Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities

Abstract

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RT with passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

Fig. 1.

Details of clinical trials conducted with proton therapy as registered with clinicaltrials.gov. (A) Clinical trials conducted with proton therapy, their overall status, and the number of trials in a specific stage. (B) Percentage of trials for different organ/sites.

Fig. 2.

Adverse events (AEs) in clinical trial NCT00915005, as reported in clinicaltrials.gov, with vocabulary Common Terminology Criteria for Adverse Events, version 4.0. The percent total of all events is not the percent of numerical total, but rather the number of events collected by systematic assessment. Several AEs can occur together in a given patient. To test the statistical significance between variables, a 1-tail t test was used assuming unequal variances between 2 samples. All serious AEs (grade ≥3) were significantly higher in the passive scattering proton therapy group compared with intensity modulated radiation therapy (P <.01), but other AEs (excluding serious) were not significantly (P <.40) different between the 2 groups. Conditional formatting in Microsoft Excel in a 2-color scale is used to depict percent AEs, with cells that contain values >10% shown in red and <10% in green. * Serious AEs are significantly higher (P < .01) in PSPT group compared to IMRT