Combined Hydroxyurea and Verapamil in the Clinical Treatment of Refractory Meningioma: Human and Orthotopic Xenograft Studies

Combined Hydroxyurea and Verapamil in the Clinical Treatment of Refractory Meningioma: Human and Orthotopic Xenograft Studies

Objective Previous in vitro and in vivo results suggested that hydroxyurea (HU) and verapamil could suppress meningioma growth individually and synergistically. We evaluated the clinical efficacy and safety of this approach for the treatment of refractory recurrent/progressive meningiomas and expand...

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Bibliographic Details
Published in:World neurosurgery Vol. 86; pp. 210 - 219
Main Authors: Karsy, Michael, Hoang, Nguyen, Barth, Talmadge, Burt, Lindsay, Dunson, William, Gillespie, David L, Jensen, Randy L
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-02-2016
Subjects:
Adult
Aged
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological Availability
Calcium channel antagonists
Calcium Channel Blockers - administration & dosage
Delayed-Action Preparations
Disease-Free Survival
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Female
Follow-Up Studies
Humans
Hydroxyurea
Hydroxyurea - administration & dosage
Male
Meningioma
Meningioma - drug therapy
Mice
Middle Aged
Neoplasm Recurrence, Local
Neurosurgery
Prospective Studies
Treatment Outcome
Verapamil
Verapamil - administration & dosage
Xenograft Model Antitumor Assays
CCA
Calcium channel antagonist
Calcium channel antagonists
World Health Organization
OS
MRI
CI
Hydroxyurea
HU
MDR1
Microvascular density
Magnetic resonance imaging
ANOVA
Verapamil
confidence interval
MVD
Multidrug resistance protein 1
Overall survival
PFS
Progression-free survival
Meningioma
Analysis of variance
WHO
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Summary:Objective Previous in vitro and in vivo results suggested that hydroxyurea (HU) and verapamil could suppress meningioma growth individually and synergistically. We evaluated the clinical efficacy and safety of this approach for the treatment of refractory recurrent/progressive meningiomas and expanded our studies in a xenograft orthotopic mouse model. Methods Six women and 1 man, aged 26–76 years (median, 56 years), with magnetic resonance imaging-proven progression of ≥25% in cross-sectional area of recurrent meningioma (2 World Health Organization grade I, 5 grade II) within the preceding 6 months received HU 1000 or 1500 mg/day (20 mg/kg/day, twice daily) as well as verapamil sustained-release tablets with dose escalation every 2 weeks (120–240 mg/day). They underwent magnetic resonance imaging every 3 months during therapy. To augment the clinical trial results, we performed mouse orthotopic xenograft experiments using similar dosing to test tumor growth, vascularity, and drug bioavailability. Results After a mean of 8.1 cycles of treatment, the patients demonstrated no significant radiographic responses during mean follow-up of 14.5 ± 4.8 months. Median progression-free survival (PFS) was 8.0 months, and 6-month PFS was 85%. Side effects occurred in 6 (86%) patients. Xenograft studies showed no effect of individual or combined treatments on meningioma growth. Neither HU nor verapamil was detectable in mouse brain tumor tissue despite adequate serum levels within therapeutic ranges. Conclusions Our results showed no effect of HU or verapamil on tumor recurrence, PFS, and in vivo tumor burden reduction. Drug delivery to the tumor may be a major limitation.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
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ISSN:1878-8750
1878-8769
DOI:10.1016/j.wneu.2015.09.060