| Currently, the mortality of Lung cancer is the highest among all the malignant tumors. About 85% of lung cancer is non-small cell lung cancer (NSCLC). With the development of molecular target therapy for cancer, epidermal growth factor receptor tyrosine inhibitor (EGFR-TKI) drugs has brought new sight for the therapy of advanced NSCLC. This study was to evaluate the efficacy and safety of EGFR-TKI drug (Gefitinib) in advanced NSCLC patients by the clinical retrospective study of 326 advanced NSCLC patients received Gefitinib monotherapy. The related molecular biology research was also performed in this study, We intent to explore the clinical and molecular biology predictors related to the efficacy and survival of the Gefitinib in advanced NSCLC. We hope all of these results can better guiding the individual treatment of EGFR-TKI drugs in advanced NSCLC.Clinical research:326 advanced NSCLC (stageⅢB orⅣ)patients receiving or have received oral Gefitinib monotherapy (250 mg/d) were collected from March 2005 to February 2009. The enrolled patients were followed up until death or July 2009.The efficacy of Gefitinib, survival and drug toxicity were evaluated according to the international standards. The univariate and multivariate statistical analysis of efficacy and survival were performed by SPSS 13.0 software.Molecular biology research:99 cases from above patients were enrolled. Pathological tissue specimens and paired peripheral blood samples were collected. Exons 19 and 21 of the EGFR gene from both tissue samples and paired peripheral blood samples were amplified by Nested-PCR, EGFR gene mutation status were detected by direct sequencing. EGFR protein concentration in plasma was detected by ELISA (enzyme-linked immunosorbent assay) for the evaluation of the EGFR protein level. EGFR gene amplification status were detected by FISH (Fluorescence In Situ Hybridization). The univariate and multivariate statistical analysis of efficacy and survival were performed by SPSS 13.0 software.Gefitinib was well tolerant in patients with advanced NSCLC. The drug toxicity of Gefitinib were rash, diarrhea which were light, Gefitinib was safe.The response rate and clinical benefit rate of Gefitinib were 42.9% and 81.3% respectively. The median survival time (MS) and median progress free survival (PFS) of all patients were 19 and 8 months respectively. One-year,2-year and 3-year survival rate were 61%,42% and 28% respectively. Logisitic regression analysis showed that patients less than 65-year-old, adenocarcinoma, non-smokers were more sensitive to Gefitinib. Cox proportional hazards regression survival analysis showed that patients with adenocarcinoma, KPS≥80 points, received surgical treatment, effective to Gefitinib treatment had survival benefit. The clinical benefit rate of Gefitinib as first-line monotherapy was significant higher than second-line or more (93% vs 78.8%,P=0.013), stratified analysis showed that female patients, adenocarcinoma, age more than 65, non-smoker, no brain metastasis and family history of tumour were sensitive to the first-line treatment. The response rate and clinical benefit rate first-line treatment in elderly patients with advanced NSCLC were significant higher than second-line or more treatment. The response rate of patients with brain metastasis was 50%.The molecular biology research showed,35(35.4%) were positive for EGFR gene mutation of the 99 samples (95%CI:25.9%-44.7%), the EGFR protein concentration is 80.43±40.4μg/L.8(22.9%) were positive for EGFR gene amplification of the 35 samples (95%CI:14.9%-36.7%). The response rate of patients with EGFR gene mutation is significant higher than those without mutation (65.7% vs 43.8%,P=0.037). The clinical benefit rate of patients with EGFR gene mutation was significant higher than those without mutation (94.3% vs 71.9%, P=0.008). The median PFS of patients with mutation was longer than those without mutation (23 months vs 10 months, P=0.014). The detection rate of mutation between two specimens(pathological tissue samples vs peripheral blood samples) was significant different (35.4% vs 12.1%, P=0.000). The EGFR protein concentration of patients with mutation was higher than those without mutation. The EGFR protein concentration of patients received clinical benefit was higher than those without. The clinical benefit rate of patients with EGFR protein high expression (concentration>55.42μg/L) was significant higher than those with low expression (90% vs 64.1%, P=0.004), and the median PFS was prolonged(21 months vs 8 months, P=0.016). The clinical benefit rate of patients with EGFR gene amplification was higher than those without amplification (100% vs 63%, P=0.012), and the median PFS was significant longer(18.6 months vs 5.4 months, P=0.008). The Correlations among EGFR gene mutation status, EGFR protein level and EGFR gene amplification status were positive. Pathological type and EGFR protein level were the independent predictors of EGFR gene mutation status. The response rate of patients both with EGFR gene mutation and protein high expression is higher than patients both negative(74.2% vs 48.6% P=0.033),the median PFS was prolonged (23 months vs 9 months, P=0.017).The response rate of EGFR protein high expression patients with mutation is higher than EGFR protein high expression patients without mutation (74.2% vs 37.9%, P=0.005), the median PFS was prolonged (23 months vs 9 months, P=0.017). 1. EGFR-TKI drug (Gefitinib) was effective,safe and well tolerate in monotherapy of advanced NSCLC.2. Pathological type, age, smoking, EGFR gene mutation status and EGFR protein level are independent predictors of the efficacy of Gefitinib in advanced NSCLC.3. Pathologic type, efficacy of Gefitinib, KPS score, surgical treatment status are independent predictors of survival in advanced NSCLC.4. The first-line monotherapy with Gefitinib in advanced NSCLC is safe and effective. The previously untreated elderly patients with advanced NSCLC are recommended for the first-line treatment.5. Pathological type and EGFR protein level are independent predictors of EGFR gene mutation status.6. Peripheral blood is not yet possible to replace the pathological tissue as specimen for clinical detection of EGFR gene mutation.7. The correlation among EGFR gene mutation status, EGFR protein level, EGFR gene amplification status is positive.8. The quantitative test of EGFR protein level with ELISA is a new methodological attempt.This method may has the clinical feasibility.9. The efficacy and survival of Gefitinib in advanced NSCLC patients both with EGFR gene mutation and EGFR protein high expression are more better. |
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