One week on/one week off: A novel active regimen of temozolomide for recurrent glioblastoma

NEUROLOGY 2004;62:2113-2115
© 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 glioblastomawere enrolled in a prospective phase II trial to determine thesafety and efficacy of a 1-week on/1-week off regimen of temozolomideadministered at 150 mg/m² on days 1 to 7 and days 15 to 21 of28-day treatment cycles. Two patients achieved a partial response(10%), and 17 patients (81%) had stable disease. The medianprogression-free survival was 5 months. The progression-freesurvival at 6 months was 48%.

The primary treatment of patients with glioblastoma producesmedian survival times in the range of 12 months.¹ Salvage therapiesmay add a median of 4 to 6 months. Using different salvage therapies,there was an overall response rate, comprising complete andpartial 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 wassuperior to procarbazine for the management of recurrent glioblastomain adults and produced an overall response rate of 5.4% anda progression-free survival rate at 6 months of 21%.⁴

A 1-week on/1-week off schedule of temozolomide at 150 mg/m²is feasible and permits a 2.1-fold greater drug exposure thanthe conventional schedule of 5 days every 28 days.⁵ This schedulewas evaluated to determine overall response rates and progression-freesurvival in patients with recurrent glioblastoma.

Patients and treatment. Twenty-eight patients with recurrent or progressive glioblastomawere assessed for eligibility. Five patients did not meet theinclusion criteria; one patient refused to participate; andone patient did not receive the first treatment although heagreed to enter the study. Clinical and demographic featuresof the remaining 21 patients are listed in table 1. Of sevenpatients with a second resection, six had a resection immediatelybefore the temozolomide regimen, but only one patient enteredthe study without MRI-assessable residual tumor. Fourteen patientswere treated at first relapse, and seven patients were treatedat second relapse.

The total number of cycles in the 1-week on/1-week off regimenwas 99. The median number of cycles per patient was five. Threepatients (14%) received only one cycle; another four patients(19%) completed only two cycles. Four patients (19%) completedmore than eight cycles. All 21 patients were assessable fortoxicity, response, and survival.

Toxicity. Toxicity was recorded for all eligible patients using the WorldHealth Organization recommendations for grading of acute andsubacute toxicity. Temozolomide was generally well tolerated,and the main toxicities seen were hematologic (table 2). Therewere no deep venous thromboses or other organ toxicities duringthe temozolomide treatment. Temozolomide did not induce relevantnausea or constipation. Follow-up evaluation after temozolomidetreatment either clinically or by neuroimaging did not indicateneurotoxicity of this regimen.

 
Response and survival. There were no complete responses, but there were two partialresponses, resulting in an overall response rate of 9.5%. Another17 patients (81%) showed stable disease at least from studyentry to the first control scan 2 months later. Only two patients(9.5%) showed progressive tumor growth during the first 8 weeksof 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 18patients who have failed to respond to this temozolomide regimento date have received further chemotherapy, mostly nitrosoureabased. The t-test for the impact of previous chemotherapy onmedian progression-free survival revealed no significant difference(p = 0.056).