The Influence of Epidermal Growth Factor Receptor Gene Mutations on the Efficacy of Postoperative Chemotherapy in Radical Non Small Cell Lung Cancer
|School||Southern Medical University,|
|Course||Thoracic and Cardiovascular Surgery|
|Keywords||Non Small Cell Lung Cancer radical surgery Chemotherapy EGFR gene mutation rate|
[Background]:The number of non-small cell lung cancer (NSCLC) accounts for about85%of all lung cancer patients, Adenocarcinoma and squamous cell carcinoma each takes30%-50%of the total,which treatment program is determined by TNM staging. Lung cancer is divided into0-Ⅳ according to the TNM staging. Stage Ⅰ,Ⅱ, and some parts of Ⅲa are acceptable to radical surgery,while some parts of Ⅲa,Ⅲb and most of Ⅳ are refused by radical resection and need receiving timely chemotherapy,on the basis of the primary lung cancer treatment criterion released by the Ministry of Health of china.In2003, The International Adjuvant Lung Cancer Trial(IALT) study is the first proof of effects of postoperative chemotherapy for prolonging survival.there were1867stage Ⅰ-Ⅲ NSCLC cases in the study,patients in postoperative chemotherapy group underwent3-4cycles of vincristine plus vp-16and selective radiotherapy,the other group was control group,the median follow-up was56months.The results showed that5year survival was increased4%by postoperative chemotherapy (44.5%vs40.4%, HR=0.86,95%CI:0.76-0.98, P<0.03) and the disease free survival (DFS) was also increased by postoperative chemotherapy (39.4%vs34.3%, HR=0.83,95%CI:0.74-0.94,P<0.003.In ASCO2008it was reported that patients in this research were followed-up to7.5years, postoperative chemotherapy had no survival benefit (HR=0.91,95%CI:0.81-1.02,P=0.10), while the DFS benefit continued (HR=0.88,95%CI:0.78-0.98, P=0.02).Several studys confirmed the role of postoperative adjuvant chemotherapy in prolonging survival of NSCLC after IALT,344patients in stage IB were included in research CALGB9633in ASCO2004, The chemotherapy group received paclitaxel plus carboplatin for four cycles and were followed-up for5years,4year survival of these patients increased12%(71%vs59%, p<0.05), while5year survival had no difference between chemotherapy group and control group (60%vs57%, p=0.32). Stratified analysis showed that postoperative chemotherapy only worked on stage IB patients with tumor≥4cm.JBR.10study in Canada showed that5year survival of stage IB or II NSCLC patients increased11%by4cycles of navelbine plus cisplatin postoperative chemotherapy (67%vs156%, P=0104), Stratified analysis is similar with CALGB9633(p=0.022).The Anita study in ASCO2005brought in840stage IB-IIIA NSCLC patients and these patients were randomly divided into navelbine plus cisplatin group and control group, the5year survival and the7year survival of postoperative chemotherapy group was8%(51%vs43%) and8.4%(45.2%vs36.8%) higher than the control group. The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis was a summary of the above clinical studies, the results showed that adjuvant chemotherapy had significantly benefit on stage II-III tumors, and different chemotherapy program had no difference in survival (P=0.26).UFT research in Japan showed that oral UFT group (especially T2N0patients) had higher survival (P=0.047).TREAT study compared different postoperative chemotherapy programs between pemetrexed plus cisplatin and vinorelbine plus cisplatin and found that patients in stage IB-IIIA had well tolerability of adjuvant chemotherapy and had higher survival and DFS.Domestic and foreign research showed that platinum-containing chemotherapy effectively extend the DFS of stage IB NSCLC patients and the NP program increased the5year survival of stage Ⅱ-Ⅲ patients13%-16%and delayed the brain metastases.Therefore, NSCLC patients after surgery in addition to IA and some of IB need chemotherapy,which improves survival of patients in stage of IB with high risk factor(Low differentiated carcinoma/neuroendocrine carcinoma、vascular invasion、 undergoing wedge resection、tumors lager than4cm、visceral pleura invasion)-IIIA.Biological therapy or chemoradiation are also selectable to stage IIIB-IV patients, depending on detection of EGFR mutation.The recognization of the role of Epidermal Growth Factor Receptor (EGFR) in lung cancer shows the most important advances in lung cancer biological targeted therapy in recent years.According to Lynch and Paze’s study,EGFR gene mutation leads to improvement of the activity of tyrosine kinase inhibitor (TKI), and is related to the sensitivity to the