© Copyright 2008 by the Society for Neuro-Oncology
Received June 7, 2007
Accepted December 4, 2007
A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood
Regina I. Jakacki 1*,
Allan Yates 2,
Susan M. Blaney 3,
Tianni Zhou 4,
Robert Timmerman 5,
Ashish M. Ingle 6,
Lynda Flom 1,
Michael D. Prados 7,
Peter C. Adamson 8,
Ian F. Pollack 1
1 Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
2 Ohio State University, Columbus, OH, USA
3 Baylor College of Medicine, Houston, TX, USA
4 University of Southern California, Los Angeles, CA, USA; Children’s Oncology Group, Arcadia, CA, USA
5 The University of Texas Southwestern Medical Center, Dallas, TX, USA
6 Children's Oncology Group, Arcadia, CA, USA
7 University of California, San Francisco, San Francisco, CA, USA
8 Children's Hospital of Philadelphia, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: regina.jakacki{at}chp.edu.
 |
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/m2 on days 1-5, along with 90 mg/m2 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/m2 dose level. One of 14 patients in the expanded MTD cohort (160 mg/m2) 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/m2 lomustine on day 1, the MTD of temozolomide is 160 mg/m2/day x 5. Radiographic changes following RT make determination of early tumor progression difficult. Metastatic disease is common prior to death.
Key Words:
CCNU (lomustine), malignant glioma, pediatrics, temozolomide
