Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme: A randomized phase II study.
BACKGROUND
Surgery followed by radiotherapy and concomitant and adjuvant temozolomide is standard therapy in newly diagnosed glioblastoma multiforme (GBM). Bevacizumab combined with irinotecan produces impressive response rates in recurrent GBM. In a randomized phase II study, we investigated the efficacy of neoadjuvant bevacizumab combined with irinotecan (Bev-Iri) versus bevacizumab combined with temozolomide (Bev-Tem) before, during and after radiotherapy in newly diagnosed GBM.


METHODS
After surgery, patients were randomized to Bev-Iri or Bev-Tem for eight weeks, followed by standard radiotherapy (60 Gy/30 fractions) and concomitant Bev-Iri or Bev-Tem followed by adjuvant Bev-Iri or Bev-Tem for another eight weeks. Bev-Iri: Bevacizumab and irinotecan were given every 14 days before, during and after radiotherapy. Bev-Tem: Bevacizumab was given as in Bev-Iri and temozolomide was given for five days every four weeks before and after radiotherapy and once daily during radiotherapy. The primary endpoint was response after neoadjuvant chemotherapy and a pre-specified response rate of 30% or more was considered of interest for future studies. Secondary endpoints were progression-free survival (PFS) and toxicity.


RESULTS
The response rate was 32% (95% CI 17-51%) for Bev-Tem (n = 32) and 23% (95% CI 9-44%) for Bev-Iri (n = 31) (p = 0.56). Median PFS was 7.7 and 7.3 months for Bev-Tem and Bev-Iri, respectively. Hematological toxicity was more frequent with Bev-Tem including one death from febrile neutropenia whereas non-hematological toxicity was manageable.


CONCLUSIONS
Only the Bev-Tem arm met the pre-specified level of activity of interest. Our results did not indicate any benefit from Bev-Iri in first-line therapy as opposed to Bev-Tem in terms of response and PFS.
Department of Oncology and Radiotherapy, Rigshospitalet , Copenhagen , Denmark.
Kenneth F
KF
Hofland
Steinbjørn
S
Hansen
Morten
M
Sorensen
Silke
S
Engelholm
Henrik P
HP
Schultz
Aida
A
Muhic
Kirsten
K
Grunnet
Anders
A
Ask
Junia C
JC
Costa
Charlotte
C
Kristiansen
Carsten
C
Thomsen
Hans Skovgaard
HS
Poulsen
Ulrik
U
Lassen
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D000077204:Temozolomide; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000077146:Irinotecan; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide