Segmental resection is associated with decreased survival in patients with stage IA non-small cell lung cancer with a tumor size of 21–30 mm

Introduction

In 2016, the International Association for the Study of Lung Cancer (IASLC) Staging Committee published the eighth edition of the Tumor, Node, and Metastasis (TNM) classification for lung cancer. Since its introduction in January 2017, it has been widely used in clinical practice (1). To allow accurate diagnosis of early-stage lung cancer, stage IA (≤30 mm) is divided into three subsets: stage IA1 (≤10 mm, T1aN0M0), stage IA2 (>10–20 mm, T1bN0M0), and stage IA3 (>20–30 mm, T1cN0M0) (1). These new cutoff points may also serve a crucial role in determining the extent of surgical resection (2-4).

A randomized controlled trial (RCT) conducted by the Lung Cancer Study Group in 1995 compared lobectomy with intentional sublobar resection (i.e., anatomical segmental resection and non-anatomical wedge resection) for patients with peripheral T1N0 (≤30 mm) non-small cell lung cancer (NSCLC). This study reported that, compared with lobectomy, intentional sublobar resection did not improve postoperative morbidity, mortality, or pulmonary function, but increased the risks of locoregional recurrence and cancer-specific death (5). Therefore, lobectomy has been the standard surgical procedure for stage I (≤30 mm) NSCLC for the past 25 years (6). However, numerous retrospective investigations have reported the survival outcomes of segmental resection and lobectomy to be similar in patients with peripheral small-sized NSCLC (≤20 mm); moreover, patients who underwent segmental resection appeared a higher perioperative quality of life (QoL) than those who underwent lobectomy for early-stage NSCLC (2,4). In addition, two ongoing multicenter phase III RCTs [Cancer and Leukemia Group B (GBCALGB-140503) and the Japan Clinical Oncology Group/West Japan Oncology Group (JCOG0802/WJOG4607L)] comparing segmental resection with lobectomy for clinical T1N0M0 (≤20 mm) NSCLC are expected to provide high-level evidence for thoracic surgeons to assess whether intentional segmental resection could be the new standard of care for stage T1a-b NSCLC without lymph node involvement or distant metastasis (7). Moreover, the development of new technologies, such as fluorescence, three-dimensional reconstruction/printed models, may help clinicians overcome technical obstacles (anatomical variations, intersegmental plan, margins etc.), allowing them to perform safe segmentectomies and simplify the surgical procedure (8).

Notably, stage IA NSCLC with a tumor size of >20–30 mm has not been included in the inclusion criteria of the RCTs mentioned above. In addition, few retrospective studies have assessed the potential utility of segmental resection for this specific population (3,9). In a comparison of propensity-score matched cohorts (37 pairs), Kamigaichi et al. observed no significant differences in recurrence-free survival (RFS) or overall survival (OS) for solid-dominant clinical stage IA lung tumors measuring 21–30 mm when lobectomy and segmental resection were compared (3). On the contrary, in a Surveillance, Epidemiology, and End Results (SEER) data analysis of patients with pathological stage I NSCLC, the subgroup analysis for tumors measuring 21–30 mm as defined under the 7th edition staging system (T1b) demonstrated that lobectomy was associated with significantly better OS (10). Therefore, the optimal the extent of surgical resection for stage T1cN0M0 (>20–30 mm) NSCLC, as defined by the 8th edition staging proposal, is still unclear.

In this study, we used data from the SEER database to evaluate whether lobectomy confers a survival advantage over anatomic segmental resection in patients with pathological T1cN0M0 (21–30 mm) NSCLC. And we present the following article in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting checklist (available at http://dx.doi.org/10.21037/tlcr-20-1217).

Methods

Patient selection

Data of patients who underwent segmental resection (surgery of primary site code: 22) and lobectomy (surgery of primary site codes: 30 and 33) for primary lung cancer between 1998 and 2016 were obtained from the SEER 18 Regs Custom Data (with additional treatment fields). Patients aged <18 years, with additional synchronous malignancies, diagnosed with pulmonary neuroendocrine tumors or melanoma (i.e., carcinoid, large cell neuroendocrine tumor, small cell lung cancer), who received neoadjuvant or intraoperative therapy, or who had incomplete clinicopathological or follow-up information, were excluded. In addition, since this study focused on patients with stage IA NSCLC with a tumor size of >20–30 mm,patients with nodal involvement, distant metastases, or a tumor size ≤20 mm or >30 mm were also excluded from the final analysis. Figure 1 shows the detailed screening process.

