© 2001 by Society
© 2001 by the Society forNeuro-Oncology
Phase I study of GliadelTM wafers plus temozolomide in adults withrecurrent supratentorial high-grade gliomas
Departments of Neurosurgery (S.G., S.E., M.L.A.,S.T.-U., J.H.S., A.H.F., H.S.F.), Medicine (I.C.,J.N.R., J.A.Q.), Community and Family Medicine(J.E.H.), Neuro-radiology (J.M.P.), and Pathology (R.E.M.), Duke University Medical Center, Durham,NC 27710; Schering-Plough Corporation (V.S.-F., S.Z.),Kenilworth, NJ 07033; and Aventis (M.E.),Collegeville, PA 19426
1 Address correspondence and reprint requests to Sridharan Gururangan, DukeUniversity Medical Center, DUMC Box 3624, Durham, NC 27710.
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Abstract |
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Both GliadelTM wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] andtemozolomide (TEMO) have been shown in independent studies to prolong survivalof patients with recurrent malignant glioma following surgery andradiotherapy. On the basis of preclinical evidence of synergism betweenGliadel wafers and TEMO, a phase I study was designed to evaluate the toxicityof combining these 2 agents in the treatment of patients with recurrentsupratentorial malignant glioma. All patients had surgical resection of thetumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in thesurgical cavity following resection. Two weeks after surgery, TEMO was givenorally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of100 mg/m2, 150 mg/m2, and 200 mg/m2,respectively. Patients were assessed for toxicity 4 weeks after start of thefirst course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease orresponse after the first cycle of TEMO were allowed to continue treatment atthe same dose every 4 weeks for 12 cycles or until disease progression orunacceptable toxicity. Ten patients with a median age of 47 years (range,22-66 years) were enrolled in this study. There were 7 patients withglioblastoma multiforme and 3 patients with anaplastic astrocytoma. Threepatients were treated with TEMO at the first dose level of 100mg/m2, 4 at the second dose level of 150 mg/m2, and 3 atthe third dose level of 200 mg/m2. The 10 patients received amedian of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadelwafers. The treatment was well tolerated, with only 1 patient suffering gradeIII thrombocytopenia at the highest dose level. Two patients at each doselevel had no evidence of disease progression after treatment. Four patientssuffered progressive disease on therapy. Our study demonstrates that TEMO canbe given safely after placement of Gliadel (3.85%) wafers. The recommendeddosage for TEMO for a phase II study of this combination is 200mg/m2 per day for 5 days.
Received December 26, 2000; Accepted March 29, 2001
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