Recurrence of Non–Small Cell Lung Cancer With Visceral Pleural Invasion: A Secondary Analysis of a Randomized Clinical Trial

Nasser Altorki; Xiaofei Wang; Bryce Damman; David R Jones; Dennis Wigle; Jeffrey Port; Massimo Conti; Ahmad S Ashrafi; Moishe Liberman; Rodney Landreneau; Kazuhiro Yasufuku; Stephen Yang; John D Mitchell; Robert Keenan; Thomas Bauer; Daniel Miller; David Kozono; Jennifer Mentlick; Everett Vokes; Thomas E Stinchcombe

doi:10.1001/jamaoncol.2024.2491

. 2024 Aug 1;10(9):1179–1186. doi: 10.1001/jamaoncol.2024.2491

Recurrence of Non–Small Cell Lung Cancer With Visceral Pleural Invasion

A Secondary Analysis of a Randomized Clinical Trial

Nasser Altorki ^1,^✉, Xiaofei Wang ², Bryce Damman ³, David R Jones ⁴, Dennis Wigle ⁵, Jeffrey Port ¹, Massimo Conti ⁶, Ahmad S Ashrafi ⁷, Moishe Liberman ⁸, Rodney Landreneau ⁹, Kazuhiro Yasufuku ¹⁰, Stephen Yang ¹¹, John D Mitchell ¹², Robert Keenan ¹³, Thomas Bauer ¹⁴, Daniel Miller ¹⁵, David Kozono ¹⁶, Jennifer Mentlick ³, Everett Vokes ¹⁷, Thomas E Stinchcombe ¹⁸

¹Weill Cornell Medicine, New York–Presbyterian Hospital, New York

²Alliance Statistics and Data Management Center, and Biostatistics and Bioinformatics, Duke University, Durham, North Carolina

³Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, Minnesota

⁴Memorial Sloan Kettering Cancer Center, New York, New York

⁵Mayo Clinic, Rochester, Minnesota

⁶Institut Universitaire de Cardiologie et Pneumologie de Québec, Quebec, Canada

⁷Surrey Memorial Hospital Thoracic Group Fraser Valley Health Authority, British Columbia, Canada

⁸Centre Hospitalier de l’Université de Montréal, Montreal, Québec, Canada

⁹Tampa General Hospital, Tampa, Florida

¹⁰University of Toronto, Toronto, Ontario, Canada

¹¹Johns Hopkins University, Baltimore, Maryland

¹²University of Colorado Hospital School of Medicine, Aurora

¹³Moffitt Cancer Center, Tampa, Florida

¹⁴Hackensack Meridian Health System, Edison, New Jersey

¹⁵Medical College of Georgia, Augusta

¹⁶Alliance Protocol Operations Office, Boston, Massachusetts

¹⁷University of Chicago Comprehensive Cancer Center, Chicago, Illinois

¹⁸Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina

Accepted for Publication: April 10, 2024.

Published Online: August 1, 2024. doi:10.1001/jamaoncol.2024.2491

^✉

Corresponding Author: Nasser Altorki, MD, Weill Cornell Medicine-New York Presbyterian Hospital, 1300 York Ave, New York, NY 10023 (nkaltork@med.cornell.edu).

Correction: This article was corrected on October 17, 2024, to fix an error in the byline.

Author Contributions Drs Altorki and Wang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Altorki and Wang were co–first authors, and Drs Vokes and Stinchcombe were co–senior authors.

Concept and design: Altorki, Wang, Jones, Port, Liberman, Mitchell, Vokes, Stinchcombe.

Acquisition, analysis, or interpretation of data: Altorki, Wang, Damman, Wigle, Port, Conti, Ashrafi, Liberman, Landreneau, Yasufuku, Yang, Mitchell, Keenan, Bauer, Miller, Kozono, Mentlick, Stinchcombe.

Drafting of the manuscript: Altorki, Wang, Vokes, Stinchcombe.

Critical review of the manuscript for important intellectual content: Wang, Damman, Jones, Wigle, Port, Conti, Ashrafi, Liberman, Landreneau, Yasufuku, Yang, Mitchell, Keenan, Bauer, Miller, Kozono, Mentlick, Stinchcombe.

