Similar overall survivals of wedge resection and segmentectomy in stage IA1 non-small cell lung cancer: a population-based study using propensity score matching and coarsened exact matching

Introduction

Lung cancer is the leading cause of death worldwide (1). Since 1960 lobectomy has become the gold standard of treatment for early-stage lung cancer, and the debate on the surgical resection range of lung cancer has never stopped (2). With the development of high-resolution computed tomography (HRCT) (3) and video-assisted thoracoscopic surgery (VATS), more small lesions can now be detected, thus sub-lobar resection (SLR) becomes the first choice in the early stage.

SLR for lung cancer has many advantages such as preserving pulmonary function (4) and providing the chance for further resection if a second primary lung cancer develops (5). However, controversy continues over the application of wedge resection and segmentectomy. Wedge resection represents a non-anatomical procedure, but it has a significantly shorter operation time and much less blood loss in patients than segmentectomy (6). Some studies reported that wedge resection was proven to be equivalent to segmentectomy in terms of survival (7,8). However, other studies observed higher recurrence in wedge resection and suggested that wedge resection was only suitable for compromised patients with an impaired cardiopulmonary reserve (4,9). Moreover, Professor Benfield (10) mentioned that the primary determinant of long-term survival after surgical resection of T1aN0M0 lung cancers was related to the biology of the malignant process rather than the excision extension, which leads to speculation about whether non-anatomical wedge resection could replace anatomic segmentectomy without affecting long-term survival if the indication for the trial had been limited to a stage of T1aN0M0.

To investigate the acceptability of wedge resection as an alternative to segmentectomy in patients with tumor size less than 1 cm, we performed a retrospective study of patients with pT1aN0M0 non-small cell lung cancer (NSCLC) from the Surveillance, Epidemiology, and End Results (SEER) database. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1211/rc).

Methods

Ethics and data source

This is a population study that involves no identifiable information for individuals throughout the analyses. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Institutional Review Boards at Nanchang university and Sun Yat-sen University gave an exemption for ethical review because the study did not involve human participants. We performed a retrospective analysis using the de-identified data from SEER database. We obtained access to the SEER database in November 2021 and conducted a survival analysis of the patients included in the SEER database from 18 national registries with custom data and additional treatment fields.

Population

A total of 742 patients were finally involved in this study, including 130 patients in the segmentectomy group and 612 patients in the wedge resection group. Patients’ inclusion criteria in this study were: (I) diagnosis of pT1aN0M0 NSCLC according to the American Joint Committee on Cancer (AJCC) 8^th tumor node metastasis (TNM) classification (11); (II) those who underwent segmentectomy or those who underwent wedge resection; (III) the patients with the size of tumor less than 1 cm; (IV) minimum follow-up of 5 years. Exclusion criteria were: (I) history of prior synchronous or metachronous malignancies; (II) patients who underwent radiation chemotherapy or other anti-tumor treatment; (III) mortality within 30 days. To enable independent replication of our analyses by others, Table S1 details patient selection criteria with variable names used and their effect on sample size.

Statistical analysis

All of the characteristics of patients were converted to the categorical variables and compared by the chi-squared test. Associations between treatment modality and patient demographic, clinical, and tumor characteristics were assessed by using the Pearson test for the qualitative data. The primary endpoint outcome of this study was overall survival (OS), patient death was considered the endpoint of the study, OS was measured from the date of diagnosis to the date of loss of follow-up or death as a result of any cause and was evaluated by Kaplan-Meier method. Log-rank test was used to compare survival between the two groups. To evaluate the variables’ association with the prognosis, the univariable Cox regression analysis was performed and hazard ratio (HR) with 95% confidence interval (CI) were assessed. The multivariable Cox analysis was used to evaluate the risk factors of surgery for the other factors with P value <0.05 in the univariable Cox analysis. The P value less than 0.02 was deemed as a statistically significant difference. All statistical analyses described in the study were performed with R software (TIBCO, Silicon Valley, CA, USA) (version 4.1.1).

