高剂量吉非替尼或厄洛替尼脉冲治疗继发性耐药晚期非小细胞肺癌疗效及安全性的单中心、单臂、Ⅱ期临床研究

目的 观察吉非替尼或厄洛替尼常规剂量继发性耐药的晚期非小细胞肺癌（NSCLC）患者接受高剂量相应表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）脉冲治疗的疗效及安全性。方法 收集2013年8月至2014年12月42例吉非替尼或厄洛替尼常规治疗1年后出现耐药的NSCLC患者,其中吉非替尼组29例,一次性给予相应4倍剂量的吉非替尼（1000 mg／次）,4天为1个周期;厄洛替尼组13例,一次性给予相应3倍剂量的厄洛替尼（450 mg／次）,3天为1个周期。治疗直至出现疾病进展或不可耐受的毒性反应。比较两种药物治疗的近期疗效和无进展生存期（PFS）。结果 42例初始接受吉非替尼或厄洛替尼治疗1年后出现疾病进展的患者中位PFS为30个月;其中,吉非替尼组为31个月,厄洛替尼组为24 个月,两组差异无统计学意义（P＞0.05）。经高剂量EGFR TKI脉冲治疗后,全组获PR 8例、SD 11例、PD 23例,有效率（RR）为19.0％,疾病控制率（DCR）为 45.2％,中位PFS为6个月。其中吉非替尼组获PR 6例、SD 9例、PD 14例,中位PFS为8个月;厄洛替尼组获PR 2例、SD 2例、PD 9例,中位PFS为6个月;两组比较差异均无统计学意义（P＞0.05）。按EGFR外显子突变情况分组,Exon 19突变组获PR 4例、SD 6例、PD 17例,Exon 21突变组获PR 4例、SD 5例、PD 6例;两组中位PFS分别为6个月和7个月,差异无统计学意义（P＞0.05）。毒副反应均为1～2级,主要表现为皮疹、乏力、纳差和皮肤干燥等,两组毒副反应发生率的差异无统计学意义（P＞0.05）。 结论对于吉非替尼或厄洛替尼常规剂量治疗后出现进展的晚期NSCLC患者,高剂量EGFR-TKI脉冲治疗能使部分患者再次获益,可能是一种安全有效的治疗方法。     

Current views on the role of Notch signaling and the pathogenesis of human leukemia

Background

Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^nd EGFR-TKI administration.

Methods

We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.

Results

Three patients (27%) were treated with gefitinib as the 2^nd EGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^nd EGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^nd EGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^nd EGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.

Conclusions

Our results indicate that a 2^nd EGFR-TKI treatment can be an effective treatment option for gefitinib responders.     

Survival of patients with brain metastases from non-small cell lung cancer harboring EGFR mutations treated with epidermal growth factor receptor tyrosine kinase inhibitors

Brain metastases (BM) is one of the most crucial distant metastases in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. There is no consensus about which EGFR tyrosine kinase inhibitor (TKI) is most effective against BM in such patients. Here, we compared prognoses of patients with EGFR-TKI naïve EGFR-positive BM treated with erlotinib or gefitinib after BM diagnosis. Of 269 patients with NSCLC treated with EGFR-TKIs at a single institution, we reviewed medical records of 205 patients with documented EGFR mutations. Eleven patients were administered erlotinib, and 52 patients were administered gefitinib as the first-line EGFR-TKI treatment after diagnosis. We used propensity score matching to balance patient backgrounds between groups, and the log-rank test to compare survival curves. Patients with BM at the induction of chemotherapy had a poorer prognosis than those without BM [median overall survival (OS) 18.5 vs. 28.0 months]. Meanwhile, there was no significant difference in OS between those with or without BM at the initiation of EGFR-TKI treatment (20.3 vs. 23.8 months). Median OS of patients treated with erlotinib was not significantly longer than that of patients treated with gefitinib (25.0 vs. 18.1 months). The presence of BM at the initiation of EGFR-TKI treatment had no apparent effect on survival. Erlotinib was deemed more effective than gefitinib in preventing intracranial lesions and prolonging survival; however, prospective studies are needed to confirm these results.     

