吉非替尼治疗局部晚期或转移性非小细胞肺癌在中国的临床研究

背景与目的:吉非替尼是一种有效的表皮生长因子受体酪氨酸激酶选择性抑制剂,国外已批准用于治疗局部晚期或转移性的非小细胞肺癌(non鄄smallcelllungcancer,NSCLC)。本项研究系吉非替尼治疗中国NSCLC的注册临床研究,旨在评估吉非替尼对既往化学治疗失败的局部晚期或转移性中国NSCLC患者的疗效和安全性。方法:159例经病理学确诊的NSCLC患者进入本研究。吉非替尼剂量为每次250mg,每天一次口服,直至肿瘤进展或出现不可耐受的不良事件。结果:全组客观有效率为27.0%,疾病控制率为54.1%,中位无进展生存时间97天,中位生存期10个月,1年生存率44%。最常见的药物相关不良事件为皮疹(44.0%)、皮肤瘙痒(15.7%)和腹泻(10.1%),大部分为Ⅰ～Ⅱ级,不需处理。结论:吉非替尼对既往化疗失败的中国局部晚期或转移性NSCLC患者有较好的疗效和安全性。     

Long-term survival in three patients with metastatic non-small cell lung cancer treated with gefitinib

Gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), produces radiographic regression and symptom relief in patients with refractory advanced non-small cell lung cancer. However, it remains controversial whether gefitinib improves patient survival. We report three cases of refractory metastatic non-small cell lung cancer who have survived approximately 3 years since they first started gefitinib. These long-term survivors were Japanese female non-smokers with adenocarcinoma, who often had multiple lung metastases and were effectively re-treated with gefitinib. One patient had a surgical specimen available for DNA extraction and showed deletions in exon 19 of EGFR. Our experience suggests that gefitinib may improve long-term survival in selected patients. Further studies are required to identify biomarkers downstream of the EGFR mutations that are involved in multiple lung metastases and which could identify those patients who may benefit from gefitinib re-treatment.     

Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer

BACKGROUND: Only 15% of patients with non-small cell lung cancer (NSCLC) treated with oral epidermal growth factor tyrosine kinase inhibitor gefitinib, as a second-line therapy have objective responses. Fifty percent will have improvement of lung cancer related symptoms. It will be critical to identify patients who will benefit clinically from this therapy even when there is no objective response seen on imaging studies. We have performed a retrospective analysis of 76 patients who received gefitinib as a therapy for previously treated metastatic NSCLC at the University of Minnesota Comprehensive Cancer Center in order to describe characteristics of patients who will likely derive benefits from gefitinib therapy. METHODS: All patients treated with gefitinib therapy at the University of Minnesota from September 2001 to January 2004 were entered into the study. The Log-rank Test and Cox proportional hazards regression were used to assess the effect of the number of previous therapy lines, histology subtype, performance status, gender, stage of disease at initial diagnosis, and presence of skin rash on time to disease progression and overall survival (OS). Fisher's Exact Test and multiple logistic regressions were used to assess the effect of these covariates on disease response. RESULTS: Seventy-six patients entered the study, with a median age of 60 years (range 37-82). There were 37 female and 39 male patients; 47 patients had adenocarcinoma, 22 had squamous and 7 had other NSCLC histologies. Six patients had no prior therapy, 23 had one, 32 had two, 8 had three, and 7 had four prior therapies for lung cancer. Fifty-six were current smokers. Median time to disease progression was 3 months (95% CI: 3.0, 6.0). There was no difference in time to disease progression whether patients had one or more prior therapies. Patients with brain metastases (26 patients) benefited from gefitinib therapy at least equally well as those without brain metastatic disease. Patients with adenocarcinoma histology with bronchoalveolar features had superior median time to progression versus other lung cancer histology (14 months versus 3 months, p=0.076), which translated into survival advantage in this group >24 months (95% CI: 0.76, 24+) versus 6.6 months (p=0.0096). Patients with EGFR positive tumors had median survival of 10.2 months (95% CI: 1.45, 16.94) versus 3.7 months (95% CI: 2.66, 4.74) with EGFR negative tumors. Patients who developed any degree of skin rash had prolonged time to disease progression with median of 6 months (95% CI: 2.56, 15.5) versus patients without skin rash median 3 months (95% CI: 1.43, 2.83) (p=0.023). This last factor was the best predictor of improved time to disease progression in multiple regression analysis (p=0.0405). CONCLUSION: A subgroup of patients with NSCLC will benefit from gefitinib therapy. Objective responses will likely be seen in half the patients with mutation of internal domain of EGFR; however, a larger group of patients will also enjoy prolonged disease stabilization and clinical benefit. We suggest that adenocarcinoma with bronchoalveolar features and the presence of skin rash may be used as predictors of gefitinib benefit.     

