Randomized phase II trial of irinotecan and bevacizumab as neo-adjuvant and adjuvant to temozolomide-based chemoradiation compared with temozolomide-chemoradiation for unresectable glioblastoma: final results of the TEMAVIR study from ANOCEF†.
BACKGROUND
Prognosis of unresectable glioblastoma (GB) remains poor, despite temozolomide (TMZ)-based chemoradiation. Activity of bevacizumab (BEV) and irinotecan (IRI) has been reported in recurrent disease. We evaluated BEV and IRI as neo-adjuvant and adjuvant treatment combined with TMZ-based chemoradiation for unresectable GB.


METHODS
Patients with unresectable GB, age 18-70, IK ≥50 were eligible. The experimental arm (BEV/IRI) consisted of neo-adjuvant intravenous BEV, 10 mg/kg, and IRI, 125 mg/m(2), every 2 weeks for four cycles before radiotherapy (RT) (60 Gy), concomitant oral TMZ, 75 mg/m(2)/day, and BEV, 10 mg/kg every 2 weeks. Adjuvant BEV and IRI were given every 2 weeks for 6 months. The control arm consisted of concomitant oral TMZ, 75 mg/m(2)/day during RT, and 150-200 mg/m(2) for 5 days every 28 days for 6 months. The use of BEV was allowed at progression in the control arm.


RESULTS
Patients (120) were included from April 2009 to January 2011. The working hypothesis was that treatment would increase the progression-free survival at 6 month (PFS-6) from 50% to 66%. The primary objective was not achieved, and only 30 out of 60 patients were alive without progression at 6 months (50.0% [IC95% (36.8; 63.1)] in the BEV/IRI arm when 37 out of 60 patients were required according to the Fleming decision rules. PFS-6 was 7.1 months in BEV/IRI versus 5.2 months in the control arm. The median overall survival was not different between the two arms (11.1 months). Main toxicities were three fatal intracranial bleedings, three bile duct or digestive perforations/infections (1 fatal), and six thrombotic episodes in the BEV/IRI arm, whereas there was one intracranial bleeding, two bile duct or digestive perforations/infections (1 fatal), and one thrombotic episode in the control arm.


CONCLUSIONS
Neo-adjuvant and adjuvant BEV/IRI, combined with TMZ-radiation, is not recommended for further evaluation in the first-line treatment of unresectable GB.


BACKGROUND
Clinical trial registered under EUDRACT number 2008-002775-28 (NCT01022918).
Department of Medical Oncology, University Hospital, EA 4666, Amiens. Electronic address: chauffert.bruno@chu-amiens.fr.
B
B
Chauffert
Department of Radiotherapy, Pitie-Salpetriere University Hospital, Paris.
L
L
Feuvret
Methodology and Quality of Life Unit, Department of Oncology, EA 3181, University Hospital, Besancon.
F
F
Bonnetain
Department of Neurology, University Hospital, Nancy.
L
L
Taillandier
Department of Oncology, Leon Berard Centre for Fight against Cancer, Lyon.
D
D
Frappaz
Department of Neurology, HIA Val de Grace, Paris.
H
H
Taillia
Department of Oncology, Paul Strauss Centre for Fight against Cancer, Strasbourg.
R
R
Schott
Department of Neurology, University Hospital, Lyon.
J
J
Honnorat
Department of Oncology, Val d'Aurelle Center for Fight against Cancer, Montpellier.
M
M
Fabbro
Department of Oncology, Henri Becquerel Center for Fight against Cancer, Rouen.
I
I
Tennevet
Department of Oncology, GF Leclerc Center for Fight against Cancer, Dijon.
F
F
Ghiringhelli
Department of Neurology, University Hospital, Caen.
J S
JS
Guillamo
Department of Oncology, Jean Perrin Center for Fight against Cancer, Clermont-Ferrand.
X
X
Durando
Clinique Saint Pierre, Perpignan.
D
D
Castera
Department of Oncology, Antoine Lacassagne Center for Fight against Cancer, Nice.
M
M
Frenay
Department of Neurology, University Hospital, Nimes.
C
C
Campello
Methodology Unit, GF Leclerc Center for Fight against Cancer, Dijon.
C
C
Dalban
Methodology Unit, GF Leclerc Center for Fight against Cancer, Dijon.
J
J
Skrzypski
Department of Neuro-Oncology, University Hospital La Timone, Marseille, France.
O
O
Chinot
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D017024:Chemotherapy, Adjuvant; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D000077204:Temozolomide
D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000077146:Irinotecan; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide
bevacizumab; glioblastoma; irinotecan; radiotherapy; temozolomide