厄洛替尼100mg/天治疗化疗后进展的晚期肺腺癌的临床研究

背景与目的厄洛替尼是一种表皮生长因子受体酪氨酸激酶抑制剂,标准治疗剂量为150mg/天。部分患者因毒副反应导致减量或终止治疗。本研究对厄洛替尼100mg治疗晚期化疗失败的肺腺癌患者的疗效和安全性进行观察总结。方法 40例经病理组织学或细胞学确诊为腺癌的晚期非小细胞肺癌患者,无吸烟史,给予厄洛替尼100mg/次/天,直至疾病进展或不良反应不能耐受为止,观察疗效、无疾病进展时间、不良反应及与临床特征之间的关系。结果 40例患者中,11例部分缓解,14例稳定,15例进展,总缓解率为27.5%,疾病控制率为62.5%。中位无疾病进展时间(progression free survival,PFS)为5.5个月。外周血检测EGFR突变共15例,占37.5%,总缓解率为33.3%,疾病控制率为73.3%,EGFR有突变者的PFS为8.4个月。ECOG评分0分-1分患者中位PFS为6.1个月,ECOG评分2分患者中位PFS为3.1个月,两组差异有统计学意义(P=0.043)。最常见的不良反应是皮疹和腹泻,对症处理后缓解。结论厄洛替尼100mg治疗晚期肺腺癌有一定的疗效,安全性高,对不吸烟的腺癌患者、体力状况好、伴EGFR突变的患者获益更多。     

厄洛替尼单药治疗EGFR突变的晚期NSCLC患者试验汇合分析

背景与目的 厄洛替尼被全球多个国家批准用于晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的二、三线治疗.有报道显示EGFR突变的患者应用厄洛替尼治疗疗效更好.本文拟探讨厄洛替尼单药治疗EGFR突变晚期NSCLC患者的疗效.方法 计算机检索MEDLINE(2004-2009)、CBMdjc(2004-2008)、CNKI(2004-2008),互联网检索以及纳入试验的参考文献.纳入相关临床试验,提取并汇总试验结果.结果 共纳入研究7篇,包括晚期非小细胞肺癌患者463例.厄洛替尼单药治疗EGFR突变的晚期非小细胞肺癌患者,有效率达到66%,1年生存率达到73%,2年生存率达到5396,中位生存时间23个月以上,无进展生存时间8.6个月以上.结论 在当前研究的基础上,厄洛替尼单药一线和二线治疗EGFR突变的晚期NSCLC有效率高,无进展生存期和总生存期长,可以推荐作为EGFR突变的晚期NSCLC的首选治疗.尚需要更详尽的证据评价厄洛替尼单药方案或厄洛替尼与化疗联合方案与标准含铂化疗方案在治疗晚期NSCLC中的地位.     

厄洛替尼治疗老年晚期NSCLC的临床观察

目的观察厄洛替尼单药治疗老年晚期非小细胞肺癌（NSCLC）的疗效和不良反应。方法对12例老年晚期NSCLC患者给予厄洛替尼150mgd口服治疗,直到疾病进展或出现不可耐受的毒副反应,评价其临床疗效、症状、生活质量、中位生存期、疾病进展时间及毒副反应。结果12例患者病灶总缓解率为25.0%,总控制率66.7%,临床症状缓解率为58.3%,治疗有效患者治疗后血清CYFRA21-1 、CEA 的水平较治疗前明显降低（P<0.01）。中位生存期为8.1月, 疾病进展时间4.2月。12例患者中不良反应主要为皮疹、腹泻,对症处理后均缓解。结论厄洛替尼是一种有效的且具有良好耐受性的分子靶向治疗药物,为老年晚期NSCLC患者提供了一条安全有效的治疗途径。     