Figure 1 Screening process of the study population. All patients were restaged according to the eighth edition of the TNM staging system.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This retrospective study based on the SEER database was approved by the Surveillance Research Program in National Cancer Institute’s Division of Cancer Control and Population Sciences (DCCPS) (No. 12101-Nov2018), and was also approved by the institutional review at the Sun Yat-sen University Cancer Center (No. B2018-011). Because of the retrospective nature of the research, the requirement for informed consent was waived.

Statistical analysis

We used the X-tile software (Copyright Yale University 2003) to determine the optimal cutoff points. The continuous variables, including age, tumor size, and the number of dissected lymph nodes, were all transformed into categorical variables. The chi-square or Fisher’s exact test were used to compare frequencies and percentages between different subgroups.

The observational outcomes of the present study were cancer-specific survival (CSS) and OS, which were measured in months. Patients who were still alive on November 31, 2019, were recorded as right-censored cases in the OS analyses. In the CSS analyses, right-censored cases also included patients who died of causes not related to lung cancer. Operative mortality was defined as any death within 30 days after surgery. In univariate survival analyses, the Kaplan-Meier method was applied, and the survival curves were plotted with the GraphPad Prism software (version 7, http://www.graphpad.com/) and compared using the log-rank test. Subsequently, the potential prognostic factors (P<0.05) for CSS and OS that were identified in the univariate analyses were included in the Cox proportional hazards models. Forest plots were drawn using the “forestplot” package in R software (version 3.5.3, https://www.r-project.org/).

All statistical analyses were conducted with SPSS software (version 24, IBM, NY, USA; https://www.ibm.com/), with a two-sided P value <0.05 set as the threshold for statistical significance.

Results

Patient characteristics

A total of 9,580 patients with stage IA NSCLC with a tumor size of 21–30 mm who met the inclusion criteria were identified from the SEER database. The clinicopathological variables of the lobectomy group (9,180, 95.8%) and the segmental resection group (400, 4.2%) were compared (Table 1). Segmental resections were more likely to be performed in patients with older age (≥60: 86.5%), smaller tumor size (21–25 mm: 64.8%), or left-sided tumors (48.8%); moreover, segmental resections became more popular in the later part of the study period (2008–2016: 52.5%). More lymph nodes were removed in the lobectomy group than in the segmental resection group (median: 8.8 vs. 4.4, P<0.001). A higher proportion of patients in the segmental resection group received radiation after surgery (3.5% vs. 1.6%, P=0.004). The operative mortality rates between the two groups were not significantly different (1.2% vs. 1.0%, P=0.707).

Table 1 Baseline characteristics of patients with pathological stage IA (21–30 mm) non-small cell lung cancer following lobectomy and segmental resection
Full table

Survival analysis

During follow-up (median: 48.0 months; range, 0–227 months), 2,075 patients died from lung cancer-specific causes, and 2,380 patients died due to other causes. The 5-year CSS and OS rates for stage IA (21–30 mm) patients were 84.1% and 63.6%, respectively. In univariate survival analysis (Table 2), lobectomy was associated with significant survival benefit in both CSS and OS (median CSS, 165 vs. 119 months, P<0.001; median OS, 94 vs. 61 months, P<0.001). Univariate analysis also revealed that age (Figure 2A,B), year of diagnosis, sex, race, tumor size (Figure 2C,D), histology, grade, number of dissected lymph nodes (Figure 2E,F), insurance, and marital status were significant prognostic factors for CSS and OS. Meanwhile, postoperative radiation and chemotherapy were associated with worse OS (all P<0.001), but were not associated with worse CSS.

Table 2 Univariate survival analyses for cancer-specific survival and overall survival in patients with pathological stage IA (21–30 mm) non-small cell lung cancer
Full table

Figure 2 Survival analysis for patients with pathological stage IA (21–30 mm) NSCLC: CSS (A) and OS (B) comparison between groups according to age (<60/60–74/≥75 years); CSS (C) and OS (D) comparison between groups according to tumor size (21–25 mm/26–30 mm); CSS (E) and OS (F) comparison between groups according to the number of lymph nodes dissected (<3/≥3); and CSS (G) and OS (H) comparison between the segmental resection group and lobectomy group. CSS, cancer-specific survival; OS, overall survival; No., number.

In the Cox proportional hazards analysis, lobectomy was consistently associated with significantly improved survival (Figure 2G,H; Table 3). Additionally, age <60 years, year of diagnosis after 2002, female sex, tumor size of 21–25 mm (but not for CSS), adenocarcinoma, well/moderately differentiated cancer (but not for CSS), >3 lymph nodes dissected, no postoperative radiation or chemotherapy (but not for CSS), any insurance (but not for CSS), and marriage were still significantly associated with longer survival.

