Lung cancer is a malignant tumor with the highest morbidity and mortality worldwide. Among cases of lung cancer, 10–15% are small cell lung cancer (SCLC). SCLC is highly malignant and often metastases when diagnosed. Following a randomized controlled study in 1973 that found no survival benefit from surgery versus radiotherapy, surgery was excluded from the standard treatment for SCLC for a long time. However, only 34 of the 71 patients in the surgical group in that study actually underwent surgery and the lack of a good systemic chemotherapy program at that time made it difficult to guide current clinical practice.
Some retrospective studies have shown that surgery could improve survival in stage I patients compared to that for radiotherapy or concurrent chemoradiotherapy.[4–7] Current American Society of Clinical Oncology, National Comprehensive Cancer Network, and European Society for Medical Oncology guidelines indicate that surgical resection should be considered only in patients with stage I SCLC. Most patients with SCLC have extensive or metastatic disease, making most cases unsuitable for radical surgery. Over the past 30 years, the treatment of SCLC has stagnated, with the comprehensive application of combined surgery, radiotherapy, and chemotherapy, the main treatment for most SCLC patients.
However, surgery has been used in both early and advanced SCLC patients in the real world, either as part of a comprehensive treatment or as a means of pathologic confirmation. Thus, the role of surgery in SCLC is controversial.[12–14] The present study analyzed Surveillance, Epidemiology, and End Results (SEER) data from 2010 to 2015 to explore whether surgery offers a survival benefit for patients with SCLC.
2.1 Ethics statement
We got internet access to SEER database with the reference number 12025-Nov2017. This study used a national dataset of deidentified patient information, which did not meet the General Hospital of Northern Theater Command's criteria for institutional review board (IRB) approval. Therefore, this study waived the need for IRB approval. The data of this observational are anonymous, and the requirement for informed consent was therefore waived.
The SEER Program of the National Cancer Institute is an authoritative source of information on cancer incidence and survival in the United States that covers approximately 34.6% of the US population. After accessing the SEER∗stat software version 8.3.5, the SEER-18 registry (with custom treatment fields) was explored to extract eligible cases. The inclusion criteria included: patients over 18 years of age, one primary SCLC only, diagnosed between 2010 and 2015, and site recode ICD-O-3/WHO 2008 of “lung and bronchus” and histologic type codes 8002 and 8041–8045. The tumor, node, and metastasis (TNM) stage for each patient was reclassified according to the 8th edition of the TNM classification. However, stages III and IV could not be divided into subgroups due to insufficient information. The exclusion criteria included: unknown survival time, unidentified surgery status, cases without a positive pathological diagnosis, multiple primary cancer, and TNM stage unable to be reclassified according to the 8th edition of the TNM classification. The following information was extracted: patient age at diagnosis, patient race, patient sex, TNM stages, tumor size and extension, primary site, histologic type, surgery procedure, radiotherapy or chemotherapy, survival (in months), and vital status.
2.3 Statistical analyses
Data were reported as means ± standard deviation for continuous variables and as n (%) for categorical variables. Continuous variables were compared using Student t tests. Categorical variables were performed using Chi-square tests. The primary exposure variable was surgery. M multivariable logistic regression model was used to identify the significant factors associated with surgery. Survival curves were constructed using the Kaplan–Meier method and compared using log-rank tests. A multivariable Cox regression model was used to identify relevant variables affecting survival. Additional Kaplan–Meier curves were created to compare the different types of surgery. Cox regression models and Forest plots were used to identify the predictors of survival in patients who underwent surgery. Two-sided P-value < .05 were considered statistically significant. Statistical analysis was performed using IBM SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, NY) and the Forest plots were drawn using GraphPad Prism 5.01 (GraphPad Software, San Diego, CA).
3.1 Patient characteristics
A total of 26,659 patients with SCLC were included in the present cohort, 627 (2.4%) of whom underwent surgery. The baseline characteristics of the patients and the univariate associations with surgery are listed in Table 1. The numbers (percentage of the entire cohort) of patients with stage IA, IB, IIA, IIB, III, and IV SCLC were 547 (2.1%), 265 (1.0%), 113 (0.4%), 599 (2.2%), 6298 (23.6%), and 18,837 (70.7%), respectively. The numbers (percentage of stage-matched cohort) of patients who underwent surgery of the primary site with stage IA, IB, IIA, IIB, III, and IV SCLC were 163 (29.8%), 80 (30.2%), 11 (9.7%), 83 (13.9%), 145 (2.3%), and 145 (0.8%), respectively.
