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The Value of Radiotherapy in Patients With Resectable Stage IIIA Non–Small-Cell Lung Cancer in the Era of Individualized Treatment: A Population-Based Analysis

Open AccessPublished:October 12, 2022DOI:https://doi.org/10.1016/j.cllc.2022.09.011

      Highlights

      • Radiotherapy should be selectively recommended for stage IIIA patients.
      • This is the first population-level analysis to demonstrate this finding based on 8th edition TNM classification.
      • A nomogram was developed and validated to predict the LCSS for IIIA NSCLC patients.

      Abstract

      Introduction

      No consensus has been achieved on the benefit of radiotherapy for resected stage IIIA NSCLC patients. The division of stage IIIA has changed significantly in 2017. This study aims to explore the effects of radiotherapy on the survival of patients with resectable stage IIIA NSCLC in the new era.

      Patients and Methods

      Patients diagnosed with NSCLC between 2010 and 2018 were identified in the 8th edition TNM classification from the Surveillance, Epidemiology, and End Results database. A nomogram was developed by integrating all independent predictors for lung cancer-specific survival (LCSS). The Propensity Score Matching (PSM) and subgroup analysis were applied to mitigate potential bias. Survival analyses were conducted using the Kaplan Meier curves and Cox proportional hazards regression.

      Results

      A total of 2632 stage IIIA NSCLC patients were enrolled. The C-index of the nomogram for the prediction of LCSS was 0.636 (95% CI, 0.616-0.656). In the group of patients with N2 stage who featured more than 5 positive regional lymph nodes, compared with non-PORT, PORT did prolong postoperative survival time (50 vs. 31 months; P= .005). N2 patients with visceral pleural invasion (VPI), older (age >65), or had a larger tumor (size >3 cm) could also benefit from adjuvant radiotherapy.

      Conclusion

      Treatment protocol for stage IIIA NSCLC patients should be individualized. Based on our findings, N2 patients with more than 5 positive regional lymph nodes, VPI, larger tumor size (greater than 3 cm), and older (age above 65) could benefit from adjuvant radiotherapy. Further well-designed randomized trials are warranted.

      Keywords

      Introduction

      Lung cancer is the leading cause of cancer-related mortality in the world,
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      with non–small-cell lung cancer (NSCLC) accounting for the vast majority of cases. The features of patients with stage IIIA NSCLC are highly heterogeneous, and the treatment for this population poses an ongoing challenge in clinical practice.
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      Upfront surgery is the preferred treatment for the majority of resectable patients. However, these patients are prone to local recurrence and distant metastasis after surgery.
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      Multidisciplinary management that incorporates consideration of surgery, chemotherapy, radiotherapy, and most recently, immunotherapy, is optimal.
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      Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.
      Perioperative chemotherapy was considered to improve the prognosis in completely resected IIIA NSCLC patients,
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      but 20% to 40% of patients still suffer from early recurrences.
      • Le Péchoux C
      Role of postoperative radiotherapy in resected non-small cell lung cancer: a reassessment based on new data.
      Therefore, patients may require preoperative radiotherapy and postoperative radiotherapy (PORT). However, the results of a series of studies vary regarding the effect of radiotherapy in the treatment of patients with stage IIIA NSCLC.
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      In stage IIIA NSCLC patients, tumor size, lymph node involvement, and comorbidities vary widely, hence, it is unfeasible to unify a treatment plan for this population. Previous studies have identified numerous clinicopathological factors that affect the impact of radiotherapy on survival.
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      Therefore, it is crucial for clinicians to identify the subgroup of stage IIIA patients who can benefit from PORT.
      The results of some large randomized controlled clinical trials have shown that radiotherapy does not improve patient prognosis.
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      However, their research is based on the 7th edition AJCC/UICC classification. In the latest 8th edition AJCC/UICC classification, many patients were re-classified into a later stage. The T stage was redefined, especially in terms of tumor size, which directly affects TNM grading. Prior to 2017, tumor sizes ≤3 cm, 3 to 7 cm, and >7 cm were classified as T1, T2, and T3, respectively. Currently, tumor sizes ≤3 cm, 3 to 5 cm, and 5 to 7 cm were reclassified into T1, T2, and T3, respectively. This resulted in IIB to IIIA for T3N1M0 and IIIA to IIIB for T3N2M0.
      • Detterbeck FC
      • Boffa DJ
      • Kim AW
      • Tanoue LT.
      The eighth edition lung cancer stage classification.
      Therefore, a study that takes the new stage classification into consideration is needed.
      This study analyzed the characteristics and prognosis of patients with IIIA NSCLC who underwent surgery using the population-based Surveillance, Epidemiology, and End Results (SEER) database. Furthermore, we used the latest data to determine which subgroups of patients with stage IIIA NSCLC may benefit from radiotherapy.

