ABSTRACT
Purpose
This study compared the local control (LC) and survival of patients with stage III lymph node–positive non‐small‐cell lung cancer (NSCLC) who received lymph node irradiation (LNs R+) and those who did not (LNs R−).
Methods
We retrospectively reviewed patients with stage III LN–positive NSCLC who underwent stereotactic body radiotherapy (SBRT) with or without lymph node irradiation between January 2013 and December 2018. Using propensity score matching (PSM) analyses, we compared the rates of LC, progression‐free survival (PFS), overall survival (OS), and acute/late toxicities between the two groups.
Results
We retrospectively analyzed 201 patients, of whom 52 received LN irradiation and 149 did not. The median LC and OS were 59.7 months (95% CI: 51.1–62.9 months) and 36.3 months (95% CI: 32.6–40.0 months), respectively. After the PSM analysis, 52 patients were included in each group. The median LC (30.6 months and not reached, HR 1.296, 95% CI: 0.733–2.294, p = 0.371) and OS (30.3 months and 31.6 months, HR 0.969, 95% CI: 0.628–1.496, p = 0.887) were similar between the LN R+ group and the LN R− group. Total tumor size, tumor location, and biologic equivalent dose (BED) were independently associated with LC (p < 0.05). The incidences of acute radiation esophagitis (p = 0.006) and late pulmonary interstitial fibrosis (p = 0.046) were significantly higher in the LN R+ group than in the LN R− group.
Conclusions
SBRT is safe and effective in stage III LN–positive NSCLC patients. Omitting elective nodal irradiation achieves comparable survival to irradiating involved lymph nodes while significantly reducing toxicity. These findings support the development of novel combination strategies.
Keywords: chemotherapy, local control, lymph node‐positive, stage III NSCLC, stereotactic body radiation therapy
1. Introduction
Approximately 20% of patients with non‐small‐cell lung cancer (NSCLC) are initially diagnosed with unresectable stage III disease [1]. Prior to the PACIFIC trial, the standard treatment for such patients consisted of 6–7 weeks of thoracic radiotherapy combined with platinum‐based chemotherapy, which achieved a 5‐year overall survival (OS) rate of 10%–30% [2, 3]. Subsequently, the PACIFIC trial established the efficacy of durvalumab as consolidation therapy in patients with unresectable stage III NSCLC who had no disease progression following chemoradiotherapy (CRT). In parallel, the LAURA trial evaluated osimertinib as adjuvant therapy following definitive CRT in patients with unresectable stage III epidermal growth factor receptor (EGFR)–mutant NSCLC. Currently, consolidative immunotherapy after chemoradiation represents the standard of care for PDL1‐positive patients without disease progression, with a reported 3‐year OS of 57% [4]. Similarly, the LAURA regimen has demonstrated durable progression‐free survival (PFS) benefits and improved control of brain metastases in EGFR‐mutated patients [5]. Both studies utilized a treatment regimen of concurrent CRT delivered with conventional fractionation. Nevertheless, a subset of stage III NSCLC patients is ineligible for concurrent CRT due to factors such as advanced age, significant comorbidities, or patient refusal. For these individuals, alternative treatment approaches beyond conventional fractionation have attracted increasing clinical interest.
Over the past decades, advances in radiation technology enabled stereotactic body radiotherapy (SBRT) to deliver precisely targeted, ablative doses with a steep dose gradient, establishing this modality as a recommended treatment option for early‐stage and metastatic NSCLC [6, 7, 8, 9, 10]. Stage III NSCLC is typically characterized by the presence of a primary lung tumor accompanied by metastatic involvement of mediastinal lymph nodes (LNs) [11]. However, delivering high‐dose SBRT to involved LNs remained challenging due to their proximity to critical organs, including the esophagus, bronchi, major vessels, and heart [12]. Early clinical experience reported grade ≥ 3 toxicities in 46% of patients irradiated for central tumors or metastatic mediastinal LNs [13]. Several studies have investigated the integration of SBRT with conventional chemoradiation or its use as a single‐modality treatment in stage III disease, observing reduced local failure rates and improved clinical outcomes [11, 14, 15]. Anatomically, metastatic mediastinal LNs are often located closer to dose‐limiting organs at risk (OARs) than primary lung lesions, which further complicated dose escalation [16]. Consequently, subsequent research prioritized strategies that enabled safe delivery of ablative doses to primary tumors via novel radiotherapy techniques without increasing toxicity [16]. In an effort to improve the safety of SBRT, some protocols reduced initial target volumes or adopted more conservative fractionation schemes [11, 17]. Furthermore, in the case of patients with poor performance status, no survival benefits may be observed when both the primary tumor and metastatic LNs are irradiated, which may be ascribed to increased risk of adverse effects. Therefore, with the advances of systemic therapy, including immunotherapy and targeted therapy, reduced volume of stereotactic body radiation therapy with only involvement of the primary tumor may be an option.
Therefore, the purpose of this study was to compare the efficacy and safety between irradiated metastatic LNs (LNs R+) and nonirradiated metastatic LNs (LNs R−).
2. Methods
2.1. Patients
This retrospective study was approved by the Institutional Review Board of Changhai Hospital with a waiver of informed consent. Data of patients with NSCLC from 2013 to 2018 were extracted from the database. Stage III patients receiving SBRT were included in the study. All patients were staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM classification. Eligible patients were required to meet all of the following: (1) age ≥ 18 years with pathologically or cytologically confirmed NSCLC, (2) a Karnofsky Performance Status (KPS) score ≥ 70, and (3) the presence of LN metastasis (patients with T4N0 disease were excluded). LNs were considered clinically malignant if they measured ≥ 1 cm in the short‐axis diameter and exhibited definitive fluorodeoxyglucose (FDG) avidity. Pathological confirmation of LN metastases was pursued whenever feasible. Patients were excluded for any of the following: (1) a prior history of thoracic surgery or radiotherapy, (2) the presence of distant metastases (DM), or (3) severe comorbidities, active interstitial lung disease, or a synchronous second primary malignancy.
Both induction and consolidation chemotherapy were allowed. According to the Radiation Therapy Oncology Group (RTOG) definition, primary central NSCLC was defined as lesions within 2 cm from the trachea, bronchial tree, esophagus, major vessels, heart, pericardium, or brachial plexus. We had de‐identified all patient details. The reporting of this study conformed to STROBE guidelines [18]. The flowchart was shown in Figure 1.
