© 2004 American Academy of Neurology
One week on/one week off: A novel active regimen of temozolomide for recurrent glioblastoma
W. Wick, MD, J. P. Steinbach, MD, W. M. Küker, MD, J. Dichgans, MD, M. Bamberg, MD and M. Weller, MD
Twenty-one patients with recurrent or progressive glioblastoma were enrolled in a prospective phase II trial to determine the safety and efficacy of a 1-week on/1-week off regimen of temozolomide administered at 150 mg/m2 on days 1 to 7 and days 15 to 21 of 28-day treatment cycles. Two patients achieved a partial response (10%), and 17 patients (81%) had stable disease. The median progression-free survival was 5 months. The progression-free survival at 6 months was 48%.
The primary treatment of patients with glioblastoma produces median survival times in the range of 12 months.1 Salvage therapies may add a median of 4 to 6 months. Using different salvage therapies, there was an overall response rate, comprising complete and partial remissions,2 of 9%.3
Temozolomide (Schering Plough Pharmaceuticals, Kenilworth, NJ) at 150 to 200 mg/m2 on the first 5 days of 28-day cycles was superior to procarbazine for the management of recurrent glioblastoma in adults and produced an overall response rate of 5.4% and a progression-free survival rate at 6 months of 21%.4
A 1-week on/1-week off schedule of temozolomide at 150 mg/m2 is feasible and permits a 2.1-fold greater drug exposure than the conventional schedule of 5 days every 28 days.5 This schedule was evaluated to determine overall response rates and progression-free survival in patients with recurrent glioblastoma.
Patients and treatment.
Twenty-eight patients with recurrent or progressive glioblastoma were assessed for eligibility. Five patients did not meet the inclusion criteria; one patient refused to participate; and one patient did not receive the first treatment although he agreed to enter the study. Clinical and demographic features of the remaining 21 patients are listed in table 1. Of seven patients with a second resection, six had a resection immediately before the temozolomide regimen, but only one patient entered the study without MRI-assessable residual tumor. Fourteen patients were treated at first relapse, and seven patients were treated at second relapse.
The total number of cycles in the 1-week on/1-week off regimen was 99. The median number of cycles per patient was five. Three patients (14%) received only one cycle; another four patients (19%) completed only two cycles. Four patients (19%) completed more than eight cycles. All 21 patients were assessable for toxicity, response, and survival.
Toxicity was recorded for all eligible patients using the World Health Organization recommendations for grading of acute and subacute toxicity. Temozolomide was generally well tolerated, and the main toxicities seen were hematologic (table 2). There were no deep venous thromboses or other organ toxicities during the temozolomide treatment. Temozolomide did not induce relevant nausea or constipation. Follow-up evaluation after temozolomide treatment either clinically or by neuroimaging did not indicate neurotoxicity of this regimen.
Response and survival.
There were no complete responses, but there were two partial responses, resulting in an overall response rate of 9.5%. Another 17 patients (81%) showed stable disease at least from study entry to the first control scan 2 months later. Only two patients (9.5%) showed progressive tumor growth during the first 8 weeks of therapy. The median progression-free survival was 21 weeks. Ten patients (48%) were free from progression at 6 months (table 3). The overall survival at 12 months was 81%. Six of the 18 patients who have failed to respond to this temozolomide regimen to date have received further chemotherapy, mostly nitrosourea based. The t-test for the impact of previous chemotherapy on median progression-free survival revealed no significant difference (p = 0.056).