非小细胞肺癌脑转移的生物学和治疗最新进展

Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion
非小细胞肺癌脑转移的生物学和治疗最新进展：多学科圆桌讨论总结山东省肿瘤医院呼吸肿瘤内科张品良

ABSTRACT摘要

This article is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose is to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non-small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context.
本文是2017年5月在日内瓦欧洲肺癌会议（ELCC）上举行的一次圆桌讨论会的结果。目的是探索和讨论非小细胞肺癌脑转移的生物学知识与治疗进展。在讨论的基础上作者们针对研究和治疗提出了系列推荐。

INTRODUCTION前言

Recent insights into the biology of non-small cell lung cancer (NSCLC) have led to a wealth of novel therapies, including targeted agents and immune checkpoint inhibitors with significant clinical activity. So far, there are limited data on the efficacy of these drugs in patients with brain metastases (BMs) but intracranial responses have been documented in emerging studies.
最近对非小细胞肺癌（NSCLC）生物学的见解带来了大量新颖疗法，包括具有显著临床活性的靶向药物和免疫检查点抑制剂。迄今为止，这些药物对脑转移瘤（BMs）患者疗效的数据有限，但在新兴研究中已经证明颅内应答。

At the meeting, a multidisciplinary group of experts discussed the biology of BMs as well as the anatomy of the blood–brain barrier (BBB). The group considered treatment options for NSCLC and their effect on BMs, focusing on targeted treatment and combination treatment for epidermal growth factor receptor (EGFR) mutated NSCLC and those with anaplastic lymphoma kinase (ALK) rearrangement.
在会议上，一个多学科专家组讨论了BMs的生物学以及血脑屏障（BBB）的解剖。专家组考虑了NSCLC的治疗方案及其对BMs的影响，重点针对表皮生长因子受体（EGFR）突变的NSCLC和间变性淋巴瘤激酶（ALK）重排患者的靶向治疗和综合治疗。

Incidence of BMs in NSCLC非小细胞肺癌脑转移的发生率

BMs are the most common intracranial neoplasms with significant morbidity and mortality. In lung cancer, 30–50% of patients will be diagnosed with BMs during their disease, with rising frequency because of the availability of novel imaging techniques and improved survival rates. Fifty per cent of lung cancer BMs occur at disease presentation and 50–60% as the only site of distant disease. BMs often present as multiple lesions, although in one third of patients BMs are singular.
脑转移瘤是最常见的颅内肿瘤，具有较高的发病率和死亡率。在肺癌中，30-50％的患者在其疾病期间将确诊为脑转移，由于新型成像技术的可用性和生存率的提高，发生率上升。50%的肺癌脑转移存在疾病症状，50-60％为唯一的远处转移部位。脑转移常常表现为多发病变，尽管三分之一的患者脑转移是单发。

BMs occur initially in 20% of patients with NSCLC, in 10–20% with advanced NSCLC, with numbers as high as 40–50% in those with stage III lung adenocarcinoma, 20–40% in those with ALK-rearranged tumours, and 45–70% in those who have ALK-rearranged NSCLCs and have been pretreated with an appropriate tyrosine kinase inhibitor (TKI).
20％的NSCLC患者最初即存在脑转移，10-20％发生在晚期NSCLC，Ⅲ期肺腺癌患者中高达40-50％，ALK重排的肿瘤患者中高达20-40％，ALK重排、已用适当酪氨酸激酶抑制剂（TKI）治疗的NSCLCs患者中为45-70％。

EGFR-activating mutations are present in about 10–20% of white patients with NSCLC. In patients with EGFR mutation, the incidence of BMs at the time of diagnosis is 25%, which is slightly higher than in unselected patients, suggesting that EGFR mutations might be associated with a metastatic tropism to the brain and then with an increased risk of BMs. Furthermore, the brain is a common site for relapse of disease in patients previously treated with TKIs in about 30–60% of EGFR-mutated NSCLCs.
约10-20％的白人NSCLC患者存在EGFR活化突变。在具有EGFR突变的患者中，确诊时脑转移的发生率为25％，略高于未经选择的患者，提示EGFR突变可能与脑转移倾向相关，因此脑转移风险增加。此外，在大约30-60％的EGFR突变的非小细胞肺癌中，大脑是既往用TKIs治疗过的患者疾病复发的常见部位。

Prognosis of BMs脑转移的预后

Overall survival (OS) of patients after the diagnosis of BMs remains poor with significant clinical problems. The prognosis depends on the patient’s age and performance status, the type of the primary tumour, the time from diagnosis of the primary, the overall disease activity, and the location and extension of extracranial and intracranial disease.
脑转移诊断后的总生存（OS）仍然很差，存在重要的临床问题。预后取决于患者的年龄和功能状态、原发肿瘤的类型、距原发灶的诊断时间、所有病变的活动性以及颅外和颅内病变的部位和范围。

Biology and molecular alterations of NSCLC BMs非小细胞肺癌脑转移的生物学和分子学改变

There are many biological aspects of growth of metastases in the brain for which scientific progress has been made and where further progress in our understanding will be helpful in developing new treatments. This extends from the biology of brain colonisation by metastatic cells from the initial stages (asymptomatic metastases) to advanced stages when the disease is clinically diagnosed.
脑转移瘤的生长有许多生物学方面的问题，这些方面已经取得了科学进展，而认识的进一步进展将有助于开发新的治疗方法。转移细胞脑定植的生物学从初期（无症状转移）扩展到临床诊断时的晚期。

The use of experimental models has allowed construction of a sequential map showing key mechanisms of a metastatic cell developing in the brain (see figure 1).
使用实验模型可以构建顺序图，显示脑内转移细胞发展的关键机制（见图1）。

Crossing the BBB穿越血脑屏障

The ability of cancer cells to cross the BBB involves general and specific mediators.癌细胞穿过血脑屏障的能力涉及普通和特殊的媒介。

The naive brain microenvironment正常情况下的脑微环境

After extravasation most metastatic cells die, partly due to reactions of the brain microenvironment responding to their presence. This suggests that a naive brain microenvironment initially repels many potential cancer cells. Some molecular mediators of natural defences have been reported. It is also true, unfortunately, that some metastatic cancer cells avoid this initial bottle-neck by blocking anti-tumour components of the reactive microenvironment. The surviving cells closely interact with pre-existing blood vessels in the brain by vascular co-option and colonisation of the crucial perivascular niche. This is all mandatory to the final progression to brain macrometastases.
大多数转移性细胞在溢出后死亡，部分是由于脑微环境对其存在的反应所致。表明正常情况下的脑微环境最初排斥许多可能存在的癌细胞。已报道了一些天然的分子防御介质。遗憾的是，某些转移性癌细胞通过阻断反应性微环境的抗肿瘤组份避开了这个初始瓶颈，这一点也是真实的。存活的细胞通过血管征用以及关键血管壁龛的定植与脑内已有的血管相互密切作用。这对于最终发展为明显的脑转移都是必不可少的。

