Abstract
Background:
Local therapy for the primary tumor is postulated to remove resistant cancer cells as well as immunosuppressive cells from the tumor microenvironment, potentially improving response to systemic therapy. We sought to determine whether resection of the primary tumor was associated with overall survival in a multicentric cohort of patients with single-site synchronous oligometastatic NSCLC.
Study Design:
Using the National Cancer Database (2018–2020), we evaluated patients with clinical stage IVA disease who received systemic therapy and stratified the cohort based on receipt of surgery for the primary tumor (S). We used multivariable and propensity-score matched analysis to study factors associated with S (logistic regression) and overall survival (Cox regression and Kaplan-Meier), respectively.
Results:
Among 12,215 patients identified, 2.9% (N=349) underwent S and 97.1% (N=11,886) systemic therapy (chemotherapy/immunotherapy) without surgery (ST). Patients who underwent S were younger, more often white, had higher income levels, more likely to have private insurance, and were more often treated at an academic facility. Among those who received S, 22.9% (N=80) also underwent resection of the distant metastatic site. On multivariable analysis, metastasis to bone, N+ disease, and higher T-stages were independently associated with less S. On Cox-regression, S and resection of the metastatic site were associated with improved survival (HR 0.67, 95%CI 0.56–0.80 and HR 0.80, 95%CI 0.72–0.88, respectively). After propensity-matching, overall survival was improved in patients undergoing S (median 36.8 vs. 20.8 months, log-rank p<0.001).
Conclusions:
Advances in systemic therapy for NSCLC may change the paradigm of eligibility for surgery. This study demonstrates that surgical resection of the primary tumor is associated with improved overall survival in selected patients with single-site oligometastatic disease.
Keywords: Non-small cell lung cancer, Oligometastasis, Resectability, Local-consolidative therapy, Stage IVA, Lung cancer
Precis:
The treatment paradigm for non-small cell lung cancer is evolving, along with the indications for surgery. In this study, we demonstrate that surgery to the primary site, improves overall survival in patients with single-site oligometastatic disease utilizing real-world data from the National Cancer Database.
Visual abstract:
Resection of the primary tumor is associated with a survival advantage in patients with single-site synchronous oligometastatic non-small cell lung cancer.
Introduction
Historically, the benefit of surgery for patients with metastatic disease from solid tumors has been questioned. (1) The presence of distant metastasis has been considered an exclusion criterion for surgical resection of the primary tumor in many centers and in most randomized clinical trials. (2) However, this paradigm is changing with newer, more effective systemic therapies. Similarly, improved understanding of metastatic disease has allowed us to acknowledge that patients who present with a limited burden of metastases have a different prognosis than those with more diffuse or polymetastatic disease. (3, 4)
Local therapy (LT) of the primary tumor, mainly delivered as radiation therapy or surgical resection, has been an area of interest in the field of lung cancer for the past decade and has been supported by numerous retrospective studies. (5–8) Additionally, prospective evidence supports LT for patients with oligometastatic disease. (9–11) In a multicentric phase II trial by Gomez et. al, 49 patients were randomly assigned to systemic therapy plus local consolidative therapy (to primary and metastasis) consisting of either surgery or radiation, or assigned to systemic therapy alone with best supportive care. (12) This landmark trial demonstrated improvement in disease-free and overall survival, (13) underscoring the potential role of LT in patients with advanced disease.
Improvements in systemic therapy have also caused opinions regarding the role of surgery in advanced NSCLC to rapidly evolve. (14–16) Currently, there are multiple ongoing phase II/III randomized trials evaluating local consolidative therapy in addition to immunotherapy (LONESTAR) (17) and targeted therapies (NORTHSTAR, BRIGHTSTAR) (18, 19) for patients with oligometastatic disease. Although this approach may not still be considered the standard of care in the United States, we anticipate local consolidative surgery to become increasingly utilized in the near future. (20) Thus, we aimed to investigate the outcomes of patients with single-site oligometastatic non-small cell lung cancer (NSCLC) who underwent resection of the primary tumor as part of their multimodal treatment regime. We utilized real-world data from a large, multicentric contemporary cohort in the United States. We hypothesized that surgery, specified as resection of the primary tumor, was associated with improved overall survival in NSCLC patients with single-site oligometastatic disease.
Methods:
a. Data Source
The National Cancer Database (NCDB) is a hospital-based tumor registry sponsored by the American Cancer Society and the American College of Surgeons. It captures data from approximately 1,500 hospitals accredited by the American College of Surgeons Commission on Cancer and includes over 80% of all newly diagnosed cancer cases nationally. All centers accredited by the Commission on Cancer are required to provide de-identified data for analysis of national outcomes. Data are coded and reported according to nationally established protocols coordinated under the North American Association of Central Cancer Registries. All data within the NCDB is de-identified and complies with the privacy requirements of the Health Insurance Portability and Accountability Act (HIPPA). The NCDB has not verified and is not responsible for the statistical validity of the data analyses or the conclusions derived by the authors or readers.
b. Study Population and Design.
For this retrospective cohort study, we used the NCDB (version 2020) and included all patients 18 years or older who received systemic treatment for single-site synchronous oligometastatic (clinical stage IVA and IVB, AJCC 8th Edition) NSCLC diagnosed from 2018 to 2020. The cohort was stratified into two groups based on whether patients underwent surgery, as resection of the primary tumor (S), or were treated with systemic therapy (ST) only. Patients were excluded if they had other clinical stages, if they did not receive systemic therapy as part of their treatment, if they had more than one site (or an unknown number) of metastasis, and if their site of metastasis was not specified in the NCDB (other sites of metastasis). Additionally, patients with discordant information on staging variables, as well as those with missing data on patient, tumor, treatment, and survival variables of interest were excluded from the study (Figure 1).
Figure 1.
Flowchart of selection criteria and cohort characteristics.
Footnote: NSCLC Non-small cell lung cancer. NCDB: National Cancer Database.
The following demographic, clinical, and pathological variables were included for analysis: age, sex, Charlson-Deyo Comorbidity Index (CCI), race/ethnicity, type of treating facility, geographic location, type of insurance, facility location, education level indicator (low defined as >10.9% without a high school degree in the patient’s zip code area, high defined as <10.9% without high school degree in the patient’s zip code area), income level (using median household income for patient’s area of residence, and categorized as below or above the median of proportioned income ranges among all United States zip codes), histologic type, clinical T-stage, clinical N-stage, site of metastasis, type of systemic therapy and sequence, receipt of radiotherapy, radiotherapy volume and sequence, type of surgical approach, extent of resection, resection of distant metastatic site, surgical margins, pathologic T and N stage, 30-day postoperative unplanned readmissions, 30- and 90-day postoperative mortality, vital status and time from diagnosis to last follow-up or death in months. A list of the NCDB variables used in the study is included in the Appendix. We used a complete-case approach to handle missing data, assuming data was missing completely at random. (21) Those patients with missing information in the variables of interest were excluded from the analysis.
c. Study Objectives
Our primary objective was to estimate the association between resection of the primary tumor and overall survival among patients who underwent systemic treatment. Our secondary objectives included studying geographic trends and patterns of local consolidative surgery in the United States and identifying factors associated with this practice in the NCDB cohort.
d. Statistical analysis
First, a comparison was performed among those who received S and those who received ST as their mainstay of treatment. Continuous variables were presented as median and interquartile ranges. Categorical variables were presented as frequencies and percentages. Categorical variables were analyzed using the Chi-Square test, and continuous variables were analyzed using the Mann-Whitney test. To graphically represent the use of local consolidative surgery by geographic region, the ChoroplethRMaps R package was used to generate a United States map.
To study the association between patient, tumor, and treatment characteristics and the receipt of S, we used a multivariable logistic regression model with stepwise backward elimination (using a p=0.10 for stepwise removal), including the following covariates: individual patient characteristics, (age, sex, race, CCI), sociodemographic characteristics, (type of facility, location, insurance, metropolitan area, education indicators, income), treatment (neoadjuvant radiotherapy and systemic therapy) and tumor characteristics (histology, clinical stage, site of metastasis). Covariates were selected based on univariable analysis and clinical reasoning following the study’s aims. Correlation coefficients and variance inflation factors were examined to rule out multicollinearity. The Hosmer-Lemeshow goodness-of-fit test was examined to evaluate the model fit. [22]
e. Propensity score matching.
To compare survival in balanced groups, propensity score matching (without replacement) was performed to control for differences between those who received S and ST. A propensity score for receiving S was created using a logistic regression algorithm, including the variables: age, sex, race, CCI, type of facility, insurance, facility location, income, radiotherapy, chemotherapy, immunotherapy, histology, and site of metastasis. A balanced cohort was created using one-to-one nearest-neighbor matching. The logit of the propensity score was used for matching, with a caliper width of 0.001. Absolute standardized mean differences were used to assess the balance of the covariates. A standardized mean difference ≤0.20 reflected adequate balance.
f. Survival analysis
The Kaplan-Meier method was applied to compute three-year overall survival estimates in the matched cohort. Overall survival was defined as the time of diagnosis to the last follow-up or death from any cause. The Kaplan-Meier curves for ST and S were compared using the log-rank test stratified by match pairs. A stratified Cox proportional hazard regression was used to estimate the hazard ratio for all-cause mortality and its corresponding 95% CI. The proportional hazards assumption was tested using the time-dependent covariate method and scaled Schoenfeld’s residuals. (22) Lastly, a subgroup analysis by age, sex, comorbidity, race, histology, clinical T-stage, clinical N-stage, and site of metastasis was performed to evaluate the association between S and overall survival among different strata. To assess for constancy among the strata, we reported the p-value of the interaction effect. For this interaction analysis, the association was considered constant when the interaction p-value was ≥0.05. All statistical tests were two-sided and considered significant with a p-value <0.05. Statistical analyses were performed using SPSS v.29 (IBM Corporation, Armonk, NY.) and R Core Team 4.1 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Sociodemographic and clinical characteristics of the cohort.
A total of 12,215 patients were included in the study. Among them, 97.1% (11,886) were treated with ST, and 2.9% (349) received S in addition to systemic therapy. In the whole cohort, the median age was 68 years (IQR 61–75), 51.4% of patients were male (6,274), 84.4% (10,305) had 0 or 1 comorbidities, and 78.2% (9,547) were white. Regarding patient characteristics, patients who underwent S were younger (median 66 vs. 68 years, p<0.001), more likely to have lower CCI (CCI 0 or 1: 88.5 vs. 84.2, p=0.029), and were more often white (82.5% vs. 78.0%, p=0.014). Additionally, those patients who received S were more often treated in an academic facility (62.2% vs. 52.2%, p<0.001), had higher rates of private insurance (36.4% vs. 27.5%, p<0.001), had better education indicators (High 53.9% vs. 48.5%, p=0.046) and were more often above median national income levels (64.8% vs. 57.3% p=0.005). There were also important differences by geographic region. In New England, the proportion of patients who underwent S was the highest at 5.2%, compared to the West South-Central region, where only 1.7% received S. (p<0.001) (Figure 2) (Appendix 1)
Figure 2.
Proportion of patients with single site oligometastatic disease who underwent surgery to the primary site by geographic region of the United States.
In terms of oncologic characteristics, patients who underwent S more often had adenocarcinoma (75.9% vs. 70.8%, p<0.001), were more likely to have cT1/cT2 tumors (cT1 29.9% vs. 20.6%, p<0.001) (cT2 26.8% vs. 24.0%, p<0.001), and were less likely to have cN2-N3 disease (cN2 20.8% vs. 39.6%, p<0.001) (cN3 6.4% vs. 23.0%, p<0.001). The site of oligometastatic disease included bone in 26.4% (3,220), brain in 23.5% (2,874), liver in 6.3% (770), lung in 34.6% (4,225), and distant lymph nodes in 9.2% (1,126) of the patients (p<0.001). A summary of baseline characteristics and inclusion criteria is included in Table 1.
Table 1:
Demographics and baseline characteristics of the cohort.
| ST n=11,886 (97.1%) | S n=349 (2.9%) | Total n=12,215 (100%) | p-value | |
|---|---|---|---|---|
|
| ||||
| Age (median, IQR) | 68 (61–75) | 66 (58–72) | 68 (61–75) | <0.001 |
|
| ||||
| Sex, N (%) | ||||
| Male | 6,111 (51.5) | 163 (46.7) | 6,274 (51.4) | 0.077 |
|
| ||||
| CCI, N (%) | ||||
| 0 or 1 | 9.996 (84.2) | 309 (88.5) | 10,305 (84.4) | 0.029 |
| ≥2 | 1,870 (15.8) | 40 (11.5) | 1,910 (15.6) | |
|
| ||||
| Race, N (%) | ||||
| White | 9,259 (78.0) | 288 (82.5) | 9,547 (78.2) | 0.014 |
| Black | 1,479 (12.5) | 23 (6.6) | 1,502 (12.3) | |
| Asian | 492 (4.1) | 20 (5.7) | 512 (4.2) | |
| Hispanic | 475 (4.0) | 14 (4.0) | 489 (4.0) | |
| Other | 161 (1.4) | 4 (1.1) | 165 (1.4) | |
|
| ||||
| Type of treating facility, N (%) | ||||
| Community Center | 5,675 (47.8) | 132(37.8) | 5,807(47.5) | <0.001 |
| Academic/Network | 6,191 (52.2) | 217(62.2) | 6,408 (52.5) | |
|
| ||||
| Type of Insurance, N (%) | ||||
| Uninsured | 277 (2.3) | 8 (2.3) | 285 (2.3) | <0.001 |
| Public | 8,534 (71.9) | 214 (61.3) | 8,748 (71.6) | |
| Private | 3,055 (27.5) | 127 (36.4) | 3,182 (26.0) | |
|
| ||||
| Facility location, N (%) | ||||
| Non-Metropolitan area | 2,238 (18.9) | 69 (19.8) | 2,307 (18.9) | 0.669 |
| Metropolitan area | 9,628 (81.1) | 280 (80.2) | 9,908 (81.1) | |
|
| ||||
| Education level indicator*, N (%) | ||||
| High | 5,750 (48.5) | 188 (53.9) | 5,938 (48.6) | 0.046 |
| Low | 6,116 (51.5) | 161 (46.1) | 6,277 (51.4) | |
|
| ||||
| Income level, N (%) | ||||
| Below national median | 5,067 (42.7) | 123 (35.2) | 5,190 (42.5) | 0.005 |
| Above national median | 6,799 (57.3) | 226 (64.8) | 7,025 (57.5) | |
|
| ||||
| Histologic type, N (%) | ||||
| Adenocarcinoma | 8,405 (70.8) | 265 (75.9) | 8,670 (71.0) | <0.001 |
| Squamous | 2,986 (25.3) | 58 (16.6) | 3,044 (24.9) | |
| Others | 475 (4.0) | 26 (7.4) | 501 (4.1) | |
|
| ||||
| Clinical T-stage, N (%) (N=10,829) | ||||
| cT1 | 2,167 (20.6) | 94 (29.9) | 2,261 (20.9) | <0.001 |
| cT2 | 2,520 (24.0) | 84 (26.8) | 2,604 (24.0) | |
| cT3 | 2,174 (20.7) | 57 (18.2) | 2,231 (20.6) | |
| cT4 | 3,654 (34.8) | 79 (25.2) | 3,733 (34.5) | |
|
| ||||
| Clinical N-stage, N (%) (N=11,426) | ||||
| cN0 | 2,970 (26.8) | 192 (58.7) | 3,162 (27.7) | <0.001 |
| cN1 | 1,174 (10.6) | 46 (14.1) | 1,220 (10.7) | |
| cN2 | 4,397 (39.6) | 68 (20.8) | 4,465 (39.1) | |
| cN3 | 2,558 (23.0) | 21 (6.4) | 2,579 (22.6) | |
|
| ||||
| Site of oligometastasis, N (%) | ||||
| Bone | 3,168 (26.7) | 52 (14.9) | 3,220 (26.4) | <0.001 |
| Brain | 2,736 (23.1) | 138 (39.5) | 2,874 (23.5) | |
| Liver | 749 (6.3) | 21 (6.0) | 770 (6.3) | |
| Lung | 4,105 (34.6) | 120 (34.4) | 4,225 (34.6) | |
| Distant LN | 1,108 (9.3) | 18 (5.2) | 1,126 (9.2) | |
Defined as above/below 15.6% of the population with high school degree in the zip-code area of patient’s residence. CCI Charlson-Deyo Comorbidity Index. IQR interquartile range.
Regarding the type of systemic treatment delivered, those in the ST group were more likely to receive immunotherapy (65.6% vs. 51.9%, p<0.001) and less likely to receive chemotherapy (79.8% vs. 87.1%, p<0.001). Radiation therapy was also given to 46.5% (5,686) of the study participants and was more commonly used in those who underwent S (53.3% vs. 46.4%, p=0.010). In patients who underwent S, radiation was primarily targeted to the central nervous system (59.7%), but also the lung (21.5%), spine/bone (15.1%), and other (non-specified) sites (3.8%). (Table 2)
Table 2.
Type of treatments delivered.
| ST n=11,886 (97.1%) | S n=349 (2.9%) | Total n=12,215 (100%) | p-value | |
|---|---|---|---|---|
|
| ||||
| Immunotherapy, N (%) (N=12,196) * | 7,767 (65.6) | 181 (51.9) | 7,948 (65.2) | <0.001 |
|
| ||||
| Chemotherapy, N (%) (N=12,206) * | 9,467 (79.8) | 304 (87.1) | 9,771 (80.1) | <0.001 |
|
| ||||
| Chemotherapy modality, N (%) (N=9,771) | ||||
| Multiagent | 7,681 (81.1) | 249 (81.9) | 7,939 (81.2) | 0.072 |
| Single agent | 1,522 (16.1) | 53 (17.4) | 1,575 (16.1) | |
| Unknown | 264 (2.8) | 2 (0.7) | 266 (2.7) | |
|
| ||||
| Radiotherapy, N (%) | 5,500 (46.4) | 186 (53.3) | 5,686 (46.5) | 0.010 |
|
| ||||
| Radiotherapy volume, N (%) | ||||
| Central nervous system | 2,029 (36.9) | 111 (59.7) | 2,140 (37.6) | <0.001 |
| Lung and mediastinum | 2,172 (39.5) | 40 (21.5) | 2,212 (38.9) | |
| Spine and bone | 1,114 (20.3) | 28 (15.1) | 1,142 (20.1) | |
| Other/Non-specified | 185 (3.4) | 7 (3.8) | 192 (3.4) | |
Percentages calculated based on the total N for each variable. For those variables with missing data, the total number observations are shown.
Among patients who underwent S, systemic therapy was given before surgery in 21.8% (76) and after surgery in 78.2% (273) of the cases. Most of the operations were performed minimally invasively (thoracoscopic 40.3%, robotic 21.9%, open 37.7%). The extent of resection was either lobectomy (56.2%, N=196) or sub-lobar resection (43.8%, N=153). Among those who underwent S, 22.9% (80) also underwent resection of their distant metastatic site. At 30-day follow-up, rates of unplanned readmission and mortality were 3.7% (13) and 0.3% (1), respectively. A summary of the treatment characteristics and operative outcomes can be found in Table 3.
Table 3.
Treatment characteristics and operative outcomes of patients that underwent surgery to primary site. (N=349)
| Sequence of ST, N (%) (N=12,187) * | |
| ST before surgery | 76 (21.8) |
| Days from systemic therapy start to S | 103 (66–136) |
| ST after surgery | 273(78.2) |
| Days from surgery to ST | 45 (29.7–63) |
|
| |
| Radiotherapy sequence, N (%) | |
| Radiation before S | 56 (16.0) |
| Radiation after S | 124 (35.5) |
| Radiation before and after | 6 (1.7) |
|
| |
| Type of approach, N (%) (N=265) | |
| Robotic | 58 (21.9) |
| Thoracoscopic | 107 (40.3) |
| Open | 100 (37.7) |
|
| |
| Extent of resection, N (%) | |
| Lobectomy | 196 (56.2) |
| Sub-lobar resection | 153 (43.8) |
|
| |
| Resection of distant metastatic site, N (%) | 80 (22.9) |
|
| |
| Surgical margins, N (%) | |
| Negative | 255 (73.1) |
| Positive | 88 (25.2) |
| Unknown | 6 (1.7) |
|
| |
| Pathologic T-stage, N (%) (N=232) | |
| T1 or in situ | 61 (26.3) |
| T2 | 70 (30.2) |
| T3 | 50 (21.6) |
| T4 | 51 (22.0) |
|
| |
| Pathologic N-stage, N (%) (N=176) | |
| N0 | 94 (53.4) |
| N1 | 43 (24.4) |
| N2 | 39 (22.2) |
| N3 | 0 (0) |
|
| |
| 30-day unplanned readmissions, N (%) | 13 (3.7) |
|
| |
| 30-day mortality, N (%) | 1 (0.3) |
|
| |
| 90-day mortality, N (%) | 15 (4.3) |
Factors associated with resection of the primary tumor.
In multivariable logistic regression analysis, older age [adjusted odds ratio (OR) 0.96, 95%CI 0.95 to 0.97], Black race (aOR 0.46, 95%CI 0.28 to 0.75), advanced clinical T (aOR 0.59, 95%CI 0.43 to 0.82) and N-stages (aOR 0.13, 95%CI 0.08 to 0.21), were independently associated with less utilization of S. In contrast, treatment at an academic facility (aOR 1.53, 95%CI 1.20 to 1.95) and national income levels above the median (aOR 1.51, 95%CI 1.16 to 1.96) were independently associated with increased utilization of S. In terms of the site of metastatic disease, bone disease was associated with less S (aOR 0.46, 95%CI 0.32 to 0.66), while the other sites showed no significant associations (Table 4).
Table 4.
Multivariable logistic regression model assessing associations with surgery to the primary site.
| Adjusted Odds ratio | 95% Confidence limits | p-value | ||
|---|---|---|---|---|
|
| ||||
| Age (continuous) | 0.96 | 0.95 | 0.97 | <0.001 |
|
| ||||
| Race | ||||
| White | Ref | Ref | Ref | 0.039 |
| Black | 0.46 | 0.28 | 0.75 | |
| Asian | 1.07 | 0.62 | 1.86 | |
| Hispanic | 1.08 | 0.61 | 1.94 | |
| Other | 0.72 | 0.22 | 2.31 | |
|
| ||||
| Academic/Network facility (Reference: Community facility) | 1.53 | 1.20 | 1.95 | <0.001 |
|
| ||||
| Above median national income level (Reference: Below median) | 1.51 | 1.16 | 1.96 | 0.002 |
|
| ||||
| Clinical T-stage | ||||
| T1 | Ref | Ref | Ref | 0.013 |
| T2 | 0.87 | 0.64 | 1.19 | |
| T3 | 0.75 | 0.53 | 1.05 | |
| T4 | 0.59 | 0.43 | 0.82 | |
|
| ||||
| Clinical N-stage | ||||
| N0 | Ref | Ref | Ref | <0.001 |
| N1 | 0.61 | 0.43 | 0.85 | |
| N2 | 0.25 | 0.18 | 0.33 | |
| N3 | 0.13 | 0.08 | 0.21 | |
|
| ||||
| Site of distant metastasis | ||||
| Lung | Ref | Ref | Ref | <0.001 |
| Bone | 0.46 | 0.32 | 0.66 | |
| Brain | 1.29 | 0.97 | 1.73 | |
| Liver | 0.87 | 0.51 | 1.47 | |
| Distant lymph-nodes | 0.86 | 0.49 | 1.49 | |
Variables included in step 1 of backwards elimination: Age, sex, race, CCI, type of facility, insurance, geographic location, income, education indicator, radiation, systemic therapy (neoadjuvant), histology, CCI, site of metastases, clinical T and clinical N stage.
Factors associated with all-cause mortality.
In multivariable Cox-proportional hazards analysis, undergoing resection of the primary tumor [adjusted hazard ratio (aHR) 0.67, 95%CI 0.56 to 0.80] and undergoing resection of the distant metastatic site (aHR 0.80, 95%CI 0.72 to 0.88), were independently associated with increased overall survival. In contrast, advanced age (aHR 1.02, 95%CI 1.01 to 1.02), increased CCI (CCI≥3 aHR 1.40, 95%CI 1.27 to 1.53), squamous cell histology (aHR 1.27, 95%CI 1.20 to 1.35), and advanced T classification (cT4: aHR 1.35, 95%CI 1.25 to 1.45) and N-stages (cN2: aHR 1.22, 95%CI 1.15 to 1.31, and cN3 aHR 1.24, 95%CI 1.15 to 1.33) were associated with worse overall survival. There was no association between the receipt of radiation therapy and survival in the analysis (aHR 0.99, 95%CI 0.93 to 1.05). Lastly, the site of metastatic disease also showed an association with survival, with the higher hazard ratios for those patients with metastases to the liver, bone, brain, and lymph nodes, respectively, when compared to lung-only metastasis as a reference (Table 5) (Figure 3).
Table 5.
Multivariable Cox proportional hazards analysis for associations with all-cause mortality.
| Adjusted Hazard Ratio | 95% Confidence limits | p-value | ||
|---|---|---|---|---|
|
| ||||
| Age (continuous) | 1.02 | 1.01 | 1.02 | <0.001 |
|
| ||||
| Female sex | 0.81 | 0.77 | 0.85 | <0.001 |
|
| ||||
| CCI | ||||
| 0 | Ref | Ref | Ref | <0.001 |
| 1 | 1.08 | 1.02 | 1.15 | |
| 2 | 1.14 | 1.04 | 1.25 | |
| ≥3 | 1.40 | 1.27 | 1.53 | |
|
| ||||
| Race | ||||
| White | Ref | Ref | Ref | <0.001 |
| Black | 0.99 | 0.92 | 1.07 | |
| Asian | 0.70 | 0.60 | 0.80 | |
| Hispanic | 0.81 | 0.70 | 0.93 | |
| Other | 0.86 | 0.68 | 1.08 | |
|
| ||||
| Academic/Network facility (Ref: Community facility) | 0.89 | 0.85 | 0.94 | <0.001 |
|
| ||||
| Insurance | ||||
| Public | Ref | Ref | Ref | 0.026 |
| Uninsured | 1.16 | 0.98 | 1.37 | |
| Private | 0.94 | 0.88 | 1.01 | |
|
| ||||
| Histology | ||||
| Adenocarcinoma | Ref | Ref | Ref | <0.001 |
| Squamous | 1.27 | 1.20 | 1.35 | |
| Other | 1.40 | 1.24 | 1.58 | |
|
| ||||
| Radiotherapy | 0.99 | 0.93 | 1.05 | 0.70 |
|
| ||||
| cT-stage | ||||
| T1 | Ref. | Ref. | Ref. | <0.001 |
| T2 | 1.09 | 1.01 | 1.17 | |
| T3 | 1.25 | 1.15 | 1.35 | |
| T4 | 1.35 | 1.25 | 1.45 | |
|
| ||||
| cN-stage | ||||
| cN0 | Ref. | Ref. | Ref. | <0.001 |
| cN1 | 1.12 | 1.03 | 1.23 | |
| cN2 | 1.22 | 1.15 | 1.31 | |
| cN3 | 1.24 | 1.15 | 1.33 | |
|
| ||||
| Site of distant metastasis | ||||
| Lung | Ref | Ref | Ref | <0.001 |
| Bone | 1.34 | 1.25 | 1.44 | |
| Brain | 1.24 | 1.14 | 1.35 | |
| Liver | 1.45 | 1.31 | 1.62 | |
| Distant lymph nodes | 1.02 | 0.93 | 1.13 | |
|
| ||||
| Resection of distant metastases | 0.80 | 0.72 | 0.88 | <0.001 |
|
| ||||
| Surgery to primary site | 0.67 | 0.56 | 0.80 | <0.001 |
Ref: Reference group.
Figure 3.
Forest plot summarizing Cox proportional hazards model for factors associated with overall survival.
Footnote: * Reference: metastasis to the lung. Full model included in Table 5.
Survival analysis in the propensity-matched cohort
A total of 698 patients were included in our propensity-score matched analysis. In this group, there were no differences in the adjusted covariates after matching (Appendix 2 and Appendix 3). The median follow-up time in the matched cohort was 20.8 months (IQR 10.1 to 31.3). In the matched cohort, patients who received S had prolonged overall survival compared to those patients who received ST only (median 36.8 vs. 20.8 months, log-rank p-value <0.001). The hazard ratio for overall survival comparing those patients who underwent S with those who received systemic therapy only was 0.56 (95%CI 0.42 to 0.73). The three-year overall survival was 49.4% and 37.7% in the S and ST groups, respectively (Table 6) (Figure 4). In our subgroup analysis, the association with survival remained constant among strata in most subgroups. (Table 7) Only a significant interaction was observed by CCI, where only those patients with 0 or 1 comorbidities appeared to benefit from resection of the primary tumor.
Table 6.
Survival analysis comparing patients who underwent surgery of the primary site with those who received systemic therapy only.
| N | No. events | Hazard ratio after PSM | 95%CI | Median Follow-up Months (IQR) | Median OS Months (95%CI) | Log-rank p-value | 3-year OS (%) | |
|---|---|---|---|---|---|---|---|---|
| ST | 349 | 187 | Ref | - | 17.2 (7.7–28.4) | 20.8 (16–25.1) | <0.001 | 37.7 |
| S | 349 | 149 | 0.56 | 0.42 –0.73 | 23.9 (12.7–33.0) | 36.8 (31.4–42.1) | 49.4 | |
| Total | 698 | 336 | - | - | 20.8 (10.1–31.1) | 31.0 (27–35) | 43.6 |
PSM Propensity score matching. HR hazard ratio. OS overall survival. S Surgery to the primary tumor. ST Systemic therapy without surgery. IQR interquartile range.
Figure 4.
Survival analysis in propensity-matched cohort.
Footnote: ST Systemic therapy. S Surgery of the primary site. OS Overall survival.
Table 7.
Subgroup analysis of the association between surgery to the primary site and all-cause mortality.
| Subgroup | No. of patients | HR for death | 95%CI | Interaction P value* |
|---|---|---|---|---|
|
| ||||
| All patients | 698 | 0.56 | 0.42 to 0.73 | Ref. |
|
| ||||
| Age at dx | ||||
| <68 | 451 | 0.52 | 0.35 to 0.79 | 0.695 |
| >68 | 247 | 0.61 | 0.36 to 1.02 | |
|
| ||||
| Sex | ||||
| Male | 325 | 0.70 | 0.44 to 1.10 | 0.189 |
| Female | 373 | 0.43 | 0.27 to 0.68 | |
|
| ||||
| CCI | ||||
| 0 or 1 | 606 | 0.48 | 0.35 to 0.65 | 0.045 |
| >2 | 92 | 1.52 | 0.55 to 4.23 | |
|
| ||||
| Race | ||||
| Non-White | 119 | 1.01 | 0.42 to 2.44 | 0.166 |
| White | 579 | 0.50 | 0.36 to 0.69 | |
|
| ||||
| Histology | ||||
| Adeno | 511 | 0.59 | 0.42 to 0.85 | 0.477 |
| Non-adeno | 187 | 0.42 | 0.19 to 0.93 | |
|
| ||||
| cT stage | ||||
| cT1 | 156 | 0.77 | 0.32 to 1.80 | 0.7570 |
| cT2 | 154 | 0.50 | 0.23 to 1.10 | |
| cT3 | 129 | 0.52 | 0.21 to 1.27 | |
| cT4 | 184 | 0.58 | 0.29 to 1.14 | |
|
| ||||
| cN+ disease | ||||
| cN0 | 280 | 0.48 | 0.25 to 0.94 | 0.3022 |
| cN1 | 81 | 0.38 | 0.10 to 1.40 | |
| cN2 | 204 | 0.76 | 0.37 to 1.55 | |
| cN3 | 88 | 0.79 | 0.24 to 2.63 | |
|
| ||||
| Site of metastases | ||||
| Lung | 232 | 0.51 | 0.28 to 0.92 | 0.4780 |
| Bone | 101 | 0.78 | 0.33 to 1.84 | |
| Brain | 294 | 0.45 | 0.26 to 0.76 | |
| Liver | 37 | 0.28 | 0.05 to 1.63 | |
| Distant nodes | 34 | 1.58 | 0.28 to 9.07 | |
p-value of adding the interaction term to the model.
Discussion
This study highlights that resection of the primary tumor is associated with improved overall survival for selected patients with single-site, synchronous oligometastatic NSCLC who received systemic therapy. Furthermore, it demonstrates that surgery is potentially underutilized and that this practice is not uniformly offered in all regions of the United States. Lastly, we identified that utilization of surgery to the primary site is influenced by patient factors, institutional differences, and socioeconomic determinants of health, highlighting actionable characteristics that may be targeted to promote more equitable delivery of treatment and to prevent widening outcome gaps for patients with lung cancer.
The rationale for resection of the primary tumor in patients with limited metastatic disease is based upon the belief that local control may improve outcomes with systemic therapy. Surgical resection may remove immunosuppressive cells in the primary tumor microenvironment, potentially improving response to immunotherapy. (23, 24) With radiation therapy, this mechanism is sometimes described as the abscopal effect. (24) Several reports also suggest that debulking surgery enhances anti-tumor immunity, including spontaneous metastasis regression in patients who undergo tumor removal. (25) There have also been descriptions of decreased immune cytotoxicity and reduced B-cell function when the primary tumor is not removed. (26) Guisier et al. recently demonstrated the synergistic effect of surgical debulking and anti-PD-1 immunotherapy in a murine NSCLC model.
Surgical resection of the primary tumor may also improve outcomes by the removal of drug resistant persister cells in the primary tumor. This may be particularly applicable for patients receiving targeted therapy, in whom on- and off-target cellular mechanisms of resistance are well described.(27) Important research from the TRACERx consortium recently demonstrated that the majority of metastatic relapses occur from growth of cells with subclonal mutations from the primary tumor. (28) Given that data, surgical removal of the primary tumor may decrease the burden of these cells and potentially delay the emergence of drug resistance. In a propensity-matched cohort of advanced EGFR mutated NSCLC from a Taiwanese center, tumor resection demonstrated improved progression-free (52 vs. 9.8 months, p<0.001) and overall survival (not reached vs. 30.6 months, p<0.001) when compared to tyrosine kinase inhibitor therapy alone. These and other recent findings suggest that resection of the primary tumor could improve the efficiency of targeted therapy. (27, 29)
Certainly, the concept of surgical resectability is changing with the addition of immunotherapy and targeted therapies to the treatment armamentarium of patients with NSCLC. This is increasingly evident in the neoadjuvant and peri-operative settings. (15, 16, 27, 29–31) More trials are including patients who were once categorized as “unresectable”. In the perioperative phase II NADIM-2 trial, 23% of patients in the nivolumab plus chemotherapy arm were stage IIIB (T3N2M0), including 39% of patients with multi-station N2 disease. (16) Similarly, the phase III trial AEGEAN included 24% of patients with stage IIIB disease in the perioperative durvalumab group, of which 9.3% had multi-station N2 disease. (30) Lastly, the Keynote 671 study included 15.6% of patients who were staged as IIIB in the perioperative pembrolizumab arm. (15)
Our study also identified patients with N+ disease who underwent resection of the primary tumor. Interestingly, the association between resection of the primary tumor and survival persisted among the subgroup of patients with N+ disease. We believe this reflects improvements in systemic therapy and the increased use of immunotherapy and targeted therapies for advanced NSCLC, which have allowed us to more clearly realize the benefit of resection in appropriately selected patients. (27) It is essential to highlight that traditional definitions of resectability precede the era of targeted agents and immunotherapy. (31) Thus, it is critical for the thoracic community to urgently reevaluate resectability criteria in the era of modern systemic therapy and to perform comprehensive biomarker testing and consider molecular features of individual tumors to identify patients more likely to benefit from surgical resection. (31)
While conceptually somewhat different, the practice of surgical resection of the primary tumor could be compared to local consolidative therapy of metastatic disease, predominantly accomplished with radiation therapy. In the prospective setting, several trials have demonstrated benefits of such local consolidative therapy. (32) Most of these included a combination of radiotherapy and/or surgery to the primary tumor and to metastatic sites. (13) Currently, there is limited data comparing surgery and radiotherapy as the preferred treatment for this paradigm. (32) In our study, radiotherapy (delivered to the primary tumor and to metastatic sites) was not associated with improved the overall survival of the cohort. However, our study design is likely inappropriate to provide such a comparison as there was significant heterogeneity in the targeted organs and volumes with radiation, the total doses delivered, and the radiotherapy modalities. In addition, our data source (NCDB) did not provide enough details to ascertain whether patients received radiotherapy to a metastatic site in addition to radiotherapy to the primary tumor. Considering this, further studies are needed to better compare the two treatment modalities in the setting of oligometastatic cancer. Notably, a high proportion of patients in our study received radiotherapy postoperatively, a setting in which recent studies have failed to demonstrate a significant benefit to survival. (33) This highlights that more studies are needed to better identify patients who may benefit from radiation as a component of a multimodal approach. We believe that both modalities play a crucial role in the management of limited metastatic disease and that we should act collaboratively, discussing these patients in multi-disciplinary fashion for better-individualized patient care plans.