      Patients and Methods

      Data Source

      In this retrospective study, the data of patients with lung cancer registered from 2010 through 2018 was extracted from SEER database using SEER*Stat program (v 8.3.9). SEER is an authoritative source for cancer statistics in the United States. The SEER database collects data on cancer cases from various locations and sources throughout the United States. Data collection began in 1973 with a limited number of registries and continues to expand to include even more areas and demographics today.
      The extraction conditions were as follows: “the location of the disease: lung” and “diagnosis year: 2010-2018.” The following variables were extracted: patient ID, age at diagnosis, year of diagnosis, race recode, sex, pathologic grade, primary tumor site, ICD-O-3 histology code and behavior, laterality, tumor size, derived AJCC T and N stages, 8th edition AJCC classification, RX Summary–Surgery Primary Site, RX Summary–Surgery/Radiation Sequence, regional nodes positive, visceral and parietal pleural invasion recode, chemotherapy recode, cause of death to site recode, SEER cause-specific death classification, survival months, and vital status recode (study cutoff used). Based on TNM staging, tumor size and other information, we adjusted the staging of all patients to the 8th edition AJCC/UICC classification. The inclusion criteria were as follows: (1) age >18 years; (2) confirmed pathology of primary NSCLC; (3) diagnosis of stage IIIA according to the 8th edition AJCC/UICC TNM classification
      • Detterbeck FC
      • Boffa DJ
      • Kim AW
      • Tanoue LT.
      The eighth edition lung cancer stage classification.
      ; (4) underwent surgical treatment; (5) complete record of radiotherapy information; and (6) available lung cancer-specific survival (LCSS) follow-up data. Patients with incomplete registration information required by the research and those whose survival time was less than 1 month were excluded from this study.

      Data Analysis

      Statistical calculations were performed using IBM SPSS Statistics version 24.0 software (IBM Corp., Armonk, NY). The χ2 test evaluated the unadjusted association between various therapies and the other clinicopathologic categorical variables of interest. Lung cancer-specific survival (LCSS) was defined as the time from the beginning of the diagnosis until the death of lung cancer or the last follow-up date. The Kaplan-Meier method with a log-rank test was employed to compare the survival of patients between the groups. The hazard ratios (HRs) were determined using univariate and multivariate Cox proportional hazards models. Propensity score matching (PSM) was applied to mitigate potential bias at baseline between the groups. Non-PORT matched in a 1:1 ratio to PORT based on the propensity score with a standard caliper width of 0.03. After matching, the degree of baseline variable balance was assessed by standardized differences. A standardized difference of 0.1 reflects a high degree of balance. The figures were illustrated using Prism 7.0 (GraphPad Software). Nomogram, C-index and calibration curve was conducted using the “rms” and “survival” packages in R version 4.1.2. X-tlie
      • Camp RL
      • Dolled-Filhart M
      • Rimm DL.
      X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization.
      software (Version 3.6.1, www.tissuearray.org) was employed to find the cut-off point of the lymph node number and age. All statistical tests were 2-sided, and P < .05 was considered statistically significant.

