Toxin Treatment of Malignant Glioma.
The treatment of malignant gliomas has advanced significantly in the past 15 years. The simultaneous development of new targeting agents and techniques to deliver these high-molecular-weight compounds has led to improved efficacy and promising results in Phase III trials. Convection-enhanced delivery (CED) of macromolecules has emerged as the leading delivery technique for the treatment of malignant gliomas. A summary of the basic principles of CED and a review of the current human trials of protein targeting agents are provided.

Despite advances in chemotherapy, malignant gliomas carry a poor prognosis. Based on data from the Central Brain Tumor Registry of the US, it was predicted that 43,800 new cases of malignant and nonmalignant brain tumors would be diagnosed in 2005. Collected data from 1998 to 2002 from this registry show that 40% of all newly diagnosed brain tumors are gliomas and that 20.3% are GBMs. Surveillance, Epidemiology, and End Results data from the National Cancer Institute includes reports of 12,760 deaths from brain and other CNS tumors in 2005.

Survival rates for patients with GBM who are treated using the current therapeutic modalities of surgery, radiotherapy, and chemotherapy remain dismal. This long-standing, three-part intervention has had a poor impact on outcome, due in part to the infiltrative nature of malignant gliomas and the protected location in which the tumor cells reside. Resection fails to rid the patient of disease because of the behavior of these tumors and the surgeon's desire not to produce a neurological deficit with this treatment. Radiotherapy focuses on the cancer cell's ability to replicate but unfortunately is limited by its toxicity to the functional but infiltrated surrounding brain tissue. Tumor-infiltrated brain tissue is protected from the systemic circulation by the BBB, which prevents most chemotherapeutic agents from effectively reaching the cancer cells. Attempts to deliver chemotherapeutic agents to the brain via intravenous or oral routes have thus been thwarted by high systemic exposure and toxicity.

To overcome systemic effects and achieve high concentrations of drug in tumors, several methods have evolved to deliver local/regional chemotherapeutic agents. These include BBB breakdown, infusions into cerebrospinal fluid, and a variety of intraparenchymal delivery techniques such as bolus injections, slow release using biodegradable vehicles, and convection-enhanced or bulk flow delivery of macromolecules.