摘要
背景：肺癌是全世界高发的恶性肿瘤之一,其发病率及死亡率均居恶性肿瘤的首位。全世界每年约有138万患者死于肺癌。2008年美国肺癌新发病例1437180人,死亡565650人。2010年美国死亡分析报告显示,肺癌已成为头号癌症杀手,约26%的肿瘤患者死于肺癌。在我国,肺癌也是发病率最高的恶性肿瘤,每十万人就有35人患肺癌。卫生部2008年公布的数据显示,过去30年间,肺癌死亡率上升了465%,成为恶性肿瘤死亡的首要原因。非小细胞肺癌(non small cell lung cancer, NSCLC)占肺癌的80%-85%,其治疗已成为关注的焦点。
按国际抗癌联盟(Union for International Cancer Control,UICC)和美国肿瘤联合会(American Joint Committee on Cancer Staging,AJCC)联合制定的2009版(最新版)TNM分期法。将肺癌分为0-Ⅳ期,0期(TisNOMO),Tis指原位癌、NO指无淋巴结转移、M0指无远处转移。IA期(Tla, bNOMO),T1a指原发瘤最大径≤2cm,任何大小的非常见的表浅肿瘤,只要局限于气管壁,即使累及主支气管,也定义为Tla；Tlb指原发瘤最大径>2cm,≤3cm。IB期(T2aN0M0),T2a是指原发瘤最大直径>3cm,≤5cm,或符合以下情况之一者：累及主支气管,但肿瘤距离隆嵴≥2cm；脏层胸膜受累；发生段或叶不张或阻塞性肺炎,但不累及全肺。ⅡA期(T2bN0M0; Tla、bN1MO; T2aN1M0),T2b是指原发瘤最大直径>5cm,≤7cm,N1是指同侧肺门淋巴结(第10组)转移,同侧肺叶间淋巴结(第11组)转移,原发瘤所在的肺叶内淋巴结(第12、13、14组)转移,包括原发肿瘤的直接侵犯。ⅡB期(T2bN1M0; T3N0M0),T3是指原发瘤最大直径>7cm或任何大小肿瘤已直接侵犯了下述结构之一者：胸壁(包括上沟瘤)、纵隔胸膜、膈神经、膈肌、心包；肿瘤位于距隆嵴2cm以内的主支气管但尚未累及隆嵴；全肺阻塞性肺炎或不张；原发瘤同一肺叶出现单个或多个卫星结节。ⅢA期(T3N1、2M0; T4N0、1M0; T1a、b,T2a、bN2M0),N2是指同侧纵隔淋巴结(第2、3、4、5、6、7、8、9组)转移,T4是指任何大小的肿瘤已直接侵及以下之一者：心脏、大血管、气管、食管、纵隔、喉返神经、隆嵴、椎体；原发肿瘤同侧不同肺叶出现单个或多个卫星结节。ⅢB期(T4N2M0,T1-4N3M0),N3是指对侧肺门、纵隔淋巴结转移,双侧斜角肌或锁骨上淋巴结转移。Ⅳ期(任何T任何NM1a、M1b),M1a是指对侧肺叶出现肿瘤结节、胸膜结节、恶性胸腔积液或恶性心包积液；Mlb是指远处器官转移,常见部位主要有脑、全身骨骼、双侧肺叶、肝脏、双侧肾上腺。
外科手术切除是可完全切除的NSCLC的最佳治疗方法,ⅠA-ⅡB期的非小细胞肺癌患者约占所有肺癌患者的20%,这部分患者可以行根治性手术,5年生存率为50%-80%,ⅢA和ⅢB期的局部晚期非小细胞肺癌(Local advanced non small cell lung cancer,LA-NSCLC)患者约占40%,其中ⅢA-N2期的患者有可能行根治性手术,但5年生存率也只有10%-30%。可切除的IIIA-N2NSCLC主要包括ⅢA1(是指将手术后系统清扫的纵隔淋巴结经病理学检查偶然发现的N2转移)、ⅢA2(术中探查见单站纵隔淋巴结可疑转移,最后经病理学检查证实)和部分的ⅢA3[术前经纵隔镜、食管镜超声引导针吸活检(esophageal endoscopic ultrasound needle aspiration, EUS-NA)和气管镜超声引导针吸活检(endobronchial ultrasound needle asp iration,EBUS-NA)发现的单站或多站纵隔淋巴结转移]。而ⅢA4(N2淋巴结巨大或多个淋巴结融合成巨快状的多站转移,并经病理学确诊)、ⅢB期及Ⅳ期肺癌患者因为有局部转移或远处转移,不能行根治性手术。