Vascular co-option and dormancy血管征用与休眠

This process is mediated by cancer cell adhesion molecules and integrins, as well as by secreted molecules from the co-opted endothelial cells. Brain metastasis can manifest many years after the diagnosis of the primary tumour. Dormancy/quiescence is thought to play an important role in brain metastasis and recent data have started to show mediators of this biology, which is also linked to the perivascular location. Eventually these cells will re-awake and start to grow aggressively. The mechanism mediating this process has been linked to the ability of cancer cells to recognise components of the basal lamina.
该过程由癌细胞粘附分子和整联蛋白以及来自征用的内皮细胞分泌的分子介导。脑转移可以在原发肿瘤诊断多年后出现。休眠/沉默被认为在脑转移中发挥重要作用，最新数据已开始证明该生物学媒介，这也与血管周围的位置有关。最终这些细胞会重新醒来并开始侵袭。介导这一过程的机制与癌细胞识别基底层组分的能力有关。

Angiogenesis血管生成

Additional ways to interact with the vasculature involve the formation of new blood vessels, called angiogenesis. This appears crucial for the formation of BMs from lung adenocarcinoma, in an entity-specific and organ-specific manner. Interestingly, inhibition of this early angiogenic switch prevented metastases from outgrowth and arrested them in a microscopic state, making angiogenesis inhibition an interesting approach for BM prevention in lung adenocarcinoma.
与脉管系统相互作用的其他方式涉及新血管的形成，称为血管生成。这对于肺腺癌脑转移的形成似乎是至关重要的，以实体特异性和器官特异性方式形成。有趣的是，抑制该早期血管生成开关阻止了转移灶的生长，并将其遏止在微小状态，使血管生成抑制成为预防肺腺癌脑转移的有趣方法。

Invasive fronts浸润前沿

Even though the mechanisms of brain colonisation are more linked to the initial stages of metastasis, some might also apply to advanced stages of the disease and thus offer opportunities for improved therapies. For instance, invasive fronts have been described in 50% of BMs, which in many cases correlates with the process of vascular co-option. The correlation of invasive fronts with poor prognosis in patients with BMs might offer a therapeutic window to target mediators of vascular co-option after surgery to reduce local relapse.
尽管脑定植的机制与转移的初期更加相关，但在某种程度上也可能适用于疾病晚期，从而为改善治疗提供了机会。例如，在50％的脑转移中已描述了浸润前沿，在许多情况下与血管征用过程相关。侵袭性前沿与脑转移患者预后不良的相关性或许为术后靶向血管征用介质以减少局部复发提供了一个治疗窗口。

Genomic alterations基因组改变

Therapies, including targeted ones that are effective outside the brain, can fail in this organ; reasons for this might include the genomic and other molecular divergence of BMs compared with primary tumours and other metastatic sites. Although still in need of more evidence for their contribution to BM progression, specific genomic alterations found in brain metastasis offer actionable mutations to be exploited. In addition, BM-specific mutations could also be found in liquid biopsies from blood or cerebrospinal fluid (CSF) and have been used to evaluate response to therapy and the presence of residual disease. This emerging field of BM would benefit from the use of recent advances in genetic engineering using CRISPR/Cas9 combined with experimental models.
包括脑外有效的靶向治疗在这个器官中可能会失败；原因可能包括，与原发肿瘤以及其他转移部位相比，脑转移瘤的基因组及其他分子学有差异。虽然仍需要更多的证据来证明其对脑转移进展的贡献，但在脑转移中发现的特定基因组改变提供可开发利用的突变。另外，脑转移瘤特异性突变也可以在血液或脑脊液（CSF）的液体活检中找到，并已用于评估治疗应答和残留疾病的存在。这一新兴的脑转移领域将受益于使用CRISPR/Cas9与实验模型相结合的基因工程最新进展的应用。

Cancer cell–brain microenvironment interaction as target for therapy and prevention
癌细胞-脑微环境相互作用作为治疗与预防靶点

The divergent evolution of metastatic cells in the brain might respond to the significant pressure generated by its environment that is made of different cellular components, and homeostatic regulation. The microenvironment thus might be a crucial pillar to explain the specificity that applies to brain metastasis. Close cancer cell–microenvironment interactions have created an interesting scenario, where experimental therapies have probed the critical support that cancer cells receive from altered components of the microenvironment. For instance, established BMs have been shown to assemble gap junctions with surrounding reactive astrocytes.
脑中转移细胞的趋异性演变可能会对由不同细胞组成的环境产生的巨大压力和稳态调节产生应答。因此微环境可能是解释脑转移特异性的一个重要支柱。关闭癌细胞与微环境的相互作用创造了一个有趣的场景，实验疗法探索了癌细胞从微环境中改变的组分获得的关键支持。例如，已证明建立的脑转移瘤与周围的活性星形胶质细胞组成间隙连接。

This interaction can allow metastatic cells to detoxify themselves from the accumulation of potentially toxic metabolites generated by various sources of stress, including chemotherapy. A combination of BBB-permeable drugs targeting gap junctions has recently supported the potential of targeting interactions with the microenvironment. This might offer BM-specific therapies and prevention strategies in the future, possibly independent of the tumour entity.
这种相互作用可以使转移细胞将自身从各种来源包括化疗应急积累产生的潜在毒性代谢物中解毒。最近针对间隙连接能透过血脑屏障药物的组合支持靶向与微环境相互作用的可能性。将来这也许可能带来特异性针对脑转移的疗法和预防策略，而与肿瘤实体无关。

THE RELEVANCE OF THE BBB FOR MEDICAL TREATMENT OF NSCLC BMS
血脑屏障对非小细胞肺癌脑转移治疗的价值

The BBB is the physical, chemical and metabolic barrier that segregates blood from the interstitial fluid of the central nervous system (CNS) for protection of the CNS against overexposure, pathogens and toxins. Molecules with a molecular weight over 500 Daltons (the molecular weight of 98% of drugs) are generally considered to not readily cross an intact BBB, but other physico-chemical properties also influence brain penetration. This is important for primary and secondary prophylaxis; however, mixed responses have been seen.
血脑屏障是隔离血液与中枢神经系统（CNS）的组织间液以保护CNS防止过度暴露于病原体和毒素的物理、化学和代谢屏障。通常认为分子量超过500道尔顿的分子（98％的药物分子量）不易穿过完整的血脑屏障，但其他理化性质也影响脑渗透。对于初级和二级预防这很重要；然而，已见到了混合疗效。

The rising incidence of BMs may be partly due to the fact that some therapeutic compounds can control tumour growth outside of the CNS but do not, or only partially, penetrate the BBB. Therefore, tumour cells that have successfully invaded the brain may not be affected by these agents, making the brain a potential ‘sanctuary site’ for cancers.
脑转移的发病率上升部分原因可能是以下事实：一些治疗性化合物可以控制CNS外的肿瘤生长但不能或仅能部分穿透血脑屏障。因此，成功侵入大脑的肿瘤细胞可能不会受到这些药物的影响，使大脑成为癌症的潜在“保护区”。

