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

Abstract

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 brain with 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 FLAIR+ volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signature was also investigated. Brain histology was analyzed by hematoxylin and eosin staining and with 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 FLAIR+ 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-term CED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. This work constitutes a proof of principle for the safety and feasibility for prolonged CED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.

Fig. 1.

Bioactivity of topotecan maintained at 37°C by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on U87 cells on days 0, 6, and 10. No decrease in antiproliferative activity is seen with prolonged exposure to physiologic temperature.

Fig. 2.

Relative volume changes in 10-day versus 3-day infusions of topotecan-gadolinium. In both time periods of infusion, the maximum relative volume was reached 2–3 days after infusion. A trend toward a decrease in enhancing volume is seen when the infusion is discontinued at day 3, although statistical significance was not achieved.

Fig. 3.

FLAIR+ volume differences between topotecan-gadolinium versus gadolinium-infused animals for 10 days. A trend toward larger FLAIR+ volume is seen in animals with topotecan present in the infusate.

Fig. 4.

Magnetic resonance spectroscopy in the presence of topotecan. SV 1H magnetic resonance spectroscopy of ∼1 cm³ on the side ipsilateral to the infusion catheter (right) or contralateral hemisphere (left). During 2-day period of gadolinium infusion, there was no difference in the metabolite spectra between the contralateral (A) and ipsilateral sides of infusion (B). In contrast, during a 2-day period of infusion of topotecan-gadolinium (t/g) mixture, N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) declined ipsilateral (D) but remained unaffected contralateral to the infusion catheter (C).

Fig. 5.

Histological sections after 10 days of topotecan-gadolinium or gadolinium alone at catheter site (*) and distant white matter. (A) Hematoxylin and eosin staining and (B) immunohistochemistry for Iba1.