Image-guided convection-enhanced delivery of gemcitabine to the brainstem.
OBJECTIVE
To determine if the potent antiglioma chemotherapeutic agent gemcitabine could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution using a surrogate magnetic resonance (MR) imaging tracer, the authors used convection-enhanced delivery to perfuse the primate brainstem with gemcitabine and Gd-diethylenetriamine pentaacetic acid (DTPA).


METHODS
Six primates underwent convective brainstem perfusion with gemcitabine (0.4 mg/ml; two animals), Gd-DTPA (5 mM; two animals), or a coinfusion of gemcitabine (0.4 mg/ml) and Gd-DTPA (5 mM; two animals), and were killed 28 days afterward. These primates were observed over time clinically (six animals), and with MR imaging (five animals), quantitative autoradiography (one animal), and histological analysis (all animals). In an additional primate, 3H-gemcitabine and Gd-DTPA were coinfused and the animal was killed immediately afterward. In the primates there was no histological evidence of infusate-related tissue toxicity. Magnetic resonance images obtained during infusate delivery demonstrated that the anatomical region infused with Gd-DTPA was clearly distinguishable from surrounding noninfused tissue. Quantitative autoradiography confirmed that Gd-DTPA tracked the distribution of 3H-gemcitabine and closely approximated its volume of distribution (mean volume of distribution difference 13.5%). Conclusions. Gemcitabine can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and at volumes that are higher than those considered clinically relevant. Moreover, MR imaging can be used to track the distribution of gemcitabine by adding Gd-DTPA to the infusate. This delivery paradigm should allow for direct therapeutic application of gemcitabine to brainstem gliomas while monitoring its distribution to ensure effective tumor coverage and to maximize safety.
Murad
Gregory J A
GJ
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
Walbridge
Stuart
S
Morrison
Paul F
PF
Szerlip
Nicholas
N
Butman
John A
JA
Oldfield
Edward H
EH
Lonser
Russell R
RR
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001933:Brain Stem / Q000378:metabolism; D003287:Contrast Media; D018481:Convection; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019786:Gadolinium DTPA; D036502:Infusions, Intralesional / Q000379:methods*; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D013813:Therapy, Computer-Assisted; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003287:Contrast Media; D003841:Deoxycytidine; D019786:Gadolinium DTPA; D000093542:Gemcitabine