Table 3 Cox proportional hazards models for cancer-specific survival and overall survival in patients with pathological stage IA (21–30 mm) non-small cell lung cancer
Full table

Subgroup analysis

Forest plot analyses for age, year of diagnosis, sex, race, tumor size, histology, lymph node dissection, radiation, chemotherapy, insurance, and marital status showed that lobectomy for stage IA (21–30 mm) NSCLC was associated with improved CSS and OS in most subgroups (Figure 3). Notably, in the subgroup of patients aged <60 years or of the black race, the segmental resection group demonstrated comparable CSS [hazard ratio (HR), 0.974, 95% confidence interval (CI): 0.401–2.366, P=0.954; and HR, 1.014, 95% CI: 0.414–2.480, P=0.976; respectively] and OS (HR, 1.141, 95% CI: 0.714–1.824, P=0.579; and HR, 1.053, 95% CI: 0.616–1.798, P=0.850, respectively) to the lobectomy group.

Figure 3 Subgroup analyses by age, year of diagnosis, sex, race, tumor size, histology, grade, the number of lymph nodes dissected, radiation, chemotherapy, insurance, and marital status for patients with pathological stage IA (21–30 mm) NSCLC. CSS, cancer-specific survival; OS, overall survival; CI, confidence interval; NR, not reached; ADC, adenocarcinoma; SCC, squamous cell carcinoma.

Discussion

This population-based study indicated that segmental resection was associated with decreased survival for patients with pathological stage IA NSCLC with a tumor size of 21–30 mm. The potential survival benefits offered by lobectomy over segmental resection were confirmed in subgroup analyses of sex, histology, grade, tumor size, and the number of dissected lymph nodes. To our knowledge, this is the first study to compare the oncological outcomes of lobectomy and segmental resection for NSCLC patients staged as pT1cN0M0 according to the 8th edition of the TNM Classification for Lung Cancer.

The extent of lung resection for patients with resectable stage IA NSCLC is still a debated issue. Compared with non-anatomical wedge resection, anatomical segmental resection is more likely to achieve safe surgical margins and to facilitate the evaluation of subsegmental and hilar lymph nodes (11,12). Therefore, a number of studies have focused on comparing oncological outcomes between lobectomy and segmental resection but have excluded wedge resections for stage IA NSCLC (2,3,9). A number of recent studies, which include retrospective propensity-score matched analyses and the SEER database analyses, have demonstrated that patients who undergo anatomical segmental resection may achieve outcomes comparable to those of patients who undergo lobectomy for stage IA NSCLC of ≤20 mm (2). However, there has been little research that has assessed the potential of segmental resection for stage IA NSCLC with tumors measuring >20–30 mm, perhaps because patients with cT1c (>20–30 mm) NSCLC have been reported to have a worse prognosis and higher risk of lymph node metastasis than those with cT1a-1b (≤20 mm) NSCLC (3,9,13,14). Therefore, we hypothesized that a larger extent of lung resection (lobectomy) may be required to obtain the sufficient margins and to examine more lymph nodes in this specific population (1,15).

In 2011, Whitson et al. used the SEER database to compare survival after segmental resection versus lobectomy in patients diagnosed with pathological stage I adenocarcinoma (ADC) or squamous cell carcinoma (SCC) between 1998 and 2007 (10). After stratifying the patients by tumor size, they found that lobectomy was associated with more favorable CSS and OS for tumors measuring 21–30 mm, which is corroborated by the results of our study (10). A more recent National Cancer Database (NCDB) study that reviewed 143,040 patients with cT1-3N0M0 NSCLC concluded that the survival advantage offered by lobectomy over segmental resection in patients with ADC >10 mm and SCC >15 mm (both categories encompass the size of interest of 21–30 mm in our study) could be confirmed in multivariate Cox regression models and subgroup analyses (16). However, in a larger single-institution retrospective cohort study of 145 cases, Carr et al. reported that there were no differences in mortality, recurrence, or CSS between the segmental resection group and the lobectomy group for confirmed T1bN0M0 (21–30 mm) NSCLC, staged according to the 7th edition of the TNM staging system (17). More recently, Chan et al. observed no differences in OS or RFS based on a comparison of segmental resection and lobectomy in 90 propensity score-matched pairs with clinical T1cN0M0 NSCLC (9). Subsequently, a Japanese single-center retrospective study also showed that the 33 matched pairs with radiologically solid-dominant clinical T1cN0M0 lung tumors who underwent lobectomy and segmental resection, had comparable OS and RFS (3). In spite of the evidence mentioned above, considerable controversy still surrounds the optimal extent of lung resection for clinical/pathological T1cN0M0 lung cancer. This may be due to the varied oncological outcomes from these small sample-sized, retrospective, single-center and population-based studies, or to the differences in the population choices and pathologies studied. Given this, prospective RCTs that consider the consolidation-to-tumor ratio should further assess the oncological performance of segmental resection for clinical stage IA lung tumors measuring 21–30 mm. The present study thus represents a first, if not modest step, in this direction.

