Abstract
Background
There is currently limited evidence for a correlation between the recommended operation and overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC).
Methods
NSCLC patients with stages III and IV, recommended for operation, were identified in the US National Cancer Institute Surveillance, Epidemiology, and End Results database (SEER).We used propensity score matching (PSM) and multivariable Cox proportional hazards regression to ensure the robustness of our findings. The cumulative rates of death were compared between patients with and without recommended operations using the Kaplan−Meier curves.
Results
Operation was recommended for 3331 patients but was not performed in 912 (27.4%) patients (then on-operative group). After PSM, 553 pairs matched. Compared to the nonoperative group, the hazard ratios (HRs) in the operative group were 0.46 (95% CI 0.23–0.95 and p=0.037) in stage IIIA and 0.54 (95% CI 0.42–0.68 and p < 0.001) in stage IVA. However, in stages IIIB, IIIC, and IVB, the recommended operative group was not associated with better OS. The OS was not different in stage IIIA-N2, stage IVA-N1, and stage IVA-N3 patients between groups (p=0.28, p=0.14, and p=0.79, respectively). Moreover, the recommended operative group had better OS than the nonoperative group in stage IIIA-N0 (p=0.00085), stage IIIA-N1 (p=0.009), stage IVA-N0 (p < 0.001), and stage IVA-N2 (p=0.034).
Conclusion
Compared to the nonoperative group, recommended operation improved survival in NSCLC patients with stage IIIA-N0, stage IIIA-N1, stage IVA-N0, and stage IVA-N2. However, in stages IIIA-N2, IIIB, IIIC, IVA-N1, IVA-N3, and IVB, recommended operation did not lead to significantly improved survival time.
1. Introduction
Lung cancer is the world's leading cause of cancer death [1–3]. Nearly 80% of all lung cancer patients are diagnosed with non-small-cell lung cancer (NSCLC) [3, 4]. In clinical practice, approximately 75% of patients already have an advanced stage of NSCLC at the time of diagnosis [5, 6]. Despite significant improvements in the treatment of advanced NSCLC in recent years, survival remains poor, with a five-year survival rate below 6% [3, 7]. The role of operation as one part of multimodality management for advanced-stage patients is persistent but controversial [8, 9].
As the primary local therapy approach, the oncologist performed operative resection of the primary tumor in selected patients with advanced NSCLC [10]. A series of small retrospective research studies provided contradicting results on the benefits of operations [11–13]. Randomized controlled trials suggested that operative resection may not enhance overall or progression-free survival in NSCLC patients with stage IIIA-N2 [14, 15], noting that one of the trials only included patients with unresectable tumors. Previous studies have mainly focused on operative treatment for stage I–IIIA NSCLC and provided less operative information on more advanced NSCLC [16, 17]. Moreover, according to the NCCN guidelines, doctors should consider aggressive local therapy for patients with limited metastases in the context of multimodality treatment [18–21]. However, there is little basis for physicians to make robust judgments about the appropriate treatment strategies and protocols for NSCLC patients [22, 23]. Hence, retrospective cohort research based on real-world populations may be valuable for clinicians to identify operative candidates who are likely to have improved survival outcomes and thus further support better treatment decisions.
Therefore, we conducted a large-scale retrospective cohort study through the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database. The primary purpose was to investigate the relationship between operative treatment and overall survival (OS) in advanced NSCLC patients. The second purpose was to determine the clinical characteristics of patients associated with overall survival benefits from the operation, consisting of patient information at the time of the initial diagnosis of NSCLC.
2. Methods
2.1. Data
This cohort research adopted the SEER database (the November 2021 submission). We obtained the patient database through SEER∗Stat software (SEER Stat 8.4.0).
2.2. Inclusion/Exclusion Criteria
Patients diagnosed with NSCLC (malignant neoplasm of the lung and bronchus, NSCLC histology, and one primary) between 2010 and 2019 were recruited from the database.
Inclusion criteria were (1) patients with pathologically confirmed NSCLC and recommended for surgery, (2) those with stage III and IV following the 8th edition of the American Joint Committee on Cancer (AJCC) TNM classification, and (3) those who were diagnosed as the first primary malignancy.
Exclusion criteria included (1) patients diagnosed with other histological types (e.g., small cell lung cancer, ICD-0-3 8041–8045) and (2) patients with incomplete data (e.g., incomplete survival months, unknown primary tumor location, or unspecified diagnostic confirmation). The data and codes were documented by the North American Association of Central Cancer Registries. The site and histology of primary cancer were coded using the International Classification of Diseases (ICD-O-3). The Research Ethics Board of the Chinese PLA General Hospital exempted the study from ethical approval because the author could not get the patient's identity information. We obtained data agreement according to the requirements of the SEER database.
2.3. Variables
Operation treatment was defined as a record of the following: (1) surgery performed or (2) recommended but not performed in “Reason no cancer-directed surgery” in the SEER database.
2.4. Covariates
According to the published guidelines and research, we obtained the following variables: (1) demographic information, (2) variables that could affect cancer-directed operation for NSCLC or OS reported by previous literature, and (3) other relevant information on account of clinical experience. The following variables were adopted to construct the adjusted models: age, sex, race, marital status, primary site, grade, laterality, histology, AJCC stage, radiation, chemotherapy, and type of surgery.
2.5. Outcomes
The outcome was OS. Since the date is a confidential variable in some US registries, a process was established so that a SAS code could be downloaded from the data site. A registry can run the SAS code locally and provide the length of survival in the month for analysis.
2.6. Statistical Analysis
All skewed or normally distributed continuous data were presented as median (Mdn) and interquartile range (IQR) or mean ± standard deviation (SD) as appropriate. Categorical data were expressed in frequency or as percentages. We compared the characteristics of the operative group with the nonoperative group using t-tests (normal distribution), Mann−Whitney tests (skewed distribution), or χ2 tests (categorical variables), where appropriate.
This article followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement. No imputation was performed because the percentage of missing data was small (0–6%). We used propensity score-matched analysis (PSM) to minimize baseline differences. Baseline matching variables consisted of age, sex, race, marital status, primary site, laterality, histology, AJCC stage, radiation, and chemotherapy. We paired the nonoperative group and the operative group using exact matching with a caliper size of 0.2 based on the propensity scores. The cumulative rates of death were compared using the Kaplan−Meier curves.
We established multivariate Cox proportional hazard models to investigate the factors associated with overall survival. We assessed the associations between operative treatment and OS using hazard ratios (HRs) and 95% confidence intervals (CIs). Due to the differences in distribution between the groups, the adjusted Cox proportional hazards models included age, sex, race, marital status, primary site, grade, laterality, histology, AJCC stage, radiation, chemotherapy, and type of surgery.
