187 - A Phase IV Surveillance Trial of Pencil Beam Scanning Proton Therapy in Children

Purpose/Objective(s): Intensity modulated pencil beam scanning proton radiotherapy (PBS-PT) was approved for the treatment of childhood cancer based on substantial equivalence to photon radiotherapy. We designed a phase IV clinical trial to study the safety and effectiveness of PBS-PT when early reports suggested an increase in adverse events.

Materials/Methods: We screened 1,000 children, enrolling 995 eligible for PBS-PT on SJPROTON1 between July 2017 and January 2022, covering 2,916 irradiated sites. The median follow-up was 4.1 years (IQR 2.8-5.7). A mixed photon/proton approach was used in 12.4% of cases. The modified SJLIFE NCI CTCAE v4.03 was applied to estimate the cumulative incidence of grade 3 or higher (G3+) non-hematologic complications attributable to PBS-PT at baseline and through five years after PBS-PT. Additional outcomes included 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. Total toxicity burden (TTB) at each timepoint was quantified as an exploratory objective. Event-free (EFS) and Overall Survival (OS) were estimated using the Kaplan Meier estimator. The cumulative incidence (CI) of events were calculated using the Aalen-Johansen estimator and Fine-Gray subdistribution hazard model was used to evaluate predictors of =grade 3 PBS-PT attributable toxicity.

Results: At four years, the EFS and OS were 66.7% (95%CI, 63.7-69.9%) and 78.4% (95%CI 75.9-81.3%) respectively. The CI of treatment- and non-treatment-related deaths at four years was 0.8% (95%CI 0.04-1.6%) and 27.7% (95%CI 24-31.4%) respectively. The CI of treatment-related malignancies and benign tumors was 1.2% (95%CI 0.6-2.4%), and 1.8% (95%CI 0.9-3.2%), respectively. Baseline and post-PBS-PT trial evaluations identified 6,348 toxicities. The CI of G3+ toxicity events at four years was 34.8%, including CNS necrosis (3.7% 95%CI 2.5-5.3%), hearing impairment (11.3% (95%CI 9.1-13.8%), neurologic deficit (11.6%), and osteoradionecrosis (0.1% 95%CI 0-0.8%). The four year CI of hospitalization and procedures due to PBS-PT-attributable toxicity was 4% (95% CI 2.9-5.4%) and 5.5% (95% CI 4.1-7.1%), respectively.

Conclusion: Children treated with PBS-PT have positive long-term outcomes and a low overall risk of severe events including hospitalization. (NCT03223766)