*4.3.1. Conventional chemotherapeutics*

Topotecan, a topoisomerase I inhibitor, is an ideal conventional chemotherapeutic agent for CED. Firstly, topotecan is more readily to accumulate in gliomas than in normal brain tissue. Secondly, it specifically kills glioma cells and is less toxic to normal brain. In addition, topoisomerase I is a natural‐product agent with a high molecular weight. As a result, topote‐ can is difficult to bypass BBB when administered intravenously. Whereas topotecan is less easily removed into systemic circulation and can be retained in the targeted site for a pro‐ longed time when it is infused via CED. Jeffery and colleagues conducted a Phase Ib trial to deliver topotecan to recurrent malignant gliomas (68). Sixteen patients were enrolled in that dose‐escalation trial. The treatment was well tolerated with the stable maintenance of quality of life and neurocognitive functioning of patients. Tumors substantially regressed without significant systemic and neurocognitive adverse effects in selected patients with recurrent malignant gliomas refractory to conventional treatment. The total response of the single topotecan infusion was 69%. The results were encouraging for relapse patients in whom previous treatment had failed, but the efficacy of this treatment requires to be confirmed in Phase II and III trials.

Another conventional chemotherapeutic agent, paclitaxel, has also been delivered through CED to treat malignant gliomas. In a Phase I/II trial, a total of 20 cycles of intratumoral CED of paclitaxel was administered to 15 patients with histologically confirmed recurrent GBM (69). Among these 15 patients, complete response was observed in five cases and partial response in six cases, respectively. The response rate reached 73%. The poor response seemed to be associated with the backflow of paclitaxel into subarachnoid spaces, ventricles, and resec‐ tion cavities. Although effective, the local delivery of paclitaxel caused significant incidence of complications including transient chemical meningitis in six patients, infection in three patients and transient neurological deficits in four patients. The treatment‐related side effects have been suggested to be the results of infusate reflux. Strategies such as sealing the burr hole with bone wax and adapting the concentration of paclitaxel were used to prevent the extrac‐ ranial leakage of the cytotoxic drug and minimize the treatment‐induced side effects (70).