Matching method

Three matching methods including propensity score matching (PSM), coarsened exact matching (CEM), and inverse probability of treatment weighting using the propensity score (IPTW) were introduced to control and minimize the potential biases such as the difference between baseline characteristics of two groups and the confounding impacts on survival analysis. PSM can match the two groups based on the propensity score of each case to help strengthen causal arguments in observational studies by reducing selection bias. IPTW, as a propensity score weighting method, uses the principle of standardization method to assign a corresponding weight to each observation object through the propensity score value, thus the propensity score distribution in each group is consistent.

We introduced CEM to avoid the data loss of PSM and IPTW analysis. This method could improve the balance for each covariate without influencing the others to achieve the maximum balance, thus we can make full use of all data (12). Population after each matching process was reanalyzed as it was done before matching. CEM introduces a parameter, multivariate imbalance measure (L1), to measure the degree of imbalance in covariates between the raw data and matching data. The value of L1 ranges from 0 to 1, with 0 indicating a complete equilibrium and 1 indicating a complete imbalance.

Results

Baseline characteristics

A total of 742 patients with pT1aN0M0 were enrolled in our study with 612 patients undergoing wedge resection and 130 patients undergoing segmentectomy (Table 1). There was no 30-day preoperative mortality in the entire cohort. Before matching, the variables of age (P=0.50), sex (P=0.60), race (P=0.80), marriage (P=0.60), site (P=0.30), laterality (P=0.045), and histology (P=0.20) showed no significant difference while grade (P=0.01) showed a significant difference between wedge resection and segmentectomy. After matching, wedge resection and segmentectomy pairs were well-matched without significant differences in all clinical and tumor factors (Table 2). Histogram showed the distribution balance for each factor before and after PSM (Figure S1). Before CEM, the overall imbalance degree was L1=0.859, which indicates a high imbalance. After matching, the overall imbalance degree was L1=0.242. In addition, it can be seen from the results of the P value that there was no statistical difference between the two groups in each matching variable (all the P>0.02).

Survival analysis

Before matching, the 3- and 5-year OS rates in the wedge resection group were 82.4% (95% CI: 79.4–85.5%) and 69.2% (95% CI: 65.4–73.2%); the 3- and 5-year OS rates in the segmentectomy group were 86.8% (95% CI: 81.1–92.8%) and 79.5% (95% CI: 72.6–87.1%), which was similar to the wedge resection (log-rank test, P=0.03; Figure 1). Among propensity score-marched, no difference in OS (log-rank test, P=0.08) was identified between patients who underwent wedge resection (3-year OS 84.5%, 95% CI: 81.0–88.2%; 5-year OS 72.0%, 95% CI: 67.5–76.9%) compared with the segmentectomy (3-year OS 86.8%, 95% CI: 81.1–92.8%; 5-year OS 79.5%, 95% CI: 72.6–87.1%). The Kaplan-Meier curves are shown in Figure 2 and IPTW analysis revealed similar results (Figure 3). The result of CEM analysis was similar to that of PSM. The 3- and 5-year OS rates in the wedge resection group were 81.9% (95% CI: 72.2–92.8%) and 70.5% (95% CI: 69.3–83.8%), the 3- and 5-year OS rates in the segmentectomy group were 87.1% (95% CI: 79.1–95.9%) and 77.9% (95% CI: 67.8–89.4%) (Figure 4).

Figure 1 The Kaplan-Meier curve analysis of OS in the W group and S group before matching. The median survival times for the W group and S group are approximately 122 and 147 months, respectively. W, wedge resection; S, segmentectomy; OS, overall survival.

Figure 2 The Kaplan-Meier curve analysis of OS in the W group and S group by PSM. The median survival times for the W group and S group are approximately 122 and 147 months, respectively. W, wedge resection; S, segmentectomy; OS, overall survival; PSM, propensity score matching.

Figure 3 The Kaplan-Meier curve analysis of OS in the W group and S group by IPTW. The median survival times for the W group and S group are approximately 122 and 147 months, respectively. W, wedge resection; S, segmentectomy; OS, overall survival; IPTW, inverse probability of treatment weighting using the propensity score.

