BACKGROUND: Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O(6)-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance. METHODS: This was a multicenter, phase 2, single-arm study of temozolomide (75-100 mg/m(2)/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). RESULTS: Fifty-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). CONCLUSIONS: Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.
BACKGROUND: Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O(6)-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance. METHODS: This was a multicenter, phase 2, single-arm study of temozolomide (75-100 mg/m(2)/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). RESULTS: Fifty-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). CONCLUSIONS: Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.
Authors: Daniel P Cahill; Kymberly K Levine; Rebecca A Betensky; Patrick J Codd; Candice A Romany; Linsey B Reavie; Tracy T Batchelor; P Andrew Futreal; Michael R Stratton; William T Curry; A John Iafrate; David N Louis Journal: Clin Cancer Res Date: 2007-04-01 Impact factor: 12.531
Authors: Roger Stupp; Warren P Mason; Martin J van den Bent; Michael Weller; Barbara Fisher; Martin J B Taphoorn; Karl Belanger; Alba A Brandes; Christine Marosi; Ulrich Bogdahn; Jürgen Curschmann; Robert C Janzer; Samuel K Ludwin; Thierry Gorlia; Anouk Allgeier; Denis Lacombe; J Gregory Cairncross; Elizabeth Eisenhauer; René O Mirimanoff Journal: N Engl J Med Date: 2005-03-10 Impact factor: 91.245
Authors: Monika E Hegi; Annie-Claire Diserens; Thierry Gorlia; Marie-France Hamou; Nicolas de Tribolet; Michael Weller; Johan M Kros; Johannes A Hainfellner; Warren Mason; Luigi Mariani; Jacoline E C Bromberg; Peter Hau; René O Mirimanoff; J Gregory Cairncross; Robert C Janzer; Roger Stupp Journal: N Engl J Med Date: 2005-03-10 Impact factor: 91.245
Authors: A W Tolcher; S L Gerson; L Denis; C Geyer; L A Hammond; A Patnaik; A D Goetz; G Schwartz; T Edwards; L Reyderman; P Statkevich; D L Cutler; E K Rowinsky Journal: Br J Cancer Date: 2003-04-07 Impact factor: 7.640
Authors: W K Yung; R E Albright; J Olson; R Fredericks; K Fink; M D Prados; M Brada; A Spence; R J Hohl; W Shapiro; M Glantz; H Greenberg; R G Selker; N A Vick; R Rampling; H Friedman; P Phillips; J Bruner; N Yue; D Osoba; S Zaknoen; V A Levin Journal: Br J Cancer Date: 2000-09 Impact factor: 7.640
Authors: A A Brandes; A Tosoni; G Cavallo; R Bertorelle; V Gioia; E Franceschi; M Biscuola; V Blatt; L Crinò; M Ermani Journal: Br J Cancer Date: 2006-10-03 Impact factor: 7.640
Authors: Victor A Levin; Peter J Tonge; James M Gallo; Marc R Birtwistle; Arvin C Dar; Antonio Iavarone; Patrick J Paddison; Timothy P Heffron; William F Elmquist; Jean E Lachowicz; Ted W Johnson; Forest M White; Joohee Sul; Quentin R Smith; Wang Shen; Jann N Sarkaria; Ramakrishna Samala; Patrick Y Wen; Donald A Berry; Russell C Petter Journal: Neuro Oncol Date: 2015-11 Impact factor: 12.300
Authors: T Hundsberger; A F Hottinger; U Roelcke; P Roth; D Migliorini; P Y Dietrich; K Conen; G Pesce; E Hermann; A Pica; M W Gross; D Brügge; L Plasswilm; M Weller; P M Putora Journal: J Neurooncol Date: 2015-10-12 Impact factor: 4.130