The statistical software package R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria) and free statistics software version 1.3 performed all statistical analyses. A p value < 0.05 (two-sided) was statistically significant.
3. Results
3.1. Baseline Characteristics of NSCLC Patients
A total of 3331 patients with NSCLC who were recommended for surgery were enrolled in this research. Of these patients, 912 (27.4%) were recommended for surgery but not performed (the nonoperative group), and the remainder underwent surgery (the operative group). After propensity score-matched analysis, patient characteristics were balanced across groups, and 1106 patients with NSCLC who were recommended for the operation were enrolled in this research (Figure 1). The demographic and clinical characteristics of NSCLC patients before and after PSM are summarized in Table 1. Additionally, 3331 advanced NSCLC patients who were recommended for surgery were alive or dead due to cancer in this study.
Figure 1.
The flow chart of the study.
Table 1.
Baseline clinical and demographic characteristics of advanced NSCLC patients.
| Characteristic | Surgery recommended (unmatched) | Surgery recommended (propensity-score-matched) | ||||||
|---|---|---|---|---|---|---|---|---|
| Total (n = 3331) | Nonoperation (n = 912) | Operation (n = 2419) | p value | Total (n = 1106) | Nonoperation (n = 553) | Operation (n = 553) | p value | |
| Age (SD, years) | 66.6 ± 11.3 | 71.4 ± 11.4 | 64.8 ± 10.8 | <0.001 | 69.0 ± 10.7 | 69.5 ± 10.9 | 68.6 ± 10.5 | 0.183 |
| Age <= 30, n (%) | 11 (0.3) | 0 (0) | 11 (0.5) | <0.001 | 2 (0.2) | 0 (0) | 2 (0.4) | 0.098 |
| 30 < age <= 60, n (%) | 847 (25.4) | 143 (15.7) | 704 (29.1) | 209 (18.9) | 109 (19.7) | 100 (18.1) | ||
| 60 < age <= 90, n (%) | 2434 (73.1) | 732 (80.3) | 1702 (70.4) | 888 (80.3) | 438 (79.2) | 450 (81.4) | ||
| Age > 90, n (%) | 39 (1.2) | 37 (4.1) | 2 (0.1) | 7 (0.6) | 6 (1.1) | 1 (0.2) | ||
| Sex, n (%) | 0.036 | 0.304 | ||||||
| Male | 1717 (51.5) | 497 (54.5) | 1220 (50.4) | 613 (55.4) | 315 (57) | 298 (53.9) | ||
| Female | 1614 (48.5) | 415 (45.5) | 1199 (49.6) | 493 (44.6) | 238 (43) | 255 (46.1) | ||
| Race, n (%) | 0.034 | 0.886 | ||||||
| Caucasian | 2651 (79.8) | 740 (81.3) | 1911 (79.3) | 897 (81.1) | 454 (82.1) | 443 (80.1) | ||
| African American | 269 (8.1) | 56 (6.2) | 213 (8.8) | 90 (8.1) | 42 (7.6) | 48 (8.7) | ||
| American Indian/Alaska native | 24 (0.7) | 10 (1.1) | 14 (0.6) | 6 (0.5) | 3 (0.5) | 3 (0.5) | ||
| Asian or Pacific Islander | 377 (11.4) | 104 (11.4) | 273 (11.3) | 113 (10.2) | 54 (9.8) | 59 (10.7) | ||
| Marital status at diagnosis, n (%) | <0.001 | 0.946 | ||||||
| Single | 480 (15.1) | 147 (17.7) | 333 (14.2) | 179 (16.2) | 91 (16.5) | 88 (15.9) | ||
| Unmarried or domestic partner | 21 (0.7) | 2 (0.2) | 19 (0.8) | 6 (0.5) | 2 (0.4) | 4 (0.7) | ||
| Married | 1818 (57.4) | 392 (47.3) | 1426 (60.9) | 582 (52.6) | 290 (52.4) | 292 (52.8) | ||
| Separated | 26 (0.8) | 8 (1) | 18 (0.8) | 10 (0.9) | 6 (1.1) | 4 (0.7) | ||
| Divorced | 407 (12.8) | 98 (11.8) | 309 (13.2) | 142 (12.8) | 69 (12.5) | 73 (13.2) | ||
| Widowed | 418 (13.2) | 182 (22) | 236 (10.1) | 187 (16.9) | 95 (17.2) | 92 (16.6) | ||
| Primary site, n (%) | <0.001 | 0.075 | ||||||
| Main bronchus | 110 (3.3) | 27 (3) | 83 (3.4) | 58 (5.2) | 18 (3.3) | 40 (7.2) | ||
| Upper lobe and lung | 1653 (49.6) | 400 (43.9) | 1253 (51.8) | 526 (47.6) | 277 (50.1) | 249 (45) | ||
| Middle lobe and lung | 166 (5.0) | 41 (4.5) | 125 (5.2) | 62 (5.6) | 31 (5.6) | 31 (5.6) | ||
| Lower lobe and lung | 957 (28.7) | 204 (22.4) | 753 (31.1) | 289 (26.1) | 144 (26) | 145 (26.2) | ||
| Overlapping lession of lung | 66 (2.0) | 6 (0.7) | 60 (2.5) | 10 (0.9) | 5 (0.9) | 5 (0.9) | ||
| Grade, n (%) | 0.039 | 0.585 | ||||||
| I: well differentiated | 159 (8.4) | 29 (8.8) | 130 (8.4) | 53 (9.6) | 23 (9.6) | 30 (9.6) | ||
| II: moderately differentiated | 722 (38.3) | 103 (31.4) | 619 (39.8) | 189 (34.2) | 88 (36.7) | 101 (32.3) | ||
| III: poorly differentiated | 950 (50.5) | 185 (56.4) | 765 (49.2) | 287 (51.9) | 121 (50.4) | 166 (53) | ||
| IV: undifferentiated anaplastic | 52 (2.8) | 11 (3.4) | 41 (2.6) | 24 (4.3) | 8 (3.3) | 16 (5.1) | ||
| Laterality, n (%) | <0.001 | 0.972 | ||||||
| Right | 1845 (55.7) | 465 (52.1) | 1380 (57.1) | 641 (58.0) | 319 (57.7) | 322 (58.2) | ||
