Dose-Effect of Proton and Photon Craniospinal Irradiation on Vertebral Growth in Pediatric Patients with Medulloblastoma

Abstract

Craniospinal irradiation (CSI) directly damages vertebral growth plates causing skeletal dysplasia leading to reduced height in pediatric long-term survivors. The objective of this study is to quantify the adjusted effect of CSI on standing and sitting height by radiation dose and modality in children. Two hundred sixty-five patients (M/F 169/96) were treated at a single institution on a clinical and molecular risk-directed trial for medulloblastoma (NCT01878617) using proton or photon therapy. Three CSI dose regimens were evaluated: 15 Gy (n = 31), 23.4 Gy (n = 103), ≥36 Gy (n = 131). Vertebral body dose was limited to 18-20 CGE for 23.4 Gy or 36 Gy proton therapy. All patients received post-CSI protocol-specified chemotherapy. Non-parametric tests were applied for baseline patient comparison. Changes in growth over time were calculated using random coefficients models using patient-specific intercepts and slopes. Dose-effects were modeled for ages 5, 10, and 18 years. Age at CSI and race were similar between the three dose levels. Females most often received 23.4 Gy and males ≥36 Gy (p = 0.001). Higher CSI doses were associated with photon therapy (p<0.001). Median follow-up was 3 years (range 0.1-7.1). Annual growth rate was significantly different between 15 Gy (3.66 cm/year) and the higher dose levels of 23.4 Gy (2.81 cm/year, p = 0.0389) and ≥36 Gy (2.46 cm/year, p = 0.0032). Lower annual growth rate in females (vs. males, p = 0.0331) was observed in models for those aged 5 (-0.17 cm/year), 10 (-0.35 cm/year), and 18 years (-0.62 cm/year). In multivariate analysis, modelled annual growth rate was dose-dependent at ages 5 and 10 years. The differences were, respectively, 1.68 cm/year between 15 and 23.4 Gy (p = 0.0005) and 0.98 cm/year between 23.4 and ≥36 Gy (p = 0.0002), and 1.13 cm/year between 15 and 23.4 Gy (p = 0.0002) and 0.68 cm/year between 23.4 and ≥36 Gy (p = 0.0003). Radiation modality did not impact standing height over time significantly. Annual sitting height growth was 2.34, 1.67 and 1.1 cm/year for the three dose levels (p<0.0001-0.001). In the multivariate model, a 5-year-old receiving 15 or 23.4 Gy had similar annual sitting height growth, but not when 23.4 Gy was compared to ≥36 Gy (0.83 cm/year, p<0.0001). In a separate model for a patient aged 10 years, there was a difference comparing all CSI regimens (0.81 cm/year, p<0.0001, 15 vs 23.4 Gy; 0.54 cm/year, p = 0.0002, 23.4 vs ≥36 Gy). Sitting height growth was affected by CSI dose at age 18 years, with a difference of 2.2 cm/year between 15 vs 23.4 Gy (p = 0.0013), and no difference between 23.4 and ≥36 Gy. Annual growth rates show a dose-response relationship, independent of treatment modality. A dose-response in sitting height growth rate is seen at any age, while the annual standing height growth rate was only affected by CSI dose in 5- and 10-year-olds. While all CSI doses had a significant impact on the annual standing height, sitting height growth rates approximated normal values for those treated with a low CSI dose.