Figure 4 The Kaplan-Meier curve analysis of OS in the W group and S group by CEM. W, wedge resection; S, segmentectomy; OS, overall survival; CEM, coarsened exact matching.

Cox analysis

In univariate analysis after PSM (Table 3), age (P<0.001), sex (P<0.001), race (P=0.03), histology (P<0.001), and grade (P<0.001) had statistical differences, while surgery (P=0.08), marriage (P=0.80), laterality (P=0.80), and site (P=0.056) showed no statistical differences. In multivariate analyses of OS after PSM (Table 3), age (P<0.001), sex (P<0.001), histology (P<0.001), and grade (P=0.004) were significant independent prognostic factors for OS, whereas surgery (P=0.04) and race (P=0.03) were not. The results were confirmed in the CEM analysis.

Discussion

Although the publication of the survival results of JCOG0802 (13) fills the gap in large randomized controlled clinical studies of SLR and establishes the role of segmentectomy in the treatment of peripheral NSCLC smaller than 2 cm, the prospective randomized controlled trials comparing the two procedures (wedge resection and segmentectomy) for SLR are still lacking. The most appropriate extent of surgical resection needed to properly manage potentially curable carcinoma of the small lesion lung cancer is still under debate. This study included 742 patients staged as pT1aN0M0 from the SEER database and found that wedge resection and anatomical segmentectomy may be oncologically equivalent methods for SLR in PSM analysis (log-rank test, P=0.08), IPTW analysis (log-rank test, P=0.09) and CEM analysis (log-rank test, P=0.03).

Tsutani et al. (6) obtained a similar result, but they did not consider the imbalance baseline characteristics including the P value of location, number of resected lymph nodes, and other factors that were less than 0.001. In this study, we used three different analysis methods to avoid confounding effects. Since there is no prospective randomized controlled trial comparing the two procedures, PSM, IPTW, and CEM done in this research may provide strong evidence, which could help diminish the potential imbalances associated with retrospective, observational studies (14).

In contrast, some researchers deemed that the OS of segmentectomy was superior to that of wedge resection (15-17). Sienel et al. (16) reported less locoregional recurrence (P=0.001) and better cancer-related survival (P=0.01) following segmentectomies compared to wedge resections. However, Professor Altorki (18) commented that these results should again be interpreted with caution since the median pathological tumor size (3 cm) was larger than that in the current report (less than 2 cm). In addition, the cutoff of 3 cm for wedge resection may be arbitrary since some investigators reported that T1N0M0 patients with a tumor less than 1.5 or 2 cm had better survival than those with a tumor of 2 to 3 cm (5,19-21). A meta-analysis published in 2016 showed that for patients with stage I NSCLC, segmentectomy resulted in higher survival rates than wedge resection, whereas the outcomes of wedge resection were comparable to those of segmentectomy for patients with tumor size <2 cm (22). This is consistent with our results. We restricted the indication of tumor size smaller than 1 cm and found that the survival of wedge resection was not inferior to that of segmentectomy.

Similarly, the first randomized controlled trial (23) which compared lobectomy with SLR of the Lung Cancer Study Group (LCSG) also demonstrated that the wedge resection had a threefold increase in locoregional recurrence rate. Patel and colleagues (24) reviewed the outcomes of the LCSG trial in which patients with SLR had worse cardiopulmonary function. Most of the previous studies also deemed wedge resection as a viable “compromise” surgical treatment which should be applied for patients with impaired cardiopulmonary function, advanced age, or other significant comorbid diseases (25-27), but our study extended the indication to general patients. Even in low-risk patients, wedge resection should be considered as an alternative procedure.

This study casts light on the therapeutic role of wedge resection in surgery strategies. Due to the promotion of low-dose computer tomography and accurate lung cancer staging, more and more small nodules can be diagnosed during physical examinations (28,29). Whole lobectomy or anatomic segmentectomy in these patients can result in a higher frequency of operative morbidity and poorer quality of postoperative life (30). Surgeons must realize that pulmonary tissue is one of the least expendables, as compared to liver or muscle tissue (9). It is unnecessarily required to extirpate the entire lobe for tiny peripheral lesions (31). Tissue loss should be prevented to avoid causing either severe pulmonary disability or death. Our study found that for NSCLC smaller than 1 cm, wedge resection which preserved more normal tissue had the same survival rate as segmentectomy.

