Experts argue against need for phase III proton Rx trials

With proton beam therapy centers proliferating in the United States, particularly for use in treating prostate cancer (see April 2008 ONI, page 1), the debate is heating up over the need for randomized clinical trials comparing proton beam therapy with conventional x-ray (photon) therapy in prostate and other cancers.

In last month’s ONI poll on www.cancernetwork.com, among the 100 readers who participated, the vote was clear: 81% said yes, randomized trials are needed before proton beam therapy is more widely adopted; 16% said no, they are not needed; and 3% said they didn’t know or weren’t sure.

In a recent issue of Radiotherapy and Oncology (86:148-153, 2008), a group from the Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, along with a radiologist from the Midwest Proton Radiotherapy Institute, Bloomington, Indiana, made the case against the need for supporting data from randomized trials prior to a wider use of proton beam therapy.

A low priority question

Lead author Herman Suit, MD, and his colleagues said that “to evaluate the clinical efficacy of proton therapy by phase III clinical trial is surely a low priority question. Our talents, patients, and resources would be much more effectively utilized in examination of the role of dose, dose fractionation, and combinations of radiation and other agents.”

The authors’ rationale is that proton beam therapy is known to provide superior dose distribution, compared with x-rays, for most clinical situations. They argued that no one disputes that receiving less dose to normal tissues is an advantage for the patient.

The authors pointed out that numerous new technologies, such as intensity modulated radiation therapy, stereotactic radiation therapy, and 4D image-guided radiation therapy (currently being brought into clinical practice), have been accepted into practice on the basis of improved distribution and dose delivery without phase III clinical trials. In fact, they believe it would be difficult, if not unethical, to recruit patients into a randomized trial of proton therapy.

The whole debate, they maintain, would not have arisen if the cost of proton therapy were equal to or less than that of photon therapy. They pointed out that since the capital costs of the new treatment are fixed, the cost of treatment per patient decreases with the number of patients treated per year. Further, a valid cost analysis, they said, would consider estimates of the costs of dealing with local regrowth and treatment-related complications, both acute and late.

Based on their review of the literature of proton and photon dose distributions and dose-response relationships, the authors said they found no evidence showing a need for a randomized phase III clinical trial prior to wide adoption of proton beam therapy.

They concluded with an anecdote from Dr. Suit about discussions in 1959 of the need for randomized trials of cobalt therapy vs 250 kVp x-ray therapy. No one thought such trials (or even discussion of such trials) were necessary.

“In fact, 60Co units were installed as rapidly as hospital funds and machines became available,” Dr. Suit wrote.