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突变的非小细胞肺癌脑转移的治疗策略

约10%的非小细胞肺癌(NSCLC)患者初诊时出现脑转移,而脑转移为肺癌死亡的主要原因之一.目前全脑放疗(WBRT)仍为脑转移的标准治疗方案,但其疗效已达平台期.酪氨酸激酶抑制剂(TKI)在NSCLC脑转移治疗中取得了可观的疗效.TKI联合WBRT可能成为表皮生长因子受体(EGFR)突变的肺癌脑转移的主要治疗手段.     

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脑转移患者的预后。回顾性研究提示先行放疗,尤其是立体定向放射外科联合治疗可能更具优势,但存在争议。因此,对EGFR基因突变NSCLC的脑转移放疗相关临床研究进展进行综述。     

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.     

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。     

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.     

非小细胞肺癌EGFR突变与脑转移的关系北大核心CSCD

目的探讨非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)突变状态与患者脑转移的关系。方法收集2010年至2014年经病理确诊的NSCLC患者资料132例,应用扩增阻滞突变系统(ARMS)方法检测原发肿瘤或者转移肿瘤组织的EGFR突变状态,随访患者疾病发展,分析EGFR突变状态与临床病理特征及脑转移之间的关系。结果 NSCLC患者发生脑转移与性别、吸烟状态无相关性(P>0.05),而与患者的年龄及EGFR突变状态有相关性(P<0.05),患者年龄越小、EGFR发生突变更易发生脑转移。经EGFR酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitor,EGFR-TKI)治疗后生存期明显延长,其中吸烟是影响脑转移患者预后的独立危险因素。结论 EGFR基因突变患者更易发生脑转移,接受TKI及脑部放疗等治疗后,生存期更长。     

非小细胞肺癌根治性放化疗后脑转移发生率及预后评估

目的肺癌脑转移预后受多种因素的影响,本研究分析Ⅱ~Ⅲ期非小细胞肺癌(NSCLC)胸部行根治性放化疗后脑转移(BM)的发生率,及影响其生存期预后的因素,并比较DS-GPA与Lung-mol GPA二种预后指数模型对该特定类BM患者预后评估的应用价值.方法分析2005年1月2014年12月在复旦大学附属肿瘤医院收治的所有经根治性放化疗的Ⅱ~Ⅲ期NSCLC患者,筛选出治疗后发生脑转移的患者共98例,收集可能影响其生存预后的各相关因素,行单因素分析和多因素分析.生存率的比较使用Log-rank检验,并通过ROC曲线下面积(AUC)比较二种预后指数模型对生存期的预测能力.结果本组资料显示Ⅱ~Ⅲ期原发性NSCLC接受根治性放化疗后脑转移的发生率为12.6%.单因素分析结果提示性别、脑转移时KPS评分、病理类型、初始临床分期、基因状态、TKI治疗、脑部放疗对患者生存期有影响(P<0.05).多因素分析显示基因状态、脑转移时KPS评分、TKI治疗与生存期密切相关(P<0.05).DS-GPA模型预测生存的AUC为0.588,Lung-mol GPA模型AUC为0.608.结论本研究中BM患者基因状态、TKI治疗、KPS评分与生存相关,DS-GPA与Lung-molGPA二种预后指数模型对该类患者预后评估的应用价值较为有限,需要在大样本人群中进一步验证及探讨新的预测模型.     

EGFR突变型非小细胞肺癌脑转移的靶向治疗和免疫治疗进展

[摘要] 表皮生长因子受体(EGFR)突变型非小细胞肺癌（NSCLC）容易出现脑转移,EGFR 酪氨酸激酶抑制剂(TKI)(EGFRTKI)则为此类患者的治疗带来极大获益。但第一、二代靶向药物脑穿透力弱和最终获得性耐药,导致颅内疾病进展,是脑转移治疗的主要挑战。近年来,随着第三代EGFR-TKI、免疫检查点抑制剂（ICB）的深入研发,EGFR突变型NSCLC脑转移的治疗发生了极大变化。本文将回顾脑转移的靶向治疗及免疫治疗方面取得的进展,并对目前存在的问题及未来发展方向进行探讨。     

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。     

Analysis of the benefit of sequential cranial radiotherapy in patients with EGFR mutant non-small cell lung cancer and brain metastasis

