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

Background: Early reports suggest adverse events following proton therapy (PT) for childhood cancer are more prevalent. We evaluated treatment-failure and toxicity following Pencil Beam Scanning (PBS)-PT in children. Methods: The single-institution Phase IV 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). The primary objective was the cumulative incidence (CI) of ≥grade 3 non-hematologic, PBS-PT attributable toxicity by CTCAE v4.0. Additional outcomes included PBS-PT toxicity attributable hospitalization, procedures, and treatment-related mortality. Toxicities including necrosis, vasculopathy, neurologic deficits, and fracture/osteoradionecrosis were further characterized (any grade). Competing risk regression was used to evaluate predictors of ≥grade 3 PBS-PT attributable toxicity. Findings: 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 CI of 16.5% (95% CI 13.1-20.4) and 6.8% (95% CI 4.6-9.5) respectively. The 4 year CI of ≥grade 3 toxicity was 24.5%; including necrosis (3.7%), neurologic deficit (2.9%), and fracture/osteoradionecrosis (0.79%). The rates of PBS-PT-toxicity attributable hospitalization and procedures were 3.9% and 7.6%. Predictors of any ≥grade 3 toxicity included baseline total toxicity burden (TTB) (HR 1.043, 95% CI 1.012-1.07, p=0.007), and mixed photon/PBS-PT (HR 2.62, 95% CI 1.51-4.54, p=0.006) in CNS patients, and pelvic radiotherapy (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 non-CNS patients.  Interpretation: PBS-PT yields a low incidence of toxicity, but subsets are at increased risk, and may require additional procedures or hospitalization. Funding: This work was supported by ALSAC and Cancer Center Core Grant CA21765. Declaration of Interest: None to declare. Ethical Approval: The SJPROTON1 trial was reviewed and approved by the Institutional Review Board at St. Jude. Informed consent was obtained from the parent, caregiver, or patient, with assent from the patient, as appropriate.