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 RTwith 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.

Does the uncertainty in relative biological effectiveness affect patient treatment in proton therapy?

“…So far, all studies reporting evidence for clinical effects of a variable RBE are considering normal tissue reactions (asymptomatic or symptomatic)mostly using late-stage imaging changes as endpoint -but for reasons discussed above, not tumour response. Current clinical trials comparing normal tissue toxicities for protons versus photons, plus future studies designed to answer questions about biological differences between the modalities have recently been reviewed and discussed in [59].…”

Radiation induced lung injury (RILI) after postoperative intensity modulated proton therapy (IMPT) in a patient with stage III locally advanced lung adenocarcinoma: a case report

“…A reasonable and conservative radiation dose was delivered in the case so that there was no evidence for the dose related RILI. Despite the control of uncertainties from intrafield target motion due to unavoidable respiration and cardiac motion and daily setup anatomical changes were managed ahead of schedule during the thoracic radiation treatment planning, IMPT is highly sensitive to the slight difference since proton pencil beam delivers different relative linear stopping powers at the path of moving into and out of the tissue due to the slight change (19,20). Daily adaptive optimization before deliver each fraction is pre-clinical to guarantee a high accuracy but is limited to the time consuming (21).…”

Incidence of clinical lymphedema in breast cancer patients treated with adjuvant proton-based radiotherapy

“…The clinical application of proton-based RT has been growing in recent years. The dosimetric benefits of proton-based RT are well documented, including a low to medium entrance dose, homogeneous dose distribution in the target area, and sharp dose falloff known as the Bragg peak, result in a significantly reduced whole-body integral dose [1][2][3]. These advantages may offer an advantage over photon-based RT for all patients in terms of minimization of late cardiovascular toxicity, as well as benefit for patients with a history of prior thoracic RT, patients with connective tissue disease or other comorbidities that increase the risk of acute and late toxicity, and very young patients.…”