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Surgical choice for cIA non-small cell lung cancer: view from regional lymph node metastasis
Journal Pre-proof Surgical choice for cIA non-small cell lung cancer: view from regional lymph node metastasis Han-Yu Deng, MD, Jie Zhou, MD, Ru-Lan Wang, MD, Rui Jiang, MD, Xiao-Ming Qiu, MD, Da-Xing Zhu, MD, Xiao-Jun Tang, MD, Qinghua Zhou, MD PII:
S0003-4975(19)31870-3
DOI:
https://doi.org/10.1016/j.athoracsur.2019.10.056
Reference:
ATS 33301
To appear in:
The Annals of Thoracic Surgery
Received Date: 16 April 2019 Revised Date:
8 August 2019
Accepted Date: 18 October 2019
Please cite this article as: Deng HY, Zhou J, Wang RL, Jiang R, Qiu XM, Zhu DX, Tang XJ, Zhou Q, Surgical choice for cIA non-small cell lung cancer: view from regional lymph node metastasis, The Annals of Thoracic Surgery (2020), doi: https://doi.org/10.1016/j.athoracsur.2019.10.056. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
Surgical choice for cIA non-small cell lung cancer: view from regional lymph node metastasis Running title: Surgical choice for early-stage NSCLC
Han-Yu Deng1, MD, Jie Zhou1, MD, Ru-Lan Wang1, MD, Rui Jiang1, MD, Xiao-Ming Qiu1, MD, Da-Xing Zhu1, MD, Xiao-Jun Tang1, MD, Qinghua Zhou1*, MD
1. Lung cancer center, West China Hospital, Sichuan University, Chengdu, China.
Word count: 4483
*Corresponding Author: Qinghua Zhou, MD. Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China. No.37 Guoxue Alley, Chengdu 610041, Sichuan, China. E-mail: [email protected]
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Abstract Background: We aimed to investigate the pattern of regional lymph node (LN) metastasis of early-stage non-small cell lung cancer (NSCLC) to provide novel rationale for surgical choice (lobectomy, segmentectomy, or wedge resection) for these patients. Methods: We retrospectively collected clinical data of patients undergoing lobectomy with systematic mediastinal LN dissection or sampling for cT1N0M0 peripheral NSCLC from January 2015 to December 2018. The regional LN metastasis pattern was analyzed based on tumor size. Results: We included a total of 354 patients for analysis. The rate of hilar/intrapulmonary LN metastasis was 13.6%. When stratified by tumor size, NSCLC ≤1cm had no hilar/intrapulmonary LN metastasis (0%) while NSCLC >2 but ≤3cm had a significantly high rate of hilar/intrapulmonary LN metastasis (18.4%) and the rates of hilar, interlobar and peripheral LN metastasis were also relatively high (5.4%, 5.4% and 12.2%, respectively). NSCLC >1.5 but ≤2cm also had relatively high rates of hilar (6.5%) and peripheral (18.3%) LN metastasis while NSCLC >1 but ≤1.5cm had significantly low rates of hilar/intrapulmonary (2.5%) and peripheral (2.5%) LN metastasis. Radiographic feature and histology were found to be independent predictors of regional LN metastasis. Conclusions: The pattern of regional LN metastasis in cIA peripheral NSCLC was significantly influenced by tumor size, which may provide evidence on surgical choice (lobectomy, segmentectomy, or wedge resection) for these early-stage NSCLC patients based on tumor size. Key words: non-small cell lung cancer; early-stage; regional lymph node metastasis; 2 / 22
lobectomy; sublobar resection.
3 / 22
Lung cancer has become the commonest diagnosed cancer and leading cause of cancer-related death worldwide (1). Pathologically, lung cancer mainly consisted of small cell lung cancer and non-small cell lung cancer (NSCLC) with the latter accounting for about 85% of all lung cancers (2). With the improvement of medical screening methods, more and more NSCLCs have been uncovered at early stage (3) and surgery still remains to be the standard of care with excellent survival outcomes. In 1995, the only completed randomized controlled trial (RCT) comparing the efficacy of lobectomy and sublobar resection (segmentectomy or wedge resection) in treating cT1N0 NSCLC found that sublobar resection yielded a significantly higher recurrence rate and a trend toward worse survival than lobectomy, which provided the evidence for lobectomy as the preferred option for treating early-stage NSCLC (4). However, this landmark trial has been widely criticized for the following limitations: first, there was a high percentage of patients receiving wedge resection in the sublobar resection group; second, plain chest radiography not chest computed tomography (CT) was applied for staging; third, there was no subgroup analysis based on tumor size (5, 6). With the advantage of preserving vital lung tissue and providing a chance for further resection for secondary lung cancer (5), sublobar resection has been intensively investigated as an alternative to lobectomy in treating early-stage NSCLC. Even though previous studies compared the efficacy of sublobar resection with lobectomy in treating early-stage NSCLC, they have drawn conflicting conclusions regarding the application of sublobar resection with obvious heterogeneities and patient selection bias (7). Therefore, the surgical choice for treating early-stage NSCLC remains challenging for thoracic surgeons. However, it should be noted that sublobar resection (particularly segmentectomy) do have a role in treating certain 4 / 22
early-stage NSCLC since current National Comprehensive Cancer Network (NCCN) guideline recommends that sublobar resection is appropriate in selected patients: those unfit for lobectomy or with peripheral NSCLC <2cm with low malignant features (8). For surgical difference, the major concern about lobectomy, segmentectomy, and wedge resection is the adequacy of resection and nodal examination. It is widely accepted that adequate resection of NSCLC requires a parenchymal resection margin ≥2cm or the size of the tumor (8). Therefore, we believe the only significant difference among the above three surgical methods is the extent of hilar/intrapulmonary nodal dissection if sufficient resection margin and systematic mediastinal lymph node (LN) dissection or sampling is achieved. Hence, in this study, we aimed to investigate the pattern of hilar/intrapulmonary LN metastasis in early-stage (cT1N0M0) peripheral NSCLC so as to provide novel perspectives on surgical choice for clinical IA peripheral NSCLC.