When considering local therapy in patients with oligometastatic cancer, a significant challenge is the heterogeneity of practice patterns, which is seen even in tertiary centers. (34) Some centers or individual surgeons offer resection of the primary site only in patients without nodal metastases and in the absence of progression after induction therapy. (20, 35) Our study shows that patient factors, institutional differences and socioeconomic determinants of health also play a role in the utilization of surgery for the primary site and highlights important differences in practice patterns by geographic region in the United States. Another major challenge is the heterogeneity of definitions for oligometastatic disease, which hinders the comparison between different studies and has prevented well-defined recommendations for local consolidative treatments. (36)
In conclusion, as advances in systemic treatment allow us to consider more aggressive local therapy approaches in patients with metastatic disease, patient selection will become critical to identify those patients who will benefit from surgery. The potential benefits of resection of the primary tumor must be balanced with the complexity and potential morbidity of the surgery. Retrospective studies have reported lower-than-expected morbidity in tertiary referral centers, suggesting that perhaps these patients are better served in high-volume centers. (37) Similar to our findings, others have reported promising long-term survival in patients who underwent resection of the primary tumor. (38) We believe that differences in patient characteristics not captured in the NCDB, explain the less robust benefit observed in our cohort compared with other studies. (38, 39) However, it is crucial to report real-world outcomes in order to broadly highlight practice patterns and outcomes.
Limitations
Our study has several limitations. First, there was significant heterogeneity in patient, demographic, tumor, and treatment characteristics at baseline. We addressed this by performing multivariable analysis to adjust for confounders and using a propensity-score matched approach to evaluate survival. Another limitation inherent to large cancer registry studies was the significant missing data in variables of interest, which can compromise the internal and external validity of the study. Assuming that data was missing completely at random, we performed a complete case analysis and excluded patients who had missing observations. (21) A further limitation that affects our survival analysis is that the NCDB does not provide data on the intention-to-treat basis and only compiles the ultimately delivered treatment. This may hinder the interpretation of survival analysis, as patients who were intended to receive surgery to the primary tumor but ultimately did not, are not identifiable. There was also no granular information available on the reason why surgery was offered, which may introduce selection bias. It is thus likely that patients who received surgery to the primary site were highly selected perhaps by characteristics not measured in the NCDB. To address this, we attempted to limit our analysis to patients who only had a known single site of oligometastatic disease to increase our certainty that patients were offered surgery aiming for disease control and relative curative intent. Another limitation was that we had no data on disease progression after surgery or the start of systemic therapy, which may have affected the selection of patients for surgery, as oligoprogressive disease has been considered a contraindication to treat these patients more aggressively. We also lacked in-depth details on the type of procedure that was performed on the metastatic site, the cause of death, and the delivery of other salvage therapies (including radiotherapy) given after disease progression. Lastly, we lack information on comprehensive molecular testing and whether targeted therapy was given. Like other studies reporting the outcomes of the NCDB, our study is subjected to information and misclassification bias. Considering this, the study intends to be hypothesis-generating and to promote further investigation of the outcomes of patients with oligometastatic disease. The results of ongoing randomized clinical trials are eagerly awaited to corroborate the validity of our findings. Despite this, our study provides insight into the outcomes of patients with oligometastatic disease who undergo surgery in a contemporary multicentric cohort of patients from the United States.
Conclusion
In patients with single-site synchronous oligometastatic NSCLC, surgical resection of the primary tumor is rarely utilized, but is associated with an overall survival advantage in carefully selected patients. Advances in systemic therapy for patients with NSCLC should arguably change the paradigm of surgical eligibility. To ensure that the opportunity for surgical resection is equitably delivered in the United States, it is critical that literature on surgical resection and local consolidative therapy is disseminated, that patients with oligometastatic NSCLC are discussed at multidisciplinary tumor boards, and that surgeons participate in these tumor boards and in the care of patients with metastatic NSCLC.
Supplementary Material
Funding:
No funding was received for this project.
Abbreviations
- CCI
Charlson-Deyo Comorbidity Index
- IQR
Interquartile range
- LT
Local therapy
- NSCLC
Non-small cell lung cancer
- NCDB
National Cancer Database
- S
Surgery, as resection of the primary tumor
- ST
Systemic therapy
- OS
Overall survival
Footnotes
Disclosures:
BS: Medtronic, AstraZeneca, Genentech, Pfizer, Arcus Biosciences, Merck, Bristol Myers Squib, BMS Foundation, Galvanize Therapeutics, and the Lung Cancer Research Foundation (Consulting fees and research support). NPC: AstraZeneca (Consulting fees). The rest of the authors have no conflicts of interest to disclose.
Meeting presentation:
This research was featured as a podium presentation during the Thoracic session of the American College of Surgeons Clinical Congress 2023 in Boston, Massachusetts.
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