Although cranial radiotherapy is considered the standard treatment for brain metastasis (BM), EGFR tyrosine kinase inhibitors (TKIs) have shown promising activity in EGFR mutant non-small cell lung cancer (NSCLC) patients with BM. However, the efficacy of sequential cranial radiotherapy in patients with EGFR mutant NSCLC who are treated with EGFR TKIs remains to be determined. Patients with NSCLC who harbored an EGFR mutation and whose BM had been treated with EGFR TKIs were retrospectively reviewed. The clinical outcomes of patients treated with EGFR TKIs alone and those treated with cranial radiotherapy followed by EGFR TKIs (additive therapy) were compared. Of the 573 patients with NSCLC with BM who harbored an EGFR mutation and had received EGFR TKIs, 121 (21.1 %) had BM at the time of initial diagnosis. Fifty-nine (49 %) patients were treated with additive therapy, whereas 62 (51 %) patients were treated only with EGFR TKIs. No significant differences were observed between the additive therapy group and the EGFR TKI alone group regarding intracranial progression-free survival (PFS) (16.6 vs 21.0 months, p = 0.492) or extracranial PFS (12.9 vs 15.0 months, p = 0.770). The 3-year survival rates were similar in both groups (71.9 vs 68.2 %, p = 0.675). Additive therapy consisting of cranial radiotherapy followed by EGFR TKI treatment did not improve OS or intracranial PFS compared with EGFR TKI treatment alone in EGFR mutant NSCLC patients with BM. Further prospective studies are needed to determine the precise benefits of sequential cranial radiotherapy in EGFR mutant NSCLC treated with EGFR TKIs.     

Epidermal growth factor receptor mutation predicts favorable outcomes in non-small cell lung cancer patients with brain metastases treated with stereotactic radiosurgery

Purpose

The impact of epidermal growth factor receptor (EGFR) mutations on radiotherapy for brain metastases (BM) is undetermined. We evaluated the effects of EGFR mutation status on responses and outcomes in non-small cell lung cancer (NSCLC) patients with BM, treated with upfront or salvage stereotactic radiosurgery (SRS).

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     

Gefitinib alone or with concomitant whole brain radiotherapy for patients with brain metastasis from non-small-cell lung cancer: a retrospective study

Background: Gefitinib, a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), is used both as a single drug and concurrently with whole brain radiotherapy (WBRT) the standard treatment for brain metastases (BM), and is reported to be effective in a few small studies of patients with BM from non-small-cell lung cancer (NSCLC). However, no study has compared the two treatment modalities. This retrospective analysis was conducted to compare the efficacy of gefitinib alone with gefitinib plus concomitant WBRT in treatment of BM from NSCLC. Methods: We retrospectively reviewed 90 patients with BM from NSCLC who received gefitinib alone (250mg/day, gefitinib group) or with concomitant WBRT (40Gy/20f/4w, gefitinib-WBRT group) between September 2005 and September 2009 at Sun Yat-Sen University Cancer Center. Forty-five patients were in each group. Results: The objective response rate of BM was significantly higher in gefitinib-WBRT group (64.4%) compared with gefitinib group (26.7%, P<0.001). The disease control rate of BM was 71.1% in gefitinib-WBRT group and 42.2% in gefitinib group (P=0.006). The median time to progression of BM was 10.6 months in gefitinib-WBRT group and 6.57 months in gefitinib group (P<0.001). The median overall survival(OS) of gefitinib-WBRT and gefitinib alone group was 23.40 months and 14.83 months, respectively (HR, 0.432, P=0.002). Conclusion: Gefitinib plus concomitant WBRT had higher response rate of BM and significant improvement in OS compared with gefitinib alone in treatment of BM from NSCLC.     

EGFR mutation status and its impact on survival of Chinese non-small cell lung cancer patients with brain metastases

Brain metastasis (BM) is a leading cause of death in patients with non-small cell lung cancer (NSCLC). EGFR mutations in primary NSCLC lesions have been associated with sensitivity to EGFR tyrosine kinase inhibitor (TKI). Therefore, it has become important to understand EGFR mutation status in BM lesions of NSCLC, and its clinical implications. BM samples of 136 NSCLC patients from South China, in which 15 had paired primary lung tumors, were retrospectively analyzed for EGFR mutation by amplification mutation refractory system (ARMS). Effect of BM EGFR mutations on progression-free survival (PFS) and overall survival (OS) was evaluated by Kaplan–Meier curves and log-rank test. EGFR mutations were detected in 52.9 % (72 of 136) of the BM lesions, with preference in female and never-smokers. A concordance rate of 93.3 % (14 of 15) was found between the primary NSCLC and corresponding BM. Positive prediction value of testing primary NSCLCs for BM EGFR mutation is 100.0 %, and negative prediction value is 87.5 %. Median PFS of BM surgery was 12 and 10 months (P?=?0.594) in the wild-type and mutant group, respectively. Median OS of BM surgery was 24.5 and 15 months (P?=?0.248) in the wild-type and mutant group, respectively. In conclusion, EGFR mutation status is highly concordant between the primary NSCLC and corresponding BM. The primary NSCLC could be used as surrogate samples to predict EGFR mutation status in BM lesions or vice versa. Moreover, EGFR mutations showed no significant effect on PFS or OS of NSCLCs with BM.     