Statistical analysis: Wang, Damman.

Administrative, technical, or material support: Ashrafi, Liberman, Yang, Keenan, Kozono, Stinchcombe.

Supervision: Wang, Ashrafi, Liberman, Yasufuku, Mitchell, Keenan, Stinchcombe.

Other - data manager: Mentlick.

Conflict of Interest Disclosures: Dr Altorki reported grants from AstraZeneca and Janssen Pharmaceuticals and research support from the National Cancer Institute and US Department of Defense outside the submitted work. Dr Jones reported advisory service for AstraZeneca and More Health, speaking fees from DAVA Oncology, and grants from Merck outside the submitted work. Dr Kozono reported personal fees from Genentech/Roche outside the submitted work. Dr Stinchcombe reported personal fees from Janssen, Daiichi Sankyo, AstraZeneca, Takeda, Eisai/H3 Biomedicine, G1 Therapeutics, Gilead Sciences, and Coherus Biosciences; research funding from AstraZeneca, Takeda, Seagen, Mirati Therapeutics, and Genentech/Roche (to institution); and data safety monitoring board service for Genentech/Roche, and GlaxoSmithKline outside the submitted work. No other disclosures were reported.

Funding/Support: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), UG1CA232760, UG1CA233184, UG1CA233247, UG1CA233253, UG1CA233290, UG1CA233327, and U10CA180863. The study was also supported in part by Covidien/Tyco/Ethicon.

Role of the Funder/Sponsor: The primary funder (National Cancer Institute) helped with and approved the trial design but had no role in the collection, interpretation, or analysis of the data or the writing of the manuscript.

Nonfederal sponsors did not contribute to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. There were no agreements concerning the confidentiality of the data between the primary funder and the authors or the participating institutions.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Data Sharing Statement: See Supplement 3.

^✉

Corresponding author.

PMCID: PMC11295064 PMID: 39088196

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.

Abstract

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.

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.

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.

Intervention

Lobar or sublobar resection.

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.

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.

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.

Trial Registration

ClinicalTrials.gov Identifier: NCT0049933

This secondary analysis of the Cancer and Leukemia Group B 140503 randomized clinical trial examines survival and recurrence rates in patients with small peripheral pT2 non–small cell lung cancer that was treated by either lobar or sublobar resection.

Introduction

Two recent large randomized clinical trials have shown that lobar and sublobar resections are associated with similar disease-free survival (DFS) and overall survival (OS) in patients with peripheral non–small lung cancers that measure 2 cm or less.^1,2 Because random assignment in both trials was based on clinical stage as determined by computed tomography (CT), some of the randomized patients were likely pathologically upstaged following resection from T1 stage (in which tumors are completely surrounded by lung parenchyma), to T2 stage (in which tumors invade the overlying visceral pleura). Although visceral pleural invasion (VPI) is known to be associated with worse survival in patients with stage I lung cancer, its association with cancer recurrence and worse OS in patients with tumors 2 cm or less is somewhat controversial.^{3,4,5,6,7,8,9,10} There are few data examining the association of VPI with survival in patients with tumors that are 2 cm or smaller. Although the data reported by investigators of the International Association for the Study of Lung Cancer staging project suggest that VPI is a significant prognostic variable in patients with tumors less than 2 cm, the difference in OS was significant only in patients with tumors 1 to 2 cm but not in patients with tumors less than 1 cm in diameter. Furthermore, in the cohort of tumors 1 to 2 cm, VPI was present in only 52 of 9750 patients, or roughly 1% of all patients with the descriptor. The uncertainty about the prognostic relevance of VPI in these small tumors has led some to argue that intraoperative suspicion of VPI should prompt lobar resection and others to posit that recurrence and survival are similar regardless of the extent of resection.^11,12 This controversy is informed almost exclusively by retrospective data generated from large case series or registry data rather than from the results of randomized clinical trials.