In multivariate analysis (Table 2), the likelihood of undergoing surgery for SCLC was significantly lower in patients older than 65 years of age than that in patients younger than 65 years (odds ratio [OR], 0.683; 95% confidence interval [CI], 0.571–0.817; P < .001). Patients who were black (OR, 0.717; 95% CI, 0.519–0.990; P = .044) or of another race (OR, 0.536; CI, 0.311–0.922; P = .024) were less likely to undergo surgery compared to white patients. Patients with combined histologic types were more likely to undergo surgery than patients with pure histologic types (OR, 8.964; 95% CI, 6.662–12.013; P < .001). Patients with upper lobe (OR, 1.602; 95% CI, 1.103–2.327; P = .018), lower lobe (OR, 1.781; 95% CI, 1.201–2.640; P = .004), and overlapping (OR, 2.609; 95% CI, 1.214–5.608; P = .014) lesions were more likely to undergo surgery compared to patients with main bronchus tumors. Patients with stage IIA (OR, 0.279; 95% CI, 0.143–0.546; P < .001), IIB (OR, 0.412; 95% CI, 0.302–0.562; P < .001), III (OR, 0.065; 95% CI, 0.050–0.084; P < .001), and IV (OR, 0.023; 95% CI, 0.018–0.030; P < .001) disease were less likely to undergo surgery compared to patients with stage IA disease.
There were no statistically significant differences in the likelihood of undergoing surgery between female and male patients (OR, 1.108; 95% CI, 0.929–1.321; P = .254), between right middle lobe and main bronchus lesions (OR, 1.454; 95% CI, 0.851–2.485; P = .171), and between stage IA and IB disease (OR, 1.000; 95% CI, 0.710–1.408; P = .998).
3.2 Survival and multivariable Cox regression analyses
The results of Kaplan–Meier survival analyses are shown in Figure 1 and Table 3. The median overall survival (OS) and 3-year OS rates for patients who underwent surgery and nonsurgery were 20.0 months and 36.2% and 7.0 months and 7.2%, respectively (P < .001). After adjusting for age, sex, race, TNM stage, histologic type, primary site, radiation, and chemotherapy, multivariate analysis of entire cohort identified surgery as an independent predictor of improved survival (HR, 0.573; 95% CI 0.512–0.643; P < .001), and that age, sex, race, TNM stage, primary site, histologic type, radiation, and chemotherapy were associated with survival (Table 4).
Surgery was associated with longer survival for all cohorts divided by stages, though the difference was not significant for patients with stage IIB disease. Surgery was associated with the greatest increase in median OS in patients with stage IA (45.0 months, 95% CI, 28.5–61.5 months vs 20.0 months, 95% CI, 17.6–22.3 months, P < .001) and IB (47.0 months, 95% CI, 8.1–85.9 months vs 19.0 months, 95% CI, 14.1–23.9 months, P = .001) disease. Furthermore, a significantly longer median OS in the surgery group was observed for stage IIA (16.0 months, 95% CI, 11.4–20.6 months vs NR, P = .007), stage III (18.0 months, 95% CI, 15.2–20.8 months vs 12.0 months, 95% CI, 11.6–12.4 months, P < .001), and stage IV (9.0 months, 95% CI, 7.5–10.5 months vs 5.0 months, 95% CI, 4.8–5.2 months, P < .001) disease. The 3-year survival rates for surgery and nonsurgery by stage were as follows: 59.7% vs 27.1% for stage IA, 52.4% vs 33.0% for stage IB, 75.0% vs 20.5% for stage IIA, 29.3% vs 16.9% for stage III, and 6.8% vs 2.7% for stage IV (Fig. 2, Table 3).
