Arsenic Trioxide as a Radiation Sensitizer for 131I-Metaiodobenzylguanidine Therapy: Results of a Phase II Study

Arsenic trioxide has in vitro and in vivo radiosensitizing properties. We hypothesized that arsenic trioxide would enhance the efficacy of the targeted radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-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 131I-MIBG (444 or 666 MBq/kg) intravenously on day 1 plus arsenic trioxide (0.15 or 0.25 mg/m2) 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 123I-MIBG or PET scans. Results: Twenty-one patients were treated: 19 with neuroblastoma and 2 with MP. Fourteen patients received 131I-MIBG and arsenic trioxide, both at maximal dosages; 2 patients received a 444 MBq/kg dose of 131I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide; and 3 patients received a 666 MBq/kg dose of 131I-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 131I-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 131I-MIBG to blood was 0.134 cGy/MBq, well below myeloablative levels in all patients. Conclusion:131I-MIBG plus arsenic trioxide was well tolerated, with an adverse event profile similar to that of 131I-MIBG therapy alone. The addition of arsenic trioxide to 131I-MIBG did not significantly improve response rates when compared with historical data with 131I-MIBG alone.