Lobectomy Versus Segmentectomy in Patients with Stage T (>2 cm and ≤3 cm) N0M0 Non-small Cell Lung Cancer: A Propensity Score Matching Study


 Background: Whether lung segmentectomy is a safe and effective surgical treatment in patients with early non-small cell lung cancer (NSCLC) remains controversial. We have therefore reviewed the clinicopathologic characteristics and survival outcomes of patients receiving a lobectomy vs. segmentectomy to treat early T (>2 cm and ≤3 cm) N0M0 NSCLC.Methods: We obtained data from the Surveillance, Epidemiology, and End Results (SEER) database for patients who underwent lobectomy or segmentectomy between 2004 and 2015. To reduce bias and imbalance between the treatment groups, propensity score matching (PSM) analysis was performed. We used Kaplan-Meier curves to estimate overall survival (OS) and lung cancer-speciﬁc survival (LCSS), performed univariate and multivariate Cox proportional hazards regression analyses to identify independent prognostic factors for OS and CSS, and applied the Cox proportional hazards model to create forest plots. Results: A total of 5783 patients from the SEER database were included. Of these, 5531 patients underwent lobectomy, and 252 patients underwent segmentectomy. Before matching, both univariate and multivariate Cox regression analyses showed that patients who underwent lobectomy had better OS (hazard ratio [HR]: 1.561; 95% confidence interval [CI] 1.292-1.885; P <0.001) and LCSS (HR: 1.551; 95% CI 1.198-2.009; P=0.001) than patients who underwent segmentectomy. However, survival differences between the groups were not significant; OS (P=0.160) and LCSS (P=0.097) after matching. Regression analyses revealed that age, sex, lymph node dissection, and grade were independent predictors of OS and LCSS (P <0.05).Conclusions: For patients with stage T (>2 cm and ≤3 cm) N0M0 non-small cell lung cancer, segmentectomy can achieve the same OS and LCSS compared with lobectomy. A large number of patients require further long-term follow-up analyses.

survival outcomes of patients with NSCLC after segmentectomy vs. lobectomy. We used a populationbased national registry, the Surveillance, Epidemiology, and End Results (SEER) database to analyze the clinical characteristics and prognoses of patients with T (> 2 cm and ≤ 3 cm) N0M0 NSCLC that received either segmentectomy or lobectomy. Based on the survival analysis results, we created forest plots using the Cox proportional hazards model.

Variables
This study was based on public data from the SEER database. The covariates included age, sex, race, marital status, laterality, primary site, histopathology, tumor grade, and TS. We classi ed age into four groups: ≤60, 61-70, 71-80, and ≥ 81. The laterality was de ned as left and right. The primary site was classi ed as upper, middle, and lower. The histopathology was de ned as adenocarcinoma (ADC), squamous cell carcinoma (SCC), and other tumor types (others). The grade was classi ed as welldifferentiated (I), moderately differentiated (II), and poorly differentiated or undifferentiated (III-IV). We followed the eighth edition of the American Joint Committee on Cancer (AJCC) lung cancer staging system, and updated TSs (> 2 cm and ≤ 3 cm) for all patients in all time periods. Overall survival (OS) was de ned as the time from diagnosis to death from any cause. Lung cancer-speci c survival (LCSS) was de ned as the time from diagnosis to lung cancer, excluding other causes of death.

Propensity score matching
To avoid bias between the treatment groups, we applied 1:1 propensity score matching (PSM) for age, sex, race, marital status, laterality, primary site, histopathology, lymph node dissection; tumor grade, SEER cause-speci c death classi cation, and vital status recode.

Statistical analysis
In this study, categorical variables are expressed as percentages, and continuous variables are expressed as means ± standard deviations (SDs). Variables were compared using the Student's t test, Chi-square test, and analysis of variance. We used the Kaplan-Meier method to generate survival curves and analyze differences between curves using the log-rank test. We used the Cox proportional hazards model to examine independent prognostic factors and calculate the HR and corresponding 95% con dence interval (CI). Speci c results are depicted as forest plots. Data were analyzed with Statistical Product and Service Solutions 25.0 software (SPSS, Inc., Chicago, IL, USA). P-values < 0.05 (two-sided) were considered statistically signi cant. Survival curves and the forest plot were drawn with GraphPad Prism software (Version 8.3.1).