| Left | 1354 (40.9) | 334 (37.4) | 1020 (42.2) | 436 (39.4) | 219 (39.6) | 217 (39.2) | ||
| Bilateral involvement | 111 (3.4) | 93 (10.4) | 18 (0.7) | 29 (2.6) | 15 (2.7) | 14 (2.5) | ||
| Histology, n (%) | <0.001 | 0.842 | ||||||
| Epithelial neoplasms | 421 (12.6) | 248 (27.2) | 173 (7.2) | 168 (15.2) | 86 (15.6) | 82 (14.8) | ||
| Squamous cell neoplasms | 733 (22.0) | 199 (21.8) | 534 (22.1) | 270 (24.4) | 141 (25.5) | 129 (23.3) | ||
| Adenomas and adenocarcinomas | 1833 (55.0) | 444 (48.7) | 1389 (57.4) | 628 (56.8) | 308 (55.7) | 320 (57.9) | ||
| Acinar cell neoplasms | 192 (5.8) | 3 (0.3) | 189 (7.8) | 8 (0.7) | 3 (0.5) | 5 (0.9) | ||
| Others† | 152 (4.6) | 18 (2) | 134 (5.5) | 32 (2.9) | 15 (2.7) | 17 (3.1) | ||
|
| ||||||||
| Type of surgery∗ | 912 (27.7) | 912 (100) | 0 (0) | <0.001 | <0.001 | |||
| Local tumor destruction | 98 (3.0) | 0 (0) | 98 (4.1) | 94 (8.6) | 0 (0) | 94 (17.4) | ||
| Resection of less than one lobe | 541 (16.4) | 0 (0) | 541 (22.7) | 328 (30.0) | 0 (0) | 328 (60.6) | ||
| Lobectomy | 1361 (41.3) | 0 (0) | 1361 (57.2) | 102 (9.3) | 0 (0) | 102 (18.9) | ||
| Lobe or bilobectomy extended | 118 (3.6) | 0 (0) | 118 (5) | 8 (0.7) | 0 (0) | 8 (1.5) | ||
| Pneumonectomy | 251 (7.6) | 0 (0) | 251 (10.5) | 7 (0.6) | 0 (0) | 7 (1.3) | ||
| Extended pneumonectomy | 11 (0.3) | 0 (0) | 11 (0.5) | 2 (0.2) | 0 (0) | 2 (0.4) | ||
| T, n (%) | 0.052 | 0.003 | ||||||
| T1a | 147 (4.8) | 24 (3.5) | 123 (5.2) | 47 (4.8) | 18 (3.8) | 29 (5.6) | ||
| T1b | 190 (6.2) | 47 (6.8) | 143 (6.1) | 56 (5.7) | 30 (6.4) | 26 (5) | ||
| T1c | 47 (1.5) | 7 (1) | 40 (1.7) | 12 (1.2) | 7 (1.5) | 5 (1) | ||
| T2a | 591 (19.4) | 118 (17) | 473 (20.1) | 174 (17.6) | 84 (17.8) | 90 (17.5) | ||
| T2b | 190 (6.2) | 51 (7.3) | 139 (5.9) | 54 (5.5) | 38 (8.1) | 16 (3.1) | ||
| T3 | 909 (29.8) | 205 (29.5) | 704 (29.9) | 274 (27.8) | 139 (29.4) | 135 (26.2) | ||
| T4 | 976 (32.0) | 243 (35) | 733 (31.1) | 370 (37.5) | 156 (33.1) | 214 (41.6) | ||
| N, n (%) | <0.001 | <0.001 | ||||||
| N0 | 826 (26.2) | 239 (31.2) | 587 (24.6) | 384 (37.0) | 144 (28.3) | 240 (45.2) | ||
| N1 | 592 (18.8) | 109 (14.2) | 483 (20.3) | 124 (11.9) | 76 (15) | 48 (9) | ||
| N2 | 1531 (48.6) | 316 (41.3) | 1215 (51) | 414 (39.8) | 224 (44.1) | 190 (35.8) | ||
| N3 | 201 (6.4) | 102 (13.3) | 99 (4.2) | 117 (11.3) | 64 (12.6) | 53 (10) | ||
| M, n (%) | <0.001 | <0.001 | ||||||
| M0 | 1871 (57.4) | 217 (25) | 1654 (69.1) | 341 (32.0) | 188 (35.6) | 153 (28.5) | ||
| M1a | 533 (16.3) | 227 (26.2) | 306 (12.8) | 317 (29.8) | 118 (22.3) | 199 (37.1) | ||
| M1b | 790 (24.2) | 400 (46.1) | 390 (16.3) | 367 (34.5) | 206 (39) | 161 (30) | ||
| M1c | 66 (2.0) | 23 (2.7) | 43 (1.8) | 40 (3.8) | 16 (3) | 24 (4.5) | ||
| AJCC stage, n (%) | <0.001 | 0.096 | ||||||
| Stage IIIA | 1359 (40.8) | 127 (13.9) | 1232 (50.9) | 201 (18.2) | 116 (21) | 85 (15.4) | ||
| Stage IIIB | 473 (14.2) | 70 (7.7) | 403 (16.7) | 120 (10.8) | 63 (11.4) | 57 (10.3) | ||
| Stage IIIC | 39 (1.2) | 20 (2.2) | 19 (0.8) | 20 (1.8) | 9 (1.6) | 11 (2) | ||
| Stage IVA | 1394 (41.8) | 672 (73.7) | 722 (29.8) | 725 (65.6) | 349 (63.1) | 376 (68) | ||
| Stage IVB | 66 (2.0) | 23 (2.5) | 43 (1.8) | 40 (3.6) | 16 (2.9) | 24 (4.3) | ||
| Radiation, n (%) | <0.001 | 0.229 | ||||||
| No/unknown | 2101 (63.1) | 685 (75.1) | 1416 (58.5) | 725 (65.6) | 372 (67.3) | 353 (63.8) | ||
| Yes | 1230 (36.9) | 227 (24.9) | 1003 (41.5) | 381 (34.4) | 181 (32.7) | 200 (36.2) | ||
| Chemotherapy, n (%) | <0.001 | 0.298 | ||||||
| No/unknown | 1407 (42.2) | 660 (72.4) | 747 (30.9) | 655 (59.2) | 336 (60.8) | 319 (57.7) | ||
| Yes | 1924 (57.8) | 252 (27.6) | 1672 (69.1) | 451 (40.8) | 217 (39.2) | 234 (42.3) | ||
| Tumor size and mean ± SD (mm) | 48.2 ± 31.7 | 48.8 ± 27.1 | 48.1 ± 32.2 | 0.858 | 47.8 ± 31.8 | 49.0 ± 27.5 | 47.3 ± 33.5 | 0.712 |
†, histology and other types included: transitional cell papillomas and carcinomas (n = 1), mucoepidermoid neoplasms (n = 5), cystic, mucinous, and serous neoplasms (n = 72), and complex epithelial neoplasms (n = 74). Abbreviations: AJCC: American Joint Committee on Cancer. ∗, local tumor destruction included laser ablation or cryosurgery and electrocautery; fulguration (included the use of hot forceps for tumor destruction). Excision or resection of less than one lobe included excision, laser excision, bronchial sleeve resection only, wedge resection, and segmental resection (including lingulectomy).
