Multicenter Phase I Dose Escalation Study of Hypofractionated Stereotactic Radiotherapy with Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma
Mené sur 15 patients atteints d'un gliome de haut grade récidivant, cet essai de phase I évalue la dose maximale tolérée de rayonnements ionisants dans le cadre d'une seconde irradiation hypofractionnée stéréotaxique en combinaison avec le bévacizumab
Purpose : It has been reported previously that the combination of bevacizumab with hypofractionated stereotactic re-irradiation (HFSR) with 30Gy (6GyX5 fractions) was safe and efficacious in recurrent glioblastomas and high-grade gliomas (HGG). Because most recurrences are local, developing intensified HFSR dosing schedules remains of interest. We hypothesized that in combination with bevacizumab, HFSR doses could be further escalated, and designed a prospective phase I trial to establish the maximum tolerated dose (MTD) of a 3-fraction HFSR delivered concomitantly with standard doses of bevacizumab. Materials and Methods : Patients with recurrent HGG with KPS ≥ 60, history of standard fractionated initial radiation, tumor volume at recurrence ≤ 40cc and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 Phase I dose escalation trial design was utilized, with dose-limiting toxicities (DLT) defined as any grade 3-5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10mg/kg every two weeks. HFSR was initiated after two bevacizumab doses, delivered in 3 fractions every other day, starting at 9 Gy/fraction. Results : A total of 3 patients were enrolled at the 9GyX3 dose level cohort, 5 enrolled in the 10GyX3 cohort and 7 in the 11GyX3 cohort. One DLT of grade 3 fatigue and cognitive deterioration possibly related to HFSR was observed in the 11GyX3 cohort, and this dose was declared the MTD in combination with bevacizumab. Although no symptomatic radionecrosis was observed, substantial treatment-related effects and necrosis were observed in resected specimens. The intent-to-treat median overall survival (OS) was 13 months. Conclusions : Re-irradiation using a 3-fraction schedule with bevacizumab support is feasible and reasonably well tolerated. Dose-escalation was possible up to 11GyX3, which achieves a near doubling in the delivered biological equivalent dose to normal brain, in comparison to our previous 6GyX5 schedule. Promising OS warrants further investigation.