Advances in the Application of Adjuvant Chemotherapy and Targeted Therapy in Postoperative Patients with Stage I Lung Adenocarcinoma

Abstract

肺癌是我国癌症负担和癌症死亡的主要原因之一，每年有近80万人新诊断为肺癌患者，其中接近一半的患者为肺腺癌（lung adenocarcinoma, LUAD）。根据目前的临床指南，手术是I期LUAD患者的主要治疗手段，但是仅靠手术I期LUAD患者的5年生存率仍不令人满意，为73%-90%，即有相当一部分患者需要其他手段来提高生存获益。化疗和靶向治疗已经在局部晚期和转移性LUAD患者的治疗中取得了巨大的成就，但是能否使I期LUAD术后患者获益仍存在争议。基于该现状，已经有很多研究者关注到了这一问题并做出了有益的探索。本综述就影响I期LUAD术后患者接受辅助化疗和靶向治疗的因素以及辅助化疗和靶向治疗在I期LUAD术后患者中应用的相关临床研究作了简单的回顾，以期更广泛地了解该问题的最新进展并为推动该领域的持续研究寻找新的突破点。

Lung cancer is one of the main causes of cancer burden and death in China, with nearly 800,000 newly diagnosed lung cancer patients each year, nearly half of whom are lung adenocarcinoma (LUAD) patients. According to current clinical guidelines, surgery is the main treatment for stage I LUAD patients, but the 5-year overall survival rate of stage I LUAD patients alone is still unsatisfactory, about 73%-90%, indicating that a considerable number of patients require other means to improve survival benefits. Chemotherapy and targeted therapy have achieved great success in the treatment of locally advanced and metastatic LUAD patients, but there is still controversy over whether they can benefit stage I LUAD postoperative patients. Under the circumstances, many researchers have paid attention to this issue and made beneficial explorations. This review provides a brief review of the factors that affect the acceptance of adjuvant chemotherapy and targeted therapy in stage I LUAD postoperative patients, as well as the relevant clinical research on the application of adjuvant chemotherapy and targeted therapy in stage I LUAD postoperative patients, in order to gain a broader understanding of the latest developments in this field and find new breakthroughs to promote sustained research in this field.

肺癌是一组起源于支气管上皮组织的恶性肿瘤，其中肺腺癌（lung adenocarcinoma, LUAD）是目前临床上最常见的类型。现在通常认为LUAD是一组具有遗传和细胞异质性的独特疾病[1,2]。由于烟草滥用、空气污染、放射性暴露以及慢性肺部疾病等原因，我国肺癌的发病率和死亡率一直居高不下[3]。

针对LUAD的治疗，要根据肿瘤原发灶-淋巴结-转移（tumor-node-metastasis, TNM）分期系统（如无特殊指出，本文提到的TNM分期指第八版）来做出最佳选择[4]，对于符合条件的患者来说，手术是治疗I-IIIA期LUAD的关键因素。但即使接受了手术，也会有10%-27%的I期患者可能在确诊后5年内去世[4]。以铂类药物为基础的辅助化疗（adjuvant chemotherapy, ACT）在II期和部分III期LUAD患者中的作用已经得到公认[5,6]，辅助靶向治疗（adjuvant targeted therapy, ATT）也在相应分期的患者中取得了令人瞩目的研究结果[7,8]，但是对于I期LUAD术后患者，是否需要接受ACT或ATT仍存在着很大的争议。本文拟梳理目前关于I期LUAD术后患者辅助治疗相关研究的进展。

1 影响LUAD患者辅助治疗疗效的因素

1.1 肿瘤病理因素

1.1.1 肿瘤分化程度 肿瘤的分化程度是影响患者治疗选择的一个重要因素。2020年6月，国际肺癌研究协会（International Association for the Study of Lung Cancer, IASLC）提出了浸润性LUAD的组织学分级系统[9]，该分级系统将浸润性LUAD分为了低级别、中级别和高级别三类，多项研究[10-12]证实，随着级别的升高，浸润性LUAD的预后依次变差。在高级别组中，ACT对IB-III期的患者有显著的总生存期（overall survival, OS）获益（P=0.048），多变量分析进一步证实，ACT是高级别组肿瘤OS的独立预后因素（P=0.002）[12]。但是靶向治疗对早期高级别浸润性LUAD患者的生存益处尚未见报道。上述研究说明，肿瘤分级系统将帮助我们筛选出能从辅助治疗中获益的早期肺癌患者。

1.1.2 肿瘤高危病理因素 脉管瘤栓目前被认为是肺癌患者的不良预后因素[13]，在I期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者中，合并脉管瘤栓的患者预后也更差[14-16]。有研究[17]指出，这种预后意义在早期LUAD中体现得更为明显，因此应当有针对性地设计辅助治疗的前瞻性试验。