After PSM, 553 pairs matched (Supplementary Figure 1). The mean age was 69.0 ± 10.7 years; 493 (44.6%) were women, and 897 (81.1%) were Caucasian. The numbers of patients in each stage were 201, 120, and 20 for stages IIIA, IIIB, and IIIC; 725 and 40 for stages IVA and IVB, respectively.
3.2. Cox Proportional Hazard Regression Analysis
We constructed multivariate models to evaluate the associations between the operation and OS (Table 2). The operation was independently associated with improved OS in the entire advanced cohort (Model 3: HR = 0.57, 95% CI 0.47–0.69, and p < 0.001). Compared to the nonoperative group, the hazard ratios (HRs) in the operative group were 0.46 (95% CI 0.23–0.95 and p=0.037) in stage IIIA and 0.54 (95% CI 0.42–0.68 and p < 0.001) in stage IVA. However, the recommended operation was not independently associated with improved OS in stages IIIB, IIIC, and IVB. Moreover, HRs were similar between the unadjusted model and the adjusted models with imputed covariate data.
Table 2.
Association between the recommended operation and OS in the crude analysis and multivariable analysis.
| Variables | Total | Event (%) | Nonadjusted model | Model 1 | Model 2 | Model 3 | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | HR (95% CI) | p value | HR (95% CI) | p value | |||
| Entire cohort | ||||||||||
| Nonoperation | 553 | 494 (89.3) | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||
| Operation | 553 | 384 (69.4) | 0.6 (0.53∼0.69) | <0.001 | 0.61 (0.53∼0.7) | <0.001 | 0.61 (0.5∼0.74) | <0.001 | 0.57 (0.47∼0.69) | <0.001 |
|
| ||||||||||
| Stage IIIA | ||||||||||
| Nonoperation | 116 | 98 (84.5) | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||
| Operation | 85 | 40 (47.1) | 0.44 (0.31∼0.64) | <0.001 | 0.4 (0.27∼0.59) | <0.001 | 0.4 (0.19∼0.82) | 0.012 | 0.46 (0.23∼0.95) | 0.037 |
|
| ||||||||||
| Stage IIIB | ||||||||||
| Nonoperation | 63 | 56 (88.9) | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||
| Operation | 57 | 43 (75.4) | 0.77 (0.52∼1.15) | 0.207 | 0.82 (0.53∼1.25) | 0.358 | 0.8 (0.41∼1.59) | 0.532 | 0.79 (0.37∼1.69) | 0.537 |
|
| ||||||||||
| Stage IIIC | ||||||||||
| Nonoperation | 9 | 8 (88.9) | 1 (ref) | 1 (ref) | ||||||
| Operation | 11 | 7 (63.6) | 0.48 (0.16∼1.39) | 0.174 | 1.01 (0.27∼3.76) | 0.985 | ||||
|
| ||||||||||
| Stage IVA | ||||||||||
| Nonoperation | 349 | 323 (92.6) | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||
| Operation | 376 | 278 (73.9) | 0.57 (0.49∼0.67) | <0.001 | 0.58 (0.49∼0.68) | <0.001 | 0.59 (0.47∼0.75) | <0.001 | 0.54 (0.42∼0.68) | <0.001 |
|
| ||||||||||
| Stage IVB | ||||||||||
| Nonoperation | 16 | 9 (56.2) | 1 (ref) | 1 (ref) | ||||||
| Operation | 24 | 16 (66.7) | 1.77 (0.78∼4.03) | 0.175 | 3.39 (1.22∼9.39) | 0.019 | ||||
Model 1: adjusted for age, sex, race, and marital status at the baseline. Model 2: adjusted for age, sex, race, marital status, primary site, grade, laterality, histology, and AJCC stage. Model 3: adjusted for age, sex, race, marital status, primary site, grade, laterality, histology, AJCC stage, radiation, and chemotherapy.
After adjustment for all covariates, in stage IIIA, compared to the reference group, Grade II (HR = 6.2, 95% CI 2.09–18.4, and p=0.001) and Grade III (HR = 4.68, 95% CI 1.51–14.5, and p=0.008) were shown to be risk predictors of OS, and adenomas and adenocarcinomas (HR = 0.12, 95% CI 0.04–0.36, and p < 0.001) were associated with a reduced hazard for OS (Table 3). In stage IVA, age (HR = 1.02, 95% CI 1.01–1.03, and p < 0.001) was an independent predictor of OS. The survival benefit might be most prominent with Asian or Pacific Islanders (HR = 0.62, 95% CI 0.4∼0.95, and p=0.028) and chemotherapy (HR = 0.52, 95% CI 0.39–0.69, and p < 0.001) (Table 4). Moreover, in both stages IIIA and IVA, the female was shown to be a significant beneficial predictor of survival in stage IIIA: HR = 0.37, 95% CI 0.17–0.82, and p=0.014 and in stage IVA: HR = 0.77, 95% CI 0.61–0.99, and p=0.039 (Tables 3 and 4).
Table 3.
The multivariable Cox proportional hazard regression analyses for stage IIIA.
