The body of evidence for advanced technology in radiation oncology.

Proton therapy has struck a nerve in the national dialogue about cancer comparative effectiveness research in the United States. Unlike photon-based radiotherapy, proton therapy delivers radiation within a finite range, depositing dose in a tumor target with essentially no residual radiation beyond the tumor. Proton therapy radiation dose distributions often appear superior to photon-based treatments like intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy, particularly in the reduction of low and intermediate radiation dose to normal tissues. However, proton therapy has greater intrinsic uncertainties than photon-based treatments, both biological and physical. For example , uncertainty exists about where the finite range of protons terminates in tissue; to compensate, proton treatment centers routinely overshoot tumor targets to ensure adequate radiation coverage (1). Proton therapy uncertainties and methods by which such uncertainties are mitigated could impact important clinical outcomes. Thus, the comparative effectiveness test for proton therapy is whether it leads to incremental reductions in morbidity or improvements in survival and disease control, not whether the dose distribution looks better or mechanism of radiation delivery is novel (2). In this issue of the Journal, Yu et al. (3) report the results of a retrospective observational comparison of proton therapy to IMRT for prostate cancer using 2008 and 2009 Medicare claims data from the Chronic Condition Warehouse, a national database of 100% of Medicare fee-for-service claims. Among men aged greater than 65 years, the investigators found that proton therapy was associated with a small reduction in genitourinary complications at 6 months relative to IMRT (5.9% vs 9.5%, respectively), but they found no statistically significant difference at 12 months. There was no statistically significant difference in gastrointestinal or other complications at 6 or 12 months. Moreover, the median Medicare reimbursement for proton therapy patients was $32 428, whereas the median for IMRT patients was $18 575. This report is the most comprehensive study to date on outcomes of proton therapy and IMRT among US men aged greater than 65 years—a population that comprises more than two-thirds of all men who receive radiation for prostate cancer— and reports marginal and transient reductions, at best, in acute genitourinary complications with proton therapy at substantially increased treatment costs. The Yu et al. report (3) is an example of careful observational comparative effectiveness research (CER) and augments the growing observational evidence base for advanced radiotherapy technologies. However, three notable systematic biases may threaten the validity of nonrandomized studies and …