EGFR-TKI治疗非小细胞肺癌脑转移的研究进展

非小细胞肺癌(NSCLC)脑转移是NSCLC患者死亡的主要原因之一.表皮生长因子受体(EGFR)突变是EGFR-酪氨酸激酶抑制剂(TKI)治疗敏感性的关键靶点.EGFR-TKI单药或与经典治疗方案的联合均为NSCLC脑转移患者提供了有效治疗方案.尤其是,具有更强的穿越血脑屏障能力的新一代EGFR-TKI在克服TKI耐药、改善NSCLC脑转移预后中具有巨大的潜能.基于此,本文将就EGFR-TKI对非小细胞肺癌脑转移患者的治疗进展及相关临床试验的疗效结果进行综述.     

EGFR突变NSCLC脑转移靶向治疗同步WBRT必要性研究

目的 通过比较WBRT联合TKI与单纯TKI对EGFR突变NSCLC脑转移预后的影响,探讨靶向治疗同步联合WBRT的必要性。方法 回顾分析2010—2014年间43例EGFR突变NSCLC脑转移病例,24例WBRT+TKI,19例单纯TKI。结果 全组24例WBRT+TKI和19例单纯TKI的有效率分别为79%和37%(P=0.002),6个月LC率分别为79%、63%(P=0.008),中位PFS期分别为23.7、8.3个月(P=0.025)。多因素分析显示原发灶控制、WBRT+TKI、脑转移灶单发是PFS有利因素(P=0.033、0.019、0.019)。23例19外显子缺失患者中12例WBRT+TKI、11例单纯TKI的有效率分别为100%、35%(P=0.000),6个月LC率分别为100%、55%(P=0.008),中位PFS期分别为23.7、8.4个月(P=0.003)。20例非19外显子缺失患者中12例WBRT+TKI、8例TKI的有效率分别为64%、50%(P=1.000),6个月LC率分别为58%、75%(P=0.642),中位PFS期分别为14.4、8.4个月(P=0.864)。结论 WBRT联合TKI治疗NSCLC脑转移优于单纯TKI,19外显子缺失患者可能获益更明显。     

新药物时代下NSCLC脑转移瘤治疗策略的改变

非小细胞肺癌(NSCLC)脑转移患者的预后极差.目前,局部放疗仍然是NSCLC脑转移的标准治疗选择.此外,酪氨酸激酶抑制剂(TKI)为驱动基因阳性NSCLC脑转移患者带来了福音,其中抗血管生成药物在NSCLC脑转移的治疗中主要发挥伴侣作用,与放疗、化疗、分子靶向治疗联合应用的疗效及安全性已有较多探索,而免疫检测点抑制剂(ICIs)在NSCLC脑转移患者尤其是驱动基因阴性患者中发挥怎样的作用,已经成为研究者关注的焦点.本文将综述新药物时代下NSCLC脑转移瘤治疗策略的改变,分析现有研究的局限和未来面临的挑战.     

厄洛替尼联合全脑放射治疗非小细胞肺癌多发脑转移的初步观察

背景与目的:非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的多发脑转移预后极差。全脑放射治疗(whole brain radiotherapy,WBRT)是标准治疗方法。大多数临床研究结果显示化疗对肺癌多发脑转移的疗效不佳。厄洛替尼(Erlotinib,TARCEVA)是表皮生长因子受体的酪氨酸激酶抑制剂,用于NSCLC的治疗,本研究目的在于探讨WBRT同期联合厄洛替尼治疗NSCLC患者多发脑转移的疗效与耐受性。方法:12例NSCLC患者伴有多发脑转移接受WBRT(40Gy/20次/4周)并同期口服厄洛替尼150mg,每日1次,共计28天。治疗结束后和每3个月一次进行临床疗效评价直至疾病进展。结果:总有效率100%,其中完全缓解率66.7%,部分缓解率33.3%。中位总生存时间10个月,中位疾病进展时间8个月。临床症状缓解率100%。3例(25%)出现1级皮疹,1例(8.3%)发生轻度腹泻。结论:厄洛替尼同期联合WBRT治疗NSCLC多发脑转移有良好的近期治疗效果和耐受性。     

非小细胞肺癌脑转移厄洛替尼结合全脑放疗治疗的理论基础和研究进展

非小细胞肺癌（NSCLC）脑转移患者预后极差,全脑放疗（WBRT）不能同时控制颅外病灶。酪氨酸激酶抑制剂（TKI）对肺腺癌脑转移瘤患者的研究结果是令人鼓舞的,表皮生长因子受体（EGFR）突变状态与疗效相关。厄洛替尼配合全脑放疗治疗肺癌脑转移患者增敏的理论基础存在。目前,小型临床试验资料显示厄洛替尼联合全脑放疗较单纯厄洛替尼疗效更佳,且不良反应可耐受。     

非小细胞肺癌脑转移治疗进展

非小细胞肺癌(NSCLC)脑转移的治疗方法包括激素、抗惊厥药物治疗、手术、放疗、化疗.近年来分子靶向治疗如表皮生长因子(EGFR)酪氨酸激酶抑制剂(TKI)成为NSCLC脑转移的新的治疗选择.     