气腔播散也被认定为是LUAD的不良预后因素[18,19]。这一结论在早期患者中尚有争议，大多数研究[20-22]支持合并气腔播散的I期LUAD患者预后更差，应当接受辅助治疗以减少复发转移，但是也有研究[16]指出在切除的早期LUAD中，气腔播散似乎不会影响患者的复发或死亡率。因此气腔播散是否能够作为影响患者术后辅助治疗的因素还需要更大规模更严谨的研究来提供证据。

1.2 临床因素

1.2.1 影像学表现 胸部计算机断层扫描（computed tomography, CT）中的一些影像学特征比如胸膜侵犯、肿瘤最大径将直接影响患者的TNM分期从而影响患者预后[4]，但还有一些特点并未影响TNM分期，但是也有一定的预后意义。一部分肿瘤在胸部CT上表现为空洞样的改变，有研究[23,24]指出，空洞样的病灶比非空洞样的病灶预后要更差，是复发和总OS的独立危险因素。当然，也有反面的研究结果不支持这一结论，比如Nguyen等[25]的研究显示CT上的空洞表现无法预测患者的生存，但此研究的样本量较小，结论需要仔细推敲。

日本临床肿瘤研究组（Japan Clinical Oncology Group, JCOG）系列研究[26-29]的结论让我们认识到肿瘤在胸部CT上的实性成分占比（consolidation tumor ratio, CTR）也对治疗方式选择有着巨大的影响，有研究者探讨了CTR与预后的关系，结果提示更高的CTR预示着更差的预后[30-32]。Park等[31]发现，纯实性的肿瘤更容易出现复发和远处转移，磨玻璃结节（ground-glass nodule, GGN）的存在与更晚的复发时间和更长的OS相关（P< 0001）。Wang等[30]的研究规模较大，纳入了2775例患者，其结果显示纯GGN组5年总OS率和无病生存（disease-free survival, DFS）率分别为98.8%和98.0%，部分实性组分别为96.0%和86.5%，纯实性组分别为88.0%和75.5%（P< 0001），说明目前TNM分期的局限性，也提示对于CT上表现为纯实性的肿瘤，辅助治疗可以适当积极一些。

正电子发射断层显像/CT（positron emission tomography/CT, PET/CT）越来越多地被应用到肺癌患者的常规诊疗当中[33]，也有多项研究[34-37]发现了PET/CT相关参数对NSCLC患者的预后意义。一项荟萃分析[36]汇集了36项研究，其结论为最大标准化摄取值（maximal standardized uptake value, SUVmax）、代谢肿瘤体积（metabolic tumor volume, MTV）和病变糖酵解总量（total lesion glycolysis, TLG）的高值预示着手术NSCLC患者的复发或死亡风险更高，这一结论在I期患者中也成立。Sharma等[37]的研究则是一项前瞻性研究，其主要结论为MTV和TLG是接受铂类化疗的NSCLC患者OS的可靠预后标志物。

1.2.2 手术切除范围 虽然亚肺叶切除已经在某些特定人群中取得了成功[26,27,29]，但是仍有部分患者的亚肺叶切除是妥协性的，常见原因包括术中发现全胸膜腔黏连、冰冻肺门、患者预期肺功能较差等。在一项根据监测、流行病学和最终结果（Surveillance, Epidemiology, and End Results, SEER）数据库的研究中，研究者发现在≤2 cm的肿瘤中，肺叶切除术的5年OS率高于亚肺叶切除术[38]。这一结果受到了一些质疑，质疑点在于研究者没有平衡两组的基线特征，并且忽略了在亚肺叶切除中淋巴结被完全解剖的可能性较小这一问题[39]，但是后续有样本量更大的研究，在通过倾向性评分平衡组间混杂因素后还是支持肺叶切除术对I期肺癌患者预后的优势地位，并且说明辅助治疗能够改善亚肺叶切除组的预后[40]。

1.3 生物标志物

1.3.1 影响ACT选择的生物标志物 既往有研究[41-43]发现了一些可能影响NSCLC患者预后以及化疗获益的基因，包括切除修复交叉互补基因1（excision repair cross complementary gene 1, ERCC1）、核苷酸还原酶1（ribenucleotide reductase M1, RRM1）、乳腺癌易感基因1（breast cancer susceptibility gene 1, BRCA1）和p53抑癌基因，但这些研究结果并未在临床上得到广泛应用，主要还是存在样本处理不够标准化、检测方法不可靠及抗体的特异性差、信使核糖核酸和蛋白检验的异质性等问题。

