Phase II study of antiangiogenic (metronomic) chemotherapy for recurrent malignant gliomas

Abstract

1569 Background: There is preclinical evidence that continuous low-dose chemotherapy may inhibit tumor endothelial proliferation and prevent tumor growth (Browder et al Cancer Res 2000;60:1878). Methods: We conducted a phase II study of continuous low-dose etoposide (VP-16), alternating with cyclophosphamide (CP), in combination with thalidomide (T) and celecoxib (C) in adult patients with recurrent malignant gliomas. There was no limit on the number of prior therapies. Patients received VP-16 [35 mg/m2 (maximum 100 mg) daily for 21 days] alternating with CP [2 mg/kg (maximum 100 mg/day) for 21 days]. Thalidomide was started at 200 mg daily and increased by 100 mg weekly to a maximum of 1200 mg/day, as tolerated. Celecoxib was started at 200 mg twice daily and increased to 400 mg twice daily. MRIs were performed every 6 weeks. Patients were treated until tumor progression or development of unacceptable toxicity. Serum was collected for measurement of angiogenic peptides. Results: 48 patients were enrolled (15 female, 33 male). 28 had glioblastomas (GBM); 20 had anaplastic gliomas (AG). Median age was 53 years (range 33–74); median KPS was 70 (range 60–100). Patients had average of 2.1 prior chemotherapies; 33% had 3 or more prior chemotherapies. Toxicities included neutropenia (8 G3, 8 G4), leukopenia (13 G3, 8 G4), lymphopenia (26 G3), anemia (1 G3), thrombocytopenia (1 G3); nausea (1 G3), vomiting (3 G3), constipation (5 G3; 2 G4), colitis (2 G4), rash (1 G3), dizziness (1 G3); hypoxia (1 G3), and infection (2 G3). 2 patients had DVT and 6 had pulmonary emboli. There were no treatment related deaths. Fatigue was common but usually mild. 12% of patients had PR, 59% had SD, 29% progressed at their first scan. For GBM patients, median progression-free survival (PFS) was 11 weeks, 6 month-PFS was 9% and median survival was 21 weeks. For AG patients, median PFS was 14 weeks; 6 month-PFS was 26% and median survival was 41.5 weeks. Correlation of angiogenic peptide levels and response will be reported. Conclusions: Although there were some responders this regimen did not significantly improve survival in this heavily pretreated group of patients. However, further studies combining metronomic chemotherapy with more potent angiogenesis inhibitors such as lenalidomide or VEGFR inhibitors may be warranted. [Table: see text]