EGFR-TKI一线治疗EGFR基因突变的晚期非小细胞肺癌临床观察

背景与目的研究表明,一线表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptortyrosine kinase inhibitor,EGFR-TKI)治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的客观缓解率及无进展生存期明显优于铂二联的化疗,且耐受性更好。本研究旨在分析EGFR-TKI一线治疗晚期EGFR突变阳性的NSCLC患者的疗效与耐受性。方法 54例晚期NSCLC患者肿瘤标本采用直接测序法证实EGFR活化突变(外显子19缺失或外显子21点突变),一线给予EGFR-TKI口服治疗直至疾病进展,观察疗效及不良反应,并进行生存随访。结果 54例患者外显子19缺失33例(61%),外显子21点突变21例(39%)。均一线接受EGFR-TKI治疗,总体缓解率为90%,中位无进展生存期(progression free survival,PFS)为8.3个月,中位生存期为19.5个月;外显子19缺失患者的中位PFS(9.0个月)较21点突变(7.0个月)时间长(P=0.002)。外显子19缺失患者的中位总生存期(overall survival,OS)(25.0个月)较21点突变(16.0个月)时间长(P=0.001);吉非替尼与厄洛替尼疗效相当,但吉非替尼组安全性更好;最常见的不良事件为皮疹和腹泻,有2例患者(4%)出现了3度皮肤毒性反应,2例患者(4%)出现了3度的转氨酶升高,1例患者(1%)出现了3度口腔炎。结论存在EGFR基因突变的晚期NSCLC患者一线接受EGFR-TKI治疗安全有效,且外显子19缺失比L858R突变疗效更优。     

Phase II Study of the EGFR-TKI Rechallenge With Afatinib in Patients With Advanced NSCLC Harboring Sensitive EGFR Mutation Without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line therapy for patients with EGFR-mutated non–small-cell lung cancer (NSCLC) have shown a significantly better objective response rate and progression-free survival than platinum doublet therapy. However, acquired resistance often occurs within 12 months. One of the potential strategies for treating acquired resistance in NSCLC is the readministration of EGFR-TKIs, a strategy that has mainly been evaluated using gefitinib or erlotinib. The aim of the present study is to investigate the efficacy and safety of EGFR-TKI readministration with afatinib in patients with advanced NSCLC harboring activating EGFR mutations without T790M. The primary endpoint is progression-free survival. The secondary endpoints include the objective response rate, disease control rate, overall survival, toxicity, and quality of life. A total of 12 patients will be enrolled in this trial.     

Influence of histological type, smoking history and chemotherapy on survival after first-line therapy in patients with advanced non-small cell lung cancer

The usual primary endpoint in clinical trials for first-line chemotherapy in advanced non-small cell lung cancer is overall survival. Second-line chemotherapy can also prolong overall survival. Non-smoking history has been associated with a treatment effect for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) versus placebo for overall survival. We performed a retrospective analysis to identify prognostic factors for progression-free survival and overall survival in patients with advanced non-small cell lung cancer treated with first-line carboplatin/paclitaxel, and to examine the effect of second-line therapy on progression-free survival and overall survival. Ninety-eight patients (median age 61 years, 35 female, 74 adenocarcinoma, 68 smokers, 56 performance status 0) fulfilled our criteria, of which 75 patients (78%) received more than second-line therapy (docetaxel [54%] gefitinib [48%] erlotinib [4%]). For overall survival, smoking history and histology were significant prognostic factors. The 2-year overall survival rates were as follows: smokers, 17%; non-smokers, 52%, P < 0.0001; adenocarcinoma, 40%; other 15%, P = 0.0017. Multivariate analysis in patients who received second-line therapy showed treatment with EGFR-TKI was an independent predictor of overall survival. Smoking history and adenocarcinoma histology were prognostic factors for an improved outcome with carboplatin/paclitaxel in patients with non-small cell lung cancer. Our study results suggest that the use of EGFR-TKI after first-line treatment may be associated with an improvement in overall survival.     

