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Surgery and Surgery Approach Affect Survival of Patients With Stage I-IIA Small-Cell Lung Cancer: A Study Based SEER Database by Propensity Score Matching Analysis

Purpose The purpose of this study was to observe the significance of surgery and its approach in stage I-IIA (according to 8th American Joint Committee on Cancer Staging Manual) small-cell lung cancer (SCLC) using the Surveillance, Epidemiology, and End Results (SEER) database. Patients and Methods A total of 1,421 patients from ages 31 to 93 years who were diagnosed with stage I-IIA SCLC in the SEER database from 2010 to 2015 were analyzed. The 1:1 propensity score matching analysis was used to minimize the effect of selection bias, and 355 pairs of patients' data was performed subsequent statistical analysis. K–M analysis and a Cox proportional hazards model were used to observe the role of surgery and other clinical features in the patients' prognoses on cancer-specific survival (CSS). Results Overall, within the whole cohort, the 3- and 5-year CSS rates were 41.0 and 34.0%, respectively. In a Cox regression that adjusted for other clinical features, patients were more likely to benefit from the surgery [hazard ratio (HR) 0.292, 95% confidence interval (CI) 0.237–0.361, P < 0.001]. Unadjusted 5-year cancer-specific survival among those with surgery was 55.0%, compared with 23.0% among those without surgery. In the propensity scored-matched dataset, however, 5-year CSS among those with surgery was 54.0%, compared with 17.0% among those without surgery (HR 0.380, 95%CI 0.315–0.457, P < 0.001). In patients who received surgery, cases with lobectomy had a better 5-year CSS than those without lobectomy (65.0 vs. 39.0%). The lobectomy might be a protective factor for patients who underwent resection in CSS (HR 0.433, 95%CI 0.310–0.604, P < 0.001). Conclusions We suggested that the surgery and lobectomy were the independent prognostic as well as the protective factors in stage I-IIA SCLC patients. We recommended that patients with no surgical contraindications receive surgery, preferably, lobectomy.


INTRODUCTION
Lung cancer is mainly divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), which still ranks second in the global cancer spectrum morbidity, and first in mortality. In the United States alone in 2021, however, it is estimated that the number of new cases will reach 235,760, and the death toll will reach 131,800 (1). About 13% of patients with lung cancer fall into the small cell lung cancer category. Because of high cellular proliferation and early metastatic spread, the 5year overall survival rate for SCLC was about 6% which was still low (2). The advanced SCLC patients were mainly treated with chemotherapy and radiotherapy (3); however, for early SCLC, studies had shown that patients can benefit from surgery (4)(5)(6)(7).
Some studies demonstrated that 5-year survival rates were approximately 40 to 60% for patients who underwent surgery in the early-stage SCLC, such as stage I, (8,9). According to the 7th American Joint Committee on Cancer (AJCC) Staging Manual (10), the American Society of Clinical Oncology (ASCO) guidelines (11), and the National Comprehensive Cancer Network (NCCN) guidelines (3) stage I-IIA SCLC patients with received surgery with adjuvant chemotherapy. The 8th edition of the AJCC Staging Manual was enacted on January 1, 2017. There were some differences between the 7th and 8th editions (12) as per Jiro Okami's study (13) which suggested that the 5year overall survival (OS) with stage IA in the 8th edition was better than that in 7th edition; however, the 5-year OS with IB and IIA in 8th was worse than that in 7th edition. For the early-stage SCLC in the 8th edition, the significance of surgery and surgical methods for survival remains to be explored.
We extracted data from the database of the Surveillance, Epidemiology, and End Results (SEER), including stage T1-4N0M0 SCLC patients who confirmed diagnosis during 2010-2015, according to 7th AJCC. We got the data of a total of 1,991 patients. We transformed their combined stage to the 8th edition. Eventually, 1,421 patients with stage IA-IIA were included in this study. We have used the early-stage SCLC patients recorded in the database of SEER, a population-based cohort of 1,421 patients, to observe the significance and the approach of surgery.

Patients
This study includes all the patients who were diagnosed with a histologically confirmed SCLC from January 2010 to December 2015. Histology and site of disease were coded in SEER according to the International Classification of Diseases (ICD) for Oncology, Edition 3 (ICD-O-3). Patients who met the following criteria were enrolled in the study: (1) patients with SCLC (ICD-0-3 histology code 8041/3, 8043/3, 8044/3, 8045/3, and 8073/3); (2) pathologically confirmed patients in stage IA-IIA according to 8th edition of AJCC Staging Manual (we translated the 7th edition of the staging into the 8th edition based on the patients' medical record); (3) patients with tumor in the main bronchi and lung (ICD-0-3 site code c34.0-c34.9) were collected for this study. Patients with the following standards were excluded. (1) those in stage IIB-IIIA and (2) who only received pathological anatomy. All patient records were anonymized before analysis. The information we collect in the SEER database includes patients' ID, age at diagnosis, gender, laterality, approach of surgery, chemotherapy situation, radiation situation, race, tumor differentiation, tumor location, pTNM stage, tumor extension, survival months, survival status, cancer causes of disease (COD), and the situation of pleura invasion and lymph nodes. Eventually, the study collected the information on 1,421 patients.