There is an ongoing controversy about the role of the BBB breakdown in affecting the activity of systemic therapies for BMs. In health, but also many CNS diseases, the specific anatomical and molecular constitution of the BBB limits access of the vast majority of molecules to the brain: specialised endothelial cells connected by tight junctions, the vascular basement membrane, pericytes, astrocytic foot processes, and specialised transporter systems strictly regulate extravasation, while active exclusion mechanisms like glycoprotein P (P-gp), breast cancer resistance protein (BCRP) and the family of multidrug-resistant proteins exclude xenobiotics effectively. Thus, the BBB remains a complex obstacle for drug delivery to the CNS. Several techniques have been tested to direct therapeutics across the BBB, including disruption of the BBB, modification of drugs, inhibition of efflux transport, and Trojan horse approaches that use endogenous transporter properties of the BBB. One problem with those approaches is that even if an active compound can cross the endothelium, it is not guaranteed that it will reach the target cell. Recent evidence suggests that lowering the affinity of an antibody directed against the transferrin receptor allows for greater release of the antibody on the abluminal surface of the vessel, and entry into the brain parenchyma.
关于破坏血脑屏障在影响脑转移瘤全身治疗效果中的作用一直存在争议。在健康者以及许多中枢神经系统疾病患者中，血脑屏障特殊的解剖和分子结构限制了绝大多数分子进入大脑：由紧密连接、血管基底膜、周细胞、星形胶质细胞足突连接专门的内皮细胞以及专门的转运蛋白系统严格控制外渗，而糖蛋白P（P-gp）、乳腺癌耐药蛋白（BCRP）和多药耐药蛋白家族等主动排除机制有效地排除了外源性物质。因此，血脑屏障仍然是药物向CNS输送的一个复杂障碍。已经试验了几种技术直接穿过血脑屏障的疗法，包括破坏血脑屏障、药物的修饰、外排转运的抑制以及利用血脑屏障的内源性转运蛋白特性的特洛伊木马法。这些方法的一个问题是，即使活性化合物可以穿过内皮，也不能保证它会到达靶细胞。最新证据表明，降低抗转铁蛋白受体抗体的亲和力，可允许在血管管腔表面释放更多的抗体，并进入脑实质。

The majority of brain macrometastases, that is, metastases of more than 1 mm diameter which are detectable with common imaging techniques, do show signs of disturbance of the BBB, although to a varying extent.
大多数脑大体转移，即可用常见成像技术检出、直径大于1mm的转移，尽管程度不同，但确实显示出血脑屏障受到干扰的迹象。

Therefore, the challenges of crossing the normal BBB do not fully apply to BMs, even though some aspects of the BBB are preserved in BMs. It is a matter of debate whether a BBB breakdown in brain tumours allows penetration of systemic chemotherapies to the single cancer cells of the brain tumour in sufficient concentrations.
因此，在脑转移中血脑屏障即使有些方面仍有保留，但跨越正常血脑屏障的挑战并不完全适用于脑转移。脑肿瘤中血脑屏障破坏是否允许全身化疗以足够的浓度渗透到脑肿瘤的单个癌细胞，是个有争议的问题。

In clinical specimens, highly variable tumour levels have been reported for different agents. Of note, lapatinib and trastuzumab, two agents with no significant activity against breast cancer BMs, can be found in relevant concentrations in BMs in clinical and preclinical specimens, which makes it highly likely that the BBB is only partially relevant for the lack of CNS activity of some drugs. In accordance with this, it has been demonstrated that trastuzumab-emtansine (T-DM1), a derivate of trastuzumab, is able to show signs of clinical effectivity in HER2-overexpressing BMs, further supporting the notion that it is not the BBB penetration but other microenvironmental mechanisms in the brain that make certain drugs ineffective.
在临床标本中，已报道不同药物的肿瘤水平差别非常大。值得注意的是，拉帕替尼和曲妥珠单抗是两种对乳腺癌脑转移无显著活性的药物，在临床和临床前的脑转移标本中可以发现有意义的浓度，这很可能说明血脑屏障与某些药物缺乏CNS活性只是部分相关。据此，业已证明，曲妥珠单抗-伊姆坦辛（T-DM1），曲妥珠单抗的一个衍生物，能够在HER2过表达的脑转移中显示出临床有效的迹象，进一步支持了它不是穿透血脑屏障的概念，但是脑中的其他微环境机制使某些药物无效。

It has been shown that increased BBB permeability is associated with accelerated metastasis growth. Two closely related mTOR/PI3K inhibitors, one of them with a minor chemical modification that allows the two main exclusion transporters constituting the BBB (P-gp and BCRP) to be bypassed, had different effects on these metastases: while the BBB non-permeable inhibitor only affected permeable metastases, the BBB permeable one had strong anti-tumour effects on non-permeable micrometastases, and even dormant cancer cells in the brain. Furthermore, nuclear morphology changes and single cell regression patterns implied that both inhibitors target cancer cells independently of their relative position to the blood vessel, making BBB permeability the limiting step for drug diffusion to cancer cells in the brain. Another preclinical study found a highly variable uptake of doxorubicin and paclitaxel of different metastases from the same breast cancer cell line, so that cytotoxic concentrations were reached in only 10% of the most permeable metastases. It is widely assumed that classical chemotherapies with proven activity on systemic metastases of many cancers have limited, if any, activity on BMs, probably with the exception of primary chemotherapy of lung cancer BM. This can be due to a lack of sufficient BBB breakdown to allow primary extravasation of the drug and rapid secondary exclusion by P-gp, but also specific resistance mechanisms that are different in the brain, such as protection of extravasated cancer cells by astrocytes or other brain resident cells.
已证明血脑屏障通透性增加与转移灶生长加速相关。与mTOR/PI3K密切相关的抑制剂有两个，其中一种具有轻微的化学修饰，允许绕过构成血脑屏障的两个主要排除性转运蛋白（P-gp和BCRP），对这些转移灶具有不同作用：尽管不能透过血脑屏障的抑制剂只影响可透过性转移灶，但是，可透过血脑屏障的抑制剂对非透过性微转移灶具有很强的抗肿瘤作用，甚至对脑中的休眠癌细胞也有作用。此外，核形态学变化以及单细胞退化模式意味着两种抑制剂均靶向癌细胞而不依赖于它们与血管的相对位置，使得血脑屏障的可透过性成为药物扩散至脑中癌细胞的限制性步骤。另一项临床前研究发现，来自同一乳腺癌细胞系的不同转移灶对多柔比星和紫杉醇的摄取差异很大，因此在最具可透过性的转移灶中仅10%达到细胞毒浓度。人们普遍认为，经证实对许多癌症的全身转移具有活性的传统化疗对脑转移瘤的活性有限（如果有的话），或许除了肺癌脑转移的新辅助化疗外。这可能是由于血脑屏障的破坏不足以允许药物初始溢出和P-gp继发性快速排出，而且还因为脑中具体的耐药机制不同，例如通过星形胶质细胞或其他的脑常驻细胞保护从脉管中渗出的癌细胞。