After adjusting for age, sex, race, histologic type, primary site, radiation, and chemotherapy, multivariate analysis identified surgery as an independent predictor of improved survival for stage IA (hazard ratio [HR], 0.410; 95% CI, 0.298–0.564; P < .001), IB (HR, 0.548; 95% CI, 0.340–0.884; P = .014), IIA (HR, 0.069; 95% CI, 0.015–0.325; P = .001), III (HR, 0.574; 95% CI, 0.468–0.704; P < .001), and IV (HR, 0.684; 95% CI, 0.570–0.820; P < .001) disease (Table 5).
3.3 Effect of surgery type on survival
Of the total 627 surgical procedures, 39 (6.2%) were local tumor destruction, 233 (37.2%) were sublobar resection, 315 (50.2%) were lobectomy, 20 (3.2%) were pneumonectomy, and 20 (3.2%) were unknown. Lobectomy was the most commonly performed procedure for stage IA, IB, IIA, and IIB SLSC in 101 (62.0%), 56 (70.0%), 8 (72.7%), and 67 (80.7%) cases, respectively. Sublobar resection and lobectomy were performed for stage III disease in 59 (40.7%) and 62 (42.8%) cases, respectively. Sublobar resection was the most commonly performed procedure for stage IV disease in 80 (55.2%) cases (Table 6).
Kaplan–Meier survival analyses showed median OS of 11.0 months (95% CI, 8.3–13.7 months), 15.0 months (95% CI, 12.5–17.5 months), 35.0 months (95% CI, 28.4–47.6 months), 17.0 months (95% CI, 9.7–24.3 months), and 13.0 months (95% CI, 10.3–15.7 months) for local tumor destruction, sublobar resection, lobectomy, pneumonectomy, and unknown types, respectively (P < .001) (Fig. 3, Table 6).
Multivariate analysis also showed that age ≥65 years (HR, 1.536; 95% CI, 1.125–1.924; P < .001), stage IIB (HR, 2.584; 95% CI, 1.669–4.001; P < .001), stage III (HR, 2.591; 95% CI, 1.822–3.684; P < .001), and stage IV (HR, 5.340; 95% CI, 3.670–7.770, P < .001) were independent predictors of poor outcomes. In addition, the outcomes of patients treated with surgery were not affected by race, sex, primary site, histologic type, or radiation (Fig. 4).
At present, the standard treatment for limited-stage SCLC is concurrent radiochemotherapy and the first-line standard treatment for extensive-stage SCLC is platinum-based systematic chemotherapy. For most patients with SCLC, surgery is not a major treatment. However, in recent years, researchers have evaluated the value of surgery for treatment of SCLC.
In this retrospective study, most patients had advanced-stage disease and 619 (2.4%) patients underwent surgery. The later the stage, the lower the proportion of patients was receiving surgical treatment. The proportion of patients younger than 65 years who received surgery was slightly higher than that in those older than 65 years, possibly because the younger patients had a better physical status and fewer complications. White Americans were more likely to receive surgery than black people and others, comparable to the results of another recent SEER-based retrospective analysis. African American patients’ perception of physicians and higher rates of implicit racial bias may play important roles in treatment choices. In terms of tumor location, patients with tumors located in the main bronchus had the lowest proportion of receiving surgery. Surgery at this site is difficult, heavily traumatic, and difficult to reach R0 resection, which explains the lower rates of surgery for this location. In addition, the proportion of patients with combined histologic type undergoing surgery was significantly higher than that of patients with pure histologic types (OR: 9.146). Combined SCLC is somewhat difficult to diagnose by preoperative biopsy. Therefore, the significant difference in the proportion of surgery may be due to selection bias.
The results of this study suggest a certain degree of survival benefits from surgical treatment of SCLC. Multivariate analysis showed that surgery was an independent prognostic factor for prolonged survival. Stage I patients had the greatest survival benefit, consistent with findings of previous studies.[5–7,18] There was no statistically significant difference in the proportion of stage I patients receiving radiotherapy and chemotherapy, indicating that surgical treatment did not affect the treatment decision to receive radiotherapy or chemotherapy.