而根治性术后辅助治疗方面,经过几十年的基础及临床研究,现已证实术后辅助化疗可使高危IB-ⅢA期NSCLC患者生存获益,可以提高5年生存率,但提高还很有限。高危IB(新版NCCN指南)是指切缘阴性,且具备以下之一者,分化差(包括神经内分泌癌)、脉管受侵、楔形切除、肿瘤直径>4cm、脏层胸膜受累及Nx(淋巴结不能明确)。而在中国版指南中,切缘<1cm也作为高危因素之一。如何进一步提高根治性术后NSCLC患者的生存率是包括胸外科医生在内的所有肺癌相关研究者共同期待的研究方向。随着分子生物学的深入探讨及分子靶向药物的临床应用,特别是酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)药物的应用,已经让晚期NSCLC患者的生存率上了一个台阶,对表皮生长因子受体(epidermal growth factor receptor, EGFR)敏感突变患者的治疗已从二线扩展到了一线。那么,是否可以进一步拓展到术后辅助治疗中,让根治性术后EGFR敏感突变的NSCLC患者也从中获益,已有一些研究初显端倪。
首先是加拿大NCIC-BR19的研究结果令人失望。是一项针对IB-ⅢA期的NSCLC根治术后吉非替尼与安慰剂对照的试验,结果表明靶向药物组未取得OS和DFS的差异。随后来自美国MSKCC一项回顾性研究显示：在167例(IB期占70%,Ⅱ期占15%,Ⅲ期占15%)均存在EGFR敏感突变的肺腺癌患者中,TKI辅助治疗(吉非替尼gefitinib或厄罗替尼erlotinib)和含铂化疗对比有延长EGFR敏感突变患者2年DFS的趋势(89%vs72%,P=0.06)。2012年ASCO会议上报告的SELECT研究探讨了厄洛替尼在EGFR突变型肺癌辅助化疗后维持治疗中的应用,该研究纳入EGFR突变、ⅠA-ⅢA期NSCLC患者,术后接受常规化疗或放化疗后,口服厄洛替尼150mg/d,持续2年,目前入组36例患者,计划入组100例。初步结果显示,厄洛替尼维持治疗后患者中位2年无疾病生存(Disease free survival,DFS)率达94%。仅有1例患者在接受厄洛替尼辅助治疗期间出现进展,10例患者停药6个月后出现进展,接受厄洛替尼二次治疗的5例患者均敏感。值得关注的是该研究中53%为Ⅰ期患者,这组病人的生存曲线甚至在Ⅲ期患者之下,提示相对早期的患者获益并不明显。研究者认为,厄洛替尼辅助治疗至少对微转移病灶有细胞生长抑制作用。
那么,TKIs药物能否引入根治性术后NSCLC患者的辅助治疗?我们的研究正是想要回答这个问题。我们对根治性术后NSCLC患者的癌组织标本进行EGFR基因突变检测,了解这些NSCLC患者的EGFR生物学特性；分析和探讨分子靶向药物在术后的辅助治疗中的价值。从而找到一种新的治疗手段,以进一步提高根治性术后NSCLC患者的治疗疗效。
[目的]：
1.研究探讨IA-IIIA期根治性术后NSCLC患者EGFR总体基因突变率,EGFR基因敏感突变与患者临床、病理特征之间的关系,并和晚期NSCLC EGFI基因敏感突变进行比较,进一步了解早中期和晚期NSCLC的EGFR生物学共性和差异。
2.观察并比较高危ⅠB-ⅢA期根治性术后NSCLC患者EGFR基因野生型接受化疗、EGFR基因敏感突变型接受化疗或者化疗+靶向TKI药物维持治疗后的6、12、18个月无疾病生存期(Disease free survival,DFS)、化疗及TKI药物的毒性反应。
[方法]:
