No Difference in Toxicity with Proton Radiotherapy vs Less Costly Intensity-modulated Radiotherapy 

Get Permission

A national sample of Medicare beneficiaries treated for prostate cancer with intensity-modulated radiation therapy or proton radiotherapy found that proton radiotherapy “was rare and expensive and associated with only a modest and transient reduction in genitourinary toxicity,” reported James B. Yu, MD, of Yale University School of Medicine, New Haven, Connecticut, and coauthors in the Journal of the National Cancer Institute.

In this retrospective study of 27,647 Medicare beneficiaries aged ≥ 66 years, 27,094 (98%) received intensity-modulated radiotherapy and 553 (2%) received proton radiotherapy for prostate cancer during 20008 and/or 2009. 

“Although [proton radiotherapy] was associated with a statistically significant reduction in genitourinary toxicity at 6 months compared with [intensity-modulated radiotherapy] (5.9% vs 9.5%; odds ratio [OR] = 0.60, 95% confidence interval [CI] = 0.38–0.96, P = .03), at 12 months post-treatment there was no difference in genitourinary toxicity (18.8% vs 17.5%; OR = 1.08, 95% CI = 0.76–1.54, P = .66). There was no statistically significant difference in gastrointestinal or other toxicity at 6 months or 12 months post-treatment,” the authors wrote.

Explanations and Limitations

“Regarding toxicity, it is plausible that differences between [proton-beam and intensity-modulated radiotherapy] would be limited to early genitourinary side effects. In prior studies, the only improvement in radiation dose distribution [for proton vs intensity-modulated radiotherapy] was a reduction in the amount of bladder exposed to low and intermediate levels of radiation,” the researchers noted. “Because the amount of bladder exposed to low doses of radiation predicts early toxicity, the reduction of radiation to the bladder may be responsible for the transient improvement in 6-month toxicity associated with [proton radiotherapy],” they speculated. 

“Although we excluded patients with a diagnosis of metastatic disease, other staging data were not available. Only 12 months of follow-up were available, so further analyses of longer-term outcomes concerning both toxicity and cancer control are warranted. In addition, patients were not randomized; however, the large pool of controls allowed us to match [proton radiotherapy] patients very closely with respect to observed risk factors,” the researchers reported. 

Travel Costs

“Patients receiving [proton radiotherapy] were younger, healthier, and from more affluent areas than patients receiving [intensity-modulated radiotherapy],” the investigators stated. Median Medicare reimbursement was $32,428 for proton radiotherapy and $18,575 for intensity-modulated radiotherapy.

Proton centers are still relatively rare in the United States, the researchers noted, and many patients traveled substantial distances to undergo proton radiotherapy. Moreover, some patients traveled past one proton radiotherapy center to receive treatment at a more distant proton center. 

“Because [proton radiotherapy] treatment involves 7 to 9 weeks of daily treatment, such travel often involves relocating for the duration of the treatment, so patients may incur substantial out of-pocket costs,” they continued. “This is perhaps an extreme example of an indirect cost associated with cancer care. Thus, the adoption pattern of [proton radiotherapy] reflects a tiered system of access to cancer care; one level involving most Americans who travel locally for cancer care, and another level where a select group of patients can afford to travel nationally to obtain the treatments that are perceived to be ‘best.’”


An accompanying editorial pointed out that two previous studies reached different conclusions: “that relative to [intensity-modulated radiotherapy], proton therapy was associated with increased long-term bowel complications and with no statistically significant difference in urinary complications.” The different studies “defined complications using such different methodologies and billing codes that a comparison of effect estimates between the three studies is not possible,” according to the editorial writers, Justin E. Bekelman, MD, and Stephen M. Hahn, MD, of the Department of Radiation Oncology, Abramson Cancer Center, University of Pennsylvania in Philadelphia. 

“Without studies to validate the surrogacy of claims-based endpoints, outcome misclassification could lead to false-negative or false-positive results.” they wrote. A randomized trial comparing proton therapy and intensity-modulated radiotherapy “would appear to be a good investment for patients and clinics,” they stated, adding, “the University of Pennsylvania and the Massachusetts General Hospital have partnered with other centers to conduct this randomized trial.”

In another accompanying editorial, Theodore S. Lawrence, MD, PhD, and Mary Feng, MD, of the Department of Radiation Oncology, University of Michigan in Ann Arbor, also stressed the need for prospective clinical trials directly comparing proton radiotherapy and intensity-modulated radiotherapy. “Although it seems unlikely that proton therapy will be superior to … photons for prostate cancer, protons may be superior for tumors in which the elimination of the low-dose regions might decrease normal tissue injury (eg, lung cancers, when combined with chemotherapy),” they wrote. ■

Yu JB, et al: J Natl Cancer Inst 105:25-32, 2013.

Bekelman JE, Hahn SM: J Natl Cancer Inst 105:6-7, 2013.

Lawrence TS, Feng M: J Natl Cancer Inst 105:7-8, 2013.