吉非替尼与厄洛替尼治疗非小细胞肺癌脑转移的临床观察

目的 探讨吉非替尼与厄洛替尼治疗非小细胞肺癌脑转移的疗效。方法 回顾性分析67例EGFR突变阳性的肺腺癌脑转移患者的病历资料,患者均口服吉非替尼250 mg/天（吉非替尼组,n=38）或厄洛替尼150 mg/天（厄洛替尼组,n=29）,直至发生颅内病变进展、死亡或不可耐受的不良反应。疗效分析采用RECIST 1.1版标准,生存分析采用Kaplan-Meier法并行Log-rank检验。结果 全组颅内病变的有效率（RR）和疾病控制率（DCR）分别为44.8％和92.5％,吉非替尼组和厄洛替尼组分别为42.1％、92.1％和48.3％、93.1％（P=0.881）。颅外病变的RR和DCR分别为53.7％和95.5％,吉非替尼组和厄洛替尼组分别为52.6％、94.7％和55.2％、96.6％（P=0.932）。全组患者的中位无进展生存期（PFS）和总生存期（OS）分别为10.8个月和15.3个月,吉非替尼组和厄洛替尼组分别为10.6个月、14.8个月和11.7个月、15.7个月（P=0.720,P=0.569）。结论 吉非替尼和厄洛替尼对EGFR突变阳性的非小细胞肺癌脑转移具有较好的疗效,可以作为脑转移患者的治疗选择,两种药物在脑转移瘤的疗效及患者的预后等方面无差异。     

Non-small-cell lung cancer harbouring mutations in the EGFR kinase domain

Key “driver” mutations have been discovered in specific subgroups of non-small-cell lung cancer (NSCLC) patients. Activating mutations in the form of deletions in exon 19 (del 19) or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict outcome to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Pooled data from several phase II studies show that gefitinib and erlotinib induce responses in over 70% of NSCLC patients harbouring EGFR mutations, with progression-free survival (PFS) ranging from 9 to 13 months and median survival of around 23 months. Two studies in Caucasian and Asian patients have confirmed that these subgroups of patients attain response rates of 70% with erlotinib and gefitinib, including complete responses, PFS up to 14 months and median survival up to 27 months. These landmark outcomes have been accompanied by new challenges: the additional role of chemotherapy and the management of tumours with the secondary T790M mutation that confers resistance to EGFR TKIs. Mechanisms of resistance to reversible EGFR TKIs should be further clarified and could be related to modifications in DNA repair. The presence of double mutations (T790M plus either L858R or del 19) at the time of diagnosis could be much more frequent than originally thought. The sensitivity to EGFR TKIs could be greatly influenced by the expression of genes involved in the repair of DNA double-strand breaks by homologous recombination and non-homologous end joining.     

厄洛替尼一线治疗老年晚期非小细胞肺癌临床观察

[目的]比较厄洛替尼靶向与紫杉醇单药一线治疗老年晚期非小细胞肺癌(NSCLC)患者的疗效和不良反应。[方法]经病理确诊的老年晚期NSCLC患者62例,厄洛替尼治疗组32例:口服厄洛替尼150mg,1次/d;紫杉醇化疗组30例:紫杉醇75mg/m2,d1、8,静脉滴注,21d为1个周期,2个周期后评价疗效。[结果]厄洛替尼治疗组和紫杉醇化疗组近期有效率(RR)分别为28.1%、36.7%,肿瘤控制率(TGCR)分别为71.9%、66.7%,差异无统计学意义(P>0.05);中位无疾病进展时间(PFS)分别为5.6个月、5.1个月;中位生存期(OS)分别为9.0个月、8.0个月。两组不良反应均可耐受,厄洛替尼治疗组骨髓抑制发生率明显低于紫杉醇化疗组(P<0.05),厄洛替尼治疗组皮疹及腹泻发生率明显较高(P<0.05)。[结论]老年晚期NSCLC患者可从厄洛替尼靶向治疗中获益,不良反应轻微。     

