Abstract
Objective
The outcomes of patients with operable non–small cell lung cancer who forgo surgery remain poorly defined in the era of modern systemic and radiation therapies. This study evaluated the survival of untreated operable non–small cell lung cancer compared with nonsurgically treated patients using contemporary data.
Methods
Using the National Cancer Database (2018-2022), we identified patients with clinical stage I to IIIB non–small cell lung cancer considered operable. Patients were classified as untreated, treated nonoperatively (stereotactic body radiotherapy, radiotherapy, chemotherapy, immunotherapy, or combinations), or surgically treated with/without perioperative therapy. Baseline characteristics and overall survival were compared using chi-square, t tests, Kaplan–Meier, and Cox regression analyses. To further address selection bias, a 1:1 propensity score–matched analysis was performed comparing untreated operable patients with those treated nonsurgically. Matching was conducted using demographic, clinical, and facility-level variables, and survival was reevaluated in the matched cohort.
Results
Among 155,693 operable patients, 149,686 (96%) underwent surgery, 4373 (3%) received nonoperative treatment, and 1634 (1%) were untreated. Untreated patients were younger (72.3 vs 73.2 years, P = .0015), more often White (79% vs 86%, P < .001), and more frequently treated at academic centers (29% vs 24%, P < .001). Median overall survival for untreated versus treated nonoperatively patients was 45 versus 64 months for stage I, 16 versus 37 months for stage II, and 9 versus 40 months for stage III disease. Five-year survival was 43%, 17%, and 14% for untreated patients versus 53%, 34%, and 40% for nonoperatively treated patients, respectively. Among patients with stage IIIB, median survival was 9 months for untreated versus 33 months with nonsurgical therapy (P < .001). On multivariable analysis, increasing age (hazard ratio, 1.04, 95% CI, 1.01-1.07, P = .02), squamous histology (hazard ratio, 2.24, 95% CI, 1.22-4.10, P = .01), and certain facility locations were independently associated with survival differences. After 1:1 propensity score matching, 1629 nonsurgically treated patients were matched to 1628 untreated patients with similar age, sex, comorbidity burden, and year of diagnosis. In the matched cohort, untreated patients continued to demonstrate significantly inferior overall survival compared with those receiving nonsurgical therapy across stages, confirming the robustness of the primary findings.
Conclusions
Patients with operable non–small cell lung cancer who undergo surgical treatment achieve the most favorable survival outcomes. Those treated nonoperatively in the modern era of precision oncology also experience a meaningful survival advantage. In contrast, untreated operable non–small cell lung cancer remains associated with poor prognosis, with median survival less than 1 year for stage III disease. These findings highlight the critical importance of offering active treatment, surgical or nonsurgical, whenever feasible.
Key Words: lung cancer, nonoperative management, non–small cell lung cancer, nonsurgical treatment, survival outcomes
Graphical Abstract
Kaplan–Meier survival curve of NSCLC (stage I-III).
Central Message.
When surgery is not feasible or declined, nonsurgical definitive therapies should still be strongly considered to improve survival outcomes.
Perspective.
This study showed that nonsurgical definitive therapies can improve overall survival of operable NSCLC. Patients who were operable but received no therapy experienced markedly shorter median survival and negligible long-term survival compared with those treated nonsurgically.
Surgical resection remains the cornerstone of curative intent therapy for operable non–small cell lung cancer (NSCLC), offering the most durable long-term survival in appropriately selected patients. Current clinical practice guidelines continue to recommend surgical resection for operable early-stage NSCLC, supported by robust evidence demonstrating superior local control and overall survival compared with nonsurgical management.1
The natural history of untreated, operable NSCLC is associated with poor outcomes, with historical data demonstrating rapid disease progression and limited survival in the absence of definitive therapy.2,3 Despite this established knowledge, a subset of patients with technically operable disease do not undergo surgery for various reasons: refusal, socioeconomic hindrances, perceived operative risk, or referral delays.
Advances in systemic therapy, immunotherapy, and radiation techniques have changed the treatment landscape of NSCLC, raising questions about outcomes when surgery is omitted in favor of nonsurgical approaches.4 More recently, perioperative systemic therapy (particularly immune checkpoint inhibitors) has demonstrated significant improvements in event-free and overall survival when combined with surgery in resectable NSCLC.5, 6, 7 These trials reinforce the central role of surgery as a necessary component of curative therapy even in the era of effective systemic treatments.
Stereotactic body radiotherapy (SBRT) has emerged as an alternative for patients who are medically inoperable or decline surgery. Although SBRT achieves high rates of local control, comparative analyses suggest inferior long-term survival compared with surgery in operable patients,8, 9, 10 and professional societies continue to endorse surgery as the preferred modality when feasible.11
Although prior population-based studies have characterized the prognosis of untreated NSCLC, most predate the introduction of immunotherapy and modern radiation techniques, limiting their applicability to current practice.2 Moreover, national patterns and outcomes of operable patients who receive no treatment versus those managed nonsurgically in the modern era remain incompletely defined.
The present study used a contemporary National Cancer Database (NCDB) to compare survival outcomes among patients with operable NSCLC who receive no treatment with those treated nonsurgically with the aforementioned, providing updated insight into the consequences of forgoing surgery in the current therapeutic landscape.
Materials and Methods
Data Source
This study is a retrospective cohort analysis using data from the NCDB Non–Small Cell Lung Cancer Participant User File (PUF). The NCDB is a nationwide oncology outcomes database jointly sponsored by the American College of Surgeons Commission on Cancer and the American Cancer Society, capturing approximately 70% of newly diagnosed invasive cancers in the United States annually. Data are abstracted from more than 1500 Commission on Cancer–accredited facilities. The present analysis used a deidentified NCDB PUF, and the study was exempt from review by the Cedars-Sinai Medical Center Institutional Review Board.
Study Design and Patient Selection
Using the 2022 NCDB PUF, we identified patients diagnosed with clinically operable NSCLC between 2018 and 2022. The primary cohort included patients with clinical stage I to IIIA disease, based on the American Joint Committee on Cancer eighth edition staging system. A separate secondary analysis was performed among patients with stage IIIB disease deemed operable.
Patients were included if they had histologically confirmed NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, neuroendocrine tumor, adenosquamous/mixed, and others). Cases were excluded if key data elements were missing, including treatment status, clinical stage, or survival time.
Clinical staging as recorded in the NCDB was used for all analyses. Operability was defined based on clinical stage and the absence of documented contraindications to surgical intervention.
Treatment Definitions and Study Groups
Patients were categorized into the groups below. Operability was defined based on clinical staging and absence of contraindications to surgery as recorded in the NCDB.
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•
Operable – Untreated: patients with operable NSCLC who did not receive any cancer-directed treatment (control cohort)
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•
Operable – Nonsurgically Treated: patients who received definitive nonsurgical therapy, including SBRT only, conventionally fractionated radiotherapy only, immunotherapy only, chemotherapy only, or any combination of these
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•
Operable – Surgically Treated: patients who underwent surgical resection, including wedge resection, segmentectomy, lobectomy, or unspecified lung resection, with or without additional perioperative therapy
Variables and Covariates
Collected variables included demographic characteristics (age, sex, race, primary insurance payer, year of diagnosis), clinical factors (Charlson–Deyo comorbidity score, tumor size, histologic subtype, and clinical stage), and facility characteristics (facility type and facility geographic location). Race was categorized as White, Black, Asian, Other, or Unknown. Comorbidity burden was assessed using the Charlson–Deyo score and categorized as 0, 1, 2, or 3 or more.
Outcomes
The primary outcome was overall survival, defined as the time from diagnosis to death from any cause or last follow-up.
Statistical Analysis
Baseline demographic and clinical characteristics were summarized using descriptive statistics, with continuous variables reported as medians with interquartile ranges and categorical variables as counts and percentages. Overall survival was estimated using the Kaplan–Meier method, and survival distributions were compared using the log-rank test. Multivariable Cox proportional hazards regression models were used to evaluate the association between clinical and treatment variables and overall survival, adjusting for age, sex, race, comorbidity index, tumor stage, tumor size, histology, grade, insurance status, socioeconomic factors, and facility type. Hazard ratios (HRs) with 95% CIs were reported. Separate multivariable models were generated for the untreated operable cohort (stage I-IIIA) and the untreated stage IIIB–only cohort. Subgroup analyses were performed for each stage. To mitigate confounding related to nonrandom treatment allocation, a propensity score–matched analysis was performed comparing untreated operable patients with those treated nonsurgically. Propensity scores were estimated using multivariable logistic regression including age, sex, race, primary payer, Charlson–Deyo comorbidity score, year of diagnosis, facility type, facility geographic location, histology, tumor size, and clinical stage. One-to-one nearest neighbor matching without replacement was performed using a caliper width of 0.2 of the SD of the logit of the propensity score. Covariate balance after matching was assessed using standardized mean differences and chi-square testing. Overall survival in the matched cohort was evaluated using Kaplan–Meier methods and compared with the log-rank test. All statistical analyses were performed using STATA 19.5 (StataCorp).