EGFR基因突变NSCLC脑转移瘤放疗联合TKI研究现状

非小细胞肺癌(NSCLC)脑转移的患者预后较差,酪氨酸酶抑制剂(TKI)显著改善了表皮生长因子受体(EGFR)基因敏感突变患者的预后。EGFR敏感突变与NSCLC的脑转移发生率相关并可能影响其放疗和药物治疗疗效,脑转移瘤的EGFR-TKI单药治疗和放疗均有效,二者联合是否较单一治疗改善EGFR基因突变的NSCLC脑转移...     

57例非小细胞肺癌脑转移综合治疗分析

随着癌症治疗手段的进步,患者生存期延长,非小细胞肺癌(NSCLC)脑转移发生率也随之升高,文献报道达30%～50 %.2004年3月至2007年4月对57例NSCLC脑转移患者采用放化同步治疗即全脑放疗(WBRT)+分次立体定向放疗(FSRT)联合多西他赛+顺铂方案化疗,现将近期疗效及副反应报道如下.     

初治晚期无症状脑转移非小细胞肺癌患者全脑放疗的时序探讨

目的:探讨无症状脑转移非小细胞肺癌(non-small cell lung cancer,NSCLC)患者进行全脑放疗(whole brain radiation therapy,WBRT)的时序.方法:对102例经CT或MRI确诊的无症状脑转移NSCLC患者进行回顾性分析,根据WBRT的时序进行分组:化疗后行WBRT(A组)、先WBRT后化疗(B组)和同步WBRT和化疗(C组).结果:A、B和C组的无进展生存(progression-free survival,PFS)时间分别为4.5、6.1和5.6个月(P=0.50),总生存(overall survival, OS)时间分别为11.1、13.0和11.7个月(P=0.18).3组患者治疗后的3～4级不良反应发生率经比较差异无统计学意义. 结论:先WBRT后行化疗可能有延长无症状脑转移NSCLC患者PFS和OS的趋势,但各组之间的生存时间和不良反应差异无统计学意义.     

EGFR突变状态对NSCLC脑转移和放疗及靶向治疗疗效影响

脑转移为肺癌患者死亡的主要原因之一。尽管予以手术、放疗为主的标准治疗,预后仍然欠佳。近年来,随着对肺癌分子机制研究的深入,EGFR突变可能成为酪氨酸激酶抑制剂(TKI)治疗NSCLC脑转移有效的关键靶点。为此,笔者就EGFR突变对非小细胞肺癌脑转移发生及预后影响的进展进行综述。     

Complete Remission of Brain Metastases in Non-Small Cell Lung Cancer Patients Harboring an EGFR Mutation Treated with Tyrosine Kinase Inhibitor without Radiotherapy: A Report of 3 Cases

Brain parenchymal metastasis from a solid tumor is a serious clinical condition associated with a poor outcome because systemic chemotherapy is usually ineffective for treating brain metastases (BM) due to the blood-brain barrier. Therefore, radiotherapy such as whole brain radiotherapy (WBRT) and stereotactic radiosurgery have taken on a central role in the management of BM. However, WBRT can delay subsequent systemic treatment or cause neurologic complications such as a decline in cognitive function. Therefore, suspending WBRT is worth considering if there is an effective alternative. Although there have been no large prospective studies, many reports are available about the favorable effect of tyrosine kinase inhibitors (TKIs) for treating BM in patients with non-small cell lung cancer (NSCLC). Here, we report 3 NSCLC cases that showed a complete response in BM after TKI treatment without WBRT. Based on these remarkable response rates of BM to a TKI, the potential toxicity of WBRT can be avoided, particularly in patients with small metastatic nodules and an epidermal growth factor receptor activating mutation.Key words: Non-small cell lung cancer, Tyrosine kinase inhibitor, Brain metastases, Whole brain radiotherapy     

Combined treatment for non-small cell lung cancer and breast cancer patients with brain metastases with whole brain radiotherapy and temozolomide: a systematic review and meta-analysis

