Abstract
The optimal combination of bevacizumab with cytotoxic or cytostatic drugs in recurrent glioblastoma is unknown. We performed a phase 2 trial of combined bevacizumab and fotemustine for patients with glioblastoma at first relapse after radiotherapy and temozolomide. The primary endpoint was 6-month progression-free survival (PFS), while secondary endpoints were overall survival (OS), response rate based on RANO criteria and toxicity. Fifty-four patients with recurrent GBM were enrolled. The authors observed a 6-month PFS rate of 42.6 % (95 % CI 29.3–55.2) and a median PFS of 5.2 months (95 % CI 3.8–6.6). The median OS was 9.1 months (95 % CI 7.3–10.3). Twenty-eight patients (52 %) had a radiographic response, and a significant neurological improvement with steroid reduction was observed in 25/42 symptomatic patients (60 %). MGMT promoter methylation was significantly associated with improved PFS in univariate analysis. Most unifocal tumors at baseline had a focal enhancing progression (76 %), while the diffuse non-enhancing progression accounted for 9.5 %. Response or survival were not associated with any pattern of progression. Survival after failure of treatment was short. Twelve out of 54 patients (22 %) discontinued fotemustine for grade 3/4 myelotoxicity, while 4/54 (7.4 %) discontinued bevacizumab. This study failed to demonstrate a superiority of the combination of bevacizumab and fotemustine over either bevacizumab or fotemustine alone as historical controls. Future studies should explore alternative regimens of combination of the two drugs.
Highlights
Glioblastoma (GBM) is the most common malignant primary brain tumor, and the standard therapy involves maximal safe surgical resection, followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ) [1, 2]
Four out of 54 patients (7.4 %) discontinued bevacizumab (1 stroke, 1 intratumoral hemorrhage, 1 GI perforation and 1 pulmonary embolism). This is the first phase II trial that has explored the combination of bevacizumab and fotemustine in patients with
A series of retrospective and prospective studies have evaluated the association of bevacizumab with miscellaneous other agents, including irinotecan, etoposide, temozolomide, carboplatin, cetuximab and erlotinib in patients with recurrent GBMs [15,16,17,18,19,20,21,22,23,24,25], and all have achieved outcomes that are not better than bevacizumab monotherapy [6,7,8, 26]
Summary
Glioblastoma (GBM) is the most common malignant primary brain tumor, and the standard therapy involves maximal safe surgical resection, followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ) [1, 2]. GBMs inevitably recur with a median survival of 15–18 months [3]. GBMs are highly vascularized tumors with elevated expression of vascular endothelial grow factor (VEGF), that drives. A humanized monoclonal antibody against VEGF, alone or associated with chemotherapy or targeted drugs, have reported higher response rates and prolongation of median and 6-month progression-free survival compared to historical controls with non-bevacizumab treatments [6,7,8]. Nitrosoureas are in Europe the standard salvage option in recurrent GBMs. Fotemustine is a chloroethylnitrosourea compound with elevated lipophilic properties that has shown some activity in recurrent GBMs [9,10,11,12]. No prospective studies are available on the combination of bevacizumab and fotemustine in recurrent GBMs
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