Results
Patient and clinicopathologic characteristics.
A total of 5783 patients who underwent segmentectomy or lobectomy between 2004 and 2015 were selected from the SEER database. Of these, 5531 (95.64%) received lobectomies, and 252 (4.36%) received segmentectomies. The patient characteristics are shown in Table 1. The two groups were similar in regard to sex, marital status, race, laterality, primary tumor site, histopathology, and tumor grade. Age and lymph node dissection were signi cantly different between the groups (P < 0.001) ( Table. 1).  (Fig. 2a, b).
We used univariate analyses to identify possible prognostic factors for lobectomy or segmentectomy in treating patients with NSCLC. We found statistically signi cant (P < 0.05) correlations between OS and LCSS with surgical procedure, age, sex, race, marital status, histopathology, lymph node dissection, and tumor grade ( Table 2). Laterality and primary site were not found to be signi cant prognostic factors in our univariate analyses (P > 0.05). For OS, patients receiving lobectomies had several parameters that were signi cantly different compared with patients receiving segmentectomies, including an age > 60 years (P < 0.05), being female (P < 0.001), male (P = 0.007), white (P < 0.001) or other race (P < 0.001); being married (P < 0.001) or not married (P = 0.012); having a right lateral (P < 0.001), upper (P = 0.004), middle (P = 0.010), or lower (P < 0.001) tumor location; having adenocarcinoma (ADC; P < 0.001), or another tumor type (P = 0.003); having 1-3 lung lobes removed (P = 0.004) and no or unknown lungs removed (P = 0.004); and grade I-III/IV tumors (P < 0.05). For LCSS, the parameters showing signi cant differences between patients receiving lobectomies vs segmentectomies included ages ≥ 61 but ≤ 70 years (P = 0.025) and ages ≥ 81 years (P = 0.007); being female (P = 0.001), white (P = 0.001), or other race (P = 0.015); being married (P = 0.001); having a right lateral (P = 0.001) or lower tumor location (P = 0.001); having ADC (P < 0.001), and grade I tumors (P = 0.003).  All variables were well-balanced between the two groups after the 1:1 PSM. The propensity scores before matching were 0.041 ± 0.047 for lobectomy and 0.099 ± 0.103 for segmentectomy (P < 0.001). After matching, the propensity scores were 0.095 ± 0.105 for lobectomy and 0.099 ± 0.103 for segmentectomy (P = 0.678). Finally, a total of 504 patients (252 lobectomy and 252 segmentectomy) were included in the study. We found no signi cant differences in baseline characteristics between the matched groups except for tumor grade ( were not signi cantly different between the lobectomy and segmentectomy groups after matching (Fig. 2c, d). Univariate analyses to identify possible prognostic factors after matching found statistically signi cant correlations between OS and LCSS for age, sex, lymph node dissection, and tumor grade (P < 0.05) ( Table 5). The multivariate analyses also revealed that age, sex, lymph node dissection, and tumor grade were independent predictors of OS times, and age and tumor grade were independent predictors of LCSS times (P < 0.05) ( Table 6). The subsequent multivariable Cox regression model showed that older and male patients with higher tumor grades (all P < 0.05) were signi cant independent and negative prognostic factors for OS. However, only older patients and higher tumor grades (both P < 0.05) were signi cant independent and negative prognostic factors for LCSS. The forest plot shows that black patients with left-sided tumors had better OS (Fig. 3) than the other patients. Black patients that were not married, and had primary tumor sites in upper locations, and other tumor types on histopathology had better LCSS (Fig. 4) according to segmentectomy vs lobectomy (P < 0.05).