Treatment
According to the record of SEER database, the main approaches of treatment include chemotherapy, radiation (radioactive implants, radioisotopes, beam radiation and combination of beam with implants or isotopes), and surgery. There were many kinds surgery recorded, such as lobectomy, sublobectomy (wedge and segmental resection), and interventional therapy (tumor destruction: excision, laser ablation, and cautery).

Follow-Up
The collected patients had a clear survival time and survival status. We regarded cancer-specific survival (CSS) as our observation endpoint. The CSS was from the date of diagnosis to the time of death caused by SCLC. Follow-up time ranged from 0.0 to 83.0 months, with an average of 21.7 ± 0.52 months.

Statistical Analysis
Statistical analysis was performed using SPSS Statistics 25.0 software (IBM SPSS, Inc., Chicago, IL, USA), R version 3.5.2 and Graph pad Prism 8. Hazard risk (HR) with 95% confidence intervals (95% CIs) were calculated by multivariate regression analysis. Unadjusted associations between clinical features and outcomes were displayed using Kaplan-Meier curves and compared using the log-rank test. A multivariable proportional hazards regression model was used to determine the association between surgery and other clinical features. A nomogram was shows the results of regression analysis. A P value < 0.05 was considered to be statistically significant. Statistical tests were based on a two-sided significance level. Similarly, the Kaplan-Meier analysis and the log-rank tests were used to compare survival curves between groups. To minimize the effect of other clinical factors, we used TNM stage, tumor location, laterality, age, gender, race, whether to receive radiation or/and chemotherapy, tumor differentiation, and first malignant as matching variables. To maximize execution performance and randomize case order when drawing matches, we used the propensity score matching analysis with a match tolerance of 0.02 by the SPSS 25.0 for clarity. After matching, the balance between the groups was checked via the χ 2 test. Cases were censored at death or the end of follow-up. The selection of CSS as a primary clinical end point was considered to be most clinically relevant.

Characteristics of Patients
The clinical characteristics of patients in the study cohort are listed in Table 1    Within the cohort, the number of patients who received surgery was 449 (31.6%); the remaining patients were 972 (68.4%) (without surgery) ( Table 1)

The Results of K-M Analysis in All Variables
In this study, patients were divided into groups according to their classification, respectively ( Table 1). We found the survival curve had a better stratification effect in the groups of age at diagnosis, race, tumor differentiation, laterality, tumor location, pTNM stage, and the situation of surgery, chemotherapy, and radiation. The p values were all < 0.05.

The χ 2 Test of Propensity Scored-Matched Dataset
We used the propensity score matching analysis to minimize the effect of the TNM stage to receive radiation or/and chemotherapy and age at diagnosis (≤65 or >65) on CSS. In the propensity scored-matched dataset, there were 355 pairs of patients and we found that the p value of χ 2 test after matching was different from primary dataset ( Table 2). We suggested that the results of matching minimized the effects of other factors.

Univariate and Multivariate Analyses
Before matching, univariate and multivariate analyses were performed to identify correlations between clinical characteristics and CSS. As shown in Table 3, univariate analyses identified the following clinical characteristics as significant CSS prognostic factors in patients with SCLC: age at diagnosis, other race, the grade III of tumor differentiation, the unknown grade of tumor differentiation, tumor location with main bronchi, pTNM stage, whether to receive surgery, chemotherapy, or radiation. Further multivariate analysis based on those characteristics confirmed that only age at diagnosis, other race, whether to receive surgery, pTNM stage, the grade III of differentiation, whether to receive chemotherapy, and whether to receive radiation were independent prognostic factors ( Table 3). Our study revealed that these factors are significantly associated with prognosis in stage I-IIA SCLC patients.
We suggested that surgery was an independent prognostic factor in SCLC, which acted as a protective factor, which might indicate a better survival rate (Figure 1). We conducted a classification analysis in stage IA-IIA and found surgery could improve the survival rates of SCLC patients in every stage (Figure 2, all P < 0.001). Besides, a nomogram was used to show the results of multivariate regression before matching (Figure 3). The surgery played the most important role in affecting prognosis for those patients.