吉非替尼治疗化疗失败的局部晚期或转移性非小细胞肺癌疗效及生存的预测因素

背景与目的吉非替尼是一种选择性表皮生长因子受体酪氨酸激酶抑制剂(EGFRTKI),已被证实为治疗化疗失败的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的有效药物,其治疗亚洲晚期NSCLC患者的疗效与联合化疗的疗效相当。国外的临床研究结果显示,种族、性别、吸烟史及组织病理类型被认为是吉非替尼疗效及生存的相关因素。但在亚洲人群中,吉非替尼疗效及生存的预测因素尚未清楚。本研究回顾分析了中国153例局部晚期或转移性NSCLC患者的接受吉非替尼治疗的情况,旨在分析疗效与生存的预测因素。方法对2003年11月至2004年6月,参加吉非替尼在中国的注册临床研究的153例NSCLC患者的临床、病理特征与疗效及生存的相关情况进行了回顾性分析。疗效相关性采用χ2检验及Logistic回归分析分别进行单因素及多因素分析;生存分析运用Logrank检验及Kaplan-Meier、Cox回归分析分别进行单因素及多因素分析。结果153例可评价的患者中,多因素分析显示年龄≤65岁及从初诊到吉非替尼治疗的时间间隔≥6个月者,与客观有效率明显相关(P<0.05)。中位随访时间10.0个月(0.5~16.8个月),中位生存期为10.3个月(95%CI,8.1~12.6个月),1年生存率为44.1%。COX回归分析显示,PS评分0~1、末次化疗达疾病控制以及吉非替尼治疗达疾病控制是生存的独立预后因素(P<0.05)。结论吉非替尼对既往化疗失败的局部晚期或转移性NSCLC的中国患者有较好的疗效。年龄≤65岁及从初诊到吉非替尼治疗的时间间隔为≥6个月是吉非替尼疗效的预测因素。PS评分0~1、末次化疗达疾病控制及吉非替尼治疗达疾病控制是生存的独立预后因素。     

吉非替尼对晚期非小细胞肺癌患者生活质量的改善

Objective  

The aim of this study was to evaluate the effect of gefitinib on improvement of quality of life (QoL) of patients with advanced non-small cell lung cancer (NSCLC).     

Prolonged survival of gefitinib treatment in patients with advanced and previously treated non-small cell lung cancer

The purpose of this study was to evaluate the survival outcome in patients with advanced and previously treated non-small cell lung cancer given gefitinib (GEF) at our institution. We reviewed the clinical records of 70 Japanese patients,among whom 33 received several chemotherapy treatment modalities including GEF monotherapy (GEF group), and the other 37 were given several chemotherapy treatment modalities without GEF monotherapy (non-GEF group). The median survival time (MST) after second-line chemotherapy in the GEF group was 527 days with 1-year and 2-year survival rates of 59% and 26%, respectively. The MST in the non-GEF group was 175 days with 1-year and 2-year survival rates of 21% and 16%, respectively. Overall survival after second-line chemotherapy in the GEF group was significantly longer than in the non-GEF group (hazard ratio 1.93; 95% confidence interval 1.15-3.53, p=0.014). In our limited clinical experience, chemotherapy treatment including GEF monotherapy appeared to have longer survival than non-GEF treatment.     