FIGURE 1.
The flowchart.
2.2. Radiation Therapy
SBRT was delivered via CyberKnife system (Accuray Incorporated, Sunnyvale, United States). Patients were immobilized in a vacuum bag in a supine position before simulations. All target volumes were delineated via computed tomography (CT) – based simulation images with at least 1.5 mm slice thickness. The acquired CT images were transferred to a three‐dimensional (3D) planning system (Accuray Incorporated, Sunnyvale, United States).
SBRT targets (the primary lesions and positive LNs) and doses would be initially determined based on the age, baseline comorbidities, TNM stage, and clinical imaging, prescribed by the treating radiation oncologist and/or based on discussion by a multidisciplinary team. According to the irradiation of the positive LNs, we divided the patients into two groups: the LN irradiation (LNs R+) group and the no LN irradiation (LNs R−) group.
The gross target volume (GTV) was defined as the primary visible tumor identified in the imaging examinations. The LN gross tumor volume (GTVnd) was defined as the mediastinal LNs with a ≥ 1‐cm diameter in the short axis. Multiple clusters of LNs on the CT images, areas of increased uptake on 18F‐ FDG‐PET, and pathologically confirmed LNs were also included in the GTVnd. In patients treated with induction chemotherapy, the post‐chemotherapy tumor volumes were defined as the GTV and GTVnd of which a short diameter was greater than 1 cm. LN with a short axis of < 1 cm after chemotherapy would no longer be irradiated.
The SBRT dose was 35–60 Gy administered in 5–10 fractions (F). GTV with the diameters of ≤ 3 cm surrounded by lung parenchyma would be given 50–60 Gy/5F. GTV with diameters > 3 cm or in contact with the chest wall would be delivered 35–60 Gy/6–7F. For GTV within 2 cm of the mediastinum or the brachial plexus, a dose of 35–60 Gy/5–10F was prescribed. The doses of GTVnd were determined by the radiation oncologists and could be consistent with or slightly lower than those of GTV.
The OARs such as the spinal cord, esophagus, heart, rest lung, trachea, proximal bronchial tree, and ipsilateral bronchus were referred to the American Association of Physicists in Medicine (AAPM) guidelines in TG‐101. The dosimetric parameters were extracted from dose‐volume histograms (DVHs) of the clinical plans' contours.
2.3. Systemic Therapy
Patients were allowed to receive a total of four cycles of chemotherapy, including induction chemotherapy and consolidation chemotherapy. Platinum‐based doublet chemotherapy, including carboplatin and cisplatin, was administered. The regimens used for squamous carcinoma and adenocarcinoma were mainly taxanes and pemetrexed, respectively. Chemotherapy schedules could be modified at physicians' discretion. Patients with extremely large tumors and a high risk of radiation‐related toxicities initially received induction chemotherapy to reduce tumor burdens. Given that the results of the PACIFIC trial were announced toward the end of our study period, patients were given the option to receive consolidative immunotherapy. For patients with driver gene‐positive mutations, targeted therapy was subsequently administered according to their specific mutation profile. For patients who were poor candidates for chemotherapy or declined chemotherapy, treatment with SBRT alone was recommended.
2.4. Statistics
To control the bias of critical clinicopathological factors between the LN R+ and LN R− groups, we utilized the propensity score matching (PSM) method [19]. In this manner, we generated 1:1 matched cohorts with a caliper width of 0.05. Initial clinicopathological and treatment characteristics were compared using the chi‐square test or Fisher's exact test and the nonparametric Wilcoxon rank sum test for univariate analysis. The absolute lymphocyte count (ALC) was also collected within 1 week before initiation of SBRT and 1 month after treatment. ΔALC was also calculated, which meant differences between pre‐ and post‐SBRT lymphocyte counts.
Locoregional control (LC), PFS, and OS were measured from the date of diagnosis. The Kaplan–Meier analysis was used to estimate LC, PFS, and OS. Cox proportional hazards regression was used for multivariate analysis. Factors with p < 0.10 in the univariable analysis were then included in the multivariable analysis.
Acute and late radiation–induced toxicities were evaluated based on the RTOG toxicity criteria [20]. We used logistic regression analysis to identify the prognostic factors of acute esophagitis and pulmonary interstitial fibrosis. All listed p values were two‐sided, and p < 0.05 was deemed significant. Statistical analyses were performed using SPSS version 25.0 (IBM Corporation, Armonk, NY, United States).
3. Results
3.1. Baseline Characteristics
We identified 311 patients with stage III NSCLC who were treated with SBRT between January 2013 and December 2018. Among these patients, 38 had incomplete clinicopathological data, 12 had no LN metastasis, 35 were excluded from surgical resection or radiotherapy before SBRT, 13 were excluded due to incomplete SBRT, and 12 were lost to follow‐up. Ultimately, 201 patients were included in this study, among which 52 received LN irradiation and 149 did not (Table 1).
TABLE 1.
Baseline patient, treatment, and tumor characteristics of stage III NSCLC patients before and after PSM, n (%).