      Results

      Clinicopathological Characteristics of Study Cohort

      This study cohort was formed by 2617 IIIA NSCLC patients based on the inclusion criteria. Of these, 1839 (70.27%) patients received surgery only, 619 (23.65%) patients received PORT, and 159 (6.07%) patients underwent preoperative radiotherapy. And we noticed that 19 patients received radiation both before and after surgery. Since they did not receive standard treatment, we decided to exclude this group. Table 1 shows the patient demographics and clinical parameters.
      Table 1Baseline Characteristics of the Study Population
      CharacteristicsSurgery Only (n = 1839)Preoperative Radiotherapy (n = 159)Postoperative Radiotherapy (PORT, n = 619)χ2P
      Gender
       Male961 (52.30%)101 (63.50%)321 (51.90%)7.771.021
       Female878 (47.70%)58 (36.50%)298 (48.10%)
      Race
       White1405 (76.50%)125 (78.60%)458 (74.00%)12.413.015
       Black182 (9.90%)23 (14.50%)59 (9.50%)
       Others251 (13.60%)11 (6.90%)102 (16.50%)
      Age at diagnosis
       ≤ge773 (42.00%)92 (57.90%)323 (52.20%)29.850<.001
       >651066 (58.00%)67 (42.10%)296 (47.80%)
      Pathologic grade
       Grade I147 (8.00%)6 (3.40%)25 (4.00%)42.534<.001
       Grade II681 (37.00%)41 (25.80%)229 (37.00%)
       Grade III735 (40.00%)68 (42.80%)241 (38.90%)
       Grade IV41 (2.20%)2 (1.30%)14 (2.30%)
       Blank(s)235 (12.80%)42 (26.40%)131 (17.80%)
      Laterality
       Right-origin of primary1022 (55.60%)97 (61.00%)331 (53.50%)2.975.226
       Left-origin of primary817 (44.40%)62 (39.00%)288 (46.50%)
      Primary site
       Upper lobe907 (49.30%)116 (73.00%)383 (61.90%)77.657<.001
       Main bronchus26 (1.40%)1 (0.50%)5 (0.80%)
       Middle lobe79 (4.30%)5 (3.10%)38 (6.10%)
       Lower lobe693 (37.70%)33 (20.80%)182 (29.40%)
       Others134 (7.30%)4 (2.50%)11 (1.80%)
      Histology
       Adenocarcinoma1161 (63.10%)88 (55.30%)426 (68.80%)12.118.016
       Squamous cell carcinoma509 (27.70%)53 (33.30%)147 (23.70%)
       Others169 (9.20%)18 (7.70%)46 (7.40%)
      Visceral pleural invasion
       Yes697 (37.90%)28 (17.60%)258 (41.70%)31.554<.001
       No1142 (62.10%)131 (82.40%)361 (58.30%)
      Chemotherapy
       Yes1068 (58.10%)155 (97.50%)563 (91.00%)297.789<.001
       No/Unknown771 (41.90%)4 (2.50%)56 (6.70%)
      Tumor size
       ≤z cm468 (25.40%)201 (32.50%)182 (29.40%)312.996.002
       >3 cm1371 (74.60%)418 (67.50%)230 (37.20%)
      N stage
       N0659 (35.80%)45 (28.30%)89 (14.40%)287.112<.001
       N1607 (33.00%)30 (18.90%)102 (16.50%)
       N2573 (31.20%)84 (52.80%)428 (69.10%)
      No. of positive lymph nodes
       <51645 (89.50%)149 (93.70%)483 (78.00%)60.174<.001
       ≥0194 (10.50%)10 (6.30%)136 (22.00%)
      The tumor size and age were discretized, and segmentation points were generated according to TNM stages (T1: tumor ≤3 cm) and by X-Tile, respectively. And the optimal cut-off point for age at diagnosis was 65 as the cut-off value and for tumor size was 3 cm.
      A statistically significant difference was reported in age, gender, primary site, pathologic grade, histology, N stage, positive lymph nodes, tumor size, visceral pleural invasion (VPI) and whether they were treated with chemotherapy among groups (P< .05). The laterality and race among the groups showed no statistical difference. Patients who had undergone surgery only (70.27%) made up the majority of the cohort included in the study, while those who underwent preoperative radiotherapy (6.07%) were the least represented. In addition, patients who received radiotherapy combined with surgery (more than 90%) were more likely to receive chemotherapy than patients who only received surgery (58.10%) (Table 1).

      Identify Risk Factors of IIIA NSCLC Patients by Univariate and Multivariate Analysis

      In the univariate Cox regression analysis of LCSS, chemotherapy was a good prognosis factor, which is consistent with previous
      • Felip E
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      reports (HR = 0.722, 95%CI (0.639, 0.816), P< .001). Poor prognosis factors include age over 65, male sex, nonadenocarcinoma and squamous cell carcinoma histology, larger tumor size (>3 cm), higher histological grade, VPI, lower lobe primary lesion, and positive lymph nodes ≥5.
      According to multivariate analysis, age, sex, tumor size, positive lymph nodes, VPI, primary site, pathologic grade, chemotherapy and radiotherapy with surgery variables were statistically significant (P< .05). The univariate and multivariate Cox regression results of LCSS prognostic factors in patients with IIIA NSCLC are listed in Table 2.
      Table 2Univariable and Multivariable Analysis for LCSS Using the Cox Proportional Hazard Model in IIIA/N2 NSCLC Surgery Patients
      VariablesLCSS
      Univariate AnalysisMultivariate Analysis
      HR (95% CI)PHR (95% CI)P
      Age
       ≤geReferenceReference
       >651.617 (1.432, 1.826)<.0011.546 (1.363, 1.754)<.001
      Gender
       FemaleReferenceReference
       Male1.305 (1.159, 1.470)<.0011.313 (1.162, 1.485)<.001
      Chemotherapy
       NoReferenceReference
       Yes0.722 (0.639, 0.816)<.0010.824 (0.632, 0.830)<.001
      Histology
       AdenocarcinomaReferenceReference
       Squamous cell carcinoma1.046 (0.912, 1.200).5190.893 (0.771, 1.035).134
       Others1.251 (1.024, 1.529).0281.039 (0.837, 1.291).729
      Pathologic grade
       Grade IReferenceReference
       Grade II1.185 (0.918, 1.531).1931.192 (0.918, 1.547).188
       Grade III1.413 (1.097, 1.821).0701.420 (1.092, 1.845).009
       Grade IV2.009 (1.325, 3.045).0011.921 (1.235, 2.989).004
       Blank(s)0.979 (0.708, 1.355).8991.005 (0.721, 1.400).977
      Visceral pleural invasion
       NoReferenceReference
       Yes1.239 (1.098, 1.397)<.0011.244 (1.100, 1.405)<.001
      Laterality
       LeftReferenceReference
       Right0.954 (0.848, 1.074).4360.943 (0.834, 1.067).354
      Primary site
       Upper lobeReferenceReference
       Main bronchus1.267 (0.746, 2.154).3821.688 (0.982, 2.903).058
       Middle lobe1.182 (0.894, 1.564).2401.174 (0.880, 1.566).277
       Lower lobe1.265 (1.114, 1.437)<.0011.220 (1.069, 1.391).003
       Others1.187 (0.927, 1.519).1741.210 (0.938, 1.561).142
      Tumor size
       ≤z cmReferenceReference
       >3 cm1.197 (1.041, 1.376).0121.208 (1.044, 1.3497).011
      No. of positive lymph nodes
       <5ReferenceReference
       ≥e1.469 (1.249, 1.727)<.0011.454 (1.229, 1.718)<.001
      Radiation with surgery
       Only surgeryReferenceReference
       Preoperative radiotherapy0.899 (0.702, 1.153).4021.229 (0.944, 1.589).125
       Postoperative radiotherapy1.049 (0.912, 1.206).5041.206 (1.036, 1.385).015