Several limitations regarding our study should be noted. First, this was a retrospective study, the differences between the two groups and the selection bias were inevitable. Although this paper used a variety of statistical methods to analyze the results, the propensity scoring techniques could only match the known possible confounding factors, and other methods are needed to deal with the unknown confounding factors. Therefore, considering the limitation of the influence of the unknown confounding factors, a well-designed randomized clinical trial is needed to confirm the benefit of wedge resection in the future. Second, using OS time as the endpoint other than recurrence rates or cancer-specific survival, the analysis may lose control for other causes of death. Furthermore, the SEER database did not have data such as the surgical margin status which must be intraoperatively assessed by frozen section examination (32), patient’s comorbidities, consolidation-to-tumor ratio (CTR) status, lymph node dissection extent, post-relapse treatment and biomarker information, postoperative pulmonary function data, and so on. Further studies are necessary to explore the extra impact of these variables on survival. However, given the large sample size of the SEER database, this study could still provide useful guidance.

Conclusions

Wedge resection could be an alternative procedure for patients with pT1aN0M0 NSCLC.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1211/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1211/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1211/coif). The 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). Institutional Review Boards at Nanchang university and Sun Yat-sen University gave an exemption for ethical review because the study did not involve human participants.

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/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Suzuki K, Watanabe SI, Wakabayashi M, et al. A single-arm study of sublobar resection for ground-glass opacity dominant peripheral lung cancer. J Thorac Cardiovasc Surg 2022;163:289-301.e2. [Crossref] [PubMed]
3. Patz EF Jr, Goodman PC, Bepler G. Screening for lung cancer. N Engl J Med 2000;343:1627-33. [Crossref] [PubMed]
4. Keenan RJ, Landreneau RJ, Maley RH Jr, et al. Segmental resection spares pulmonary function in patients with stage I lung cancer. Ann Thorac Surg 2004;78:228-33; discussion 228-33. [Crossref] [PubMed]
5. Tasoudis P, Loufopoulos G, Manaki V, et al. Long term outcomes after lobar versus sublobar resection for patients with Non-Small cell lung Cancer: Systematic review and individual patient data Meta-Analysis. Lung Cancer 2024;195:107929. [Crossref] [PubMed]
6. Tsutani Y, Kagimoto A, Handa Y, et al. Wedge resection versus segmentectomy in patients with stage I non-small-cell lung cancer unfit for lobectomy. Jpn J Clin Oncol 2019;49:1134-42. [Crossref] [PubMed]
7. Mery CM, Pappas AN, Bueno R, et al. Similar long-term survival of elderly patients with non-small cell lung cancer treated with lobectomy or wedge resection within the surveillance, epidemiology, and end results database. Chest 2005;128:237-45. [Crossref] [PubMed]
8. Wisnivesky JP, Henschke CI, Swanson S, et al. Limited resection for the treatment of patients with stage IA lung cancer. Ann Surg 2010;251:550-4. [Crossref] [PubMed]
9. Jensik RJ, Faber LP, Milloy FJ, et al. Segmental resection for lung cancer. A fifteen-year experience. J Thorac Cardiovasc Surg 1973;66:563-72.
10. Benfield JR. The lung cancer dilemma. Chest 1991;100:510-1. [Crossref] [PubMed]
11. Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017;67:93-9.
12. Iacus SM, King G, Porro G, et al. Causal Inference Without Balance Checking: Coarsened Exact Matching. Political Analysis 2012;20:1-24.