1.入组标准及EGFR基因检测收集2011-2月至2012-12月南方医院胸心血管外科同一个医疗组的ⅠA-ⅢA期根治术后的NSCLC患者64例,手术方式全部为全胸腔镜下单向式肺叶切除加纵隔淋巴结系统清扫,切除的肿瘤组织标本除常规进行组织病理学确定分型、分化、病理分期(按国际抗癌联盟(UICC)和美国肿瘤联合会(AJCC)联合制定的最新版即2009版TNM分期法。)外,术中取一部分肿瘤新鲜组织行EGFR基因检测,采用目前肺癌分子生物学研究领域比较认可的检测方法即蝎形探针扩增阻滞突变系统(scorpions amplification refractory mutation system, Scorpions, ARMS法)对待测的癌组织行EGFR基因检测。项目包括外显子19上的缺失突变,外显子21上的L858R突变即858位精氨酸替代亮氨酸的突变、外显子21上的L861Q突变即861位异亮氨酸替代丝氨酸的突变、外显子20上T790M突变即790位甲硫氨酸替代苏氨酸的突变以及外显子18上G719X突变包括G719A、G719S、G719C3种突变,即719位丙氨酸、丝氨酸或者半胱氨酸替代甘氨酸的突变。
2.临床治疗分组根据患者EGFR检测结果及入组标准,在64例患者中共纳入44例ⅠB-ⅢA期根治术后的NSCLC患者,EGFR基因野生型患者20例,EGFR基因敏感突变型患者24例。根据EGFR基因检测结果、患者实际情况及临床治疗方法分为三组：A组：EGFR基因野生型患者(20例)给予4个周期含铂两药方案化疗,每3个星期一次；B组：EGFR基因突变型患者(突变患者中的13例)接受4个周期含铂两药方案化疗,每3个星期一次；C组：EGFR基因突变型患者(突变患者中的11例)接受4个周期含铂两药方案化疗,每3个星期一次,化疗结束两周后给予口服TKI药物维持治疗,特罗凯150mg/d,或易瑞沙250mg/d,或凯美纳125mg/次、3次/d,口服治疗,持续用药4-8个月或出现不可耐受的毒副反应停药。
3.定期检查项目所有三组病人每次化疗前先行胸部正侧位片或胸部增强CT、常规心电图及三大常规化验,第四次化疗前行全身检查,给予全身PET-CT或头颅磁共振+胸部增强CT+全身骨显像+腹部超声,以观察患者病情变化,四次化疗结束后定期观察,每三个月行胸部正侧位片或胸部增强CT复查,每半年行全身检查一次。
4.随访收集所有病例的临床病理资料并对患者进行电话或通信随访,随访时间定为18月,患者总生存时间小于18月则随访至患者死亡结束。
[结果]：
1.EGFR基因突变的检出率64例ⅠA-ⅢA期根治性手术的NSCLC组织中,EGFR基因突变率为42.2%。鳞癌患者共26例,EGFR基因突变6例,突变率为23.1%；腺癌患者共38例,EGFR基因突变21例,突变率为55.3%,两组间比较p<0.05,有显著性差异。女性患者13例,EGFR基因突变9例,突变率为69.2%,男性患者51例,EGFR基因突变18例,突变率为35.3%,两组间比较p<0.05,有显著性差异。肿瘤病理学高分化患者17例,EGFR基因突变12例,突变率70.6%；中-低分化患者47例,EGFR基因突变15例,突变率31.9%,两组间比较p<0.05,有显著性差异。肿瘤最大径>3cm患者35例,EGFR基因突变10例,突变率28.6%；肿瘤最大径≤3cm患者29例,EGFR基因突变17例,突变率58.6%,两组间比较p<0.05,有显著性差异。吸烟患者共33例,EGFR基因突变11例,突变率为33.3%,不吸烟肺癌患者共31例,EGFR基因突变16例,突变率为51.6%,两组间比较p>0.05,无显著性差异。淋巴结无转移者44例,EGFR基因突变16例,突变率36.4%；淋巴结有转移者20例,EGFR基因突变11例,突变率55.0%,两组间比较p>0.05,无显著性差异。年龄≤60岁患者42例,EGFR基因突变21例,突变率50%；年龄>60岁患者22例,EGFR基因突变6例,突变率27.3%,两组间比较p>0.05,无显著性差异。pTNM分期Ⅰ-Ⅱ期47例,突变17例,突变率36.2%,19号染色体突变5例,21号染色体突变10例,19号及21号染色体均突变2例。Ⅲ期17例,突变10例,突变率58.8%,19号染色体突变4例,21号染色体突变6例。两组间比较p>0.05,无显著性差异。
