| BackgroundLung cancer is one of the most frequent cancers in the world, incidence and mortality of which are first in malignant tumors. About1.38million patients died of lung cancer each year in the world. There were1,437,180new cases and565,650deaths with lung cancer in the United States in2008. In2010, American deaths analysis reported that lung caner account for26%cancer death, which had become the leading cause of it. Lung cancer was also the most common cancer in China. There are35people per one hundred thousand people suffering from lung cance. According to the data of ministry of health in2008, Lung cancer has become the primary reason of cancer death, the mortality rate of which rised465%over the past30years. The therapy of Non-small cell lung cancer (NSCLC) which accounted for80%～85%of lung cancer, has become the focus.The TNM system, currently used for the classification of NSCLC, was adapted by Union for International Cancer Control(UICC) and American Joint Committee for Cancer Staging(AJCC). This staging system since went through further revisions and, more recently, in2009. Lung cancer is divided into four stage. Stage0(TisNOMO), Tis:Focus of in situ cancer; NO No regional lymph nodes metastasis; MO No distant metastasis. Stage IA (T1a、bNOMO), Tla:Tumor≤2cm, surrounded by lung or visceral pleura, not more proximal than the lobar bronchus; T1b:Tumor>2but<3cm. Stage IB (T2aN0M0), T2a:Tumor>3but<5cm or tumor with any of the following:Invades visceral pleura, involves main bronchus≥2cm distal to the carina, atelectasis/obstructive pneumonia extending to hilum but not involving the entire lung. Stage ⅡA (T2bN0M0; T1a,bNlM0; T2aN1M0), T2b:Tumor>5but<7; N1: Metastasis in ipsilateral peribronchial and/or perihilar lymph nodes and intrapulmonary nodes, including involvement by direct extension. Stage IIB (T2bN1M0; T3N0M0), T3:Tumor>7cm; or directly invading chest wall, diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium; or tumor in the main bronchus<2cm distal to the carina;or atelectasis/obstructive pneumonitis of entire lung; or separate tumor nodules in the same lobe. Stage ⅢA (T3N1,2M0; T4N0,1M0;T1a、b, T2a,bN2M0), N2:Metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes; T4:Tumor of any size with invasion of heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; or separate tumor nodules in a different ipsilateral lobe. Stage ⅢB (T4N2M0,T1-4N3M0), N3: Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes. Stage Ⅳ(TanyNanyM1a,1b), M1a Separate tumor nodules in a contralateral lobe or tumor with pleural nodules or malignant pleural dissemination; Mlb Distant metastasis, such as brain, bone, the lobes of the lungs, liver, suprarenal gland.Surgical resection is the best treatment for completely removing NSCLC. Patients with stage ⅠA-ⅡB accounts for about20%of all NSCLC patients. This part of patients can accept radical surgery, and the5-year survival rate is50%-80%. Stage ⅢA and ⅢB called local advanced NSCLC(LA-NSCLC) occupies about40%, in which patients is stage ⅢA N2are likely to undergoing radical surgery, but the5-year survival rate is only10%to30%. Resectable patients with stage ⅢA(N2) include Ⅲ A1(The lymph node found N2metastasis by pathological examination by the system cleaning up after the operation), ⅢA2(Suspicious metastasis of single station mediastinal lymph nodes was fround intraoperative, and finally confirmed by pathological examination) and partial IIIA3(The metastasis of single station or multi station mediastinal lymph nodes were identified preoperative by esophageal endoscopic ultrasound needle aspiration or endobronchial ultrasound needle asp iration. ⅢA4(The pathology diagnosed Large N2or multiple lymph node metastasis). Patients with stage ⅢB and Ⅳ can not accept radical surgery because of local invasion or distant metastasis.Based on the basic and clinical research in decade years, it is comfirmed the postoperative adjuvant chemotherapy could make survival benefit in the high-risk NSCLC patients with stage IB-IIIA, and improve the5-year survival rate, but it is still very limited. High-risk stage IB refers to cut edge negative, and have one of the following, poorly differentiated (including neuroendocrine carcinoma), vascular invaded, wedge resection, tumor diameter>4cm, invasion of visceral pleura and Nx (lymph node status not able to be assessed). Cut edge<lcm is one of risk factors in Chinese guidlines. How to further improve the radical postoperative surial for patients with NSCLC is the direction of all researchers of lung cancer, including cardiothoracic