Neuro Oncol. 2013 Apr 3. [Epub ahead of print]

 

 

Norden AD, Lesser GJ, Drappatz J, Ligon KL, Hammond SN, Lee EQ, Reardon DR, Fadul CE, Plotkin SR, Batchelor TT, Zhu JJ, Beroukhim R, Muzikansky A, Doherty L, Lafrankie D, Smith K, Tafoya V, Lis R, Stack EC, Rosenfeld MR, Wen PY.

Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (A.D.N., S.N.H., E.Q.L., L.D., D.L., K.S., V.T., P.Y.W.); Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts (A.D.N., E.Q.L., P.Y.W.); Section of Hematology and Oncology, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina (G.J.L.); Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (J.D.); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (K.L.L., R.B.); Neuro-oncology Program, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire (C.E.F.); Massachusetts General Hospital Cancer Center, Pappas Center for Neuro-Oncology, Boston, Massachusetts (S.R.P., T.T.B.); The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Mischer Neuroscience Institute, Memorial Hermann Hospital, Houston, Texas (J-J.Z.); Massachusetts General Hospital Biostatistics Center, Boston, Massachusetts (A.M.), Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (R.L., E.C.S., K.L.L.), Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts (R.L., E.C.S., K.L.L.); Division of Neuro-Oncology, Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania (M.R.R.).

 

 

Abstract

 

BackgroundAmong patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O6-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance.MethodsThis was a multicenter, phase 2, single-arm study of temozolomide (75-100 mg/m2/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6).ResultsFifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25-79 years) and a median Karnofsky performance score of 90 (range, 60-100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2).ConclusionsDose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.