Rationale for a phase III study of erythropoietin as a neurocognitive protectant in patients with lung cancer receiving prophylactic cranial irradiation.
Recent meta-analysis of patients with small cell lung cancer has confirmed the effectiveness of prophylactic cranial irradiation in reducing the cumulative incidence of brain metastases and contributing to a significant increase in 3-year survival. Likewise, with increased median survivals being documented in patients with stage IIIA/B non-small cell lung cancer, there is evidence that the brain is emerging as a significant metastatic target site. Although prophylactic cranial irradiation is a reasonable option to explore, the potential for long-term neuropsychologic adverse effects is of concern in both diagnostic groups. Radiation-induced reactive oxygen intermediates and reactive nitrogen intermediates appear to play a major role in mediating this toxicity. Hypoxic stress results in a significant increase in erythropoietin (EPO) mRNA in mouse brain and, in two models, the administration of EPO improves performance function and prevents cognitive impairment. With the demonstration of EPO receptors in astrocytes, neurons, and brain capillary endothelial cells as well as the ability of EPO to cross the blood-brain barrier, a potential for EPO-mediated central nervous system radioprotection is postulated. The rationale and preliminary design for a phase III study of EPO as a neurocognitive protectant in patients with lung cancer receiving prophylactic cranial irradiation is presented.
Senzer
Neil
N
Department of Radiation Oncology, Sammons Cancer Center, US Oncology, Dallas, TX 75246, USA.
D000818:Animals; D001932:Brain Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000628:therapy; D018288:Carcinoma, Small Cell / Q000473:pathology / Q000628:therapy; D015687:Cell Hypoxia; D017326:Clinical Trials, Phase III as Topic; D003071:Cognition; D016371:Cranial Irradiation; D019610:Cytoprotection; D004353:Drug Evaluation, Preclinical; D004921:Erythropoietin / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology* / Q000628:therapy*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D015398:Signal Transduction
D018696:Neuroprotective Agents; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D004921:Erythropoietin