CURRENT THERAPIES

An important goal following surgical excision of a malignant glioblastoma is to prevent local recurrence which may improve progression-free survival. Options for treating a tumor located in or on the brain currently include surgery, radiation, chemotherapy and local intratumoral therapy. Each of these prior methods of treating a brain tumor has demonstrated some very limited form of success. However, each of them also contains various deficiencies and pitfalls that make them less than ideal when treating a patient with a malignant brain tumor. 

An effective local anticancer drug delivery system should ideally have the following three capabilities in order to achieve the goal of preventing local recurrence and improving progression-free survival:

Administration of multiple drugs simultaneously in a precisely controlled fashion over an extended period of time, i.e. weeks to months

Active pumping of drugs into brain tissue that results in a large area of drug distribution that extends well beyond the tumor bed

Monitor the physiological response of the tumor to therapy and adjust drug therapy based on this data when clinically appropriate

Currently, no such localized drug delivery system is available. Local intratumoral therapies used at the present time include chemotherapy wafers, direct injections, and convection enhanced deliveries via an external pumping device. Chemotherapy wafers and direct injections have limited efficacy, most probably due to the short duration of treatment and limited circumference of drug delivery. Convection enhanced delivery has been used to increase the circumference of drug delivery. It is usually given by an externalized catheter, and the drug is delivered for a cycle of 4-6 days. At the end of that time, the catheter must be removed. If the drug is to be delivered again, another surgical procedure for convection enhanced delivery must be performed. This experimental procedure has not demonstrated increased survival. Furthermore, this intratumoral therapy can be very expensive and painful, exposing the brain to an externalized catheter for long periods of time and requiring complicated implantations of temporary catheters and other medical devices.

By contrast, the MBP allows for an implanted device to metronomically deliver chemotherapy in a continuous fashion over time while monitoring tumor response and allowing adjustments in therapy.

The effectiveness of continuous metronomic local delivery of chemotherapy over prolonged time was illustrated in a recent study funded by PKC at the University of Southern California using mice implanted with glioma cells and treated with chemotherapeutic agents, both systemically and via implanted minipumps. Figure 2 demonstrates the survival curves of the animals treated. Control animals treated with saline alone were all dead by 30 days post implantation. Animals treated with intravenous Avastin, intraperitoneal CPT-11, and intravenous Avastin with intraperitoneal CPT-11, survived longer than control mice by approximately 10 days. Mice treated with intratumoral Avastin alone survived longer than mice treated with intravenous Avastin, intraperitoneal CPT-11, or in combination. The greatest survival advantage was in mice treated through intratumoral delivery via the minipump with Avastin in combination with intraperitoneal CPT-11. These mice demonstrated greatly increased survival compared to mice treated through systemic delivery, with a survival time close to 60 days in the last surviving animal. These results demonstrate that survival of mice implanted with the mini-pump and receiving local drug delivery was significantly increased compared with mice receiving chemotherapy by systemic delivery.