| Variables | Unadjusted model | Adjusted model | ||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Nonoperation | Reference | Reference | ||
| Operation | 0.44 (0.31∼0.64) | <0.001 | 0.2 (0.04∼1) | 0.051 |
| Age | 1.01 (0.99∼1.02) | 0.611 | 1.04 (1∼1.07) | 0.058 |
| Sex | ||||
| Male | Reference | Reference | ||
| Female | 0.54 (0.38∼0.76) | <0.001 | 0.37 (0.17∼0.82) | 0.014 |
| Race | ||||
| Caucasian | Reference | Reference | ||
| African American | 0.56 (0.24∼1.27) | 0.163 | 0.11 (0.03∼0.39) | 0.001 |
| American Indian/Alaska native | NA (NA∼NA) | NA | NA (NA∼NA) | NA |
| Asian or Pacific Islander | 0.82 (0.51∼1.32) | 0.408 | 0.35 (0.14∼0.88) | 0.025 |
| Marital status at diagnosis, n (%) | ||||
| Single | Reference | Reference | ||
| Unmarried or domestic partner | 1.6 (0.37∼6.87) | 0.524 | 0 (0∼Inf) | 0.998 |
| Married | 1.08 (0.66∼1.77) | 0.773 | 0.69 (0.28∼1.73) | 0.427 |
| Separated | 3.15 (0.42∼23.58) | 0.265 | NA (NA∼NA) | NA |
| Divorced | 1.34 (0.75∼2.39) | 0.328 | 0.45 (0.13∼1.54) | 0.203 |
| Widowed | 1.06 (0.62∼1.82) | 0.826 | 0.78 (0.26∼2.31) | 0.647 |
| Primary site | ||||
| Main bronchus | Reference | Reference | ||
| Upper lobe and lung | 0.26 (0.11∼0.66) | 0.004 | 1.4 (0.13∼15.42) | 0.784 |
| Middle lobe and lung | 0.25 (0.08∼0.76) | 0.015 | 0.72 (0.05∼10.37) | 0.807 |
| Lower lobe and lung | 0.3 (0.12∼0.77) | 0.012 | 1.29 (0.11∼15.76) | 0.841 |
| Overlapping lesion of lung | 0 (0∼Inf) | 0.995 | NA (NA∼NA) | NA |
| Grade | ||||
| I: well differentiated | Reference | Reference | ||
| II: moderately differentiated | 3.43 (1.46∼8.09) | 0.005 | 6.2 (2.09∼18.4) | 0.001 |
| III: poorly differentiated | 4.06 (1.75∼9.4) | 0.001 | 4.68 (1.51∼14.5) | 0.008 |
| IV: undifferentiated anaplastic | 1.29 (0.27∼6.2) | 0.755 | 0.43 (0.06∼2.96) | 0.392 |
| Laterality | ||||
| Right | Reference | Reference | ||
| Left | 0.99 (0.7∼1.4) | 0.957 | 0.72 (0.37∼1.39) | 0.322 |
| Bilateral involvement | 1.74 (0.43∼7.11) | 0.441 | 1.05 (0.17∼6.64) | 0.959 |
| Histology | ||||
| Epithelial neoplasms | Reference | Reference | ||
| Squamous cell neoplasms | 0.66 (0.42∼1.03) | 0.069 | 0.21 (0.07∼0.66) | 0.008 |
| Adenomas and adenocarcinomas | 0.28 (0.18∼0.46) | <0.001 | 0.12 (0.04∼0.36) | <0.001 |
| Acinar cell neoplasms | 0 (0∼Inf) | 0.994 | 0 (0∼Inf) | 0.997 |
| Others† | 0.23 (0.05∼0.96) | 0.044 | 0.49 (0.07∼3.59) | 0.482 |
| Radiation | 0.91 (0.65∼1.29) | 0.609 | 1.82 (0.72∼4.59) | 0.205 |
| Chemotherapy | 0.84 (0.58∼1.2) | 0.337 | 0.44 (0.19∼1.05) | 0.064 |
| Type of surgery∗ | ||||
| Nonoperation | Reference | Reference | ||
| Local tumor destruction | 1.38 (0.64∼2.98) | 0.418 | 15.3 (1.29∼181.18) | 0.031 |
| Resection of less than one lobe | 0.4 (0.26∼0.6) | <0.001 | 2.13 (0.47∼9.64) | 0.324 |
| Lobectomy | 0.33 (0.12∼0.89) | 0.028 | NA (NA ∼ NA) | NA |
| Lobe or bilobectomy extended | NA (NA ∼ NA) | NA | NA (NA ∼ NA) | NA |
| Pneumonectomy | NA (NA ∼ NA) | NA | NA (NA ∼ NA) | NA |
| Extended pneumonectomy | NA (NA ∼ NA) | NA | NA (NA ∼ NA) | NA |
†, histology and other types included: transitional cell papillomas and carcinomas (n = 1), mucoepidermoid neoplasms (n = 5), cystic, mucinous, and serous neoplasms (n = 72), and complex epithelial neoplasms (n = 74). ∗, local tumor destruction included laser ablation or cryosurgery and electrocautery; fulguration (included the use of hot forceps for tumor destruction). Excision or resection of less than one lobe included excision, laser excision, bronchial sleeve resection only, wedge resection, and segmental resection (including lingulectomy). The model adjusted for age, sex, race, marital status, primary site, grade, laterality, histology, AJCC stage, radiation, chemotherapy, and type of surgery.
Table 4.
The multivariable Cox proportional hazard regression analyses for stage IVA.
| Variable | Unadjusted model | Adjusted model | ||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Nonoperation | Reference | Reference | ||
| Operation | 0.57 (0.49∼0.67) | <0.001 | 0.2 (0.06∼0.65) | 0.007 |
| Age | 1.01 (1∼1.02) | 0.005 | 1.02 (1.01∼1.03) | <0.001 |
| Sex | ||||
| Male | Reference | Reference | ||
| Female | 0.78 (0.66∼0.92) | 0.003 | 0.77 (0.61∼0.99) | 0.039 |
| Race | ||||
| Caucasian | Reference | Reference | ||
| African American | 1.1 (0.84∼1.46) | 0.488 | 0.98 (0.62∼1.54) | 0.915 |
| American Indian/Alaska native | 1.31 (0.54∼3.17) | 0.544 | 2.41 (0.57∼10.15) | 0.229 |
| Asian or Pacific Islander | 0.59 (0.43∼0.81) | 0.001 | 0.62 (0.4∼0.95) | 0.028 |
| Marital status at diagnosis, n (%) | ||||
| Single | Reference | Reference | ||
| Unmarried or domestic partner | 0 (0∼Inf) | 0.989 | NA (NA∼NA) | NA |
| Married | 1.06 (0.85∼1.33) | 0.589 | 0.74 (0.53∼1.03) | 0.076 |
| Separated | 0.94 (0.38∼2.32) | 0.9 | NA (NA∼NA) | NA |
| Divorced | 1.16 (0.86∼1.56) | 0.325 | 0.93 (0.61∼1.41) | 0.729 |
| Widowed | 1.07 (0.81∼1.41) | 0.646 | 0.71 (0.46∼1.1) | 0.129 |
| Primary site | ||||
| Main bronchus | Reference | Reference | ||
| Upper lobe and lung | 0.67 (0.46∼0.99) | 0.043 | 1.11 (0.62∼2.01) | 0.724 |
| Middle lobe and lung | 0.58 (0.35∼0.98) | 0.043 | 1.1 (0.53∼2.27) | 0.805 |
| Lower lobe and lung | 0.71 (0.48∼1.06) | 0.097 | 1.16 (0.64∼2.12) | 0.622 |
| Overlapping lesion of lung | 0.75 (0.31∼1.8) | 0.515 | 1.65 (0.5∼5.48) | 0.414 |
| Grade | ||||
| I: well differentiated | Reference | Reference | ||
