Non small cell lung cancer (NSCLC) is the leading cause of cancer related deaths in the United States. Traditional radiotherapy delivered with standard fractionation to standard doses is ineffective at sterilizing the primary tumor and results in local control rates of 20-40 percent. The overall outcome for patients with inoperable NSCLC is a five year survival rate of less than 10 percent. Advances using combined modality therapy and altered radiation fractionation schedules have resulted in modest improvements in survival, although local and distant failure rates remain high. There is increasing evidence that pro-inflammatory cytokines (chemokines) can be induced in response to ionizing radiation. Macrophage inflammatory protein 1-alpha (MIP-1alpha) appears to be an important cytokine mediator of pulmonary inflammation and injury. Growing preclinical and clinical data suggest a potential relationship between serum MIP-1alpha levels and the risk of lung injury following thoracic radiation. A pilot study to determine the clinical significance of MIP-1alpha levels in patients receiving thoracic radiation will be evaluated in this study. A phase I/II trial has been initiated to determine the toxicity of induction/concurrent chemotherapy and 3-dimensionally planned - thoracic radiation therapy for patients with locally advanced NSCLC. In conjunction with this clinical trial, we will collect and analyze pre-treatment, weekly (during treatment) and post-treatment MIP-1alpha levels.
Our specific aims are to: Ia) define the temporal changes in MIP-1alpha levels over the course of therapy and in follow-up to ascertain if these changes are predictive for the clinical development of radiation pneumonitis, Ib) define these same temporal changes in MIP-l-alpha and ascertain if they are predictive for the clinical development of pulmonary fibrosis, and II) discern if the temporal changes in MIP-1alpha can be correlated with the lung volume irradiated, changes in pulmonary function after therapy or overall clinical outcome. By determining that changes in MIP-1alpha levels correlate with the acute and chronic lung injuries associated with thoracic irradiation, we may more rationally develop and incorporate their use in future clinical trials employing thoracic radiation therapy. Even further, understanding the temporal expression of MIP-1alpha during thoracic radiation may allow the future utilization of anticytokine reagents, e.g. antibodies, receptor and synthesis blockers during treatment.
|Blackstock, A William; Ho, Coty; Butler, Jerome et al. (2006) Phase Ia/Ib chemo-radiation trial of gemcitabine and dose-escalated thoracic radiation in patients with stage III A/B non-small cell lung cancer. J Thorac Oncol 1:434-40|