目前比较有前景的方法是循环肿瘤DNA（circulating tumor DNA, ctDNA）指导早期NSCLC的干预和个性化辅助治疗。Qiu等[44]的研究指出，ctDNA可作为NSCLC术后和ACT后风险分层和早期检测复发的可靠生物标志物，并且能筛选从ACT中获益的优势人群。此外，肿瘤突变负荷（tumor mutational burden, TMB）也有一定的指导意义，Song等[45]的研究发现，低TMB的患者更能从化疗中获益，其无进展生存期（progression-free survival, PFS）明显长于高TMB的患者[风险比（hazard ratio, HR）=0.554, P=0.036]。

1.3.2 影响ATT选择的生物标志物 作为精准医学的代表治疗方法，酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）等靶向治疗主要应用在LUAD患者当中。表皮生长因子受体（epidermal growth factor receptor, EGFR）、间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）、c-ros肉瘤致癌因子1（ROS proto-oncogene 1, ROS1）、间质表皮转化因子（mesenchymal to epithelial transition factor, MET）以及RET等靶点本身就是预测靶向治疗效果的标志物，但针对这些靶点的大多数药物尚未在I期患者的辅助治疗中得到广泛的应用[46-49]。在此，我们简单介绍一些新兴的可能改变临床实践的靶点。

有研究[50,51]认为神经调节蛋白-1（neuregulin-1, NRG1）融合在浸润性肺黏液性腺癌中富集（约30%的黏液腺癌患者中存在NRG1突变）。已经发现泛ERBB抑制剂类药物（如阿法替尼）对浸润性肺黏液性腺癌的治疗具有潜在的敏感性[52-54]。Kirsten大鼠肉瘤病毒癌基因同源物（Kirsten rat arcomaviral oncogene homolog, KRAS）突变见于高达20%-30%的NSCLC患者，是最常见的肺癌致癌驱动因素。虽然目前针对KRAS的药物尚停留在I期研究[55,56]，但由于它和许多其他主要驱动基因相互排斥，可用于排除样本进行其他可成药改变（如EGFR突变和ALK融合）的进一步检测[57]。

2 辅助治疗在I期LUAD术后患者中应用的相关临床研究

2.1 ACT在I期LUAD术后患者中应用的相关临床研究

最新版的美国国立综合癌症网络（National Comprehensive Cancer Network, NCCN）指南已经不再推荐对高危的IB期术后患者进行ACT[58]，这主要是因为既往的大规模随机对照研究（randomized controlled trial, RCT）均未得出辅助治疗对I期术后患者有利的结论，而以第八版TNM分期为基础的研究又非常少。我们也未检索到近期的针对I期LUAD术后患者辅助化疗的前瞻性RCT，仅有多篇回顾性研究提供了有争议的结论。

2013年一项韩国的回顾性研究[59]指出，对于肿瘤大小介于3-4 cm且没有淋巴结和远处转移的患者，铂类ACT是OS（HR=0.428, P=0.049）和DFS（HR=0.57, P=0.043）的良好预后因素，但是该研究的入组人群有偏倚，观察组患者的平均年龄较高，而治疗组患者的体能状态较好。Morgensztern等[60]的研究样本量更大，纳入10,587例IB期患者，其中接受ACT的有1608例，结果发现接受ACT的IB期患者的中位生存期较观察组延长了33.4个月（P< 0001）。

Tu等[61]的基于SEER数据库的研究纳入16,765例患者，其中LUAD患者6103例，ACT组的LUAD患者有1027例，经过倾向性评分匹配后的结果显示ACT组的OS优于非ACT组（HR=0.775, 95%CI: 0.704-0.853, P< 00001），尤其是肿瘤大小在2 cm以上的患者。但这一研究纳入了肺段切除和肺楔形切除等手术方式，而且ACT组和非ACT组分别有约26.0%和26.7%的患者切除的淋巴结< 4，这些因素很可能导致一些分期更高的患者被纳入了研究，从而产生结论的偏倚。另一篇基于SEER数据库的研究[62]结论也支持ACT的生存益处，但是该研究在吸烟、手术并发症、淋巴血管浸润、体能状态和驱动基因突变等可能影响预后的因素上存在缺失。

Zhang等[63]的研究则得出相反的结论，在IB期NSCLC患者（超过80%的入组患者均为LUAD患者）中，ACT与5年OS率的改善没有显著相关性，仅仅在肿瘤大小介于3-4 cm之间且合并脏层胸膜受侵的亚组中才看到OS率的显著差异（93.98% vs 68.93%, P< 001）。Cheng等[64]的研究也认为仅有在大小介于3-4 cm之间且为低分化肿瘤的亚组中，ACT才能带来更好的2年OS率。另一项重点针对IB期患者的研究[65]则是回顾了569例因原发性NSCLC接受肺切除术的患者，该研究发现对于IB期术后NSCLC患者，观察组的5年OS为87.6%，治疗组则为82.4%（P=0.021），ACT反而带来了更差的预后。

