Abstract
The purpose of this phase I/II, open-label, single-arm trial is to investigate the safety, tolerability, maximum tolerated dose and preliminary efficacy of the potential radiosensitizer gemcitabine, administered concomitantly to radiotherapy, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Six doses of weekly gemcitabine were administered intravenously, concomitantly to 6 weeks of hyperfractionated radiotherapy. Successive cohorts received increasing doses of 140, 175 and 200 mg/m2 gemcitabine, respectively, following a 3 + 3 dose-escalation schedule without expansion cohort. Dose-limiting toxicities (DLT) were monitored during treatment period. Clinical response was assessed using predefined case report forms and radiological response was assessed using the modified RANO criteria. Quality of life (QoL) was assessed using PedsQL questionnaires. Between June 2012 and December 2016, nine patients were enrolled. Treatment was well tolerated, and no DLTs were observed up to the maximum dose of 200 mg/m2. All patients experienced reduction of tumor-related symptoms. QoL tended to improve during treatment. PFS and MOS were 4.8 months (95% CI 4.0–5.7) and 8.7 months (95% CI 7.0–10.4). Classifying patients according to the recently developed DIPG survival prediction model, intermediate risk patients (n = 4), showed a PFS and MOS of 6.4 and 12.4 months, respectively, versus a PFS and MOS of 4.5 and 8.1 months, respectively, in high risk patient (n = 5). Gemcitabine up to 200 mg/m2/once weekly, added to radiotherapy, is safe and well tolerated in children with newly diagnosed DIPG. PFS and MOS were not significantly different from literature.
Highlights
Patients with diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis, with less than 10% of the patients being alive at 2 years after initial diagnosis, and a median overall survival (MOS) of 9 months [1, 2]
The radiosensitizing doses in the current trial were based on studies by Fabi et al [6] and Metro et al [7], showing a maximum tolerated dose (MTD) of 175 mg/m2 gemcitabine once weekly, concomitant to radiotherapy in adult glioblastoma multiforme (GBM) [6, 7]
The use of gemcitabine has been approved by U.S Food and Drug Administration (FDA) and European Medicines Agency (EMA) for adults, and has been tested and proven to be safe in children up to 1000 mg/m2/dose when combined with other chemotherapeutic drugs [12]
Summary
Patients with diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis, with less than 10% of the patients being alive at 2 years after initial diagnosis, and a median overall survival (MOS) of 9 months [1, 2]. The radiosensitizing doses in the current trial were based on studies by Fabi et al [6] and Metro et al [7], showing a maximum tolerated dose (MTD) of 175 mg/m2 gemcitabine once weekly, concomitant to radiotherapy in adult GBM [6, 7]. Gemcitabine monotherapy has proven to be safe and tolerable up to cytotoxic dosages of 3600 mg/m2/week in leukemia, Hodgkin’s lymphoma and solid tumor patients [8,9,10,11]. Toxicities observed in these pediatric studies are mainly myelotoxicity, elevation of liver enzymes and mucositis. Since the present study aims for the radiosensitizing effect of gemcitabine, much lower doses were used, and only limited additional toxicity was not expected
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