In a recent large randomized clinical trial (Cancer and Leukemia Group B [CALGB] 140503), we reported that sublobar resection was noninferior to lobectomy for the primary end point of DFS and was associated with similar OS in patients clinically staged by CT and nodal assessment as T1aN0.¹ We also showed that there were no differences in recurrence rates or recurrence-free survival (RFS) between the 2 groups. However, because CT is associated with poor sensitivity for detecting VPI, the trial likely included patients whose tumors had VPI (T2). In this article, we report results from a post hoc analysis of CALGB 140503 that suggest that compared with patients with pathologically confirmed T1 tumors, patients found to have VPI on pathological examination (pathological stage 1B) have a significantly worse DFS and RFS and a higher rate of cancer recurrence that is independent of the extent of parenchymal resection. The observed higher risk of distant recurrence raises the question of whether such patients may benefit from adjuvant therapy.

Methods

Study Design and Participants

CALGB 140503 was a multicenter, international, randomized, noninferiority phase 3 clinical trial in patients with non–small cell lung cancer (NSCLC) with a clinical stage of T1aN0 based on the 7th edition of the TNM staging system (Supplement 1). CALGB is now part of the Alliance for Clinical Trials in Oncology. Patients were registered for the trial if they met the preoperative eligibility criteria and randomized after meeting intraoperative eligibility criteria (eFigure 1 in Supplement 2). Preoperative eligibility criteria were previously reported.¹ Patients were registered for the trial if on a CT scan they had a peripheral lung nodule with a solid component 2 cm or smaller that was presumed or confirmed to be NSCLC. Patients with pure ground-glass opacities or pathologically confirmed N1 or N2 disease were not eligible.

Intraoperative eligibility criteria included histological confirmation of NSCLC (if not already obtained) and confirmation of N0 status by frozen section examination (for right-sided tumors, node levels 4, 7, and 10; for left-sided tumors, node levels 5 or 6, 7, and 10). Nodes previously sampled by mediastinoscopy, endobronchial ultrasonography, or endoscopic ultrasonography within 6 weeks of the definitive surgical procedure did not need to be resampled.

Trial Oversight

The trial was conducted according to the principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines. The protocol was approved by the National Cancer Institute central institutional review board and the institutional review board at each participating institution. All patients provided written informed consent before trial enrollment. Since activation, CALGB/Alliance 140503 has been monitored by the Alliance Data and Safety Monitoring Board twice annually. There were no agreements concerning the confidentiality of the data between the primary funder and the authors or the participating institutions.

Randomization and Procedures

Eligible patients were preregistered to the trial using the OPEN registration system, a web-based system for patients’ enrollment into National Cancer Institute (NCI)–sponsored cooperative group clinical trials. Once intraoperative eligibility, as described previously, was confirmed, patients underwent randomization (1:1) to either lobar or sublobar resection, based on a permuted-block randomization scheme with stratification for radiographic tumor size (<1 cm, 1-1.5 cm, and >1.5 to 2 cm), histology (squamous cell carcinoma, adenocarcinoma, and other), and smoking status (never, former, and current). Treatment assignment was not concealed from patients, surgeons, nurses, data managers, or statisticians. The type of sublobar resection (wedge resection or segmentectomy) and the choice of surgical approach (thoracotomy vs video-assisted thoracoscopic surgery or robotic-assisted surgery) was at the surgeon’s discretion. Following surgery, patients underwent CT scans every 6 months for 1 year, then annually for a minimum of 5 years. In a subsequent trial, amendment surveillance imaging was changed to CT scans every 6 months for 2 years, then annually for 5 additional years (7 years after surgery).

End Points

The primary outcome of this post hoc analysis was to compare DFS between patients with a pathological stage of T1 or T2 based on the presence or absence of VPI. There was no central pathology review of resected tumors. Pathological staging of the index tumor was extracted from submitted case report forms and source documents. Secondary outcomes included the determination of intergroup differences in OS, RFS, and the rates of locoregional and systemic recurrence. DFS was defined as the time between randomization and disease recurrence or death of all causes, whichever came first. Patients who did not experience a DFS event were censored at the time of last follow-up. OS was defined as the time between randomization and death of all causes. Patients who were alive were censored at the time of the last follow-up. RFS was defined as the time between randomization and any disease recurrence of the index cancer. Patients who did not experience recurrence were censored at the time of death or at the time of the last clinical follow-up. Locoregional recurrence was defined as recurrent disease in the lung and/or the hilar nodes of the index lobe. Regional recurrence was defined as isolated mediastinal nodal recurrence. All other recurrence was deemed systemic. Data quality was ensured by review of data by the Alliance Statistical and Data Management Center and the study chairperson, following Alliance policies.