| Variable | Before PSM | After PSM | |||||
|---|---|---|---|---|---|---|---|
| All patient percentage (%) | LNs irradiation N = 52 | LNs non‐irradiation N = 149 | p | LN irradiation N = 52 | LNs non‐irradiation N = 52 | p | |
| Age (yr) | |||||||
| Md (range) | 72 (38–89) | 69.5 (45–86) | 72 (38–89) | 0.583 | 69.5 (45–86) | 70.5 (45–88) | 0.789 |
| Gender | |||||||
| Male | 38 (18.9) | 39 (75.0) | 124 (83.2) | 0.219 | 39 (75.0) | 44 (84.6) | 0.329 |
| Female | 163 (81.1) | 13 (25.0) | 25 (16.8) | 13 (25.0) | 8 (15.4) | ||
| KPS | |||||||
| 90 | 68 (33.8) | 19 (36.5) | 49 (32.9) | 0.626 | 19 (36.5) | 14 (26.9) | 0.452 |
| 80 | 118 (58.7) | 28 (53.8) | 90 (60.4) | 28 (53.8) | 35 (67.3) | ||
| 70 | 15 (7.5) | 5 (9.6) | 10 (6.7) | 5 (9.6) | 3 (5.8) | ||
| History of smoking | |||||||
| Yes | 125 (62.2) | 30 (57.7) | 95 (63.8) | 0.507 | 30 (57.7) | 35 (67.3) | 0.418 |
| No | 76 (37.8) | 22 (42.3) | 54 (36.2) | 22 (42.3) | 17 (32.7) | ||
| Primary pulmonary diseases | |||||||
| Yes | 80 (39.8) | 14 (26.9) | 66 (44.3) | 0.033 | 14 (26.9) | 21 (40.4) | 0.213 |
| No | 121 (60.2) | 38 (73.1) | 83 (55.7) | 38 (73.1) | 31 (59.6) | ||
| T stage | |||||||
| T1 | 36 (17.9) | 9 (17.3) | 27 (18.1) | 0.952 | 9 (17.3) | 4 (7.7) | 0.042 |
| T2 | 71 (35.3) | 17 (32.7) | 54 (36.2) | 17 (32.7) | 8 (15.4) | ||
| T3 | 49 (24.4) | 13 (25.0) | 36 (24.2) | 13 (25.0) | 22 (42.3) | ||
| T4 | 45 (22.4) | 13 (25.0) | 32 (21.5) | 13 (25.0) | 18 (34.6) | ||
| N stage | |||||||
| N1 | 22 (10.9) | 4 (7.7) | 18 (12.1) | 0.071 | 4 (7.7) | 13 (25.0) | 0.042 |
| N2 | 102 (50.7) | 21 (40.4) | 81 (54.4) | 21 (40.4) | 20 (38.5) | ||
| N3 | 77 (38.3) | 27 (51.9) | 50 (33.6) | 27 (51.9) | 19 (36.5) | ||
| TNM stage | |||||||
| IIIa | 96 (47.8) | 17 (32.7) | 79 (53.0) | 0.037 | 17 (32.7) | 17 (32.7) | 0.772 |
| IIIb | 61 (30.3) | 21 (40.4) | 40 (26.8) | 21 (40.4) | 24 (46.2) | ||
| IIIc | 44 (21.9) | 14 (26.9) | 30 (20.1) | 14 (26.9) | 11 (21.2) | ||
| Total tumor size (cm) | |||||||
| Md (range) | 4.2 (1.2–13.2) | 5.5 (2.5–13.2) | 4.0 (1.2–11.5) | 0.176 | 5.5 (2.5–13.2) | 5.5 (1.4–11.5) | 0.813 |
| Pathologic pattern | |||||||
| Squamous cell carcinoma | 88 (43.8) | 26 (50.0) | 62 (41.6) | 0.656 | 26 (50.0) | 28 (53.8) | 0.565 |
| Adenocarcinoma | 103 (51.2) | 24 (46.2) | 79 (53.0) | 24 (46.2) | 20 (38.5) | ||
| NOS | 10 (5.0) | 2 (3.8) | 8 (5.4) | 2 (3.8) | 4 (7.7) | ||
| Location | |||||||
| Central | 81 (40.3) | 28 (53.8) | 53 (35.6) | 0.023 | 28 (53.8) | 24 (46.2) | 0.557 |
| Peripheral | 120 (59.7) | 24 (46.2) | 96 (64.4) | 24 (46.2) | 28 (53.8) | ||
| BED10 | |||||||
| Md (range) | 86.4 (52.7–132.0) | 82.1 (52.7–69) | 88.3 (56–132) | < 0.001 | 82.1 (52.7–132.0) | 83.3 (59.5–132.0) | 0.495 |
| SUVmax | |||||||
| Md (range) | 11.5 (1.0–39.4) | 12.2 (1.0–30.2) | 11.4 (2.9–39.4) | 0.480 | 12.2 (1.0–30.2) | 14.4 (2.9–39.4) | 0.646 |
| ΔALC (K/mL) | 0.002 | 0.022 | |||||
| Md (range) | 0.6 (−1.2–7.6) | 0.9 (−1.2–7.6) | 0.5 (−1.2–7.6) | 0.9 (−1.2–7.6) | 0.5 (−0.7–7.6) | ||
| Type of systemic therapy | |||||||
| Induction CT + SBRT | 105 (52.2) | 20 (38.5) | 85 (57.0) | 0.030 | 20 (38.5) | 30 (57.7) | 0.194 |
| Induction CT + SBRT + consolidation CT | 19 (9.5) | 10 (19.2) | 9 (6.0) | 10 (19.2) | 4 (7.7) | ||
| Induction CT + SBRT + consolidation CT + immunotherapy | 4 (2.0) | 1 (1.9) | 3 (2.0) | 1 (1.9) | 1 (1.9) | ||
| SBRT + consolidation CT | 15 (7.5) | 3 (5.8) | 12 (8.1) | 3 (5.8) | 1 (1.9) | ||
| SBRT alone | 58 (28.9) | 18 (34.6) | 40 (26.8) | 18 (34.6) | 16 (30.8) | ||
Abbreviations: ALC, absolute lymphocyte count; BED, biologically effective dose; CT, chemotherapy; KPS, Karnofsky Performance Status; LNs, lymph nodes; NOS, non‐small‐cell lung cancer not otherwise specified; NSCLC, non‐small‐cell lung cancer; PSM, propensity score matching; SBRT, stereotactic body radiotherapy; SUV, standard uptake value.
The median follow‐up was 40.00 (range 5.28–100.70) months. The median LC was 59.7 months (95% CI: 51.1–62.9 months). The median OS and PFS were 36.3 months (95% CI: 32.6–40.0 months) and 16.0 months (95% CI: 14.6–17.4 months), respectively.
The median prescription dose of GTV in the LN R+ group and the LN R− group was 47.8 Gy (range: 35.0–60.0 Gy/5–8 f) and 48.0 Gy (range: 35.0–60.0 Gy/5–8 f) (p = 0.081). However, patients in the LN R+ group had lower BED10 of GTV than those in the LN R− group (median BED10: 82.1 Gy versus 88.3 Gy, p < 0.001). The median prescription dose of GTVnd in the LN R+ group was 42 Gy (range: 25.0–60.0 Gy/5–8 f). The median BED10 of GTVnd was 71.4 Gy (37.5–132.0 Gy). Among them, 25 patients (48.1%) had a lower dose of GTVnd than GTV (p < 0.001).
