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Imatinib (STI 571)/ plus hydroxyurea:
Safety and efficacy in pre-treated, progressive Glioblastoma
Multiforme (GBM) patients (pts): An update on the initial 30 pts
G. Dresemann
Franz-Hospital Dülmen, Dülmen,
Germany
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%.
In recurrent GBM prognosis is even worse.
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.
26 deaths occurred.
2 pts died of pulmonary embolism and 24 pts of disease
progression, 1 pt after a 2 years period of SD.
Six months PFS was 32%, 2 years PFS was 13%, 4 pts remain alive without
progression for 34, 28, 25 and 23 months, respectively.
Conclusions. Combination
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.
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