Results
Study Cohort
Between 2018 and 2022, a total of 155,693 patients with clinically operable stage I to IIIA NSCLC were identified. Of these, 149,686 patients (96%) underwent surgical resection with or without additional therapy, 4373 patients (3%) received nonsurgical treatment, and 1634 patients (1%) received no treatment. Among nonsurgically managed patients, treatment strategies included SBRT, conventionally fractionated radiotherapy, immunotherapy alone, chemotherapy alone, or combinations of these modalities.
Patient Characteristics
Baseline characteristics of patients are summarized in Table 1. Untreated patients were slightly younger than nonsurgically treated patients (mean age 72.3 vs 73.2 years, P = .0015) and were more frequently female (55% vs 52%, P = .032). Untreated patients were less likely to be White (79% vs 86%) and more likely to be Black (15% vs 10%) compared with nonsurgically treated patients (P < .001).
Table 1.
Characteristics of patients with untreated operable and nonsurgically treated operable non–small cell lung cancer
| Characteristics | Nonsurgically treated (n = 4373) |
Untreated (control) (n = 1634) |
P value |
|---|---|---|---|
| Sex, no. (%) | .032 | ||
| Male | 2089 (48) | 730 (45) | |
| Female | 2284 (52) | 904 (55) | |
| Age, y, mean (SD) | 73.2 (8.7) | 72.3 (9.1) | .0015 |
| Race, no. (%) | <.001 | ||
| White | 3761 (86) | 1296 (79) | |
| Black | 438 (10) | 247 (15) | |
| Asian | 91 (2) | 50 (3) | |
| Others | 54 (1) | 27 (2) | |
| Unknown | 29 (1) | 14 (1) | |
| Primary payor, no. (%) | <.001 | ||
| Medicaid | 248 (6) | 132 (8) | |
| Medicare | 3364 (77) | 1190 (73) | |
| No insurance | 38 (1) | 36 (2) | |
| Other government | 172 (4) | 706 (3) | |
| Private insurance/managed care | 513 (12) | 231 (14) | |
| Unknown | 38 (1) | 22 (1) | |
| Charlson-Deyo score, no. (%) | .719 | ||
| 0 | 2344 (54) | 869 (53) | |
| 1 | 1038 (24) | 378 (23) | |
| 2 | 537 (12) | 201 (12) | |
| 3+ | 454 (10) | 186 (11) | |
| Year of diagnosis, no. (%) | .003 | ||
| 2018 | 853 (20) | 357 (22) | |
| 2019 | 842 (19) | 364 (22) | |
| 2020 | 845 (19) | 303 (19) | |
| 2021 | 934 (21) | 324 (20) | |
| 2022 | 899 (21) | 286 (18) | |
| Facility type, no. (%) | <.000 | ||
| Academic program | 1068 (24) | 475 (29) | |
| Nonacademic program | 3303 (76) | 1150 (71) | |
| Facility location, no. (%) | <.001 | ||
| New England | 299 (7) | 114 (7) | |
| Middle Atlantic | 610 (14) | 246 (15) | |
| South Atlantic | 878 (20) | 311 (19) | |
| East North Central | 1011 (23) | 348 (21) | |
| East South Central | 396 (9) | 118 (7) | |
| West South Central | 447 (10) | 130 (8) | |
| Mountain | 194 (4) | 123 (8) | |
| West North Central | 149 (3) | 69 (4) | |
| Pacific | 387 (9) | 166 (10) | |
| Unknown | 2 (0) | 9 (1) | |
| Histology, no. (%) | <.001 | ||
| Adenocarcinoma | 2644 (60) | 816 (50) | |
| Squamous cell carcinoma | 1509 (35) | 542 (33) | |
| Large cell carcinoma | 17 (2) | 6 (0) | |
| Neuroendocrine tumor | 70 (2) | 228 (14) | |
| Adenosquamous/mixed | 102 (2) | 31 (2) | |
| Other | 31 (1) | 11 (1) | |
| Tumor size, no. (%) | <.001 | ||
| No mass/tumor found | 1 (0) | 2 (0) | |
| <1 cm | 4212 (96) | 1536 (94) | |
| 1 cm ≤T < 2 cm | 12 (0) | 20 (1) | |
| ≥2 cm | 2 (0) | 1 (0) | |
| Unknown | 146 (3) | 75 (5) | |
| Clinical stage, no. (%) | <.001 | ||
| I | 3237 (74) | 1010 (62) | |
| II | 678 (16) | 340 (21) | |
| III | 458 (10) | 284 (17) |
Untreated patients more frequently uninsured or covered by Medicaid (P < .001). Charlson–Deyo comorbidity scores were similar between groups (P = .719). Untreated patients were more commonly treated at academic centers (29% vs 24%, P < .001) and demonstrated regional variation in location of facility (P < .001).
Histologic subtype differed between cohorts, with a higher proportion of adenocarcinoma among nonsurgically treated patients (60% vs 50%) and a markedly higher proportion of neuroendocrine tumors among untreated patients (14% vs 2%, P < .001). Clinical stage distribution also differed, with untreated patients more likely to present with stage II or III disease (P < .001). The distribution of treatment strategies by clinical stage is shown in Table 2. Figure E1 shows Kaplan–Meier curves exhibiting different survival trajectories across SBRT, radiotherapy, chemotherapy, immunotherapy, and combination regimens across stages.
Table 2.
Number of patients who underwent each treatment strategy by clinical stage from 2018 to 2022
| Clinical stage | Total | Surgical (± other treatments) no. (%) |
Nonsurgical treatment no. (%) |
No treatment no. (%) |
|---|---|---|---|---|
| Stage I | 121,864 (78) | 117,617 (79) | 3237 (74) | 1010 (62) |
| Stage II | 22,384 (14) | 21,366 (17) | 678 (16) | 340 (21) |
| Stage III | 11,445 (7) | 10,703 (12) | 458 (10) | 284 (17) |
| Stage IIIB only | 2764 | 2499 | 150 | 115 |
Figure E1.
Kaplan–Meier survival curves for (A) all stages, clinical stage (B) I, (C) II, (D), III, and (E) IIIB for surgically treated patients, nonsurgically treated operable patients (disaggregated), and untreated operable patients. SBRT, Stereotactic body radiation therapy.
Overall Survival
Overall survival differed substantially between untreated operable patients and those treated nonsurgically across all stages (Table 3 and Figure 1, B-D). Among patients with stage I disease, median overall survival was 45.3 months for untreated patients compared with 64.4 months for those treated nonsurgically, with corresponding 5-year survivals of 42.7% and 52.6%, respectively.
Table 3.
Stage-specific median and 5-year survival of operable patients who were treated nonsurgically and untreated
| Clinical stage | Treated nonsurgically |
Untreated |
||
|---|---|---|---|---|
| Median survival (mo) | 5-y survival (%) | Median survival (mo) | 5-y survival (%) | |
| Stage I | 64.4 | 52.6 | 45.3 | 42.7 |
| Stage II | 36.6 | 34.0 | 16.1 | 16.8 |
| Stage III | 40.2 | 40.0 | 9.0 | 14.1 |
| Stage IIIB only | 33.4 | 24.1 | 9.0 | 0 |
Figure 1.
Kaplan–Meier survival curves for (A) all stages, clinical stage (B) I, (C) II, (D) III, and (E) IIIB for surgically treated patients (blue), nonsurgically treated operable patients (red), and untreated operable patients (green) (95% CI).
For stage II disease, median survival was 16.1 months among untreated patients versus 36.6 months among nonsurgically treated patients, with 5-year survivals of 16.8% and 34.0%, respectively. In stage III disease, untreated patients demonstrated a median survival of 9.0 months and a 5-year survival of 14.1%, compared with a median survival of 40.2 months and a 5-year survival of 40.0% among nonsurgically treated patients. Among patients with stage IIIB disease specifically, median survival was 9 months for untreated patients compared with 33 months for those receiving nonsurgical therapy (P < .001).
Multivariable Analysis
On multivariable Cox proportional hazards modeling among untreated operable patients (Table 4), increasing age was independently associated with worse overall survival (HR, 1.04 per year, 95% CI, 1.03-1.04; P < .001). Higher Charlson–Deyo comorbidity scores were also associated with increased mortality, with HRs of 1.49 (95% CI, 1.20-1.89) for a score of 2 and 1.71 (95% CI 1.26-1.98) for a score of 3 or more compared with a score of 0.
Table 4.
Cox proportional hazards model of patients with untreated, operable non–small cell lung cancer
| Covariate | Level | HR (95% CI) | P value |
|---|---|---|---|
| Sex | Male | Reference | .129 |
| Female | 0.89 (0.76-1.04) | ||
| Age | 1.04 (1.03-1.04) | <.001 | |
| Race | White | Reference | |
| Black | 0.87 (0.70-1.09) | .22 | |
| Asian | 0.61 (0.36-1.02) | .06 | |
| Others | 0.56 (0.27-1.20) | .14 | |
| Unknown | 1.99 (0.93-4.24) | .08 | |
| Charlson-Deyo Score | 0 | Reference | |
| 1 | 1.16 (0.96-1.41) | .125 | |
| 2 | 1.49 (1.20-1.89) | <.001 | |
| 3+ | 1.71 (1.26-1.98) | <.001 | |
| Facility location | New England | Reference | |
| Middle Atlantic | 0.94 (0.67-1.32) | .73 | |
| South Atlantic | 0.99 (0.72-1.36) | .93 | |
| East North Central | 1.22 (0.83-1.79) | .31 | |
| East South Central | 0.77 (0.52-1.14) | .78 | |
| West South Central | 0.91 (0.71-1.14) | .39 | |
| Mountain | 1.04 (0.70-1.54) | .84 | |
| West North Central | 1.23 (0.76-2.00) | .40 | |
| Pacific | 1.03 (0.72-1.47) | .86 | |
| Histology, no. (%) | Adenocarcinoma | Reference | |
| Squamous cell carcinoma | 1.70 (1.45-1.99) | <.001 | |
| Large cell carcinoma | 1.57 (0.50-4.98) | .44 | |
| Neuroendocrine tumor | 0.26 (0.17-0.39) | <.001 | |
| Adenosquamous/mixed | 0.70 (0.39-1.26) | .24 | |
| Other | 2.72 (1.10-6.72) | .03 | |
| Clinical stage | I | Reference | |
| II | 1.83 (1.52-2.21) | <.001 | |
| III | 2.80 (2.31-3.39) | <.001 |
HR, Hazard ratio.
Histology was independently associated with survival, with squamous cell carcinoma demonstrating significantly worse outcomes compared with adenocarcinoma (HR, 1.70, 95% CI, 1.45-1.99; P < .001). Neuroendocrine tumors were associated with improved survival relative to adenocarcinoma (HR, 0.26, 95% CI, 0.17-0.39; P < .001), whereas adenosquamous or mixed histology was associated with increased mortality (HR, 2.72, 95% CI, 1.10-6.72; P = .03). An analysis excluding neuroendocrine tumors yielded results consistent with the primary analysis (Online Data Supplement and Figure E2).
Figure E2.
Kaplan-Meier survival curves for (A) all stages, clinical stage (B) I, (C) II, (D), III, and (E) IIIB for surgically treated patients (blue), nonsurgically treated operable patients (red), and untreated operable patients (green), excluding neuroendocrine tumors.
Advancing clinical stage remained a strong predictor of mortality, with HRs of 1.83 (95% CI, 1.52-2.21) for stage II disease and 2.80 (95% CI, 2.31-3.39) for stage III disease compared with stage I (both P < .001). Facility location was also independently associated with survival, although no single region demonstrated a consistently superior outcome.
Stage IIIB–Only Subanalysis
A prespecified subanalysis was performed among patients with stage IIIB NSCLC deemed operable with or without prior perioperative therapy.
Study Population and Treatment Distribution
Among 2764 patients with operable stage IIIB disease, 2499 underwent surgical resection with or without additional therapy, 150 received nonsurgical treatment, and 115 received no treatment (Table 2). Nonsurgical therapies included SBRT, conventionally fractionated radiotherapy, immunotherapy alone, chemotherapy alone, or combinations of these modalities. Untreated patients comprised 4.2% of the operable stage IIIB cohort.
Patient Characteristics
Baseline characteristics of untreated and nonsurgically treated operable stage IIIB patients are summarized in Online Data Supplement. Untreated patients were significantly older than nonsurgically treated patients (mean age 73.9 ± 1.0 vs 70.0 ± 0.7 years, P = .002). Sex distribution did not differ between groups (P = .629).
Race, Charlson–Deyo comorbidity score, year of diagnosis, facility type, facility location, histologic subtype, and tumor size distribution were similar between untreated and nonsurgically treated patients (all P > .05). Differences were observed in primary insurance status, with untreated patients more frequently insured by Medicare or uninsured (P = .010).
Overall Survival
Overall survival for patients with stage IIIB differed markedly by treatment strategy (Table 3). Median survival among patients with nonsurgically treated stage IIIB was 33.4 months, with a 5-year survival of 24.1%, whereas untreated patients had a median survival of 9.0 months and no 5-year survivors. These findings were consistent with the broader stage III analysis and highlight the poor prognosis associated with absence of treatment even among operable patients.
Multivariable Analysis
Multivariable Cox proportional hazards modeling was performed among untreated, operable stage IIIB patients to identify factors associated with overall survival (Online Data Supplement). Increasing age was independently associated with worse survival (HR, 1.04 per year, 95% CI, 1.01-1.07; P = .02). Sex was not independently associated with survival.
Histologic subtype was significantly associated with mortality. Compared with adenocarcinoma, squamous cell carcinoma was associated with increased risk of death (HR, 2.24, 95% CI, 1.22-4.10; P = .01). Neuroendocrine tumors and adenosquamous or mixed histology tumors were not significantly associated with survival differences.
Treatment in the South Atlantic and East North Central regions was associated with improved survival compared with New England (HR, 0.15, 95% CI, 0.04-0.56, P = .01 and HR, 0.14, 95% CI, 0.03-0.63, P = .01, respectively). Charlson–Deyo comorbidity score and race were not independently associated with survival in this stage IIIB-only cohort.
Propensity Matched Score Analysis
To further account for baseline differences between untreated and nonsurgically treated patients, a 1:1 propensity-matched analysis was performed. This yielded 1629 patients who were treated nonsurgically matched to 1628 untreated patients (Table 5).
Table 5.
Characteristics of untreated operable and nonsurgically treated operable non–small cell lung cancer among propensity score–matched patients
| Characteristics | Nonsurgically treated (n = 1629) |
Untreated (control) (n = 1628) |
P value |
|---|---|---|---|
| Sex, no. (%) | .537 | ||
| Male | 745 (46) | 727 (45) | |
| Female | 884 (54) | 901 (55) | |
| Age, y, mean (SD) | 72.8 (9.0) | 72.3 (10.2) | .097 |
| Race, no. (%) | <.001 | ||
| White | 1389 (85) | 1291 (79) | |
| Black | 163 (10) | 247 (15) | |
| Asian | 40 (2) | 49 (3) | |
| Others | 17 (1) | 27 (2) | |
| Unknown | 20 (1) | 14 (1) | |
| Primary payor, no. (%) | <.001 | ||
| Medicaid | 118 (8) | 131 (8) | |
| Medicare | 1226 (75) | 1187 (73) | |
| No insurance | 20 (1) | 35 (2) | |
| Other government | 55 (3) | 23 (1) | |
| Private insurance/managed care | 199 (13) | 230 (14) | |
| Unknown | 11 (1) | 22 (1) | |
| Charlson-Deyo score, no. (%) | .875 | ||
| 0 | 857 (53) | 866 (53) | |
| 1 | 379 (23) | 378 (23) | |
| 2 | 214 (13) | 199 (12) | |
| 3+ | 179 (11) | 185 (11) | |
| Year of diagnosis, no. (%) | .004 | ||
| 2018 | 319 (20) | 357 (22) | |
| 2019 | 298 (18) | 364 (22) | |
| 2020 | 321 (20) | 302 (19) | |
| 2021 | 356 (22) | 321 (20) | |
| 2022 | 335 (21) | 284 (17) | |
| Facility type, no. (%) | .014 | ||
| Academic program | 412 (25) | 472 (29) | |
| Nonacademic program | 1216 (75) | 1147 (71) | |
| Facility location, no. (%) | .012 | ||
| New England | 111 (7) | 114 (7) | |
| Middle Atlantic | 234 (14) | 244 (15) | |
| South Atlantic | 330 (20) | 311 (19) | |
| East North Central | 400 (25) | 346 (21) | |
| East South Central | 159 (10) | 118 (7) | |
| West South Central | 141 (9) | 130 (8) | |
| Mountain | 65 (4) | 122 (7) | |
| West North Central | 50 (3) | 68 (4) | |
| Pacific | 138 (8) | 166 (10) | |
| Unknown | 1 (0) | 9 (1) | |
| Histology, no. (%) | <.001 | ||
| Adenocarcinoma | 805 (49) | 816 (50) | |
| Squamous cell carcinoma | 663 (41) | 542 (33) | |
| Large cell carcinoma | 13 (1) | 6 (0) | |
| Neuroendocrine tumor | 60 (4) | 225 (14) | |
| Adenosquamous/mixed | 64 (4) | 30 (2) | |
| Other | 24 (1) | 9 (1) | |
| Tumor size, no. (%) | <.001 | ||
| No mass/tumor found | 1 (0) | 2 (0) | |
| <1 cm | 1571 (96) | 1530 (94) | |
| 1 cm ≤T < 2 cm | 10 (0) | 20 (1) | |
| ≥2 cm | 1 (0) | 1 (0) | |
| Unknown | 46 (3) | 75 (5) | |
| Clinical stage, no. (%) | .009 | ||
| I | 938 (58) | 1010 (62) | |
| II | 348 (21) | 339 (21) | |
| III | 343 (21) | 279 (17) |
After matching, age and Charlson-Deyo comorbidity score were well balanced between groups. Sex distribution was also similar (P = .537), and mean age did not significantly differ. Comorbidity burden was also comparable. Year of diagnosis and facility type remained statistically different, although absolute differences were small.
Some residual differences persisted in race, insurance status, histology, tumor size, and stage distribution. Notably, untreated patients continued to demonstrate a higher proportion of neuroendocrine tumors and stage III disease.
Despite matching, untreated operable patients continued to exhibit significantly worse overall survival compared with nonsurgically treated patients across stages (Figure 2). The magnitude and direction of survival differences were consistent with the unmatched analysis, reinforcing that receipt of nonsurgical therapy was independently associated with improved survival relative to no treatment.
Figure 2.
Kaplan–Meier survival curves of propensity score–matched patients for (A) all stages, clinical stage (B) I, (C) II, (D) III, and (E) IIIB for nonsurgically treated operable patients (blue), and untreated operable patients (red) (95% CI).
Discussion
In this large and contemporary analysis of patients with operable NSCLC from the NCDB, we found that patients with operable disease who received no treatment experienced substantially worse overall survival compared with those treated nonsurgically across clinical stages. Untreated operable patients had median survival measured in months rather than years, and 5-year survivals were markedly lower than those of nonsurgically treated counterparts.
Our results align with prior population-based reports that untreated early-stage NSCLC is generally associated with low long-term survival. A historical analysis of untreated patients with stage I NSCLC in the California Cancer Registry demonstrated a very low probability of 5-year survival (<10%) and median survival often measured in less than 14 months, with most deaths due to lung cancer in the absence of definitive therapy.3 This underscores that despite stage stratification and improvements in staging accuracy, the natural progression of untreated early-stage disease remains poor.
Nonsurgical local therapies, particularly SBRT, were associated with improved survival compared with no treatment in our cohort, consistent with prior studies. In a propensity-matched analysis of localized NSCLC, SBRT was associated with markedly improved median overall survival (47 vs 11 months) and relative 5-year survival compared with no treatment.12 These data support the notion that nonsurgical definitive therapy is preferable to observation when surgery is not an option, including for patients with operable disease who decline surgery or cannot undergo resection.