During the study period, only four patients (2%) underwent consolidation immunotherapy. In total, 63 patients (31.3%) received immune checkpoint inhibitors (ICIs) in the later‐line setting. Of the 201 patients enrolled, 33 (16.4%) harbored EGFR mutations, with no other actionable genomic alterations identified. After PSM, the overall proportion of EGFR mutations was 32.0%, comprising 10 patients in the LN R+ group and 23 patients in the LN R− group. After completion of study treatment, four patients in the LN R+ group and 10 patients in the LN R− group received osimertinib or other tyrosine kinase inhibitors (TKIs), respectively.
3.2. Clinical Characteristics and Survival of Propensity Score–Adjusted Patients
The baseline TNM stage and BED10 were used as independent variables for the PSM analysis. After propensity matching, there were 52 patients of each group included in the analysis (Table 1); there was no significant difference between the two groups in the case of total prescription doses and numbers of fractions. The ΔALC was higher in the LN R+ group than that in the LN R− group (p = 0.022). The doses of OARs were similar except that the esophagus mean dose and lung V5 in the LN R+ group were higher than those in the LN R− group (Table 2).
TABLE 2.
Comparison of target coverage and normal tissue sparing with PSM groups.
| Variable | LN irradiation median (range) | LN non‐irradiation median (range) | p |
|---|---|---|---|
| Total dose, Gy | 47.8(35.0–60) | 45.8 (35.0–60.0) | 0.981 |
| Number of fractions | 6 (5–10) | 6 (5–8) | 0.111 |
| BED10, Gy | 82.1 (52.7–132.0) | 83.3 (59.5–132.0) | 0.495 |
| Coverage(%) | 88.1 (54.1–99.5) | 90.6 (71.5–97.5) | 0.056 |
| PTV (Dmax), Gy | 49.0 (40.6–56.8) | 56.6 (35.2–72.3) | 0.347 |
| Spinal cord (Dmax), Gy | 6.9 (1.4–17.3) | 7.5 (1.8–18.8) | 0.758 |
| Spinal cord (D 0.35cm3), Gy | 10.2 (4.5–18.0) | 11.9 (1.5–24.3) | 0.711 |
| Heart mean dose, Gy | 5.3 (3.9–8.8) | 3.8 (0.9–11.3) | 0.499 |
| Heart (D 15cm3), Gy | 13.4 (6.6–24.6) | 15.3 (2.47–31.2) | 0.060 |
| Esophagus mean dose, Gy | 6.9 (2.8–8.7) | 4.0 (1.3–12.3) | 0.041 |
| Esophagus (D 5cm3), Gy | 10.8 (5.3–14.52) | 12.7 (2.58–22.6) | 0.427 |
| Lung mean dose, Gy | 7.8 (4.9–13.0) | 6.1 (0.3–11.7) | 0.239 |
| Lung V5, % | 52.4 (25.7–70.4) | 25.4 (8.2–54.9) | 0.005 |
| Lung V20, % | 4.9 (0.0–9.5) | 4.6 (0.0–11.1) | 0.530 |
Abbreviations: BED, biologically effective dose; D 0.35cm3, D 15cm3, D 5cm3, dose received 0.35, 15, and 5 cm3 volume of organ at risk, respectively; Dmax, maximum point dose; LNs, lymph nodes; Lung V5, V20, volume of total lungs receiving 5Gy, 20 Gy, or more; PSM, propensity score matching; PTV, planning target volume.
The total median LC for the PSM groups was 33.6 months. The median LC was 30.6 months (95% CI: 15.2–46.0 months) and not reached for the LN R+ group and the LN R− group, respectively (p = 0.371) (Figure 2a). The estimated 1‐, 2‐, 3‐, and 5‐year LC rates for the LN R+ group were 86.5%, 54.9%, 41.0%, and 37.3%, respectively. The estimated 1‐, 2‐, 3‐, and 5‐year LC rates for the LN R− group were 83.5%, 58.0%, 55.3%, and 55.3%, respectively. Disease progression was recorded in 91.3% of patients (n = 95). The median PFS in the LN R+ group and the LN R− group were 14.3 months (95% CI: 12.6–15.9 months) and 12.2 months (95% CI: 9.1–15.3 months), respectively (p = 0.921) (Figure 2b). The estimated 1‐, 2‐, 3‐, and 5‐year PFS rates for the LN R+ group were 61.5%, 15.4%, 3.8%, and 3.8%, respectively. The estimated 1‐, 2‐, 3‐, and 5‐year PFS rates for the LN R− group were 51.9%, 19.2%, 13.5%, and 13.5%, respectively.
FIGURE 2.
Survival curves for OS (A), PFS (B), and LC (C) stratified by with or without LN irradiation group. LC, local control; OS, overall survival; PFS, progression‐free survival.
The median OS was 30.3 months (95% CI: 24.7–35.9 months) and 31.6 months (95% CI: 23.7–39.5 months) for the LN R+ group and the LN R− group, respectively (p = 0.887) (Figure 2c). The estimated 1‐, 2‐, 3‐, and 5‐year OS rates for the LN R+ group were 94.2%, 65.4%, 41.9%, and 17.7%, respectively. The estimated 1‐, 2‐, 3‐, and 5‐year OS rates for the LN R− group were 80.8%, 59.6%, 42.3%, and 23.9%, respectively.
The univariate and multivariate Cox regression analyses were shown in Table 3. Total tumor size, tumor location, and BED10 were independently associated with LC. The independent prognostic factor for PFS and OS was total tumor size. Overall, total tumor size was the only predictor of LC (p < 0.001), PFS (p = 0.007), and OS (p = 0.003). After propensity matching, 34.6% of patients subsequently received ICIs as part of their later‐line therapy. The median OS of the ICI group and the no ICI group were 35.3 months (95% CI: 13.3–57.3 months) and 30.3 months (95% CI: 26.7–33.9 months), respectively (p = 0.266).
TABLE 3.
