The survival of tumor-bearing animals was improved with local delivery of TMZ compared with systemic administration. XRT in combination with intracranial TMZ did not cause additional toxicity and prolonged the survival even further.

Randomized trials have demonstrated Gliadel improves survival for appropriately selected patients with newly diagnosed malignant glioma. As only limited information is available to guide the management of patients who have Gliadel controlled-release BCNU wafers implanted in the cranial resection cavity prior to radiotherapy (RT), this retrospective review was conducted to describe clinical course, toxicity, and pathologic findings after this therapy for newly diagnosed malignant glioma. Forty-six consecutive patients receiving Gliadel (3.8% BCNU impregnated wafers) followed by radiotherapy for newly diagnosed malignant glioma at Johns Hopkins Hospital from 1990 to August 1999 were identified, although one was lost to follow up and is excluded. Patients were evaluated for postoperative infection, pathology at reoperation, and survival. Twenty-eight patients received radiotherapy at Johns Hopkins and these patients are also evaluable for toxicity experienced during and one month after completion of RT. The median age of all patients is 57 years. Eighty-nine percent had glioblastoma, and median follow-up of surviving glioblastoma patients is 16.8 (12-20) months. Postoperative infection or need for reoperation within 30 days was uncommon after Gliadel placement. Full-dose radiotherapy was tolerable after Gliadel implantation. Five patients (19%) developed neurologic symptoms during radiotherapy responding to increased steroids and/or anticonvulsants, whereas an additional 8 of 27 (30%) developed neurologic symptoms during dexamethasone taper that responded to increases in dexamethasone dose. At one month after RT, 58% of patients were still on dexamethasone despite attempted taper. Fifteen of 45 patients, 33% underwent reoperation or biopsy for a new local contrast-enhancing lesion. In five of 15 (33%) the reoperation revealed necrosis or treatment effect without active tumor. Two of five patients with treatment/effect necrosis has a third surgery 2.9 and 3.2 months after the initial reoperation, and treatment effect/necrosis without tumor was demonstrated in both cases. The Kaplan-Meier median survival for all the glioblastoma patients is 12.8 (95% CI 9.6, 15.9) months. For glioblastoma patients under 55 years old, median survival is 15.9 (95% CI 13.5, too few events) months whereas for older patients it is 9.6 (7.7, 14.4) months. We conclude that Gliadel followed by full-dose standard radiotherapy is acutely well tolerated, although, close supervision should be emphasized during dexamethasone taper. Median survival in excess of one year suggests that there are not complications that result in overall premature death. The finding of necrosis/treatment effect was noted in five of 45 (11%) of all patients and five of 15 (33%) of those undergoing reoperation. Therefore, the possibility of necrosis/treatment effect should be considered for each patient with radiographic findings suspicious for local recurrence.

Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 µg/mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All dose-escalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated.

Introduction: Paclitaxel, a microtubule binding agent with potent anti-glioma activity in vitro, exhibits poor penetrance to the CNS when delivered systemically. To minimize toxicity and reach therapeutic concentrations in the CNS, paclitaxel was previously incorporated into biodegradable microspheres (Paclimer®), and the efficacy of Paclimer® was determined in a rat model of malignant glioma. In this study we report the safety of intracranial Paclimer® in a canine dose escalation toxicity study to prepare its translation into clinical scenarios.