Proton beam radiation: a systematic review

A recent article in the Annals of Internal Medicine, commissioned by the Agency for Healthcare Research and Quality (AHRQ) and carried out by investigators at the Tufts Medical Center Evidence-based Practice Center in Boston, concludes that “Evidence on the comparative effectiveness and safety of charged-particle radiation therapy in cancer is needed to assess the benefits, risks, and costs of treatment alternatives.”

What this report by Terasawa et al. is effectively saying is that there is not yet sufficient data to assess whether proton beam radiation therapy (PBRT) is any better or any worse, in terms of effectiveness and safety, than other forms of radiation therapy in the treatment of any type of cancer.

Given the sparsity of sound clinical trial data on the use of PBRT available in the literature, this conclusion should hardly come as a surprise. Of the 243 articles identified by the research team on the clinical use of PBRT:

  • 185 were single-group retrospective studies.
  • Eight randomized and 9 non-randomized clinical trials compared treatments with or without charged particles.
  • No comparative study reported statistically significant or important differences in overall or cancer-specific survival or in total serious adverse events.

A commentary on this article that appears on OncologySTAT states that, according to the authors:

  • “[F]our trials reported statistically significant differences in various other outcomes.”
  • “In 3 of 4 trials, the results favored the charged-particle radiation therapy group.”

Two of the four trials that showed a significant results were in patients with uveal melanoma. However:

  • One of the three positive trials showed better local control and freedom from biochemical failure of prostate cancer with higher vs. lower doses of PBRT.
  • The unfavorable trial reported a significantly lower incidence of rectal bleeding with conventional radiotherapy vs. PBRT in prostate cancer patients.

The bottom line here, from a prostate cancer point of view, is that the failure to collect, analyze, and publish well-structured data from the PBRT center at Loma Linda over the past 15 years has delayed any chance of clearly demonstrating the clinical value of PBRT in the treatment of prostate cancer. One may not like this conclusion, but it is very straightforward.

As a consequence, it may well take another 15 years before we can collect enough data to demonstrate with any degree of conviction that PBRT is a valuable form of treatment for localized prostate cancer.

In the words of Anthony Zeitman, MD, professor of radiation oncology at Harvard Medical School, the AHRQ report, “is a call to the radiation oncology community to come up with the evidence and not to make any assumptions. It’s incumbent upon us to do that, and the AHRQ is open to that.”

He continued by saying that, “It’s really only been over the last 5-10 years that it has become feasible to develop proton beam facilities in the United States, and during that time, [the therapy] has established itself as the treatment of choice for several types of [relatively uncommon] cancer. … For [the technology] to become commercially viable, however, we have to look to the more common cancers.”

Prostate cancer is quite certainly one of those more common cancers.

8 Responses

  1. You’ve got to wonder why these studies weren’t begun when the extremely expensive equipment PBRT requires was implemented for use.

    Given the costs, wouldn’t it be incumbent on the proponents to show significant improvement over the older types of radiation therapy?

    As positive on the proton as many prostate cancer patients seem to be, you just hope that it won’t ultimately turn out to be a gizmo poster child for common cancers.

  2. Good summation about this technology.

  3. As someone who is facing prostate cancer and having to make a decision about therapy, it is frustrating to read generalities about how much better proton therapy is with respect to side effects, yet see no statistical summary to demonstrate this. This is the problem with the Loma Linda web site. It should have been a simple matter to collect data about major side effects such as incontinence and erectile dysfunction. I agree with this article — more needs to be done to demonstrate the effectiveness of proton therapy for prostate cancer.

  4. I know my memory is not what it was, but I don’t recall seeing the original studies that demonstrated, prospectively, that photon beam radiation is a valuable form of treatment for localized prostate cancer. I know there are many retrospective studies, but they don’t count do they — else the Loma Linda data could be mined and some of the question marks raised be resolved.

    But then that would be so simple and unscientific wouldn’t it?

  5. My suspicion has long been that the Loma Linda data is actually of very poor quality and therefore not “minable” in any meaningful way. The only other possible reason for not mining it and publishing it would be that it doesn’t actually support the claims that are made for the technique — and I would not want to think that that was the case!

  6. Re proton beam therapy (PBT), here is the reference about the Loma Linda (LL) experience, including side effects exclusive of erectile dysfunction.

    Patients received 74-75 grays (technically, grays or gray equivalents) to their prostates, as protons or protons + photons. 3.5 years ago, I got their standard dose, which had become 79.2 grays. I declined to join an experimental group getting more.

    LL patients currently get 79 to 81 grays, in 44 treatment sessions, the dose being determined on an individualized basis, probably affected by the riskiness of their disease. Other centers have other formulas, and, for example, I heard that the Florida center also prescribes doses individually. An experimental group at LL is currently getting 60 grays in 20 sessions, i.e., hypofractionation.

    I deplore publicity for PBT that relies on anecdotal evidence. You may be right in your suspicions, Mr. Sitemaster (we all need to be a bit skeptical), but I am inclined to a more generous assessment of LL. The failure to publish more data may be due to inertia and the “moving target” character of this therapy. (I’m referring to the science, not prostate position changes; that’s another story.)

    One can perhaps infer that an honest sense of the advantages of proton beam therapy, based on less radiation outside the target area, has given PBT workers the confidence to change methodology, including, importantly, dose escalation to as much as 81 grays. More grays may kill the cancer more definitively; one can only hope that they do not increase side effects proportionately.

    I think that a key word for PBT for prostate cancer is “promising.” As one iota of anecdotal evidence, I have personally done well after receiving PBT by a method that soon may be called crude. It created a high radiation zone around my prostate with less radiation remote from it, but there have been problems precisely planting that high radiation zone where it belongs. One or more U.S. centers are now implementing pencil beam scanning or spot scanning (synonyms), which ought to be an improvement.

    One investigator wrote (in a slide presentation), “Protons are good. Whether the current state of the art is good enough is questionable. But can be much better. Achieving [what you see] = [what you get] is essential. And is equivalent to going from faith-based PT to faithful PT.”


  7. Dear Herb:

    I suppose the truth is that I am angry with Loma Linda. Whether their excuse for not publishing a stream of really well documented data is laziness or whatever, as the only PBRT center in the US for a decade after the old Harvard PBRT system shut down, they had a moral obligation to document and publish their data in a well organized manner. They published one paper of (IMHO) very dubious quality, which you link to, and I think they should be ashamed of this.

    The result is still that we really don’t have good, well-structured data on PBRT in treatment of prostate cancer, and we certainly have wasted the best part of 15 years as a consequence.

  8. I won’t go out of my way to defend them. I don’t really know the answer. I’m for openness and I deplore the fanaticism that I have seen on both sides of the issue. Why, indeed, can’t folks just share the facts and deal with the issues forthrightly?

    Let’s hope that with the involvement of more centers, the situation will improve. It will take time in any case. I still think that protons are promising.

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