Prognostic factors for LC, PFS, and OS in PSM groups.
| Locoregional control | Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|---|
| Variables | Reference vs. | HR | 95% CI | p | HR | 95% CI | p |
| Lymph node irradiation | No vs. yes | 1.296 | 0.733–2.294 | 0.373 | NI | ||
| Age (yr) | < 70 vs. ≥ 70 | 1.326 | 0.756–2.326 | 0.324 | NI | ||
| Sex | Female vs. male | 1.289 | 0.643–2.588 | 0.474 | NI | ||
| History of smoking | No vs. yes | 1.298 | 0.725–2.322 | 0.380 | NI | ||
| Primary pulmonary diseases | No vs. yes | 0.875 | 0.476–1.607 | 0.666 | NI | ||
| TNM stage | IIIA vs. IIIB‐IIIC | 1.539 | 0.815–2.906 | 0.183 | NI | ||
| T stage | T1–2 vs. T3–4 | 1.692 | 0.928–3.084 | 0.086 | 1.540 | 0.734–3.231 | 0.254 |
| N stage | N1–2 vs. N3 | 1.192 | 0.681–2.089 | 0.538 | NI | ||
| Pathologic pattern | ADC vs. non‐ADC | 1.635 | 0.918–2.910 | 0.095 | 1.375 | 0.755–2.505 | 0.297 |
| Total tumor size (cm) | ≤ 5.5 vs. > 5.5 | 2.638 | 1.484–4.689 | 0.001 | 3.345 | 1.797–6.225 | < 0.001 |
| Location | Central vs. peripheral | 0.409 | 0.228–0.734 | 0.003 | 0.502 | 0.276–0.912 | 0.024 |
| BED10 (Gy) | ≤ 83.3 vs. > 83.3 | 0.096 | 0.038–0.243 | < 0.001 | 0.081 | 0.031–0.210 | < 0.001 |
| ΔALC (K/mL) | ≤ 0.6 vs. > 0.6 | 0.520 | 0.289–0.937 | 0.030 | 0.646 | 0.342–1.219 | 0.177 |
| Progression‐free survival | Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|---|
| Variables | Reference vs. | HR | 95% CI | p | HR | 95% CI | p |
| Lymph node irradiation | No vs. yes | 0.980 | 0.653–1.470 | 0.921 | NI | ||
| Age (yr) | < 70 vs. ≥ 70 | 0.814 | 0.542–1.223 | 0.323 | NI | ||
| Sex | Demale vs. male | 1.430 | 0.871–2.350 | 0.157 | NI | ||
| History of smoking | No vs. yes | 1.261 | 0.832–1.913 | 0.274 | NI | ||
| Primary pulmonary diseases | No vs. yes | 0.825 | 0.532–1.280 | 0.390 | NI | ||
| TNM stage | IIIA vs. IIIB‐IIIC | 1.284 | 0.823–2.005 | 0.271 | NI | ||
| T stage | T1–2 vs. T3–4 | 1.522 | 1.001–2.315 | 0.049 | 1.341 | 0.570–3.156 | 0.501 |
| N stage | N1–2 vs. N3 | 1.134 | 0.752–1.710 | 0.548 | NI | ||
| Pathologic pattern | ADC vs. non‐ADC | 1.071 | 0.712–1.609 | 0.742 | NI | ||
| Total tumor size (cm) | ≤ 5.5 vs. > 5.5 | 2.271 | 1.505–3.427 | < 0.001 | 2.381 | 1.264–4.484 | 0.007 |
| Location | Central vs. peripheral | 0.662 | 0.441–0.994 | 0.047 | 0.657 | 0.359–1.202 | 0.173 |
| BED10 (Gy) | ≤ 83.3 vs. > 83.3 | 0.927 | 0.618–1.389 | 0.713 | NI | ||
| ΔALC (K/mL) | ≤ 0.6 vs. > 0.6 | 1.012 | 0.676–1.516 | 0.954 | NI | ||
| Overall survival | Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|---|
| Variables | Reference vs. | HR | 95% CI | p | HR | 95% CI | p |
| Lymph node irradiation | No vs. yes | 0.969 | 0.628–1.496 | 0.887 | NI | ||
| Age (yr) | < 70 vs. ≥ 70 | 1.193 | 0.772–1.844 | 0.426 | NI | ||
| Sex | female vs. male | 1.446 | 0.834–2.506 | 0.189 | NI | ||
| History of smoking | No vs. yes | 1.133 | 0.724–1.771 | 0.585 | NI | ||
| Primary pulmonary diseases | No vs. yes | 0.886 | 0.553–1.419 | 0.614 | NI | ||
| TNM stage | IIIA vs. IIIB‐IIIC | 1.309 | 0.813–2.108 | 0.268 | NI | ||
| T stage | T1–2 vs. T3–4 | 1.964 | 1.229–3.139 | 0.005 | 1.379 | 0.529–3.595 | 0.510 |
| N stage | N1–2 vs. N3 | 0.933 | 0.603–1.443 | 0.756 | NI | ||
| Pathologic pattern | ADC vs. non‐ADC | 0.886 | 0.553–1.419 | 0.614 | NI | ||
| Total tumor size (cm) | ≤ 5.5 vs. > 5.5 | 1.570 | 1.017–2.425 | 0.042 | 2.698 | 1.407–5.175 | 0.003 |
| Location | Central vs. peripheral | 0.524 | 0.338–0.813 | 0.004 | 0.648 | 0.337–1.246 | 0.193 |
| BED10 (Gy) | ≤ 83.3 vs. > 83.3 | 0.814 | 0.525–1.264 | 0.360 | NI | ||
| ΔALC (K/mL) | ≤ 0.6 vs. > 0.6 | 0.900 | 0.583–1.389 | 0.633 | NI | ||
Abbreviations: ALC, absolute lymphocyte count; BED, biologically effective dose; LC, local control; NI, not included in the multivariate model; OS, overall survival; PFS, progression‐free survival; PSM, propensity score matching.
3.3. Patterns of Local Failure of Propensity Score–Adjusted Patients
A total of 49 (47.1%) patients had local failure (Figure 3). Among these patients, 26 (53.1%) patients had in‐field and out‐field failure and DM; three (6.1%) patients had in‐field and out‐field failure; three (6.1%) patients developed out‐field failure and DM, while only out‐field and in‐field were observed in 6 (12.2%) and 11 (22.5%) patients. There was no statistical difference in the recurrence pattern between the two groups (p = 0.245).
FIGURE 3.
Locoregional failure patterns among (A) 29 patients with recurrent tumors in patients with LN irradiation; (B) 20 patients with recurrent tumors in patients with LN non‐irradiation; (C) 49 patients with recurrent tumors in the PSM cohort.
In the LN non‐irradiation (LN R−) group, 35 patients (67.3%) received systematic treatment prior to SBRT. After systematic treatment, 65.7% (23/35) of patients had PR, 28.6% (10/35) had SD, and 5.7% (2/35) had PD, respectively. The reason for patients with PD was the enlargement of the primary lesion. After SBRT, 37.1% (13/35) of patients had locoregional progression, of which 12 patients experienced primary tumor enlargement and 10 patients had positive LN enlargement or the appearance of new positive LNs. Nine patients had both primary lesions enlargement and metastatic LNs, with only one patient experiencing regional LN metastases.
After PSM, 84 (80.8%) patients had a BED10 less than 100 Gy, in which 77 (91.7%) patients experienced disease progression. The rate of local progression and DM were 56.0% and 70.2%, respectively. However, in the BED10 ≥ 100 Gy group, only two patients (10%) experienced local progression.
3.4. Toxicity of Propensity Score–Adjusted Patients
The reported toxicities were summarized in Table 4. There were 18.3% patients (n = 19) with ≥ grade 3 acute toxicities in the PSM cohort. The acute radiation esophagitis was more frequent in the LN R+ group than in the LN R− group (32.7% vs. 11.5%, p = 0.006). In the LN R+ group, there were two patients with grade 3 acute esophagitis while no patients suffered this adverse event (p = 0.153). Grade 3 acute pneumonia was observed in eight (15.4%) and six (11.5%) patients in the LN R+ group and the LN R− group (p = 0.566). In the meanwhile, one patient died from radiation pneumonitis without evident disease progression 3 months after SBRT in the LN R− group. Additionally, 28 (26.9%) patients developed ≤ grade 2 late toxicities, whereas only one patient developed grade 3 late toxicities. The incidence of late pulmonary interstitial fibrosis (p = 0.046) was also significantly higher in the LN R+ group than in the LN R− group.
TABLE 4.
Treatment‐related adverse events in PSM groups.
| Variable | Grade |
LNs irradiation N = 52 N, (%) |
LNs non‐irradiation N = 52 N, (%) |
p |
|---|---|---|---|---|
| Acute toxicity | ||||
| Hematological toxicities | Grade 0 | 45 (86.5) | 46 (88.5) | 0.102 |
| Grade 1 | 3 (5.8) | 4 (7.7) | ||
| Grade 2 | 2 (3.8) | 2 (3.8) | ||
| Grade 3 | 2 (3.8) | 0 (0.0) | ||
| Radiation esophagitis | Grade 0 | 35 (67.3) | 46 (88.5) | 0.006 |
| Grade 1 | 10 (19.2) | 4 (7.7) | ||
| Grade 2 | 5 (9.6) | 2 (3.8) | ||
| Grade 3 | 1 (1.9) | 0 (0.0) | ||
| Grade 4 | 1 (1.9) | 0 (0.0) | ||
| Radiation pneumonia | Grade 0 | 36 (69.2) | 41 (78.8) | 0.177 |
| Grade 1 | 0 (0.0) | 1 (1.9) | ||
| Grade 2 | 8 (15.4) | 4 (7.7) | ||
| Grade 3 | 5 (9.6) | 4 (7.7) | ||
| Grade 4 | 3 (5.8) | 1 (1.9) | ||
| Grade 5 | 0 (0.0) | 1 (1.9) | ||
| Bronchopulmonary hemorrhage | Grade 0 | 50 (96.2) | 52 (100.0) | 0.180 |
| Grade 2 | 1 (1.9) | 0 (0) | ||
| Grade 3 | 1 (1.9) | 0 (0) | ||
| Late toxicity | ||||
| Pulmonary interstitial fibrosis | Grade 0 | 39 (75.0) | 45 (86.5) | 0.046 |
| Grade 1 | 10 (19.2) | 6 (11.5) | ||
| Grade 2 | 3 (5.8) | 1 (1.9) | ||
| Radiation esophagitis | Grade 0 | 47 (90.4) | 48 (92.3) | 0.180 |
| Grade 1 | 2 (3.8) | 3 (5.8) | ||
| Grade 2 | 2 (3.8) | 1 (1.9) | ||
| Grade 3 | 1 (1.9) | 0 (0.0) | ||
Abbreviation: PSM, propensity score matching.
In further analysis, univariate analysis showed that LN irradiation (p = 0.009) and esophagus D 5cm3 (p = 0.043) were associated with acute radiation esophagitis. The LN irradiation and age were independent influencing factors for radiation esophagitis and pulmonary interstitial fibrosis in multivariable analysis, respectively (Table 5). We also compared the relationship between the toxicity and survival outcomes, but there was no relationship between toxicity and LC, PFS, or OS in the two groups.
TABLE 5.
Prognostic factors for acute esophagitis and pulmonary interstitial fibrosis in PSM groups.