In this study, the data indicated that surgery was an independent prognostic factor for survival in patients with stage IIA and III SCLC. There was no statistically significant difference in survival between the surgery and the nonsurgery groups in patients with stage IIB disease. Jin et al analyzed data of early SCLC patients in the SEER database from 2004 to 2013 and also reported no survival benefits for surgery compared to radiotherapy in patients with stage IIB disease. Patients who underwent surgery did not have a higher 5-year OS than that in patients who received radiotherapy (T3N0: 16.2% vs 26.5%; T1-2N1: 20.3% vs 29.0%). However, Yang et al reported improved 5-year survival for surgery with adjuvant chemotherapy with or without radiation compared to concurrent chemoradiation (31.4% vs 26.3%) in patients with stage cT1-3N1M0 (approximately equivalent to AJCC 8th edition stage IIB/IIIA) SCLC in the National Cancer Database (NCDB) from 2003 to 2011. Wakeam et al showed longer survival with surgery for IIB/IIIA but node-negative (T3/T4N0) disease (median overall survival 33.0 vs 16.8 months, P = .008) in SCLC patients in the NCDB from 2004 to 2013. Therefore, whether patients with stage II/III can benefit from surgical treatment requires further study.
To our knowledge, this study is the first to investigate the effect of surgery on survival in patients with stage IV SCLC. Although the proportion of patients with stage IV disease who underwent surgery was very low, there was a significant difference in survival between the surgery and the nonsurgery groups and multivariate analysis showed surgery to be an independent prognostic factor for survival in patients with stage IV disease.
Considering the retrospective study design, the effect of selection bias on the results cannot be ruled out; however, to a certain extent, the selection of appropriate patients to include surgery in their comprehensive treatment may have had survival benefits. The SEER database had no specific information about the purpose, timing, and results of surgery; moreover, patients with extensive or metastatic disease are often complicated. Therefore, multidisciplinary comprehensive evaluations are needed to determine which patients should be recommended surgical treatment in clinical practice. At present, with the continuous progress of surgical technology to reduce surgical trauma and reduce postoperative recovery times, surgery may play a role in patients with advanced-stage disease without affecting their physical status or systemic treatment.
In this study, lobectomy was the most common type of surgery, followed by sublobectomy. Most patients with stage I disease were treated with lobectomy. Survival analysis showed that patients undergoing lobectomy had a longer survival time, consistent with previous studies. The prognosis of the surgical group was better for patients aged is less than 65 years; therefore, age should be an important factor in deciding whether to perform surgery in clinical practice. Chemotherapy was an independent prognostic factor for survival in the surgical group, while radiotherapy was not. This finding suggested that systemic chemotherapy should be recommended even for patients undergoing surgery.
Because it is difficult to perform randomized controlled trials in SCLC, the results of retrospective studies can provide important references for clinical practice. To our knowledge, this is the first comprehensive and systematic study to investigate the status and significance of surgery in patients with various stages of SCLC. The results indicate that surgery has some positive significance in patients with various stages of SCLC. In particular, we found for the first time that patients with stage IV disease who underwent surgery had longer survival times than those in patients in the nonsurgery group. These results indicate the need for more in-depth studies on the application of surgery in various stages of SCLC.
This study had some limitations. First, this was a retrospective study; thus, selection bias was inevitable. Second, the proportion of patients in the surgery group was lower than that in the nonsurgery group, especially for stage IV patients. This objective reality may lead to a decrease in statistical efficiency. Third, we only knew which patients received surgical treatment but not the conditions, timing, and reasons that these patients received surgical treatment and other detailed information that is important for making treatment decisions in clinical practice. Thus, the results of this study can only be used as a reference for clinical decision-making.
In summary, surgery has been used in the minority of patients with SCLC in the real world and has shown the benefits of survival. These results support an increased role of surgery in multimodal therapy for SCLC.
Conceptualization: Long Xu.
Data curation: Long Xu.
Formal analysis: Long Xu, Guanzhong Zhang.
Investigation: Guanzhong Zhang, Zhendong Zheng.
Project administration: Guanzhong Zhang, Shuxi Song, Zhendong Zheng.
Resources: Shuxi Song.
Writing – original draft: Long Xu, Shuxi Song.
Writing – review & editing: Zhendong Zheng.
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