培美曲塞单药或联合吉非替尼治疗EGFR-TKI耐药后晚期非小细胞肺癌临床观察

背景与目的:生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)获得性耐药后尚无标准的治疗方案,亟待探寻有效的后续治疗方法.为临床应用提供指导,该研究旨在比较后续治疗采用培美曲塞单药或联合吉非替尼治疗EGFR-TKI获得性耐药的晚期NSCLC的临床疗效及安全性.方法:入组既往接受过EGFR-TKI治疗后进展的晚期NSCLC患者62例.其中32接受培美曲塞联合吉非替尼治疗,设为联合组;30例单用培美曲塞治疗,设为化疗组.评价临床疗效及不良反应.结果:联合组客观有效率(objective response rate,ORR)为46.9%,高于化疗组的20%,差异有统计学意义(χ2=4.933,P<0.05);两组疾病控制率(disease control rate,DCR)差异无统计学意义(P>0.05);联合组的中位无病生存期(progression-free survival,PFS)为8.0个月,化疗组中位PFS为6.3个月,差异有统计学意义(χ2=8.063,P<0.05),两组总生存期(overall survival,OS)差异无统计学意义(P>0.05).联合组中性粒细胞减少、皮疹的发生率高于化疗组,差异有统计学意义(P<0.05),Ⅲ~Ⅳ不良反应两组差异无统计学意义(P>0.05).结论:晚期NSCLC患者EGFR-TKI获得性耐药后,采用培美曲塞联合吉非替尼较单用培美曲塞显示出更优势临床有效率和中位PFS,不良反应可耐受,值得临床推广运用.     

Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: A meta-analysis from six phase III randomized controlled trials

Gefiinib and erlotinib are two similar small molecules of selective and reversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), which have been approved for second-line or third-line indication in previously treated advanced Non-small-cell lung cancer (NSCLC) patients. The results of comparing the EGFR-TKI with standard platinum-based doublet chemotherapy as the first-line treatment in advanced NSCLC patients with activated EGFR mutation were still controversial. A meta-analysis was performed to derive a more precise estimation of these regimens. Finally, six eligible trials involved 1,021 patients were identified. The patients receiving EGFR-TKI as front-line therapy had a significantly longer progression-free survival (PFS) than patients treated with chemotherapy [median PFS was 9.5 versus 5.9 months; hazard ratio (HR)=0.37; 95% confidence intervals (CI)=0.27-0.52; p<0.001]. The overall response rate (ORR) of EGFR-TKI was 66.60%, whereas the ORR of chemotherapy regimen was 30.62%, which was also a statistically significant favor for EGFR-TKI [relative risk (RR)=5.68; 95% CI=3.17-10.18; p<0.001]. The overall survival (OS) was numerically longer in the patients received EGFR-TKI than patients treated by chemotherapy, although the difference did not reach a statistical significance (median OS was 30.5 vs. 23.6 months; HR=0.94; 95% CI=0.77-1.15; p=0.57). Comparing with first-line chemotherapy, treatment of EGFR-TKI achieved a statistical significantly longer PFS, higher ORR and numerically longer OS in the advanced NSCLC patients harboring activated EGFR mutations, thus, it should be the first choice in the previously untreated NSCLC patients with activated EGFR mutation.     

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation

Purpose

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib and erlotinib have shown dramatic response rate (RR) and significant prolongation of progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Since only a few patients with non-adenocarcinoma histology have been enrolled in clinical trials, the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation has not yet been fully determined.

Methods

We retrospectively analyzed clinical outcomes, including RR, PFS, and OS, in patients who were treated with the EGFR TKIs gefitinib or erlotinib and compared the results with those of adenocarcinoma patients with EGFR mutation and non-adenocarcinoma patients with wild-type EGFR.

