Among large series, the incidence of leptomeningeal (LM) or CNS parenchymal disease in relapsed patients is 6-8%
Among large series, the incidence of leptomeningeal (LM) or CNS parenchymal disease in relapsed patients is 6-8%.[2, 3] CNS relapses have been almost always fatal[1-3] Chence the need for innovative treatments. cRIT-salvage regimen for CNS metastases was well tolerated by young patients, despite their prior history of rigorous cytotoxic therapies. It has the potential to increase survival with better than expected quality of life. strong class=”kwd-title” Keywords: Neuroblastoma, Radioimmunotherapy, CNS metastases, intrathecal Introduction Neuroblastoma (NB) is the most common extracranial solid tumor in children. Recurrent metastatic NB is usually difficult to remedy, particularly in patients with central nervous system (CNS) disease. The CNS has emerged as a sanctuary site leading to relapse. Among large series, the incidence of leptomeningeal (LM) or CNS parenchymal disease in relapsed patients is usually 6-8%.[2, 3] CNS relapses have been almost always fatal[1-3] Chence the need for innovative treatments. Compartmental radioimmunotherapy (cRIT) using radioiodinated monoclonal antibodies (MoAbs) administered intrathecally results in a favorable cerebrospinal fluid (CSF) to blood activity concentrations and radiation dose ratios and may be useful in the treatment of LM disease.[4-6] For example, cRIT using 131I-labeled murine anti-tenascin MoAbs in patients with malignant glioma was feasible, well tolerated and improved survival.[7-9] A phase I study at Memorial Sloan-Kettering Cancer Center (MSKCC) demonstrated the feasibility of cRIT for Rabbit polyclonal to ZFAND2B patients with GD2-expressing LM neoplasms using the anti-GD2 murine MoAb 3F8 labeled with 131I. Another murine MoAb, 8H9, is specific for 4Ig-B7H3, a 58 kD surface immunomodulatory glycoprotein that inhibits natural killer cells and T cells. The B7-H3 protein is distributed around the cell membrane of a broad spectrum of pediatric and adult solid tumors, preferentially expressed on tumors as compared to normal human tissues. When radiolabeled with 131I, 8H9 can deliver therapeutic doses of radiation to solid tumors and suppress tumor cell growth in established xenografts. We now report the PS-1145 survival of patients with relapsed CNS NB treated with a cRIT-based salvage regimen targeting minimal residual disease. Methods Staging was carried out according to the International Neuroblastoma Staging System. CNS NB was defined as LM disease or metastatic deposits in the CNS parenchyma excluding skull bone-based metastases. Disease was confirmed pathologically PS-1145 in 20 patients, and radiographically in 1 patient with numerous enhancing masses. Overall Treatment Plan The overall salvage regimen in 17 patients from July 2003 through March 2009 is usually summarized in table 1. Parenchymal CNS disease was immediately resected when possible, with concurrent placement of an intraventricular Ommaya catheter to deliver intrathecal therapy. Craniospinal irradiation (1080-2160 cGy) was delivered in twice daily fractions over a 3 week period, with a boost to parenchymal masses (up to 3000 cGy total) when possible. Craniospinal irradiation was delivered in the outpatient setting in conjunction with a course of irinotecan followed by a course of irinotecan-temozolomide carboplatin. The resulting myelosuppression was reversed by infusion of previously collected peripheral blood stem cells when necessary. Consolidation with cRIT then began (observe below). After completing the cRIT protocol, outpatient maintenance systemic therapy consisted of immunotherapy using intravenous 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) as previously explained,[15, 16] oral 13-cis-retinoic acid, and oral temozolomide.  This study was approved by MSKCC IRB, and informed written consents for all those treatments were obtained from guardians prior to treatment after they understood the potential side-effects of each agent and the possibility of unforeseen toxicities. Table 1 General cRIT- based treatment plan for patients PS-1145 with relapsed CNS NB thead th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Time /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Intervention /th /thead Day 0Resection of CNS disease when possible; Ommaya catheter placementDay 7Irinotecan 50 mg/m2/dose IV daily 5Day 14Craniospinal irradiation 1080- 2160 cGy/boost 2560-3000 cGyWeek 7Irinotecan 50 mg/m2/dose IV daily 5Temozolamide 250 mg/m2/dose daily 5Carboplatin 500 mg/m2/dose daily 2 (only if systemic NB present) Stem cell rescue*Week 14Serial injections of intra-Ommaya 131I-MoAbsWeek 30GMCSF/IV 3F8 every 3-4 weeks (4 cycles)Weeks 40-104Oral Cis-retinoic acid 160 mg/m2 day 14 days (6 cycles) alternating with Oral temozolomide 75 mg/m2/day 42 days (5 cycles) Open in a separate window *if needed; MoAbs- monoclonal antibodies; GMCSF-granulocyte macrophage colony stimulating factor; 3F8 C monoclonal anti-GD2 antibody cRIT treatment Patients were enrolled.