title: Arsenic Trioxide as a Radiation Sensitizer for 131I-Metaiodobenzylguanidine Therapy: Results of a Phase II Study.
abstract: Arsenic trioxide has in vitro and in vivo radiosensitizing properties. We hypothesized that arsenic trioxide would enhance the efficacy of the targeted radiotherapeutic agent (131)I-metaiodobenzylguanidine ((131)I-MIBG) and tested the combination in a phase II clinical trial.
  
  
  METHODS
  Patients with recurrent or refractory stage 4 neuroblastoma or metastatic paraganglioma/pheochromocytoma (MP) were treated using an institutional review board-approved protocol (Clinicaltrials.gov identifier NCT00107289). The planned treatment was (131)I-MIBG (444 or 666 MBq/kg) intravenously on day 1 plus arsenic trioxide (0.15 or 0.25 mg/m(2)) intravenously on days 6-10 and 13-17. Toxicity was evaluated using National Cancer Institute Common Toxicity Criteria, version 3.0. Response was assessed by International Neuroblastoma Response Criteria or (for MP) by changes in (123)I-MIBG or PET scans.
  
  
  RESULTS
  Twenty-one patients were treated: 19 with neuroblastoma and 2 with MP. Fourteen patients received (131)I-MIBG and arsenic trioxide, both at maximal dosages; 2 patients received a 444 MBq/kg dose of (131)I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide; and 3 patients received a 666 MBq/kg dose of (131)I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide. One did not receive arsenic trioxide because of transient central line-induced cardiac arrhythmia, and another received only 6 of 10 planned doses of arsenic trioxide because of grade 3 diarrhea and vomiting with concurrent grade 3 hypokalemia and hyponatremia. Nineteen patients experienced myelosuppression higher than grade 2, most frequently thrombocytopenia (n = 18), though none required autologous stem cell rescue. Twelve of 13 evaluable patients experienced hyperamylasemia higher than grade 2 from transient sialoadenitis. By International Neuroblastoma Response Criteria, 12 neuroblastoma patients had no response and 7 had progressive disease, including 6 of 8 entering the study with progressive disease. Objective improvements in semiquantitative (131)I-MIBG scores were observed in 6 patients. No response was seen in MP. Seventeen of 19 neuroblastoma patients continued on further chemotherapy or immunotherapy. Mean 5-year overall survival (±SD) for neuroblastoma was 37% ± 11%. Mean absorbed dose of (131)I-MIBG to blood was 0.134 cGy/MBq, well below myeloablative levels in all patients.
  
  
  CONCLUSIONS
  (131)I-MIBG plus arsenic trioxide was well tolerated, with an adverse event profile similar to that of (131)I-MIBG therapy alone. The addition of arsenic trioxide to (131)I-MIBG did not significantly improve response rates when compared with historical data with (131)I-MIBG alone.
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York modaks@mskcc.org.
authors.forename: Shakeel
authors.initials: S
authors.lastname: Modak
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York; and.
authors.forename: Pat
authors.initials: P
authors.lastname: Zanzonico
authors.affiliation: Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Carrasquillo
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Kushner
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kim
authors.initials: K
authors.lastname: Kramer
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nai-Kong V
authors.initials: NK
authors.lastname: Cheung
authors.affiliation: Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.affiliation: Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Neeta
authors.initials: N
authors.lastname: Pandit-Taskar
mesh_terms: D019797:3-Iodobenzylguanidine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000532:radiotherapy*; D000328:Adult; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000532:radiotherapy*; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000532:radiotherapy*; D010087:Oxides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010235:Paraganglioma / Q000532:radiotherapy*; D010673:Pheochromocytoma / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D001152:Arsenicals; D010087:Oxides; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D019797:3-Iodobenzylguanidine; D000077237:Arsenic Trioxide
keywords: MIBG therapy; malignant pheochromocytoma/paraganglioma; neuroblastoma; radiosensitization