Stereotaxic implantation of 5‐fluorouracil‐releasing microspheres in malignant glioma

Abstract

BACKGROUND The authors developed a new method of drug delivery into the brain using implantable, biodegradable microspheres. The strategy was evaluated initially to provide localized and sustained delivery of the radiosensitizer 5‐fluorouracil (5‐FU) after patients underwent surgical resection of malignant glioma. In this study, the microspheres were implanted by stereotaxy into deeply situated and inoperable brain tumors. METHODS Ten patients with newly diagnosed, inoperable, malignant gliomas were included in the study, and 1 dose of 5‐FU was studied (132 mg). After histologic confirmation, a suspension of poly(D‐L lactide‐co‐glycolide) 5‐FU‐loaded microspheres was implanted by stereotaxy into the tumor in one or several trajectories with one to seven deposits per trajectory. External beam radiation (59.4 grays) was started before postoperative Day 7. Patients were followed by clinical examination, computed tomography scanning, magnetic resonance imaging, and 5‐FU assays in blood and cerebrospinal fluid (CSF). RESULTS The number of trajectories was adapted to the size and shape of the tumor. Microsphere implantation was tolerated well, except in four patients who received a single trajectory and experienced a transitory worsening of preexisting neurologic symptoms. There were no episodes of edema or hematologic complications. 5‐FU was detected in CSF and blood in some patients at very low concentrations. The median overall survival was 40 weeks, with 2 patients who had longer survival (71 weeks and 89 weeks, respectively). CONCLUSIONS In this study, the authors demonstrated that biodegradable microspheres could be implanted by stereotaxy and were efficient systems for drug delivery into brain tumors. This method may have future applications in the treatment of patients other malignancies. Cancer 2004;100:405–10. © 2003 American Cancer Society.

Towards More Realistic In Vitro Release Measurement Techniques for Biodegradable Microparticles

“…Poly(lactic-co-glycolic acid) (PLGA)-based microparticles are steadily gaining in importance as advanced parenteral drug delivery systems, because they offer various major advantages, including: (i) the possibility to accurately control the resulting drug release kinetics over periods of days to months (1,2); (ii) complete biodegradability (avoiding the removal of empty remnants upon drug exhaustion) (3,4); (iii) good biocompatibility (5,6), even if directly administered into brain tissue (intracranially) (7,8); and (iv) easy administration (compared to implants) using standard syringes and needles. Various products based on PLGA-based controlled release microparticles are commercially available, for instance Lupron Depot, containing the anticancer drug leuprolide acetate for the treatment of prostate cancer, and Risperdal Consta containing the antipsychotic drug risperidone for the treatment of schizophrenia.…”

Model simulation and experimental validation of intratumoral chemotherapy using multiple polymer implants

“…For treating gliomas, up to 8 BCNU-impregnated polyanhydride implants (Gliadel ® wafers) are placed into the resection cavity after surgery [9]. Clinical trials have used up to 5 stereotactic injections per patient of 5-fluorouracil (5-FU)-containing microspheres into brain tumors [15,16]. One recent report on the placement of multiple doxorubicin implants into dog prostates indicated that multiple implants could be highly effective in locally delivering chemotherapy to potential tumors [17].…”

A safety and toxicity assessment of the administration of multiple intracerebral injections of irinotecan or doxorubicin drug-eluting beads

“…In this regard it is important to note that with the Gliadel™ wafer there is no close contact between targeted brain tissue and the implant, which may impair the penetration of the chemotherapeutic drug from the implant into the tissue. It was recognised that smaller dimensioned polymeric carrier structures, which can be implanted directly into the brain tissue surrounding the tumour cavity, may improve the penetration of the drug from the polymeric carrier into the brain tissue [8]. Considering the limited diffusional penetration of drugs through the brain tissue, mathematical modelling and experimental studies have shown that, for example, the entire volume of a tumour 2 cm in diameter may be targeted with four peripherally placed implants, while the centrally placed single implant never reached 100% tumour coverage during a simulated treatment period of 8 days [9].…”