© 2003 by Society
© 2003 by the Society forNeuro-Oncology
Phase 2 study of idarubicin in pediatric brain tumors: Pediatric OncologyGroup study POG 9237
Department of Pediatric Oncology, Texas Children'sCancer Center at Baylor College of Medicine, Houston, TX 77030 (Z.E.D.,D.H.M.); Department of Hematology/Oncology, Children'sHospital San Diego, San Diego, CA 92123 (R.P.K.); Departments of Pharmaceutical Sciences (C.F.S.) and Radiation Oncology (L.E.K.), St. Jude Children's ResearchHospital, Memphis, TN 38105; Department of Surgery,Duke University Medical Center, Durham, NC 27710 (H.S.F.); St. Luke's Episcopal Hospital, Houston, TX 77030(C.W.M.); Department of Pathology, Johns HopkinsHospital, Baltimore, MD 21287 (P.C.B.); Department ofClinical Biostatistics, Roswell Park Cancer Institute, Buffalo, NY 14263(J.K.); Division of Pediatric Hematology/Oncology,University of New Mexico School of Medicine, Albuquerque, NM 87131 (R.L.H.);USA
1 Address correspondence to ZoAnn E. Dreyer, Texas Children's Cancer Center atBaylor College of Medicine, Pediatric Oncology, 6621 Fannin Street CC1510,Houston, TX 77030-2399, USA(zdreyer{at}bcm.tmc.edu).
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Abstract |
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Idarubicin (IDA), the 4-demethoxy analog of daunomycin, has had significantcytotoxicity in many malignancies. In previous reports, the alcohol metaboliteof IDA, 4-demethoxydaunorubicinol (idarubicinol, or IDOL), had cytotoxicactivity and the ability to penetrate the blood-brain barrier. For thisreason, the Pediatric Oncology Group conducted a Phase 2 trial of IDA forchildren with recurrent or progressive brain tumors. Ninety-one eligiblechildren were entered on this study, with ages ranging from 3 months to 19years. Patients were stratified by tumor types into 6 categories: stratum 1,low-grade astrocytoma; stratum 2, malignant glioma (glioblastoma multiformeand anaplastic astrocytoma); stratum 3, medulloblastoma; stratum 4, brainstemglioma; stratum 5, ependymoma; and stratum 6, miscellaneous malignant tumorsnot included in the previous diagnoses. IDA (18 mg/m2) was infusedover 4 h and followed by granulocyte colony-stimulating factor (G-CSF)beginning day 5 after infusion of IDA. G-CSF was continued until blood cellcount recovery. Cycles were repeated at approximately 21-day intervals untilpatients developed progressive disease or had completed 6 cycles with stableor improved disease. Pharmacokinetic plasma and cerebrospinal fluid (CSF)samples were collected from a subset of these patients. Response was poor inall strata. Most patients developed progressive disease; however, in 21patients with medulloblastoma there was 1 partial response, and 6 patients hadstable disease (SD) that in 4 patients lasted more than 20 weeks. Grades 3/4hematopoietic toxicities were the most common toxic events, and 14infection-related events resulted in hospitalization of patients. Only 1patient developed reduced cardiac function. The systemic clearance data forIDA and IDOL were nearly identical to those published on patients withleukemia, and the plasma elimination of the IDOL metabolite was substantiallylonger than that of the parent drug IDA. The peak CSF:plasma ratios of IDA andIDOL were very low. The overall response rates to IDA were disappointingdespite periods of prolonged SD in nearly a fourth of the patients. Weconclude from this data and from that in nonhuman primates that it is unlikelythat IDA, daunomycin, or other related anthracyclines will be useful fortreating primary CNS tumors.
Received December 11, 2002; Accepted June 17, 2003