各位好！今日与大家分享两篇有关淋巴结转移负荷得文献。第一篇文章基于NCDB和单中心数据，验证了淋巴结转移数目1以上与1以下的患者预后有显著性差异。第二篇文献对术前评估单站N2患者的病理淋巴结分期进行了回顾，向大家揭示到底术前的单站N2有哪些需要注意的临床决策考量。
Role of Pathological Single- and Multiple-N Descriptors in Resected Non-small Cell Lung Cancer
Shinkichi Takamori, MD, PhD, Atsushi Osoegawa, MD, PhD, Asato Hashinokuchi, MD, Takashi Karashima, MD, Yohei Takumi, MD, PhD, Miyuki Abe, MD, PhD, Masafumi Yamaguchi, MD, PhD, Tomoyoshi Takenaka, MD, PhD, Tomoharu Yoshizumi, MD, PhD, Junjia Zhu, PhD, Takefumi Komiya, MD, PhD
JTO June 03, 2024
Background: The 8th edition of lung cancer N staging assignment includes the location of lymph node metastasis, but does not include single- and multiple-N descriptors.
背景：8版肺癌N分期的内容包括淋巴结转移的位置，但不包括单N和多N描述符。
Research Question: Do the single- and multiple-N statuses stratify the prognosis of patients with non-small cell lung cancer (NSCLC)?
研究问题：单N状态和多N状态是否会对非小细胞肺癌（NSCLC）患者的预后进行分层？
Study Design and Methods: Using the National Cancer Database, we analyzed patients with pathologically staged N1–2 NSCLC. N descriptors were classified into pathological single N1 (pSingle-N1), pathological multiple N1 (pMulti-N1), pSingle-N2, and pMulti-N2. Survival analysis was performed using Kaplan–Meier method and multivariate Cox regression models.
方法：基于国家癌症数据库，我们分析了病理分期的N1-2非小细胞肺癌患者。N个描述符分为病理单一N1（pSingle-N1）、病理多重N1（pMulti-N1）、pSingle-N2和pMulti-N2。使用Kaplan-Meier方法和多元Cox回归模型进行生存分析。
RESULTS: In the general analysis cohort, 24,531, 22,256, 8,528, and 21,949 NSCLC patients had pSingle-N1, pMulti-N1, pSingle-N2, and pMulti-N2, respectively. Patients with pMulti-N1 and pMulti-N2 had a shorter survival than those with pSingle-N1 and pSingle-N2, respectively (hazard ratio [HR]: 1.22, P < 0.0001 for N1 and 1.39, P < 0.0001 for N2). After adjusting age, sex, and histology, the HR for pSingle-N2 compared with pMulti-N1 was 1.05 (P = 0.0031). Patients with pN1 were categorized by metastatic lymph node count (1, 2, 3, 4+), showing significant prognostic differences among groups (P < 0.0001). In the sensitivity analysis cohort (limited to R0 resection, lobectomy or more, survival ≥ 30 days, ≥ 10 examined lymph nodes, and without neoadjuvant therapy; n = 34,904) and the external validation cohort (n = 708) analyses supported these results.
结果：在普适分析队列中，分别有24，531、22，256、8，528和21，949名非小细胞肺癌患者患有pSingle-N1、pMulti-N1、pSingle-N2和pMulti-N2。pMulti-N1和pMulti-N2患者的生存期分别短于pSingle-N1和pSingle-N2患者（危险比[HR]：N1为1.22，P < 0.0001; N2为1.39，P < 0.0001）。调整年龄、性别和组织学后，pSingle-N2与pMulti-N1相比的HR为1.05（P = 0.0031）。pN 1患者按转移淋巴结计数（1、2、3、4+）进行分类，各组之间的预后差异显著（P < 0.0001）。在敏感性分析队列（仅限于R0切除、肺叶切除或更多、生存时间& 30天、检查淋巴结&且未进行新辅助治疗; n = 34，904）和外部验证队列（n = 708）分析支持这些结果。
Interpretation: NSCLC patients with 1 metastatic lymph node, whether in N1 or N2 stations, had better survival than those with more than 1 lymph node involved. NSCLC patients with a single skip N2 lymph node metastasis had survival similar to patients with multiple N1 lymph nodes, and the number of lymph nodes involved in N1 resections up to ≥ 4 was sequentially prognostic.
