各位好！今天与大家分享一篇近期发表在JAMA上的一篇文献。研究是基于CALGB140503的事后分析，该研究对比了2cm以下早期肺癌患者的肺叶切除和亚肺叶切除的长期生存。研究结论表明亚肺叶切除的远期生存不差于肺叶切除术。而本文则呈现了140503中T1人群和因VPI而升期到T2人群的长期预后，研究表明在该RCT人群中VPI仍然是影响预后的重要分层因素！
Recurrence of Non–Small Cell Lung Cancer With Visceral Pleural Invasion
A Seconday Analysis of a Randomized Clinical Trial
Nasser Altorki, MD1; Xiaofei Wang, PhD2; Bryce Damman, MS3; David R. Jones, MD4; Dennis Wigle, MD, PhD5; Jeffrey Port, MD1; Massimo Conti, MD6; Ahmad S. Ashrafi, MD7; Moishe Lieberman, MD, PhD8; Rodney Landreneau, MD9; Kazuhiro Yasufuku, MD, PhD10; Stephen Yang, MD11; John D. Mitchell, MD12; Robert Keenan, MD13; Thomas Bauer, MD14; Daniel Miller, MD15; David Kozono, MD, PhD16; Jennifer Mentlick3; Everett Vokes, MD17; Thomas E. Stinchcombe, MD18
JAMA Oncology 1 August 2024
Importance The randomized clinical trial Cancer and Leukemia Group B (CALGB) 140503 showed that for patients with clinically staged T1N0 non–small cell lung cancer (NSCLC; ≤2 cm), sublobar resections were associated with similar oncological outcomes to those after lobar resection. The association of the extent of parenchymal resection with recurrence and survival in patients with tumors pathologically upstaged to T2 based on visceral pleural invasion (VPI) is controversial.
背景：随机临床试验癌症和白血病B组（CalibGB）140503表明，对于临床分期的T1 N 0非小细胞肺癌（SOC）患者，叶下切除术与叶切除术后的肿瘤学结局相似。对于基于脏层胸腔侵犯（VPI）病理分期为T2的肿瘤患者，肺切除范围与复发和生存率的关系存在争议。
Objective To determine survival and recurrence rates in patients with small peripheral pT2 NSCLC (≤2 cm) that was treated by either lobar or sublobar resection in CALGB 140503.
目的：确定在CAGB 140503中接受肺叶或亚肺叶切除术治疗的小周围pT 2非小细胞肺癌（< 2厘米）患者的生存率和复发率。
Design, Participants, and Setting CALGB 140503, a randomized multicenter noninferiority trial, included 697 patients with small peripheral NSCLC that was clinically staged as T1N0. Enrollment was from June 2007 through March 2017 at 83 participating institutions, and after a median follow-up of 7 years, the primary outcome of disease-free survival after sublobar resection was noninferior to that after lobar resection.
结果：CalibGB 140503是一项随机多中心非劣效性试验，纳入了697名临床分期为T1 N 0的小周围型非小细胞肺癌患者。入组时间为2007年6月至2017年3月，在83家参与机构中进行，中位随访7年后，亚肺叶切除术后无病生存的主要结果不低于肺叶切除术后的结果。
Intervention Lobar or sublobar resection.
干预：肺叶和亚肺叶切除术
Main Outcomes and Measures Survival end points were estimated by the Kaplan-Meier estimator. Hazard ratios and 95% CIs were estimated using stratified Cox proportional hazard models.
主要结果和方法：生存终点由Kaplan-Meier法估计。使用分层Cox比例风险模型估计风险比和95% CI。
Results Of 679 participants, 390 (57.4%) were female, and the median (range) age was 67.8 (37.8-89.7) years. Among 697 patients randomized, 566 (81.2%) had pT1 tumors (no VPI) and 113 (16.2%) had pT2 tumors (VPI). Five-year disease-free survival was 65.9% (95% CI, 61.9%-70.2%) in patients with pT1 compared with 53.3% (95% CI, 44.3%-64.1%) in patients with pT2 tumors (stratified log-rank: P = .02). Disease recurrence developed in 27.6% of patients with pT1 (locoregional only: 60 [10.8%]; distant only: 81 [14.6%]) and 41.6% of those with pT2 (locoregional only: 17 [15.0%]; distant only: 27 [23.9%]). Five-year recurrence-free survival was 73.1% (95% CI, 69.2%-77.1%) for pT1 tumors and 58.2% (95% CI, 49.2%-68.8%) for pT2 tumors (stratified log-rank: P = .01). There were no intergroup differences in disease-free or recurrence-free survival based on the extent of parenchymal resection.
