Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme.
BACKGROUND
The primary objective of the current prospective Phase II study of cyclophosphamide (CYC) in adult patients with recurrent, temozolomide-refractory glioblastoma multiforme was to evaluate 6-month progression-free survival (PFS).


METHODS
Forty patients (28 men and 12 women) ages 28-67 years (median age, 51.5 years), with recurrent glioblastoma multiforme were treated. All patients had been treated previously with surgery and involved-field radiotherapy (median dose, 60 grays [Gy]; range, 59-61 Gy). In addition, all patients were treated adjuvantly with either nitrosourea-based chemotherapy (21 patients: procarbazine, lomustine, and vincristine in 13 patients; carmustine in 8 patients) or temozolomide (19 patients). Twenty-one patients who were treated previously with a nitrosourea were treated with temozolomide at the time of first recurrence. Twenty-one patients were treated with CYC at the time of second recurrence, and 19 patients were treated with CYC at the time of first recurrence. CYC was administered intravenously on 2 consecutive days (750 mg/m2 per day) every 4 weeks (operationally defined as a single cycle). Neurologic and neuroradiographic evaluations were performed every 8 weeks.


RESULTS
All patients were evaluable. In total, 170 cycles of CYC (median, 2 cycles; range, 2-12 cycles) were administered. CYC-related toxicity included alopecia in all patients (100%), anemia in 6 patients (3.5%), thrombocytopenia in 7 patients (4.1%), and neutropenia in 9 patients (5.3%). Four patients required transfusions (two required red blood cell transfusion, and two required platelet transfusion). One patient developed neutropenic fever without bacteriologic confirmation. No treatment-related deaths occurred. Seven patients (17.5%; 95% confidence interval [95% CI], 8-33%) exhibited a neuroradiographic partial response, 11 patients (27.5%; 95% CI, 15-44%) had stable disease, and 22 patients (55%) had progressive disease after a single cycle of CYC. The time to tumor progression ranged from 2 months to 18 months (median, 2 months). Survival ranged from 3 months to 24 months (median, 4 months). In patients with either a neuroradiographic response or stable disease (n = 18 [45%]), the median time to tumor progression was 6 months (range, 4-18 months; 95% CI, 6-8 months), and the median survival was 10 months (range, 5-24 months; 95% CI, 8-10 months). The 6-month PFS rate was 20%.


CONCLUSIONS
CYC exhibited modest efficacy with acceptable toxicity in the current cohort of adult patients with recurrent glioblastoma multiforme, all of whom had previously experienced treatment failure after temozolomide chemotherapy.
Chamberlain
Marc C
MC
Department of Neurology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA. chamberl@usc.edu
Tsao-Wei
Denice D
DD
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D011446:Prospective Studies; D016879:Salvage Therapy; D000077204:Temozolomide; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D003520:Cyclophosphamide; D000077204:Temozolomide