Statistical Analysis

The trial was designed to have approximately 80% power, with 351 events to reject the null hypothesis that the hazard ratio of sublobar resection vs lobectomy would be less than Δ = 1.306 by a stratified log-rank test for noninferiority at a 1-sided significance level of 5% when the true hazard ratio was 1. Δ denotes the prespecified noninferiority margin, for which there was 5% chance that the null hypothesis would be rejected when the hazard rate of sublobar resection was 30.6% higher than lobectomy. The trial accrued 697 patients between June 2007 and March 2017. Based on interim analyses conducted up to November 2021 and a validation analysis in March 2022, the Alliance data safety monitoring board recommended unanimously to release the data and terminate further data safety monitoring of the trial.

This post hoc analysis focused on differences in survival and recurrence based on pathological T stage. Intergroup comparisons of survival based on the extent of pulmonary resection were performed based on the intention-to-treat assignments. Survival end points were characterized using the Kaplan-Meier estimator and compared by the stratified log-rank test with tumor size, histology, and smoking status as stratification factors. A sensitivity analysis on survival end points was also conducted on a subset of randomized patients with a pathological tumor size of 2 cm or smaller.

All statistical analyses were conducted by the Alliance study statisticians and statistical programmers, with the data locked down on June 21, 2022. Data management and statistical analysis were done in SAS, version 9.4 (SAS Institute), and graphs were generated in R, version 4.2.2 (R Foundation).

Results

Between June 15, 2007, and March 13, 2017, 697 patients met preoperative and intraoperative eligibility criteria and were randomly assigned to undergo either lobar (357 patients [51.2%]) or sublobar resection (340 patients [48.8%]). For this post hoc analysis,11 patients were excluded due to multiple tumors within the index lobe that made the tumor pathologically T3, 3 patients due to tumors in more than 1 lobe, 2 who had adenocarcinoma in situ, and 2 patients with missing data. A total of 566 patients (81.2%) had pT1 tumors, and 113 (16.2%) had pT2 tumors. Baseline demographic, clinical, and pathological characteristics were balanced between the 2 groups (Table 1). Within each group, a similar proportion of patients underwent lobar or sublobar resections. Although clinical tumor size did not exceed 2 cm, pathologically determined tumor size exceeded 2 cm for 60 patients (10.6%) who had pT1 tumors and 23 patients (20.3%) who had pT2 tumors, nearly all of whom had tumors ranging from 2.1 to 3.0 cm.

Table 1. Baseline Demographic, Clinical, and Pathological Characteristics.

