title: A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood.
abstract: A phase I trial was conducted to determine the maximum tolerated dose (MTD) of temozolomide given in combination with lomustine in newly diagnosed pediatric patients with high-grade gliomas. Response was assessed following two courses of therapy at the MTD. Temozolomide was administered to cohorts of patients at doses of 100, 125, 160, or 200 mg/m(2) on days 1-5, along with 90 mg/m(2) lomustine on day 1. Two courses of lomustine/temozolomide were given prior to radiation therapy (RT) and up to six courses were administered afterward. Thirty-two patients were enrolled. Dose-limiting myelosuppression was seen in two of three patients enrolled at the 200 mg/m(2) dose level. One of 14 patients in the expanded MTD cohort (160 mg/m(2)) experienced dose-limiting thrombocytopenia. After two courses at the MTD, one patient with a 5-mm enhancing nodule postoperatively had a complete response, one patient with a large residual temporal lobe glioblastoma had a partial response, and eight patients had stable disease. Several patients developed transient radiographic worsening after completing RT. Median 1- and 2-year overall survivals at the MTD were 60% +/- 13% and 40% +/- 13% with a median of 17.6 months. Thirteen of 20 patients (65%) who underwent MRI scans within 6 months prior to death developed metastatic disease. In conclusion, when administered with 90 mg/m(2) lomustine on day 1, the MTD of temozolomide is 160 mg/m(2)/day x 5. Radiographic changes following RT make determination of early tumor progression difficult. Metastatic disease is common prior to death.
authors.affiliation: Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA. regina.jakacki@chp.edu
authors.forename: Regina I
authors.initials: RI
authors.lastname: Jakacki
authors.forename: Allan
authors.initials: A
authors.lastname: Yates
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Tianni
authors.initials: T
authors.lastname: Zhou
authors.forename: Robert
authors.initials: R
authors.lastname: Timmerman
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Lynda
authors.initials: L
authors.lastname: Flom
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
mesh_terms: D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008130:Lomustine / Q000008:administration & dosage / Q000009:adverse effects; D020714:Maximum Tolerated Dose; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008130:Lomustine; D003606:Dacarbazine; D000077204:Temozolomide