The Significance of Surgery Approach in SCLC Patients Receiving Resection
We screened patients of stage I-IIA SCLC who underwent surgery from the recruits. We found that 449 patients had  received surgery and analyzed their data. There were 271 (60.1%) and 172 (38.1%) patients received lobectomy and sublobectomy, respectively ( Table 4). The age at diagnosis and lobectomy were considered to be independent prognostic factors in SCLC patients undergoing surgery by univariate and multivariate analysis ( Table 5). The lobectomy of surgery approach was a protective factor and an indicator of better survival (Figure 4).
We also compared all approaches of surgery with significance of survival in early-stage SCLC patients, and the results suggested that lobectomy was better than other approaches (Supplementary Figure 1).

Cancer-Specific Survival
On the whole, unadjusted 3-and 5-year cancer-specific survival among those who received surgery was 63.0 and 55.0%, respectively, compared with 31.0 and 23.0% among those without surgery (HR 0.380, 95%CI 0.315-0.457, P < 0.001; Figure 1A). The median survival time of patients without surgery was 22 months; however, there was no median survival time in patients who received surgery. In a Cox regression that adjusted for age, other race, pTNM stage, the grade III of differentiation, whether to receive chemotherapy or radiation, tumor location of main bronchi, and unknown differentiation ( Table 3), patients were more likely to benefit from surgery compared with those without surgery ( Figure 1A).
In the propensity scored-matched dataset, we found that 3and 5-year CSS had an evident difference between two groups of patients who received surgery and without surgery, respectively. The 3-and 5-year CSS among those with surgery were 61.0 and 54.0%, compared with 24.0 and 17.0% among those without surgery (P < 0.001, Figure 1B). The median survival time of patients without surgery was 18 months, however, there was no median survival time in patients that received surgery. After minimizing the effect of other clinical factors, the results of 1:1 match analysis revealed that patients with surgery had an increasing advantage of survival than those without surgery in the early-stage SCLC (HR 0.292, 95%CI 0.237-0.361, P < 0.00, Table 3; Figure 1B).
In the cohort which SCLC patients received surgery, we found that unadjusted 3-and 5-year cancer-specific survival among those that received lobectomy was 74.0 and 65.0%, respectively, compared with 45.0 and 39.0% among those without lobectomy (HR 0.433, 95%CI 0.310-0.604, P< 0.001; Figure 4). The median survival time of patients without lobectomy was 38.0 months; however, there was no median survival time in patients who received lobectomy. In a Cox multivariate regression, patients that received lobectomy had a better survival HR 0.462, 95%CI 0.330-0.645, P< 0.001, Table 5).

DISCUSSION
The occurrence and development of SCLC is complex, and the decision about treatment still requires multidisciplinary participation. For advanced SCLC, patients were mainly treated with chemotherapy and radiotherapy (3,11,14,15); however, for early SCLC, studies had shown that patients can benefit from surgery (4,(16)(17)(18)(19)(20)(21). Because SCLC is prone to recurrence and This study aimed to provide useful information to support clinicians' decisions. During this research, the patient's clinical information was analyzed, including the indicators shown in Table 1. We found that age at diagnosis, other race, whether to receive surgery, pTNM stage, the grade III of differentiation, whether to receive chemotherapy, and whether to receive radiation were independent prognostic factors. We used propensity score matching to minimize the effect of other variables on CSS (22). After balancing these factors, we suggested that the influence of surgery on survival in patients with stage I-IIA was more precise. Through this and other studies, we compared the survival advantage in different surgical approaches (Supplementary Figure 1), and suggested that the surgery and lobectomy were the independent prognostic and protective factors in limited SCLC. If there were no surgical contraindications, we recommended that patients with limited SCLC should receive lobectomy. We also have found the importance of early screening in small cell lung cancer. For patients of SCLC with stage T1-2N0M0, accurate judgment of the disease before surgery makes it possible to undergo surgery as soon as possible to improve the prognosis.
This study has some limitations. First, the retrospective study used the SEER database wherein the distribution of ethnic groups is not balanced. Second, it is recommended that data from other regions be included in this study to make the results more generalized. Third, in limited SCLC, this study had not analyzed the role of surgery in multidisciplinary treatment (chemotherapy, radiation and so on), and the number of patients who received pneumonectomy or tumor destruction was too small. Fourth, only patients with stage I-IIA SCLC were enrolled. We suggest that further prospective research is necessary to confirm our findings.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Ethics Committee of Ningbo Yinzhou People's Hospital. The Ethics Committee waived the requirement of written informed consent for participation.

AUTHOR CONTRIBUTIONS
WY conceptualized the study. XC, HW, and TX curated the data. XC, J-LZ, and HW did the formal analysis. HW and TX designed the methodology and validated the study. XC and WY were involved in project administration and supervision. XC and HW wrote the original draft. XC, HW, TX, and WY were involved in writing, reviewing, and editing. XC and J-LZ revised the manuscript. All authors have read and agreed to the published version of the manuscript.