结论：具有1个转移性淋巴结的非小细胞肺癌患者（无论是N1站还是N2站）的生存率都比具有1个以上淋巴结受累的患者更好。单次跳跃N2淋巴结转移的非小细胞肺癌患者的生存率与多个N1淋巴结转移的患者相似，并且N1切除涉及的淋巴结数量达到至少4个，预后递次变差。
Keywords: non-small cell lung cancer; surgery; prognosis; lymph node metastasis; TNM stage
What is the accuracy of clinical staging for stage III-single station N2 NSCLC? A multi-centre UK study
Christopher Craig, Janet Johnston, Patrick Goodley, Paul Bishop, Haider Al-Najjar, Louise Brown, Joanna Gallagher, Ram Sundar, Sara Upperton, Matthew Callister, David Meek, Laura Succony, Wadood Parez, Muhammad Tufail, Geeshath Jayasekera, John Maclay, Alana Livesey, Ian Woolhouse, Natalie Smith, Anna Bibby, Matthew Evison
JTO CRR May 30, 2024
Background: Single station N2 (ssN2) versus multistation N2 (msN2) has been used a selection criterion for treatment recommendations between surgical versus non-surgical multimodality treatment in stage III-N2 non-small cell lung cancer (NSCLC). We hypothesised that clinical staging would be prone to upstaging on pathological staging and, therefore, challenge this practice.
背景：单站N2（ssN 2）与多站N2（msN 2）已被用作III-N2期非小细胞肺癌（SOC）手术与非手术多模式治疗之间治疗建议的选择标准。我们假设临床分期容易在病理分期上升级，对临床实践的决策形成了挑战。
Methods: A retrospective study of prospectively collected routine clinical data for patients with stage III-N2 NSCLC that had completed CT, PET and staging EBUS and had been confirmed clinical stage III-ssN2 at MDT discussion and went on to complete surgical resection as first treatment to provide pathological staging. The study was completed in two cohorts A) across a single cancer alliance in England (Greater Manchester) 01/01/2015 – 31/12/2018 and B) across five UK centres to validate the findings in part A 01/01/2016 – 31/12/2020.
方法：该研究是一项前瞻性收集的III-N2期非小细胞肺癌患者的常规临床数据的回顾性研究，纳入已完成CT、PET和EBUS分期的患者，并在IDT讨论中确诊为临床III-ssN 2期，并继续完成手术切除，作为提供病理分期的第一种治疗。该研究在两个队列中完成：A）在英格兰（大曼彻斯特）的一个癌症联盟（2015年1月1日至2018年12月31日，B）在英国五个中心完成，以验证A部分1/01/2016 - 2020年12月31日的发现。
RESULTS: A total of 115 patients met the inclusion criteria across Cohort A (56 patients) and Cohort B (59 patients) across 15 UK hospitals. The proportion of cases in which clinical stage III-ssN2 was upstaged to pathological stage III-msN2 was 34% (19/56) in cohort A, 32% in cohort B (19/59) and 33% across the combined study cohort (38/115). The majority of patients had a single radiologically abnormal lymph node on CT and PET (88%, 105/115). In the majority, the reasons for missed N2 disease on staging EBUS were due to inaccessible (stations 5, 6, 8, 9) N2 nodes at EBUS (34%, 13/38) and accessible lymph nodes not sampled during staging EBUS as not meeting sampling threshold (40%, 15/38) rather than false negative sampling during EBUS (26%, 10/38).
结果：英国15家医院的队列A（56名患者）和队列B（59名患者）中共有115名患者符合入选标准。A组临床分期III-ssN 2升级为病理分期III-msN 2的病例比例为34%（19/56），B组为32%（19/59），合并研究队列为33%（38/115）。大多数患者的CT和PET显示单个放射学异常淋巴结（88%，105/115）。在大多数情况下，EBUS分期遗漏N2疾病的原因是由于EBUS时无法到达（站点5、6、8、9）N2淋巴结（34%，13/38）以及EBUS分期期间未采样的可到达淋巴结，因为不满足采样阈值（40%，15/38），而不是EBUS期间的假阴性采样（26%，10/38）。
Interpretation: During MDT discussions, clinicians must be aware that one third of patients with stage III-ssN2 based on CT, PET and staging EBUS do not truly have ssN2 and this questions the use of this criterion to define treatment recommendations.
结论：在MDT讨论期间，临床医生必须意识到，基于CT、PET和EBUS分期的III-ssN 2患者中，三分之一并没有真正患有ssN 2，这对使用该标准来定义治疗建议提出了质疑。
1. 大背景是NSCLC 9th分期更新，CHEST杂志又一次展示了自己对肺癌外科的研究品味。在IASLC委员会无数次强调了the enumeration of lymph nodes is less reliable的背景下，NCDB数据库的预后分析只能用numbers来衡量转移淋巴结负荷。虽然NCDB自诩hospital-based data，侧面说明了NCDB数据库的临床数据更新和维护碰到了困难，已经无法赶上IASLC 5年期的数据库更新了（老美的虚弱）。
2. 其次看研究细节。
①第一个研究由日本学者开展，方法上可圈可点的是区分了general analysis cohort和sensitivity analysis cohort，重要的section侧重点放在了multiple N1，为什么没有中JTO？一个可能的是因为IASLC 9th 的proposal明确写了Unlike N1 stations, which may be difficult to distinguish in clinical staging, N2 nodes are readily distinguished in radiologic imaging and invasive clinical staging procedures.