Brain metastasis is the leading cause of death among advanced non-small cell lung cancer (NSCLC) and breast cancer patients. The standard treatment for brain metastases is radiotherapy. The combination of radiotherapy and chemotherapy has been tested. However, the management of brain metastases has yet to be successful. Here, we aimed to determine the efficacy and safety of whole brain radiotherapy (WBRT) alone or in combination with temozolomide (TMZ) in NSCLC and breast cancer patients with brain metastases. A systematic review of PubMed, CNKI (China National Knowledge Infrastructure) and WANFANG (WANGFANG data) involving 870 patients were conducted. Fourteen randomized controlled trials (RCTs) were independently identified by two reviewers. The primary outcome measures were objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicity. The ORR was better with combination therapy of WBRT and TMZ than with WBRT alone (RR?=?1.34, p?<?0.00001) and subgroup analysis showed a significantly superior ORR in NSCLC patients (RR?=?1.38, p?<?0.00001), but not in breast cancer patients (RR?=?1.03, p?=?0.86). OS and PFS did not significantly differ between combination therapy and WBRT alone. A higher rate of toxicity was observed in combination therapy than in WBRT alone (RR?=?1.83, p?=?0.0006). No advantages of concurrent WBRT and TMZ were observed in breast cancer patients with brain metastases. Combination therapy was associated with improved ORR in NSCLC patients, especially in Chinese patients. As a “surrogate endpoint” for OS, ORR may allow a conclusion to be made about the management of NSCLC with brain metastases with the combination of WBRT and TMZ. However, it needs to be validated to show that improved ORR predicts the treatment effects on the clinical benefit. The ORR may be valid for a particular indication such as status of MGMT promoter methylation.     

The theoretical foundation and research progress for WBRT combined with erlotinib for the treatment of multiple brain metastases in patients with lung adenocarcinoma

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung adenocarcinoma, and a theoretical basis exists for utilising whole brain radiotherapy (WBRT) combined with erlotinib for the treatment for brain metastases in patients with lung adenocarcinoma. This therapeutic regimen has the potential to be a revolutionary treatment for which the most appropriate indication is lung adenocarcinoma. Currently, there is no difference in the treatment of brain metastasis, especially multiple brain metastases, in patients with lung adenocarcinoma of patients with other lung carcinomas. Furthermore, limited clinical trials that combine a TKI with WBRT to treat multiple lung adenocarcinoma metastases have been conducted, and many clinical questions remain unanswered. Lung adenocarcinoma has a high propensity to metastasize to the brain, and targeted therapy has been widely used; however, clinical trials are necessary to provide data to support the combination of erlotinib and WBRT.     

非小细胞肺癌62例脑转移行全脑放射治疗联合立体定向放射治疗的疗效及预后因素分析

目的:评估全脑放射治疗联合立体定向放射治疗非小细胞肺癌合并脑转移瘤患者的生存率和肿瘤局部控制率,以及影响生存率的预后因素。方法:回顾性分析62例接受全脑联合立体定向放射治疗的非小细胞肺癌合并1～3个脑转移瘤患者的临床资料,评估生存率,并进行生存相关因素的单因素和多因素分析。结果:62例患者的中位生存期为16个月(95%可信区间为11.27～20.73)。多因素分析结果显示,年龄、病理类型、病灶部位、病灶放射总剂量及全脑放射治疗后接受生物靶向治疗是影响患者生存率的独立预后因素。全组患者的中位肿瘤局部控制时间为20个月(95%可信区间为18.21～22.45),6个月、1年和2年的肿瘤局部控制率分别为96.6%、82.5%和48.9%。全组患者未发现放射治疗相关致死性病例。治疗后1个月,健康相关生活质量评分较治疗前明显改善,差异有统计学意义(P<0.05)。结论:年龄、病理类型、病灶部位、病灶放射总剂量及全脑放射治疗后接受生物靶向治疗是影响患者生存率的独立预后因素。对非小细胞肺癌合并1～3个脑转移瘤的患者,有选择地进行全脑放疗联合立体定向放射治疗是安全而有效的。     

Paradigm shift of therapeutic management of brain metastases in EGFR-mutant non-small cell lung cancer in the era of targeted therapy

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations commonly present brain metastases (BM) at the time of NSCLC diagnosis or during the clinical course. Conventionally, the prognosis of BM has been extremely poor, but the advent of EGFR-tyrosine kinase inhibitors (TKIs) has drastically improved the prognosis in these patients. Despite the presence of the blood–brain barrier, EGFR-TKIs have dramatic therapeutic effects on both BM and extracranial disease. In addition, recent systemic chemotherapies reportedly play a role in controlling BM. These treatment modalities can potentially replace whole brain radiotherapy (WBRT) to prevent or delay neurocognitive decline. Therefore, how to utilize these treatments is one issue. The other issue is what kind of treatment is best for recurrence after TKI therapy. Recent reports have shown a positive effect of a combination therapy of EGFR-TKI and radiotherapy on BM. Although neurocognitive decline is underscored when WBRT is considered, a survival benefit from WBRT has been proven especially in the potential long survivors with good prognostic index, especially disease-specific graded prognostic index (DS-GPA). In this review, treatment strategy including chemotherapeutic agents and radiotherapy is discussed in terms of risk–benefit balance in conjunction with DS-GPA.     