Results

Among 250 patients with non-adenocarcinoma of the lung who underwent EGFR mutation genotyping, 21 were found to have an EGFR mutation (8.4?%). Twelve of the 21 patients were treated with the EGFR TKIs gefitinib (n?=?6) or erlotinib (n?=?6). The most common mutation was exon 19 deletion (n?=?7). The RR and disease control rate for 12 patients receiving EGFR TKIs were 50 and 75?%, respectively. The median PFS was 3.67?months (95?% CI: 1.34?C5.99), which was significantly lower than that of 269 adenocarcinoma patients with EGFR mutation (13.53?months) but better than that of 32 non-adenocarcinoma patients with wild-type EGFR (1.83?months) who were treated with EGFR TKIs.

Conclusions

The results of this study show that the EGFR mutation rate in Korean patients with non-adenocarcinoma of the lung is relatively high and that the clinical outcomes of EGFR TKIs are modest.     

Duration of prior gefitinib treatment predicts survival potential in patients with lung adenocarcinoma receiving subsequent erlotinib

Purpose

We investigated survival potential in patients receiving erlotinib after failure of gefitinib, focusing on response and time to progression (TTP) with gefitinib.

Methods

We retrospectively reviewed lung adenocarcinoma patients who received erlotinib after experiencing progression with gefitinib. Our primary objective was to evaluate the prognostic significance of erlotinib therapy.

Results

A total 42 lung adenocarcinoma patients were included in this study. Overall disease control rate was 59.5% (partial response [PR], 2.4%; stable disease [SD], 57.1%). Median overall survival was 7.1 months, and median progression-free survival was 3.4 months. The number of patients who achieved PR and non-PR (SD+ progressive disease [PD]) with gefitinib were 22 (52%) and 20 (48%), respectively. Patients with PR for gefitinib showed significantly longer survival times than those with non-PR (9.2 vs. 4.7 months; p = 0.014). In particular, among PR patients, those with TTP <12 months on gefitinib showed significantly longer survival times than those with TTP ≥12 months (10.3 vs. 6.4 months; p = 0.04).

Conclusions

Erlotinib may exert survival benefit for lung adenocarcinoma patients with less than 12 months of TTP of prior gefitinib who achieved PR for gefitinib.     

Effect of gefitinib on the survival of patients with recurrence of lung adenocarcinoma after surgery: A retrospective case-matching cohort study

BackgroundPatients with lung adenocarcinoma who carry epidermal growth factor receptor (EGFR) gene mutations respond remarkably well to EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, or erlotinib. However, the effect of EGFR-TKI treatment on the prolongation of overall survival (OS) of these patients remains uncertain, although several recent studies have shown prolongation of progression free survival compared with cytotoxic chemotherapy.MethodsA total of 304 patients with lung adenocarcinoma who had postoperative recurrent disease were studied. To eliminate potential biases as possible, the matching of four potential predictive factors of responsiveness to EGFR-TKI led to the identification of 81 pairs of patients (those who were treated with gefitinib and those who were not). A deletion mutation in exon 19 and a point mutation (L858R) in exon 21 of the EGFR gene were also analyzed. We compared the OS between the two groups.ResultsOS in the gefitinib group was significantly longer than in the control group (median, 63 vs. 41 months; p = 0.015). EGFR mutations were detected in 65 out of 129 patients (50%) in the whole sample. EGFR mutational status was not an independent prognostic factor of gefitinib benefit; rather, it was a predictive factor.ConclusionsThis study strongly suggested that gefitinib treatment improved OS of lung adenocarcinoma patients who had postoperative recurrence, especially those carrying EGFR mutations.     

