Interstitial docetaxel (Taxotere), carmustine and combined interstitial therapy: a novel treatment for experimental malignant glioma

Docetaxel (Taxotere) is a hemisynthetic, anti-cancer compound with good preclinical and clinical activity in a variety of systemic neoplasms. We tested its activity against malignant gliomas using local delivery methods. Antitumor activity was assessed in vitro against human (U87 and U80 glioma) and rat brain-tumor (9L gliosarcoma and F98 glioma) cell lines. For in vivo evaluation, we incorporated docetaxel into a biodegradable polymer matrix, determined associated toxicity in the rat brain, and measured efficacy at extending survival in a rat model of malignant glioma. Also, we examined the combined local delivery of docetaxel with carmustine (BCNU) against the experimental intracranial glioma. Rats bearing intracranial 9L gliosarcomas were treated 5 days after tumor implantation with various polymers (placebo, 5% docetaxel, 3.8% BCNU, or 5% docetaxel and 3.8% BCNU combination). Animals receiving docetaxel polymers (n=15, median survival 39.1 days) had significantly improved survival over control animals (n=12, median survival 22.5 days, P=0.01). Similarly, animals receiving BCNU polymers (n=15, median survival 39.3 days, 13.3% long-term survivors) demonstrated an increase in survival compared to the controls (P=0.04). Animals receiving the combination polymers demonstrated a modest increase in survival compared to either chemotherapeutic agent alone (n=14, median survival 54.9 days, 28.6% long-term survivors) with markedly improved survival over controls (P=0.003). We conclude that locally delivered docetaxel shows promise as a novel anti-glioma therapy and that the combination of drug regimens via biodegradable polymers may be a great therapeutic benefit to patients with malignant glioma

Stereotactic body radiotherapy for spinal metastases: what are the risks and how do we minimize them?

Study Design. Systematic literature review. Objectives. To summarize the risks of, key complications of stereotactic body radiotherapy, SBRT, for spinal metastases, that is, radiation myelopathy, RM, vertebral compression fracture, VCF, and epidural disease progression, and to discuss strategies for minimizing them. Summary of Background Data. RM, VCF and epidural disease progression are now recognized as important risks following SBRT for spine metastases. It is unclear at this stage exactly how large these risks are and what strategies can be employed to minimize these risks. Methods. A systematic review of the literature using MEDLINE and a review of the bibliographies of reviewed articles on SBRT for spinal metastases were conducted. Results. The initial literature search revealed a total of, articles, of which, were pertinent to the study objectives. The risk of RM following SBRT was found to be dependent on the maximum dose to the spinal cord and estimated to be, if the recommended published thecal sac dose constraints are adhered to. The crude risk of VCF was, ., range, ., ., and, on average, were surgically salvaged. It has been shown that the risk of VCF is dependent on several anatomic and tumor-related factors including the SBRT dose per fraction. The crude risk of local failure at, year was, ., range, of which, range, occurred within the epidural space. The grade of epidural disease has been shown to be associated with the risk of local failure. Conclusion. The risk of RM after spinal SBRT is low in particular if recommended dose metrics are adhered to. There is a significant risk of both VCF and epidural disease progression after spinal SBRT. These risks can potentially be minimized by identifying the risk factors for these complications, and performing careful radiotherapy and surgical planning.Joe H. Chang, John H. Shin, Yoshiya J. Yamada, Addisu Mesfin, Michael G. Fehlings, Laurence D. Rhines and Arjun Sahga

Local immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma

OBJECTIVE: Local delivery of carmustine (BCNU) from biodegradable polymers prolongs survival against experimental brain tumors. Moreover, paracrine administration of interleukin-2 (IL-2) has been shown to elicit a potent antitumor immune response and to improve survival in animal brain tumor models. We report the use of a novel polymeric microsphere delivery vehicle to release IL-2. We demonstrate both in vitro release of cytokine from the microspheres and histological evidence of the inflammatory response elicited by IL-2 released from the microspheres in the rat brain. These microspheres are and biodegradable polymer wafers are used to deliver BCNU, directly used to deliver IL-2, glioma in the rat. The two agents administered at the site of an intracranially implanted glioma in the rat. The two agents administered locally show a synergistic effect. METHODS: Fischer'344 rats challenged intracranially with 9L gliosarcoma received an intracranial implant of either empty microspheres or microspheres containing IL-2 (IL-2 MS). Five days later, animals in each group were randomized to receive polymer implants loaded with 0, 3.8, or 10% BCNU at the tumor site. RESULTS: Animals that received the combination of IL-2 MS and 3.8% BCNLJ polymer (median survival, 28.5 d) or IL-2 MS and 10% BCNU polymer (median survival, 45.5 d) Showed significantly improved survival compared with animals that received monotherapy with IL-2 microspheres (median survival, 24 d), 3.8% BCNU polymer (median survival, 24 d), or 10% BCNU polymer (median survival, 32.5 d). Control animals had a median survival of 18 days. The combination of either 3.8 or 10% BCNU polymer with IL-2 MS resulted in 7 and 25% long-term survivors, respectively. CONCLUSION: By showing synergy of IL-2 and BCNLJ in an animal glioma model and using a reproducible synthetic delivery system for each agent (i.e., one that did not rely on genetically engineered cells or viruses), we hope that the combination of local immunotherapy and chemotherapy can take an important step closer to clinical application in patients with malignant brain tumor