TREATMENT OF NSCLC BMS

非小细胞肺癌脑转移的治疗

Overview

概述

For a long time, BMs in lung cancer have been considered a final event and were treated either by whole brain radiation therapy (WBRT) or palliative care. However, since the arrival of new systemic and targeted therapies, more effective treatments for BMs are available with the aim to increase local control, and if possible survival, without affecting neurocognition.
很长时间以来，在肺癌中脑转移被认为是最后的一个事件，通过全脑放疗（WBRT）或姑息治疗（和缓医疗）来进行治疗。然而，自从新的全身治疗和靶向治疗到来后，为了增加局部控制，并且如果可能在不影响神经认知的情况下，可用更有效的脑转移治疗。

Current treatment algorithms of NSCLC BMs offer symptom control measures and therapeutic measures.
非小细胞肺癌脑转移当前的治疗工作步骤提供症状控制和治疗策略。

Modern disease-directed management includes:
现代疾病导向管理包括：

· surgical resection,手术切除，

· radiotherapy,放疗，

· chemotherapy,化疗，

· targeted drugs,靶向药物，

· multi-modality approaches.综合方法。

Limited metastatic lesions局限转移病变

For limited metastatic lesions (one to three metastases) neurosurgical resection is one of the main therapeutic options, with stereotactic radiosurgery (SRS) being the main alternative, known to be equivalent to surgery in term of local control.
对于局限转移病变（1～3个转移灶），神经外科切除术是主要的治疗选择之一，立体定向放射外科（SRS）是主要的替代手段，已知局部控制与手术相当。

Resection can also be combined with radiotherapy, such as SRS or WBRT. These combinations have been addressed in two recent randomised trials, which showed that postoperative SRS was associated with a significant increase in local control compared with observation and that postoperative WBRT was associated with an increase in neurocognitive deterioration compared with postoperative SRS without any difference in OS.
切除术也可以结合放疗，如SRS或WBRT。这些组合已在最近的两项随机试验中被确定，试验表明，与观察相比，术后SRS与局部控制显著增加有关，并且，与术后SRS相比，术后WBRT与神经认知功能恶化增加，而OS没有任何差异。

Another approach is the combination of SRS and WBRT. One recent randomised trial has shown that even if WBRT combined with SRS is associated with better brain control, WBRT induces significant higher neurocognitive deterioration compared with SRS alone, without any difference in OS. However, another randomised trial comparing WBRT plus SRS with SRS alone showed that for a subgroup of patients with good graded prognostic assessment, a benefit of adding WBRT to SRS was obtained in OS.
另一种方法是SRS与WBRT联合。最近一项随机试验表明，即便WBRT联合SRS具有更好的脑控制，但是，与单独SRS相比，WBRT引起显著更高的神经认知功能恶化，而OS没有任何差异。然而，另一项比较WBRT联合SRS和单独SRS的随机试验显示，对于具有良好分级预后评估的亚组患者，将WBRT加入SRS得到了OS获益。

While treating patients with WBRT, neurocognition can be preserved by performing hippocampal sparing or adding mementine. A randomised phase III clinical trial aiming to compare time to neurocognitive failure between WBRT plus mementine to WBRT with hippocampal preservation and mementine is currently being performed (ClinicalTrials. gov identifier: NCT02360215).
在治疗WBRT患者时，通过实施海马保护或添加美金刚可以保护神经认知功能。目前正在进行一项随机Ⅲ期临床试验，旨在比较WBRT加美金刚和海马保护的WBRT加美金刚之间的至神经认知失败的时间（ClinicalTrials.gov 识别码：NCT02360215）。

Multiple metastatic lesions多发转移病变

In multiple metastatic lesions (more than three BMs) WBRT is still an option for most patients, alone or in combination with SRS, a radio-sensitiser or chemotherapy. However, SRS on more than four and up to 10 BMs is feasible, with no more late toxicity in neurocognition compared with patients with one to four brain metastases. Some patients, especially those with a poor performance status, receive chemotherapy or steroids alone. The addition of targeted drugs such as erlotinib as radio-sensitisers to WBRT has failed to show benefit in local controls or OS but has increased toxicity. The addition of chemotherapeutic agents such as temozolomide to radiation has also failed to improve survival but increases toxicity.
对于大多数多发转移病变（超过三个脑转移）的患者来说，WBRT仍是一个选择，单独或联合SRS、放射增敏剂或化疗。然而，对于超过4-10个脑转移SRS是可行的，与1-4个脑转移的患者相比，没有更晚的神经认知毒性。某些患者，尤其是那些一般情况差者，单独接受化疗或类固醇治疗。靶向药物如厄洛替尼作为放射增敏剂加入到WBRT，未能显示局部控制或OS获益，毒性却增加。化疗药物如替莫唑胺加入到放疗中也未能改善生存，却增加了毒性。

Systemic chemotherapy

全身化疗

Chemotherapy plays a limited role in the treatment of BMs because of its inability to cross the BBB. However, response rates as high as 30–40% have been reported in the brain with platinum-based chemotherapy, similar to rates observed extracranially.
在脑转移的治疗中化疗作用有限，因为它无法穿过血脑屏障。然而，已报道铂基化疗的脑有效率高达30-40％，与颅外观察到的相似。

Targeted drugs

靶向药物

EGFR TKI therapy
EGFR TKI治疗

Among patients with NSCLC with EGFR mutations, TKIs seem more effective than chemotherapy in controlling intracranial disease. EGFR TKIs are low molecular weight organic compounds with low to moderate CSF penetration rates differing between first-generation to third-generation drugs. EGFR TKIs of the first generation, such as gefitinib and erlotinib, and of the second generation, such as afatinib, have recently been integrated in the treatment algorithm of advanced metastatic mutated NSCLC as first-line therapy, replacing conventional chemotherapy because of improved response and survival rates.
在EGFR突变的NSCLC患者当中，TKIs在控制颅内病变方面似乎比化疗更有效。EGFR TKIs是低分子量有机化合物，第一代至第三代药物的CSF穿透率低至中等不等。第一代EGFR TKIs，如吉非替尼和厄洛替尼，以及第二代的，如阿法替尼，由于提高了疗效和生存率，最近已被纳入晚期转移性突变NSCLC的治疗工作步骤中作为一线治疗，取代了传统化疗。

Retrospective data and phase II study experiences have indicated that gefitinib and erlotinib have significant intracranial activity.
回顾性数据和Ⅱ期研究经验表明，吉非替尼和厄洛替尼具有显著的颅内活性。