晚期非小细胞肺癌3种EGFR-TKI 治疗的临床疗效及药物经济学分析

目的：从药物经济学角度对治疗晚期非小细胞肺癌的3种表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的临床疗效和成本原效果进行评价和分析,为临床合理用药提供参考。方法118例一线采用EGFR-TKI 治疗的晚期非小细胞肺癌患者分为3组：厄洛替尼组（38例）,吉非替尼组（43例）和埃克替尼组（37例）,均在治疗后评价疗效和药物不良事件,并运用药物经济学的成本原效果分析法进行研究。结果厄洛替尼组、吉非替尼组、埃克替尼组的有效率分别为71.05%、74.42%和67.57%（P >0.05）;药物不良事件发生率比较差异均无统计学意义（P 均>0.05）。3组的成本原效果比分别为268.30、201.63、182.28,埃克替尼组显著低于厄洛替尼组、吉非替尼组。结论本研究的3种 EGFR-TKI 用于晚期非小细胞肺癌的治疗均具有较好的治疗效果和安全性,其中埃克替尼是最经济的。     

Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: clinical benefit with optimal patient selection

Background

Recent reports have suggested that erlotinib therapy after gefitinib failure requires optimal patient selection to obtain clinical benefits in relapsed non-small cell lung cancer (NSCLC). However, insufficient evidence exists to determine which clinical factors best identify patients who benefit from erlotinib therapy.

Methods

One hundred twenty-five patients with relapsed NSCLC who had received erlotinib therapy after gefitinib failure were retrospectively evaluated between January 2008 and May 2009.

Results

The response rate (RR), disease control rate (DCR), and median progression-free survival (PFS) for all patients were 9% (95% confidence interval [CI], 5-15%), 44% (95% CI, 35-53%), and 2.0 months (95% CI, 1.4-2.5 months), respectively. The median survival time was estimated to be 11.8 months (95% CI, 6.4-16.0 months). Using multivariate analysis, good performance status (PS), EGFR mutation-positive status, and benefit from prior gefitinib therapy were identified as significant predictive factors for disease control. Using a proportional hazards model, benefit from prior gefitinib therapy, good PS, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies emerged as significant predictive factors for longer PFS. Thirty-two patients with concomitant PS 0/1, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies benefitted more from erlotinib therapy: RR, 25% (95% CI, 12-43%); DCR, 72% (95% CI, 53-86%); and median PFS, 3.4 months (95% CI, 2.4-4.9 months).

Conclusions

Higher efficacy of erlotinib after gefitinib failure can be achieved with proper patient selection criteria, including good PS, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies.     

靶向药物同步个体化放疗治疗晚期/转移性非小细胞肺癌的Ⅱ期临床研究

目的探索靶向药物吉非替尼或厄洛替尼同步个体化放疗治疗晚期/转移性非小细胞肺癌(NSCLC)的安全性和有效性,探索肿瘤综合治疗的新模式。方法 21例经病理组织学确诊的Ⅳ期NSCLC接受表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)吉非替尼或厄洛替尼同步胸部放疗。胸部放疗采用根治性为目的的适形放疗(CRT)和/或伽马射线立体定向放疗(γ-SBRT)。不良反应依据美国国立癌症研究院常见不良反应标准(NCI-CTCAE3.0)评价。主要研究终点为安全性,总生存(OS)和中位生存时间(MST)。次要研究终点为肿瘤局部控制率、肿瘤进展时间(TTP)、无进展生存(PFS)。结果吉非替尼或厄洛替尼同步个体化放疗的皮肤不良反应、消化道反应和血液学不良反应可控,没有导致严重的肺部不良反应。接受胸部放疗计划的患者中位肿瘤靶区容积(GTV)是55 cm~3(范围,5～420 cm~3),GTV边缘中位剂量是70Gy(范围,42～70Gy),中位生物等效剂量(BED)是105Gy(范围,60～119Gy)。EGFR-TKIs中位维持治疗时间是8.1个月(范围,1.9～29.0个月),EGFR-TKIs同步放疗没有发生治疗相关性死亡。中位随访10.0个月(范围,1.1～38.3个月),胸部肿瘤局部控制率为95%,中位TTP为5.8个月(范围,1.2～18.6个月),中位PFS为7.8个月(95%的可信区间,1.7～13.9个月),MST为21.8个月(95%的可信区间,5.3～38.4个月),1年PFS为39%,1年、2年和3年的OS分别为41%、24%和24%。结论靶向药物同步放疗安全有效,可以作为晚期/转移性NSCLC的治疗选择。     

