Cognitive outcomes following proton vs. photon radiotherapy for CNS non-germinomatous germ cell tumors: A Children’s Oncology Group study.

Abstract

10016 Background: The Children’s Oncology Group (COG) study ACNS1123 (stratum 1) treated children with localized non-germinomatous germ cell tumors (NGGCT) of the brain with chemotherapy followed by whole ventricular (WV) radiotherapy (RT, 30.6 Gy) followed by a focal tumor bed boost (54 Gy total dose). Previous work has shown that WVRT with proton therapy, compared to photon RT, resulted in lower RT doses to the brain. However, it was unclear whether this dosimetric difference led to superior cognitive outcomes. Methods: The ACNS1123 study was a prospective, phase II trial conducted by the COG that enrolled 107 patients. Evaluation of cognitive functioning of children was a co-primary objective of the study. Cognition was prospectively examined at 9, 30 and 60 months post-diagnosis, using the COG Standard Neuropsychological and Behavioral Battery. The primary endpoints were attention/concentration, estimated intelligence quotient (IQ), and processing speed. Linear mixed-effect models were created to model cognitive endpoints with treatment exposures, including RT modality (proton vs. photon RT) or RT dose to brain structures. Cognitive evaluations completed post-recurrence were excluded. Results: Seventy patients were evaluable and received WVRT followed by RT boost, of which 20 received proton therapy. Mean age of all patients was 11.8 ± 4.3 years old at the start WVRT, and were predominantly male (n = 52). Mean doses to the brain were significantly lower with proton vs. photon RT (mean 18.8 ± 1.8 [SD] vs. 24.7 ± 3.7 Gy, p < 0.0001), left hippocampus (41.1 ± 5.2 vs 46.2 ± 5.3 Gy, p = 0.0005), and right hippocampus (41.8 ± 5.1 vs 46.0 ± 5.3Gy, p = 0.0038). A total of 56, 60 and 61 patients were evaluable for attention/concentration, estimated IQ and processing speed, respectively, with 1 or more evaluation. Nine, 20 and 20 patients had data at all 3 time points for attention/concentration, estimated IQ and processing speed, respectively. Multivariable modelling demonstrated that photon therapy was associated with a decline in IQ over time (p = 0.0401), as compared with proton RT, adjusted for age at RT and gender. In a separate multivariable model, higher mean brain dose was also associated with poorer recovery of IQ over time (p = 0.0216), adjusted for gender. There were no identified associations between use of proton RT or hippocampal dose with processing speed or attention/concentration. Conclusions: Compared to proton therapy,WVRT delivered with photons was associated with a significant decline in IQ and adverse recovery of IQ over time. To our knowledge, this data is the first to demonstrate such an association for children with NGGCT.