We Can Conduct Clinical Trials of Protons

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A great deal has been written about proton therapy, with a good deal of heat and only a modest amount of light. I would like to comment on an aspect of the proton vs photon controversy that I believe has not been adequately addressed: Should we run clinical trials that would allow us to prove that proton therapy is superior? This becomes a general question of how do we assess “new” technologies that are “clearly” superior to the “old” technology, because “new” is always better (at least in the United States).

The Physics

For the purposes of this opinion piece, the physics can be easily summarized. High-energy photons (x-rays) spare the skin but travel through the body beyond the tumor (called the “exit dose”). Treatment plans deliver a higher dose to the tumor than to the surrounding normal tissue by the use of multiple beams that intersect on the tumor. Protons deposit their dose over a narrow region that depends on their energy (the Bragg peak); there is no exit dose. In order to treat a tumor (which is typically at least a few centimeters in width), several energies are used (the “smoothed-out Bragg peak”). Because there is no exit dose, protons should deliver less overall radiation to the normal tissues than photons for the same tumor dose.

I have just given you the definition of “protons are better than photons” for a medical physicist and many radiation oncologists. In fact, there are a number of technical issues that are beyond the scope of this brief opinion piece that may make protons inferior to photons in some settings. But let’s ignore these and assume that the pure physics advantage of protons can be exploited, if not now, then in the near future.

The Controversy

Given the physics (and ignoring current technical limitations), why would there be any controversy? Unfortunately, protons are at least four times as expensive as photons, so it would seem that in the era of comparative effectiveness, a theoretical advantage should not be a sufficient reason to justify the far greater expense. To make matters worse, there is at this time no convincing clinical evidence that protons are superior to photons in any disease, especially prostate cancer, the cancer that accounts for the great majority of proton treatments.

Some have written that it is so obvious that proton therapy is superior to photon therapy that it would be unethical to conduct studies that address the question of whether protons are, in fact, superior. I disagree. Health-care resources are not infinite, and we should ask for data to support our beliefs so that resources can be applied rationally.

But does that new data need to come from a randomized trial of “old” technology vs “new” technology? Proton advocates claim that it is unethical to run a trial of photon vs protons. Even if it is not unethical, they say it will be impossible: People will demand the better technology.

The Questions

Now we come to the point of my essay. It may surprise some to find out that the field of radiation oncology has asked this general question before, but we did it in the 1980s and 1990s with regard to the then new three-dimensional (3D) treatment planning. How could we ask if 3D, which was more labor intensive and required complex software, was worth the effort compared to standard 2D? The question was broken down into two steps, forming the basis of what was known as the “3D hypothesis”:

Can the dose be escalated with the new technology? Indeed, with 3D (and, subsequently, intensity-modulated radiation therapy, or IMRT), one could escalate the dose to most tumors, with the most studied example being prostate cancer. In the 2D era, 68 to 70 Gy was the maximum dose before encountering unacceptable rectal toxicity. 3D and IMRT permitted the dose to be escalated to approximately 78 Gy.

Lawrence quoteDoes that escalated dose improve local control and/or survival? This question has been resoundingly answered yes, with at least four randomized trials demonstrating improved local control of prostate cancer at the higher dose. These randomized trials were successful because they were focused on dose, not technology (but only the improved technology could safely deliver the higher dose).

A corollary to this approach comes from tumors that are already fairly well controlled with current treatment (such as head and neck cancer), with the goal of delivering the same tumor dose while using the better technology to decrease dose to the normal organs and, thereby, to preserve normal organ function (eg, parotid and other salivary glands). Here, too, it has been shown that IMRT is superior to older techniques.

The Bottom Line

Thus, the big question is, where is the evidence that protons can be used to safely deliver a higher dose of radiation than photons to, for example, the prostate? Or that the rectum and bladder can be better protected by protons at the same tumor dose? If proton facilities could generate such evidence, it could be used to support a trial testing whether the increase in tumor dose permitted by protons controls more tumors, or whether the decrease in dose to normal tissue decreases toxicity.

Our field has shown that randomized dose trials can be successfully conducted. In my opinion, proton facilities should not be permitted to continue to produce results that cannot be distinguished—except by the far greater price—from those produced by IMRT photons. Our patients deserve true improvements in outcome, rather than the hype and added expense that currently dominates the field. ■

Disclosure: Dr. Lawrence reported no potential conflicts of interest.

Dr. Lawrence is Professor and Chair, Department of Radiation Oncology, University of Michigan, Ann Arbor.