For afatinib, phase II data, results from a compassionate use programme as well as pre-specified subgroup analyses suggest significant intracranial efficacy. This substantiates preclinical and clinical observations that afatinib can penetrate the BBB at concentrations sufficient for initiating anti-tumour activity.
关于阿法替尼，来自一项慈善用药计划的Ⅱ期数据结果以及事先指定的亚组分析表明，具有显著的颅内疗效。这证实了临床前和临床观察到的结果，即阿法替尼可以以足以启动抗肿瘤活性的浓度穿透血脑屏障。

EGFR TKIs of the third generation, such as AZD 3759 and osimertinib, have recently accelerated the debate over the role of modern targeted therapy for the treatment of BMs in mutated NSCLC as a potential substitute for brain radiation. This is because of preclinical and clinical evidence proving them to be more effective, showing a promising blood brain penetration and the potential to overcome EGFR TKI resistance. They also challenge the concept of upfront WBRT by being potentially more effective but less neurotoxic.
第三代EGFR TKIs如AZD 3759和奥希替尼，对于突变NSCLC脑转移的治疗最近加速了对现代靶向治疗作为脑放疗潜在替代治疗地位的争论。这是因为临床前和临床证据证明它们更有效，显示出有希望血脑穿透和克服EGFR TKI耐药的潜力。他们还由于可能更有效神经毒性却更少来挑战预防性全脑放疗的概念。

Preclinical studies have shown that osimertinib induces sustained tumour regression in an EGFR-mutated PC9 mouse brain metastasis model, and exhibits a greater distribution into mouse brain tissue than gefitinib, rociletinib or afatinib. Clinically, osimertinib has greater efficacy than platinum/pemetrexed in patients with T790M-positive NSCLC, including those with CNS metastases in a second-line setting.
临床前研究显示，奥希替尼诱导EGFR突变PC9小鼠脑转移模型中的持续肿瘤退缩，并且证实比吉非替尼、罗西替尼或阿法替尼更多分布至小鼠脑组织。临床上，在T790M阳性NSCLC患者中，包括CNS转移者的二线治疗情况下，奥希替尼比铂/培美曲塞更有效。

AZD 3759 has primarily been designed for crossing the BBB. Clinical experience for AZD 3759 exists from a phase I study in pretreated patients. By dosing up to 300 mg twice a day, there has been a significantly higher tumour shrinkage intracranially than extracranially. Grade 4 toxicity of less than 10% was reported for rash, diarrhoea and pruritus.
AZD 3759主要是为穿过血脑屏障设计的。从既往治疗过的患者的一项Ⅰ期研究中获得AZD 3759的临床经验。剂量达300mg bid，肿瘤缩小颅内显著高于颅外。据报道，皮疹、腹泻和瘙痒的4级毒性不到10％。

TKIs for patients with ALK-rearranged NSCLC
TKIs用于ALK重排的NSCLC患者

Currently, there are five compounds registered for patients with NSCLC and ALK rearrangement: these are the TKIs crizotinib, ceritinib, alectinib, lorlatinib and brigatinib. All these compounds have been registered with the US Food and Drug Administration (FDA); crizotinib, ceritinib and alectinib have also been approved by the European Medicines Agency (EMA) with an approval of brigatinib currently pending.
目前，有5种化合物注册用于ALK重排的NSCLC患者：这些化合物是TKIs克唑替尼、色瑞替尼、艾乐替尼、劳拉替尼和布加替尼。所有这些化合物均已经在美国食品和药物管理局（FDA）注册；克唑替尼、色瑞替尼和艾乐替尼也已获得欧洲医药管理局（EMA）批准，目前正在审批布加替尼。

The development of the ALK-directed TKI crizotinib took a rather short time between the discovery of the importance of ALK rearrangement and the introduction of the drug. In the PROFILE 1014 trial, crizotinib showed a significant improvement in progression-free survival (PFS) compared with chemotherapy in patients with ALK rearrangement.
在发现ALK重排的重要性和引入药物之间，ALK指导的TKI克唑替尼的开发花了很短的时间。在PROFILE 1014试验中，对于ALK重排的患者，与化疗相比，克唑替尼显著改善无进展生存（PFS）。

The incidence of BMs constitutes a major problem in patients with NSCLC and ALK rearrangement. About one third of TKI-resistant tumours harbour ALK mutations, including an amplification which occurs in 10% of mutations of the remaining 25%.
在ALK重排NSCLC患者中，脑转移的发生率是个主要问题。约三分之一的TKI耐药肿瘤携带ALK突变，其余25％的突变包括10％出现扩增。

Therefore, the question arises whether the CNS acts as a ‘sanctuary’ for the development of metastases, as up to 70% of recurrences occur within this anatomic area.
因此，由此产生的问题是CNS是否会充当一个转移发展的“庇护所”，因为多达70％的复发出现在这个解剖区域内。

Drugs developed after crizotinib, targeting ALK rearrangement, such as ceritinib, alectinib and brigatinib, have the ability to induce a remarkable CNS response in patients who have been pretreated with crizotinib. They have quite a different side-effect profile however.
在克唑替尼后开发的靶向ALK重排药物，如色瑞替尼、艾乐替尼和布加替尼，能够在既往克唑替尼治疗的患者中诱导显著的CNS应答。然而，他们具有完全不同的副作用。

When considering alectinib, responses in the CNS were complete in 20% in patients with measurable CNS metastases, whereas the use of brigatinib in the identical setting produced intracranial overall response rates in 42%–67% of patients.
在考虑艾乐替尼时，在具有可测量的中枢神经系统转移灶患者中，有20％CNS完全缓解，而在同样情况下使用布加替尼则颅内总有效率为42％-67％。

Very recent data have shown a significant superiority of alectinib over crizotinib in untreated ALK-positive NSCLC regarding the duration of PFS and the time until CNS progression.
最新数据显示，在未经治疗的ALK阳性NSCLC中，PFS的持续时间和至CNS进展时间艾乐替尼比克唑替尼有显著优势。

Nevertheless, the question of the best treatment sequence – if any - emerges and will have to be the topic of further clinical investigations.
然而，最佳治疗顺序的问题——如果有的话——将不得不成为进一步临床调查的主题。

Radiotherapy

放射治疗

Apart from surgery and targeted drugs, radiotherapy (especially radiosurgery or hypo-fractionated stereotactic radiotherapy (HFSRT)) is one of the main weapons to increase local control, and if possible survival, without affecting neurocognition.
除了手术和靶向药物之外，放射治疗（特别是放射外科或低分割立体定向放射治疗（HFSRT））是增加局部控制的主要武器之一，并且如果可能存活的话，而不影响神经认知。

Because the combination of WBRT with SRS or surgery does not increase OS but neurocognitive deficit and because SRS alone compared with the combination of SRS with WBRT has been shown to lead to the same OS and less neurocognitive deficit, with a shorter time to intracranial failure, SRS is now considered a standard treatment for patients with BMs.
由于WBRT联合SRS或手术不会改善OS，但会增加神经认知缺陷，并且由于与SRS联合WBRT相比，已证明单纯SRS带来相同的OS和更少的神经认知缺陷，至颅内失败的时间更短，因此，目前认为SRS是脑转移患者的一种标准治疗。