An additional advantage of lobectomy, compared to segmental resection, is that it allows the interlobar/hilar lymph nodes (N1) and mediastinal lymph nodes (N2) to be fully assessed to obtain more accurate pathological staging and possibly favorable survival (9,11,17). In the present study, for patients with pathological stage IA (21–30 mm) NSCLC, a survival benefit was observed when the number of dissected lymph nodes was ≥3, and the lobectomy group had consistent survival advantages compared to the segmental resection group when the patients were stratified by the number of dissected lymph nodes (<3 vs. ≥3). These findings support those of another SEER database study that compared segmental resection and lobectomy in patients with stage I (≤30 mm) NSCLC divided into three subgroups according to the analogous number of lymph nodes removed (0/1–3/>3) (11). Moreover, many studies have reported that >3 lymph node stations or 10 dissected lymph nodes in clinical node-negative early-stage NSCLC not only significantly increases pathological nodal upstaging, but may also improve the long-term survival outcomes, regardless of whether segmental resection or lobectomy is used as treatment (18-20). Therefore, in consideration of the fact that a tumor size of 21–30 mm is a strong predictor of lymph node metastasis in cN0 NSCLC (14), a minimum of 3 lymph node stations or 10 lymph nodes should be dissected for this specific population during anatomical lung resection.

Additionally, we found that the proportion of patients who underwent radiation therapy after surgery in the segmental resection group was significantly higher than that in the lobectomy group (3.5% vs. 1.6%, P=0.004). Moreover, multivariate Cox regression analysis indicated that radiation after surgery for pathological stage IA (21–30 mm) NSCLC was associated with a worse OS, and the results from Qu et al.’s study support these findings (11). Although the SEER database contains no detailed information on the indication for postoperative radiotherapy in early-stage NSCLC, we hypothesized that radiation oncologist might have recommended this multimodal therapy for cases with positive surgical margins, pathological high-risk factors, a lack of lymph node assessment, or local recurrence (6). Consequently, the present study provides further support that maintaining a safe surgical margin and implementing extended lymph node removal are important oncological principles in surgery for node-negative early-stage NSCLC.

This population-based study had several limitations, and its results should be interpreted with caution. First, this retrospective study cohort is abstracted from a national database and the years of diagnosis spans 19 years; this inevitably caused selection bias and attrition bias. Second, many studies have reported a high rate of local recurrence in patients who undergo segmental resection rather than lobectomy, which may result in poorer survival. However, information on disease recurrence status and RFS are not recorded in the SEER database. Third, there was a lack of information on comorbidities, physical status, QoL, and pulmonary function, which made it challenging to establish whether patients treated with segmental resection could also tolerate lobectomy; thus, selection bias might have affected the survival analyses. Fourth, several recent investigations have emphasized the value of the consolidation-to-tumor ratio (≤0.25 or ≤0.5) and pathological subtypes (micropapillary, solid, lepidic etc.) as important factors in choosing the surgical procedure. The lack of radiological and pathological data on the SEER database forced us to extract cases only on the basis of a tumor size measuring 21–30 mm, and thus enrolling some part-solid nodules and high-risk subtypes was inevitable. The current results should be further verified through RCTs that factor in the consolidation-to-tumor ratio and pathological examination. Finally, the large range of subgroup sizes rendered any direct comparison between them difficult. Even the results in our study that reached statistical significance cannot preclude the possibility of group size imbalance which should also be considered when interpreting and drawing conclusions from these results.

In conclusion, as indicated by the relevant literature and guidelines, anatomical lobectomy with the extended removal of lymph nodes should be the standard of care for patients with resectable clinical/pathological T1cN0M0 NSCLC.

Acknowledgments

We thank Dr. A. Gillibert (Rouen University Hospital, Normandy, France) for reviewing the methodology and statistical analyses.

Funding: This study was funded by the National Key Research and Development Plan (No. 2016YFC0905400) of the Ministry of Science and Technology of the People’s Republic of China.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/tlcr-20-1217

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-1217). RHP reports that he received speaker fee from Medtronic. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This retrospective study based on the SEER database was approved by the Surveillance Research Program in National Cancer Institute’s Division of Cancer Control and Population Sciences (DCCPS) (No. 12101-Nov2018), and was also approved by the institutional review at the Sun Yat-sen University Cancer Center (No. B2018-011). Because of the retrospective nature of the research, the requirement for informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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