Characteristic	No. (%)			P value
	Pathological T stage		Total (n = 679)
	T1 (n = 566)	T2 (n = 113)	Total (n = 679)
Age, median (range), y	68.0 (46.2-89.7)	66.8 (37.8-83.7)	67.8 (37.8-89.7)	.38^a
Sex
Female	329 (58.1)	61 (54.0)	390 (57.4)	.41^a
Male	237 (41.9)	52 (46.0)	289 (42.6)	.41^a
ECOG performance status
0	424 (74.9)	76 (67.3)	500 (73.6)	.09^a
0.5	142 (25.1)	37 (32.7)	179 (26.4)	.09^a
Maximum diameter of tumor using lung window settings, median (range), cm	1.5 (0.4-3.0)	1.5 (0.8-2.2)	1.5 (0.4-3.0)
Tumor size, cm
<1.0	53 (9.4)	4 (3.5)	57 (8.4)	.11^a
1.0-1.5	286 (50.5)	59 (52.2)	345 (50.8)
>1.5-2.0	227 (40.1)	50 (44.2)	277 (40.8)
Smoking status
Never	54 (9.5)	7 (6.2)	61 (9.0)	.42^a
Former	283 (50.0)	55 (48.7)	338 (49.8)
Current	229 (40.5)	51 (45.1)	280 (41.2)
Histology
Squamous cell carcinoma	84 (14.8)	13 (11.5)	97 (14.3)	.22^a
Adenocarcinoma	361 (63.8)	68 (60.2)	429 (63.2)
Other	121 (21.4)	32 (28.3)	153 (22.5)
Tumor location area
Right upper lobe	200 (35.3)	43 (38.1)	243 (35.8)	.32^a
Right middle lobe	28 (4.9)	6 (5.3)	34 (5.0)
Right lower lobe	80 (14.1)	14 (12.4)	94 (13.8)
Left upper lobe	152 (26.9)	33 (29.2)	185 (27.2)
Left lower lobe	102 (18.0)	14 (12.4)	116 (17.1)
Lingula	4 (0.7)	3 (2.7)	7 (1.0)
Predicted FEV 1, %
Median	83.0	83.0	83.0	.92^b
Resection
Lobar	292 (51.6)	56 (49.6)	348 (51.3)	.69^a
Sublobar	274 (48.4)	57 (50.4)	331 (48.7)	.69^a
Type of mediastinal lymph node dissection
Complete mediastinal lymph node dissection	153 (27.1)	26 (23.4)	179 (26.5)	.28^a
Systematic sampling	281 (49.8)	57 (51.4)	338 (50.1)
Simple sampling	128 (22.7)	26 (23.4)	154 (22.8)
None	2 (0.4)	2 (1.8)	4 (0.6)
Missing	2	2	4
No. of lymph nodes sampled, median (range)	4.0 (1.0-10.0)	4.0 (1.0-10.0)	4.0 (1.0-10.0)	.39^b
Pathological N stage
N04^c	541 (95.6)	106 (93.8)	647 (95.3)	.61^d
N15^e	18 (3.2)	5 (4.4)	23 (3.4)
N26^f	7 (1.2)	2 (1.8)	9 (1.3)

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Abbreviations: ECOG, Eastern Cooperative Oncology Group; FEV, forced expiratory volume 1; N, pathological N stage.

^{^a}

χ² P value.

^{^b}

Kruskal-Wallis P value.

^{^c}

No regional lymph node metastasis.

^{^d}

Fisher exact P value.

^{^e}

Metastasis to peribronchial or the ipsilateral hilar region or both, including direct extension.

^{^f}

Metastasis to ipsilateral mediastinal lymph nodes and subcarinal lymph nodes.

Survival

After a median follow-up of 7 years, 5-year DFS was 65.9% (95% CI, 61.9%-70.2%) in patients with pT1 tumors compared with 53.3% (95% CI, 44.3%-64.1%) in patients with pT2 tumors (stratified log-rank P = .02) (Figure 1A). Within each group, there were no differences in DFS based on the extent of parenchymal resection (Figure 1B). Patients with pT1 tumors had a 5-year DFS of 66.3% (95% CI, 60.8%-72.2%) after lobectomy and 65.6% (95% CI, 59.9%-71.8%) after sublobar resection. Patients with pT2 tumors had a 5-year DFS of 53.1% (95% CI, 40.7%-69.3%) after lobectomy and 53.5% (95% CI, 41.3%-69.2%) after sublobar resection. There were no differences in DFS when the analysis was restricted to tumors pathologically measured to be 2 cm or smaller (506 patients with pT1 and 90 with pT2a tumors; Figure 1C).

Figure 1. — A, DFS in pT1 and pT2 tumors. B, DFS for pT1 and pT2 tumors based on the extent of parenchymal resection. C, DFS for pT1 and pT2 tumors 2 cm or smaller based on the extent of pulmonary resection. HR indicates hazard ratio.

OS was similar between patients with pT1 and pT2 tumors. Five-year OS was 80.5% (95% CI, 77.2%-83.9%) in patients with pT1 tumors and 74.7% (95% CI, 66.7%-83.6%) in patients with pT2 tumors (P = .31) (eFigure 2 in Supplement 2).