13. Saji H, Okada M, Tsuboi M, et al. Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. Lancet 2022;399:1607-17. [Crossref] [PubMed]
14. Johnson SR, Tomlinson GA, Hawker GA, et al. Propensity Score Methods for Bias Reduction in Observational Studies of Treatment Effect. Rheum Dis Clin North Am 2018;44:203-13. [Crossref] [PubMed]
15. Smith CB, Swanson SJ, Mhango G, et al. Survival after segmentectomy and wedge resection in stage I non-small-cell lung cancer. J Thorac Oncol 2013;8:73-8. [Crossref] [PubMed]
16. Sienel W, Dango S, Kirschbaum A, et al. Sublobar resections in stage IA non-small cell lung cancer: segmentectomies result in significantly better cancer-related survival than wedge resections. Eur J Cardiothorac Surg 2008;33:728-34. [Crossref] [PubMed]
17. El-Sherif A, Fernando HC, Santos R, et al. Margin and local recurrence after sublobar resection of non-small cell lung cancer. Ann Surg Oncol 2007;14:2400-5. [Crossref] [PubMed]
18. Altorki NK, Kamel MK, Narula N, et al. Anatomical Segmentectomy and Wedge Resections Are Associated with Comparable Outcomes for Patients with Small cT1N0 Non-Small Cell Lung Cancer. J Thorac Oncol 2016;11:1984-92. [Crossref] [PubMed]
19. Godfrey CM, Marmor HN, Lambright ES, et al. Minimally Invasive and Sublobar Resections for Lung Cancer. Surg Clin North Am 2022;102:483-92. [Crossref] [PubMed]
20. Ji Y, Bai G, Qiu B, et al. The surgical management of early-stage lung adenocarcinoma: is wedge resection effective? J Thorac Dis 2021;13:2137-47. [Crossref] [PubMed]
21. Tuminello S, Wolf A, Taioli E, et al. Comparison of Wedge Versus Lobar Resection for Stage 1 Non-Small Cell Lung Cancer: A SEER-Medicare Analysis. Ann Thorac Surg 2018;106:1260-1. [Crossref] [PubMed]
22. Hou B, Deng XF, Zhou D, et al. Segmentectomy versus wedge resection for the treatment of high-risk operable patients with stage I non-small cell lung cancer: a meta-analysis. Ther Adv Respir Dis 2016;10:435-43. [Crossref] [PubMed]
23. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615-22; discussion 622-3. [Crossref] [PubMed]
24. Patel AN, Santos RS, De Hoyos A, et al. Clinical trials of peripheral stage I (T1N0M0) non-small cell lung cancer. Semin Thorac Cardiovasc Surg 2003;15:421-30. [Crossref] [PubMed]
25. Landreneau RJ, Sugarbaker DJ, Mack MJ, et al. Wedge resection versus lobectomy for stage I (T1 N0 M0) non-small-cell lung cancer. J Thorac Cardiovasc Surg 1997;113:691-8; discussion 698-700. [Crossref] [PubMed]
26. Fernando HC, Schuchert M, Landreneau R, et al. Approaching the high-risk patient: sublobar resection, stereotactic body radiation therapy, or radiofrequency ablation. Ann Thorac Surg 2010;89:S2123-7. [Crossref] [PubMed]
27. Cao C, Wang D, Chung C, et al. A systematic review and meta-analysis of stereotactic body radiation therapy versus surgery for patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 2019;157:362-373.e8. [Crossref] [PubMed]
28. The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409. [Crossref] [PubMed]
29. Kang HR, Cho JY, Lee SH, et al. Role of Low-Dose Computerized Tomography in Lung Cancer Screening among Never-Smokers. J Thorac Oncol 2019;14:436-44. [Crossref] [PubMed]
30. Celli JP, Spring BQ, Rizvi I, et al. Imaging and photodynamic therapy: mechanisms, monitoring, and optimization. Chem Rev 2010;110:2795-838. [Crossref] [PubMed]
31. Okada M, Koike T, Higashiyama M, et al. Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study. J Thorac Cardiovasc Surg 2006;132:769-75. [Crossref] [PubMed]
32. Fernando HC, Landreneau RJ, Mandrekar SJ, et al. Impact of brachytherapy on local recurrence rates after sublobar resection: results from ACOSOG Z4032 (Alliance), a phase III randomized trial for high-risk operable non-small-cell lung cancer. J Clin Oncol 2014;32:2456-62. [Crossref] [PubMed]