A Phase IV Trial of Proton Therapy in Children: The First Report from the SJPROTON1 Study

Importance Early reports suggest adverse events following proton therapy (PT) for childhood cancer are more prevalent given the increased number of PT centers and use in clinical trials. Objective To assess treatment-failure and toxicity events following Pencil Beam Scanning (PBS)-PT in children. Design, Setting, and Participants The single-institution Phase IV surveillance trial screened 856 children, of which 528 were eligible for PBS-PT, and 500 enrolled in SJPROTON1 from 2017–2020. The median follow-up was 2.1 years (range 1.1-4.4). PBS-RT attributable toxicities were systematically identified, and graded at baseline to four years following PBS-PT. Interventions All patients underwent PBS-PT or combined photon/PBS-PT. Main Outcomes and Measures The primary objective was the CI of ≥grade 3 non-hematologic, PBS-PT attributable Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. Additional outcomes included PBS-PT attributable hospitalization, toxicity related procedures, and treatment-related mortality. Pre-specified toxicities including necrosis, vasculopathy, neurologic deficits, and fracture/osteoradionecrosis were further characterized (any grade) as a secondary objective. Medical record review augmented in-person visits for failure and adverse event reporting. Competing risk regression was used to evaluate predictors of ≥grade 3 PBS-PT attributable toxicity. Results At two years, the event-free survival was 73.2% (95% CI, 68.9%-77.8%). Distant and local failure predominated with a 2-year cumulative incidence (CI) of 16.5% (95% CI 13.1-20.4) and 6.8% (95% CI 4.6-9.5) respectively. The CI of ≥ grade 3 toxicity events at four years was 24.5%; including necrosis (3.7%), permanent neurologic deficit (2.9%), and fracture/osteoradionecrosis (0.79%). The rates of hospitalization and procedures due to PBS-PT– attributable toxicity was 3.9% and 7.6%, respectively. Predictors of an increased event-specific hazard for any ≥ grade 3 toxicity included baseline total toxicity burden (TTB) (HR 1.043, 95% CI 1.012-1.07, p=0.007), use of mixed photon/PBS-PT (HR 2.62, 95% CI 1.51-4.54, p=0.006) in the CNS population, and treatment of the pelvic body site (HR 4.25, 95% CI 1.08-16.72, p=0.038), and TTB (HR 1.1, 95% CI 1.04-1.16, p=0.002) in the non-CNS population, respectively. Conclusions and Relevance Children treated with PBS-PT experience a low incidence of toxicity, but subsets may be at increased risk, and experience toxicity that requires additional procedures or hospitalization. Question What is the efficacy and safety profile of Pencil Beam Scanning Proton therapy (PBS-PT) in children? Findings In this single institution phase IV trial, the rate of local failure and clinically significant ≥grade 3 PBS-RT attributable toxicity were low, but a subset of patients may be at increased risk for hospitalization and procedures related to managing PBS-RT attributable adverse events. Meaning PBS-RT has an acceptable therapeutic ratio in children but the risk of adverse events requiring hospitalization or subsequent procedures may be increased in select populations. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03223766 ### Clinical Protocols ### Funding Statement This work was supported by ALSAC and Cancer Center Core Grant CA21765. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The St. Jude Children's Research Hospital IRB gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors