吉非替尼治疗男性晚期非小细胞肺癌59例报告

目的探讨吉非替尼单药治疗男性晚期非小细胞肺癌(NSCLC)的疗效及安全性。方法男性NSCLCⅣ期患者59例,其中腺癌、细支气管肺泡癌占86.4%,既往化疗2个方案以上者占66.1%。口服吉非替尼至病情进展或出现不可耐受不良反应。患者分别于治疗1个月、治疗3个月、治疗3个月以后每隔2个月复查。结果59例患者均可评价疗效,无完全缓解患者,部分缓解14例,稳定10例,进展35例,有效率为23.7%,稳定率为16.9%,疾病控制率为40.7%。中位肿瘤进展时间为1.8个月。中位生存时间为8.5个月,生存时间与最佳疗效及一般状况有关。1、2和3年生存率分别为42.4%、17.1%和13.3%。常见不良反应为皮肤改变和腹泻,多为1、2度。结论吉非替尼单药治疗男性晚期NSCLC疗效明确,疾病控制后患者生存时间延长,不良反应较易耐受,是二线、三线用药的良好选择。     

Estrogen receptors as the novel therapeutic biomarker in non-small cell lung cancer

Although a wide range of studies have addressed the relationship between estrogen receptor (ER) expression and prognosis in non-small cell lung cancer (NSCLC), that relationship remains controversial. This is in large part because there is no consensus on the rate of ER expression in NSCLC or on the intracellular distribution of ER expression. This suggests that establishing the relationship between ER expression and prognosis will require standardization of the antibodies used as well as the definition of a positive response. For example, it is supposed from previous studies that ERs in the cytoplasm and nucleus have different relationships to prognosis than ERs in the cytoplasm. Moreover, ER signaling in NSCLC is known to be affected by aromatase, progesterone receptor and epidermal growth factor receptor mutation. However, there has been little functional analysis these mutants and subtypes. This review will focus on what is known about the role of ERs in NSCLC and whether ER can be a useful prognostic marker or therapeutic target in NSCLC.     

易瑞沙在24例化疗后进展的晚期非小细胞肺癌中的作用

背景与目的 易瑞沙（Iressa）是小分子表皮生长因子受体酪氨酸激酶抑制剂，主要用于治疗晚期非小细胞肺癌（NSCLC）。本研究探讨易瑞沙单药治疗化疗后进展的晚期非小细胞肺癌的疗效与不良反应。方法 24例化疗后进展的晚期NSCLC患者接受治疗，其中二线以上治疗后进展者占62．5％。易瑞沙250mg口服，每日1次，服用至疾病进展或出现不可耐受的不良反应。治疗后每4周复查一次，16周后每8周复查一次。结果本组24例患者均可评价疗效。其中完全缓解1例，部分缓解8例，无变化3例，进展12例。有效率为37．5％，稳定率为12．5％，临床获益率为50．0％，中位肿瘤进展时间为87天。随访2年，1和2年生存率分别为33．3％和12．5％。常见不良反应为Ⅰ、Ⅱ度皮肤改变和腹泻，未发生Ⅲ度以上不良反应。有2例患者因怀疑发生肺部间质性改变而结束治疗。结论 易瑞沙治疗化疗后进展的晚期NSCLC的疗效显著，不良反应轻，是晚期NSCLC患者二、三线用药的最佳选择之一。     

吉非替尼治疗晚期非小细胞肺癌的临床研究

目的:总结吉非替尼治疗晚期非小细胞肺癌的近期疗效及副作用。方法:40例经放化疗失败的非小细胞肺癌患者进入本研究,其中8例局限于胸腔内,32例已有远处转移。口服吉非替尼250mg/次,每天1次。全组服药的中位时间为5个月。按照WHO标准统一评定疗效及副反应。结果:40例可评价病例中完全缓解2例,部分缓解10例,病情稳定12例,病情进展16例。全组有效率为30%,疾病控制率为60%,症状缓解率为30%,缓解最明显的症状为咳嗽和疼痛。中位生存期5·6个月(1~20个月),中位进展时间(TTP)为(6·6±1·8)个月,1年生存率为45%。主要的毒副作用是皮疹,共发生25例,占全组的62·5%,其它副作用有腹泻、恶心、脱发,无1例因毒副反应退出。结论:吉非替尼对晚期非小细胞肺癌有明显的抗肿瘤作用,是一种有效且具有良好耐受性的治疗药物。     

Relevance of EGFR mutation with micropapillary pattern according to the novel IASLC/ATS/ERS lung adenocarcinoma classification and correlation with prognosis in Chinese patients

Background

A new histological classification by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) for lung adenocarcinoma (LAC) was proposed recently, in which a micropapillary pattern (MPP) was described.

Objectives

This study aimed to evaluate the clinicopathological characteristics of LAC with MPP (LAC-MPP) and to investigate the correlation between LAC-MPP and epidermal growth factor receptor (EGFR) mutation status with the prognosis in Chinese patients.

Patients and methods

From May 2007 and February 2012, two hundred and forty-eight patients underwent resection and pathologically confirmed LAC. We classified all cases histologically according to the IASLC/ATS/ERS classification; an MPP ratio ≥5% was considered MPP-positive. Used Pearson's chi-square test to evaluate the relationships between EGFR mutation status and MPP status with patient clinicopathological characteristics.

Results

There were MPP-positive tumors (MPP ratio ≥5%) in 31.9% of cases (79/248); the MPP ratio correlated with TNM stage (p = 0.001) and lymph node metastasis (p = 0.03). EGFR mutation (EGFR-mut) was detected in 87 cases (34.3%); 161 cases had wild-type EGFR (EGFR-wt). EGFR mutation was present in 65% of the MPP-positive subtype. Patients with EGFR-mut tumors had significantly longer overall survival (OS) (p = 0.002). OS was also significantly longer in MPP-negative EGFR-mut or EGFR-wt patients (p < 0.001).

Conclusion

These findings indicate that EGFR-mut tumors are likelier to be MPP-positive subtypes and that MPP may be a novel potential pathological marker of poor prognosis in Chinese LAC patients.     

广西壮族非小细胞肺癌患者EGFR基因突变的研究

目的研究广西壮族非小细胞肺癌患者表皮生长因子受体（EGFR）基因突变的情况。方法收集163例广西壮族非小细胞肺癌（NSCLC）组织,采用ARMS（amplificationrefractorymutationsystem,ARMS）法PCR扩增检测EGFR基因外显子18、19、20及21的突变,进一步分析其突变与临床特征的关系,并与文献报道国内8个省、市的数据进行比较。结果163例NSCLC中共检出73例EGFR基因突变,EGFR突变阳性率为44．8％,显著高于文献报道国内8个省市的总体水平（30．0％）（P〈0．05）。其中,外显子19和21突变各占突变总数38．4％。腺癌和腺鳞癌突变发生率占突变总数的80．8％,女性EGFR基因突变率（57．7％）显著高于男性（38．7％）（P〈0．05）。结论广西壮族NSCLC患者EGFR基因突变率显著高于中国8个省、市的总体水平,其中以外显子19和21突变为多见。女性、腺癌和腺鳞癌患者是选用EGFR酪氨酸激酶抑制剂的优势人群。     

EGFR不同突变亚型与肺腺癌脑转移预后的相关性分析

目的 探讨肺腺癌脑转移患者EGFR不同突变亚型与预后的相关性。方法 回顾分析2010—2015年本院收治的经EGFR基因突变检测的肺腺癌脑转移患者256例临床资料,筛选脑转移的预后影响因素。Kaplan-Meier法计算生存率Logrank法检验和单因素预后分析,Cox模型多因素预后分析。结果 全组患者中位生存期为10.13个月。单因素分析显示性别、EGFR突变状态、19外显子缺失突变、脑转移时KPS评分、靶向治疗与预后有关(P=0.006、0.001、0.010、0.000、0.003),多因素分析显示脑转移时KPS评分、19外显子缺失突变为脑转移患者预后影响因素(P=0.000、0.045)。将全组病例纳入RPA预后分级指数,检验显示差异有统计学意义(P=0.000)。结论 19外显子缺失突变是肺腺癌脑转移患者的预后影响因素,可以考虑将其纳入肺腺癌脑转移瘤预后评分系统。EGFR-TKI使EGFR基因突变肺腺癌脑转移患者生存获益,尤其是19外显子缺失突变患者。     

厄洛替尼治疗中国晚期非小细胞肺癌患者的疗效和安全性

目的 观察厄洛替尼治疗中国晚期非小细胞肺癌(NSCLC)患者的疗效和安全性.方法 2005年11月至2009年3月,用厄洛替尼150 mg/d治疗519例中国晚期NSCLC患者,持续治疗至疾病进展或发生不能耐受的不良反应、或由于任何其他原因退出试验为止,评价缓解率、疾病进展时间(TTP)、总生存期(OS)和药物不良反应.结果 519例患者中,有38例未进行肿瘤评价或无肿瘤评价数据,有2例不可评价近期疗效.479例可评价近期疗效的患者中,完全缓解(CR)1例,部分缓解(PR)127例,疾病稳定(SD)263例,疾病进展(PD)88例,总缓解率为26.7%,疾病稳定率为54.9%,疾病控制率为81.6%.全组患者的中位TTP为6.44个月,中位OS为15.37个月,1年生存率为60.3%.厄洛替尼治疗过程中常见的不良反应有皮疹、瘙痒、皮肤干燥、腹泻、恶心、呕吐、口腔炎、腹痛、疲劳、呼吸困难、咳嗽、食欲减退、感染、结膜炎及干性角膜结膜炎,大部分为轻到中度,仅有3例(0.6%)患者发生与厄洛替尼治疗相关的严重不良反应,其中1例因间质性肺病并发呼吸衰竭而死亡.结论 厄洛替尼治疗中国晚期NSCLC患者的疗效明确,耐受性较好,是治疗晚期NSCLC的最佳选择之一.     

Efficacy of third-line pemetrexed monotherapy versus pemetrexed combination with bevacizumab in patients with advanced EGFR mutation-positive lung adenocarcinoma

Objective

The purposes of this study were to observe the effects of different treatment strategies, including third-line pemetrexed alone versus its combination with bevacizumab, in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, and to analyze the effects of the different medication orders of first- and second-line drugs on third-line efficacy.

Patients and methods

One hundred and sixteen cases of patients with EGFR-positive lung adenocarcinoma who had received third-line pemetrexed alone or in combination with bevacizumab between March 2010 and March 2014 at Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively. Additionally, all the patients were treated with first-line gemcitabine and cisplatin (GP) chemotherapy and second-line EGFR tyrosine kinase inhibitor (TKI) or with first-line EGFR-TKI and second-line GP chemotherapy.

Results

The median survival of 61 cases with third-line pemetrexed monotherapy was 36.22 months, the median survival time of 55 cases with third-line pemetrexed plus bevacizumab was 38.76 months, and there was a significant difference in survival time between the two groups (P=0.04). Subgroup analysis revealed that among the 55 cases with third-line bevacizumab plus pemetrexed treatment, the median survival of 29 patients with first-line GP and second-line EGFR-TKI was 42.80 months, while the median survival of 26 patients with first-line EGFR-TKI and second-line GP was only 34.46 months; additionally, there was a significant difference in the survival time between the two subgroups (P=0.001). Among 61 cases with third-line pemetrexed treatment, the median survival of 34 patients with first-line GP and second-line EGFR-TKI was 38.72 months, while the median survival of 27 patients with first-line EGFR-TKI and second-line GP was only 32.94 months; the survival time of the two subgroups was significantly different (P=0.001).

Conclusions

Regardless of the order of the first- and second-line chemotherapy and TKI therapy, the pemetrexed plus bevacizumab regimen was superior to the pemetrexed monotherapy as the third-line therapy in patients with advanced EGFR-positive lung adenocarcinoma. However, this strategy is worth further investigation in prospective studies.     

表皮生长因子受体抑制剂gefitinib对改善晚期非小细胞肺癌患者生活质量的作用

背景与目的生活质量是评价非小细胞肺癌治疗方法的重要指标。本研究的目的是观察表皮生长因子受体抑制剂gefitinib对晚期非小细胞肺癌患者生活质量的影响。方法对gefitinib慈善用药计划中31例晚期非小细胞肺癌患者进行研究。患者每日口服gefitinib250mg,直至病情进展或出现严重的副反应。采用中文版EORTCQLQ-C30和QLQ-LC13问卷对治疗前后症状和生活质量的改变进行评价。结果25例接受gefitinib治疗的患者完成问卷。和治疗前相比,治疗8周后,患者4种功能状态(体格、角色、情感、社会)和整体生活质量评分的均值显著增加,全身症状(乏力和食欲不振)以及疾病相关症状(呼吸困难、咳嗽、胸痛、手臂和肩膀疼痛、身体其他部位疼痛)评分的均值显著降低。治疗后5种功能状态和整体生活质量的有效率均超过50%。主要的全身症状和疾病相关症状的有效率也达到44%~84%。症状和生活质量的改善与临床客观疗效相一致。结论gefitinib对于常规治疗失败的晚期非小细胞肺癌仍能够改善患者的症状和生活质量。     

吉非替尼治疗晚期复治性非小细胞肺癌的临床研究

目的探讨应用吉非替尼(IRESSA)治疗晚期非小细胞肺癌(NSCLC)患者的疗效及其对生活质量的影响。方法既往化疗失败的Ⅲb-Ⅳ期NSCLC患者41例,其中二线化疗失败者占85.4%(35/41)。IRESSA 250 mg口服,每日1次,服药至病情进展或出现不能耐受的不良反应。患者分别在治疗后1个月、2个月和以后每3个月复查。结果本组41例患者均可评价疗效,其中PR 18例,SD 14例,PD 9例,有效率为43.9%(18/41),疾病控制率(PR SD)为78.0%(32/41)。男性患者和女性患者的有效率分别为42.1%和45.5%(P>0.05)。至随访结束,41例患者中,有22例(53.7%)存活,其中位生存时间(MST)为10.1个月;19例死亡患者的疾病进展时间(TTP)为2.7个月,MST为5.0个月;PR患者的MST为13.3个月。全组患者症状改善率为78.0%。服药28 d,KPS评分提高20±5分,无Ⅲ-Ⅳ度毒性反应。结论IRESSA单药对化疗失败的晚期NSCLC疗效确切,并可用于一般状况评分较差的患者,其不良反应轻,是二三线用药的良好选择。     

EGFR mutation frequency and effectiveness of erlotinib: A prospective observational study in Danish patients with non-small cell lung cancer

Objectives

In 2008, we initiated a prospective study to explore the frequency and predictive value of epidermal growth factor receptor (EGFR) mutations in an unselected population of Danish patients with non-small cell lung cancer offered treatment with erlotinib, mainly in second-line.

Materials and methods

Four hundred and eighty eight patients with advanced NSCLC were included. The mutation status was assessed using the cobas^® EGFR Mutation Test. Erlotinib was administrated (150 mg/d) until disease progression or unacceptable toxicities occurred. The primary endpoint was progression-free survival. Secondary endpoints were overall survival and response.

Results

Biopsies were retrieved from 467 patients, and mutation results obtained for 462. We identified 57 (12%) patients with EGFR mutations: 33 exon 19 deletions, 13 exon 21 mutations, 5 exon 18 mutations, 3 exon 20 insertions, 1 exon 20 point mutation (S768I), and two complex mutations. Seven percent of the patients were never smokers. The differences in median progression-free survival and overall survival between the mutated group and the wild-type group were 8.0 vs. 2.5 months, p < 0.001 and 12.1 vs. 3.9 months, p < 0.001. Performance status (0–1 vs. 2–3) and line of treatment (1st vs. 2nd and 3rd) had no influence on outcome in EGFR-mutated patients.

Conclusion

We found a higher frequency of EGFR mutations than expected in a cohort with less than 10% never smokers. The outcome after treatment with erlotinib was much better in patients with EGFR mutations than in patients with wild-type EGFR and was independent of performance status and treatment line in EGFR-mutated patients.     

肺腺癌患者EGFR和KRAS基因突变与预后的相关性研究

目的 探讨肺腺癌患者表皮生长因子受体(EGFR)和KRAS基因突变与预后的相关性.方法 选取134例肺腺癌患者的肺腺癌组织标本,应用探针扩增阻滞突变系统在PCR仪上进行EGFR和KRAS基因突变检测,分析EGFR和KRAS基因突变与肺腺癌患者临床病理特征及预后的关系.结果 134例患者中,EGFR基因突变53例,突变率为39.55%,KRAS基因突变6例,突变率为4.48%.肺腺癌患者EGFR基因突变率与年龄、吸烟史有关(P﹤0.01).EGFR基因突变型患者的KRAS基因突变率低于EGFR基因野生型患者(P﹤0.05).EGFR基因突变型患者的无进展生存期(PFS)长于EGFR基因野生型患者(P﹤0.05),KRAS基因野生型患者的PFS长于KRAS基因突变型患者(P﹤0.05).结论 EGFR基因突变的肺腺癌患者KRAS基因更倾向于野生型,EGFR基因突变型或KRAS基因野生型的肺腺癌患者PFS更长.     

吉非替尼治疗晚期肺腺癌多脏器转移的临床观察

为了探讨吉非替尼（易瑞沙）单药治疗进展的晚期肺腺癌多脏器转移患者的疗效与不良反应，18例合并多脏器转移的进展的晚期肺腺癌患者接受治疗。易瑞沙250mg口服，每日1次，服用至疾病进展或出现不可耐受的不良反应。治疗后每4周复查1次，16周后每8周复查1次。结果：本组18例患者均可评价疗效。其中完全缓解1例，部分缓解6例，无变化4例，进展7例。有效率为38．8％，疾病控制率61．1％。临床获益率为44．4％，常见不良反应为I、Ⅱ度皮肤改变和腹泻，未发生Ⅲ度以上不良反应。初步研究结果提示，易瑞沙治疗化疗后进展的晚期肺腺癌合并多脏器转移的疗效显著，不良反应轻，是晚期肺腺癌多脏器转移患者的最佳选择之一。     

吉非替尼治疗晚期难治性小细胞肺癌合并急性上腔静脉综合征

目的：探索吉非替尼治疗晚期难治性小细胞肺癌(SCLC)的有效性和安全性。方法：口服吉非替尼250～500mg／d,按照WHO标准严密观察患的临床症状、体征、生活质量的客观疗效。结果：1例反复多药、多疗程化疗失败的SCLC患,合并急性上腔静脉综合征(SVCS),经脱水、利尿、大剂量环磷酰胺冲击化疗无效,2次应用吉非替尼均取得病情缓解,临床症状、体征消失,生活质量明显提高,而胸部瘤灶稳定,未见明显毒副反应。结论：吉非替尼治疗晚期难治性SCLC可能有效,值得临床进一步研究和观察。     