| II: moderately differentiated | 1.09 (0.71∼1.67) | 0.707 | 1.26 (0.79∼2.01) | 0.335 |
| III: poorly differentiated | 1.2 (0.79∼1.83) | 0.384 | 1.53 (0.97∼2.41) | 0.068 |
| IV: undifferentiated anaplastic | 1.29 (0.69∼2.42) | 0.428 | 1.97 (1∼3.89) | 0.05 |
| Laterality | ||||
| Right | Reference | Reference | ||
| Left | 0.98 (0.83∼1.16) | 0.806 | 0.95 (0.75∼1.21) | 0.684 |
| Bilateral involvement | 0.61 (0.37∼1) | 0.051 | 0.99 (0.41∼2.43) | 0.99 |
| Histology | ||||
| Epithelial neoplasms | Reference | Reference | ||
| Squamous cell neoplasms | 1.13 (0.86∼1.49) | 0.371 | 1.09 (0.73∼1.62) | 0.685 |
| Adenomas and adenocarcinomas | 0.76 (0.6∼0.96) | 0.021 | 0.82 (0.58∼1.17) | 0.281 |
| Acinar cell neoplasms | 0.47 (0.17∼1.28) | 0.139 | 0.35 (0.11∼1.19) | 0.092 |
| Others† | 1.07 (0.67∼1.71) | 0.775 | 0.82 (0.41∼1.65) | 0.583 |
| Radiation | 1.01 (0.85∼1.2) | 0.923 | 1.1 (0.86∼1.41) | 0.438 |
| Chemotherapy | 0.66 (0.56∼0.77) | <0.001 | 0.51 (0.4∼0.66) | <0.001 |
| Type of surgery∗ | ||||
| Nonoperation | Reference | Reference | ||
| Local tumor destruction | 0.92 (0.67∼1.27) | 0.629 | 5.65 (1.63∼19.61) | 0.006 |
| Resection of less than one lobe | 0.59 (0.49∼0.71) | <0.001 | 3.05 (0.93∼10) | 0.065 |
| Lobectomy | 0.38 (0.28∼0.52) | <0.001 | 1.49 (0.45∼4.91) | 0.512 |
| Lobe or bilobectomy extended | 0.25 (0.08∼0.79) | 0.018 | 1.01 (0.2∼5.27) | 0.987 |
| Pneumonectomy | 0.33 (0.11∼1.03) | 0.056 | NA (NA ∼ NA) | NA |
| Extended pneumonectomy | 0.58 (0.08∼4.13) | 0.586 | NA (NA ∼ NA) | NA |
†, histology and other types included: transitional cell papillomas and carcinomas (n = 1), mucoepidermoid neoplasms (n = 5), cystic, mucinous, and serous neoplasms (n = 72), and complex epithelial neoplasms (n = 74). ∗, local tumor destruction included laser ablation or cryosurgery, electrocautery; fulguration (included the use of hot forceps for tumor destruction). Excision or resection of less than one lobe included excision, laser excision, bronchial sleeve resection only, wedge resection, and segmental resection (including lingulectomy). The model adjusted for age, sex, race, marital status, primary site, grade, laterality, histology, AJCC stage, radiation, chemotherapy, and type of surgery.
3.3. Survival Analysis
We conducted Kaplan−Meier analyses to compare the survival rates of the operative and nonoperative groups. The operative patients had better OS than the nonoperative patients in stages IIIA and IVA (p < 0.001, Figure 2). However, the improved OS was not significantly different between the operative and nonoperative groups in stage IIIB, IIIC, and IVB patients (p=0.21, p=0.16, and p=0.16, respectively, Figure 2).
Figure 2.
Kaplan−Meier plots for overall survival. (a) Entire cohort; (b) stage IIIA; (c) stage IIIB; (d) stage IIIC; (e) stage IVA; (f) stage IVB.
We evaluated several secondary outcomes to investigate potential factors that might have contributed to the benefits of the operation in stages IIIA and IVA. The operative patients had better OS than the nonoperative patients in stages IIIA-N0 and N1 (p=0.00085 and p=0.009, respectively); however, there was no difference in stage IIIA-N2 patients between the groups (p=0.28) (Figure 3). In stage IVA-N0 and N2, the operative group had better OS than the nonoperative group (p < 0.001 and p=0.034, respectively); however, there was no difference in stage IVA-N1 and N3 patients between the groups (p=0.14 and p=0.79, respectively) (Figure 4).
Figure 3.
Kaplan−Meier plots for overall survival. (a) Stage IIIA-N0; (b) stage IIIA-N1; (c) stage IIIA-N2.
Figure 4.
Kaplan−Meier plots for overall survival. (a) Stage IVA-N0; (b) stage IVA-N1; (c) stage IVA-N2; (d) stage IVA-N3.
4. Discussion
Recently, for patients with advanced-stage NSCLC, chemotherapy and radiation therapy have been the primary management modalities [24], and the role of recommended operative treatment remains ambiguous. Our study found that recommended operative treatment was not significantly associated with improved survival outcomes in NSCLC patients with stages IIIB, IIIC, and IVB. In addition, our results showed that recommended operative treatment appeared to result in improved survival for NSCLC patients with stages IIIA-N0, IIIA-N1, IVA-N0, and IVA-N2. Our findings will provide the basis for clinicians to select which kinds of advanced NSCLC patients would benefit from recommended operative treatment.
Among patients with stages IIIA-N2, IIIB, and IIIC, we found that recommended surgery did not significantly enhance overall survival, but patients with stages IIIA-N0 and N1 did. As mentioned previously, randomized controlled trials suggested that in the selected stage IIIA-N2 patients with responses to induction chemotherapy, the effect of operative treatment on overall or progression-free survival was not significantly better than radiotherapy [14]. In view of this, clinicians might adopt radiotherapy as the preferred choice of local treatment for these advanced NSCLC patients [14, 15]. Their conclusions are consistent with our findings, and our research further strengthens the previous results. However, the abundance of this patient cohort allowed us to further investigate the potential benefits of having recommended the surgery in appropriately selected NSCLC patients with stage III.