厄洛替尼治疗晚期非小细胞肺癌的临床研究

背景与目的 厄洛替尼在NSCLC患者中已有广泛应用,并能使部分NSCLC患者明显获益.本研究探讨厄洛替尼单药一线或二、三线治疗晚期非小细胞肺癌的临床疗效及毒副反应.方法 研究对象为2007年6月-2008年8月接受过化疗或未化疗过的Ⅲb或Ⅳ期非小细胞肺癌患者,给予厄洛替尼口服150mg/d,直至疾病进展,观察疗效及毒副反应.结果 共有42例患者入组,随访至2009年7月10日,中位随访期为17个月,依从性为100%.42例患者中CR2.4%(1/42)、PR 35.8%(15/42)、SD 47.6%(20/42)、PD 14.396(6/42)、疾病控制率(CR+PR+SD)85.7%;中位疾病进展时间和中位生存时间分别为7个月和12.2个月;1年肿瘤无进展生存率和1年生存率分别为29%和56%.毒副反应为痤疮样皮疹78.6%(33/42)、腹泻35.7%(15/42)、转氨酶升高7.1%(3/42)、急性间质性肺病2.4%(1/42).结论 不管作为一线或者二、三线治疗,厄洛替尼治疗晚期非小细胞肺癌疗效较好.毒副反应轻微,临床获益率高,能明显改善患者的生活质量.     

二次厄罗替尼治疗晚期肺腺癌1例报告

1病例介绍 患者男性，43岁，无吸烟史，2007年7月因体检发现“右肺占位”，进一步CT检查：右肺中叶内侧段见一不规则病变，呈串珠样长条形，最大截面6．8cm×2．2cm，胸膜增厚，双肺多发结节，大的约0．8cm，部分结节内可见小空洞。纵膈2R、4R、4L、5区可见多发肿大淋巴结，大的约1．6cm×1．1cm。     

同步放化疗联合厄罗替尼治疗食管癌24例

[目的]探讨同步放化疗联合厄罗替尼治疗食管癌的可行性和疗效。[方法]24例初治食管癌患者,采用根治性同步放化疗,放疗剂量60Gy（分两阶段进行）,放疗的第一周和第四周给予紫杉醇和顺铂化疗。放疗第1d起口服厄罗替尼片150mg/d直至放疗结束。[结果]83.3%的患者完成了足量的治疗,治疗有效率达95%。总的2年生存率为68.31%,2年局控率为87.50%,2年无复发生存率为54.57%。Ⅲ级以上白细胞下降和血小板减少发生率分别为16.68%（4/24）和8.33%（2/24）。Ⅰ～Ⅱ期患者2年生存率及无复发生存率优于Ⅲ～Ⅳ期患者,但无显著性差异。[结论]同步放化疗联合厄罗替尼治疗食管癌生存率和局控率较好,毒副反应可耐受。     

厄洛替尼致间质性肺病4例并文献复习

厄洛替尼是一种口服表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine ki-nase inhibitor,EGFR-TKI),广泛应用于晚期非小细胞肺癌的治疗。尽管目前认为这类药物安全性良好,但可诱发严重的间质性肺病(interstitial lung disease,ILD)。文献中对吉非替尼所致ILD的报道较多,而对厄洛替尼所致的ILD报道较少。现报道上海市肺科医院4例厄洛替尼所致ILD,并复习相关文献,以使临床医生提高警惕。监测正在服用厄洛替尼患者的肺部症状、体征,做到及时诊断、尽早治疗对于厄洛替尼所致ILD的预后尤为重要。     

厄罗替尼治疗晚期肺腺癌合并胰腺癌一例

患者男,61岁,2009年10月因“胸闷气急1个月”入院。入院后行腹部增强CT检查提示,胰腺体部占位,大小约1.8 cm×2.1 cm,右肝及两侧肾上腺转移,胰腺周围、后腹膜淋巴结转移可能。胸部增强CT检查提示,左上肺肺癌伴两肺广泛转移,左侧胸膜多发转移伴左侧大量胸腔积液。     

