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Phase II trial of irinotecan and metronomic temozolomide in patients with recurrent glioblastoma

Reynés, Gaspara; Martínez-Sales, Vicentab; Vila, Virtudesb; Balañá, Carmend; Pérez-Segura, Pedroe; Vaz, María A.f; Benavides, Manuelh; Gallego, Oscari; Palomero, Isabelg; Gil-Gil, Miguelj; Fleitas, Taniac; Reche, Encarnacióna

doi: 10.1097/CAD.0000000000000314

This phase II study was conducted to determine the efficacy and safety of metronomic temozolomide (TMZ) in combination with irinotecan in glioblastoma (GB) at first relapse. Patients with GB at first relapse received TMZ 50 mg/m2/day divided into three doses, except for a single 100 mg/m2 dose, administered between 3 and 6 h before every irinotecan infusion. Irinotecan was given intravenously at the previously established dose of 100 mg/m2 on days 8 and 22 of 28-day cycles. Treatment was given for a maximum of nine cycles or until progression or unacceptable toxicity occurred. Vascular endothelial growth factor and its soluble receptor 1, thrombospondin-1, microparticles, and microparticle-dependent procoagulant activity were measured in blood before treatment. The primary objective was 6-month progression-free survival (PFS). Twenty-seven evaluable patients were enrolled. Six-month PFS was 20.8%. Median PFS was 11.6 weeks (95% confidence interval: 7.5–15.7). Stable disease was the best response for nine (37.5%) patients, with a median duration of 11.2 weeks (4.2–35.85 weeks). No differences in PFS or response were observed among patients who relapsed during or after completion of adjuvant TMZ. Grade 3/4 adverse events included lymphopenia (15%), fatigue, diarrhea and febrile neutropenia (3.7% each), lymphopenia, neutropenia, and nausea/vomiting (11.1% each). One patient died from pneumonia and one patient died from pulmonary thromboembolism. Pretreatment levels of angiogenesis biomarkers, microparticles, and microparticle-related procoagulant activity were elevated in patients compared with healthy volunteers. This regimen is feasible, but failed to improve the results obtained with other second-line therapies in recurrent GB.

aDepartment of Medical Oncology

bResearch Center, Hospital Universitari i Politècnic La Fe

cDepartment of Hematology and Medical Oncology, Hospital Clínico Universitario de Valencia, Valencia

dDepartment of Medical Oncology, Institut Català d’Oncologia, Badalona

eDepartment of Medical Oncology, Hospital Clínico Universitario San Carlos

fDepartment of Medical Oncology, Hospital Universitario Ramón y Cajal

gDepartment of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid

hDepartment of Medical Oncology, Hospital Regional Universitario Carlos Haya, Málaga

iDepartment of Medical Oncology, Hospital Sant Pau

jDepartment of Medical Oncology, Institut Català d’Oncologia-IDIBELL, l’Hospitalet de Llobregat, Barcelona, Spain

Correspondence to Gaspar Reynés, MD, Department of Medical Oncology, Hospital Universitari i Politècnic La Fe, Avda. Fernando Abril Martorell no. 106, 46026 Valencia, Spain Tel: +34 961 244 000; fax: +34 961246243; e-mail:

Received April 8, 2015

Accepted October 13, 2015

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.