Abstract
Intra-parenchymal injection and delivery of therapeutic agents have been used in clinical trials for brain cancer and other neurodegenerative diseases. The complexity of transport pathways in tissue makes it difficult to envision therapeutic agent distribution from clinical MR images. Computer-assisted planning has been proposed to mitigate risk for inadequate delivery through quantitative understanding of infusion characteristics. We present results from human studies and simulations of intratumoral infusions of immunotoxins in glioblastoma patients. Gd-DTPA and 124I-labeled human serum albumin (124I-HSA) were co-infused with the therapeutic, and their distributions measured in MRI and PET. Simulations were created by modeling tissue fluid mechanics and physiology and suggested that reduced distribution of tracer molecules within tumor is primarily related to elevated loss rates computed from DCE. PET-tracer on the other hand shows that the larger albumin molecule had longer but heterogeneous residence times within the tumor. We found over two orders of magnitude variation in distribution volumes for the same infusion volumes, with relative error ~20%, allowing understanding of even anomalous infusions. Modeling and measurement revealed that key determinants of flow include infusion-induced expansion and loss through compromised BBB. Opportunities are described to improve computer-assisted CED through iterative feedback between simulations and imaging.
Highlights
Intrathecal, and intraventricular therapies in general do not go past the blood–brain barrier, and a drug’s impact may be significantly reduced since only a small percentage of brain volume is treated while most of the agent is cleared with no therapeutic effect
We have been developing a computational simulation procedure for planning infusions, upon which we have reported in detail in the past [1]
The purpose of this paper is threefold: (1) to describe the improvements made to the original algorithms, available commercially in BrainLab’s iPlanFlowTM; (2) to describe its performance with data taken in human clinical trials at Duke University; and (3) to describe the lessons we may learn from the observations and the models about the interstitial pathways for transport of therapeutics
Summary
Experienced neurosurgeons can reliably create drug distributions in a small volume near the tip of the catheter Our work in this area is based on the premise that one cannot infer the final distribution of a large infusion by looking at an MRI image prior to or early in an infusion. Pharmaceutical and academic communities pursuing cures for rare diseases require evidence that widespread, robust infusions are achievable, and that individual dosage is verifiable. For these purposes, we have been developing a computational simulation procedure for planning infusions, upon which we have reported in detail in the past [1]. We have published most of our developments, and so we refer to these publications for details, confining ourselves here for the most part to the concepts involved
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