Material and Methods Patients We retrospectively collected clinical data of patients undergoing lobectomy with systematic mediastinal LN dissection or sampling in our center from January 2015 to December 2018. For preoperative clinical staging, contrast-enhanced chest and upper abdominal CT, contrast-enhanced magnetic resonance imaging of brain, bone scanning, and cardiopulmonary tests were routinely performed for these patients. Positive LN metastasis was defined as LN with a short-axis diameter >1cm on the transverse chest CT. We included patients with following criteria: 1) patients received lobectomy with lymphadenectomy without 5 / 22
any preoperative chemoradiotherapy; 2) patients were preoperatively staged as clinical stage IA (T1N0M0, tumor size ≤3cm); 3) patients should be pathologically confirmed with peripherally located primary NSCLC according to the NCCN guideline (outer one third of the hemithorax) (9); 4) patients who underwent systematic lymph node sampling or dissection based on the European Society of Thoracic Surgeons criteria (10) . We excluded the following patients: 1) patients with preoperative chemoradiotherapy; 2) patients who did not receive systematic lymph node assessment; 3) patients with small cell lung cancer or synchronous multiple primary NSCLC or secondary lung cancer.; 4) patients with centrally located NSCLC (inner two-thirds of the hemithorax); 5) patients with intraoperative finding of pleural metastasis. In our center, we would perform systematic mediastinal lymph node sampling only for tumors with pure ground glass opacity (GGO) less than 2cm on CT scan. Otherwise, we would always perform systematic lymph node dissection. Since our study was a retrospective study and analyzed anonymously, the Ethic Committee of our hospital waived the need for consent. In this study, we analyzed the regional LN metastasis pattern of these early-stage NSCLC patients based on tumor size in accordance with the eighth edition of TNM staging system for NSCLC (11). For tumor size evaluation, we measured the maximum diameter of the tumor including both GGO part and solid part in the lung window of chest CT. Here we subgrouped these patients into three groups according to tumor size (NSCLC ≤1cm; NSCLC >1 but ≤2cm; NSCLC >2 but ≤3cm). Data for analysis consisted of age, gender, radiographic feature (GGO/part-solid/pure solid), tumor location, tumor size, pathologic findings and status of LN metastasis. Pathologic findings included histology, tumor differentiation, and visceral pleural 6 / 22
invasion (VPI). LNs were subrgouped into N1 (hilar/intrapulmonary LNs) and N2 stations (mediastinal LNs) (11). For N1 LNs, we further subgrouped them into hilar LNs (10#), interlobar LNs (11#), and peripheral LNs (12-14#) according to the International Association for the Study of Lung Cancer LN map (12).
Statistical analysis All statistical analyses were performed by applying the IBM SPSS software (version 22.0; IBM Corp., Armonk, NY, USA). Data were presented as mean ± standard deviation for continuous data and number with percentage for categorical data. For comparison of categorical data between groups, Chi-squared test or Fisher’s exact test would be used while for
continuous
data,
independent-sample
Student’s
t-test
or
the
Mann–Whitney
non-parametric U-test or one-way ANOVA test would be used for comparison. Multivariate regression analysis was conducted to identify risk factors of hilar/intrapulmonary LN metastasis. Here, we set the statistical significance as a two-sided P value <0.05.
Results Baseline characteristics of these included early-stage (cIA) NSCLC patients From January 2015 to December 2018, we finally included a total of 354 patients (accounting for about 15.8% of all cases undergoing lung cancer surgery) who underwent upfront lobectomy with systematic LN dissection or sampling for clinical early-stage (cT1N0M0, IA) NSCLC. The baseline characteristics of all these patient (ever or current smokers: 101 patients, 28.5%) were presented in Table 1. The mean age of all patients was 7 / 22
57.5±9.9 years old with a male to female ratio of 0.7:1. On preoperative CT scan, about 71.2% of the tumors presented as pure solid nodules. The majority of the patients were pathologically diagnosed with lung adenocarcinoma (318 cases, 89.8%) and the mean tumor size was 1.90±0.65cm. About half of the tumors (50.6%) were moderately differentiated. Most of the patients (83.1%) were found to have N0 disease while only 8.2% and 8.8% of them were found to have N1 and N2 disease, respectively. The detailed LN evaluation of these early-stage NSCLC patients were presented in Table 2. The mean total number of dissected N1 and N2 LNs for all patients was 5.6±3.0 and 8.1±4.0, respectively. The rate of positive LN metastasis was 16.9%. For regional LN metastasis pattern, the rate of positive N1 LN metastasis was 13.6% and it was 4.2%, 3.4%, and 10.5% for hilar, interlobar, and peripheral LN metastasis, respectively. The rate of N2 LN metastasis was 8.8%.
Baseline characteristics and regional LN metastasis pattern of early-stage NSCLC stratified by tumor size We subgrouped these patients into three groups according to tumor size (NSCLC ≤1cm; NSCLC >1 but ≤2cm; NSCLC >2 but ≤3cm). The baseline characteristics and LN metastasis pattern of these early-stage NSCLC patients with different tumor size were compared in Table 1 and Table 2. There was significant difference of age, radiographic feature, tumor size, tumor differentiation, pT stage, pN stage, status of VPI among the three groups stratified by tumor size. However, there was no significant difference regarding gender, histology, and tumor location among them (Table 1). For nodal evaluation, significant difference of total dissection N1 (P<0.001) and N2 (P=0.008) LN number was observed among the three groups. Moreover, 8 / 22
the rates of LN metastasis for patients with NSCLC ≤1cm, NSCLC >1 but ≤2cm, and NSCLC >2 but ≤3cm were 0%, 14.5%, and 23.8%, respectively (P=0.002). Patients with NSCLC ≤1cm had no N1 LN metastasis (0%) and the rates of hilar, interlobar, and peripheral LN metastasis were all 0%. Moreover, patients with NSCLC ≤1cm had no N2 LN metastasis either (0%). However, for patients with NSCLC >2 but ≤3cm, the rates of N1 and N2 LN metastasis were as high as 18.4% and 11.6%, respectively. Moreover, the rates of hilar, interlobar, and peripheral LN metastasis for patients with NSCLC >2 but ≤3cm were 5.4%, 5.4%, and 12.2%, respectively. For patients with NSCLC >1 but ≤2cm, the rates of N1 and N2 LN metastasis were 12.2% and 8.1%, respectively. Moreover, the rates of hilar, interlobar, and peripheral LN metastasis for these patients were 4.1%, 2.3%, and 11.0%, respectively (Table 2).
Baseline characteristics and regional LN metastasis pattern of NSCLC >1 but ≤2cm further stratified by tumor size Because of the very low rate of interlobar LN metastasis but high rate of peripheral LN metastasis in patients with NSCLC >1 but ≤2cm, we further subgrouped these patients into two groups by tumor size (NSCLC >1 but ≤1.5cm; NSCLC >1.5 but ≤2cm). The baseline characteristics of the two groups were presented in Supplementary table 1. There was significant difference of age, radiographic feature, tumor size, tumor differentiation, pT stage, pN stage, status of VPI between the two groups. We compared the regional LN metastasis pattern of the two groups in Table 3. Significant different LN metastasis rates were observed between the two groups (6.3% VS 21.5%; P=0.005). Patients with NSCLC >1 but ≤1.5cm had 9 / 22
a significant lower rate of N1 LN metastasis (2.5% VS 20.4%; P<0.001) but a comparable rate of N2 LN metastasis (5.1% VS 10.8%; P=0.174) compared to patients with NSCLC >1.5 but ≤2cm. Moreover, there was no interlobar LN metastasis (0%) in patients with NSCLC >1 but ≤1.5cm and the rate of peripheral LN metastasis in these patients was 2.5%, which was significantly lower than patients with NSCLC >1.5 but ≤2cm (18.3%).
Multivariate analysis of hilar/intrapulmonary LN metastasis in clinical IA NSCLC In order to further identify potential factors significantly influencing the risk of hilar/intrapulmonary LN metastasis, we conducted a multivariate regression analysis (Supplementary Table 2). For N1 LN metastasis, radiographic feature (pure solid) and histology (nonadenocarcinoma) were independent predictors while for peripheral LN metastasis, only histology (nonadenocarcinoma) was found to be independent predictor.