Clinical prognostic model for older patients with advanced non-small cell lung cancer

BackgroundOlder patients with non-small cell lung cancer (NSCLC) are often not prescribed standard therapy. It is important to know which older patients would be candidates for aggressive therapy based on their prognosis, and to develop a model that can help determine prognosis.MethodsData on older patients (≥70 years) enrolled on 38 NCI cooperative group trials of advanced NSCLC from 1991 to 2011 were analyzed. Multivariable Cox PH model was built with a stepwise selection. We derived a prognostic score using the estimated Cox PH regression coefficient. We then calculated the area under receiver operating characteristic (ROC) curve of survival in the testing set.ResultsThe final analysis included 1467 patients, who were randomly divided into a training (n = 963) and a testing set (n = 504). The prognostic risk score was calculated as: 3 (if male) + 3 (if PS = 1) + 8 (if PS = 2) + 11 (if initial stage = IV) + 4 (if weight loss). Patients were classified into two prognostic groups: good (0–8) and poor (≥9). The median survival in the two groups in the testing set were 13.15 (95% CI, 10.82–15.91) and 8.52 months (95% CI, 7.5–9.63), respectively. The model had area under the 1-year and 2-year ROCs (0.6 and 0.65, respectively) that were higher than existing models.ConclusionsMale gender, poor performance status, distant metastases and recent weight loss predict for poor overall survival (OS) in older patients with advanced NSCLC. This study proposes a simple prognostic model for older adults with advanced NSCLC.     

Phase II study of plitidepsin in pretreated patients with locally advanced or metastatic non-small cell lung cancer

OBJECTIVE: To evaluate the progression-free rate (PFR) at 3 months (13+/-1 weeks), antitumor response, time-to-event efficacy endpoints, and toxicity profile of plitidepsin administered as a 3-h continuous i.v. infusion at a dose of 5mg/m(2), every 2 weeks, to patients with chemotherapy pretreated advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a multicenter, non-randomized, exploratory, phase II study. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. PFR (primary efficacy endpoint) and objective response rate (secondary efficacy endpoint) were evaluated according to RECIST, while the toxic profile of plitidepsin was assessed using the NCI-CTC, version 2.0. RESULTS: A total of 21 patients with a median age of 61 years and with locally advanced or metastatic non-resectable NSCLC, who had previously received only one line of chemotherapy in an advanced setting, received a total of 54 cycles of treatment (median of two cycles per patient; range: 1-8). Antitumor activity was seen in 3 (1 PR, 2 SD) out of 17 evaluable patients according to RECIST. One patient was responder for the primary (PFR at 13+/-1 weeks) and secondary efficacy endpoint (stable disease according to RECIST). Other two patients were non-responders for the primary efficacy endpoint, but had stable disease (not confirmed at weeks 13+/-1 due to previous withdrawal due to adverse events). With a median follow-up of 12.3 months, the median time to progression (TTP) and the median overall survival (OS) were 1.2 months and 4.3 months, respectively. The incidence of plitidepsin-related toxicities was low and most of them were mild-to-moderate in severity. The most common side effects were anemia, and asymptomatic and non-cumulative increases of gamma-glutamyltransferase (GGT) and liver transaminase levels. CONCLUSION: This study shows that plitidepsin 3-h continuous i.v. infusion (5mg/m(2)) every 2 weeks, was feasible and well tolerated in patients with pretreated NSCLC. The lack of evidence of antitumor activity precludes further studies with this plitidepsin schedule in this tumor setting.     

EGFR基因CA—SSR多态与晚期非小细胞肺癌吉非替尼临床疗效的关系

目的 研究EGFR基因第1内含子区CA-SSR多态性与晚期非小细胞肺癌患者吉非替尼临床疗效的相关性.方法 对80例接受过吉非替尼治疗的晚期非小细胞肺癌患者进行了分析.采用PCR扩增和直接序列测定的方法确定这80例肺癌患者外周血DNA样本中CA-SSR多态的基因型,统计学分析CA-SSR多态性与患者临床疗效的相关性.结果 80例患者中共检测到11种不同CA-SSR等位基因型,包含的cA重复序列数为10-24.携带短CA重复序列的患者(至少一条等位基因CA重复数≤16)吉非替尼治疗后的临床获益率为88.0%,而在长CA重复序列的患者(两条等位基因CA重复数均＞16)为50.9%,CA-SSR多态性与近期疗效具有显著的相关性(P=0.005),但两组患者的无进展生存和总生存差异均无显著性.结论 EGFR基因第1内含子区CA-SSR多态性可以应用于临床预测晚期非小细胞肺癌患者吉非替尼的近期疗效.     