      Compare the Prognosis in the Whole Study Cohort and Matched Study Cohort

      In LCSS, the median follow-up time of the entire cohort was 55 months (Figure 1A). The median follow-up time for the surgery only, preoperative radiotherapy and PORT groups were 57, 68, and 52 months, respectively. Kaplan-Meier survival analysis showed no statistical difference among the groups (Figure 1B).
      Figure 1
      Figure 1Kaplan-Meier analysis on LCSS of IIIA NSCLC patients. (A) With the whole population; (B) with different radiotherapy sequences. (C) LCSS for the matched study cohort. Kaplan-Meier survival analysis for matched cohort showed that PORT had shorter LCSS than non-PORT (HR = 1.197, CI, 1.089-1.427, P = .035).
      Number at risk: The number of patients at risk in different time periods was under survival curves. Abbreviations: LCSS = lung cancer-specific survival; non-PORT = only surgery; NSCLC = nonCsmall-cell lung cancer; PORT = postoperative radiotherapy.
      To assess the efficacy of radiotherapy, propensity score matching (PSM) was used. The most representative PSM was selected for patients who underwent surgery only and PORT. A total of 1220 patients were included in the analysis after PSM. All baseline characteristics were well matched, with standardized differences for all variables of 0.1 or less (Table 3). In the matched analyses, the median survival time of PORT and non-PORT groups was 52 and 65 months (HR = 1.197, CI (1.089-1.427), P< .05) (Figure 1C).
      Table 3Baseline Characteristics of the Propensity-Score Matched Population
      CharacteristicsSurgery Only (n = 610)Postoperative Radiotherapy (PORT, n = 610)PSMD
      Gender
       Male290 (47.50%)3216 (51.80%).1370.085
       Female320 (52.50%)294 (48.20%)
      Race
       White473 (77.50%)451 (73.90%).2520.090
       Black55 (9.00%)57 (9.30%)
       Others82 (13.40%)102 (16.70%)
      Age at diagnosis
       ≤ge322 (52.80%)3219 (52.30%).8630.010
       >65288 (47.20%)291 (47.70%)
      Laterality
       Right-origin of primary311 (51.00%)326 (53.40%).3900.049
       Left-origin of primary299 (49.00%)284 (46.60%)
      Primary site
       Upper lobe378 (62.00%)376 (61.60%).2410.001
       Main bronchus11 (1.80%)5 (0.80%)
       Middle lobe26 (4.30%)37 (6.10%)
       Lower lobe6178 (29.20%)181 (29.70%)
       Others17 (2.80%)11 (1.80%)
      Histology
       Adenocarcinoma440 (72.10%)417 (68.40%).1980.053
       Squamous cell carcinoma121 (19.80%)147 (54.90%)
       Others49 (8.00%)46 (7.50%)
      Visceral pleural invasion
       Yes244 (40.00%)254 (41.60%).560−0.033
       No366 (60.00%)356 (58.40%)
      Chemotherapy
       Yes543 (89.00%)554 (90.80%).2960.062
       No/Unknown67 (11.00%)56 (9.20%)
      No. of positive lymph nodes
       <5475 (77.90%)483 (79.20%).577−0.032
       ≥.135 (22.10%)127 (20.80%)