Recurrence

After excluding 10 patients who died of treatment-related adverse events within 90 days after their surgical procedure (all had T1 tumors), 669 patients were available for assessment of disease recurrence (556 [83.1%] with pT1 tumors and 113 [16.9%] with pT2 tumors). Disease recurrence developed in 153 patients with pT1 tumors (27.5%) and 47 patients with pT2 tumors (41.6%) (Table 2). Locoregional recurrence occurred in 60 patients with pT1 tumors (10.8%) and 17 patients with pT2 tumors (15.0%). More than 50% of recurrences in each group were systemic. The rate of distant recurrence in pT1 and pT2 tumors was 14.6% and 23.9%, respectively (P = .01). The median time to recurrence was not reached in either group. However, 63.4% of all recurrences in patients with pT1 tumors and 70.2% of all recurrences in patients with pT2 tumors occurred within the first 3 postoperative years. In an unplanned subgroup analysis, 5-year RFS was 73.1% (95% CI, 69.2%-77.1%) for patients who had pT1 tumors and 58.2% (95% CI, 49.2%-68.8%) for patients who had pT2 tumors (stratified log-rank: P = .01) (Figure 2A). Within each group, there were no differences in RFS based on the extent of parenchymal resection (Figure 2B). Patients with pT1 tumors had a 5-year RFS of 74.4% (95% CI, 69.2%-79.9%) after lobectomy and 71.7% (95% CI, 66.2%-77.7%) after sublobar resection. Patients with pT2 tumors had a 5-year RFS of 53.1% (95% CI, 40.7%-69.3%) after lobectomy and 63.7% (95% CI, 51.8%-78.2%) after sublobar resection. There were no differences in RFS when the analysis was restricted to tumors 2 cm or smaller (eFigure 3 in Supplement 2).

Table 2. Rates of Recurrence Among Patients With T1 and T2 Disease.

Recurrence	No. (%)			P value
	Pathological T stage		Total (N = 669)
	T1 (n = 556)	T2 (n = 113)	Total (N = 669)
Overall progression of disease	153 (27.6)	47 (41.6)	200 (29.9)	.002^a
Locoregional recurrence	60 (10.8)	17 (15.0)	77 (11.5)	.19^a
Distant recurrence	81 (14.6)	27 (23.9)	108 (16.1)	.01^a
Regional only	12 (2.2)	3 (2.8)	15 (2.3)	.71

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^{^a}

χ² P value.

Figure 2. — A, RFS for pT1 and pT2 tumors. B, RFS for pT1 and pT2 tumors by extent of parenchymal resection. HR indicates hazard ratio.

Discussion

In this post hoc, exploratory secondary analysis of CALGB/Alliance 140503, we found that small (≤2 cm) peripheral node-negative lung cancers that invade the visceral pleura were associated with unexpectedly high recurrence rates and significantly worse DFS and RFS compared with patients with tumors without VPI. Most recurrences in both groups were systemic despite the early clinical stage at presentation. We also found that these high recurrence rates were not mitigated by larger parenchymal resections, suggesting the presence of micrometastatic disease at diagnosis despite the small tumor size and absence of nodal metastases. The observed higher risk of distant recurrence raises the question of whether these patients should receive adjuvant therapy. Nearly all patients at this early stage of lung cancer are traditionally excluded from adjuvant trials. This is based mainly on data from adjuvant chemotherapy trials performed during the early 2000s that suggested that adjuvant chemotherapy is not only ineffective but potentially harmful in patients with stage I disease.¹³ The lower recurrence rate, as well as the limited efficacy and poor tolerability of chemotherapy, probably contributed to this observation. Whether these results apply to the currently available adjuvant targeted therapies and immunotherapy is unknown.

Among the potential challenges facing the design and execution of future adjuvant trials for this subgroup of patients is that, regardless of the observation that 64% to 75% of recurrences occur within 3 years, the median time to recurrence has not been reached in either group. Adjuvant trials that include all patients with this stage of disease would require a potentially prohibitive number of participants and impractical duration of follow-up. A potential alternative approach may be including a highly selected group of patients based on clinical, pathological, and molecular characteristics (such as circulating tumor DNA) that are potentially associated with biologically more aggressive behavior and a higher risk of recurrence.

