Second tumor risk in children treated with proton therapy

Abstract

Background: Out-of-field neutron dissemination during double-scattered proton therapy has raised concerns of increased second malignancies, disproportionally affecting pediatric patients due to the proportion of body exposed to scatter dose and inherent radiosensitivity of developing tissue. We sought to provide empiric data on the incidence of early second tumors. Methods: Between 2006 and 2019, 1713 consecutive children underwent doublescattered proton therapy. Median age at treatment was 9.1 years; 371 were ≤3 years old. Thirty-seven patients (2.2%) had tumor predisposition syndromes. Median prescription dose was 54 Gy (range 15-75.6). Median follow-up was 3.3 years (range 0.1-12.8), including 6587 total person-years. Five hundred forty-nine patients had ≥5 years of follow-up. A second tumor was defined as any solid neoplasm throughout the body.Results: Eleven patients developed second tumors; the 5-and 10-year cumulative incidences were 0.8% (95% CI, 0.4-1.9%) and 3.1% (95% CI, 1.5-6.2%), respectively. Using age-and gender-specific data from the Surveillance, Epidemiology, and End Results (SEER) program, the standardized incidence ratio was 13.5; the absolute excess risk was 1.5/1000 person-years. All but one patient who developed second tumors were irradiated at ≤5 years old (p < .0005). There was also a statistically significant correlation between patients with tumor predisposition syndromes and second tumors (p < .0001). Excluding patients with tumor predisposition syndromes, 5-and 10-year rates were 0.6% (95% CI, 0.2-1.7%) and 1.7% (95% CI, 0.7-4.0%), respectively, with all five malignant second tumors occurring in the high-dose region. Conclusion:Second tumors are rare within the decade following double-scattered proton therapy, particularly among children irradiated at >5 years old and those without tumor predisposition syndrome.

Second cancer risk in childhood cancer survivors treated with intensity‐modulated radiation therapy: An updated analysis of more than 10 years of follow‐up

“…30,31 Younger age is a known risk factor for radiation sensitivity and second cancer development, which was supported by other analyses including the recent study on subsequent neoplasm risk after proton beam RT. 20 This association was not clear in our data, as 9% of the 90 patients aged ≤5 years at IMRT developed a second cancer. Interestingly, of the six hematologic malignancies, two patients were ≤5 years of age at time of IMRT, one of whom developed AML/MDS <5 years after IMRT.…”

“…19 To address this question, a recent study published reported second cancer risks among 1713 children treated with double-scattered proton therapy with a median of 3.3 years of follow-up. 20 While their study differed from our report by including both benign and malignant tumors, as well as including patients with less than 5 years of follow-up, they do report results on a subset of 549 patients with at least 5 years of follow-up. In this subset, with a median 7.1 years of follow-up, the 10-year cumulative incidence of any second solid neoplasm (benign or malignant) was 2.3%, which is less than our preliminary report (3.3%), leading to their conclusion that proton beam RT does not seem to increase the risk of second cancers and may in fact reduce the risk as seen in adults.…”

“…On the contrary, it has been theorized that the passive modulation proton technique can potentially expose the patient to an even higher dose of radiation distant from the target compared to IMRT as a function of neutron production from the scattering foil 19 . To address this question, a recent study published reported second cancer risks among 1713 children treated with double‐scattered proton therapy with a median of 3.3 years of follow‐up 20 . While their study differed from our report by including both benign and malignant tumors, as well as including patients with less than 5 years of follow‐up, they do report results on a subset of 549 patients with at least 5 years of follow‐up.…”

Overall survival and secondary malignant neoplasms in children receiving passively scattered proton or photon craniospinal irradiation for medulloblastoma

“…Unlike our study, that study treated different types of tumors, including those outside the brain, with different RT fields and doses, with Cancer October 15, 2021 or without CT, and excluded children with tumor predisposition syndromes. 20 In 1 study from the St Jude-Washington University Pediatric Cancer Genome Project, 8.5% of children and adolescents had germline mutations identified in cancer predisposing genes. 21 We did not have any patients with a known tumor predisposition syndrome; however, as the Pediatric Cancer Genome Project reported, some of our patients probably have undetected mutations in cancer predisposing genes.…”

Patterns of Care and Utilization Disparities in Proton Radiation Therapy for Pediatric Central Nervous System Malignancies

“…Proton radiation therapy (PR) is well established in the treatment of pediatric primary central nervous system (CNS) malignancies, with known dosimetric advantages compared with traditional photon radiation and increasing retrospective evidence showing reduced risk of late effects including cognitive decline and secondary malignancy. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Prior publications have reported on national PR practice patterns, which were notable for racial and sociodemographic disparities in the application of proton therapy. 19 In the years since the most recent national level database analysis was published, the number of available proton therapy centers increased by about 200%.…”