Second line treatment of recurrent glioblastoma with sunitinib: results of a phase II study and systematic review of literature.
BACKGROUND
Second line treatment of recurrent or progressive glioblastoma multiforme (GBM) is not standardized. Anti-angiogenic strategies with tyrosine-kinase inhibitors have been tested with conflicting results. We tested the association of sunitinib plus irinotecan (CPT-11) in a phase II trial in terms of response rate (RR) and 6-months progression-free survival (6-PFS). We also reviewed the clinical evidence from all the trials with sunitinib in this setting published to date and summarized it in a meta-analysis.


METHODS
Patients with GBM recurrent or progressive after surgery and standard chemo-radiotherapy were treated with sunitinib 37.5 mg/day for 14 days + CPT-11 125 mg/sqm every 14 days in a Simon's two-stage phase II study. A summary data meta-analysis was performed to establish the 6-PFS in patients with ascertained histological diagnosis of GBM treated with sunitinib.


RESULTS
Six patients were enrolled in the stage I of the trial and only one had a stable disease. The overall response rate was 17% and 6-PFS was not reached. Therefore, the trial was stopped early for insufficient activity. All toxicities were grade 1-2. Systematic review of the literature identified 9 studies (including the present one) for a total of 221 patients. Pooled 6-PFS was 15.1% (95% CI: 9.0-24.4). Subgroup analysis by different schedule revealed a 6-PFS of 17.5% (95% CI: 10.3-28.1) in the weekly setting which was consistent across all the studies (I2=0%, P=0.66) and a pooled 6-PFS of 12.7% (95% CI: 4.9-29.1) in the daily setting with a substantial amount of heterogeneity (I2=65%, P=0.01).


CONCLUSIONS
Results of this trial and those of the systematic review indicate that, compared to conventional chemotherapy or bevacizumab, sunitinib has insufficient activity in the setting of recurrent GBM. Better patient's molecular stratification for second-line treatment in GBM is warranted.
Department of Medical Oncology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy - salvatore.grisanti@tin.it.
Salvatore
S
Grisanti
Department of Medical Oncology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Vittorio D
VD
Ferrari
Department of Radiation Oncology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Michela
M
Buglione
Department of Medical Oncology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Giorgio M
GM
Agazzi
Department of Neuro-Radiology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Roberto
R
Liserre
Department of Pathology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Luigi
L
Poliani
Department of Neuro-Surgery, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Luciano
L
Buttolo
Department of Neurology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Stefano
S
Gipponi
Department of Medical Oncology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Rebecca
R
Pedersini
Department of Medical Oncology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Francesca
F
Consoli
Department of Neuro-Surgery, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Pierpaolo
P
Panciani
Department of Medical Oncology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Elisa
E
Roca
Department of Neuro-Surgery, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Giannantonio
G
Spena
Department of Radiation Oncology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Luca
L
Triggiani
Department of Medical Oncology, Spedali Civili di Brescia and University of Brescia, Brescia, Italy.
Alfredo
A
Berruti
D000068258:Bevacizumab / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D000077210:Sunitinib / Q000627:therapeutic use*
D000068258:Bevacizumab; D000077210:Sunitinib