molecular targeting drug Gefitinib.In summary, NSCLC therapy can be simply expressed as:→Operable (IA-IIIA)→postoperative follow-up (IA、parts of IB) TNM→postoperative chemoradiation (IB with high risk factor-ⅢA)→Inoperable (ⅢB-Ⅳ)→chemoradiation (non-mutant wild-type)→EGFR-TKI Maintenance after chemotherapy (EGFR-mutant)Studies of domestic and international scholars show that in non-small cell lung cancer, adenocarcinoma has a high mutation rate, nearly50%,of which bronchioloalveolar carcinoma has a higher mutation rate;there is also a higher mutation rate in Asian people、women and non smokers; while the mutation rate of squamous cell carcinoma is very low, about5%to10%o Are there any differences between the efficacy of chemotherapy of IB-IIIA NSCLC patients with EGFR gene mutations and patients without mutations?[Objective]:1、Observing the overall EGFR gene mutation rate of IA-IIIA patients by ARMS, the influence of pathological type and gender and smoking to EGFR gene mutation rate;2、Observing the progression-free survival and overall survival between IB-IIIA NSCLC patients with EGFR gene mutations and patients without mutations after postoperative chemotherapy.[Method]:1、From March2011-1-1to March2011-6-1, we collected40locally paraffin sections of IA-IIIA postoperative NSCLC patients, and count the EGFR gene mutation rate by ARMS,the kit was AmoyDx ARMS.2、IB with high risk factor to IIIA patients were treated with four cycles chemotherapy which contained Platinum, once every three-four week. Chemotherapy dose was determined by body surface area。3、After chemotherapy all patients were given chest X-rays or chest enhanced CT every two months,also we gave PET-CT or head-enhanced MR+breast enhancement CT+whole body bone scan+abdominal B ultrasound to observe the disease progression.4、Divide patients undergoing chemotherapy into EGFR-mutant group and Wild-type group, followed up the two groups in eighteen months.The follow-up was mainly for disease free survival and chemotherapy toxicity.When the overall survival time of patients was less than eighteen months,we followed up until they died.[Results]:There were19patients with EGFR gene mutations in all40patients,the rate of EGFR gene mutation was47.5%;4were squamous cell carcinoma (total:18,rate:22.2%),15were adenocarcinoma (total:22,rate:68.2%);mutation rate comparison p<0.05;7mutations on Chromosome19(36.8%),10mutations on Chromosome21(52.6%),2mutations on both Chromosome19and21(10.5%);7were smokers (total:18,rate:38.9%),12were smokers (total:22,rate:54.5%), mutation rate comparison p>0.05;8were females(total:18,rate:72.7%),11were males(total:29,rate:37.9%), mutation rate comparison p<0.05。No one lost to followed up in all patients,the rate of following up was100%.11patients (3were squamous cell carcinoma and8were adenocarcinoma) with EGFR gene mutations and17without mutations in all28on the stage IB with high risk factor to IV, all the28patients received four cycles chemotherapy which contained Platinum。 Gastrointestinal side effects on11patients with EGFR mutation:7in0(63.6%),3in I (27.3%),1in II (9.1%),0in Ⅲ(0%),0in IV(0%); Gastrointestinal side effects on17patients without EGFR mutation:10in O (58.8%),5in Ⅰ(29.4%),2inⅡ (11.8%),0in Ⅲ(0%),0in IV(0%); no significant difference in the comparison。 Bone marrow suppression side effects on11patients with EGFR mutation:9in0(82.0%),2in I (18.0%),0in Ⅱ(9.1%),0in Ⅲ(0%),0in Ⅳ(0%); bone marrow suppression side effects on17patients without EGFR mutation:11in0(65.0%),6in I (35.0%),0in11(9.1%),0in Ⅲ(0%),0in Ⅳ(0%); no significant difference in the comparison。 Other side effects including Liver and kidney dysfunction、Neurotoxicity、Allergy、 Cardiovascular responses were rare or not found, the chemotherapy treatment were all finished successfully.The disease free survival of mutation group:6months100%、12months100%、18months90.9%; The disease free survival of wild type group:6months70.6%、12months47.1%、18months35.3%。Both12months DFS and18months DFS comparison have significant difference.[Conclusion]:The rate of EGFR gene mutation is related to the pathological type, rate of squamous cell carcinoma is lower than rate of adenocarcinoma;rate of mutation is also related to gender (women higher than men) but there is no significant difference between non-smokers and smokers.The12months DFS and18months DFS of postoperative chemotherapy of radical postoperative lung carcinoma is higher in patients with EGFR gene mutation group, while there is no difference of side effects between patients with and without mutation.