Serum tumor markers as predictors for survival in advanced non-small cell lung cancer patients treated with gefitinib

BACKGROUND: Though the imaging-based response (IBR) is the most frequently used index of the therapeutic effect in cancer patients, an index based on serum tumor markers might prove to be useful, especially in patients without measurable tumors. METHODS: Paired pre- and post-treatment serum tumor markers (CEA, CA-125, and CA-199) were measured in 89 of 100 registered non-small cell lung cancer (NSCLC) patients who received gefitinib. Correlation and agreement analyses between the IBR at the 8th week and the tumor marker response (TMR) at the 4th or the 8th week were performed in patients with measurable lesions (n=68). Analysis of survival in relation to TMR was performed in all patients and in patients with no measurable lesions (n=21). RESULTS: IBR was closely correlated with individual tumor marker responses and the response of all 3 markers combined at 4 weeks (P values ranged from <0.001 to 0.002). The agreements were also significant (P values ranged from 0.001 to 0.004). In the whole group, 4-week TMR was predictive for progression-free survival (P values ranged from <0.0001 to 0.0086). In patients without measurable lesions, differences in progression-free survival and overall survival were closely correlated with the 4-week CA-125 response, CA-199 response, and TMR(overall) (P values ranged from 0.0002 to 0.0399). However, the correlation between the 8-week TMR and either IBR or survival was not significant. CONCLUSIONS: In gefitinib-treated NSCLC patients, correlation was good between 4-week TMR and IBR. Four-week TMR was predictive for survival. TMR may serve as a tool for assessing the gefitinib response in patients without measurable lesions.     

加速康复外科理念在行腹腔镜膀胱根治性切除术患者围术期中应用的临床观察#br#

目的探讨加速康复外科（ERAS）理念在腹腔镜膀胱根治性切除中应用的有效性和安全性。 方法收集2015年6月至2017年6月潍坊市人民医院收治的58例膀胱癌患者,分为传统组（n=28）和ERAS组（n=30）。比较两组患者的手术时间、手术出血量、术后排气时间、术后重度疼痛的发生数、麻醉苏醒时间、盆腔引流时间、术后住院天数以及术后并发症的发生情况。 结果ERAS组和传统组手术时间分别为（1722±379）min和（1873±218）min;术中出血量分别为（1597±465）ml 和（1771±469）ml,差异均无统计学意义（P＞005）。ERAS组和传统组麻醉苏醒时间分别为（254±54）min和（417±98）min;术后排气时间分别为（16±07）d和（22±07）d;盆腔引流时间分别为（25±11）d和（50±16）d;术后住院天数分比为（76±14）d和（110±18）d;术后疼痛VAS评分＞7分发生率分别为100％（3／30）和429％（12／28）;两组差异均有统计学意义（P＜005）。ERAS组1例刀口液化,1例发生肾结石;传统组2例肠梗阻,1例发生坠积性肺炎,1例发生肾结石。两组患者中均无尿瘘患者。 结论加速康复外科理念在腹腔镜下膀胱根治性切除术患者中的临床应用是安全、有效的,可加速患者的术后康复,值得临床推广应用。     

晚期非小细胞肺癌吉非替尼治疗性别与疗效相关性分析

目的:探讨吉非替尼对不同性别晚期非小细胞肺癌(NSCLC)患者的疗效和安全性。方法:选择化疗失败的晚期NSCLC患者74例,分为女性组(36例)和男性组(38例),应用吉非替尼进行单药治疗,口服剂量为250 mg/d。分析两组治疗疗效和安全性。结果:女性组和男性组的总有效率(47.2%vs 26.3%,P=0.062)以及中位无进展生存期(7.9个月vs 5.7个月,P=0.093)差异均无统计学意义;而其中女性腺癌患者的有效率(53.8%)与以及中位无进展生存期(10.1个月)明显优于男性鳞癌患者,差异均有统计学意义,P值均<0.05。两组的不良反应相似主要为皮疹和腹泻。结论:对于晚期NSCLC患者,在无检测表皮生长因子受体(EGFR)情况下,合理选择优势人群,应用分子靶向药物吉非替尼治疗,疗效较高,能有助于提高NSCLC临床个体化治疗水平。     