结果：在679名参与者中，390名（57.4%）为女性，中位（范围）年龄为67.8（37.8-89.7）岁。在随机分配的697名患者中，566名（81.2%）患有pT1肿瘤（无LDI），113名（16.2%）患有pT 2肿瘤（LDI）。pT1患者的五年无病生存率为65.9%（95%CI，61.9%-70.2%），而pT 2肿瘤患者的五年无病生存率为53.3%（95%CI，44.3%-64.1%）（分层log rank：P = .02）。27.6%的pT 1患者（仅局部区域患者：60 [10.8%];仅远处患者：81 [14.6%]）和41.6%的pT 2患者（仅局部区域患者：17 [15.0%];仅远处患者：27 [23.9%]）复发。pT1肿瘤的五年无复发生存率为73.1%（95%CI，69.2%-77.1%），pT2肿瘤的五年无复发生存率为58.2%（95%CI，49.2%-68.8%）（分层log rank：P = .01）。根据肺实质切除的范围，无病或无复发生存期没有组间差异。
Conclusions and Relevance The results of this secondary analysis suggest that compared with patients with tumors without VPI, patients who had tumors with VPI had worse disease-free and recurrence-free survival and a higher rate of local and distant disease recurrence. These high rates of recurrence were independent of the extent of parenchymal resection, and these data support the inclusion of these patients in adjuvant therapy trials.
结论：本次二次分析的结果表明，与无VPI的患者相比，有VPI肿瘤患者的无病和无复发生存率较差，局部和远处疾病复发率较高。这些高复发率与肺切除的范围无关，这些数据支持将这些患者纳入辅助治疗试验。
Trial Registration ClinicalTrials.gov Identifier: NCT0049933
Key Points
Question What are the oncologic outcomes following lobar or sublobar resection in patients with peripheral small (≤2 cm) non–small cell lung cancer (NSCLC) with visceral pleural invasion (VPI)?
Findings In this secondary analysis of a randomized clinical trial of 697 patients with NSCLC, patients who had small (≤2cm) peripheral NSCLC with VPI (pT2) had unexpectedly higher recurrence rates and worse survival compared with patients with tumors without VPI, regardless of the extent of parenchymal resection.
Meaning The results of this study suggest that unexpectedly high recurrence rates, including distant recurrences, and worse survival of small peripheral NSCLCs with VPI are not mitigated by larger parenchymal resection.
1.背景上虽然学术界都在提140503研究是一项奠基之作，但是相较JCOG0802而言品控并不算精良。
而140503一系列并不是特别出彩的事后分析的顺利发表，也让学者们认识到，拥有学术话语权的一方拥有双标的能力。构建独立自主的学术话语权，首先从破除对这些顶刊的迷信开始。当然类似观点上，佛陀的表述方式是：依法不依人 依义不依语 依智不依识 依了义不依不了义
2.上细节：
首先本文是基于大型RCT研究的事后分析，有得天独厚的优势。JCOG的肺外科学组也拟基于前期的系列研究开展JCOG2208A研究。
其次140503不是第一次干这种事情了，上次发表在JCO上的第二原发肺癌的事后分析就并没有很深入的分析深度。既然是事后分析好好量一下实性成分占比就那么难么（老美最后的傲娇）？以VPI为题目，不光试验设计之初并没有记录PL0/PL1/PL2/PL3，而且也不进行切片的重新复阅，就全都把没做到的事情写到局限性里，Nasser Altorki果真是老了~！Table 1里面的ECOG performance status 还有0.5？！真天才
第三，JAMA oncology由Jay M. Lee 针对本文配发的社论也直言不讳，针对140503粗放的病理评估、捉襟见肘的中位淋巴结清扫、浅尝辄止的Distant recurrence分析进行了批判性思考。就这还能硬扯到辅助治疗上，不得不说140503某种意义上展示了老美在外科学术的自大与傲娇。
3.探讨I期高危复发患者的干预性辅助治疗研究较为知名的是ADAURA2研究。I期NSCLC High risk患者的治疗决策优化、术前识别高危人群将在未来一段时间内成为胸外科与肿瘤科的研究热点。
目录
1. INTRODUCTION
2. METHODS
2.1 Study Design and Participants (Supplement 1)(eFigure 1 in Supplement 2)
2.2 Trial Oversight
2.3 Randomization and Procedures
2.4 End Points
2.5 Statistical Analysis
3. Results (Table 1)
3.1 Survival (Figure 1)(eFigure 2 in Supplement 2)
3.2 Recurrence (Table 2)(Figure 2)(eFigure 3 in Supplement 2)
4. Discussion
— 图表汇总—
2. METHODS
2.1 Study Design and Participants
Supplement 1
3. Results
3.1 Survival
eFigure 2 in Supplement 2. Overall survival
3.2 Recurrence