The latest treatment guidelines have recommended operative resection in selected NSCLC patients with stage IV, such as those cases with early-stage lung cancer and limited extrathoracic metastatic tumors, but there was minimal evidence [19]. Our result proved that stage IVB NSCLC patients who undergo the recommended surgery are unlikely to have better OS than the nonoperative group, but those with stages IVA-N0 and IVA-N2 might have a better OS. Previous studies have shown that surgery for cT1-2, N0-1, M1 or cT3, N0, and M1 disease did not seem to affect prognosis when compared with nonoperative therapy; however, because surgery does not provide an obvious benefit, they should not be recommended to stage IV patients with mediastinal nodal cases or more locally advanced tumors [13]. These conclusions are inconsistent with our findings. However, some other studies were consistent with our results. Yamaguchi et al. [12] reported that by utilizing the local treatment for distant metastases and therapeutic pneumonectomy, some M1b-cStage IV NSCLC patients had more prolonged survival than others. Kawano et al. [11] reported that operative treatment could prolong the survival of NSCLC patients with stage IV on the premise that patients can tolerate surgery. In the clinical setting, stage IV NSCLC patients rarely undergo curative-intent resections. However, a strength of our study was that we were able to use a robust statistical method and an extensive comprehensive population-based SEER database to determine the OS gain among NSCLC patients. After controlling for age, sex, race, marital status, primary site, grade, laterality, histology, AJCC stage, radiation, chemotherapy, and type of surgery. We found that stage IVA patients with chemotherapy might have a significantly better impact on the survival benefits. This finding implied that chemotherapy might have a more positive effect in determining the survival benefits of stage IV patients.
A logistic univariate analysis revealed the following possible reasons for refusal to recommend surgery for patients with advanced NSCLC: stage at diagnosis, age, gender, race, marital status, and histology. Surgery is the preferred treatment for stage I lung cancer since it is curable. There are other powerful and healing therapies available. However, some patients only receive palliative treatment, while others get no treatment at all [25]. According to the search [25], comorbidities, patient preferences, and illness progression are the main causes of treatment refusal. Therefore, in addition to the previously mentioned reasons in this study, the impact of comorbidities, patient decisions, disease progression, patients' financial ability, and acceptance of doctors and techniques on whether advanced NSCLC patients refuse recommended surgery is thus poorly understood and requires further research.
Primary treatment strategies might be changing as systemic therapies develop, but some researchers have suggested that positive responses to systemic therapy would make more NSCLC patients eligible for operative management [18, 26, 27]. According to the Robinson classification, specific cases of N2-patients had a higher possibility of survival as a part of multimodal therapy after an operative therapy [28, 29]. Immunotherapies have revolutionized the treatment of advanced NSCLC. Evidence has emerged that it can be used for stage III disease [30, 31]. However, how best to combine surgery with other new therapies needs more studies. In addition, for stage III and IV patients, further studies are needed to find better therapeutic options for NSCLC patients.
Nevertheless, this study has several limitations. Firstly, our analysis is based on the assumption that clinicians followed consistent criteria (e.g., NCCN guidelines) to recommend the most appropriate treatments to patients. Secondly, our study was powerless to assess the effect of other therapies (e.g., the multimodality approach) on survival when combined with resection surgery. Although we recruited 3331 advanced NSCLC patients who were recommended for surgery, all of whom were alive or dead due to cancer, we were unable to assess the impact of comorbidities on outcomes. Thirdly, although recommended primary tumor resection might not have an impact on the survival benefits in stage IVA-N1 and N3 patients, the sample size was limited. Finally, this article relies heavily on statistical analysis, and we must acknowledge the limitations of statistics. In future studies, a larger sample size would be preferred to validate the findings shown in this study. Besides, we would like to emphasize that correlation does not imply causation. Further study is required to understand the direct cause of improved OS in the specific advanced NSCLC patients after recommended resection surgery.
In conclusion, this NSCLC population-based study found that recommended operation was associated with prolonged survival in stage IIIA-N0, stage IIIA-N1, stage IVA-N0, and stage IVA-N2 patients compared with those who were recommended for operation but not performed. However, in NSCLC patients with stages IIIA-N2, IIIB, IIIC, IVA-N1, IVA-N3, and IVB, no evidence suggests that the recommended operation could significantly improve survival time.
Data Availability
The data used to support the findings of this study have been deposited in the SEER repository (https://seer.cancer.gov/).
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
Hui Wang, Di Yang, and Yan Lv contributed equally to this work.
Supplementary Materials
Supplemental Figure 1: SMD plot of each variable after processing using different methods. IPTW: the inverse probability of treatment weighting; SMRW: the standardized mortality ratio weighting; PA: pairwise algorithmic; OW: overlap weight.
References
- 1.Chen W., Zheng R., Baade P. D., et al. Cancer statistics in China, 2015. CA: A Cancer Journal for Clinicians . 2016;66(2):115–132. doi: 10.3322/caac.21338. [DOI] [PubMed] [Google Scholar]
- 2.Herbst R. S., Morgensztern D., Boshoff C. The biology and management of non-small cell lung cancer. Nature . 2018;553(7689):446–454. doi: 10.1038/nature25183. [DOI] [PubMed] [Google Scholar]
- 3.Siegel R. L., Miller K. D., Fuchs H. E., Jemal A. Cancer statistics, 2021. CA: A Cancer Journal for Clinicians . 2021;71(1):7–33. doi: 10.3322/caac.21654. [DOI] [PubMed] [Google Scholar]
- 4.Sosa E., D’Souza G., Raz D. J., et al. Racial and socioeconomic disparities in lung cancer screening in the United States: a systematic review. CA: A Cancer Journal for Clinicians . 2021;71(4):299–314. doi: 10.3322/caac.21671. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Blandin Knight S., Crosbie P. A., Balata H., Chudziak J., Hussell T., Dive C. Progress and prospects of early detection in lung cancer. Open Biol . 2017;7(9) doi: 10.1098/rsob.170070.170070 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Aggarwal C., Rolfo C. D., Oxnard G. R., Gray J. E., Sholl L. M., Gandara D. R. Strategies for the successful implementation of plasma-based NSCLC genotyping in clinical practice. Nature Reviews Clinical Oncology . 2021;18(1):56–62. doi: 10.1038/s41571-020-0423-x. [DOI] [PubMed] [Google Scholar]