The role of SBRT in operable patients has been previously evaluated, with radiotherapy outcomes often compared with both conventional radiation and surgical approaches. Retrospective and prospective studies show that SBRT improves local control and overall survival compared with conventional radiotherapy in early-stage NSCLC and achieves high local control rates in medically operable patients.13 Emerging long-term data from clinical trials also suggest that for selected small, early-stage tumors, survival outcomes after stereotactic radiotherapy may approach those seen with surgery, although randomized evidence remains limited with specific lack of information regarding its lack of mediastinal lymph node sampling.14 In the context of our findings, nonsurgical treatment (including SBRT) is associated with a substantial survival benefit over no treatment, underscoring its value for patients unable or unwilling to undergo surgery.
The markedly inferior survival observed among patients with untreated stage IIIB compared with those receiving nonsurgical therapy highlights the persistent lethality of advanced locoregional disease when systemic therapy is not delivered. Although chemotherapy and immunotherapy have become increasingly central to the management of advanced stage NSCLC,15 our findings suggest that a meaningful subset of patients who are otherwise considered operable still fail to receive any systemic treatment, with survival measured in months rather than years. This is particularly relevant in the modern era, where multimodality systemic approaches, including platinum-based chemotherapy with immune checkpoint inhibition, have demonstrated the ability to improve disease control and long-term survival in stage III disease.16 Of note, the substantial survival difference in our data support the idea that even when definitive local therapy is not pursued, initiation of systemic treatment may represent the single most impactful intervention to avoid the extremely poor natural history of untreated stage IIIB NSCLC. Together, these data reinforce the need to identify barriers to chemotherapy and immunotherapy receipt in “operable” stage IIIB patients (particularly older and socioeconomically vulnerable populations) to prevent avoidable undertreatment in a disease state where systemic therapy can meaningfully alter outcomes.
Our multivariable analysis also highlights several clinical features associated with worse survival in untreated operable patients, notably advanced age, higher clinical stage, and higher comorbidity burden. In regard to the latter, the Charlson–Deyo index has been validated to predict long-term outcomes after lung cancer treatment, and higher scores correlate with poorer survival irrespective of treatment modality.17
An important implication of our data is that foregoing all treatment for operable NSCLC carries significant survival outcomes, especially in an era with advanced systemic and radiation therapies. Although various factors undoubtedly contribute to the decision to forgo treatment (eg, frailty, comorbidities, patient preferences), our multivariable models accounted for key demographic and clinical variables, and untreated status remained associated with inferior outcomes across stages. These findings may help with patient discussions regarding the risks of observation and support shared decision-making when patients express doubts about options.
Limitations
Limitations of our study include its retrospective nature that is subject to confounding and selection biases. Lack of information regarding performance status, pulmonary function, and surgical practices, as well as therapy regimens, are also inherent to the registry used. Additionally, causes of treatment refusal or omission are not captured and may reflect unrecorded clinical judgments.
Our analysis demonstrates that untreated operable NSCLC is associated with markedly inferior survival compared with nonsurgical definitive therapies. These real-world outcomes reinforce the urgency of pursuing treatment (whether surgical or nonsurgical) when feasible and underscore the importance of multidisciplinary evaluation to optimize survival outcomes across all stages of operable NSCLC.
Conclusions
In this national cohort of patients with operable NSCLC, omission of treatment was associated with profoundly inferior overall survival across all stages examined. Patients who were operable but received no therapy experienced markedly shorter median survival and negligible long-term survival compared with those treated nonsurgically. These findings add to the existing literature regarding the natural history of untreated operable NSCLC using the most contemporary data considering the latest advances in nonsurgical treatments and demonstrate that observation alone carries substantial mortality risk.
Nonsurgical treatment strategies, including radiation or systemic approaches, were associated with meaningful survival advantages over no treatment, underscoring the value of attempted therapy even when surgical resection is not pursued. Although patient age, comorbidity burden, and disease stage influenced outcomes, untreated status remained strongly associated with worse survival, emphasizing that treatment omission itself is a critical determinant of prognosis.
Collectively, these data support the need for early multidisciplinary evaluation and proactive treatment discussions for all patients with “operable” NSCLC. When surgery is not feasible or declined, nonsurgical definitive therapies should be strongly considered to improve survival outcomes. This study highlights an ongoing opportunity to reduce preventable mortality by minimizing treatment omission in patients with potentially curable lung cancer.
Conflict of Interest Statement
Drs Soukiasian and Brownlee are consultants for Intuitive. All other authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
Supplementary Data
Appendix E1
References
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