The current post hoc analysis further emphasized our previously reported recommendation that sublobar resection is a viable alternative to lobectomy even in the presence of visceral pleural invasion. However, this recommendation should be restricted to patients with peripheral NSCLC 2 cm or smaller that are associated with pathologically confirmed absence of nodal metastases.¹ Patients with larger or more central tumors than those included in our trial may have higher rates of disease recurrence, and in those instances, to our knowledge, equivalence in survival and recurrence between lobar and sublobar resection has not been shown. We had previously reported that even among patients who were registered to the trial and deemed to be node negative by imaging criteria, 6.4% had positive major hilar or mediastinal nodes precluding randomization.¹⁴

Limitations

These results will become increasingly relevant as the proportion of patients with early-stage lung cancer increases with the expanded implementation of lung cancer screening. Although our results may contribute to clinical practice, they are limited by the unplanned exploratory nature of the analysis and by the fact that the trial was not powered to detect differences in survival based on pathological staging. Therefore, our results should be interpreted cautiously and construed as hypothesis-generating rather than hypothesis-testing. However, to our knowledge, these results represent the only data derived from a prospective randomized setting with robust extended follow-up and mandatory tracking of disease recurrence. In this regard, our findings differ from nearly all prior case series and registry data for which the primary end point was OS rather than documented disease recurrence. Another potential limitation was that the trial design did not mandate central pathology review of resected specimens, so information was lacking on pathological variables beyond VPI, such as adenocarcinoma subtypes, lymphovascular invasion, or spread through the airspaces. These variables were not considered prognostically valuable at the initiation of the trial and to our knowledge are still unvalidated in the clinic. Despite these limitations, the results presented in this article should encourage the inclusion of this subset of patients in adjuvant trials and help inform the design and execution of these trials.

Conclusions

In this secondary analysis of the results of a randomized clinical trial comparing lobectomy with sublobar resection in patients with clinical stage IA NSCLC 2 cm or less, the presence of VPI was associated with worse DFS and RFS and higher rates of local and distant disease recurrence. These high rates of recurrence were independent of the extent of parenchymal resection. These data support the inclusion of these patients in adjuvant therapy trials.

Supplement 1.

Trial protocol

jamaoncol-e242491-s001.pdf^{(1.1MB, pdf)}

Supplement 2.

eFigure 1. CONSORT diagram for CALGB 140503

eFigure 2. Overall survival

eFigure 3. Recurrence-free survival for tumors ≤2 cm in size

eTable. CONSORT 2010 checklist of information to include when reporting a randomized trial

jamaoncol-e242491-s002.pdf^{(433.3KB, pdf)}

Supplement 3.

Data sharing statement

jamaoncol-e242491-s003.pdf^{(15KB, pdf)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial protocol

jamaoncol-e242491-s001.pdf^{(1.1MB, pdf)}

Supplement 2.

eFigure 1. CONSORT diagram for CALGB 140503

eFigure 2. Overall survival

eFigure 3. Recurrence-free survival for tumors ≤2 cm in size

eTable. CONSORT 2010 checklist of information to include when reporting a randomized trial

jamaoncol-e242491-s002.pdf^{(433.3KB, pdf)}

Supplement 3.

Data sharing statement

jamaoncol-e242491-s003.pdf^{(15KB, pdf)}

[coi240035r1] 1.Altorki N, Wang X, Kozono D, et al. Lobar or sublobar resection for peripheral stage IA non–small-cell lung cancer. N Engl J Med. 2023;388(6):489-498. doi: 10.1056/NEJMoa2212083 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi240035r2] 2.Saji H, Okada M, Tsuboi M, et al. ; West Japan Oncology Group and Japan Clinical Oncology Group . Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. Lancet. 2022;399(10335):1607-1617. doi: 10.1016/S0140-6736(21)02333-3 [DOI] [PubMed] [Google Scholar]

[coi240035r3] 3.Goldstraw P, Chansky K, Crowley J, et al. ; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Advisory Boards and Participating Institutions . The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11(1):39-51. doi: 10.1016/j.jtho.2015.09.009 [DOI] [PubMed] [Google Scholar]

[coi240035r4] 4.Rami-Porta R, Bolejack V, Crowley J, et al. ; IASLC Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions . The IASLC lung cancer staging project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10(7):990-1003. doi: 10.1097/JTO.0000000000000559 [DOI] [PubMed] [Google Scholar]

