“Show me the [proton beam radiation therapy data]!”


A new article in this month’s issue of The ASCO Post addresses the need for concrete evidence that proton beam radiation therapy (PBRT) is actually “better” than modern forms of photon-based external beam radiation therapy (EBRT) in the management of prostate cancer (and other forms of cancer).

The article, by Theodore Lawrence, who is professor and chairman of the Department of Radiation Oncology at the University of Michigan, will likely infuriate some members of the proton beam brotherhood. For those of us who like good data to support our faith, it seems like a very rational commentary on a very complex topic.

Dr. Lawrence suggests that — if this is really the case — it ought to be relatively easy for the proton beam radiation facilities to develop data to show that either

  • “Protons can be used to safely deliver a higher dose of radiation than photons to … the prostate “

or

  • Protons can be used to better protect the rectum and bladder than photons at the same tumor dose as delivered by modern IMRT.

He notes that if such evidence is forthcoming, then the onus will be clearly placed on the entire radiation oncology community to conduct the randomized clinical trial(s) needed to prove that PBRT is a superior form of clinical treatment compared to photon-based therapy.

As Dr. Lawrence also observes, this is not the first time that the radiation oncology community has had to deal with a controversy like this. An analogous controversy back in the 1980s and early 1990s required radiation oncologists to “prove” that three-diemsional treatment planning produced better outcomes for patients than the earlier two-dimensional treatment planning. The radiation oncology community was able to overcome that challenge, so why not the current one?

The “New” Prostate Cancer InfoLink believes that the proton beam advocacy community needs to actually be able to prove its case. Whatever one’s beliefs, there are no good data to support the supposed clinical benefits of PBRT compared to IMRT today. The most basic principles of evidence-based medicine and patient-centered outcomes research require us to insist on data that can justify the use of PBRT as an improvement over modern EBRT — as opposed to just an expensive alternative with similar outcomes.

15 Responses

  1. Question: Does Dr. Lawrence believe in immutable laws of physics? For instance, science tells us that momentum equals the mass of an object multiplied by its velocity (p = m * v). Suppose you ran a 2-ton truck into a free-standing brick wall at 50 mph, surveyed the damage, and then speculated aloud what would happen if you instead ran a 1-ton truck into the wall at the same velocity? Would it do more or less damage? Hmmm …. What if speculation is all you had, since the wall could not be satisfactorily reconstructed to perform the actual experiment? Fortunately, physics could step in to fill the void here, mathematically proving less damage with the smaller vehicle. Any first-year physics student could easily perform the calculation.

    Fast forward to proton beam radiation therapy (PBRT). The physics with PBRT are as solid as it is with momentum. The entry radition dose is markedly less with PBRT than with IMRT (photons), largely sparing healthy tissue between the machine nozzle and the tumor target. Once at the desired target, PBRT explodes its dose in the tumor, according to the well-substantiated Bragg peak phenomenon. Thereafter, the PBRT radiation path apruptly comes to a halt (i.e., no residual radiation beyond the target), whereas with IMRT the beam continues past the target and completely through the patient. The net result of all the foregoing is, indisputably, a lower integral dose of radiation to the patient with PBRT. There is ZERO doubt about that. Now, given such a fact, tell me again how LESS integral radiation to the patient can be inferior IF the efficicacy of PBRT in tumor control is at least as good as with IMRT, if not better (due to a higher dose hitting the tumor via the Bragg Peak)? Keep in mind that with IMRT, the largest dose hits the patient within an inch or two of entry into the body, relatively far from its ultimate destination (in this case, the prostate); that’s not true with PBRT.

    I understand the natural desire for proof and additional data (BTW, it’s not like NO studies have been published on PBRT’s safety and efficacy). Nevertheless, please let’s not overlook the overwhelming physics supporting PBRT’s superiority in protecting the patient from unnecessary radiation exposure to healthy tissue while delivering highly effective tumor control.

  2. I would note only that we are addressing not simply “the [supposedly] immutable laws of physics” (which actually tend to “mute” on a regular basis , and that’s before one starts to consider things like the Heisenberg uncertainty principle) but also the very definitely mutable “laws” of biology and physiology in this discussion. There are many specialists in radiation oncology and radiation physics (of whom I think we can probably accept that Dr. Lawrence is one) who do not, in fact, find the biologic impact of proton therapy to be quite as simple in its physics as its advocates proclaim.