Discussion
Surgery is the rst choice for the treatment of NSCLC, and it is also the only method that can cure lung cancer. Radical lobectomy resection remains the preferred treatment for early NSCLC. With the popularization of low-dose computed tomography (LDCT) for lung cancer screening, the detection rate for patients with early lung cancer has improved [7], and segmentectomy is more widely used as a surgical treatment. Recent studies have shown that NSCLC patients that received segmentectomies for lesions < 2 cm had similar oncologic effects compared with those that received lobectomies [8,9,10,11]. Patients receiving segmentectomies also had more protected lung function [12,13]. The NCCN guidelines indicate that the standard recommendation for the treatment of early NSCLC patients is anatomic pulmonary resection. These guidelines further state that sublobar resection (i.e., segmentectomy or wedge resection) can be appropriate in select patients with the following indications if the technical conditions permit and do not increase the risk of surgery: (1) Poor pulmonary reserve or another major comorbidity that contraindicates lobectomy; (2) Peripheral nodules ≤ 2 cm with at least one of the following, pure ADC in situ (AIS) on histopathology, nodules with ≥ 50% ground-glass appearance on CT scans, and radiologic surveillance con rming a long doubling time (≥ 400 days) [14].
However, many debates regarding the most suitable operation method for the surgical treatment of patients with early-stage NSCLC are still present [15]. As a minimally invasive procedure, lobectomies do not retain as much normal lung tissue as possible under the premise of ensuring e cacy [16].
Segmentectomy requires more anatomic complexity and variation than lobectomy. This procedure also involves precise lesion positioning during surgery and the identi cation of lung boundaries [17,18,19].
Therefore, technical segmentectomy is a more di cult and demanding procedure than lobectomy. However, TS is an in uencing factor for early NSCLC prognoses [20]. The results of an ongoing Randomized Controlled Trial (RCT), such as JCOG0802, have not reach a conclusion [21]. However, Dai et al. [22] found that NSCLC patients with tumors < 1 cm or between 1 cm and 2 cm receiving segmentectomies had worse OS and LCSS than patients receiving lobectomies. Veluswamy et al. [23] showed that in patients with ADC tumors of less than 2 cm, the OS and LCSS after segmentectomy were similar to those of lobectomy. For SCCs, the OS and LCSS after segmentectomy were inferior to those of lobectomy. For the surgical process in our study, we found that before PSM, regardless of OS or CSS, lobectomy had a better outcome than segmentectomy to treat early T (> 2 cm and ≤ 3 cm) N0N0 NSCLC lung cancer. However, after PSM, and similar to recent studies [24], no signi cant differences in patient survival were seen between those receiving lobectomy vs. segmentectomy. Our research shows that for the T (> 2 cm and ≤ 3 cm) N0N0 stage, segmentectomy and lobectomy achieved the same clinical bene t and prognoses for OS and LCSS in NSCLC patients. However, further studies are needed looking at the solid component effects and pathologic tumor types regarding segmentectomies. In addition, age has been identi ed as a prognostic factor for OS and LCSS. With the cancer screening and the wide use of LDCT, more and more patients tend to be younger [25]. Recently, some researchers suggested that postoperative complications are similar between the two procedures [26]. Therefore, whether segmentectomy can be safely and effectively applied to early NSCLC, surgical treatments require further research. This study provides a clinical basis for further investigation by the JCOG0802/WJOG4607L, JCOG1211, JCOG0804/WJOG4507L clinical trials [12,27].
Compared with lobectomies, the advantages of segmentectomies are the preservation of lung function. In theory, segmentectomies remove less lung tissue; however, preservation depends on residual lung function after surgery. Therefore, the impact of the two procedures on lung function remains uncertain [28]. Harada et al. [29] described that segmentectomies better preserved lung function compared with lobectomies with less lung function losses after surgery. Gu et al. [30] believed that segmentectomies could help minimize forced vital capacity (FVC) loss, but not forced expiratory volume in 1 minute (FEV1) or the diffusion capacity of the lungs (DLCO). For a single lung segment resected after segmentectomy, the loss of lung function is twice that after lobectomy. For multiple pulmonary nodules, segmentectomy can potentially reduce the loss of lung function even further. Waller et al. [31] found that for multiple primary lung cancer types, segmentectomy is recommended, and lung resection should be avoided; segmentectomy can also allow for the ability to perform future lobectomies. Therefore, segmentectomy compared with lobectomy could have more advantages for the retention of lung function in the shortterm. The advantages of long-term lung function retention after segmentectomy needs further exploration. In this study, we were unable to compare the differences in lung function concerning longterm survival after lobectomy vs segmentectomy because of database limitations.
Because our data were collected from the SEER database, some biases and errors existed even though we used the PSM analysis. Several limitations to this study included (1) a lack of detailed information regarding Pre-, peri-, and postoperative patient details and outcomes; (2) none or unknown variables (such as tumor component) were grouped into one group, which could lead to data biases; (3) the 8th AJCC staging system was used, which had some inconsistencies in the data transformation process compared with earlier versions; and (4) the SEER database lacked information on imaging, smoking history, tumor markers, as well as several other parameters; and therefore, our study did not address the impact of these factors on patient prognoses after segmentectomy or lobectomy, even though they could have played signi cant roles.

Conclusions
For patients with stage T (> 2 cm and ≤ 3 cm) N0M0 NSCLC, segmentectomy can achieve the same OS and LCSS compared with lobectomy. Theoretically, the advantage of segmentectomy vs lobectomy is that segmentectomies can reduce postoperative lung function losses, complication rates, and perioperative mortalities. The disadvantage of segmentectomy is that an insu cient scope of the tissue resections and lymph node dissections increases postoperative recurrence rates and tumor-related mortalities. Additional long-term survival and outcome analyses should be conducted with a larger number of patients. Declarations