Comment Current available surgical resection methods for early-stage NSCLC mainly consisted of lobectomy and sublobar resection (including segmentectomy and wedge resection). However, the choice of surgical resection for early-stage NSCLC still remains debatable. Therefore, in this study, we tried to answer the question of how to choose surgical option for cIA peripheral NSCLC patients by exploring the pattern of regional LN metastasis. After subgrouping these patients by tumor size, we found that there was no N1 LN metastasis in patients with NSCLC ≤1cm, which indicated that dissection or sampling of intrapulmonary LNs may not be required for NSCLC ≤1cm and as a result, sublobar resection (both segmentectomy and wedge 10 / 22
resection) can be utilized for NSCLC ≤1cm provided that sufficient resection margin could be achieved. However, patients with NSCLC >2 but ≤3cm had a significantly high rate of N1 LN metastasis (18.4%) and the rates of hilar, interlobar and peripheral LN metastasis were also relatively high (all >5%), which suggested that extensive intrapulmonary LN evaluation should be achieved for these patients. Therefore, lobectomy which could remove all relevant intrapulmonary LNs should be preferred for NSCLC >2 but ≤3cm. Moreover, we further subgrouped patients with NSCLC >1 but ≤2cm into two groups (NSCLC >1 but ≤1.5cm; NSCLC >1.5 but ≤2cm). We found that patients with NSCLC >1.5 but ≤2cm also had a relatively high rate of hilar (>5%) and peripheral LN metastasis (18.3%). Therefore, lobectomy should still be preferred for NSCLC >1.5 but ≤2cm. However, we found a significantly low rate of N1 (2.5%) and peripheral (2.5%) LN metastasis in patients with NSCLC >1 but ≤1.5cm, which suggested that segmentectomy, not only allowing intrapulmonary LN sampling but also preserving vital lung tissue, could be the utilized for NSCLC >1 but ≤1.5cm. Moreover, we found that radiographic feature (pure solid) and nonadenocarcinoma histology were independent predictors of hilar/intrapulmonary LN metastasis. Therefore, the above recommendations for surgical choice of clinical stage IA peripheral NSCLC may be more applicable to early-stage NSCLCs with GGO component and those with adenocarcinoma subtype. Previous studies comparing the effects of sublobar resection and lobectomy in treating early-stage NSCLC have drawn controversial conclusions even though they were conducted based on the same large database of the Surveillance, Epidemiology, and End Results (13-16). Some studies found that sublobar resection yielded significantly more recurrence and 11 / 22
worse survival than lobectomy in treating early-stage NSCLC (13, 14). Other studies found that sublobar resection could achieve similar survival to lobectomy in treating early-stage NSCLC, particularly in these <2cm and these treated during the late period of time (15, 16). Even in previous meta-analyses (17-19), similar dilemma has also been encountered and controversy still exists during the comparison between sublobar resection and lobectomy in treating early-stage NSCLC. However, it is widely acknowledged that sublobar resection (particularly segmentectomy) do have a role in treating certain patients with NSCLC ≤2cm (8). According to the eighth edition of TNM staging system, NSCLC ≤2cm (known as T1a in the seventh edition staging system) could be further divided into NSCLC ≤1cm (T1a) and NSCLC >1 but ≤2cm (T1b) (20), indicating that tumor size should remain as an extremely important parameter in determining prognosis of early-stage NSCLC. Therefore, it seems important to choose surgical options for early-stage NSCLC based on tumor size. In our study, we found that there was no hilar/intrapulmonary LN metastasis in NSCLC ≤1cm. Previously, Kates et al (21) reported that in patients with NSCLC ≤1cm, sublobar resection (segmentectomy or wedge resection) could yield equivalent survival to lobectomy. Moreover, a recent meta-analysis also found that there was no significant difference of survival between patients receiving segmentectomy and those with wedge resection for NSCLC ≤1cm (22). Therefore, we believe that both wedge resection and segmentectomy could be recommended for these patients provided that sufficient resection margin could be achieved. Patients with NSCLC >1 but ≤2cm could be further divided into two subgroups based on tumor size (NSCLC >1 but ≤1.5cm; NSCLC >1.5 but ≤2cm) and significant different characteristics and regional LN metastasis patterns were observed between the two groups, indicating that 12 / 22
significant heterogeneities may exist even in NSCLC >1 but ≤2cm. Therefore, our findings may explain to some degrees why previous studies have drawn controversial conclusions regarding the comparison between sublobar resection and lobectomy in treating NSCLC ≤2cm (13, 23). Considering the high rate of hilar/intrapulmonary LN metastasis in NSCLC >1.5 but ≤2cm, an extensive resection of intrapulmonary LNs may be required and therefore, lobectomy should be the preferred option. However, NSCLC >1 but ≤1.5cm had a relatively
low
rate
of
hilar/intrapulmonary
LN
metastasis
(2.5%)
and
therefore,
segmentectomy could be recommended for them. Taken together, we recommended the choice of surgical resection for cT1N0M0 peripheral NSCLC based on tumor size as follow: for NSCLC ≤1cm, both segmentectomy and wedge resection could be utilized, and for NSCLC >1 but ≤1.5cm, segmentectomy could be utilized, while for NSCLC >1.5cm, lobectomy should be preferred, which seems especially justifiable for NSCLCs with GGO component and those with adenocarcinoma subtype. Our study still suffered from several limitations. First, including pure GGO lesions and categorizing them by total size to be, in essence, equivalent to a solid lesion was flawed in our study. Second, we drew our conclusions only from the regional LN metastasis pattern without survival analysis from direct comparison between surgical treatments. Hence, the impact of our conclusions on long-term oncological outcomes remains unclear and it is inherently risky to recommend sublobar resection based on our retrospective, single arm series of lobectomy with a relatively small sample size. Third, our results may be biased by the different level of LNs examined by the size of the tumor even though sufficient nodal evaluation has been made for each patient. Furthermore, our recommendations implied less extensive nodal 13 / 22
dissection for smaller lesions, which may limit the accuracy of nodal examination for them. Moreover, positron emission tomography (PET)/CT scan was not routinely applied for preoperative staging in our study because this examination is extremely expensive and not covered by medical insurance in China yet, which may limit generalization of our conclusions to other populations who routinely undergo PET/CT. Finally, we drew above conclusions only in a non-representative Chinese population of NSCLC patients (predominantly female, adenocarcinomas and never smokers), but whether the conclusions would hold in representative populations or Western populations requires further investigation. Therefore, direct evidence from the Japanese trial (JCOG0802/WJOG4607L) and North American trial (CALGB140503) (24) will be greatly needed.
Conclusions In this retrospective study, we found that NSCLC ≤1cm had no hilar/intrapulmonary LN metastasis while NSCLC >2 but ≤3cm had a significantly high rate of hilar/intrapulmonary LN metastasis. Moreover, NSCLC >1 but ≤2cm could further be divided into subgroups by tumor size based on the pattern of regional LN metastasis. Therefore, surgical choice for cIA peripheral NSCLC could be recommended as follow: for NSCLC ≤1cm, both segmentectomy and wedge resection could be utilized, and for NSCLC >1 but ≤1.5cm, segmentectomy could be utilized provided that sufficient resection margin could be achieved, while for NSCLC >1.5cm, lobectomy should be preferred, which seemed more reasonable for NSCLCs with GGO component and those with adenocarcinoma subtype.
