吉非替尼记名供药计划治疗晚期复发非小细胞肺癌的疗效和预后因素分析

目的 研究吉非替尼治疗中国晚期非小细胞肺癌(NSCLC)患者的安全性和疗效.方法 2002年9月至2005年3月共入选晚期复发NSCLC患者120例,其中可评价疗效者103例.给予吉非替尼口服每次250 mg,每天1次,用药1个月后首次进行影像学疗效评价,此后每2～3个月复查影像学,直至出现病情进展或出现不能耐受的不良反应.停止吉非替尼治疗后,每6个月随访1次,直至患者死亡或随访结束.结果 103例患者的客观有效率为18.4%(19/103),疾病控制率为51.5%(53/103),中位疾病进展时间(TTP)为3个月(0.2～40个月),中位生存时间(MST)为9.8个月(0.5～51个月),1、2和3年生存率分别为44.7%、26.4%和13.2%.全组共有41例患者的TTP≥6个月,其MST为25.5个月.Cox多因素分析显示,腺癌、治疗后出现皮疹、体力状态(PS)评分<2分的患者具有更长的,TTP,而PS评分<2分、获得疾病控制的患者具有更长的生存期.本组患者的不良反应主要为皮疹、皮肤干燥、腹泻和转氨酶升高,多为Ⅰ～Ⅱ度.结论 吉非替尼对于部分晚期复发的NSCLC患者有效,部分疾病控制者具有较长的生存期,而不良反应可耐受.     

吉非替尼治疗化疗失败的晚期非小细胞肺癌临床观察

目的：评价吉非替尼治疗化疗失败的晚期非小细胞肺癌（NSCLC）的疗效及不良反应。方法：对68例化疗失败的经病理或细胞学证实的晚期NSCLC患者给予吉非替尼250mg,qd,口服,至病情进展或出现不可耐受的不良反应。结果：68例患者中,CR 1例,PR 20例,SD 23例,PD 24例。有效率30.88%（21/68）,疾病控制率为64.71%（44/68）;全组中位疾病进展时间（TTP）为5.2个月,中位生存时间为9.3个月,1年生存率为52.94%（36/68）。与药物相关的不良反应主要为Ⅰ、Ⅱ度皮疹和腹泻,皮疹发生率为26.47%（18/68）,腹泻发生率为19.12%（13/68）,多在用药后1周内出现,症状轻不需特殊处理。1例出现Ⅰ度转氨酶升高。结论：吉非替尼治疗化疗失败的晚期非小细胞肺癌安全有效,不良反应轻微,患者耐受性和依从性良好。     

吉非替尼治疗化疗失败的晚期非小细胞肺癌临床观察

目的:评价吉非替尼治疗化疗失败的晚期非小细胞肺癌(NSCLC)的疗效及不良反应。方法:对68例化疗失败的经病理或细胞学证实的晚期NSCLC患者给予吉非替尼250mg,qd,口服,至病情进展或出现不可耐受的不良反应。结果:68例患者中,CR 1例,PR 20例,SD 23例,PD 24例。有效率30.88%(21/68),疾病控制率为64.71%(44/68);全组中位疾病进展时间(TTP)为5.2个月,中位生存时间为9.3个月,1年生存率为52.94%(36/68)。与药物相关的不良反应主要为Ⅰ、Ⅱ度皮疹和腹泻,皮疹发生率为26.47%(18/68),腹泻发生率为19.12%(13/68),多在用药后1周内出现,症状轻不需特殊处理。1例出现Ⅰ度转氨酶升高。结论:吉非替尼治疗化疗失败的晚期非小细胞肺癌安全有效,不良反应轻微,患者耐受性和依从性良好。     

吉非替尼治疗晚期非小细胞肺癌的临床观察

肺癌是目前全世界发病率和死亡率最高的恶性肿瘤,其中非小细胞肺癌（non—smallcelllungcancer,NSCLC）占肺癌的80％～85％,其5年生存率〈15％。非小细胞肺癌患者就诊时25％-30％已是局部晚期,40％～50％有远处转移,这类患者无法手术,只能进行放、化疗。常用一线治疗方案是铂类药物联合第三代细胞毒性药物联合化疗,但有效率仅为35％～40％,中位生存期为8—10个月,1年生存率约为35％。     

吉非替尼治疗非小细胞肺癌研究进展

表皮生长因子受体(EGFR)是一种受体型酪氨酸激酶,在非小细胞肺癌中过表达或突变,通过其下游的信号传导通路,促进细胞的增殖和血管形成,同时抑制肿瘤细胞凋亡.因此,选择性地抑制表皮生长因子受体介导的信号传导途径以达到肿瘤治疗的目的已成为近年来研究的热点.其中研究较多的是酪氨酸酶抑制剂吉非替尼,本文从吉非替尼的作用机制和临床应用,对吉非替尼敏感的非小细胞肺癌患者的筛选,吉非替尼的获得性耐药问题这三个方面,对近年来的研究综述如下.     