surgeon. Along with the development of molecular biology and molecular targeted drugs in clinical application, especially the tyrosine kinase inhibitors(TKIs), surial rate for patients with advanced NSCLC have obviously increased. The targeted treatment of NSCLC patients with sensitive mutation of the epidermal growth factor receptor (EGFR) is not limited in Second-line but extended to first-line. Then, we want to know whether this targeted treatment can expand to the postoperative adjuvant therapy and to benefit the EGFR sensitive mutation patient after radical surgery. Some researcher have made a preliminary study about that.First, the Canadian NCIC-BR19research showed us a disappointing result, which is a Gefitinib and placebo-controlled clinical trials on postoperative NSCLC patients with stage IB-Ⅲ. The results is that the targeted drugs group has not obtained statistical significance in Disease free survival(DFS) and overall survival(OS). However, a retrospective study from the MSKCC indicated that compared to platinum-based chemotherapy, the adjuvant treatment with tyrosine kinase inhibitors(TKI)(gefitinib or erlotinib) might prolong2years DFS (89%vs72%, P=0.06) in patients with sensitive EGFR mutation. These work included167cases, in which patients with stage Ib occupied70%, stage Ⅱ15%, and stage Ⅲ15%. SELECT research reported on american society of clinical oncology (ASCO) meeting in2012discussed maintenance treatment of erlotinib for EGFR mutation lung cancer patients after accepting the adjuvant chemotherapy. NSCLC patients with Stage Ⅰ A to Ⅲ A were analyzed. All the patients received standard chemotherapy or both radiotherapy and chemotherapy after surgery. They were treated with150mg daily erlotinib orally in2years.100cases were planted in this study, and36cases were got. Preliminary results found that the rate of2years DFS reached94%in erlotinib group. Only one patient during the adjuvant therapy with erlotinib, and it appeared10patients had progressive disease after withdrawing erlotinib for6months. Five patients were sensitive to secondary treatment of erlotinib. We should pay attention to that the patients with stage I did not get better survival benifit than stage Ⅲ.. Researchers believed that the adjuvant therapy of erlotinib could inhibt growth of tiny metastatic lesions.So, Can TKIs drugs be used for adjuvant therapy in NSCLC patients after radical operation? Our research is designed to answer this question. We detected the EGFR mutation status of NSCLC patients after radical operation in order to know the biological characteristics of them, and analysed the role of molecular targeted drugs in postoperative adjuvant therapy. The purpose of our study is try to find a suitable treatment which can help to further improve the therapeutic efficacy of postoperative NSCLC patients.Objective1. Detected the EGFR gene mutation rates of all NSCLC patients after radical surgery with stage ⅠA to ⅢA, discussed the relationship of EGFR gene mutation and the clinical and pathological characteristics of patients, and finded more biologic commonalities and differences early or intermediate stage and advanced NSCLC by comparing the sensitive EGFR gene mutation with the patients in advanced stage.2. To observe and compare the disease free survival(DFS) in6,12,18months after treatment and the toxic effests in high-risk postoperative NSCLC patients with stage Ib to ⅢA. All patients was divided to three groups. Gr.up1, patients with wild-type EGFR gene were accepted chemotherapy; Group2, patients with EGFR gene mutation were accepted chemotherapy; Group3, patients with EGFR gene mutation were accepted chemotherapy and TKI targeted maintenance treatment.Patients and Methods1. Inclusion criteria and EGFR gene detection. Patient Selection We collected64cases of postoperative NSCLC patients with stage Ⅰb to ⅢA from February2011until December2012in the department of thoracic cardiovascular surgery in Nanfang hospital. All patients underwent the thoracoscope unilateral lobectomy plus mediastinal lymph nodes system cleaning. The classification and differentiation were histologically or cytologically confirmed and the pathological staging was based on2009TNM staging symterm.EGFR Mutation Analysis Tumor fresch specimens were collected from previous diagnostic or surgical procedures. No specific requirements were prospectively mandated for the type of tumor specimen. The primary correlative science analysis was determination of the presence of EGFR mutations. For patients with sufficient tissue for direct DNA