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Table 1. Baseline characteristics of these clinical T1N0M0 peripheral non-small cell lung cancers stratified by tumor size. Characteristics
Total(N=354)
Tumor size group ≤1cm(N=35)
Age(Mean±SD ,years)
57.5±9.9
48.0±10.4
>1
P value
but >2
≤2cm(N=172)
≤3cm(N=147)
57.9±9.7
59.3±8.7
Gender
<0.001 0.258
Male
150(42.4%)
11(31.4%)
71(41.3%)
68(46.3%)
Female
204(57.6%)
24(68.6%)
101(58.7%)
79(53.7%)
Radiographic feature
<0.001
Pure ground glass
41(11.6%)
17(48.6%)
21(12.2%)
3(2.0%)
Part-solid
61(17.2%)
11(31.4%)
30(17.4%)
20(13.6%)
Pure solid
252(71.2%)
7(20.0%)
121(70.3%)
124(84.4%)
Histology
0.138*
Adenocarcinoma
318(89.8%)
35(100%)
157(91.3%)
126(85.7%)
Squamous cell carcinoma
27(7.6%)
0(0%)
11(6.4%)
16(10.9%)
Others
9(2.5%)
0(0%)
4(2.3%)
5(3.4%)
1.90±0.65
0.84±0.16
1.57±0.30
2.55±0.30
Tumor size(Mean±SD, cm)
but
Tumor location
<0.001 0.860
15 / 22
Right upper lobe
136(38.4%)
15(42.9%)
67(39.0%)
54(36.7%)
Right middle lobe
19(5.4%)
2(5.7%)
8(4.7%)
9(6.1%)
Right lower lobe
43(12.1%)
3(8.7%)
24(14.0%)
16(10.9%)
Left upper lobe
99(28.0%)
12(34.3%)
46(26.7%)
41(27.9%)
Left lower lobe
57(16.1%)
3(8.6%)
27(15.7%)
27(18.4%)
Tumor differentiation
<0.001
G1
74(20.9%)
21(60.0%)
41(23.8%)
12(8.2%)
G2
179(50.6%)
14(40.0%)
91(52.9%)
74(50.3%)
G3
101(28.5%)
0(0%)
40(23.3%)
61(41.5%)
pT stage
<0.001*
Tis
7(2.0%)
6(17.1%)
1(0.6%)
0(0%)
T1mi
25(7.1%)
10(28.6%)
13(7.6%)
2(1.4%)
T1a
16(4.5%)
16(45.7%)
0(0%)
0(0%)
T1b
120(33.9%)
1(2.9%)
119(69.2%)
0(0%)
T1c
87(24.6%)
0(0%)
0(0%)
87(59.2%)
T2a#
99(28.0%)
2(5.7%)
39(22.7%)
58(39.5%)
pN stage
0.008*
N0
294(83.1%)
35(100%)
147(85.5%)
112(76.2%)
N1
29(8.2%)
0(0%)
11(6.4%)
18(12.2%)
N2
31(8.8%)
0(0%)
14(8.1%)
17(11.6%)
Visceral pleural invasion Yes
<0.001 99(28.0%)
2(5.7%) 16 / 22
39 (22.7.3%)
58(39.5%)
No
255(72.0%)
33 (94.3%)
133(77.3%)
89(60.5%)
Note: SD=standard deviation. *Fisher’s exact test; #: due to visceral pleural invasion.
Table 2. Regional LN metastasis pattern among clinical T1N0M0 peripheral non-small cell lung cancers with different tumor size. Characteristics
Total(N=354)
Tumor size group ≤1cm(N=35)
Total
dissected
>1
but >2
≤2cm(N=172)
≤3cm(N=147)
P value but
N1
LN 5.6±3.0
3.6±1.9
5.4±2.7
6.3±3.3
<0.001
N2
LN 8.1±4.0
7.0±3.4
7.6±3.6
8.8±4.4
0.008
number(Mean±SD) Total
dissected
number(Mean±SD) LN metastasis rate
16.9%(60/354)
0(0/35)
14.5%(25/172)
23.8%(35/147)
0.002
N1 LN metastasis rate(10-14#)
13.6%(48/354)
0(0/35)
12.2%(21/172)
18.4%(27/147)
0.013
Hilar LN metastasis rate(10#)
4.2%(15/354)
0(0/35)
4.1%(7/172)
5.4%(8/147)
0.348
LN
metastasis 3.4%(12/354)
0(0/35)
2.3%(4/172)
5.4%(8/147)
0.263*
LN
metastasis 10.5%(37/354)
0(0/35)
11.0%(19/172)
12.2%(18/147)
0.092
0(0/35)
8.1%(14/172)
11.6%(17/147)
0.088
Interlobar rate(11#) Peripheral rate(12-14#)
N2 LN metastasis rate(1-9#)
8.8%(31/354)
Note: LN=lymph node; SD=standard deviation. *Fisher’s exact test
17 / 22
Table 3. Regional LN metastasis of non-small cell lung cancer >1 but ≤2cm further stratified by tumor size. Characteristics
Tumor size >1 but ≤1.5cm(N=79)
Total
dissected
P value
>1.5 but ≤2cm(N=93)
N1
LN 5.5±2.9
5.3±2.6
0.724
N2
LN 7.3±3.8
7.9±3.5
0.268
number(Mean±SD) Total
dissected
number(Mean±SD) LN metastasis rate
6.3%(5/79)
21.5%(20/93)
0.005
N1 LN metastasis rate(10-14#)
2.5%(2/79)
20.4%(19/93)
<0.001
Hilar LN metastasis rate(10#)
1.3%(1/79)
6.5%(6/93)
0.126
Interlobar LN metastasis rate(11#)
0(0/79)
4.3%(4/93)
0.126*
Peripheral LN metastasis rate(12-14#)
2.5%(2/79)
18.3%(17/93)
0.001
N2 LN metastasis rate(1-9#)
5.1%(4/79)
10.8%(10/93)
0.174
Note: LN=lymph node; SD=standard deviation. *Fisher’s exact test.