吉非替尼与厄洛替尼二线治疗EGFR基因敏感突变晚期NSCLC患者的疗效观察

目的 探讨吉非替尼与厄洛替尼二线治疗EGFR基因敏感突变非小细胞肺癌（non-small cell lung cancer,NSCLC）患者的临床疗效和安全性。方法 选择我院2013年3月至2015年2月收治的一线化疗失败的EGFR基因敏感突变晚期NSCLC患者50例,按随机数字表法平均分为两组,一组接受吉非替尼（吉非替尼组）250 mg/d治疗,另一组接受厄洛替尼（厄洛替尼组）150 mg/d治疗,观察无进展生存时间（PFS）、总有效率（ORR）、疾病控制率 （DCR）和药物的毒副反应。结果 吉非替尼组和厄洛替尼组的中位PFS、ORR、DCR分别为（6.5±1.2）个月、60%、92%和（7.2±0.9）个月、56%、88%,差异均无统计学意义（P＞0.05）。吉非替尼组和厄洛替尼组的毒副反应发生率分别为32%和60%,差异具有统计学意义（P＜0.05）。结论 吉非替尼和厄洛替尼均能有效地二线治疗EGFR基因敏感突变晚期NSCLC患者,疗效相当,但吉非替尼治疗的毒副反应发生率明显低于厄洛替尼。     

The relationship between drug exposure and clinical outcomes of non-small cell lung cancer patients treated with gefitinib

The objective of this study was to explore the relationship between gefitinib exposure and clinical outcome in gefitinib-treated patients with advanced non-small cell lung cancer. Thirty patients participated in this pharmacokinetic study and received 250-mg oral doses of gefitinib once daily. Blood samples were collected before dosing and on days 7, 14, 21, and 28. The plasma concentrations of gefitinib were evaluated using a validated high-performance liquid chromatographic method with tandem mass spectrometric detection. Univariate and multivariate analyses were performed to determine predictive factors for response and survival of patients. EGFR mutations were analyzed retrospectively. Median survival time (MST) was 9.97 months (95%CI 2.79–17.14 months). The geometric mean trough gefitinib plasma concentration (C _min^ss) was 266 ng/ml (range 94–538 ng/ml). In the multivariate analysis, only skin rash was associated with gefitinib-induced disease control (P = 0.017); Adenocarcinoma, skin rash, and ‘high’ C _min^ss (C _min^ss ≥ 200 ng/ml) were independently associated with overall survival (P = 0.004, 0.028,0.007, respectively). MST of EGFR wild-type patients with ‘high’ C _min^ss was longer than that with ‘low’ C _min^ss (P = 0.002). Our study results show that pharmacokinetic variability may also account for the different outcomes following treatment with gefitinib for patients with wild-type EGFR. Further studies are needed to confirm these results.     

吉非替尼治疗晚期非小细胞肺癌49例疗效分析

肺癌是临床上最常见的恶性肿瘤,约占所有恶性肿瘤死亡的25%～30%。大多数患者在明确诊断时已为局部晚期或远处转移,失去根治性手术的机会。吉非替尼是表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor- tyrosine kinase inhibitor,EGFR-TKI),既能抑制肿瘤的增殖、侵犯,又能抑制肿瘤新生血管生成,同时还能诱导肿瘤细胞     

吉非替尼治疗晚期非小细胞肺癌的临床观察

目的:研究吉非替尼对晚期非小细胞肺癌(NSCLC)的疗效.方法:收集13例晚期NSCLC患者,口服吉非替尼250mg/d,直到病情进展或因不良反应不能耐受为止,观察其疗效及不良反应.结果:21例中部分缓解(PR)10例,稳定(SD)7例,进展(PD)4例,缓解率47.6%,疾病控制率80.9%.结论:吉非替尼治疗晚期NSCLC患者有一定疗效,不良反应轻.     