    I am not arguing for one side or the other. What I find interesting is that the proton therapists have (as yet) not even tried to make a strong clinical case, based on well documented clinical data, that their process is any safer or more effective than standard IMRT. Physics is interesting. Clinical outcomes in carefully defined sets of patients is what is important in the application of any form of actual treatment.

  3. Just to be clear: Are you suggesting that a greater integral dose of radiation to the human body is under any comparable situation preferable to a lesser dose, even if the efficacy (tumor control) is equivalent? Do you dispute that for an identical RT treatment plan (say, 78 Gy delivered in 39 fractions), IMRT patients receive more radiation dose to healthy tissues than PBRT patients do?

  4. I’m not “suggesting” or “disputing” anything. I am stating that if PBRT is “better” than IMRT then it should be able to clearly demonstrate superior clinical outcomes in an appropriate clinical trial. Those superior clinical outcomes could take one or both of two forms in comparable patient cohorts: (a) better long-term biochemical recurrence, a higher rate of metastatis-free survival, and a higher rate of overall survival and/or (b) a documentably superior safety profile in terms of side effects in association with an equivalent efficacy outcome. In all honesty the underlying science is of minimal interest to me, although it is obviously of considerable interest to those who specialize in radiation physics. Are you a radiation physicist?

  5. Nerf,

    There is no evidence that PBRT is more or less effective than IMRT or IGRT. Also, there has never been a study that can prove it has less side effects that the latest IMRT technologies. There is only clear evidence that you will pay up to three times as much for therapy. …

    Mike’s point is not unfair. Same with the writer. What we are all asking for is not just proof it is equally as effective but also that it’s worth the extraordinary money. I certainly understand that precision is probably better, but is it necessary to treat prostate cancer?

    One very real question is, “Geez, how long has Loma Linda been doing this?” (I know the answer.) It certainly is suspicious that PBRT sites are about the only RT sites that have never run even retrospective analyses.

    I will say the former resident at the Harvard Radiation Center is a good friend of mine. He says PBRT is just as effective but he also questions whether we are using a diamond studded prom dress for a Sadie Hawkins dance.

  6. I have heard a plausible argument that there is a physical basis for doubting the superiority of proton radiation. The proton beam is comparatively narrow, and to get it to cover the breadth of a prostate, one must cause the beam to scatter, which results in unknown collateral damage. If that analysis is good, then the argument from physics presented above is no slam dunk.

  7. Sitemaster states clearly, “I am not arguing for one side or the other. What I find interesting is that the proton therapists have (as yet) not even tried to make a strong clinical case, based on well documented clinical data, that their process is any safer or more effective than standard IMRT.” And therein lies the crux to the situation. We forever read comments like that provided by nerf12345 and other “patients,” but for whatever reason, the therapists providing PBRT continue to hold back providing their statistics and irrefutable evidence to support this therapy option over photon-based EBRT.

  8. There are two reputable studies comparing radiation modalities, the ACER 2009 report and the Prostate Cancer Study Group. Neither of these studies show any benefit of proton therapy in either cancer control or side effects over other conventional forms of radiation.

  9. Try reading, Proton Therapy, James M. Metz, ed. Pages 460-462 list 58 proton therapy trials.

    — IMRT = 60% proximal healthy tissue damage and 20% distal tissue damage. 20% damages the tumor!
    — PT = LET (linear energy transfer) charged particles (hydrogen stripped of its electron) weighing 1,800 times more than an electron. The Bragg peak delivers this punch directly to the tumor (+/- 1 mm). This completely destroys tumor cells; smashing both strands of DNA.

    Protons are a different modality then x-rays/gamma rays, which ionize tissue leading to delayed cell death or fused DNA (new cancer cells). IMRT depends on a good oxygen supply which many tumors lack.

    Neither IMRT or charged particles (protons/carbon) are the best answer to cancer. We now understand that there is no safe dose of radiation. Look to the MRI/HIFU trials being done at Bethesda, MD. (Walter Reed was original site but they have now moved to the National Naval Medical Center.) This has the potential to cure (destroy) solid tumor cancers at a reasonable price with minimal side effects. Here is a link to a trial that is recruiting in England.

    Good Health to ALL!

  10. Dear Bob:

    (1) I think that many of us are aware that several of the newer proton therapy centers are very focused on the need for data that can actually justify the clinical effectiveness of proton beam therapy — and not just in prostate cancer. This only makes the failure of Loma Linda to collect and publish extensive and detailed data over the years more sad.