因此更多的研究将目标人群设定为高危的IB期术后患者，比如内脏胸膜受侵、脉管瘤栓、实性生长模式、微乳头生长模式以及淋巴结清扫数目较少（< 1个），结果均提示ACT带来了生存益处[66-69]，但各项研究的入组标准均不统一。这些研究结论以及本文1.1和1.2中的内容提示我们，未来应当首先在合并高危因素的I期术后患者中开展RCT来明确ACT的治疗意义。

值得一提的是，Tsutani等[69]的研究还在IA3期的患者中发现了ACT的生存获益。这一结论与2010年进行的一项大型荟萃分析研究结论类似，该研究纳入了26项临床研究，结论为在手术的基础上加用化疗可使5年OS率从29%提高到33%，这种增加似乎不随患者分期而改变，即使是IA期患者也获得了2%的5年OS率提升[70]，虽然存活比例上升非常有限，但是由于肺癌患者数量巨大，ACT仍有可能为数万名患者带来生存获益，这说明未来ACT的治疗窗 仍有可能前移。

2.2 ATT在I期LUAD术后患者中应用的相关临床研究

在ATT方面，针对IB期术后患者的辅助治疗已经获得了重大突破。ADAURA研究[7]是一项III期的前瞻性RCT，目的是比较在肿瘤完全切除后，与安慰剂相比，辅助奥希替尼治疗EGFR突变的IB-IIIA期（第七版TNM分期）NSCLC（入组患者主要为LUAD患者）具有临床意义的DFS。在得出最终结果后，研究者对入组患者进行了重新分期，有199例患者被分为第八版的IB期，结果显示，奥希替尼组的5年DFS率为78%（95%CI: 67%-86%），安慰剂则只有55%（95%CI: 43%-65%）；DFS的HR为0.44（95%CI: 0.25-0.76）。该研究的次要结果还显示，奥希替尼可使研究全人群（IB-IIIA期患者）死亡风险相对下降51%，HR=0.49，5年OS率绝对值提高近10%（87.6% vs 77.7%），这让奥希替尼成为目前唯一在EGFR突变阳性NSCLC辅助治疗中达到显著OS获益的靶向药物。

ADAURA2研究[71]旨在探索奥希替尼对于接受完全切除的、复发高危的IA2、IA3期NSCLC患者（入组患者主要为LUAD患者）DFS的影响，目前研究尚在招募受试者中，主要终点的中期结果预计将于2027年8月公布。目前着眼于ATT在IA期LUAD术后患者中治疗意义的研究较为罕见。笔者最近发表的一项研究[72]发现，辅助靶向治疗可以显著降低合并高危病理因素的I期术后患者的复发风险（HR=0.34, 95%CI: 0.17-0.71, P=0.004），这一结论在IA2-IA3期亚组患者中同样成立。

CORIN研究[73]则是一项II期的开放标签随机研究，旨在评估完全切除的EGFR突变型IB期NSCLC患者（入组患者主要为LUAD患者）接受埃克替尼辅助治疗对DFS的影响，按照第八版TNM重新分期后，埃克替尼组的DFS显著长于观察组（HR=0.25, 95%CI: 0.07-0.87, P=0.018），此结果尚待后续III期RCT进一步验证。

对于合并ALK变异的LUAD患者，针对克唑替尼的ALCHEMIST研究和针对阿来替尼的ALINA研究[74,75]均未纳入第八版分期中I期的患者。Selpercatinib是一种首创、高选择性和强效的中枢神经系统活性RET抑制剂[76]，目前正在进行一项全球性、随机、双盲、III期试验的患者招募[77]，评估Selpercatinib与安慰剂在IB-IIIA期（第八版TNM分期）、RET融合阳性、接受根治手术的NSCLC患者中的疗效，其最终结果值得期待。其余靶点由于更为罕见，鲜有大规模的临床研究报道。

3 小结

目前关于I期LUAD术后的辅助治疗是否必要仍未能找到确定的答案，从目前的研究结果来看，合并EGFR敏感突变的IB期患者应当接受靶向治疗，而其他IB期患者（无论是否合并高危因素）应当首先被考虑进入到ACT的范围内，而对于IA3期和IA2期的患者，可以考虑对预期结局较差的患者尝试应用辅助治疗，但这需要谨慎的临床判断和与患者充分的讨论，以弥补前瞻性数据的空白。未来需要组织大规模的前瞻性RCT来阐明ACT和ATT对I期LUAD患者的真实意义。

Competing interests

The authors declare that they have no competing interests.

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