吉非替尼获得性耐药的非小细胞肺癌患者临床特点

背景与目的：以吉非替尼为代表的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)在改善晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)疗效与生活质量中的作用已经得到国际多中心临床研究的充分肯定。但对EGFR-TKI有良好疗效的NSCLC患者不可避免地会发生获得性耐药,这将直接影响到EGFR-TKI的疗效。本研究旨在分析NSCLC患者经过吉非替尼治疗后引起获得性耐药的临床特点。方法：回顾性分析了从吉非替尼中获益的NSCLC患者。所有的资料来自2007年1月—2014年1月新疆肿瘤医院的住院患者。对吉非替尼治疗失败患者的获得性耐药的临床表现、疾病进展时间(time to progress,TTP)及进展后生存时间(post-progression survival,PPS)进行回顾性分析。结果：共收集417例NSCLC患者。中位TTP为10.2个月(95%CI：9.5~10.9)。其中女性、不吸烟、肺腺癌患者的TTP显著延长。发生获得性耐药时,63.3%的患者出现恶化症状。疾病进展情况如下：209例(58.4%)原发肺部病变出现进展,137例(38.3%)既往有转移的病变出现进展,194例(54.2%)出现新发转移。表皮生长因子受体(epidermal growth factor receptor,EGFR)野生型比突变型患者有更多的症状恶化、新发的中枢神经系统(central nervous system,CNS)转移的倾向。外显子19缺失和L858R突变的患者在新发转移上有很大不同(41.4% vs 6.3%,P=0.02)。PPS为8.9个月(95%CI：7.4~10.4)。吸烟史、体能状况(performance status,PS)评分、新CNS病变和随后的化疗是PPS的独立因素。结论：获得性耐药的临床表现根据EGFR突变状态和EGFR突变基因型可能会有所不同。此外,在吉非替尼治疗后获得性耐药的NSCLC患者,再进行后续的化疗也带来与PPS有关的临床受益。     

吉非替尼治疗非小细胞肺癌研究进展

表皮生长因子受体（EGFR）是一种受体型酪氨酸激酶,在非小细胞肺癌中过表达或突变,通过其下游的信号传导通路,促进细胞的增殖和血管形成,同时抑制肿瘤细胞凋亡。因此,选择性地抑制表皮生长因子受体介导的信号传导途径以达到肿瘤治疗的目的已成为近年来研究的热点。其中研究较多的是酪氨酸酶抑制剂吉非替尼,本文从吉非替尼的作用机制和临床应用,对吉非替尼敏感的非小细胞肺癌患者的筛选,吉非替尼的获得性耐药问题这三个方面,对近年来的研究综述如下。     

吉非替尼治疗晚期非小细胞肺癌36例临床观察

目的吉非替尼(gefitinib,iressa,ZD1839)系一表皮生长因子受体(EG- FR)酪氨酸激酶抑制剂(TKI),主要治疗非小细胞肺癌(NSCLC),临床观察吉非替尼治疗晚期非小细胞肺癌的疗效及毒副作用。方法不能耐受化疗或化疗失败的晚期非小细胞肺癌患者36例,其中属于二线或二线以上治疗者占66.7%(24/36),使用吉非替尼250mg,1次/日,口服,服药时间至少30天,定期进行客观疗效及毒副作用评价,一旦出现不可耐受的毒副作用或疾病进展即停药。结果使用吉非替尼口服治疗晚期NSCLC共36例,全组随访时间2～22个月,其中CR1例,PR13例,NC12例,PD11例,客观缓解率38.9%(14/36),有效患者中位缓解时间为7.5个月,疾病控制率(CR PR NC)为69.4%(26/36)。中位肿瘤进展时间(mTTP)为3.5个月。1年生存率为38.9%(14/36),肿瘤相关症状缓解率为55.6%(20/36)。常见毒副作用为Ⅰ、Ⅱ度皮疹和腹泻,Ⅲ度不良反应仅占5.6%(2/36),且无因毒副作用严重而停药者。结论gefitinib治疗晚期非小细胞肺癌疗效明显,临床获益率高达69.4%,不吸烟、腺癌、女性患者客观缓解率及生存期更好。不良反应轻,耐受性和顺从性较好,是晚期NSCLC患者最佳选择之一。对不能耐受化疗的晚期非小细胞肺癌患者一线治疗可获得较好的疗效,(症状好转比病灶缓解对生存期更有益),有望成为晚期非小细胞肺癌二线或一线的标准治疗。     

