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

ImportanceEarly 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. ObjectiveTo assess treatment-failure and toxicity events following Pencil Beam Scanning (PBS)-PT in children. Design, Setting, and ParticipantsThe 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. InterventionsAll patients underwent PBS-PT or combined photon/PBS-PT. Main Outcomes and MeasuresThe 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. ResultsAt 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 RelevanceChildren 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. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the efficacy and safety profile of Pencil Beam Scanning Proton therapy (PBS-PT) in children? FindingsIn 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. MeaningPBS-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.