②研究在最后部分竭尽所能地进行了内部队列的验证，很勉强。而且请问为什么预后分析只校正了年龄性别和组织学类型？当然懂得兄弟一看到他pT居然搞了二分类，也无怪乎单多因素都很有意义了。并且没有进行辅助治疗的校正、分层分析？好吧不能深究，一深究就都是问题。结论上四平八稳。
③再来标题Single- and Multiple-N Descriptors这个就不能直白点说是lymph node count么？属实标题党了，还以为天纵英才，增加了什么新的descriptors....
3. 实际上较为有趣的是第二个研究，就用最简单的话告诉大家：经过严谨术前纵隔分期的单站N2+患者中有1/3的患者手术病理为多站N2。N2的术前单多站准确区分可能并不具有高准确性，其对诊疗决策的影响需要谨慎对待。并且在文章中旗帜鲜明地怼了EORTC
目录
1. INTRODUCTION
2. Study Design and Methods
2.1 NCDB (Figure 1 and e-Figure 1)
2.2 Definition of four categories for N-descriptors
2.3 Validation data source
2.4 Statistical Analysis
3. Results
3.1 Patient Characteristics (Table 1 and e-Table 1)(e-Figure 2)
3.2 Survival Analysis in Patients with Resected NSCLC in Accordance with pN Classifications (Figure 1-2)(e-Figure 1)(e-Figure 3-4)
3.3 Survival Analysis in Patients with Resected NSCLC in Accordance with the Number of Metastatic Lymph Nodes in pN1 Disease (Figure 3)(e-Figure 5)
3.4 Univariate and Multivariate Analyses of OS in Patients with Resected NSCLC (Table 2)(e-Table 2)
3.5 Validation of Survival Analysis in Accordance with pN Classifications in Patients with Resected NSCLC (e-Figure 6)
4. Discussion
5. Interpretation
— 图表汇总—
2.1 NCDB
Figure 1. Diagram of patient selection in the general analysis cohort.
e-Figure 1. Diagram of patient selection in the sensitivity analysis cohort.
3. Results
3.1 Patient Characteristics
Table 1. Clinical characteristics of non-small cell lung cancer patients in the general analysis cohort in accordance with pathological nodal status (n = 77,264).
e-Table 1. Clinical characteristics of non-small cell lung cancer patients in the sensitivity analysis cohort in accordance with pathological nodal status (n = 34,904).
e-Figure 2. Distributions of (a) the total lymph nodes removed and (b) the metastasized lymph nodes in the general analysis cohort.
3.2 Survival Analysis in Patients with Resected NSCLC in Accordance with pN Classifications
Figure 1. Diagram of patient selection in the general analysis cohort.
Figure 2. Kaplan–Meier curves of overall survival in the general analysis cohort of non-small cell lung cancer patients with pathological N0 (pN0), pathological single-N1 (pSingle-N1), pathological multiple-N1 (pMulti-N1), pathological single-N2 (pSingle-N2), and pathological multiple-N2 (pMulti-N2) are shown.
e-Figure 1. Diagram of patient selection in the sensitivity analysis cohort.
e-Figure 3. Kaplan–Meier curves of overall survival in the sensitivity analysis cohort of non-small cell lung cancer patients with pathological single-N1 (pSingle-N1), pathological multiple-N1 (pMulti-N1), pathological single-N2 (pSingle-N2), and pathological multiple-N2 (pMulti-N2) are shown.
e-Figure 4. Kaplan–Meier curves of overall survival in non-small cell lung cancer patients by year (a) 2004-2010 and (b) 2011-2019 in the sensitivity cohort.
3.3 Survival Analysis in Patients with Resected NSCLC in Accordance with the Number of Metastatic Lymph Nodes in pN1 Disease
Figure 3. Kaplan–Meier curves of overall survival in non-small cell lung cancer patients with pathological N1 in accordance with the number of metastatic lymph nodes (1, 2, 3, and 4 or more) in the general analysis cohort are shown.
e-Figure 5. Kaplan–Meier curves of overall survival in non-small cell lung cancer patients with pathological N1 in accordance with the number of metastatic lymph nodes (1, 2, 3, and 4 or more) in the sensitivity analysis cohort are shown.
3.4 Univariate and Multivariate Analyses of OS in Patients with Resected NSCLC
Table 2. Univariate and multivariable analyses of overall survival in non-small cell lung cancer patients in the general analysis cohort with pathological nodal metastasis (pathological N stage: Single-N1 vs. Multi-N1 vs. Single-N2 vs. Multi-N2) (n = 77,264).
e-Table 2. Univariate and multivariable analyses of overall survival in non-small cell lung cancer patients in the sensitivity analysis cohort with pathological nodal metastasis (pathological N stage: Single-N1 vs. Multi-N1 vs. Single-N2 vs. Multi-N2) (n = 34,904).
3.5 Validation of Survival Analysis in Accordance with pN Classifications in Patients with Resected NSCLC
e-Figure 6. Kaplan–Meier curves of overall survival in non-small cell lung cancer patients from the validation group with pN1a, pN1b, pN2a, and pN2b are shown.
