The “best” form of first-line treatment for clinically significant, localized prostate cancer


From the perspective of the disinterested observer, one of the very least edifying aspects of issues related to the management of prostate cancer has been the nearly 50-year-long “discussion” between the urology community and the radiation oncology community about the most appropriate way(s) to treat localized disease.

Prior to the initiation of the ongoing ProtecT trial in the UK, there had only ever been three, very small, “completed” trials that made any attempt to randomize patients with localized prostate cancer to radical prostatectomy or radiation therapy. These three trials were conducted by the Uro-Oncology Research Group between 1974 and 1978, and the results were reported by Paulson et al. between (if memory serves) 1979 and 1984. The trial results were based on data from small subsets of the patients, and for a summary of the list of problems said to be associated with at least one of these studies and the supposed trial outcomes, I refer readers to this commentary by Moghanaki on one of the papers published by Paulson et al. in 1982. If the waters weren’t already poisoned before 1974, they were quite certainly irretrievably poisoned after the publication of that paper by Paulson and his colleagues.

The loser for the ensuing 35 or so years has been the patient. We really have no clear idea at all what “the best” way is to treat a man with clinically significant, localized prostate cancer who really does need early whole gland treatment, … and we haven’t known for decades. The only thing we are absolutely sure about is that individual outcomes of individual patients after every one of the currently available forms of treatment are very highly dependent on the experience, skill, and degree of attention to detail of the treating physician and his or her support team at the time of treatment.

Again, from the perspective of the disinterested observer, the urology and radiation oncology communities have failed to display any serious interest — on either side — in attempting to resolve this very significant problem. And the prostate cancer literature is replete with articles of dubious validity in which members of select interest groups “puff” the value of the data that support their favored treatment and cast aspersions on the data reported by other select interest groups (both within the urology community and the radiation oncology community themselves and between these two communities as well). If there is any doubt in your mind about the ferocity of these “discussions”, just look at the literature on such topics as:

  • The relative merits of open vs. laparoscopic and robot-assisted laparoscopic surgery
  • The relative merits of brachytherapy and external beam radiation therapy
  • The relative merits of photon beam as opposed to proton beam radiation therapy
  • The relative merits of high-intensity focused ultrasound as opposed to anything

and that’s without even thinking about comparisons of radiation therapy to surgery!

There is little to no doubt whatsoever that large numbers of patients with prostate cancer have, over the past 40 years, been referred for surgery that they didn’t need; been told that either surgery or radiation therapy of some type would be “better” for them on the basis of little more than opinion; and generally not given honest, neutral advice and guidance by large numbers of physicians who took an oath to act in the best interests of their patients. Almost every study published on either side of the various debates can be shown to come with some level of bias based on patient selection criteria if nothing else.

Because of the lack of any good Level 1 data, there are only two forms of management that I have ever felt completely comfortable in actively recommending to specific types of patient with localized prostate cancer: watchful waiting for (usually elderly) men with a demonstrably short life expectancy — on the grounds that they would probably never actually need treatment for their prostate cancer anyway — and active surveillance for men with favorable risk disease because such prostate cancers can clearly be treated later with curative intent and a high degree of success should the need for such treatment become apparent. As far as I am concerned the relative values of all invasive first-line treatments for localized prostate cancer remain ill-defined.

It is my sincere hope that data from the ProtecT trial, once these data start to come available — perhaps as early as next year, may at least start to resolve some of these problems. But these data are unlikely to be sufficient to provide a real resolution.

What could provide a real resolution would be a large, highly defined, prospective, and carefully planned registry study in which patients diagnosed with intermediate- or high-risk prostate cancer (clinical stage T2-4NxM0, a Gleason score of ≥ 7, and a PSA level of perhaps < 25 ng/ml) that was expected to be lymph node negative at time of treatment, were permitted to choose from any one of several forms of reasonable and approved first-line treatments for their cancer after discussion with a trained nurse who (a) had no interest in how the patient elected to be treated and (b) gave the patient a full and neutral explanation of all the possible treatments for which that patient appeared to be eligible. Standard follow-up protocols, regardless of treatment type, would be required for all patients to address short- and long-term outcomes and issues related to quality of life. The forms of treatment that (at present) would seem to be appropriate possibilities include various types of surgery, various types of photon-based external beam radiation therapy, proton-based external beam radiation therapy, low- and high-dose-rate brachytherapy, cryotherapy, and high-intensity focused ultrasound. Actual treatments would only be carried out by clinicians with appropriate levels of skill and experience in specific forms of therapy as evaluated by their peers. Adjuvant and salvage treatments for men who progressed after first-line treatment could be defined as a secondary element of the study, but the primary endpoints of the study would be the proportions of patients who received each of the predefined types of treatment and who achieved 5-, 10- and 15-year progression-free survival with quality of life criteria that were also predefined and consistent regardless of treatment type.

There is no possibility that we could conduct randomized trials of the different types of treatment for localized prostate cancer here in America today. Patients simply wouldn’t accept this idea any more — and I don’t blame them for that. But a sophisticated registry trial of the type described above is a real possibility and could be conducted in ways that provided Level 1 evidence of the relative outcomes of the various types of treatment. Of course it would probably take 15+ years to complete, but if it resolved the issue of “the best” way or ways to treat clinically significant, localized prostate cancer it would be well worth the effort … because we are unlikely to develop other completely new ways to treat this set of prostate cancer patients during that 15- to 20-year time frame.

How many patients might be needed to participate in such a study? I am no statistician, but it might be surprisingly easy to enroll something like 10,000 patients to a study like this over as little as 2 or 3 years. All that it really requires is the will of patients and at least a subset of their doctors and some not insignificant funding for the actual research portion of the trial. Basic diagnostic and treatment costs could and should still be covered by patients’ insurance. A strength of this study is that every participating physician would be highly motivated to ensure high quality of care for the patients they were treating!

