© 2002 by Society
© 2002 by the Society forNeuro-Oncology
A phase II trial of thymidine and carboplatin for recurrent malignantglioma: A North American Brain Tumor Consortium Study
Department of Medicine, University of Wisconsin,Madison, WI 53792 (H.I.R., M.M.); University ofCalifornia at San Francisco, San Francisco, CA 94143 (S.M.C., M.D.P.,K.N.); University of Texas MD Anderson Cancer Center,Houston, TX 77030 (W.K.A.Y., K.H.); University ofPittsburgh, Pittsburgh, PA 15213 (D.S.); Department ofNeurology, University of Michigan, MI 48109 (L.J., H.G.); University of Texas Southwestern at Dallas, Dallas, TX75390 (K.F.); University of Texas at San Antonio, SanAntonio, TX 78284 (J.G.K.); University of Californiaat Los Angeles, Los Angeles, CA 90095 (T.C.)
2 Address correspondence and reprint requests to H. Ian Robins, Department ofMedicine, University of Wisconsin Comprehensive Cancer Center K4/666, 600Highland Ave., Madison, WI 53792.
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Abstract |
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This phase II study in recurrent high-grade glioma evaluated the responserate, toxicities, and time to treatment failure of high-dose carboplatinmodulated by a 24-h infusion of thymidine (75 g/m2). The trial wasbased on preclinical data and a prior phase I study (J. Clin. Oncol.17, 2922-2931, 1999); a phase II recurrent high-grade glioma study wasinitiated in July of 1998. Thymidine was given over 24 h; carboplatin wasgiven over 20 min at hour 20 of the thymidine infusion. The starting dose ofcarboplatin had a value of 7 for the area under the curve (AUC), withallowance for dose escalation of 1 AUC unit per cycle if grade 2 toxicity wasobserved. Treatment cycles were repeated every 4 weeks. Accrual as ofSeptember 1999 was 45 patients [4 were unevaluable]: 76% with glioblastomamultiforme (GBM), 20% with anaplastic oligodendroglioma, 2% with mixed type,and 2% with anaplastic astrocytoma. Most patients had prior chemotherapy(78%). As observed in the earlier phase I study (in which carboplatinpharmacokinetics were unaltered by thymidine or antiseizure medications),thymidine was myeloprotective, resulting in a minimal need for dose reductionfor patients having a >2 grade toxicity (in only 4% of the courses oftreatment). Of 101 total courses, the number of courses (at the AUCs) was 3(5), 4 (6), 58 (7), 20 (8), 11 (9), and 5 (10). Grade 3 non-hematologictoxicities included headache (4%), altered consciousness (3%), fatigue (1%),and nausea (3%). Responses included 2 partial (1 oligodendroglioma, 1 GBM;5%); 3 minor (1 anaplastic astrocytoma, 2 GBM; 7.3%); 6 stable disease(14.6%); and 30 progressive disease (73.2%). For GBM patients, median survivalwas 23 weeks (with a 95% confidence interval of 20 to 50 weeks), andprogression-free survival was 8 weeks (with a 95% confidence interval of 7-16weeks). These results in GBM were comparable to other phase II GBM trials andthus do not represent a therapeutic advance in the treatment of GBM. Takencollectively, however, results are consistent with continued investigation ofthymidine in combination with chemotherapeutic agents for high-grade gliomaand other malignant diseases. The significant myeloprotection afforded bythymidine may have particular relevance to polychemotherapeutic regimens.
Received September 10, 2001; Accepted October 26, 2001
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