title: Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults.
abstract: Preclinical evidence suggests that continuous low-dose daily (metronomic) chemotherapy may inhibit tumor endothelial cell proliferation (angiogenesis) and prevent tumor growth. This phase II study evaluated the feasibility of this antiangiogenic chemotherapy regimen in adults with recurrent malignant gliomas. The regimen consisted of low-dose etoposide (35 mg/m2 [maximum, 100 mg/day] daily for 21 days), alternating every 21 days with cyclophosphamide (2 mg/kg [maximum, 100 mg/day] daily for 21 days), in combination with daily thalidomide and celecoxib, in adult patients with recurrent malignant gliomas. Serum and urine samples were collected for measurement of angiogenic peptides. Forty-eight patients were enrolled (15 female, 33 male). Twenty-eight patients had glioblastoma multiforme (GBMs), and 20 had anaplastic gliomas (AGs). Median age was 53 years (range, 33-74 years), and median KPS was 70 (range, 60-100). Therapy was reasonably well tolerated in this heavily pretreated population. Two percent of patients had partial response, 9% had a minor response, 59% had stable disease, and 30% had progressive disease. For GBM patients, median progression-free survival (PFS) was 11 weeks, six-month PFS (6M-PFS) was 9%, and median overall survival (OS) was 21 weeks. For AG patients, median PFS was 14 weeks, 6M-PFS was 26%, and median OS was 41.5 weeks. In a limited subset of patients, serum and urine angiogenic peptides did not correlate with response or survival (p > 0.05). Although there were some responders, this four-drug, oral metronomic regimen did not significantly improve OS in this heavily pretreated group of patients who were generally not eligible for conventional protocols. While metronomic chemotherapy may not be useful in patients with advanced disease, further studies using metronomic chemotherapy combined with more potent antiangiogenic agents in patients with less advanced disease may be warranted.
authors: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Santosh
authors: S
authors: Kesari
authors: David
authors: D
authors: Schiff
authors: Lisa
authors: L
authors: Doherty
authors: Debra C
authors: DC
authors: Gigas
authors: Tracy T
authors: TT
authors: Batchelor
authors: Alona
authors: A
authors: Muzikansky
authors: Alison
authors: A
authors: O'Neill
authors: Jan
authors: J
authors: Drappatz
authors: Alice S
authors: AS
authors: Chen-Plotkin
authors: Naren
authors: N
authors: Ramakrishna
authors: Stephanie E
authors: SE
authors: Weiss
authors: Brenda
authors: B
authors: Levy
authors: Joanna
authors: J
authors: Bradshaw
authors: Jean
authors: J
authors: Kracher
authors: Andrea
authors: A
authors: Laforme
authors: Peter McL
authors: PM
authors: Black
authors: Judah
authors: J
authors: Folkman
authors: Mark
authors: M
authors: Kieran
authors: Patrick Y
authors: PY
authors: Wen
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy*; D000068579:Celecoxib; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011720:Pyrazoles / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D013792:Thalidomide / Q000008:administration & dosage
chemical_list: D020533:Angiogenesis Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D013792:Thalidomide; D005047:Etoposide; D003520:Cyclophosphamide; D000068579:Celecoxib