Gemcitabine Plus Radiation Therapy for High Grade Glioma: Long-term Results of a Phase I Dose-Escalation Study
Mené sur 29 patients adultes atteints d'un gliome malin de haut grade (durée médiane de suivi : 38,1 mois), cet essai de phase I évalue la tolérabilité d'un traitement combinant de manière concomitante gemcitabine et radiothérapie
Purpose/Objective(s) : Advancements are needed in the treatment of malignant glioma (HGG), but the benefit of radiosensitizing chemotherapy in all patient subgroups is unknown. We evaluated the tolerability and efficacy of gemcitabine plus radiation (RT) in this phase I study of patients with newly diagnosed HGG. Methods/Materials : Between 2004-2012, 29 adults with HGG were enrolled. After any extent of resection, RT (60 Gy over 6 weeks) was given concurrent with escalating doses of weekly gemcitabine. Using a time-to-event continual reassessment method (TITE-CRM), 5 dose levels were evaluated starting at 500 mg/m2 during the last 2 weeks of RT and advanced stepwise into earlier weeks. The primary objective was to determine the recommended Phase II dose of gemcitabine plus RT. Secondary objectives included progression-free survival (PFS), overall survival (OS) and long-term toxicity. Results : Median follow-up was 38.1 months (range, 8.9-117.5); 24 patients were evaluable for toxicity. After 2005 when standard practice changed, patients with WHO grade IV tumors were no longer enrolled. Median PFS for 22 patients with grade III tumors was 26.0 months (95%CI 15.6-inestimable) and OS was 48.5 months (95%CI 26.8-inestimable). In 4 IDH mutated, 1p/19q codeleted patients, no failures occurred, with all but 1 alive at time of last follow-up. Seven with IDH mutated, non-codeleted tumors with ATRX loss had intermediate OS of 73.5 months (95%CI 32.8-inestimable). Six non-mutated, non-codeleted patients had a median OS of 26.5 months (95% CI 25.4-inestimable). The recommended Phase II dose of gemcitabine plus RT was 750 mg/m2/week given the last 4 weeks of RT. Dose-reductions were most commonly due to grade 3 neutropenia; no grade 4 or 5 toxicities were seen. Conclusions : Gemcitabine concurrent with RT is well-tolerated and yields promising outcomes, including in patients with adverse molecular features. It is a candidate for further study, particularly for poor-prognosis patient subgroups with HGG.