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。     

厄洛替尼治疗老年转移性非小细胞肺癌患者的临床观察

背景与目的 厄洛替尼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(non-small cell lung cancer,NSCLC),本研究探讨厄洛替尼单药治疗老年转移性非小细胞肺癌患者的有效性与安全性.方法 33例老年NSCLC多发转移患者接受厄洛替尼150 mg/d治疗,服药至疾病进展或死亡.结果 共有30例患者可以评价疗效,无病例完全缓解(complete regression,CR),部分缓解(Partial regression,PR)6例(20%),稳定(stable disease,SD)16例(53.33%),疾病进展(progressive disease,pD)8例(26.68%).缓解率(CR+PR)为20.0%;疾病控制率(CR+PR+SD)为73.3%.腺癌组与鳞癌组中位生存期无统计学差异(13.592±1.914个月vs9.846±1.598个月,P=0.301);两组无疾病进展时间无统计学差异(7.367±0.923个月vs 6.615±1.366个月,p=0.488).多因素Cox回归分析显示.有肝脏转移、胸腔积液、脑膜转移是影响厄洛替尼治疗客观疗效而影响生存期的因素.主要不良反应为皮疹和腹泻,不需要特殊处理.结论 老年NSCLC多发转移患者对厄洛替尼的治疗能很好耐受,并有一定的生存获益.     

分子靶抗癌药:埃洛替尼治疗非小细胞肺癌的新进展

埃洛替尼(erlotinib,tarceva,OSI-774)是一种口服、高选择性、可逆的表皮生长因子受体(HER-1/EGFR)酪氨酸激酶抑制剂.本文综述埃洛替尼治疗NSCLC的进展.Ⅰ期试验表明,埃洛替尼耐受良好,对NSCLC患者有抗肿瘤作用,常见的不良反应是皮疹和腹泻.在Ⅱ期试验中,难治性NSCLC患者150mg/d,有效率为12.3%～25%,总的疾病控制率＞40%,中位生存期8.4个月,1年生存率40%,皮疹是临床益处的替代标志,但需进一步证实.随机、双盲、安慰剂对照的Ⅲ期试验检测埃洛替尼作为单剂(BR.21研究)或合并标准的化疗方案(TALEN-卡铂/紫杉醇试验和TRIBUTE-顺铂/健择试验)治疗NSCLC,结果没有改善生存期,但亚型分析TRIBUTE试验表明,对无吸烟史的患者有很大的生存期益处,相反,单用埃洛替尼(BR.21研究)具有生存期益处.Ⅱ期试验评价贝伐单抗(bevacizumab)合并埃洛替尼治疗复发的NSCLC有明显效果(PR=20%,SD=65%)且安全.人们希望埃洛替尼治疗晚期NSCLC的临床效果能够用于早期病例,包括辅助治疗和预防.     

厄洛替尼联合最佳支持疗法治疗晚期非小细胞肺癌的临床观察

目的：观察厄洛替尼联合最佳支持疗法治疗体力评分较差的晚期非小细胞肺癌患者的疗效。方法：研究对象为曾经接受一线化疗方案治疗失败或复发的Ⅲb／Ⅳ期的非小细胞肺癌患者共21人。给予最佳支持治疗,并给予厄洛替尼口服150mg／d,直至疾病进展;观察疗效和不良反应,并进行随访。结果：中位随访时间13个月,随访率100％。21例患者中完全缓解（CR）0％（0／20）,部分缓解（PR）23．8％（5／21）,疾病稳定（so）57．1％（12／21）,疾病控制率80．9％（17／21）,疾病进展（PD）19．0％（4／21）;中位生存时间为5．9个月;1年生存率为38．1％（8／21）。出现皮疹患者的肿瘤缓解率与疾病控制率要显著高于无皮疹患者。结论：给予晚期非小细胞肺癌患者厄洛替尼联合最佳支持治疗,可延长总生存期和无进展生存期且耐受性良好。出现皮疹者治疗效果更佳。     

厄洛替尼与吉非替尼治疗非小细胞肺癌脑转移患者的疗效比较研究

目的：观察并比较厄洛替尼和吉非替尼靶向治疗非小细胞肺癌脑转移的疗效和不良反应发生情况。方法将100例非小细胞肺癌脑转移患者按随机数字表法分为两组各50例,分别给予吉非替尼和厄洛替尼治疗,比较两组不良反应及治疗效果。结果吉非替尼组和厄洛替尼组的疾病控制率分别为96.0%、92.0%,总有效率分别为76.0%、76.0%,两组比较,差异无统计学意义（P﹥0.05）;在不良反应方面,两组患者治疗后均出现不良反应,厄洛替尼组皮疹、恶心呕吐不良反应的发生率高于吉非替尼组（P﹤0.05）,但在腹泻和肝功能损害发生率方面,两组比较差异无统计学意义（P﹥0.05）,吉非替尼组总不良反应发生率低于厄洛替尼组（P﹤0.05）。结论非小细胞肺癌脑转移患者应用厄洛替尼和吉非替尼靶向治疗效果相当,但吉非替尼导致的总不良反应发生率低于厄洛替尼,值得在非小细胞肺癌脑转移患者治疗中临床推广。     

Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer

Treatment with EGFR kinase inhibitors improves progression-free survival of patients with EGFR-mutant lung cancer. However, all patients with initial response will eventually acquire resistance and die from tumor recurrence. We found that intermittent high-dose treatment with erlotinib induced apoptosis more potently and improved tumor shrinkage significantly than the established low doses. In mice carrying EGFR-mutant xenografts intermittent high-dose treatment (200 mg/kg every other day) was tolerable and prolonged progression-free survival and reduced the frequency of acquired resistance. Intermittent EGFR-targeted high-dose schedules induce more profound as well as sustained target inhibition and may afford enhanced therapeutic efficacy.     

非小细胞肺癌脑转移厄洛替尼和吉非替尼治疗临床比较

目的比较和评价厄洛替尼和吉非替尼靶向治疗非小细胞肺癌脑转移的疗效。方法回顾性分析2009-01-01-2012-11-25广州医科大学附属第一医院81例晚期NSCLC初诊有脑转移患者和111例晚期NSCLC初诊无脑转移患者,192例患者均为肺腺癌合并EGFR基因突变,分为吉非替尼和厄洛替尼治疗组,生存分析采用Kaplan-Meier法统计,组间生存率比较采用Log-rank检验。结果初诊有脑转移患者颅内病灶,客观有效率为45.68%(37/81),疾病控制率为90.12%(73/81)。吉非替尼、厄洛替尼治疗的无进展生存期(progression-free survival,PFS)分别为9.5和9.0个月,P=0.344;不同EGFR突变类型(19外显子序列缺失突变、21外显子突变)PFS比较分别为10.4和8.6个月,P=0.408。初诊无脑转移患者PFS分别为14.0和15.0个月,P=0.369;不同EGFR突变类型的PFS分别为14.0和15.0个月,P=0.408。结论厄洛替尼和吉非替尼一线治疗肺癌EGFR突变脑转移效果无显著性差异。     

NABTT 0502: a phase II and pharmacokinetic study of erlotinib and sorafenib for patients with progressive or recurrent glioblastoma multiforme

Background

The signal transduction pathways of epidermal growth factor receptor and Ras are both important in the growth of glioblastoma multiforme (GBM). We hypothesized that inhibition of both pathways would improve the survival time of patients with recurrent GBM.

Methods

Patients with recurrent/progressive GBM with 0–2 prior chemotherapy regimens received erlotinib 150 mg once daily and sorafenib 400 mg twice daily until progression. The primary endpoint was overall survival. Pharmacokinetic sampling was performed during cycle 1.

Results

The median overall survival was 5.7 months. Progression-free survival at 6 months was 14%. Toxicity was manageable. Clearance of erlotinib was markedly enhanced by sorafenib.

Conclusion

The study did not meet its objective of a 30% increase in overall survival time compared with historical controls. Erlotinib and sorafenib have significant pharmacokinetic interactions that may negatively impact the efficacy of the combination regimen.     

Metformin and erlotinib synergize to inhibit basal breast cancer

Basal-like breast cancers (BBCs) are enriched for increased EGFR expression and decreased expression of PTEN. We found that treatment with metformin and erlotinib synergistically induced apoptosis in a subset of BBC cell lines. The drug combination led to enhanced reduction of EGFR, AKT, S6 and 4EBP1 phosphorylation, as well as prevented colony formation and inhibited mammosphere outgrowth. Our data with other compounds suggested that biguanides combined with EGFR inhibitors have the potential to outperform other targeted drug combinations and could be employed in other breast cancer subtypes, as well as other tumor types, with activated EGFR and PI3K signaling. Analysis of BBC cell line alterations led to the hypothesis that loss of PTEN sensitized cells to the drug combination which was confirmed using isogenic cell line models with and without PTEN expression. Combined metformin and erlotinib led to partial regression of PTEN-null and EGFR-amplified xenografted MDA-MB-468 BBC tumors with evidence of significant apoptosis, reduction of EGFR and AKT signaling, and lack of altered plasma insulin levels. Combined treatment also inhibited xenografted PTEN null HCC-70 BBC cells. Measurement of trough plasma drug levels in xenografted mice and a separately performed pharmacokinetics modeling study support possible clinical translation.     