      Subgroup Analysis to Select Postoperative Radiotherapy Candidates

      Subgroup analyses were conducted to determine the populations that could benefit from postoperative radiotherapy. Age, tumor size, lymph node and VPI were independent risk factors for limited survival. A subgroup analysis of the cohort was performed based on these factors.
      In patients with N0 and N1 metastasis, PORT showed shorter LCSS compare to non-PORT. The Kaplan-Meier curve is shown in Figure 2A and B. The median survival was higher in the PORT group than in the non-PORT group in N2(+) patients (58 months vs. 48 months), but the differences did not reach statistical significance (Figure 2C). In N2 patients who received chemotherapy, there is no significant difference between PORT and non-PORT (P= .758, Figure 2D).
      Figure 2
      Figure 2LCSS of patients with (A) N0 stage disease treated with PORT (n = 89; HR = 1.377; 95% CI, 1.099-1.961; P = .043) versus non-PORT (n = 659); (B) N1 stage disease treated with PORT (n = 102; HR = 1.463; 95% CI, 1.054-2.032; P = .013) versus non-PORT (n = 607); (C) N2 stage disease treated with PORT (n = 428; HR = 0.850; 95% CI, 0.700-1.032; P = .103) versus non-PORT (n = 573); (D) N2 stage disease treated with POCT combined with PORT (n = 403; HR = 1.037; 95% CI, 0.824-1.306; P = .758) versus POCT along (n = 367); (E) N2 stage disease who featured P5 positive regional lymph nodes treated with PORT (n = 122 HR = 0.606; 95% CI, 0.426-0.862; P = .005) versus non-PORT (n = 135); (F) N2 stage disease who featured <5 positive regional lymph nodes treated with PORT (n = 306 HR = 0.946; 95% CI, 0.747-1.198; P = .212) versus non-PORT (n = 438).
      In patients with stage IIIA/N2 NSCLC, on analyzing the data using the exhaustive method, X-Tile stratified this cohort into 2 groups: positive lymph nodes <5 (n = 744) or positive lymph nodes ≥ 5 (n = 257). A significant difference in survival was observed between whether patients received PORT or not in the group of N2 stage patients with ≥ 5 positive regional lymph nodes (50 vs. 31 months; P= .005) (Figure 2E). In the group of 744 patients with N2 stage with less than 5 positive regional lymph nodes, compared with non-PORT, PORT did not prolong postoperative survival time (P= .212) (Figure 2F). Among 209 patients with N2 stage who had 5 positive regional lymph nodes and received postoperative chemotherapy (POCT), PORT prolonged the median survival compared with non-PORT (50 vs. 28 months, respectively; P = .003) (Figure S1A). Additionally, results showed that in N2 patients with VPI, the median survival time in patients treated with PORT was significantly longer compared to surgery only (81 months vs. 46 months; P= .011) (Figure 3A), we also found that in IIIA/N2 patients, the older population (age >65) showed a trend of better prognosis in the PORT group (P= .043) (Figure 3B). Moreover, PORT prolonged the median survival time (61 vs. 44 months; P< .001) in N2 patients with tumor size >3 cm (Figure 3C). In N2 patients with tumor size ≤3 cm, there was no significant difference in survival time between the 2 groups (P = .619) (Figure 3F). A similar conclusion was reached for N2 patients who received chemotherapy (Figure S1B-1D).
      Figure 3
      Figure 3LCSS of N2 (A) and VPI patient treated with PORT (n = 157; HR = 0.649; 95% CI, 0.465-0.906; P = 0.011) versus non-PORT (n = 204); (B) patient who age >65 treated with PORT (n = 201; HR = 0.778; 95% CI, 0.600-0.953; P = 0.043) versus non-PORT (n = 321); and (C) patient who tumor sizes >3 cm treated with PORT (n = 255; HR = 0.700; 95% CI, 0.536-0.914; P = .003) versus non-PORT (n = 308).

      Nomogram Predicts Prognosis of Resectable Stage IIIA Patients

      A nomogram predicted by LCSS was developed based on multivariate Cox regression analysis (Figure 4A). Nine prognostic factors were scored in the nomogram (gender, age, grade, chemotherapy, VPI, tumor size, radiotherapy, VPI, and primary site). The 12-, 36-, and 60-month LCSS probabilities for a particular patient were calculated by cumulative scoring.
      Figure 4
      Figure 4(A) Nomogram developed from our data for predicting 12-, 36-, and 60-month LCSS in NSCLC stage IIIA patients after surgical resection. (B) Calibration curve of the nomograms. a: 12-, 36-, and 06-month LCSS nomogram calibration curves. The results showed good agreement between prediction and observation in probability.
      The C-index for the prediction of LCSS was 0.636 (95% CI, 0.616-0.658). The calibration curve also showed good congruence between the predicted probability and observed probability of LCSS (Figure 4B). The Hosmer-Lemeshow test showed no significant deviation between the observed and predicted LCSS (P> .05). We developed a web-based applet: https://xjtuwww.shinyapps.io/DynNomapp/. Doctors can input information about the patient to evaluate whether the integration of PORT can positively affect the prognosis (Figure S2A-2B).