非小细胞肺癌脑转移全脑及病灶局部大分割放射治疗

高达40%的非小细胞肺癌患者在疾病进程中出现脑转移,且非小细胞肺癌脑转移常为多发转移。脑转移患者的预后较差,中位生存期不到1年。脑转移的放射治疗已经从全脑放疗逐渐发展到多种放射治疗策略广泛应用的时代。目前已证实单纯全脑放疗、手术+全脑放疗、立体定向放射治疗+全脑放射治疗、同步调强全脑放射治疗等对比未治疗患者能提高总生存期。近年来,全脑放疗对认知功能的损害受到广泛关注,针对预期生存时间较长的患者,采取何种放疗模式尚存在争议。本文将分别论述非小细胞肺癌脑转移不同的全脑放射治疗策略及治疗副作用。     

大分割立体定向放射治疗对非小细胞肺癌脑转移瘤的疗效评估

背景与目的：立体定向放疗（stereotacticradiotherapv,SRT）与全脑放疗（wholebrainradiationtherapy’WBRT）是治疗脑转移瘤的主要手段。本文旨在探讨伽玛射线大分割SRT加或不加WBRT对肺癌有限脑转移瘤治疗的疗效。方法：回顾性分析非小细胞肺癌多发脑转移瘤（1～4枚）患者66例,其中单纯SRT30例,SRT＋WBRT36例。分析两组患者的临床特征并应用Kaplan-Meier法计算生存率．用Logrank法对各因素进行预后分析。结果：两组患者的临床特点无明显区别：SRT组与WBRT＋SRT组的中位生存期（MST）分别为12．1与1313个月,二者无显著性差异（P=0．216）。Logrank分析显示卡氏评分（P=0．017）和颅外病变的控制情况（P=0．032）是影响预后的主要因素。结论：SRT是非小细胞肺癌有限脑转移瘤患者有效治疗手段．单纯SRT可取得与WBRT＋SRT相似的生存期．     

ALK融合基因阳性非小细胞肺癌脑转移的靶向治疗进展

间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)基因融合在非小细胞肺癌(non-small cell lung cancer,NSCLC)中发生率约为2%~7%,此类肺癌更易出现脑转移,严重影响患者生存质量,缩短患者的生存期。近年来,随着ALK-酪氨酸激酶抑制剂(ALK-tyrosine kinase inhibitor,ALK-TKI)的不断研发,ALK-NSCLC脑转移患者的生存期显著延长。本文对ALK-TKI治疗肺癌脑转移的研究进展进行综述,旨在为临床工作提供参考和借鉴。     

Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis

BACKGROUND: Solitary brain metastases occur in about 50% of patients with brain metastases from nonsmall cell lung cancer (NSCLC). The standard of care is surgical resection of solitary brain metastases, or stereotactic radiosurgery (SRS) plus whole brain radiation therapy (WBRT). However, the optimal treatment for the primary site of newly diagnosed NSCLC with a solitary brain metastasis is not well defined. The goal was to distinguish which patients might benefit from aggressive treatment of their lung primary in patients whose solitary brain metastasis was treated with surgery or SRS. METHODS: The cases of 84 newly diagnosed NSCLC patients presenting with a solitary brain metastasis and treated from December 1993 through June 2004 were retrospectively reviewed at The University of Texas M. D. Anderson Cancer Center. All patients had undergone either craniotomy (n = 53) or SRS (n = 31) for management of the solitary brain metastasis. Forty-four patients received treatment of their primary lung cancer using thoracic radiation therapy (median dose 45 Gy; n = 8), chemotherapy (n = 23), or both (n = 13). RESULTS: The median Karnofsky performance status score was 80 (range, 60-100). Excluding the presence of the brain metastasis, 12 patients had AJCC Stage I primary cancer, 27 had Stage II disease, and 45 had Stage III disease. The median follow-up was 9.7 months (range, 1-86 months). The 1-, 2-, 3-, and 5-year overall survival rates from time of lung cancer diagnosis were 49.8%, 16.3%, 12.7%, and 7.6%, respectively. The median survival times for patients by thoracic stage (I, II, and III) were 25.6, 9.5, and 9.9 months, respectively (P = .006). CONCLUSIONS: By applying American Joint Committee on Cancer staging to only the primary site, the thoracic Stage I patients in our study with solitary brain metastases had a more favorable outcome than would be expected and was comparable to Stage I NSCLC without brain metastases. Aggressive treatment to the lung may be justified for newly diagnosed thoracic Stage I NSCLC patients with a solitary brain metastasis, but not for locally advanced NSCLC patients with a solitary brain metastasis.