18 / 22
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of an online survey. Annals of the American Thoracic Society 2017;14(1):118-123. 10. Lardinois D, De Leyn P, Van Schil P et al. Ests guidelines for intraoperative lymph node staging in non-small cell lung cancer. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2006;30(5):787-792. 11. Goldstraw P, Chansky K, Crowley J et al. 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. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2016;11(1):39-51. 12. Rusch VW, Asamura H, Watanabe H, Giroux DJ, Rami-Porta R, Goldstraw P. The iaslc lung cancer staging project: A proposal for a new international lymph node map in the forthcoming seventh edition of the tnm classification for lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2009;4(5):568-577. 13. Dai C, Shen J, Ren Y et al. Choice of surgical procedure for patients with non-small-cell lung cancer 1 to 2 cm among lobectomy, segmentectomy, and wedge resection: A population-based study. Journal of clinical oncology : official journal of the American Society 20 / 22
of Clinical Oncology 2016;34(26):3175-3182. 14. Veluswamy RR, Ezer N, Mhango G et al. Limited resection versus lobectomy for older patients with early-stage lung cancer: Impact of histology. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2015;33(30):3447-3453. 15. Wisnivesky JP, Henschke CI, Swanson S et al. Limited resection for the treatment of patients with stage ia lung cancer. Annals of surgery 2010;251(3):550-554. 16. Yendamuri S, Sharma R, Demmy M et al. Temporal trends in outcomes following sublobar and lobar resections for small (
end
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21. Kates M, Swanson S, Wisnivesky JP. Survival following lobectomy and limited resection for the treatment of stage i non-small cell lung cancer<=1 cm in size: A review of seer data. Chest 2011;139(3):491-496. 22. Xue W, Duan G, Zhang X, Zhang H, Zhao Q, Xin Z. Meta-analysis of segmentectomy versus wedge resection in stage ia non-small-cell lung cancer. OncoTargets and therapy 2018;11:3369-3375. 23. Moon MH, Moon YK. Segmentectomy versus lobectomy in early non-small cell lung cancer of 2 cm or less in size: A population-based study. Respirology 2018;23(7):695-703. 24. Ghanem S, El Bitar S, Hossri S, Weerasinghe C, Atallah JP. What we know about surgical therapy in early-stage non-small-cell lung cancer: A guide for the medical oncologist. Cancer management and research 2017;9:267-278.
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S0003-4975(19)31870-3
DOI:
https://doi.org/10.1016/j.athoracsur.2019.10.056
Reference:
ATS 33301
To appear in:
The Annals of Thoracic Surgery
Received Date: 16 April 2019 Revised Date:
8 August 2019
Accepted Date: 18 October 2019
Please cite this article as: Deng HY, Zhou J, Wang RL, Jiang R, Qiu XM, Zhu DX, Tang XJ, Zhou Q, Surgical choice for cIA non-small cell lung cancer: view from regional lymph node metastasis, The Annals of Thoracic Surgery (2020), doi: https://doi.org/10.1016/j.athoracsur.2019.10.056. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
Surgical choice for cIA non-small cell lung cancer: view from regional lymph node metastasis Running title: Surgical choice for early-stage NSCLC
Han-Yu Deng1, MD, Jie Zhou1, MD, Ru-Lan Wang1, MD, Rui Jiang1, MD, Xiao-Ming Qiu1, MD, Da-Xing Zhu1, MD, Xiao-Jun Tang1, MD, Qinghua Zhou1*, MD
1. Lung cancer center, West China Hospital, Sichuan University, Chengdu, China.
Word count: 4483
*Corresponding Author: Qinghua Zhou, MD. Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China. No.37 Guoxue Alley, Chengdu 610041, Sichuan, China. E-mail: [email protected]
1 / 22
Abstract Background: We aimed to investigate the pattern of regional lymph node (LN) metastasis of early-stage non-small cell lung cancer (NSCLC) to provide novel rationale for surgical choice (lobectomy, segmentectomy, or wedge resection) for these patients. Methods: We retrospectively collected clinical data of patients undergoing lobectomy with systematic mediastinal LN dissection or sampling for cT1N0M0 peripheral NSCLC from January 2015 to December 2018. The regional LN metastasis pattern was analyzed based on tumor size. Results: We included a total of 354 patients for analysis. The rate of hilar/intrapulmonary LN metastasis was 13.6%. When stratified by tumor size, NSCLC ≤1cm had no hilar/intrapulmonary LN metastasis (0%) while NSCLC >2 but ≤3cm had a significantly high rate of hilar/intrapulmonary LN metastasis (18.4%) and the rates of hilar, interlobar and peripheral LN metastasis were also relatively high (5.4%, 5.4% and 12.2%, respectively). NSCLC >1.5 but ≤2cm also had relatively high rates of hilar (6.5%) and peripheral (18.3%) LN metastasis while NSCLC >1 but ≤1.5cm had significantly low rates of hilar/intrapulmonary (2.5%) and peripheral (2.5%) LN metastasis. Radiographic feature and histology were found to be independent predictors of regional LN metastasis. Conclusions: The pattern of regional LN metastasis in cIA peripheral NSCLC was significantly influenced by tumor size, which may provide evidence on surgical choice (lobectomy, segmentectomy, or wedge resection) for these early-stage NSCLC patients based on tumor size. Key words: non-small cell lung cancer; early-stage; regional lymph node metastasis; 2 / 22
lobectomy; sublobar resection.
3 / 22
Lung cancer has become the commonest diagnosed cancer and leading cause of cancer-related death worldwide (1). Pathologically, lung cancer mainly consisted of small cell lung cancer and non-small cell lung cancer (NSCLC) with the latter accounting for about 85% of all lung cancers (2). With the improvement of medical screening methods, more and more NSCLCs have been uncovered at early stage (3) and surgery still remains to be the standard of care with excellent survival outcomes. In 1995, the only completed randomized controlled trial (RCT) comparing the efficacy of lobectomy and sublobar resection (segmentectomy or wedge resection) in treating cT1N0 NSCLC found that sublobar resection yielded a significantly higher recurrence rate and a trend toward worse survival than lobectomy, which provided the evidence for lobectomy as the preferred option for treating early-stage NSCLC (4). However, this landmark trial has been widely criticized for the following limitations: first, there was a high percentage of patients receiving wedge resection in the sublobar resection group; second, plain chest radiography not chest computed tomography (CT) was applied for staging; third, there was no subgroup analysis based on tumor size (5, 6). With the advantage of preserving vital lung tissue and providing a chance for further resection for secondary lung cancer (5), sublobar resection has been intensively investigated as an alternative to lobectomy in treating early-stage NSCLC. Even though previous studies compared the efficacy of sublobar resection with lobectomy in treating early-stage NSCLC, they have drawn conflicting conclusions regarding the application of sublobar resection with obvious heterogeneities and patient selection bias (7). Therefore, the surgical choice for treating early-stage NSCLC remains challenging for thoracic surgeons. However, it should be noted that sublobar resection (particularly segmentectomy) do have a role in treating certain 4 / 22
early-stage NSCLC since current National Comprehensive Cancer Network (NCCN) guideline recommends that sublobar resection is appropriate in selected patients: those unfit for lobectomy or with peripheral NSCLC <2cm with low malignant features (8). For surgical difference, the major concern about lobectomy, segmentectomy, and wedge resection is the adequacy of resection and nodal examination. It is widely accepted that adequate resection of NSCLC requires a parenchymal resection margin ≥2cm or the size of the tumor (8). Therefore, we believe the only significant difference among the above three surgical methods is the extent of hilar/intrapulmonary nodal dissection if sufficient resection margin and systematic mediastinal lymph node (LN) dissection or sampling is achieved. Hence, in this study, we aimed to investigate the pattern of hilar/intrapulmonary LN metastasis in early-stage (cT1N0M0) peripheral NSCLC so as to provide novel perspectives on surgical choice for clinical IA peripheral NSCLC.
