title: Convection enhanced delivery of carboplatin in combination with radiotherapy for the treatment of brain tumors.
abstract: The purpose of this study was to further evaluate the therapeutic efficacy of convection enhanced delivery (CED) of carboplatin in combination with radiotherapy for treatment of the F98 rat glioma. Tumor cells were implanted stereotactically into the brains of syngeneic Fischer rats, and 13 or 17 d. later carboplatin (20 μg/10 μl) was administered by either CED over 30 min or by Alzet osmotic pumps (0.5 μg/μl/h for 168 h.) beginning at 7 d after tumor implantation. Rats were irradiated with a 15 Gy fractionated dose (5 Gy × 3) of 6 MV photons to the whole brain beginning on the day after drug administration. Other groups of rats received either carboplatin or X-irradiation alone. The tumor carboplatin concentration following CED of 20 μg in 10 μl was 10.4 μg/g, which was equal to that observed following i.v. administration of 100 mg/kg b.w. Rats bearing small tumors, treated with carboplatin and X-irradiation, had a mean survival time (MST) of 83.4 d following CED and 111.8 d following pump delivery with 40% of the latter surviving >180 d (i.e. cured) compared to 55.2 d for CED and 77.2 d. for pump delivery of carboplatin alone and 31.8 d and 24.2 d, respectively, for X-irradiated and untreated controls. There was no microscopic evidence of residual tumor in the brains of all long-term survivors. Not surprisingly, rats with large tumors had much shorter MSTs. Only modest increases in MSTs were observed in animals that received either oral administration or CED of temozolomide plus X-irradiation (23.2 d and 29.3 d) compared to X-irradiation alone. The present survival data, and those previously reported by us, are among the best ever obtained with the F98 glioma model. Initially, they could provide a platform for a Phase I clinical trial to evaluate the safety and potential therapeutic efficacy of CED of carboplatin in patients with recurrent glioblastomas, and ultimately a Phase II trial of carboplatin in combination with radiation therapy.
authors.affiliation: Department of Pathology, The Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA.
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.forename: Tianyao
authors.initials: T
authors.lastname: Huo
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Nilendu
authors.initials: N
authors.lastname: Gupta
authors.forename: Michael
authors.initials: M
authors.lastname: Weldon
authors.forename: John C
authors.initials: JC
authors.lastname: Grecula
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Hoff
authors.forename: Ting-Chao
authors.initials: TC
authors.lastname: Chou
authors.forename: Julia
authors.initials: J
authors.lastname: Rousseau
authors.forename: Hélène
authors.initials: H
authors.lastname: Elleaume
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D016190:Carboplatin / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D018481:Convection; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D005910:Glioma / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D011829:Radiation Dosage; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate; D014018:Tissue Distribution; D014964:X-Ray Therapy
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D016190:Carboplatin; D005038:Ethylnitrosourea