Abstract
This phase II study evaluates the activity of temozolomide and cisplatin administered before radiation therapy in newly diagnosed glioblastoma multiforme patients, in terms of response, time to progression and survival.
Patients and methods: Forty patients with measurable disease after surgery, a Karnofsky status> 60, and Barthel Index> 10 were included. They were treated with three cycles of temozolomide 200 mg/m2/day for 5 days and cisplatin 100 mg/m2 on day 1. Conventional focal radiation therapy to 60 Gy was administered after response evaluation.
Results: Three patients were not evaluable for central reviewed response but all 40 were evaluable for toxicity, time to progression and survival. Objective responses by Macdonald criteria on an intent to treat basis were 45% including complete response in three patients (7.5%), and partial response in 15 patients (37.5%). Responses were seen in biopsy-only patients (33.4%) as well as in partial surgery patients (52%). Median survival for all patients was 12.5 months. Biopsy-only patients had a median survival of 12.8 months. Grade 3 to 4 neutropenia was the most important toxicity, and occurred in 37.5% of patients. A delay in 18.2% and a dose reduction in 9.6% of cycles were necessary due to myelosuppression on day 28. Two patients had neutropenic fever resulting in one treatment-related death. Eighty-two percent of patients received radiotherapy.
Conclusion: This regimen has significant activity, as it induces objective responses even in biopsy-only patients, appearing to improve their median survival. A better combination schedule is needed to improve the toxicity profile.
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References
FG Davis S Freels J Grutsch S Barlas S Brem (1998) ArticleTitleSurvival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973–1991 J Neurosurg 88 1–10
D Afra B Baron G Bonadonna S Burdett MKB Parmer SP Stenning LA Stewart WJ Curran SuffixJr SB Green J Hildebrand CB Scott W Shapiro RL Souhami D Thomas C Trojanowski RC Urtasun MD Walker (2002) ArticleTitleGlioma Meta-analysis Trialists (GMT) Group. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359 1011–1018
WJ Curran CB Scott J Horton JS Nelson AS Weinstein AJ Fischbach CH Chang M Rotman SO Asbell RE Krisch (1993) ArticleTitleRecursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials J Natl Cancer Inst 85 704–710
WK Yung RE Albright J Olson R Fredericks K Fink MD Prados M Brada A Spence RJ Hohl W Shapiro M Glantz H Greenberg RG Selker NA Vick R Rampling H Friedman P Phillips J Bruner N Yue D Osoba S Zakhoen VA Levin (2000) ArticleTitleA phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83 588–593
M Brada K Hoang-Xuan R Rampling PY Dietrich LY Dirix D Macdonald JJ Heimans BA Zonnenberg JM Bravo Marques R Henriksson R Stupp N Yue J Bruner M Dugan S Rao S Zaknoen (2001) ArticleTitleMulticenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol 12 259–266
HS Friedman RE McLendon T Kerby M Dugan SH Bigner AJ Henry DM Ashley J Krischer S Lovell K Rasheed F Marchev AJ Seman I Cokgor J Rich E Stewart OM Colvin JM Provenzale DD Bigner MM Haglund AH Friedman PL Modrich (1998) ArticleTitleDNA Mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to temodal in newly diagnosed malignant glioma J Clin Oncol 16 3851–3857
MR Gilbert HS Friedman JF Kuttesch MD Prados JJ Olson GH Reaman SL Zaknoen (2002) ArticleTitleA phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy Neuro-Oncology 4 261–267
InstitutionalAuthorNamePegg AE (2000) ArticleTitleRepair of O6-alkylguanine by alkyltransferases Mutation Research/Reviews in Mutation Research 462 83–100
PM Lacal S D’Atri L Orlando E Bonmassar G Graziani (1996) ArticleTitleIn vitro inactivation of human O6-alkylguanine DNA alkyltransferase by antitumor triazene compounds. J Pharmacol Exp Ther 279 416–422
SR Wedge JK Porteous BL May ES Newlands (1996) ArticleTitlePotentiation of temozolomide and BCNU cytotoxicity by O6-benzylguanine: a comparative study in vitro Br J Cancer 73 482–490
JA Quinn J Pluda ME Dolan S Delaney R Kaplan JN Rich AH Friedman DA Reardon JH Sampson OM Colvin MM Haglund AE Pegg RC Moschel RE McLendon JM Provenzale S Gururangan S Tourt Uhlig JE Herndon DD Bigner HS Friedman (2002) ArticleTitlePhase II trial of carmustine plus O6-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma J Clin Oncol 20 2277–2283
AM Fichtinger-Schepman JL Veer ParticleVan der JHJ Hartog Particleden PH Lohman J Reedijk (1985) ArticleTitleAdducts of the antitumor drug cis-diamminedichloroplatinum (II) with DNA: formation, identification and quantitation Biochem 25 701–713
LG Wang RB Setlow (1989) ArticleTitleInactivation of O6-alkylguanine-DNA alkyltransferase in HeLa cells by cisplatin Carcinogenesis 10 1681–1684
S D’Atri G Graziani PM Lacal V Nistico S Gilberti I Faraoni AJ Watson E Bonmassar GP Margison (1999) ArticleTitleAttenuation of O(6)-methylguanine-DNA a meta analysis J Cancer Res Clin Oncol 125 481–486
DJ Stewart RM O’Bryan M Al-Sarraf JJ Costanzi N Oishi (1983) ArticleTitlePhase II study of cisplatin in recurrent astrocytomas in adults: a Southwest Oncology Group Study J NeuroOncol 1 145–147