A study from 2016 showed the relevance of postoperative SRS compared with observation, bringing better local control without toxicity and no difference in OS. More recently this has been confirmed by a randomised clinical trial showing that postoperative SRS led to significantly higher local control than observation, with the same OS. The trial showed a higher benefit of postoperative SRS for small cavities (0–2.5 cm) compared with large ones.
2016年的一项研究显示，与观察相比，术后SRS带来更好的局部控制而没有毒性，OS也没有差异。最近的一项随机临床试验已证实了这一点，术后SRS的局部控制明显高于观察，OS相同。该试验显示，与大残腔相比，小残腔（0-2.5cm）术后SRS的获益更大。

Another randomised trial comparing postoperative radiation with WBRT plus SRS on non-resected BMs versus SRS on the cavity of resected metastases plus SRS on non-resected BMs showed that postoperative WBRT led to a higher neurocognitive deficit and the same OS compared with SRS alone. However, this trial showed poorer local control and worse brain control for patients treated with postoperative SRS compared with those treated with WBRT. These conflicting results could be due, at least in part, to the presence of microscopic tumour infiltration not targeted by postoperative SRS. If local control is important, we have to address and aim to obtain better brain control without neurocognitive deficit, as well as a better OS. This is when the combination of radiotherapy, especially SRS or HFSRT, with targeted drugs or immunotherapy comes in to optimise BM treatment.
另一项随机试验比较WBRT+SRS术后放疗治疗未切除的脑转移瘤与转移灶切除后的空腔SRS+未切除脑转移瘤SRS，结果显示，与单独SRS相比，术后WBRT的神经认知缺陷较高而OS相同。然而，这项试验显示，与WBRT治疗者相比，术后SRS治疗的患者局部控制较差，脑控制更差。这些矛盾的结果可能至少部分是由于术后SRS存在不能针对镜下肿瘤浸润。如果局部控制很重要，我们必须解决并努力获得更好的脑部控制，而不会出现神经认知缺陷以及更好的OS。这是当放疗特别是SRS或HFSRT联合靶向药物或免疫治疗来优化脑转移的治疗时。

Combination and sequencing of medical therapies with radiotherapy for NSCLC BMs
NSCLC脑转移内科治疗与放射治疗的联合与顺序

The irradiation anti-tumour effect is driven by direct and indirect effects. Irradiation can induce tumour cell death as mitotic cell death, apoptosis, but also autophagy and senescence.
辐射抗肿瘤效应分为直接和间接效应。辐射以有丝分裂细胞死亡、程序性细胞死亡的方式诱导肿瘤细胞死亡，但也可诱导自噬和衰老。

SRS or HFSRT acts through the induction of apoptosis of endothelial cells, thus leading to tumour radio-sensitisation. More recently it has been shown that irradiation can induce an immune cell death through CD8 T-cell infiltration and by the stimulation of tumour antigen presentation. It has been shown that SRS could induce the expression of programmed death ligand 1 (PDL1) in tumours and that association of SRS and programmed cell death protein 1 (PD1) treatment led to radio-sensitisation in preclinical models.
SRS或HFSRT通过诱导内皮细胞凋亡起作用，从而导致肿瘤放射敏化。最近已证明，辐射可通过CD8 Ｔ细胞浸润和刺激肿瘤抗原呈递诱导免疫细胞死亡。已证明，SRS可诱导肿瘤中程序性死亡配体1（PDL1）的表达，在临床前模型中SRS与程序性细胞死亡蛋白1（PD1）联合治疗导致放射敏化。

In addition to the local effect of radiotherapy in combination with immunotherapy, radiotherapy is also able to induce an abscopal effect, that is, an anti-tumour effect outside the irradiation field. This could be of great interest in tumours with high metastasis potential, such as lung cancer.
放疗与免疫治疗联合除了局部效应之外，放疗还能够诱导远隔效应，即在照射野外的抗肿瘤作用。这可能对具有高转移潜能的肿瘤如肺癌引起极大的兴趣。

Radiotherapy and TKIs
放疗和TKIs

To optimise the effect of SRS or HFSRT in NSCLC BMs, the combination of targeted drugs with such irradiation is a promising treatment. EGFR-mutated as well as ALK-positive NSCLCs have a higher risk of BMs, and EGFR as well as ALK pathways are known to control radio resistance. The association of EGFR inhibitors or ALK inhibitors with radiotherapy will lead to radio-sensitisation.
为了优化SRS或HFSRT治疗NSCLC脑转移的效果，靶向药物与这种照射联合是一种有前途的治疗。已知EGFR突变以及ALK阳性NSCLC具有更高的脑转移风险，并且已知EGFR以及ALK路径控制放射抵抗。EGFR抑制剂或ALK抑制剂与放疗联合会引起放射敏化。

Even if such inhibitors already penetrate the BBB, radiotherapy is known to disrupt the BBB and will help these inhibitors to penetrate. Several studies have shown the relevance of the combination of SRS or WBRT with TKIs with regards to intracranial progression but also, for some of them, in terms of OS. A pooled analysis showed that the combination of radiotherapy and TKIs had significant benefits in terms of objective response rate, time to intra-cranial progression and OS. A recent retrospective study showed that WBRT and TKI treatment led to longer time to intracranial progression compared with SRS and TKI, or TKI alone. Another retrospective study showed that patients with exon 21 mutation, when treated with WBRT and TKI, had a significantly higher OS and PFS compared with those treated with TKI alone. No difference was seen for patients with exon 19 deletions. Also, a recent study showed that performing radiotherapy (SRS or WBRT) before TKI treatment significantly increased the median OS compared with radiotherapy only in the case of failure, suggesting that SRS before EGFR TKI treatment is better than TKIs alone, at least for patients with exon 21 mutations. However, randomised trials need to be performed in this area.
即使这种抑制剂已经穿透血脑屏障，已知放射治疗会破坏血脑屏障并帮助这些抑制剂渗透。若干研究已经证明，SRS或WBRT与TKIs联合不仅与颅内进展相关，而且，其中的一些研究表明也与OS相关。汇总分析表明，放疗和TKIs联合在客观缓解率、至颅内进展时间和OS方面均显著获益。最近的一项回顾性研究显示，与SRS+TKI或单独TKI相比，WBRT+TKI治疗的至颅内进展时间更长。另一项回顾性研究显示，外显子21突变的患者，与单独TKI治疗者相比，WBRT+TKI治疗的OS和PFS显著更高。对于外显子19缺失的患者没有观察到差异。此外，最近的一项研究表明，在失败的患者中，与单纯放疗相比，在TKI治疗前进行放射治疗（SRS或WBRT）显著增加中位OS，提示在EGFR TKI治疗前SRS优于单独的TKI，至少对于外显子21突变的患者是如此。然而，这一领域需要进行随机试验。