| Acute esophagitis | Univariate analysis | Multivariable analysis | |||||
|---|---|---|---|---|---|---|---|
| Variables | Reference vs. | OR | 95% CI | p | OR | 95% CI | p |
| Lymph node irradiation | No vs. yes | 0.267 | 0.054–1.308 | 0.103 | NI | ||
| Age (yr) | < 70 vs. ≥ 70 | 1.111 | 0.242–5.107 | 0.892 | NI | ||
| Sex | Female vs. male | 2.852 | 0.313–25.983 | 0.353 | NI | ||
| History of smoking | No vs. yes | 1.852 | 0.387–8.871 | 0.441 | NI | ||
| Primary pulmonary diseases | No vs. yes | 2.059 | 0.429–9.873 | 0.367 | NI | ||
| TNM stage | IIIA vs. IIIB‐IIIC | 0.810 | 0.176–3.725 | 0.786 | NI | ||
| T stage | T1–2 vs. T3–4 | 7.000 | 0.784–62.525 | 0.082 | 1.573 | 0.095–26.002 | 0.837 |
| N stage | N1–2 vs. N3 | 0.540 | 0.113–2.587 | 0.441 | NI | ||
| Total tumor size (cm) | ≤ 5.5 vs. > 5.5 | 0.113 | 0.021–0.601 | 0.011 | 9.559 | 0.946–96.549 | 0.056 |
| Location | Central vs. peripheral | 2.172 | 0.235–29.097 | 0.494 | NI | ||
| BED10 (Gy) | ≤ 83.3 vs. > 83.3 | 0.143 | 0.016–1.276 | 0.082 | 0.680 | 0.033–14.108 | 0.803 |
| ΔALC (K/mL) | ≤ 0.6 vs. > 0.6 | 0.706 | 0.136–3.658 | 0.678 | NI | ||
| PTV Dmax (Gy) | ≤ 55.0 vs. > 55.0 | 6.300 | 0.705–56.287 | 0.099 | 1.128 | 0.068–18.632 | 0.933 |
| Esophagus mean dose (Gy) | ≤ 4.2 vs. > 4.2 | 3.706 | 0.661–20.765 | 0.136 | NI | ||
| Esophagus D5cm3 (Gy) | ≤ 11.0 vs. > 11.0 | 9.625 | 1.075–86.175 | 0.043 | 9.939 | 0.542–182.296 | 0.122 |
| Pulmonary interstitial fibrosis | Univariate analysis | Multivariable analysis | |||||
|---|---|---|---|---|---|---|---|
| Variables | Reference vs. | OR | 95% CI | p | OR | 95% CI | p |
| Lymph node irradiation | No vs. yes | 0.519 | 0.120–2.233 | 0.378 | NI | ||
| Age (yr) | < 70 vs. ≥ 70 | 0.882 | 0.227–3.436 | 0.857 | NI | ||
| Sex | Female vs. male | NI | |||||
| History of smoking | No vs. yes | 1.271 | 0.326–4.947 | 0.730 | NI | ||
| Primary pulmonary diseases | No vs. yes | NI | |||||
| TNM stage | IIIA vs. IIIB‐IIIC | 0.625 | 0.160–2.441 | 0.499 | NI | ||
| T stage | T1–2 vs. T3–4 | 1.474 | 0.365–5.958 | 0.586 | NI | ||
| N stage | N1–2 vs. N3 | 0.481 | 0.119–1.945 | 0.305 | NI | ||
| Total tumor size (cm) | ≤ 5.5 vs. > 5.5 | 2.286 | 0.519–10.057 | 0.274 | NI | ||
| Location | Central vs. peripheral | 1.333 | 0.238–7.471 | 0.744 | NI | ||
| BED10 (Gy) | ≤ 83.3 vs. > 83.3 | 0.679 | 0.168–2.743 | 0.586 | NI | ||
| ΔALC (K/mL) | ≤ 0.6 vs. > 0.6 | 0.259 | 0.045–1.486 | 0.130 | |||
| PTV Dmax (Gy) | ≤ 55.0 vs. > 55.0 | 2.246 | 0.509–9.907 | 0.285 | NI | ||
| Lung mean dose (Gy) | ≤ 6.7 vs. > 6.7 | 1.271 | 0.326–4.947 | 0.730 | NI | ||
| Lung V5, % | ≤ 39.8 vs. > 39.8 | 1.429 | 0.342–5.974 | 0.625 | NI | ||
| Lung V20, % | ≤ 4.8 vs. > 4.8 | 2.083 | 0.516–8.407 | 0.302 | NI | ||
Abbreviations: ALC, absolute lymphocyte count; BED, biologically effective dose; D 5cm3, dose received 5 cm3 volume of organ at risk; Dmax, maximum point dose; PSM, propensity score matching; PTV, planning target volume.
4. Discussion
We retrospectively analyzed 201 patients with stage III LN–positive NSCLC. With a median follow‐up of 40 months, PSM analysis revealed that irradiation of metastatic LNs (LNs R+) did not confer additional benefits in LC, PFS, or OS compared with no irradiation of metastatic LNs (LNs R−); instead, it was associated with increased toxicity. To our knowledge, this is the first study to employ PSM analysis to compare outcomes of stage III NSCLC patients receiving LNs R+ with those receiving LNs R−.
In the case of recurrence patterns of stage III NSCLC, distant recurrence occurs in 50%–66% of cases and locoregional relapse occurred in 34%–50% [21], with in‐field failure at the primary site being the most common pattern of local relapse [22]. The most common toxicity is radiation‐induced esophagitis, which is closely associated with both dosimetric factors (i.e., the dose and volume of irradiated esophagus) and the use of concurrent chemotherapy [23, 24]. In light of these findings, priority should be given to delivering ablative doses to the primary tumor with accurate radiotherapy techniques, while minimizing the risk of toxicity. However, no consensus on the optimal target volume delineation for SBRT in node‐positive stage III NSCLC has yet been reached.
Recent studies have demonstrated the efficacy of SBRT for stage III NSCLC patients. In Cong et al.’s study, both the primary tumor and LNs were irradiated with a moderate median BED10 of 59.5 Gy. The LC rate was 61%, and the incidence of grade ≥ 3 toxicities was 9.8% [17]. In another study, SBRT was delivered for a dose boost following conventional CRT, achieving safe and effective local control in 37 patients with inoperable stage II‐III NSCLC. The SBRT boost was delivered to the residual disease (excluding LNs) 1 month after completion of CRT [25]. These divergent strategies highlight the ongoing uncertainty regarding optimal target volume selection.
One concern regarding SBRT only for primary tumors without metastatic LNs in these patients is the potential risk of locoregional relapse. However, previous studies have demonstrated that the role of radiotherapy in locally advanced NSCLC has shifted from a purely locoregional treatment to an immunomodulatory agent that synergizes with the immune system and reshapes the tumor microenvironment [26, 27]. Integration of SBRT with systemic therapy represents a mainstream strategy to improve therapeutic efficacy [28]. Emerging evidence from the neoadjuvant setting provides strong support for this paradigm shift. In the randomized, controlled Phase 2 trial by Altorki et al. [29], SBRT to the primary tumor followed by neoadjuvant immunotherapy yielded a major pathological response (MPR) rate of 53%, half of which were pathological complete responses (pCR) with acceptable safety. Among patients with stage IIIA disease, the MPR rate was 33.3%, and the pCR rate was 25.0%. In the study by Zhao et al. [28], SBRT achieved an MPR rate of 76% in patients with IIB‐IIIA stage. These encouraging neoadjuvant data demonstrated that SBRT to the primary tumor alone, combined with effective systemic therapy, can achieve high pathologic response rates without irradiating involved LNs. In our cohort, 49 (41.7%) patients developed local failure, of whom 26 (53.1%) also had concurrent DM. Out‐of‐field failure occurred in only 6 (12.2%) patients. The local failure rate was acceptably low in node‐positive stage III NSCLC, suggesting that omitting LN irradiation did not compromise LC. Notably, a large proportion of patients experienced both local failure and DM. This suggests that more intensive adjuvant systemic regimens and active surveillance should be prioritized over sole local irradiation of metastatic LNs. Our study contributes to this evolving paradigm by exploring optimal target volume delineation for SBRT in stage III NSCLC.