- 7.Osarogiagbon R. U., Veronesi G., Fang W., et al. Early-stage NSCLC: advances in thoracic oncology 2018. Journal of Thoracic Oncology . 2019;14(6):968–978. doi: 10.1016/j.jtho.2019.02.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Puig C. A., Wigle D. Surgery for stage IV non-small cell lung cancer. Journal of Thoracic Disease . 2020;12(4):1612–1614. doi: 10.21037/jtd.2020.03.32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Rami-Porta R., Wittekind C., Goldstraw P. Complete resection in lung cancer surgery: from definition to validation and beyond. Journal of Thoracic Oncology . 2020;15(12):1815–1818. doi: 10.1016/j.jtho.2020.09.006. [DOI] [PubMed] [Google Scholar]
- 10.Sun Z., Sui X., Yang F., Wang J. Effects of primary tumor resection on the survival of patients with stage IV extrathoracic metastatic non-small cell lung cancer: a population-based study. Lung Cancer . 2019;129:98–106. doi: 10.1016/j.lungcan.2018.11.012. [DOI] [PubMed] [Google Scholar]
- 11.Kawano D., Takeo S., Katsura M., Tsukamoto S., Masuyama E., Nakaji Y. Surgical treatment of stage IV non-small cell lung cancer. Interactive Cardiovascular and Thoracic Surgery . 2012;14(2):167–170. doi: 10.1093/icvts/ivr036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Yamaguchi M., Edagawa M., Suzuki Y., et al. Pulmonary resection for synchronous m1b-cStage IV non-small cell lung cancer patients. The Annals of Thoracic Surgery . 2017;103(5):1594–1599. doi: 10.1016/j.athoracsur.2016.08.098. [DOI] [PubMed] [Google Scholar]
- 13.Yang C. F. J., Gu L., Shah S. A., et al. Long-term outcomes of surgical resection for stage IV non-small-cell lung cancer: a national analysis. Lung Cancer . 2018;115:75–83. doi: 10.1016/j.lungcan.2017.11.021. [DOI] [PubMed] [Google Scholar]
- 14.van Meerbeeck J. P., Kramer G. W. P. M., Van Schil P. E. Y., et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. JNCI Journal of the National Cancer Institute . 2007;99(6):442–450. doi: 10.1093/jnci/djk093. [DOI] [PubMed] [Google Scholar]
- 15.Albain K. S., Swann R. S., Rusch V. W., et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. The Lancet . 2009;374(9687):379–386. doi: 10.1016/S0140-6736(09)60737-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Evison M., Edwards J., McDonald F., Popat S. Stage III non-small cell lung cancer: a UK national survey of practice. Clinical Oncology . 2020;32(8):527–536. doi: 10.1016/j.clon.2020.03.001. [DOI] [PubMed] [Google Scholar]
- 17.Jazieh A. R., Zeitouni M., Alghamdi M., et al. Management guidelines for stage III non-small cell lung cancer. Critical Reviews in Oncology . 2021;157 doi: 10.1016/j.critrevonc.2020.103144.103144 [DOI] [PubMed] [Google Scholar]
- 18.David E. A., Canter R. J., Chen Y., Cooke D. T., Cress R. D. Surgical management of advanced non-small cell lung cancer is decreasing but is associated with improved survival. The Annals of Thoracic Surgery . 2016;102(4):1101–1109. doi: 10.1016/j.athoracsur.2016.04.058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Ettinger D. S., Wood D. E., Aggarwal C., et al. OCN NCCN guidelines insights: non-small cell lung cancer, version 1.2020. Journal of the National Comprehensive Cancer Network . 2019;17(12):1464–1472. doi: 10.6004/jnccn.2019.0059. [DOI] [PubMed] [Google Scholar]
- 20.Hanna N. H., Schneider B. J., Temin S., et al. Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) Joint guideline update. Journal of Clinical Oncology . 2020;38(14):1608–1632. doi: 10.1200/JCO.19.03022. [DOI] [PubMed] [Google Scholar]
- 21.Schneider B. J., Ismaila N., Aerts J., et al. Lung cancer surveillance after definitive curative-intent therapy: ASCO guideline. Journal of Clinical Oncology . 2020;38(7):753–766. doi: 10.1200/JCO.19.02748. [DOI] [PubMed] [Google Scholar]
- 22.Dai C., Shen J., Ren Y., et al. Choice of surgical procedure for patients with non-small-cell lung cancer ≤ 1 cm or > 1 to 2 cm among lobectomy, segmentectomy, and wedge resection: a population-based study. Journal of Clinical Oncology . 2016;34(26):3175–3182. doi: 10.1200/JCO.2015.64.6729. [DOI] [PubMed] [Google Scholar]
- 23.Choe G., Carr R., Molena D. New surgical approaches in the treatment of non-small cell lung cancer. Clinics in Chest Medicine . 2020;41(2):175–183. doi: 10.1016/j.ccm.2020.02.00. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Ettinger D. S., Wood D. E., Aisner D. L., et al. Non-small cell lung cancer, version 5.2017, NCCN clinical practice guidelines in oncology. Jounrnal of National Comprehensive Cancer Network . 2017;15(4):504–535. doi: 10.6004/jnccn.2017.0050. [DOI] [PubMed] [Google Scholar]
- 25.Christensen N. L., Dalton S., Ravn J., Christensen J., Jakobsen E., Rasmussen T. R. Treatment no treatment and early death in Danish stage I lung cancer patients. Lung Cancer . 2019;131:1–5. doi: 10.1016/j.lungcan.2019.03.007. [DOI] [PubMed] [Google Scholar]
- 26.Friedlaender A., Addeo A., Russo A., Gregorc V., Cortinovis D., Rolfo C. D. Targeted therapies in early stage NSCLC: hype or hope. International Journal of Molecular Sciences . 2020;21(17):p. 6329. doi: 10.3390/ijms21176329. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Duan H., Liang L., Xie S., Wang C. The impact of order with radiation therapy in stage IIIA pathologic N2 NSCLC patients: a population-based study. BMC Cancer . 2020;20(1):p. 809. doi: 10.1186/s12885-020-07309-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Robinson L. A., Ruckdeschel J. C., Wagner H., Stevens C. W. Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines (2nd edition) Chest . 2007;132(3):243S–265S. doi: 10.1378/chest.07-1379. [DOI] [PubMed] [Google Scholar]
- 29.Hofmann H. S., Braess J., Leipelt S., et al. Multimodality therapy in subclassified stage IIIA-N2 non-small cell lung cancer patients according to the Robinson classification: heterogeneity and management. Journal of Thoracic Disease . 2018;10(6):3585–3594. doi: 10.21037/jtd.2018.05.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Bryan D. S., Donington J. S. The role of surgery in management of locally advanced non-small cell lung cancer. Current Treatment Options in Oncology . 2019;20(4):p. 27. doi: 10.1007/s11864-019-0624-7. [DOI] [PubMed] [Google Scholar]
- 31.Shang S., Wang R., Wang F., Wu M., Chen D., Yu J. Treatment patterns for patients with unresected stage III NSCLC: analysis of the surveillance, Epidemiology, and End results (SEER) database. Frontiers in Oncology . 2022;12 doi: 10.3389/fonc.2022.874022.874022 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Figure 1: SMD plot of each variable after processing using different methods. IPTW: the inverse probability of treatment weighting; SMRW: the standardized mortality ratio weighting; PA: pairwise algorithmic; OW: overlap weight.
Data Availability Statement
The data used to support the findings of this study have been deposited in the SEER repository (https://seer.cancer.gov/).