      Discussion

      The 2-year survival rate of patients with stage IIIA NSCLC is only half (55%), and the 5-year survival rate is only 36%.
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      Now or later: evaluating the importance of chemotherapy timing in resectable stage III (N2) lung cancer in the National Cancer Database.
      ,
      • Koshy M
      • Fedewa SA
      • Malik R
      • et al.
      Improved survival associated with neoadjuvant chemoradiation in patients with clinical stage IIIA(N2) non-small-cell lung cancer.
      Moreover, with the introduction of immune checkpoint inhibitors, PD-(L)1 can prolong the disease-free survival of NSCLC patients.
      • Forde PM
      • Spicer J
      • Lu S
      • et al.
      Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.
      ,
      • Felip E
      • Altorki N
      • Zhou C
      • et al.
      Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.
      However, whether the integration of radiotherapy is beneficial to patients with stage IIIA NSCLC has been a controversial topic for many years. Since the late 1990s, many randomized trials have been conducted to prove the effectiveness of radiotherapy, but the results remain to be contradictory.
      • Feng QF
      • Wang M
      • Wang LJ
      • et al.
      A study of postoperative radiotherapy in patients with non-small-cell lung cancer: a randomized trial.
      ,
      • Shen WY
      • Ji J
      • Zuo YS
      • et al.
      Comparison of efficacy for postoperative chemotherapy and concurrent radiochemotherapy in patients with IIIA-pN2 non-small cell lung cancer: an early closed randomized controlled trial.
      The meta-analysis trial group published 9 randomized trials, which showed that radiotherapy increased the risk of death by 21% compared with surgery alone.
      • S Burdett
      • MKB Parmar
      • LA Stewart
      • et al.
      Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group.
      Kim et al.
      • Kim BH
      • Kim HJ
      • Wu HG
      • et al.
      Role of postoperative radiotherapy after curative resection and adjuvant chemotherapy for patients with pathological stage N2 non-small-cell lung cancer: a propensity score matching analysis.
      evaluated the effect of radiotherapy on stage IIIA NSCLC and found no prolongation of OS rates (non-PORT group 58.2% vs. 49.9% PORT group, P= .466). At the same time, some studies implicated that patients may benefit from radiotherapy.
      • Douillard JY
      • Rosell R
      • De Lena M
      • et al.
      Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial.
      ,
      • Lally BE
      • Zelterman D
      • Colasanto JM
      • Haffty BG
      • Detterbeck FC
      • Wilson LD.
      Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database.
      In this study, we initially explored the role of radiotherapy, and it seems irrelevant to survival. The Kaplan-Meier survival analysis showed no difference in patients on whether they received radiotherapy or not (P= .69). This may indicate that radiotherapy cannot benefit the entire stage IIIA population for the heterogeneity of this cohort. The need to be further stratified the population to explore the relationship between radiotherapy and prognosis is still unmet.
      So, PSM was adopted although it may not eliminate all confounding variables.
      • Bosco JL
      • Silliman RA
      • Thwin SS
      • et al.
      A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies.
      In observational research, they are typically more practical and statistically more effective than multivariate Cox statistical methods.
      • Haukoos JS
      • Lewis RJ.
      The propensity score.
      There is a broader debate about the use of PORT. Based on these factors, the application of PSM in this study provides new information about the impact of PORT on patients with resectable IIIA NSCLC. Notably, the results obtained demonstrate that, for resectable IIIA NSCLC patients, the survival time of those who received PORT is significantly shorter than that of the non-PORT counterparts. In the 8th edition AJCC/UICC classification, a large number of patients were reclassified into a later stage, from IIB to IIIA for T3N1 and from IIIA to IIIB for T3N2.
      • Detterbeck FC
      • Boffa DJ
      • Kim AW
      • Tanoue LT.
      The eighth edition lung cancer stage classification.
      Adding the old stage IIB patients into this analysis would be expected to further shrink the potential benefit and perhaps further decrease DFS and OS. However, the positive effects of PORT remain, probably due to the relevant small population of T3N1 patients.
      Subgroup analyses were necessary to identify potential populations that could benefit from PORT. The first section of the survey was concerned with N stage. N staging may be a key indicator in determining the efficacy of radiotherapy. Similar to prior studies,
      • Lally BE
      • Zelterman D
      • Colasanto JM
      • Haffty BG
      • Detterbeck FC
      • Wilson LD.
      Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database.
      ,
      • Gao F
      • Li N
      • Xu Y
      • Yang G.
      Effects of postoperative radiotherapy on survival of patients with stage IIIA resected non-small cell lung cancer: analysis of the SEER database.
      PORT may not be required for patients with N0 and N1.
      The treatment of stage IIIA/N2 NSCLC has been controversial. In 2006, the ANITA study
      • Douillard JY
      • Rosell R
      • De Lena M
      • et al.
      Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.
      show that postoperative radiotherapy improved the 5-year survival of IIIA N2 patients regardless of chemotherapy status (Chemotherapy group: 47% vs. 34%; Control group: 21% vs. 17%). The publication of the results of this study led to a series of similar subsequent studies. Recently, numerous researchers
      • Gao F
      • Li N
      • Xu Y
      • Yang G.
      Effects of postoperative radiotherapy on survival of patients with stage IIIA resected non-small cell lung cancer: analysis of the SEER database.
      ,
      • 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.
      ,
      • Gao F
      • Li N
      • Xu Y
      • Yang G.
      Evaluation of postoperative radiotherapy effect on survival of resected stage III-N2 non-small cell lung cancer patients.
      have analyzed the role of PORT in N2 patients using the SEER database, demonstrating that PORT could improve survival. Mikell et al.
      • Mikell JL
      • Gillespie TW
      • Hall WA
      • et al.
      Postoperative radiotherapy is associated with better survival in non-small cell lung cancer with involved N2 lymph nodes: results of an analysis of the National Cancer Data Base.
      evaluated the benefits of PORT through NCBD database. PORT was associated with improved OS in pN2 patients who were treated on linear accelerators in 3D conformal radiotherapy era. This study is a conducted analysis of NCDB database. It provided information that we believe may be crucial to the outcome of PORT, ie, the specific treatment modality and dose applied for patients. But the benefit for this group of patients was indirectly confirmed by prospective studies. Recently, the Lung-ART
      • Le Pechoux C
      • Pourel N
      • Barlesi F
      • et al.
      Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial.
      study and the PROT-C study
      • Hui Z
      • Men Y
      • Hu C
      • et al.
      Effect of postoperative radiotherapy for patients with pIIIA-N2 non-small cell lung cancer after complete resection and adjuvant chemotherapy: the phase 3 PORT-C randomized clinical trial.
      revealed that in patients with stage IIIA/N2 NSCLC, PORT did not provide an OS benefit. The difference in 3-year DFS and OS in Lung-ART study was not statistically significant. These studies point out that PORT cannot be recommended as the standard of care in patients with stage IIIA N2 NSCLC.
      Nevertheless, we believe PORT can still benefit some IIIA N2 patients. Previous clinical trials were based on the 7th edition TNM classification, but in the 8th edition classification, patients with IIIA/N2 excluded tumor size larger than 5 cm, invasion of chest wall, phrenic nerve, pericardium or separate tumor nodule(s) in the same lobe. the composition of stage IIIA patients has changed in the new edition, which may affect treatment decisions. Therefore, it makes sense to screen the population that may benefit from radiotherapy based on clinical characteristics in the 8th classification.