sequencing, tumor cells were isolated by microdissection. EGFR gene mutation was detected by scorpions amplification refractory mutation system(ARMS method). All detected mutations were confirmed by repeat analysis. The items include the deletion mutation in exon19, the L858R mutation in exon21resulting from the substitution of leucine by arginine in the858point,the L861Q mutation in exon21resulting from the substitution of serine by isoleucine in the861point, T790M in exon20resulting from the substitution of threonine by methionine in the790point and the G719X mutation in exon18including G719A,G719S and G719C mutations respectively resulting from the substitution of glycine by alanine, serine or cysteamine in the719point.2. Clinical grouping. Study Procedures and Treatment. According to the EGFR test results and inclusion criteria, in64patients,44cases of IB-IIIA NSCLC patients after radical surgery were included,which contains20cases with wild-type EGFR gene and24cases with EGFR gene sensitive mutant. According to the EGFR gene test results, the actual situation of the patients and clinical treatment, the patients were divided into three groups:Group A:the patients with wild-type EGFR gene (n=20) were given four cycles of platinum-containing regimen of two drugs, once every three weeks; Group B:the patients with EGFR gene mutations (13cases of mutational patients) accepted four cycles of platinum-drug regimen every three weeks; Group C:the patients with EGFR gene mutations (11cases of mutational patients) accepted four cycles of platinum-containing regimen of two drugs, once every three weeks, then the patients were given oral TKI drug for maintenance therapy after two weeks of the end of Chemotherapy, Tarceva150mg/d, or Iressa250mg/d, or Conmana 125mg per time、3times/d, oral treatment. The treatment were terminated until4-8months of continuous medication or the occurrence of intolerable toxicity.3. Regular inspection items. For observing the changes in the patient’s condition, All patients of three groups accpeted firstly chest radiograph or enhanced chest CT scanning, ECG and three routine examination laboratory before each chemotherapy, body check involving systemic PET-CT or the combine of brain magnetic resonance, enhanced chest CT, systemic bone scintigraphy and abdominal ultrasound before the fourth chemotherapy. After four cycles of chemotherapy, chest radiograph or enhanced chest CT scans was observed every three months regularly checked,and the whole body check once every six months.4. Follow-up. All clinicopathological data were collected and every patient was followed up by telephone or communication. The follow-up is scheduled for18months. If the overall survival time is less than18months, the follow-up was ended until the patients died.Results1. EGFR gene mutation detection rate. The EGFR gene mutation rate was42.2%in the Ⅰ A-ⅢA NSCLC tissues of64cases of radical surgery.6patients had EGFR gene mutations in26cases of squamous cell carcinoma patients, the mutation rate was23.1%;21cases have EGFR gene mutation in adenocarcinoma patients with a total of38cases, the mutation rate was55.3%. Significant difference between the two groups was statistically significant (p<0.05). In13cases of female patients.9cases had EGFR gene mutations, so the mutation rate was69.2%.18cases of EGFR gene mutations in male patients with51cases,,the mutation rate was35.3%. Significant difference between the two groups was statistically significant (p<0.05).In tumor pathology,12patients had EGFR gene mutations in17cases of well-differentiated, the mutation rate was70.6%.15patients with EGFR mutations was in47cases of moderately-poorly differentiated patients, the mutation rate was31.9%. The mutation difference between the two groups was statistically significant (p<0.05). In35patients with tumor maximum diameter>3cm,10patients presented EGFR gene mutations, the mutation rate accounted for28.6%; In29cases with tumor maximum size<3cm,17cases showed EGFR gene mutations, the mutation rate was58.6%. There is significant difference between the two groups was statistically significant (p<0.05). Smoking patients with a total of33cases, EGFR gene mutations in11cases, the mutation rate was33.3%; a total of31cases of non-smoking lung cancer patients, EGFR gene mutations in16cases, the mutation rate was51.6%, In44cases without lymph nodes metastasis,16cases had EGFR gene mutations, the mutation rate was36.4%; in20cases with lymph node metastasis, EGFR gene mutations were appeared in11cases, the mutation rate was55.0%, no significant