11 Responses

  1. For what it’s worth, Johns Hopkins is gathering data from their patients who had RP regarding post-op progress including PSA, additional treatments if any, bladder control, and ED issues. Not sure if it’s being done for RT patients. I know this because I had open RP at Johns Hopkins in September 2013.

    Bob

  2. Bob:

    Many series of prostate cancer patients have been followed like this over the years. The longest one that I am aware of is the one at the Virginia Mason Clinic, which has monitored patients originally operated on by Dr. Gibbons for nearly 50 years now. This does not address the problem of the comparative effectiveness of surgery to other forms of treatment (for all sorts of different reasons, starting with the fact that these patients all met certain initial selection criteria at the specific institution as opposed to a predetermined set of selection criteria adopted by a wide range of institutions and applied regardless of treatment type).

  3. For the near-decade I’ve been a prostate cancer patient, I’ve often thought the diagnosis and treatment of same a “weird science.” Now at last I know I’m not alone. Thank you, Sitemaster! This is one of your very best, and should be required reading for every new patient. And, dare I say, all board-certified urologists and referring providers.

  4. For now, the last sentence of Sitemaster’s third paragraph continues in importance no matter what form of treatment.

  5. Following my diagnosis of prostate cancer 4 years ago, here in the UK under the NHS, I was referred to both a surgeon and a radiologist. Both offered treatment. As it happens, I went for the superb da Vinci surgical team at Addenbrooke’s Cambridge, But the point is that the funding model of the NHS, free at the point of delivery and without commercial pressure on the practitioners, makes it more likely that you will have the choice and will receive less partisan advice.

    As the Sitemaster points out, there remains the problem that there is very limited information upon which to base your own, personal radiation/surgery choice. However illogically, I wanted the cancer removed from me, and anyway I have always thought of radiation as a crude tool and didn’t want to subject myself to it. So as usual in my life I made my decision based on how I felt, rather than attempting a detailed cost-benefit analysis (which would have failed anyway due to lack of reliable data!)

    Fortunately, no regrets so far, and no detectable PSA either.

  6. I doubt that the grand registry study proposed here will ever happen, nor is it likely to be of great value should it actually happen. The problem is that in the 15 years it would take to get to the end point of the study the standard treatments are all likely to have changed. Major advances in imaging, already on the horizon, will make the current treatments, as seen in retrospect, obsolete.

    Or so it seems to me.

    Richard W.

  7. Dear Richard:

    I am at a loss to understand how you think that the major advances in imaging over the next decade or so (which may well become available) are going to change the methods of treatment for men with known, localized, clinically significant prostate cancer. They may well change the methods of treatment for men with non-localized and progressive forms of cancer (and for men with low-risk prostate cancer who should probably just go onto active surveillance anyway), but those men are not the primary focus of the registry proposal.

    If a 65-year-old man is diagnosed with three clearly identifiable sites of Gleason 3 + 4 = 7 cancer in his prostate, based on sophisticated imaging techniques and confirmed by targeted biopsy 10 years from now, I will make a bet with you that nearly every competent clinician is still going to tell him he needs some type of whole gland therapy because there is a very strong likelihood that there are more, microscopically small, sites of Gleason 7 disease in development that are still too small to see using the sophisticated imaging techniques you envisage. Prostate cancer will still be a multifocal disease, and the imaging techniques we are discussing are not (as far as I am aware) of electron-microscopic quality.

    One of the great advantages of the registry trial that I am proposing is that as new forms of treatment come available, they can be added to the eligible range of first-line therapies on which data are collected in the registry. And even the initial 5-year endpoint would probably produce some really meaningful data in terms of relative biochemical progression-free survival and side effects of treatment.

    This does not, of course, mean that I actually think anyone is going to do the grand registry — but that has more to do with politics than value. If we did the grand registry trial, we could immediately stop funding a whole bunch of smaller trials at individual institutions that are actually telling us very little.

  8. Thank you for such an honest description of the current morass that exists today for the newly diagnosed man with potentially lethal prostate cancer.

    I always felt a need to make a strong case before recommending radiation therapy or a radical prostatectomy for my patients. I always send my patients to a radiation oncologist for a discussion of RT from their perspective.

    I became quite expert at performing an open nerve-sparing radical retropubic prostatectomy. Typically, skin to skin in less than 2 hours, rare transfusions, home in 36 to 48 hours and excellent continence, margin, and potency results.

    This experience has been largely retired by the efforts of Intuitive to sell the robotic approach, which has hypnotized the public that they are getting a minimally invasive procedure. It is minimally invasive in concept, not reality. Transitioning to robotic surgery has one advantage for me, and that is I’ll probably be able to operate when I’m 80, as long as the chair has good lumbar support!

  9. Great article. Thank you.

    For some reason, the link to commentary by Moghanaki in the second paragraph doesn’t seem to be working for me.

  10. Reblogged this on Dan's Journey through Prostate Cancer and commented:

    “This is a compelling read for anyone newly diagnosed, highlighting why it’s so difficult to determine the best course of treatment. To me, the most compelling statement in the article was:

    ” ‘The loser for the ensuing 35 or so years has been the patient. We really have no clear idea at all what “the best” way is to treat a man with clinically significant, localized prostate cancer who really does need early whole gland treatment, … and we haven’t known for decades.’

    “If the experts can’t figure out the best treatment option, then how are we as laymen supposed to be able to figure it out?”

  11. Dear Dan:

    (1) The link to the Moghanaki material should work again now.

    (2) Many of the experts have figured out the best treatment option. For many of them it is the form of treatment that they provide.

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