We examined the efficacy of five commonly used drugs, teniposide (VM26), cisplatin (CDDP), cyclophosphamide (CPM), doxorubicin (DOXO), and vincristine (VCR) in a retrospective analysis of 44 clinical trials of induction chemotherapy for stage IV neuroblastoma patients newly diagnosed at older than 1 year of age. Dose intensity (DI) of each drug was calculated as milligrams per square meter per week. Linear regression analyses showed that the Dls of VM26 and CDDP had the greatest influence on clinical outcomes (ie, proportion of major response, median survival, and median progression-free survival [PFS]), while those of CPM and DOXO were less significant. VCR had no influence on the three clinical end points. Although many protocols extended treatment to more than 1 year, none of these end points correlated positively with the duration of therapy. Twenty-one weeks appeared adequate for achieving superior response, median survival, and median PFS. These results suggest that maximal dose intensification of selective drugs over a short duration may improve the outcome of patients with poor-risk neuroblastoma.

Purpose Monoclonal antibodies (MAbs) have the potential to target therapy for high-grade gliomas. MAb 8H9 is specific for membrane protein B7H3 and is reactive with the majority of human high-grade gliomas. We tested the 8H9scFv-PE38 recombinant Pseudomonas-immunotoxin in a preclinical model of high-grade glioma. Experimental Design The IC50 of 8H9scFv-PE38 in vitro was determined using glioblastoma cell lines U87 and U251. Maximum tolerated infusion dose (MTID) of 8H9scFv-PE38 following interstitial infusion to the striatum and pons was defined using athymic rats. MTID of 8H9scFv-PE38 or PBS control were interstitially delivered to athymic rats xenografted with U87 in the striatum or brain stem. Radiographic response and survivals were measured and compared between treatment groups. Results The in vitro IC50 of 8H9scFv-PE38 for U87 was 1265 ng/ml, and for U251, 91 ng/ml. The MTIDs of interstitially infused 8H9scFv-PE38 to the striatum and brain stem were 0.75 μg and 1.8 μg, respectively. For rats harboring intracranial U87 xenografts, infusion of 8H9scFv-PE38 increased mean survival (striatum: 43.4 days versus 24.6 days; brain stem: 80.6 days versus 45.5 days, n=28 total) and produced 3 long term survivors past 120 days. None of the 14 placebo-treated animals survived longer than 54 days. Tumors also showed volumetric response to infusion of 8H9scFv-PE38 by MRI. Conclusion Interstitial infusion of 8H9scFv-PE38 shows potential for the treatment of hemispheric and brain stem glioma.