诱导化疗后吉非替尼维持治疗晚期非小细胞肺癌的临床研究

目的：评价晚期非小细胞肺癌（ＮＳＣＬＣ）诱导化疗后给予吉非替尼单药维持治疗的临床价值。方法：２００２年５月～２００５年２月,晚期ＮＳＣＬＣ患者根据最后一个化疗方案疗效分为两组,疗效为部分缓解（ＰＲ）或稳定（ＳＤ）的为吉非替尼维持治疗组,疗效为进展（ＰＤ）的为吉非替尼解救治疗组。入组后给予口服吉非替尼治疗,每日１次,每次２５０ｍｇ,持续服用到疾病进展。结果：共有１１９例患者入组,其中吉非替尼维持治疗组为７９例,解救治疗组为４０例。维持治疗组总有效率（ＲＲ）３１.６％（２５／７７）,其中３例ＣＲ,解救治疗组ＲＲ为２７.５％（１１／４０）,两组之间无统计学差异（Ｐ＝０.６４５）。吉非替尼维持治疗组的进展时间（ＴＴＰ）为６.０个月,显著长于解救治疗组的４.０个月（Ｐ＝０.０３）。维持治疗中位生存期（ＯＳ）为１１.０个月,而解救治疗组的中位ＯＳ为７.０个月,二者差异具有统计学意义（Ｐ＝０.０１９）。维持治疗组中腺癌患者的有效率显著高于鳞癌患者（３９.７％ ｖｓ.１２.５％,Ｐ＝０.０４１）,ＴＴＰ也显著长于鳞癌患者（７.５个月ｖｓ．３.０个月,Ｐ＝０.０２）;女性患者的中位ＯＳ显著长于男性患者（１８.５个月ｖｓ．９.０个月,Ｐ＝０.００２）。毒副作用多数较轻,且可逆,以１、２级为主。结论：吉非替尼作为晚期ＮＳＣＬＣ诱导化疗后的维持治疗,有较好的疗效和安全性。与化疗进展后再使用吉非替尼方案相比,化疗未进展时使用能更好地发挥该药的优势,给予患者更大的生存获益。     

吉非替尼治疗晚期非小细胞肺癌的临床观察

目的：研究吉非替尼对晚期非小细胞肺癌（NSCLC）的疗效。方法：收集13例晚期NSCLC患者,口服吉非替尼250mg/d,直到病情进展或因不良反应不能耐受为止,观察其疗效及不良反应。结果：21例中部分缓解（PR）10例,稳定（SD）7例,进展（PD）4例,缓解率47.6%,疾病控制率80.9%。结论：吉非替尼治疗晚期NSCLC患者有一定疗效,不良反应轻。     

Efficacy and safety of gefitinib in chemonaive patients with advanced non-small cell lung cancer treated in an Expanded Access Program

Chemotherapy (CT) is recommended in numerous clinical guidelines for advanced non-small cell lung cancer (NSCLC) and offers improved survival over best supportive care. However, many patients with advanced NSCLC never receive CT because of advanced age, poor performance status, comorbidities, or patient refusal. The epidermal growth factor receptor tyrosine kinase inhibitor gefitinib has shown antitumor activity and a favorable toxicity profile in pretreated patients with recurrent advanced NSCLC and was made available in a worldwide Expanded Access Program (EAP) to >37,000 patients who did not respond to standard treatment or were ineligible for or refused CT. A retrospective chart review of 1671 consecutive patients enrolled at 11 sites in the US arm of the EAP identified 198 patients with advanced NSCLC who had not received previous CT. All patients were treated with gefitinib 250 mg/d until treatment failure or toxicity occurred. Patients were treated for a mean of 4.7 months. The most common adverse events were diarrhea (31.3%) and rash (31.3%). Complete and partial response rates were 0.7 and 5.6%, respectively, and 40.6% had stable disease. Median survival was 6 months, and estimated 1-year survival was 29.7%. The majority of patients did not receive subsequent CT.