厄洛替尼治疗非小细胞肺癌脑转移的回顾性分析

背景与目的:非小细胞肺癌(non-small-cell lung cancer,NSCLC)脑转移预后差,缺乏有效的治疗方法。厄洛替尼是小分子EGFR酪氨酸激酶抑制剂,广泛应用于晚期NSCLC患者,可延长患者的中位无进展生存及总生存期,经选择患者获益更为明显。目前厄洛替尼也逐渐用于NSCLC脑转移的治疗。本文通过分析厄洛替尼治疗NSCLC脑转移的疗效及安全性,探讨NSCLC脑转移的靶向治疗。方法:回顾性分析中山大学肿瘤防治中心2006年至2011年间收治的53例NSCLC脑转移患者的临床资料。所有患者均口服厄洛替尼150mg/d直至疾病进展、死亡或不良反应不可耐受,每2～3月评估疗效。结果:53例患者均可评价疗效。厄洛替尼对脑转移灶客观缓解率和疾病控制率分别为35.8%和81.1%,其中完全缓解(complete response,CR)3例,部分缓解(partialresponse,PR)16例,稳定(stable disease,SD)24例。全身病灶的客观缓解率和疾病控制率分别为35.8%和64.2%,其中CR 1例,PR 18例,SD 15例。脑转移灶的中位进展时间为7.3个月,全组中位无进展生存时间及中位总生存时间分别为5.6个月和15.9个月。1年、2年生存率分别为37.7%和11.3%。多因素分析显示,年龄、PS评分及EGFR状态为影响生存的因素。最常见的不良反应为皮疹和腹泻,发生率分别为75.5%和37.7%。结论:厄洛替尼对NSCLC脑转移有一定疗效,且毒性可以耐受。     

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.     

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.     

酪氨酸激酶抑制剂抑制非小细胞肺癌脑转移

[目的]评价酪氨酸激酶抑制剂（tyrosine kinase inhibitors,TKI）对控制脑转移的作用。[方法]83例Ⅳ期（或复发）非小细胞肺癌（NSCLC）患者接受吉非替尼或厄洛替尼治疗,同期67例化疗患者作为对照,随访脑转移出现的时间和生存时间。[结果]经中位11.4个月的随访,TKI组脑转移发生率低于化疗组（18.29%vs 35.38%,χ2=5.5,P=0.019）。TKI组中发生脑转移的中位时间为7.6个月（6.9~8.3个月）,明显长于单纯化疗组4.9个月（4.4~5.4个月）（χ2=15.6,P=0.001）。TKI组中位总生存时间为11.4个月（95%CI：10.3~12.6）,长于单纯化疗组的7.5个月（95%CI：6.6~8.5）（χ2=19.3,P〈0.001）。[结论]TKI降低晚期NSCLC患者脑转移的风险,延长患者的生存时间。     

First‐line epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor alone or with whole‐brain radiotherapy for brain metastases in patients with EGFR‐mutated lung adenocarcinoma

We proposed to compare the outcomes of first‐line epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR‐TKI) alone with EGFR‐TKI plus whole‐brain radiotherapy (WBRT) for the treatment of brain metastases (BM) in patients with EGFR‐mutated lung adenocarcinoma. A total of 1665 patients were screened from 2008 to 2014, and 132 were enrolled in our study. Among the 132 patients, 72 (54.5%) harbored a deletion in exon 19, 97 (73.5%) showed multiple intracranial lesions, and 67 (50.8%) had asymptomatic BM. Seventy‐nine patients (59.8%) were treated with EGFR‐TKI alone, 53 with concomitant WBRT. The intracranial objective response rate was significantly higher in the EGFR‐TKI plus WBRT treatment group (67.9%) compared with the EGFR‐TKI alone group (39.2%) (P = 0.001). After a median follow‐up of 36.2 months, 62.1% of patients were still alive. The median intracranial TTP was 24.7 months (95% CI, 19.5–29.9) in patients who received WBRT, which was significantly longer than in those who received EGFR‐TKI alone, with the median intracranial TTP of 18.2 months (95% CI, 12.5–23.9) (P = 0.004). There was no significant difference in overall survival between WBRT and EGFR‐TKI alone groups, (median, 48.0 vs 41.1 months; P = 0.740). The overall survival is significantly prolonged in patients who had an intracranial TTP exceeding 22 months compared to those who developed intracranial progression <22 months after treatment, (median, 58.0 vs 28.0 months; P = 0.001). For EGFR‐mutated lung adenocarcinoma patients with BM, treatment with concomitant WBRT achieved a higher response rate of BM and significant improvement in intracranial progression‐free survival compared with EGFR‐TKI alone.