Importantly, we analyzed the incidence of local failure and identified factors associated with LC. Multivariate Cox regression analysis revealed that total tumor size, tumor location, and BED10 were independently associated with LC. Specifically, large tumor size was the only independent prognostic factor of poorer LC, PFS, and OS. These findings underscored the importance of patient selection and sufficient dose delivery to optimize outcomes.
Beyond failure patterns and prognostic factors, potential immune biomarkers were investigated. First, omitting LN irradiation may preserve antitumor immunity. We found that metastatic LN irradiation significantly reduced the ALC, a marker of post‐radiotherapy immune status [30] and prognostic factor in NSCLC [31, 32]. This aligned with preclinical data from Marciscano et al., who demonstrated that irradiation of tumor‐draining LNs decreased tumor‐infiltrating immune cells, suppressed chemokine expressions, and impaired survival when combined with immunotherapy [27]. These findings highlighted the importance of taking immunomodulatory effects of SBRT into target volume delineations. Consistent with this, our results suggested that unnecessary nodal irradiation may weaken the abscopal effect potentially triggered by high‐dose SBRT [33]. The absence of significant differences in recurrence patterns or OS between groups supported that SBRT alone may stimulate systemic immune effects, which may be compromised by elective nodal irradiation (ENI).
In parallel with immune considerations, our data emphasized the paramount importance of adequate dose delivery to the primary tumor. The local progression rate was 56.0% in the BED10 < 100 Gy group and 10.0% in the BED10 ≥ 100 Gy group. This suggested that for locally advanced NSCLC, BED10 ≥ 100 Gy to the primary tumor was crucial for achieving optimal LC. Similarly, many studies [34, 35] have shown that BED10 ≥ 100 Gy confers survival benefits in stage III NSCLC. In the Phase II study by Heinzelling et al. [34], all patients received SBRT (BED10 ≥ 100 Gy) to the primary tumor followed by conventionally fractionated chemoradiation to 60 Gy in 2 Gy fractions to the involved LNs. The median OS was 40.8 months, with DM being the main reason for failure in 26% of patients. Notably, only 2% of patients experienced local failure after SBRT and 6% experienced regional recurrence. These findings collectively stressed the importance of delivering ablative doses to the primary tumor.
Having established the efficacy of primary tumor‐focused SBRT, we also evaluated its impact on treatment‐related toxicity. Radiation‐induced acute and late toxicities are critically dependent on the volume of irradiated normal tissue, particularly in stage III NSCLC patients who commonly receive concurrent systemic therapy [36]. Severe (≥ Grade 3) esophageal and pulmonary toxicities remain the primary dose‐limiting concerns. In this context, minimizing the irradiated volume offers a direct strategy to improve the therapeutic index. Our study provides clear dosimetric and clinical evidence supporting this approach. The LN R+ group exhibited significantly higher lung V5 and mean esophageal dose, which directly translated into increased risk of toxicity. Patients receiving metastatic LN irradiation experienced significantly higher rates of acute radiation esophagitis and late pulmonary interstitial fibrosis. Multivariate analysis confirmed LN irradiation as an independent risk factor for radiation‐induced esophagitis. Although we observed no direct relationship between these toxicities and OS in this cohort, smaller mediastinal radiation fields would substantially decrease radiation exposure of adjacent OARs, thereby lowering the incidence of adverse effects. Importantly, this toxicity mitigation strategy may also create opportunities for safe dose escalation to the primary tumor, potentially further improving LC. These findings aligned with historical comparisons between ENI and involved‐field radiotherapy (IFRT). Studies from the pre‐immunotherapy era consistently demonstrated that ENI increased toxicity without conferring a clear survival benefit compared with more limited IFRT [36, 37, 38]. More recent prospective studies of hypofractionated regimens continued to report considerable toxicity, with grade 3 or greater pneumonitis ranging from 9.5% to 14% and grade 3 esophagitis from 2% to 5.3% [39]. These results reinforced that careful patient selection and target volume reduction can meaningfully improve the therapeutic ratio in stage III NSCLC, enhancing treatment tolerability without compromising oncologic efficacy.
Our study has several limitations. First, as this was a retrospective study, some patients did not receive uniform systemic treatment, which may have affected survival outcomes. Second, following PSM analysis, the sample size in each group was relatively small. Some baseline clinical pathological factors were different between groups, which may also have influenced our results. Finally, most patients were treated before the publication of the PACIFIC trial and LAURA trials [4, 5] and did not receive maintenance therapy. Future prospective studies may further reveal more surprising results regarding the combination of SBRT with immunotherapy that exempts LNs irradiation.
5. Conclusions
Our study demonstrates that SBRT is safe and effective for selected patients with stage III LN–positive NSCLC. Omitting metastatic LN irradiation yields survival outcomes comparable with nodal irradiation, with the critical benefits of reduced acute esophagitis, lower late pulmonary fibrosis, and preserved ALC—a potential biomarker that may indicate the improved efficacy of immunotherapy. These findings challenge the routine practice of nodal irradiation in the SBRT era and support primary tumor‐focused dose escalation with reduced target volumes, providing a rationale for future combination strategies with immunotherapy.
Author Contributions
All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by F.F., Z.J., X.Z., Y.S.C., and H.Z. The first draft of the manuscript was written by Z.J., and all authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the Shanghai Health Commission Leading Talent Program (2022LJ019), and Changhai Hospital, Navy Medical University [2020YPT004].
Ethics Statement
This study was performed in accordance with the Declaration of Helsinki. This human study was approved by Ethics Committee of Medical Faculty, Changhai Hospital Affiliated to Navy Medical University—approval: CHEC2024‐140. The study was not registered as a clinical trial because this study was a retrospective analysis of hospital medical records. Adult participant consent was not required because the data were only analyzed in an anonymized form.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
We thank all staff of the radiation oncology section.
Data Availability Statement
The data presented in this study are available on request from the corresponding author in an anonymized form after data privacy check. The data are not publicly available due to data privacy regulations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data presented in this study are available on request from the corresponding author in an anonymized form after data privacy check. The data are not publicly available due to data privacy regulations.