# Acute Toxicities During Proton Therapy with or Without Simultaneous Chemotherapy in Pediatric CNS Tumors: A Retrospective Cohort Study

## TL;DR

This study examines the acute toxicities in children undergoing proton therapy with or without chemotherapy for CNS tumors, finding that chemotherapy increases severe side effects.

## Contribution

The study provides new insights into the acute toxicity risks of combining proton therapy with chemotherapy in pediatric CNS tumor patients.

## Key findings

- Chemotherapy combined with proton therapy significantly increases high-grade adverse events in children.
- Infections and hematotoxicity are the most common severe side effects in patients receiving combined therapy.
- Treatment interruptions are more frequent with combined proton therapy and chemotherapy.

## Abstract

Simultaneous chemotherapy (sCTx) with radiotherapy has been used for several decades in the treatment of primary CNS tumors in children and adolescents mostly in curative intention and with the aim to improve local tumor control by radiosensitizing effects and in order to retain systemic tumor control in- and outside the CNS. The technique of proton therapy, as an alternative to classical photon therapy, allows high-precision radiotherapy as part of a multimodal treatment in primary CNS tumors in childhood. The purpose of our study was to evaluate the acute toxicity and to demonstrate the feasibility during proton therapy with or without sCTx in children and adolescents and the problems in dealing with acute side effects and complications especially in young patients. Simultaneous CTX has proven to be a significant factor for the occurrence of acute high-grade adverse events and for interruptions of radiotherapy.

Background: Proton beam therapy (PBT) is a valuable alternative to photon radiotherapy of CNS tumors in children and adolescents. While most recent studies deal with the outcome or long-term side effects of PBT, the aim of this study was to investigate the feasibility of PBT with a particular focus on the acute toxicity of a simultaneous radiochemotherapy (sPBCT). Patients and methods: We enrolled 199 children [median age 7.4 years (range, 0.9–17.9)], who received altogether 200 courses of PBT/sPBCT at initial diagnosis (n = 121) or at relapse (n = 79) with sPBCT in 52 (26%) courses. Data collection to PBT/sPBCT was based on the medical records and the KiProReg (Registry study of Standard Proton Therapy in Children at West German Proton Therapy Center) with a primarily descriptive-statistical and logistic regression analysis. Results: During PBT/sPBCT a total of n = 704 adverse events (AEs, mean 3.4 per course) were observed. Eighty-seven of them were graded as high-grade adverse events (HGAEs, Common Terminology Criteria for Adverse Eventº ≥3 (CTCAE)) which occurred in 67 (33.5%) PBT/sPBCT courses. HGAEs were in particular hematotoxicity (n = 43; 64.1%) and infections (n = 18; 26.8%). A significantly higher rate of HGAEs was documented in patients treated with sPBCT (n = 33/52; 63.5%) compared to those with PBT only (n = 34/148; 23.0%) (p = 0.001). In children with sPBCT, 15 (28.8%) patients could not receive the recommended dose or schedule of the planned chemotherapy (CTx) due to HGAEs, with the rate of planned CTx courses performed being significantly lower in patients receiving intensive intravenous CTx (p < 0.001). Interruptions of PBT and of simultaneous CTx were both significantly associated with the occurrence of infections [Odds ratios 3.002 (95% CI 1.005–8.971, p = 0.049) and 3.905 (95% CI 1.005–15.174, p = 0.049)]. Total discontinuation of treatment did not occur. Conclusions: Concurrent CTx during proton therapy is associated with a significant increased risk for HGAE occurrence and therapy interruptions requiring individual dose and schedule adjustments dependent on CTx intensity, very experienced interdisciplinary teams as well as intensive care and in-/out-patient oncology facilities on site.