本研究共入组的64例ⅠA-ⅢA期根治性术后NSCLC患者,EGFR基因突变率为42.2%。而EGFR基因突变的病人主要集中于女性、腺癌、高分化、肿瘤≤3cm的人群,各组两两比较有统计学差异。而吸烟、非吸烟,淋巴结无转移、转移,年龄>60岁、≤60岁,Ⅰ-Ⅱ期、Ⅲ期各组两两之间比较无统计学差异。
2.A、B、C三组患者临床特征的比较EGFR基因野生化疗组(A组)与EGFR基因突变化疗靶向组(C组)的病理类型存在统计学差异(p=0.023),即C组的腺癌多于鳞癌,而A组的鳞癌多于腺癌。EGFR基因野生化疗组(A组)与EGFR基因突变化疗组(B组)的病理类型无统计学差异(p=0.08),EGFR基因突变化疗组(B组)与EGFR基因突变化疗靶向组(C组)的病理类型无统计学差异(p=0.649)。
3.A、B、C三组患者的化疗毒副反应情况三组患者均集中表现为骨髓抑制和胃肠道反应,但均较轻,主要集中于0度和Ⅰ度,少数为Ⅱ度,未发生Ⅲ度,亦未发生不可耐受的毒副反应。EGFR基因突变化疗靶向组(C组)患者术后接受含铂两药化疗+口服TKI药物维持治疗,在口服TKI药物期间患者耐受性良好,仅3例患者出现Ⅰ度腹泻反应,6例患者出现Ⅰ度皮疹反应,仅1例患者口服特罗凯4个月后,出现Ⅲ度皮疹反应,停服2周后改服易瑞沙,症状得到控制。
4.A、B、C三组患者的无疾病生存期(DFS) A组(野生化疗组)DFS6个月为75%,12个月为55%,18个月为45%；B组(突变化疗组)DFS6个月为100%,12个月为84.6%,18个月为84.6%；C组(突变化疗靶向组)DFS6个月为100%,12个月为100%,18个月为90.9%。三组病例间12月及18月DFS比较有显著性差异(P<0.0125),其中,12月DFS野生化疗组(A组)与突变化疗靶向组(C组)存在显著性差异(p=0.012),野生化疗组(A组)与突变化疗组(B组)(p=0.057)、突变化疗组(B组)与突变化疗靶向组(C组)(p=0.183)均不存在显著性差异；18月DFS野生化疗组(A组)与突变化疗靶向组(C组)存在显著性差异(p=0.012),野生化疗组(A组)与突变化疗组(B组)(p=0.020)、突变化疗组(B组)与突变化疗靶向组(C组)(p=0.625)均不存在显著性差异。
[结论]:
1、根治性术后NSCLC患者行EGFR基因突变检测,可帮助我们了解其生物学特性,并为这类患者后续治疗方案的制定提供初步依据。
2、根治性术后NSCLC患者EGFR基因突变状态主要集中于女性、腺癌、高分化、肿瘤≤3cm的人群。
3、根治性术后NSCLC患者EGFR基因状态可能影响术后辅助化疗的疗效,突变型患者较野生型患者DFS有延长的趋势。
4、根治性术后NSCLC EGFR敏感突变患者术后化疗加TKI辅助治疗,12、18月的DFS明显优于EGFR野生型患者术后单纯化疗的疗效。
5、根治性术后NSCLC EGFR敏感突变患者,术后化疗加TKI辅助治疗组较单纯化疗组,12、18月的DFS有延长的趋势。
Background
Lung 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 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.
Objective
1. 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 Methods
1. 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.
Results
1. 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.
Conclusion
1The 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.
引文
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