Second Tumors in Pediatric Patients Treated with Double-Scattered Proton Therapy

Abstract

We hypothesize that double-scattered proton therapy results in neutron dissemination far beyond the treatment field, resulting in an increased risk of second malignancies that disproportionally affect pediatric patients. Between 2006 and 2019, 1708 consecutive children ≤ 21 years old were treated with double-scattered proton therapy at a single institution. Most common indications included CNS tumors (60%), sarcomas (28%), and head/neck tumors (5%). The median age at treatment was 9.2 years, and 370 children were ≤ 3 years. Thirty-five patients (2%) had tumor predisposition syndromes: 18 with neurofibromatosis (NF), 11 with retinoblastoma, and 6 with Li-Fraumeni (LF). Across the cohort, the median prescription dose was 54 Gy (range, 15 - 75.6 Gy). The median follow-up duration was 3.5 years (range, 0.1 - 12.8 years) and includes 6886 total person-years in follow-up. Four hundred patients have ≥ 5 years of follow-up. Seven patients (0.4%) were lost to follow-up. A second tumor was defined as any solid neoplasm throughout the body. The Kaplan-Meier product limit method estimated freedom from second tumor and the log-rank test statistic estimated the level of statistical significance between strata of patients with tumor predisposition syndromes and those patients without. Standardized incidence ratio (SIR) was assessed as the ratio of the observed/expected cases for second solid tumor development using general pediatric incidence rates from the Surveillance, Epidemiology, and End Results (SEER) Program. Seven patients overall developed second tumors resulting in a 5- and 10-year cumulative incidence of 0.4% (95% CI: 0.1-1.1%) and 1.9% (95% CI: 0.8%-4.4%), respectively. The SIR was 7.9. All patients who developed second tumors were irradiated at ≤ 5 years old. There was a statistically significant correlation between patients with NF or LF and second tumors (p < 0.0001). Excluding these patients, 5- and 10-year rates were 0.2% (95% CI: 0-1.1%) and 1.1% (95% CI: 0.4- 3.6%), respectively, and no second tumors developed in regions receiving < 50 Gy. Two patients overall developed hematologic second malignancies < 12 months following chemotherapy and radiation. Second tumors are rare within the decade following double-scattered proton therapy, particularly among children irradiated at > 5 years of age and those without tumor predisposition syndrome. Longer follow-up is needed to empirically validate claims that proton therapy results in less overall second tumors in children, but it is unlikely that neutrons from double-scattered proton therapy in children result in an increased rate of “out-of-field” second tumors.