    (2) Re: “We now understand that there is no safe dose of radiation.” The idea that there was ever a “safe” dose of radiation that could have therapeutic effect is not an idea that I (or I suspect many others) have ever held. All forms of radiation come with the potential for side effects. That includes things like radio waves and HIFU. Why do you think that there is all the fuss there is over cell phones and cancer risk? The question is exactly what do the different forms of radiation at different dose levels do to normal tissue as opposed to cancerous tissue. If you use too high a dose of HIFU, it will “cook” normal tissue, and the HIFU dose that effectively kills tumorous tissue does have effects all on the surrounding normal tissues — but it may be so minimal as to be acceptable, and if the targeting is good enough, then very little normal tissue should be affected.

    (3) As with proton beam therapy, the question that Emberton and Ahmed and their colleagues in London (and others elsewhere) are trying to answer with targeted HIFU is, “Can whole gland HIFU and focal HIFU provide long-term remission of localized prostate cancer in appropriately selected patients comparable to traditional treatments with a lower risk for complications and long-term side effects?” The difference between what Emberton et al. have been doing and what Loma Linda never did is that Emberton and his colleagues have been carefully collecting and reporting detailed outcome data on their patients from day 1. It will still take several years before we have definitive information on the 10-year survival of patients treated with the most recent generations of HIFU technology. Long-term data from the early HIFU technology was not as promising as people had originally hoped, but that may reflect the quality of the technology and the lack of experience. The early results from robot-assisted surgery appeared to be worse than from open surgery too, but that problem seems to have been resolved with experience.

    With both HIFU and PBRT, the underlying science is important to the potential that a technology will have clinical value. It still requires clinical data to demonstrate that value. I can show you lists of thousands of drugs that — based on their chemistry and on their pharmacology (and data from clinical models) — would theoretically have been highly effective in clinical practice. However, all of them failed to provide a clinical benefit or were only able to offer that benefit in combination with unacceptable levels of side effects. It is time that we all accepted that technical advances in medicine all need to be subjected to clinical studies that really demonstrate their efficacy and their safety compared to the current standards of care. The FDA has required this of HIFU in prostate cancer therapy. It will likely be required of many other new technologies in the future.

  11. Mr. Maack:

    Are you seriously claiming that PBRT “therapists” have conspired to “hold back” data on PBRT?

    Although being but a mere patient, I am highly confident that my therapist, Dr. Anthony Zietman, is not a member of that cabal.

  12. The article by Michael Goitein and James Cox in the Journal of Clinical Oncology, Voume 26, Number 2, January 10, 2008, “Should randomized clinical trials be required for proton radiotherapy”, provides another point of view.

  13. JB:

    I don’t think anyone is suggesting that there is or has been any sort of “conspiracy.” All that I think anyone is saying is that the available clinical data do not provide a compelling argument that PBRT is any better than any any other form of modern radiation therapy for the treatment of localized disease. Dr. Zietman is clearly on the record as stating that he believes a randomized clinical trial would be advisable.

  14. John:

    I would point out that in the same journal shortly after Goitein and Cox’s article, there was an article by Eli Glatstein et al., with the title “Should randomized clinical trials be required for proton radiotherapy: an alternative view” arguing that such clinical trials were most definitely needed.

    It is the very fact that there is such a major difference of opinion within the radiation oncology community itself that is one of the signals to me (as a mere layperson) that trials are indeed needed to resolve this issue. There is clearly no agreement among experts about the clinical significance of the underlying science. Three years after these two articles were published, there is still no agreement on the need for such trials. I find that simply sad. It is a sign that the radiation oncology community is unable to put aside its interpersonal opinions and act in the best interests of patients as opposed to the self-interests of the advocates for and against PBRT.

    Let me be clear. I am not “anti” PBRT. I simply want to see good clinical data that resolves this controversy. The repetitive discussion of things like Bragg peaks is clinically meaningless.

  15. Yes, there were several comments on Goitein and Cox’s article and an interesting reply by the authors. With more emphasis on evidence-based medicine, RCTs will no doubt be required. The impact this will have on new technology or improvements to existing technology may be significant (for example, I don’t think an RCT was done for IMRT, an improvement to photon therapy, but would now probably be required by evidence-based medicine).

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