Material and Methods Patients We retrospectively collected clinical data of patients undergoing lobectomy with systematic mediastinal LN dissection or sampling in our center from January 2015 to December 2018. For preoperative clinical staging, contrast-enhanced chest and upper abdominal CT, contrast-enhanced magnetic resonance imaging of brain, bone scanning, and cardiopulmonary tests were routinely performed for these patients. Positive LN metastasis was defined as LN with a short-axis diameter >1cm on the transverse chest CT. We included patients with following criteria: 1) patients received lobectomy with lymphadenectomy without 5 / 22
any preoperative chemoradiotherapy; 2) patients were preoperatively staged as clinical stage IA (T1N0M0, tumor size ≤3cm); 3) patients should be pathologically confirmed with peripherally located primary NSCLC according to the NCCN guideline (outer one third of the hemithorax) (9); 4) patients who underwent systematic lymph node sampling or dissection based on the European Society of Thoracic Surgeons criteria (10) . We excluded the following patients: 1) patients with preoperative chemoradiotherapy; 2) patients who did not receive systematic lymph node assessment; 3) patients with small cell lung cancer or synchronous multiple primary NSCLC or secondary lung cancer.; 4) patients with centrally located NSCLC (inner two-thirds of the hemithorax); 5) patients with intraoperative finding of pleural metastasis. In our center, we would perform systematic mediastinal lymph node sampling only for tumors with pure ground glass opacity (GGO) less than 2cm on CT scan. Otherwise, we would always perform systematic lymph node dissection. Since our study was a retrospective study and analyzed anonymously, the Ethic Committee of our hospital waived the need for consent. In this study, we analyzed the regional LN metastasis pattern of these early-stage NSCLC patients based on tumor size in accordance with the eighth edition of TNM staging system for NSCLC (11). For tumor size evaluation, we measured the maximum diameter of the tumor including both GGO part and solid part in the lung window of chest CT. Here we subgrouped these patients into three groups according to tumor size (NSCLC ≤1cm; NSCLC >1 but ≤2cm; NSCLC >2 but ≤3cm). Data for analysis consisted of age, gender, radiographic feature (GGO/part-solid/pure solid), tumor location, tumor size, pathologic findings and status of LN metastasis. Pathologic findings included histology, tumor differentiation, and visceral pleural 6 / 22
invasion (VPI). LNs were subrgouped into N1 (hilar/intrapulmonary LNs) and N2 stations (mediastinal LNs) (11). For N1 LNs, we further subgrouped them into hilar LNs (10#), interlobar LNs (11#), and peripheral LNs (12-14#) according to the International Association for the Study of Lung Cancer LN map (12).
Statistical analysis All statistical analyses were performed by applying the IBM SPSS software (version 22.0; IBM Corp., Armonk, NY, USA). Data were presented as mean ± standard deviation for continuous data and number with percentage for categorical data. For comparison of categorical data between groups, Chi-squared test or Fisher’s exact test would be used while for
continuous
data,
independent-sample
Student’s
t-test
or
the
Mann–Whitney
non-parametric U-test or one-way ANOVA test would be used for comparison. Multivariate regression analysis was conducted to identify risk factors of hilar/intrapulmonary LN metastasis. Here, we set the statistical significance as a two-sided P value <0.05.
Results Baseline characteristics of these included early-stage (cIA) NSCLC patients From January 2015 to December 2018, we finally included a total of 354 patients (accounting for about 15.8% of all cases undergoing lung cancer surgery) who underwent upfront lobectomy with systematic LN dissection or sampling for clinical early-stage (cT1N0M0, IA) NSCLC. The baseline characteristics of all these patient (ever or current smokers: 101 patients, 28.5%) were presented in Table 1. The mean age of all patients was 7 / 22
57.5±9.9 years old with a male to female ratio of 0.7:1. On preoperative CT scan, about 71.2% of the tumors presented as pure solid nodules. The majority of the patients were pathologically diagnosed with lung adenocarcinoma (318 cases, 89.8%) and the mean tumor size was 1.90±0.65cm. About half of the tumors (50.6%) were moderately differentiated. Most of the patients (83.1%) were found to have N0 disease while only 8.2% and 8.8% of them were found to have N1 and N2 disease, respectively. The detailed LN evaluation of these early-stage NSCLC patients were presented in Table 2. The mean total number of dissected N1 and N2 LNs for all patients was 5.6±3.0 and 8.1±4.0, respectively. The rate of positive LN metastasis was 16.9%. For regional LN metastasis pattern, the rate of positive N1 LN metastasis was 13.6% and it was 4.2%, 3.4%, and 10.5% for hilar, interlobar, and peripheral LN metastasis, respectively. The rate of N2 LN metastasis was 8.8%.
Baseline characteristics and regional LN metastasis pattern of early-stage NSCLC stratified by tumor size We subgrouped these patients into three groups according to tumor size (NSCLC ≤1cm; NSCLC >1 but ≤2cm; NSCLC >2 but ≤3cm). The baseline characteristics and LN metastasis pattern of these early-stage NSCLC patients with different tumor size were compared in Table 1 and Table 2. There was significant difference of age, radiographic feature, tumor size, tumor differentiation, pT stage, pN stage, status of VPI among the three groups stratified by tumor size. However, there was no significant difference regarding gender, histology, and tumor location among them (Table 1). For nodal evaluation, significant difference of total dissection N1 (P<0.001) and N2 (P=0.008) LN number was observed among the three groups. Moreover, 8 / 22
the rates of LN metastasis for patients with NSCLC ≤1cm, NSCLC >1 but ≤2cm, and NSCLC >2 but ≤3cm were 0%, 14.5%, and 23.8%, respectively (P=0.002). Patients with NSCLC ≤1cm had no N1 LN metastasis (0%) and the rates of hilar, interlobar, and peripheral LN metastasis were all 0%. Moreover, patients with NSCLC ≤1cm had no N2 LN metastasis either (0%). However, for patients with NSCLC >2 but ≤3cm, the rates of N1 and N2 LN metastasis were as high as 18.4% and 11.6%, respectively. Moreover, the rates of hilar, interlobar, and peripheral LN metastasis for patients with NSCLC >2 but ≤3cm were 5.4%, 5.4%, and 12.2%, respectively. For patients with NSCLC >1 but ≤2cm, the rates of N1 and N2 LN metastasis were 12.2% and 8.1%, respectively. Moreover, the rates of hilar, interlobar, and peripheral LN metastasis for these patients were 4.1%, 2.3%, and 11.0%, respectively (Table 2).
Baseline characteristics and regional LN metastasis pattern of NSCLC >1 but ≤2cm further stratified by tumor size Because of the very low rate of interlobar LN metastasis but high rate of peripheral LN metastasis in patients with NSCLC >1 but ≤2cm, we further subgrouped these patients into two groups by tumor size (NSCLC >1 but ≤1.5cm; NSCLC >1.5 but ≤2cm). The baseline characteristics of the two groups were presented in Supplementary table 1. There was significant difference of age, radiographic feature, tumor size, tumor differentiation, pT stage, pN stage, status of VPI between the two groups. We compared the regional LN metastasis pattern of the two groups in Table 3. Significant different LN metastasis rates were observed between the two groups (6.3% VS 21.5%; P=0.005). Patients with NSCLC >1 but ≤1.5cm had 9 / 22
a significant lower rate of N1 LN metastasis (2.5% VS 20.4%; P<0.001) but a comparable rate of N2 LN metastasis (5.1% VS 10.8%; P=0.174) compared to patients with NSCLC >1.5 but ≤2cm. Moreover, there was no interlobar LN metastasis (0%) in patients with NSCLC >1 but ≤1.5cm and the rate of peripheral LN metastasis in these patients was 2.5%, which was significantly lower than patients with NSCLC >1.5 but ≤2cm (18.3%).