Comparison of gefitinib versus erlotinib in patients with nonsmall cell lung cancer who failed previous chemotherapy

BACKGROUND:

Gefitinib and erlotinib are commonly used for salvage therapy in patients with nonsmall cell lung cancer (NSCLC) who have progressed on prior therapies. Although both agents have similar structure and have demonstrated efficacy in NSCLC, gefitinib and erlotinib have not been directly compared in terms of efficacy and other clinical outcomes in patients with NSCLC who have failed prior chemotherapy. This prompted us to analyze the clinical outcomes between gefitinib‐treated and erlotinib‐treated patients with metastatic or recurrent NSCLC.

METHODS:

A total of 467 patients with metastatic or recurrent NSCLC who had progressed on prior therapies and received gefitinib or erlotinib therapy between January 2006 and December 2008 were retrospectively reviewed. By using a matched‐pair case‐control study design, 171 pairs of gefitinib‐treated and erlotinib‐treated patients were matched according to sex, Eastern Cooperative Oncology Group (ECOG) performance status, histologic type, and smoking history.

RESULTS:

The median age of all patients was 58 years (range, 20‐85 years), and the median ECOG performance status was 1 (range, 0‐3). Of 342 patients, 294 (86%) received an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor as second‐line or third‐line therapy, whereas the remaining 14% had received >2 prior chemotherapy regimens before starting EGFR TK inhibitor therapy. The confirmed overall response rate was 35.1%, and the disease control rate was 64%. With 13.2 months of follow‐up, the median overall survival (OS) for the total 342 patients was 12.4 months (95% confidence interval [95% CI], 10.66‐14.14 months), and the median progression‐free survival (PFS) was 3.2 months (95% CI, 2.65‐3.75 months). The overall response rates and disease control rates in the gefitinib‐treated and erlotinib‐treated groups were 38% versus 32.2% (P = .273) and 63.2% versus 64.9%, respectively (P = .677). There was no statistically significant difference noted with regard to OS (median, 12.6 vs 12.1 months; P = 0.99) and PFS (median, 4.6 vs 2.7 months; P = .06) between the gefitinib‐treated and erlotinib‐treated groups.

CONCLUSIONS:

This retrospective analysis shows that gefitinib and erlotinib appear to have similar antitumor activity in terms of response rate and OS in pretreated patients with metastatic or recurrent NSCLC. Further prospective studies are warranted to elucidate any potential differences in toxicity and in dose intensity between gefitinib‐ and erlotinib‐treated patients. Cancer 2010. © 2010 American Cancer Society.     

Successful treatment of gefitinib-induced acute interstitial pneumonitis with high-dose corticosteroid: a case report and literature review

Cytotoxic chemotherapy offers a modest benefit for patients with advanced non-small cell lung cancer (NSCLC), with response rates of 20–35% and median survival of 10–12 months. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib are active against lung cancer. In retrospective studies, EGFR-TKI therapy among patients harboring EGFR mutations showed response rates higher than 65% and a median survival of 20–30 months. Gefitinib is well tolerated and less toxic compared to conventional cytotoxic drugs, but gefitinib-related interstitial lung disease (ILD) has been reported as a serious adverse effect. Although the mechanism remains unknown, multivariate analysis revealed male sex, history of smoking, and the coexistence of interstitial pneumonia or pre-existence of pulmonary fibrosis and poor performance status were all significant risk factors. Here, we reported a case of gefitinib pneumonitis with severe hypoxemia and impending respiratory failure who showed poor response to intermediate dose of systemic steroids but good recovery with high-dose pulse therapy.     

EGFR-TKI治疗非小细胞肺癌研究进展

吉非替尼和厄洛替尼均为小分子量表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),已在化疗失败的晚期非小细胞肺癌(NSCLC)解救治疗中取得疗效,但仅对特定人群发挥作用。EGFR- TKI联合化疗一线治疗NSCLC并未能提高疗效;正在进行的临床研究聚焦于优势人群EGFR-TKI一线治疗或联合化疗的研究。