TY - JOUR
T1 - A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma
AU - Veldhuijzen van Zanten, Sophie E M
AU - El-Khouly, Fatma E
AU - Jansen, Marc H A
AU - Bakker, Dewi P
AU - Sanchez Aliaga, Esther
AU - Haasbeek, Cornelis J A
AU - Wolf, Nicole I
AU - Zwaan, C Michel
AU - Vandertop, W Peter
AU - van Vuurden, Dannis G
AU - Kaspers, Gertjan J L
N1 - Publisher Copyright:
© 2017, The Author(s).
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
KW - Administration, Intravenous
KW - Adolescent
KW - Antimetabolites, Antineoplastic/adverse effects
KW - Brain Stem Neoplasms/therapy
KW - Chemoradiotherapy/adverse effects
KW - Child
KW - Child, Preschool
KW - Deoxycytidine/adverse effects
KW - Female
KW - Glioma/therapy
KW - Humans
KW - Male
KW - Quality of Life
KW - Radiation-Sensitizing Agents/adverse effects
KW - Treatment Outcome
UR - http://www.scopus.com/inward/record.url?scp=85026914198&partnerID=8YFLogxK
U2 - 10.1007/s11060-017-2575-9
DO - 10.1007/s11060-017-2575-9
M3 - Article
C2 - 28748343
SN - 0167-594X
VL - 135
SP - 307
EP - 315
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 2
ER -