gms | German Medical Science

Background: GBM is one of the most aggressive malignancies with a median survival of about 1 year. In newly diagnosed GBM combined treatment including surgery and chemo-/ radiotherapy leads to 2 years progression free survival (PFS) of 11 % and 2 years overall survival of 26 %. The prognosis is even worse in pts with recurrent GBM. Many malignancies of the brain including GBM express platelet derived growth factor receptors (PDGF-R). Imatinib, a tyrosine kinase inhibitor of Bcr-Abl, PDGF-Rs and the Kit receptor, showed remarkable clinical efficacy in chronic myeloid leukaemia and gastrointestinal stromal tumours . In GBM, however, single agent efficacy was limited due to the blood brain barrier (BBB). Therefore Hydroxyurea (HU) which freely penetrates and potentially modulates the BBB was combined with imatinib to study if efficacy could be improved.

Methods: From June 2001 to September 2003 30 GBM pts refractory to radiation therapy and chemotherapy containing ACNU and temozolomide were treated with imatinib 400 mg/day and HU 1000 mg/day as continuous daily, oral dosing, followed by clinical examination and magnetic resonance imaging every 6 weeks.

Results: All 30 pts are evaluable for safety and efficacy. Initial ECOG-performance status was 1-2, the median age was 44 yrs (16-71). Results after a median treatment period of 19 weeks (4-145) were one complete response (CR) lasting 12 months, 4 partial responses (PR) lasting a median of 3 months (3-29), 11 stable diseases (SD) for a median of 6 months (3-33) and 13 progressive disease (PD). There were no grade 3 or 4 toxicities. 27 deaths occurred: 2 pts died of pulmonary embolism and 25 pts of disease progression, 2 pts after a period of SD of 25 and 34 months. In 2005, November, 3 pts remain alive, 2 pts without progression for 32 and 28 months respectively, 1 pt had a disease progression after 26 months of SD and is in another period of SD since 7 months with the combination chemotherapy temozolomide plus pegylated liposomal doxorubicin. Six months PFS was 32 %, 2 years PFS was 16 %.

Conclusions: Combination therapy of imatinib and HU was well tolerated and effective in this group of recurrent, refractory GBM pts, with a response rate of 20 % (CR + PR) and a clinical benefit rate of 57 % (including SD), 2 years PFS was 13 %. Based on these results, additional studies have been initiated to further explore this regimen.