Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump

Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brainwith the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), with or without topotecan (136 μM), was infused at 0.7 mL/24 h for 3 or 10 days. Pigs underwent magnetic resonance imaging before and at 6 times points after surgery. Enhancement and FLAIR1 volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signaturewas also investigated.Brain histologywas analyzed by hematoxylin and eosin staining andwith immunoperoxidase for a microglial antigen. CED of topotecan/gadolinium was well tolerated in all cases (n=6). Maximum enhancement volume was reached at day 3 and remained stable if CED was continued for 10 days, but it decreased if CED was stopped at day 3. Magnetic resonance spectroscopy revealed a decrease in parenchymal metabolites in the presence of topotecan. Similarly, the combination of topotecan and gadolinium infusion led to a FLAIR1 volume that tended to be larger than that seen after the infusion of gadolinium alone. Histological analysis of the brains showed an area of macrophage infiltrate in the ipsilateral white matter upon infusion with topotecan/gadolinium. Intracerebral topotecan CED is well tolerated in a large animal brain for up to 10 days. Intracerebral long-termCED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. Thiswork constitutes a proof of principle for the safety and feasibility for prolongedCED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.