Multivariate analysis of hilar/intrapulmonary LN metastasis in clinical IA NSCLC In order to further identify potential factors significantly influencing the risk of hilar/intrapulmonary LN metastasis, we conducted a multivariate regression analysis (Supplementary Table 2). For N1 LN metastasis, radiographic feature (pure solid) and histology (nonadenocarcinoma) were independent predictors while for peripheral LN metastasis, only histology (nonadenocarcinoma) was found to be independent predictor.
Comment Current available surgical resection methods for early-stage NSCLC mainly consisted of lobectomy and sublobar resection (including segmentectomy and wedge resection). However, the choice of surgical resection for early-stage NSCLC still remains debatable. Therefore, in this study, we tried to answer the question of how to choose surgical option for cIA peripheral NSCLC patients by exploring the pattern of regional LN metastasis. After subgrouping these patients by tumor size, we found that there was no N1 LN metastasis in patients with NSCLC ≤1cm, which indicated that dissection or sampling of intrapulmonary LNs may not be required for NSCLC ≤1cm and as a result, sublobar resection (both segmentectomy and wedge 10 / 22
resection) can be utilized for NSCLC ≤1cm provided that sufficient resection margin could be achieved. However, patients with NSCLC >2 but ≤3cm had a significantly high rate of N1 LN metastasis (18.4%) and the rates of hilar, interlobar and peripheral LN metastasis were also relatively high (all >5%), which suggested that extensive intrapulmonary LN evaluation should be achieved for these patients. Therefore, lobectomy which could remove all relevant intrapulmonary LNs should be preferred for NSCLC >2 but ≤3cm. Moreover, we further subgrouped patients with NSCLC >1 but ≤2cm into two groups (NSCLC >1 but ≤1.5cm; NSCLC >1.5 but ≤2cm). We found that patients with NSCLC >1.5 but ≤2cm also had a relatively high rate of hilar (>5%) and peripheral LN metastasis (18.3%). Therefore, lobectomy should still be preferred for NSCLC >1.5 but ≤2cm. However, we found a significantly low rate of N1 (2.5%) and peripheral (2.5%) LN metastasis in patients with NSCLC >1 but ≤1.5cm, which suggested that segmentectomy, not only allowing intrapulmonary LN sampling but also preserving vital lung tissue, could be the utilized for NSCLC >1 but ≤1.5cm. Moreover, we found that radiographic feature (pure solid) and nonadenocarcinoma histology were independent predictors of hilar/intrapulmonary LN metastasis. Therefore, the above recommendations for surgical choice of clinical stage IA peripheral NSCLC may be more applicable to early-stage NSCLCs with GGO component and those with adenocarcinoma subtype. Previous studies comparing the effects of sublobar resection and lobectomy in treating early-stage NSCLC have drawn controversial conclusions even though they were conducted based on the same large database of the Surveillance, Epidemiology, and End Results (13-16). Some studies found that sublobar resection yielded significantly more recurrence and 11 / 22
worse survival than lobectomy in treating early-stage NSCLC (13, 14). Other studies found that sublobar resection could achieve similar survival to lobectomy in treating early-stage NSCLC, particularly in these <2cm and these treated during the late period of time (15, 16). Even in previous meta-analyses (17-19), similar dilemma has also been encountered and controversy still exists during the comparison between sublobar resection and lobectomy in treating early-stage NSCLC. However, it is widely acknowledged that sublobar resection (particularly segmentectomy) do have a role in treating certain patients with NSCLC ≤2cm (8). According to the eighth edition of TNM staging system, NSCLC ≤2cm (known as T1a in the seventh edition staging system) could be further divided into NSCLC ≤1cm (T1a) and NSCLC >1 but ≤2cm (T1b) (20), indicating that tumor size should remain as an extremely important parameter in determining prognosis of early-stage NSCLC. Therefore, it seems important to choose surgical options for early-stage NSCLC based on tumor size. In our study, we found that there was no hilar/intrapulmonary LN metastasis in NSCLC ≤1cm. Previously, Kates et al (21) reported that in patients with NSCLC ≤1cm, sublobar resection (segmentectomy or wedge resection) could yield equivalent survival to lobectomy. Moreover, a recent meta-analysis also found that there was no significant difference of survival between patients receiving segmentectomy and those with wedge resection for NSCLC ≤1cm (22). Therefore, we believe that both wedge resection and segmentectomy could be recommended for these patients provided that sufficient resection margin could be achieved. Patients with NSCLC >1 but ≤2cm could be further divided into two subgroups based on tumor size (NSCLC >1 but ≤1.5cm; NSCLC >1.5 but ≤2cm) and significant different characteristics and regional LN metastasis patterns were observed between the two groups, indicating that 12 / 22
significant heterogeneities may exist even in NSCLC >1 but ≤2cm. Therefore, our findings may explain to some degrees why previous studies have drawn controversial conclusions regarding the comparison between sublobar resection and lobectomy in treating NSCLC ≤2cm (13, 23). Considering the high rate of hilar/intrapulmonary LN metastasis in NSCLC >1.5 but ≤2cm, an extensive resection of intrapulmonary LNs may be required and therefore, lobectomy should be the preferred option. However, NSCLC >1 but ≤1.5cm had a relatively
low
rate
of
hilar/intrapulmonary
LN
metastasis
(2.5%)
and
therefore,
segmentectomy could be recommended for them. Taken together, we recommended the choice of surgical resection for cT1N0M0 peripheral NSCLC based on tumor size as follow: for NSCLC ≤1cm, both segmentectomy and wedge resection could be utilized, and for NSCLC >1 but ≤1.5cm, segmentectomy could be utilized, while for NSCLC >1.5cm, lobectomy should be preferred, which seems especially justifiable for NSCLCs with GGO component and those with adenocarcinoma subtype. Our study still suffered from several limitations. First, including pure GGO lesions and categorizing them by total size to be, in essence, equivalent to a solid lesion was flawed in our study. Second, we drew our conclusions only from the regional LN metastasis pattern without survival analysis from direct comparison between surgical treatments. Hence, the impact of our conclusions on long-term oncological outcomes remains unclear and it is inherently risky to recommend sublobar resection based on our retrospective, single arm series of lobectomy with a relatively small sample size. Third, our results may be biased by the different level of LNs examined by the size of the tumor even though sufficient nodal evaluation has been made for each patient. Furthermore, our recommendations implied less extensive nodal 13 / 22
dissection for smaller lesions, which may limit the accuracy of nodal examination for them. Moreover, positron emission tomography (PET)/CT scan was not routinely applied for preoperative staging in our study because this examination is extremely expensive and not covered by medical insurance in China yet, which may limit generalization of our conclusions to other populations who routinely undergo PET/CT. Finally, we drew above conclusions only in a non-representative Chinese population of NSCLC patients (predominantly female, adenocarcinomas and never smokers), but whether the conclusions would hold in representative populations or Western populations requires further investigation. Therefore, direct evidence from the Japanese trial (JCOG0802/WJOG4607L) and North American trial (CALGB140503) (24) will be greatly needed.