M Huncharek J Muscat (1998) ArticleTitleTreatment of recurrent high grade astrocytoma; results of a systematic review of 1,415 patients Anticancer Res 18 1303–1312
SA Grossman M Wharam L Sheidler L Kleinberg M Zeltzman N Yue S Piantadosi (1997) ArticleTitlePhase II study of continuous infusion carmustine and cisplatin followed by cranial irradiation in adults with newly diagnosed high-grade astroctytoma J Clin Oncol 15 2596–2603
M Gilbert A O’Neill S Grossman M Grunnet M Mehta S Jubelirer R Hellman (2000) ArticleTitleA phase II study of preradiation chemotherapy followed by external beam radiotherapy for the treatment of patients with newly diagnosed glioblastoma multiforme: an Eastern Cooperative Oncology Group study (E2393) J Neuro Oncol 47 145–152
CD Britten EK Rowinsky SD Baker SS Agarwala JR Eckardt R Barrington SG Diab LA Hammond T Johnson M Villalona Calero U Fraass P Statkevich DD Hoff ParticleVon SG Eckhardt (1999) ArticleTitleA Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies Clin Cancer Res 5 1629–1637
L Brazil R Thomas F Laing F Hines D Guerrero S Ashley M Brada (1997) ArticleTitleVerbally administered Barthel Index as functional assessment in brain tumor patients J Neuro-Oncology 34 187–192
P Kleihues WK Cavenne (Eds) (2000) World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Nervous System. IARC Press Lyon
DR MacDonald TL Cascino SC Schold JG Cairncross (1990) ArticleTitleResponse criteria for phase II studies of supratentorial malignant glioma J Clin Oncol 8 1277–1280
Gehan EA: The determination on the number of patients required in a preliminary and a follow up trial of a new chemotherapeutic agents. J Chronic Dis 13: 346–353.
FK Albert M Forsting K Sartor HP Adams S Kunze (1994) ArticleTitleEarly post-operative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis Neurosurgery 34 45–60
MJ Vos BMJ Uitdehaag F Barkhof JJ Heimans HC Baaywn W Boogerd JA Castelijns PH Eikhuizen TJ Postma (2003) ArticleTitleInter-observer variability in the radiological assessment of response to chemotherapy in glioma Neurology 60 826–830
SA Grossman JD Fisher S Piantadosi H Brem (1998) ArticleTitleThe New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium: organization, objectives, and activities Cancer Control. J Moffitt Cancer Center 5 107–114
LE Gaspar BJ Fisher DR Macdonald DV Leber EC Halperin SC Schold JG Cairncross (1993) ArticleTitleMalignant glioma-timing or response to radiation therapy Int J Radiat Oncol Biol Phys 25 877–879
R Grant BC Liang J Slattery HS Greenberg L Junck (1997) ArticleTitleChemotherapy response criteria in malignant glioma Neurology 48 1336–1340
VA Levin (1999) ArticleTitleChemotherapy for brain tumor of astrocytic and oligodendroglial lineage: the past decade and where we are heading. Neuro-Oncology 1 69
C Balaña JL Ramirez M Tarón Y Roussos A Ariza R Ballester C Sarries P Mendez JJ Sanchez R Rosell (2003) ArticleTitleMGMT methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolomide plus cisplatin in glioblastoma multiforme Clin Cancer Res 9 1461–1468
R Stupp P Dietrich S Ostermann Kraljevic A Pica I Maillard P Maeder R Meuli R Janzer G Pizzolato R Miralbell F Porchet L Regli N Tribolet Particlede RO Mirimanoff S Leyvraz (2002) ArticleTitlePromising survival of patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide J Clin Oncol 20 1375–1382
O Chinot M Barrié C Couprie H Dufour D Figarella-Branger X Muracciole C Bouvier PM Braguer JC Martin JC Peragut F Grisoli (2002) ArticleTitleCombination of temozolomide and BCNU as primary treatment before radiotherapy in newly diagnosed glioblastoma multiforme. Neuro-Oncology 4 215
H Colman KR Hess VK Turner VK Puduvalli MR Gilbert (2002) ArticleTitleImpact of duration of temozolomide therapy on progression-free survival in recurrent malignant glioma. Neuro-Oncology 4 218
AW Tolcher SL Gerson L Denis C Geyer LA Hammond A Patnaik AD Goetz G Schwartz T Edwards L Reyderman P Statkevich DL Cutler EK Rowinsky (2003) ArticleTitleMarked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules Br J Cancer 88 1004–1011
SA Grossman A O’Neill M Grunnet M Mehta JL Pearlman H Wagner M Gilbert HB Newton R Hellman (2003) ArticleTitleCollective Name Eastern Cooperative Oncoloy Group: Phase III study comparing three cycles of infusional carmustine and cisplatin followed by radiation therapy with radiation therapy and concurrent carmustine in patients with newly diagnosed supratentorial glioblastoma multiforme: Eastern Cooperative Oncology Group Trial 2394. J Clin Oncol 21 1485–1491
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Balaña, C., López-pousa, A., Berrocal, A. et al. Phase II study of temozolomide and cisplatin as primary treatment prior to radiotherapy in newly diagnosed glioblastoma multiforme patients with measurable disease. A study of the Spanish Medical Neuro-Oncology Group (GENOM). J Neurooncol 70, 359–370 (2004). https://doi.org/10.1007/s11060-004-9175-1
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DOI: https://doi.org/10.1007/s11060-004-9175-1