      Our study identified several groups of stage IIIA patients who may benefit from radiotherapy. Although AJCC classification did not use the number of lymph nodes as a determining factor, the number of positive lymph nodes has proven to have an important relationship with the prognosis.
      • Haque W
      • Verma V
      • Butler EB
      • Teh BS.
      Pathologic nodal clearance and complete response following neoadjuvant chemoradiation for clinical N2 non-small cell lung cancer: predictors and long-term outcomes.
      ,
      • Sakao Y
      • Miyamoto H
      • Yamazaki A
      • et al.
      Prognostic significance of metastasis to the highest mediastinal lymph node in nonsmall cell lung cancer.
      Yoo et al.
      • Yoo C
      • Yoon S
      • Lee DH
      • et al.
      Prognostic significance of the number of metastatic pN2 lymph nodes in stage IIIA-N2 non-small-cell lung cancer after curative resection.
      showed that the number of positive lymph nodes is an independent prognostic factor of OS. Haager et al.
      • Han H
      • Zhao Y
      • Gao Z
      • et al.
      A prognostic score system with lymph node ratio in stage IIIA-N2 NSCLC patients after surgery and adjuvant chemotherapy.
      ,
      • Haager B
      • Wiesemann S
      • Passlick B
      • Schmid S.
      Prognostic value of lymph node ratio after induction therapy in stage IIIA/N2 non-small cell lung cancer: a monocentric clinical study.
      investigated the relationship between lymph node ratio (LNR) and survival of IIIA N2 patients with chemotherapy; they suggested that higher LNR had a worse prognosis. Consequently, it can be decided whether to use radiotherapy or not according to this factor. This is also resonated in the present study, patients with <5 positive lymph nodes, we found no difference in LCSS between PORT and non-PORT. Due to potentially significant toxicity, the oncologic benefit of radiotherapy may be offset. However, according to our findings, PORT was necessary for patients with ≥ 5 positive lymph nodes and could reduce the risk of cancer-related death. Meanwhile, VPI and tumor size have been reported to be poor prognostic factors in patients with NSCLC. Andrea et al.
      • De Giglio A
      • Di Federico A
      • Gelsomino F
      • Ardizzoni A.
      Prognostic relevance of pleural invasion for resected NSCLC patients undergoing adjuvant treatments: a propensity score-matched analysis of SEER database.
      proposed chemotherapy should be strongly recommended in NSCLC patients with positive nodes or tumors ≥ 4 cm with pleural invasion based on SEER database. Kaplan-Meier survival analysis showed that PORT shared better LCSS with non-PORT in N2 patients with VPI or tumor size >3 cm. In addition, we found that PORT prolonged the survival time of N2 patients with age over 65. Radiotherapy may have its unique advantages in elderly patients. The nutritional status of tumors in elderly patients may be worse than that in younger patients, providing radiotherapy enough space and time to control local conditions. This may be one of the factors, and the specific reasons may need further investigation.
      In addition, we have attempted to explore the association between risk factors and the prognosis of patients who underwent radiotherapy. We identified age, sex, tumor size, positive lymph nodes, VPI, primary site, pathologic grade, chemotherapy, and radiotherapy with surgery as independent prognostic factors for LCSS. Based on the controversy of radiotherapy, patients with resectable IIIA NSCLC were accurately included as the study participants. According to the clinical significance and statistical methods, we included 9 prognostic factors and used X-tile to determine the grouping of the variables. We also reported the prediction of individual survival probability of patients to avoid the influence of additional unmeasurable factors related to the health status of patients. This nomogram can be effectively applied in clinical practice with good discrimination (the C-index was 0.636 (95% CI, 0.616-0.656)) and excellent calibration. In this study, a new model was established, and clinicians can easily conduct an individualized survival prediction for stage IIIA NSCLC patients who underwent surgery in clinical practice. For clinicians to use it more directly and conveniently, we have also developed a web-based applet: https://xjtuwww.shinyapps.io/DynNomapp/. Doctors can input the information of the patient to evaluate whether the integration of PORT can positively affect prognosis. Users can make a judgment by entering the clinical and pathological characteristics of patients and it can generate the predicted survival curve (Figure S2A). Moreover, users can choose the length of follow-up time to predict the survival rate and 95% confidence interval at various time points (Figure S2B).
      As techniques continue to evolve, certain high-risk N2 patients may benefit from new technologies. Remick et al.
      • Remick JS
      • Schonewolf C
      • Gabriel P
      • et al.
      First clinical report of proton beam therapy for postoperative radiotherapy for non-small-cell lung cancer.
      first reported the role of proton beam therapy (PBT) in NSCLC patients with better prognosis and less toxicity. Besides, in the era of immunotherapy and following the CheckMate-816
      • Forde PM
      • Spicer J
      • Lu S
      • et al.
      Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.
      report of neoadjuvant nivolumab with chemotherapy in resected stage III patients, Checkmate-816 has verified the clinical value of neoadjuvant combination immunotherapy for NSCLC. This mode will definitely change the dominant position of chemotherapy in the perioperative period, and the personalized scheme of multidisciplinary management will become a new trend in the near future. The effect of radiotherapy and chemotherapy plus immunotherapy should also be further evaluated. Additionally, on the basis of detecting postoperative minimal residual diseases by analyzing circulating tumor DNA, patients with a high risk of disease recurrence can be better identified
      • Levy A
      • Mercier O
      • Le Pechoux C
      Indications and parameters around postoperative radiation therapy for lung cancer.
      and may thus be candidates for aggressive treatment such as PORT.
      It is worthy to point out some limitations in this research. First, the details of radiotherapy, such as the dose of radiotherapy, and techniques of radiotherapy (3D conformal radiotherapy or intensity-modulated radiation therapy (IMRT)), are not indicated in the database. New radiotherapy techniques, such as PBT and IMRT, may potentially reduce complications and improve OS. However, the old dose method may weaken the value of radiotherapy in NSCLC patients. Second, because the evaluation index was LCSS, many patients who died from reasons unrelated to lung cancer or had no records were excluded, and selection bias was inevitable. Third, local recurrence data does not exist in SEER database, so the relationship between radiotherapy and recurrence was not investigated. Fourth, due to the retrospective nature and limitations of SEER database, it is impossible to assess the proportion of patients treated with PORT. If these are high-risk patients, and the survival rate is the same as that of patients who have not received PORT, this may be an active intervention for these patients. Finally, although the nomogram, which predicts the potential survival benefit, has an important reference value, it should not be regarded as the sole criterion for decision-making. Additionally, cardiovascular events, R0/R1 resection, etc., are prognostic factors that should be considered for PORT. Therefore, more well-designed study cohorts are required to further validate our conclusions.
      Based on the above, the role of PORT needs to be re-examined and investigated. Due to the limitations inherent in the database, and the nature of this study, the level of evidence remains weak, and further trials and real-world prospective cohorts are warranted.

