WHITE-MATTER CHANGES ARE CORRELATED SIGNIFICANTLY WITH RADIATION-DOSE- OBSERVATIONS FROM A RANDOMIZED DOSE-ESCALATION TRIAL FOR MALIGNANT GLIOMA (RADIATION-THERAPY-ONCOLOGY-GROUP-83-02)

Background. A Phase I/II randomized dose-seeking trial was performed t o document the severity, time course, and significance of white matter changes seen on serial imaging scans (magnetic resonance imaging, com puted tomography) associated with bis-chlorethyl nitrosourea (BCNU) an d hyperfractionated cranial irradiation. Methods. Long term survivors (greater than or equal to 18 months) were identified from a prospectiv e randomized dose-escalation Phase I/II trial designed to evaluate twi ce-daily radiotherapy for supratentorial high grade malignant gliomas. All scans were reviewed by a neuroradiologist who had no information about the prescribed dose and fractionation. In the trial, patients we re assigned to receive 64.8 Gy, 72.0 Gy, 76.8 Gy, or 81.4 Gy (all frac tionated as 1.2 Gy twice a day [bid]), or 48.0 Gy or 54.4 Gy (both in 1.6-Gy bid fractions). Bis-chlorethyl nitrosourea was administered eve ry 8 weeks for 1 year. Of 747 randomized patients, 177 had analyzable scans. The scans reviewed were those acquired preoperatively, immediat ely postoperatively, 3, 6, 12, and 18 months after radiotherapy. Radio graphic endpoints included no white matter change (Grade 0), minimal p atchy white matter foci (Grade 1), start of confluence of white matter disease (Grade 2), large confluent areas (Grade 3), confluence with c ortical/subcortical involvement (Grade 4), leukoencephalopathy (Grade 5), and possible necrosis (Grade 6) according to the classification of F. Fazekas et al.9 The effects were scored relative to the baseline p reoperative scans, The dose pairs of 48 Gy and 54.4 Gy, 64.8 Gy and 72 Gy, and 76.8 Gy and 81.4 Gy were grouped together for analysis (low, intermediate, and high dose, respectively). Toxicity was analyzed in t hree ways: Grade 2 or worse, Grade 3 or worse, and Grade 6. Results. G rade 2 or worse changes were observed in 26.8, 27.6, and 40.4% of pati ents in the low, intermediate, and high dose groups, respectively. Gra de 3 or worse changes were observed in 8.3, 20.0, and 36.5% of patient s in the low, intermediate, and high dose groups, respectively. Grade 6 changes were observed in 1.6, 4.6, and 19.2% of patients in the low, intermediate, and high dose groups, respectively. No statistically si gnificant differences were observed among treatment groups when toxici ty was evaluated as Grade 2 or worse. For toxicity of Grade 3 or worse , an chi-square test revealed P values of 0.04 (low vs. intermediate d ose), 0.09 (intermediate vs. high dose), and 0.0005 (low vs. high dose ). With the endpoint of possible necrosis (Grade 6), P values were 0.2 1 (flow vs. intermediate dose), 0.05 (intermediate vs. high dose), and 0.003 (low vs. high dose), The median time to radiographic appearance of an effect (15 months) was not influenced by total dose or fraction size. Conclusions. A well described toxicity scale for white matter i njury was applied successfully to patients with malignant glioma treat ed with definitive irradiation. Severe white matter changes continued to increase significantly as the total dose of hyperfractionated crani al irradiation was escalated. The time to onset of the white matter ab normalities appeared to be independent of dose. An ongoing Radiation T herapy Oncology Group study will allow correlation of white matter inj ury with prospective neuropsychometric testing.