吉非替尼治疗化疗失败的晚期非小细胞肺癌疗效观察

目的观察吉非替尼治疗化疗失败的晚期非小细胞肺癌(NSCLC)的疗效及毒副反应。方法对32例化疗失败的晚期NSCLC患者给予吉非替尼250 mg,口服,每天1次,至病情进展或出现不可耐受的毒副反应。结果 32例患者中,CR 0例(0.00%),PR 8例(25.00%),SD 13例(40.62%),PD 11例(34.38%),有效率为25.00%,疾病控制率为65.62%,中位疾病进展时间为5.2个月,中位生存时间为9.3个月,1 a生存率为34.38%。结论吉非替尼治疗晚期NSCLC有较好的疗效,毒副反应可耐受。     

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。     

Efficacy and tolerability of gefitinib in pretreated elderly patients with advanced non-small-cell lung cancer (NSCLC)

The activity and toxicity profile of gefitinib in non-small cell lung cancer (NSCLC) patients aged 70 years or older has been only partially evaluated. The aim of this study was to evaluate the response rate and safety of gefitinib in elderly NSCLC patients. Elderly NSCLC patients pretreated with chemotherapy and with at least one measurable lesion received gefitinib at the daily dose of 250 mg until disease progression, unacceptable toxicity or refusal. From August 2001 to May 2003, 40 consecutive elderly patients have been enrolled onto the study in three Italian institutions. We observed one complete (2.5%) and one partial response (2.5%), 18 disease stabilisations (NC: 45%) lasting at least 2 months, including six patients (15%) who had disease stabilisation of 6 months or longer, for an overall disease control rate of 50% (95% CI: 34.5-65.5%). The median duration of response was 4.4 months (range 1.7-9.2). The side effects were generally mild and consisted of diarrhoea and skin toxicity. Grade 1-2 diarrhoea occurred in 23.6%, and one patient experienced grade 4 diarrhoea, requiring hospitalisation. Grade 1-2 skin toxicity, including rash, pruritus, dry skin, and acne, occurred in 20 patients (52.6%). Gefitinib is safe and well tolerated in elderly pretreated NSCLC patients. The disease-control rate achieved suggests that this drug could represent a valid option in the management of this unfavourable subgroup of patients.     

Paclitaxel/cisplatin in advanced non-small-cell lung cancer (NSCLC)

Background: Paclitaxel (Taxol^®) as single agent has shownpromising activity in advanced non-small-cell lung cancer (NSCLC).Because paclitaxel lends itself to combination with other anticancerdrugs, we have determined the efficacy of paclitaxel combinedwith cisplatin in patients with advanced NSCLC in a phase IItrial Patients and methods: Twenty patients with NSCLC stage IIIBor IV were treated with paclitaxel (175 mg/m²) as a 3-hour infusionafter standard premedication on day 1 and cisplatin (50 mg/m²daily) on days 1 and 2. Treatment was repeated every 3 weeks Results: All 20 patients were evaluable for response and toxiceffects. Partial responses were seen in 7 (35%) patients andno change in 9 (45%) patients. Major side effects included leukopenia,anemia, alopecia and dose-limiting neurotoxicity chemotherapy, cisplatin, neurotoxicity, non-small-cell lung cancer, paclitaxel, phase II trial, Taxol^®     

Predictive factors associated with prolonged survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib

This study aimed to identify predictive factors associated with prognostic benefits of gefitinib. A total of 221 Japanese patients who received gefitinib (250 mg day(-1)) were examined retrospectively and potential predictive factors analysed. Overall response rate (ORR) was 24.4% and median survival time (MST) was 8.0 months. In a log-rank test, survival was significantly better in females, patients with adenocarcinoma, never-smokers, favourable performance status (PS) and patients with epidermal growth factor receptor (EGFR) mutation. The lower the smoking exposure (Brinkman Index (BI)=cigarettes per day x years smoked), the better the MST (BI 0: 14.5 months, BI <500: 9.5 months, BI 500 to <1000: 6.9 months, BI > or =1000: 4.0 months). Positive-EGFR mutation status and PS 0-1 were independent predictors of favourable prognosis by multivariate analysis. Prognosis was significantly different according to EGFR mutation status (with the same smoking status), but not according to smoking status (with the same EGFR mutation status). EGFR mutation status is the most important independent predictor of survival benefit with gefitinib treatment. Although differences in prognosis were observed according to relative smoking status and smoking exposure, the results suggested that smoking is not a direct predictor of prognosis, yet is a surrogate marker of EGFR mutation status.     

