3DRT/IMRT With Concurrent Gefitinib In Non-small Cell Lung Cancer Patients After Failure Of Platinum-based Chemotherapy:Dose Escalation Study And Translational Reasearch

Purpose/Objective (s):Preclinical data suggests that gefitinib (An epidermal growth factor receptor tyrosine kinase inhibitor) in combination with radiation resulted in additive to synergistic anti-proliferative effect against NSCLC. This study was designed to evaluate the safety and activity of radiotherapy (RT) with concurrent daily gefitinib250mg in patients with ⅢB/Ⅳ of NSCLC after failure of platinum-based chemotherapy. The potential impact of EGFR-mutation status on the safety and clinical outcomes for combined Gefitinib and RT was studied.Materials/Methods:Patients with stage ⅢB or stage IV, failure of platinum-based chemotherapy regimen NSCLC were eligible. Four Cohorts of eight patients each were planned to be treated with escalating doses from54to60Gy of conformal or intensity-modulated radiotherapy (2Gy/Fx) in combination with gefitinib250mg daily during RT and60days after the completion of RT. Toxicities are evaluated according to Common Terminology Criteria for Adverse Events version3.0(CTCAE v3.0). Tumor specimens and plasma for EGFR mutation detection using Amplification Refractory Mutation System (ARMS) assay.Results:4cohorts, a total of40were enrolled with medium age of55yr (32-79):28male and12female;18stage ⅢB and22stage IV;35adenocarcinomas (86%),4squamous carcinomas and1poor differentiated carcinoma;20smokers and20nonsmokers;One patient developed acute ILD in both lung one week after the completion of radiation therapy, and died of respiratory failure30days after. Except of this patient, other adverse events were generally mild to moderate.29(73%) experienced grade1to2pulmonary infiltrates/pneumonitis.4paients experienced1-2rash (60%), and16developed grade1-3esophagitis (40%).Total response rate was28%,disease contral rate was82%.From2007to2009, median overall survival time was14.2months (95%CI:11.7-16.7months). Median progression-free survival time was6.2months (95%CI:3.4-8.9months).1-year survival rate was60%.40tumor tissue were assessed by experenced pathologist,26of which was qualified.EGFR mutation was found in4tumor samples (15%),2were19del and2were L858R. In80plasma samples,4mutation were detected,1was T790M,3were19del. There was no excessive toxicity in EGFR mutation-positive patients treated with concurrent RT and gefitinib. Patients with activating mutations as a group had a higher RR and longer survival time than patients with wild type EGFR.Patients with better PS had longer survival time, other clincal factors including age,gender,smoking history,staging were not related with EGFR mutation detection rate significantly.Conclusions:In our study,thoracic radiotherapy up to60Gy concurrent with gefitinib250mg daily was feasible and clinically active in this group of pretreated advanced NSCLC patients. EGFR mutation status were associated with mild toxicities and better response. Using ARMS assay can find certain proportion EGFR mutation in tumor tissue and plasma.The value of EGFR mutation assessment with plasma samples needs validation.