good morning Prostatefree. You wrote:
    Quote:
    Originally Posted by Prostatefree View Post
    ADT is a treatment, not a solution.
    Your statement could be a separate thread, and I would be happy to contribute, including ADT as sole treatment, where it has a role but does not exactly shine brightly as a beacon of hope.

    But focusing on ADT itself is kind of a distraction from the focus of this thread, which is how we score clinical trials for prostate cancer, with radiation in the background because it is the main reason we are having this discussion of scoring, with ADT coming up as related but a tangent because of its key role in supporting radiation. I will hold off on any further thoughts on ADT itself on this thread.

    Jim

     
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    Old 06-26-2021, 07:22 AM   #8
    Prostatefree
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    I'm not focusing on ADT. I'm focusing on the use of language and the integrity of the conversation. You have a bias for ADT and it sneaks into your use of language.

    I have a friend who is now resistant after four years. He is preparing to die. His overall survival may be 2 more years. He is a five year survival statistic. And, he started with surgery with what appeared to be a very treatable pathology. The treatment is failing. A solution doesn't fail. As a solution it's working for you, after a fashion. As a treatment, it's failing for him.

    ADT is not an acceptable solution, imo. I'll take it if I have to, willingly, but it's not a failsafe.

     
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    Old 07-07-2021, 05:27 AM   #9
    IADT3since2000
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    Let's keep this thread about how we keep score in clinical trials. Again, I would be happy to discuss the role of ADT as therapy on another thread.

    Last edited by IADT3since2000; 07-07-2021 at 05:28 AM. Reason: Typo

     
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    Old 07-07-2021, 05:41 AM   #10
    Prostatefree
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    I agree. I'll only mention it if it comes up again.
    __________________
    Born 1953;family w/PCa-grandfather, 3 brothers
    7-12-04 PSA 1.9; 7-10-06 PSA 2.0; 8-30-07 PSA 3.2; 12-1-11 PSA 5.7; 5-16-12 PSA 4.76; 12-11-12 PSA 5.2; 3-7-16 PSA 7.2
    3-14-16 TRUS biopsy, PCa 1%-60% across 8 of 12 samples, G3+3
    5-4-16 DaVinci RP, Path-65g, lymph nodes, seminal vesicles, capsule, margin all neg, upgraded to G3+4, Tumor vol 35%, +pT2c, No Incontinence-6mos, Erections-14 months
    7-9-21 PSA less than 0.02; zero club 6yrs

     
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    Old 07-07-2021, 05:50 AM   #11
    DjinTonic
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    My concerns about the newer RT modalities are:

    (1) It remains to be seen if the long-term results of SBRT match the shorter-term ones based on BCR. They very well may be. But what if the men in the good cohort (those that get RT and do not encounter BCR) fall disproportionally in the group of men who would have gone on to BCR but without the BCR going on to clinical recurrence? Much effort went into the recent studies aimed at the early salvage vs. adjuvant therapy for post-RP men with rising PSA because we know that adjuvant therapy results in much overtreatment.

    (2)The optimum strategies for hypofractionation are still being worked out. The total dosage given is necessarily based on the worst lesion in the biopsy, but we know a good portion of men who go the RP route are upgraded after surgery, so their counterparts among those choosing RT will be under-dosed. In addition, as the MSK study concluded, dosages under 40 grey appear to be suboptimal, but is still in wide use.

    (4) We simply do not know the rates of long-term toxicities, second primary cancers, and oncological outcomes of many regimes. I just saw a study that the rate of second primary tumors from men who got EBRT when they were (relatively) young appears to be higher than that thought. Hypofractionation is now more frequently adopted than the standard schedule. Yes, early EBRT wasn't as precise as what is currently given, but that isn't the point. Rather, the 30-year results can be known only after 30 years.

    Djin
    __________________
    69 yr at Dx, BPH x 20 yr, 9 (!) neg. Bx, PCA3-
    7-05-13 TURP for BPH (90→30 g) path neg. for PCa, then 6-mo. checks
    6-06-17 Nodule on R + PSA rise on finasteride: 3.6→4.3
    6-28-17 Bx #10: 2/14 cores: G10 (5+5) 50% RB, G9 (4+5) 3% RLM
    Nodule negative for PCa. Bone scan, CTs, X-rays: neg.
    8-7-17 Open RP, negative frozen sections, Duke Regional Hosp.
    SM EPE BNI LVI SVI LNI(5L, 11R): negative, PNI+, nerves spared
    pT2c pN0 pMX, G9 (4+5) 5% of prostate (4.5x5x4 cm, 64 g)
    Dry; ED OK with sildenafil
    Decipher 0.37 (Low Risk), uPSA: 0.010 (3 mo.)...0.023 (4 yr. 6 mo.)

     
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    Old 07-07-2021, 06:05 AM   #12
    Prostatefree
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    Re: The Fine Print for Trial Score Keeping: Overall Survival, Met. Free Survival, and

    In my example of my brother with adjuvant radiation, the pathology of the removed tumor provided the information allowing radiation to be directed to the location of the G4 margin and avoided sweeping over treatment. His post RP PSA was 0.03. One small clinical trial generated this possibility for him.

    Waiting for a 0.1, 0.2 or 0.4 PSA would have been a disaster for him. The G4 margin was adjacent to his colon. There is no solution in his case that comes anywhere close, so far, to this one specific successful scenario without the information collected through a trus biopsy, surgery, and PSA testing.

    Clinical trials that eventually identify the sweet spot for each treatment modality will be very useful. Each will have a different method of measure and will create the possibility of a critical path method matrix through the many possible paths to diagnosis and treatment, imo.

    Men who took/take testosterone supplements should be a clinical group in these studies somewhere, imo.

    PS: I just took my 5 year post RP PSA test. Now a couple of days of PSA anxiety and fingers crossed. Here's a question considering no change in my PSA test. Should I now switch to once a year (same <0.02 test) or stay with every six months? Their protocols are to track me for 10 years. Doctor's visit is next week and occurs once a year.

    PPS: my brother has no lingering side effects from the surgery. Time will tell about long term side effects from the radiation to his colon and collateral exposure to his erectile nerve pathways. He is 5 years younger than me with the same long lived family history as myself.
    __________________
    Born 1953;family w/PCa-grandfather, 3 brothers
    7-12-04 PSA 1.9; 7-10-06 PSA 2.0; 8-30-07 PSA 3.2; 12-1-11 PSA 5.7; 5-16-12 PSA 4.76; 12-11-12 PSA 5.2; 3-7-16 PSA 7.2
    3-14-16 TRUS biopsy, PCa 1%-60% across 8 of 12 samples, G3+3
    5-4-16 DaVinci RP, Path-65g, lymph nodes, seminal vesicles, capsule, margin all neg, upgraded to G3+4, Tumor vol 35%, +pT2c, No Incontinence-6mos, Erections-14 months
    7-9-21 PSA less than 0.02; zero club 6yrs

     
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