厄洛替尼治疗晚期非小细胞肺癌的临床观察

目的 观察厄洛替尼单药治疗晚期非小细胞肺癌(NSCLC)的疗效和不良反应.方法 104例晚期NSCLC患者给予厄洛替尼150 mg口服治疗,每日1次,服用至疾病进展或出现不可耐受的不良反应.采用实体瘤的疗效评价标准评价疗效.采用美国国家癌症研究所毒性评价标准评价不良反应.结果 104例患者均可评价疗效,客观有效率为27.9%(29/104),疾病控制率为76.0%(79/104),中位无进展生存时间为5.1个月,中位生存时间为13.1个月,1年总生存率为61.5%.多因素生存分析显示,PS评分为0～1分、腺癌和治疗后出现皮疹的患者具有显著的生存优势(均P<0.05);而吸烟和肝转移则显著增加了死亡风险(均P<0.05).厄洛替尼治疗晚期NSCLC最常见的不良反应是皮疹和腹泻,发生率分别为73.1%和41.3%.不良反应多为1～2级,3～4级不良反应的发生率仅为6.7%.结论 厄洛替尼治疗晚期NSCLC的疗效确切,患者耐受性良好,可作为化疗失败、不适合或拒绝接受化疗的晚期NSCLC患者的治疗选择.     

Prospective study of gefitinib readministration after chemotherapy in patients with advanced non-small-cell lung cancer who previously responded to gefitinib

IntroductionSalvage treatment for acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor in patients with non–small-cell lung cancer is a matter of clinical concern. Several retrospective reports have indicated the usefulness of epidermal growth factor receptor tyrosine kinase inhibitor readministration; however, there have been few prospective studies.Materials and MethodsThis study was designed to prospectively evaluate the clinical efficacy of gefitinib readministration in patients with advanced or metastatic non–small-cell lung cancer who responded well to initial gefitinib treatment. The subjects received at least 1 regimen of cytotoxic chemotherapy after progressive disease with the initial gefitinib therapy. Gefitinib administration (250 mg/d, orally) was started after progressive disease with the previous chemotherapeutic regimen. The primary endpoint in the present study was the response rate.ResultsTwenty patients were enrolled between April 2007 and May 2011. Three patients achieved partial response, and 6 showed stable disease. Thus, the overall response rate and disease control rate of gefitinib readministration were 15% (95% CI, 3.21-37.9) and 45% (95% CI, 23.1-68.5), respectively. Median progression-free survival and overall survival from the start of gefitinib readministration were 2.0 months (95% CI, 0.9-3.1 months) and 12.0 months (95% CI, 8.0-16.0 months), respectively.ConclusionThese results suggest that gefitinib readministration may be an option, albeit with a low response rate and short progression-free survival, for patients who responded well to initial gefitinib followed by systemic chemotherapy. These findings provide valuable information for the management of previous gefitinib responders.     

Erlotinib in advanced non-small-cell lung cancer after gefitinib failure

Purpose  To evaluate the efficacy and safety of erlotinib in advanced non-small-cell lung cancer after failure of gefitinib treatment. Patients and methods  Patients with advanced or metastatic NSCLC, who had progressed after gefitinib treatment, were included in this study; patients received erlotinib 150 mg/day until disease progression or intolerable toxicity. Results  Twenty-one patients were included in this study. Among them, 14 (66.7%) were male and 7 (33.3%) were female; median age was 63 years; 10 (47.6%) patients were smokers; 9 (42.9%)patients had squamous cell carcinoma subtype; 8 (38.1%) patients had adenocarcinoma subtype and 4 (19%) patients had the other NSCLC subtype. Out of 21 patients, 2 (9.5%) had PR and 4 (19.0%) had SD, giving an overall response rate of 9.5% and a disease control rate of 28.5%. The median TTP were 55 days, the median OS were 135 days. Two patients with PR to erlotinib treatment were female never smokers with adenocarcinoma histology and both had partial response to prior gefitinib treatment. Three of four patients with a SD to erlotinib treatment also had SD from prior gefitinib therapy. Smoking history, histology and response to erlotinib were significantly correlated with survival. The most common toxic effects were skin rash. Conclusions  Erlotinib may be an option for a more highly selected subset of patients, especially those who had already benefited from prior gefitinib treatment.     

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03.

BACKGROUND: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. PATIENTS AND METHODS: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. RESULTS: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. CONCLUSIONS: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warranted.