      Conclusion

      Lung-Art and PORT-C studies do not mean that radiotherapy is useless for all stage IIIA NSCLC patients. Combined with our results, we suggest that a comprehensive assessment is crucial to determine whether radiotherapy is needed in stage IIIA patients. Based on the results obtained, IIIA/N2 patients with ≥5 positive regional lymph nodes could benefit from postoperative radiotherapy. N2 patients with VPI, older age or larger tumor size may also benefit from postoperative radiotherapy. Patients with stage IIIA should not be recommended for radiotherapy indiscriminately, and the method for providing a basis for radiotherapy intervention merits further investigation.

      Clinical Practice Points

      • We restaged all data to the 8th edition classification and evaluated the effect of radiotherapy on survival in operable IIIA NSCLC patients.
      • Our study identified specific populations that could benefit from radiotherapy.
      • IIIA/N2 patients with ≥5 positive regional lymph nodes could benefit from postoperative radiotherapy.
      • N2 patients with VPI, older age, or larger tumor size may also benefit from postoperative radiotherapy.

      Data Availability Statements

      The datasets pertaining to this study are available in the Surveillance, Epidemiology, and End Results (SEER) Program database.

      Disclosure

      The authors have stated that they have no conflicts of interest.

      Acknowledgments

      This work was supported by grants from The Key Research and Development Program of Shannxi ( 2020GXLH-Y-012 ). The Key Research and Development Program of Shannxi ( 2021SF-034 ). The Key Science and Technology Program of Shaanxi Province ( 2022SF-026 ). The Key Science and Technology Program of Shaanxi Province ( 2019JM-559 ).

      Appendix. Supplementary materials

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