Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series

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Abstract
Background: Grade IV malignancies of the brain, such as glioblastoma multiforme (GBM), are associated with a dismal prognosis. Autocrine and paracrine loops of platelet-derived growth factor (PDGF) signaling, as well as other signal transduction pathways, have been postulated to play a role in glioblastoma transformation, and molecules involved in these pathways can potentially serve as targets for therapeutic inhibitory agents. Imatinib, an inhibitor of PDGF receptors α and β, as well as other selected tyrosine kinases, is indicated for treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST). Unfortunately, imatinib, as with many conventional chemotherapeutic agents, has limited efficacy as monotherapy in GBM. In preclinical studies, the chemotherapeutic agent hydroxyurea is demonstrated to have cytotoxic effects additive with imatinib. Patients and methods: We tested the combination of hydroxyurea and imatinib in 30 grade IV progressive GBM patients refractory to chemo- and radiotherapy. All 30 patients were evaluable after a median 19 weeks observation time. Results: Combination therapy with imatinib and hydroxyurea resulted in a 20% response rate, including complete and partial responses. Patients experiencing response or stable disease yielded a combined clinical benefit rate of 57%. Median time to progression was 10 weeks and median overall survival was 19 weeks. Three patients continue to survive on combination therapy, with the shortest duration being 106 weeks. Six-month and 2-year progression-free survival rates were 32% and 16%, respectively. Conclusion: The efficacy results, combined with findings that imatinib and hydroxyurea were well tolerated, suggest that this combination shows promise as therapy for GBM.