厄洛替尼治疗EGFR野生型晚期非小细胞肺癌的疗效分析

目的:评价厄洛替尼治疗EGFR野生型NSCLC的疗效及安全性.方法:31名Ⅲ/Ⅳ期或术后复发,不携带EGFR敏感突变(外显子18、19、21)的NSCLC患者服用厄洛替尼(150 mg/d).结果:术后再发的,EGFR野生型的,Ⅲ期或Ⅳ期患者服用厄洛替尼(150 mg/d),1例完全缓解,4例部分缓解,8例疾病稳定.缓解率为17.2%,疾病控制率为44.8%.皮疹是最常见的不良反应(80.6%).有两名患者出现了间质性肺病.但所有这些不良反应均为可逆的,没有出现治疗相关死亡.中位无进展生存时间及中位生存时间分别为2.1个月与7.7个月.结论:厄洛替尼可能会成为化疗耐受的EGFR野生型NSCLC患者的一个替代方案.     

Mer receptor tyrosine kinase is frequently overexpressed in human non-small cell lung cancer,confirming resistance to erlotinib

Mer is a receptor tyrosine kinase (RTK) with oncogenic properties that is often overexpressed or activated in various malignancies. Using both immunohistochemistry and microarray analyses, we demonstrated that Mer was overexpressed in both tumoral and stromal compartments of about 70% of non-small cell lung cancer (NSCLC) samples relative to surrounding normal lung tissue. This was validated in freshly harvested NSCLC samples; however, no associations were found between Mer expression and patient features. Although Mer overexpression did not render normal lung epithelial cell tumorigenic in vivo, it promoted the in vitro cell proliferation, clonogenic colony formation and migration of normal lung epithelial cells as well as NSCLC cells primarily depending on MAPK and FAK signaling, respectively. Importantly, Mer overexpression induced resistance to erlotinib (EGFR inhibitor) in otherwise erlotinib-sensitive cells. Furthermore, Mer-specific inhibitor rendered erlotinib-resistant cells sensitive to erlotinib. We conclude that Mer enhances malignant phenotype and pharmacological inhibition of Mer overcomes resistance of NSCLC to EGFR-targeted agents.     

Markers in the epidermal growth factor receptor pathway and skin toxicity during erlotinib treatment.

BACKGROUND: Skin toxicity is a common adverse effect of erlotinib and other anti-epidermal growth factor receptor (EGFR) agents. The aim of the study was to explore the relationship between markers in the EGFR pathway and skin rash. PATIENTS AND METHODS: Eighteen patients with metastatic breast cancer were treated with daily oral erlotinib at 150 mg. Skin biopsies were obtained at baseline and after 1 month of treatment in 15 patients. EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated Akt (pAkt) or Ki67 were examined quantitatively by immunohistochemistry. RESULTS: 11 of 18 (61%, 95% confidence interval 35.7% to 82.7%) patients developed skin rash. pAkt at baseline was significantly higher in patients with no rash than those with a grade 1 or 2 rash (18.8 +/- 8.3 versus 2.4 +/- 1.2 versus 3.3 +/- 3.3; P = 0.0017 for trend). There was a trend towards a significant increase of pMAPK in skin posttreatment with increasing grade of rash (no rash versus grade 1 versus grade 2 rash: 4.5 +/- 2.3 versus 8.4 +/- 4.2 versus 19.4 +/- 4.6; P = 0.036). Other markers were not associated with rash. CONCLUSIONS: pAkt was significantly associated with not developing a rash and may have a predictive utility for skin toxicity in patients treated with erlotinib and possibly with other anti-EGFR agents.