突变特异性免疫组织化学法检测非小细胞肺癌EGFR基因突变

背景与目的：表皮生长因子受体(epidermal growth factor receptor,EGFR)基因的突变状态是非小细胞肺癌(non-small cell lung cancer,NSCLC)患者使用EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)的重要疗效预测指标。该研究旨在探讨突变特异性免疫组织化学(immunohistochemistry,IHC)法检测NSCLC标本EGFR基因突变的临床实用价值。方法：同时采用突变特异性IHC法和扩增阻滞突变系统(amplifi-cation refractory mutation system,ARMS)法检测290例NSCLC患者的EGFR基因突变状态,计算突变特异性IHC法检测EGFR基因突变的灵敏度、特异度、阳性预测值(positive predictive value,PPV)和阴性预测值(negative predictive value,NPV);比较ARMS法和突变特异性IHC法检测EGFR突变的一致性。结果：以ARMS法检测结果为金标准,当染色评分≥1+为阳性时,突变特异性IHC法诊断EGFR基因突变的灵敏度为72.92%,特异度为95.20%,PPV为93.75%,NPV为78.08%。突变特异性IHC法诊断不同类型EGFR基因突变的准确性相差明显：诊断19外显子缺失突变的灵敏度只有55.55%,但其特异度在99%以上;当染色评分为1+时,诊断L858R突变的灵敏度为90.27%,特异度为95.86%,当染色评分为2+或3+时,其特异度则为98.63%~100%。突变特异性IHC法与ARMS法检测结果有较好的一致性(P<0.001,Kappa值：0.612~0.864)。突变特异性IHC法能直观判断EGFR基因突变细胞丰度。结论：突变特异性IHC法是EGFR突变分子检测的有效补充。     

非小细胞肺癌中磷酸化Akt蛋白表达研究

背景与目的表皮生长因子受体(EGFR)信号传导通路下游分子Akt的激活在肺癌进展的过程中有重要作用,但磷酸化Akt蛋白的表达是否与EGFR表达存在相关性以及是否能提示患者的预后目前尚无定论。本研究旨在评价国人非小细胞肺癌组织中磷酸化Akt蛋白表达的意义。方法应用组织微阵列和免疫组织化学技术检测167例NSCLC手术标本中磷酸化Akt蛋白的表达。结果磷酸化Akt蛋白在NSCLC中的阳性表达率为52.1%(87/167),阳性表达率与性别、发病年龄、吸烟情况、病理类型、分化程度、病理分期及预后之间的相关性无统计学显著意义(P>0.05),并且磷酸化Akt与表皮生长因子受体蛋白表达之间的相关性亦无统计学意义(P=0.122)。结论国人非小细胞肺癌组织中磷酸化Akt阳性表达与患者临床病理特征无明显相关性,并且磷酸化Akt蛋白对患者预后无提示意义。     

Second-line therapy with gefitinib in combination with docetaxel for advanced non-small cell lung cancer: a phase II randomized study

This randomized, open-label, parallel-group, phase II study evaluated the efficacy and safety of gefitinib and docetaxel in combination, as second-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC). Eighty-nine patients who had failed first-line, platinum-based chemotherapy were randomly assigned to gefitinib (250 mg/day orally) in combination with docetaxel (75 mg/m² every 3 weeks) or single-agent docetaxel (75 mg/m² every 3 weeks). Objective response rates were 6.8% with gefitinib plus docetaxel and 9.1% with docetaxel alone. Disease control was experienced by a higher proportion of patients receiving gefitinib plus docetaxel (59.1%) versus docetaxel alone (34.1%). Median progression-free and overall survival appeared to be longer with gefitinib plus docetaxel (3.9 months [95% CI:2.3–5.4] and 7.6 months [95% CI:5.4–10.4], respectively) than with docetaxel alone (2.1 months [95% CI:2.1–3.7] and 6.2 months [95% CI:5.2–7.2], respectively). The most common non-hematological adverse events were diarrhea, alopecia, rash and dry skin in the combination arm, and vomiting and asthenia with docetaxel alone. Gefitinib and docetaxel combination therapy has antitumor activity and may be a feasible treatment option in patients with advanced NSCLC who have failed platinum-based chemotherapy.