A few trials are currently being undertaken associating SRS with ALK inhibitors and these should be developed.
目前正在进行少量试验，将SRS与ALK抑制剂联合使用，这些试验应得到发展。

Radiotherapy and immunotherapy放射治疗和免疫治疗

Another possibility is the combination of immunotherapy and radiotherapy, particularly SRS with checkpoint inhibitors. These combinations have been mostly studied in melanoma BMs, with SRS and ipilimumab treatment, but anti-PD1 and SRS combinations have also been reported. Some studies report encouraging results even for OS, while others do not. Some recent retrospective studies have shown that SRS performed before and concurrently to immunotherapy would have better results than SRS performed after.
另一种可能是免疫治疗和放射治疗的联合，特别是SRS与检查点抑制剂。这些联合大多在黑色素瘤脑转移中进行研究，用SRS和伊匹单抗治疗，但是也有报道抗PD1与SRS联合。一些研究报告甚至OS的结果令人鼓舞，而另一些则没有。最近的一些回顾性研究已证明，在进行免疫治疗之前和同时实施SRS比之后实施的结果更好。

Because of the incidence of pseudo-progression with these combined treatments, the evaluation of their efficacy needs to be performed with multimodal imaging (see figure 2).
由于这些联合治疗会出现假性进展，因此，需要用多模式影像学评估其疗效（见图2）。

Again, clinical trials for the evaluation of such combinations in NSCLC BMs in patients without mutation, but also in those with EGFR mutation, are needed.
再次，不仅需要在无突变患者中，而且需要在那些EGFR突变的NSCLC脑转移患者中进行临床试验以评估这种联合。

Neurosurgical resection of NSCLC BMs
NSCLC脑转移的神经外科切除术

Neurosurgical resection of BMs in patients with NSCLC is an indispensable treatment option in the multimodal management of such tumours. The subsequent initiation of postoperative radiotherapy in these tumours has demonstrated a positive impact on OS. Furthermore, the extent of resection in NSCLC BMs is an important factor for patient prognosis. Thus, a complete ‘macroscopic’ removal of surgically treated BMs results in a significantly better patient prognosis than an incomplete tumour resection. However, local recurrence of BMs after neurosurgical resection is not uncommon in clinical practice even after macroscopic complete resection and postoperative radiotherapy.
在NSCLC患者中，脑转移的神经外科切除术是这种肿瘤多模式管理中一个不可或缺的治疗选择。随后对这些肿瘤开始术后放疗已经证明对OS有益。此外，NSCLC脑转移的切除范围是患者预后的一个重要因素。因此，手术治疗脑转移的完全“肉眼”切除比不完全肿瘤切除术患者的预后更好。然而，即使在肉眼完全切除和术后放疗后，神经外科切除术后脑转移局部复发在临床实践中并不罕见。

It was long assumed that BMs are well demarcated from the surrounding brain tissue. In 2013 Berghoff et al found in an autopsy study that only about half of the BMs show a well demarcated growth pattern. Tumour infiltration of the surrounding brain tissue of metastases was observed in the other half of cases. Perivascular growth into the brain parenchyma distant from the brain metastasis (‘vascular co-option’) was present in 18% of cases and diffuse infiltration of the surrounding brain tissue (‘diffuse infiltration’, like in a malignant glioma) was observed in 32% of cases.
长期以来一直认为脑转移与周围脑组织界限分明。2013年，Berghoff等在一项尸检研究中发现，大约只有一半的脑转移呈现界限分明的生长模式。在另一半的病例中观察到转移灶周围的脑组织肿瘤浸润。在18％的病例中存在血管周生长进入远隔脑转移（“血管征用”）的脑实质中，在32%的病例中观察到周围脑组织的弥漫性浸润（像恶性胶质瘤中的“弥漫性浸润”）。

In a recent prospective study, Siam et al found that tumour infiltration of the surrounding brain tissue is a common finding especially in BMs from NSCLC, present in 75% of cases. In some of these NSCLC BMs the tumour infiltration was observed more than 2 mm away from the resection cavity. Thus, tumour cells might remain in the surrounding brain tissue despite a complete ‘macroscopic’ resection of BMs and result in local recurrence.
在最近一项前瞻性研究中，Siam等发现肿瘤浸润周围脑组织是一种常见现象，尤其是在NSCLC脑转移中，存在于75％的病例中。在部分NSCLC脑转移中观察到肿瘤浸润到远离切除空腔的2mm以上。因此，尽管对脑转移瘤进行了完整的“肉眼”切除，但肿瘤细胞可能仍残存在周围的脑组织中，并导致局部复发。

To overcome this limitation, Yoo et al proposed a ‘microscopic total resection’ of single BMs in non-eloquent areas with additional removal of at least 5 mm of surrounding brain tissue. Such a microscopic total resection resulted in a significantly better local tumour control rate in BMs than conventional complete resections. However, this 5 mm safety margin in microscopic total resections was arbitrarily selected and thus a more selective tool to visualise tumour infiltration of the surrounding brain tissue of BMs would be of interest.
为了克服这种局限性，Yoo等提出非功能区单个脑转移的“显微全切除”，并另外去除至少5mm的周围脑组织。这种显微全切除的结果是脑转移的局部肿瘤控制率显著优于传统的完全切除。然而，这种显微全切除的5mm安全界限是任意选择的，因此更有选择性可视化脑转移瘤周围脑组织肿瘤浸润的工具将会令人感兴趣。

5-Aminolevulinic acid
5-氨基乙酰丙酸

One innovative approach might be the selective visualisation of brain metastasis tissue with the intraoperative fluorescence marker 5-aminolevulinic acid (5-ALA). In a recent study, Kamp et al found that BMs can be visualised during surgery with the assistance of 5-ALA in about two thirds of cases (see figure 3). It is not clear so far if the 5-ALA fluorescence technique is also able to visualise tumour infiltration of the surrounding tissue of BMs. This should be investigated in multi-centre studies.
一种创新方法可能是术中用荧光标记物5-氨基乙酰丙酸（5-ALA）选择性可视化脑转移组织。在最近一项研究中，Kamp等发现在约2/3的病例中，手术期间在5-ALA的辅助下可以观察到脑转移瘤（见图3）。迄今为止尚不清楚，5-ALA荧光技术是否还能够显示脑转移瘤周围组织的肿瘤浸润。这应该进行多中心研究。

Neurosurgical interventions for the analysis of drug concentrations and biomarkers
神经外科参与分析药物浓度和生物标志物

Concept of ‘window of opportunity’ studies: measurement of tissue concentrations of antineoplastic agents in BMs
‘时机之窗’研究的概念：测量脑转移瘤中抗肿瘤药物的组织浓度