difference existed between the two groups was statistically significant (p>0.05). In42cases of less than or equal to60years old,21patients had EGFR gene mutations, the mutation rate was50%; in22patients older than60years old, EGFR gene mutations existed in six cases, the mutation rate was27.3%. No significant difference was showed between the two groups was statistically significant (p>0.05). In47cases of pTNM stage Ⅰ-Ⅱ patients, the mutations appered in17cases and its mutation rate was36.2%, in which five cases chromosome had19mutations, chromosome21mutations was presented in10cases, two cases mutated in both chromosome19and chromosome21. In17cases of stage Ⅲ patients,10cases had mutations and its mutation rate was58.8%, in which contained four chromosome9mutations rate and6cases chromosome21mutations. No significant difference appeared between the two groups was statistically significant (p>0.05).In this study,64IA-ⅢA NSCLC patients were enrolled after radical surgery, EGFR gene mutation rate was42.2%. Patients with EGFR mutations are mainly common in populations of female, adenocarcinoma, well-differentiated and tumor≤3cm, and pairwise comparisons of each group were significantly different. The comparisons of mutation rate between smoking and non-smoking, with and without lymph node metastasis, age>60years and≤60years, or Ⅰ-Ⅱ and Ⅲ Phase showed no significant difference.2. Pairwise comparisons between clinical features of patients in group A, B and C. The chemotherapy group with EGFR wild gene is Group A, the chemotherapy group with EGFR gene mutations is Group B and the chemotherapy and targeted therapy group with EGFR gene mutation is Group C. There is a statistically significant difference (p=0.023) in pathological type between Group A and C. Adenocarcinoma is more than squamous cell carcinoma in group C, but group A had more squamous cell carcinoma than adenocarcinoma. The pathological type between group A and B was no significant difference (p=0.08), and that between group B and C no significant difference (p=0.649).3. The side effects of chemotherapy in patients of group A, B and C. All three groups concentrated on of bone marrow suppression and gastrointestinal reactions, which were mild and mainly at0degree and Ⅰ, a small number at Ⅱ degree, no Ⅲ degree, nor occurrence of intolerable toxicity. Group C received maintenance therapy constituted by postoperative two drugs chemotherapy with platinum and oral TKI drug. During taking TKI drug, the patient had good tolerance, only three patients present Ⅰ°iarrhea,6Ⅰ°ash, only1case (oral Tarceva) Ⅲ°rash, which all had good control after treatment.4. The disease-free survival period (DFS) of group A, B and C. DFS of group A (wild-chemotherapy group) in6months was75%,55%in12months,45%18in months; DFS of group B (mutation-chemotherapy group) in6months was100%,84.6%in12months,84.6%in18months; DFS of group C (mutation-chemotherapy-targeting group) in6months was100%,100%in12months,90.9%in18months. DFS in12months and18months of the three groups have more significant difference (p<0.0125). DFS in12months between group A and C showed a significant difference (p=0.012), DFS in12months between group A and B (p=0.057),or group B and C (p=0.183) had no significant difference. DFS in18months between group A and C showed a significant difference (p=0.012), DFS in18months between group A and B (p=0.020),or Group B and C (p=0.625) had no significant difference.Conclusion1The detection of EGFR mutations in radical postoperative NSCLC patients gene can help us understand its biological characteristics and provide a preliminary basis for the formulation of these patients’ follow-up treatment programs.2. EGFR gene mutation in radical postoperative NSCLC patients mainly exists in the population of female, adenocarcinoma, well-differentiation and tumor<3cm.3. EGFR gene status of radical postoperative NSCLC patients may affect the efficacy of postoperative adjuvant chemotherapy.Compared with wild-type patients, DFS extended in the the mutant patients.4.The radical postoperative NSCLC patients with EGFR sensitive mutations accepted postoperative chemotherapy and TKI adjuvant therapy, DFS in12and18months were significantly superior to the efficacy of simple chemotherapy to EGFR wild-type patients.5. In the radical postoperative NSCLC patients with EGFR sensitive mutations, compared with the group of simple chemotherapy, the DFS of12and18months extended in the group of postoperative chemotherapy and TKI adjuvant therapy extended. |
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