Conclusions In this retrospective study, we found that NSCLC ≤1cm had no hilar/intrapulmonary LN metastasis while NSCLC >2 but ≤3cm had a significantly high rate of hilar/intrapulmonary LN metastasis. Moreover, NSCLC >1 but ≤2cm could further be divided into subgroups by tumor size based on the pattern of regional LN metastasis. Therefore, surgical choice for cIA peripheral NSCLC could be recommended as follow: for NSCLC ≤1cm, both segmentectomy and wedge resection could be utilized, and for NSCLC >1 but ≤1.5cm, segmentectomy could be utilized provided that sufficient resection margin could be achieved, while for NSCLC >1.5cm, lobectomy should be preferred, which seemed more reasonable for NSCLCs with GGO component and those with adenocarcinoma subtype.
14 / 22
Table 1. Baseline characteristics of these clinical T1N0M0 peripheral non-small cell lung cancers stratified by tumor size. Characteristics
Total(N=354)
Tumor size group ≤1cm(N=35)
Age(Mean±SD ,years)
57.5±9.9
48.0±10.4
>1
P value
but >2
≤2cm(N=172)
≤3cm(N=147)
57.9±9.7
59.3±8.7
Gender
<0.001 0.258
Male
150(42.4%)
11(31.4%)
71(41.3%)
68(46.3%)
Female
204(57.6%)
24(68.6%)
101(58.7%)
79(53.7%)
Radiographic feature
<0.001
Pure ground glass
41(11.6%)
17(48.6%)
21(12.2%)
3(2.0%)
Part-solid
61(17.2%)
11(31.4%)
30(17.4%)
20(13.6%)
Pure solid
252(71.2%)
7(20.0%)
121(70.3%)
124(84.4%)
Histology
0.138*
Adenocarcinoma
318(89.8%)
35(100%)
157(91.3%)
126(85.7%)
Squamous cell carcinoma
27(7.6%)
0(0%)
11(6.4%)
16(10.9%)
Others
9(2.5%)
0(0%)
4(2.3%)
5(3.4%)
1.90±0.65
0.84±0.16
1.57±0.30
2.55±0.30
Tumor size(Mean±SD, cm)
but
Tumor location
<0.001 0.860
15 / 22
Right upper lobe
136(38.4%)
15(42.9%)
67(39.0%)
54(36.7%)
Right middle lobe
19(5.4%)
2(5.7%)
8(4.7%)
9(6.1%)
Right lower lobe
43(12.1%)
3(8.7%)
24(14.0%)
16(10.9%)
Left upper lobe
99(28.0%)
12(34.3%)
46(26.7%)
41(27.9%)
Left lower lobe
57(16.1%)
3(8.6%)
27(15.7%)
27(18.4%)
Tumor differentiation
<0.001
G1
74(20.9%)
21(60.0%)
41(23.8%)
12(8.2%)
G2
179(50.6%)
14(40.0%)
91(52.9%)
74(50.3%)
G3
101(28.5%)
0(0%)
40(23.3%)
61(41.5%)
pT stage
<0.001*
Tis
7(2.0%)
6(17.1%)
1(0.6%)
0(0%)
T1mi
25(7.1%)
10(28.6%)
13(7.6%)
2(1.4%)
T1a
16(4.5%)
16(45.7%)
0(0%)
0(0%)
T1b
120(33.9%)
1(2.9%)
119(69.2%)
0(0%)
T1c
87(24.6%)
0(0%)
0(0%)
87(59.2%)
T2a#
99(28.0%)
2(5.7%)
39(22.7%)
58(39.5%)
pN stage
0.008*
N0
294(83.1%)
35(100%)
147(85.5%)
112(76.2%)
N1
29(8.2%)
0(0%)
11(6.4%)
18(12.2%)
N2
31(8.8%)
0(0%)
14(8.1%)
17(11.6%)
Visceral pleural invasion Yes
<0.001 99(28.0%)
2(5.7%) 16 / 22
39 (22.7.3%)
58(39.5%)
No
255(72.0%)
33 (94.3%)
133(77.3%)
89(60.5%)
Note: SD=standard deviation. *Fisher’s exact test; #: due to visceral pleural invasion.
Table 2. Regional LN metastasis pattern among clinical T1N0M0 peripheral non-small cell lung cancers with different tumor size. Characteristics
Total(N=354)
Tumor size group ≤1cm(N=35)
Total
dissected
>1
but >2
≤2cm(N=172)
≤3cm(N=147)
P value but
N1
LN 5.6±3.0
3.6±1.9
5.4±2.7
6.3±3.3
<0.001
N2
LN 8.1±4.0
7.0±3.4
7.6±3.6
8.8±4.4
0.008
number(Mean±SD) Total
dissected
number(Mean±SD) LN metastasis rate
16.9%(60/354)
0(0/35)
14.5%(25/172)
23.8%(35/147)
0.002
N1 LN metastasis rate(10-14#)
13.6%(48/354)
0(0/35)
12.2%(21/172)
18.4%(27/147)
0.013
Hilar LN metastasis rate(10#)
4.2%(15/354)
0(0/35)
4.1%(7/172)
5.4%(8/147)
0.348
LN
metastasis 3.4%(12/354)
0(0/35)
2.3%(4/172)
5.4%(8/147)
0.263*
LN
metastasis 10.5%(37/354)
0(0/35)
11.0%(19/172)
12.2%(18/147)
0.092
0(0/35)
8.1%(14/172)
11.6%(17/147)
0.088
Interlobar rate(11#) Peripheral rate(12-14#)
N2 LN metastasis rate(1-9#)
8.8%(31/354)
Note: LN=lymph node; SD=standard deviation. *Fisher’s exact test
17 / 22
Table 3. Regional LN metastasis of non-small cell lung cancer >1 but ≤2cm further stratified by tumor size. Characteristics
Tumor size >1 but ≤1.5cm(N=79)
Total
dissected
P value
>1.5 but ≤2cm(N=93)
N1
LN 5.5±2.9
5.3±2.6
0.724
N2
LN 7.3±3.8
7.9±3.5
0.268
number(Mean±SD) Total
dissected
number(Mean±SD) LN metastasis rate
6.3%(5/79)
21.5%(20/93)
0.005
N1 LN metastasis rate(10-14#)
2.5%(2/79)
20.4%(19/93)
<0.001
Hilar LN metastasis rate(10#)
1.3%(1/79)
6.5%(6/93)
0.126
Interlobar LN metastasis rate(11#)
0(0/79)
4.3%(4/93)
0.126*
Peripheral LN metastasis rate(12-14#)
2.5%(2/79)
18.3%(17/93)
0.001
N2 LN metastasis rate(1-9#)
5.1%(4/79)
10.8%(10/93)
0.174
Note: LN=lymph node; SD=standard deviation. *Fisher’s exact test.
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