BMs have been widely considered ‘extra-axial’ lesions, thus not being restricted by the BBB. In contrast to gliomas, penetration of antineoplastic drugs from the intravascular space into the tumour tissue of BMs is less a matter of debate. However, solid data are scarce. Mostly, there has been indirect evidence for drug tissue penetration into BMs due to observation of any response in MRI scans after systemic chemotherapy. Recently, scores derived from blood values have been described to estimate survival of patients with BMs. Only a few studies are available dealing with the measurement of tissue concentrations of antineoplastic agents in BMs. In a meta-analysis of 1441 potentially relevant publications, only 12 turned out to provide solid data on tissue concentrations of chemotherapeutic drugs in BMs. The tissue-to-blood ratio showed huge variations between different drugs which had also been used for solid tumours with subsequent BMs. As microsurgical resection offers direct access to the tissue, exposure of the patient to systemic therapy prior to surgery would allow the tissue concentration within the specimen to be quantified. Since the intravascular space contributes hereto, pharmacodynamics and pharmacokinetics of the compound must be considered to correct the values measured accordingly.
普遍认为脑转移瘤是‘颅外’病变，因此不受血脑屏障的限制。与胶质瘤相反，抗肿瘤药物从血管内空间渗透进入脑转移瘤的肿瘤组织并不是一个争议问题。但是，可靠的数据很少。大多数情况下，由于全身化疗后MRI扫描观察到一些应答，因此，药物组织渗透进入脑转移瘤已有间接证据。最近，从血液指标得出的分数被用来评估脑转移瘤患者的生存。目前仅有少数研究涉及脑转移瘤中抗肿瘤药物组织浓度的测量。在对1441篇可能相关的出版物进行的一项meta分析中，只有12篇最终提供了关于脑转移瘤中化疗药物组织浓度的可靠数据。不同药物之间的组织/血液比呈现巨大的差异，这些药物也被用于随后脑转移的实体瘤。由于显微手术切除可以直接进入组织，因此在手术之前将患者暴露于全身治疗将允许量化标本内的组织浓度。由于血管内空间会增加该浓度，因此必须考虑化合物的药效学和药代动力学以校正相应的测量值。

Prerequisites of such a study would be:
上述研究的前提是：

· the drug should be in use for cancer therapy,该药应该用于癌症治疗，

· phase I studies are already completed,已经完成Ⅰ期研究，

· the toxicity is known and reasonably low,毒性已知且相当低，

· there are no side effects which could be relevant for surgery (significant immediate or early bone marrow toxicity, embolic or bleeding disorders),没有可能与手术有关的副作用（显著的即刻或早期骨髓毒性、栓塞或出血性疾病），

· the serum half-life (tissue half-life) is known to find the most appropriate timing of drug delivery in relation to tissue sampling,已知血清半衰期（组织半衰期）以找到与组织采样相关的最合适的给药时机，

· there is a calculation of serum level to estimate the influence of the intravasal drug, 可计算血清水平以估计血管内药物的影响，

· intra-operative pharmacokinetics if applicable.
如果适用，术中药代动力学。

Morikawa et al conducted such a study for capecitabine and lapatinib in BMs of breast cancer. Capecitabine and lapatinib were shown to penetrate to a significant but variable degree into BMs of breast cancer. However, drug delivery to the BM tissue was variable and appeared in some cases too low to be effective. Overall, the tissue concentration varied considerably between the few cases under investigation, especially according to different preoperative dosages and timing of drug administration in relation to the surgical procedure. This highlights the importance of standardising such protocols to generate meaningful data. Thus, it could be crucial to elucidate mechanisms which limit drug concentration.
Morikawa等对乳腺癌脑转移瘤中的卡培他滨和拉帕替尼进行了上述研究。结果显示卡培他滨和拉帕替尼以显著但不同程度的进入乳腺癌的脑转移瘤中。然而，药物进入脑转移瘤组织是不定的，并且在某些病例中浓度太低而无效。总体而言，在调查研究的少数病例之间，组织浓度差异很大，特别是根据不同的术前剂量和给药时机与外科手术的关系进行调查时。强调上述流程标准化对获得有意义的数据是重要的。因此，阐明药物浓度的制约机制可能是至关重要的。

Such window-of-opportunity studies could be a promising tool to obtain information about inter-individual variation of drug concentrations and optimal drug dosage of new compounds for systemic treatment of BMs to reduce the risk of using ineffective drugs (waste of opportunity) and missing effective drugs (loss of opportunity) for efficient and evidence-based planning of early phase II trials (see figure 4).
这种时机之窗研究可能是获得个体间药物浓度变化信息以及用于脑转移瘤全身治疗新化合物最佳药物剂量的一个有前途的工具，以有效减少使用无效药物（浪费机会）和错过有效药物（失去机会）的风险并进行循证设计的早期Ⅱ期试验（见图4）。

Identification of genetic/molecular signature
基因/分子标记的识别

Several genetic signatures have been characterised in solid tumours, which are not only relevant prognostically but determine the oncological management. However, little is known about whether BMs share the signature of the primary tumour and whether multiple BMs are of clonal origin with the same molecular pattern. Especially in cases where the molecular profile determines the therapeutic management, it would be mandatory to know the profile of the BMs as well. Assuming the BMs and primary lesion would not necessarily match in terms of their molecular signature, at least a stereotactic biopsy of the BMs would be necessary to tailor the treatment. The strive to personalise cancer treatment, also for BMs, might increase the demand for tissue analysis of BMs even in the case of a known primary lesion.
已经在实体瘤中描述了几种基因特征，这不仅与预后有关，而且决定肿瘤的管理。然而，关于脑转移瘤是否具有原发肿瘤的特征以及多个脑转移瘤是否是具有相同分子模式的克隆来源知之甚少。特别是在分子图谱决定治疗管理的病例中，同样必须了解脑转移瘤的分子图谱。假设脑转移瘤和原发病灶就其分子特征而言不一定匹配，至少脑转移瘤的立体定向活检对设计治疗是必要的。力求个体化治疗癌症以及脑转移瘤，即使在已知原发病灶的情况下，也可能增加对脑转移瘤组织分析的需求。

Molecular analysis of CSF samples has been shown to be a useful tool to identify clinically relevant genomic alterations, including aberrations not found in primary tumours in patients with BMs. Thus, liquid biopsies from CSF may improve personalised therapy of patients with BMs.
已证明CSF标本的分子分析是鉴定临床相关基因组改变的有用工具，包括在脑转移患者的原发肿瘤中未发现的变异。因此，CSF液体活检可以改善脑转移患者的个体化治疗。

CONCLUSION

结论

The roundtable discussion highlighted the urgent need to define better treatments for prophylaxis and treatment of BMs in patients with NSCLC. The growing insights into the pathobiology of BMs and molecular treatment targets lead to novel therapy approaches that need to be tested in clinical trials enrolling patients with BMs.
圆桌讨论强调急需阐明预防和治疗NSCLC患者脑转移更好的治疗方法。对脑转移的病理生物学和分子治疗靶点的不断深入了解需要在招募脑转移患者的临床试验中研究新颖的治疗方法。