[coi240035r5] 5.Shimizu K, Yoshida J, Nagai K, et al. Visceral pleural invasion is an invasive and aggressive indicator of non-small cell lung cancer. J Thorac Cardiovasc Surg. 2005;130(1):160-165. doi: 10.1016/j.jtcvs.2004.11.021 [DOI] [PubMed] [Google Scholar]

[coi240035r6] 6.Huang H, Wang T, Hu B, Pan C. Visceral pleural invasion remains a size-independent prognostic factor in stage I non-small cell lung cancer. Ann Thorac Surg. 2015;99(4):1130-1139. doi: 10.1016/j.athoracsur.2014.11.052 [DOI] [PubMed] [Google Scholar]

[coi240035r7] 7.Chen T, Luo J, Wang R, et al. Visceral pleural invasion predict a poor survival among lung adenocarcinoma patients with tumor size ≤ 3cm. Oncotarget. 2017;8(39):66576-66583. doi: 10.18632/oncotarget.16476 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi240035r8] 8.Nitadori JI, Colovos C, Kadota K, et al. Visceral pleural invasion does not affect recurrence or overall survival among patients with lung adenocarcinoma ≤ 2 cm: a proposal to reclassify T1 lung adenocarcinoma. Chest. 2013;144(5):1622-1631. doi: 10.1378/chest.13-0394 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi240035r9] 9.David E, Thall PF, Kalhor N, et al. Visceral pleural invasion is not predictive of survival in patients with lung cancer and smaller tumor size. Ann Thorac Surg. 2013;95(6):1872-1877. doi: 10.1016/j.athoracsur.2013.03.085 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi240035r10] 10.Wang T, Zhou C, Zhou Q. Extent of visceral pleural invasion affects prognosis of resected non–small cell lung cancer: a meta-analysis. Sci Rep. 2017;7(1):1527. doi: 10.1038/s41598-017-01845-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi240035r11] 11.Mathey-Andrews C, Abruzzo AR, Venkateswaran S, et al. Segmentectomy vs lobectomy for early non–small cell lung cancer with visceral pleural invasion. Ann Thorac Surg. 2024;117(5):1007-1014. doi: 10.1016/j.athoracsur.2023.06.020 [DOI] [PubMed] [Google Scholar]

[coi240035r12] 12.Yu Y, Huang R, Wang P, et al. Sublobectomy versus lobectomy for long-term survival outcomes of early-stage non-small cell lung cancer with a tumor size ≤2 cm accompanied by visceral pleural invasion: a SEER population-based study. J Thorac Dis. 2020;12(3):592-604. doi: 10.21037/jtd.2019.12.121 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi240035r13] 13.Pignon JP, Tribodet H, Scagliotti GV, et al. ; LACE Collaborative Group . Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552-3559. doi: 10.1200/JCO.2007.13.9030 [DOI] [PubMed] [Google Scholar]

[coi240035r14] 14.Kohman LJ, Gu L, Altorki N, et al. Biopsy first: lessons learned from Cancer and Leukemia Group B (CALGB) 140503. J Thorac Cardiovasc Surg. 2017;153(6):1592-1597. doi: 10.1016/j.jtcvs.2016.12.045 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Recurrence of Non–Small Cell Lung Cancer With Visceral Pleural Invasion

Nasser Altorki, MD

Xiaofei Wang, PhD

Bryce Damman, MS

David R Jones, MD

Dennis Wigle, MD, PhD

Jeffrey Port, MD

Massimo Conti, MD

Ahmad S Ashrafi, MD

Moishe Liberman, MD, PhD

Rodney Landreneau, MD

Kazuhiro Yasufuku, MD, PhD

Stephen Yang, MD

John D Mitchell, MD

Robert Keenan, MD

Thomas Bauer, MD

Daniel Miller, MD

David Kozono, MD, PhD

Jennifer Mentlick

Everett Vokes, MD

Thomas E Stinchcombe, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Participants, and Setting

Intervention

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Participants

Trial Oversight

Randomization and Procedures

End Points

Statistical Analysis

Results

Table 1. Baseline Demographic, Clinical, and Pathological Characteristics.

Survival

Figure 1. Disease-Free Survival (DFS).

Recurrence

Table 2. Rates of Recurrence Among Patients With T1 and T2 Disease.

Figure 2. Recurrence-Free Survival (RFS).

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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