Stereotactic body radiotherapy to the primary lung lesion improves the survival of the selected patients with non-oligometastatic NSCLC harboring EGFR activating mutation with first-line EGFR-TKIs: a real-world study

Abstract

Purpose

This study aimed to explore the clinical value of SBRT for primary lung lesions of EGFR-mutant NSCLC patients with non-oligometastatic disease during first-line EGFR-TKI treatment.

Methods

We identified patients with stage IV EGFR-mutant non-oligometastatic NSCLC who were suitable to receive SBRT for the primary tumors after EGFR-TKI treatment. All selected patients were treated with first-line EGFR-TKIs and SBRT for their primary lesions. The primary endpoints were the progression-free survival 1 (PFS1, time of first TKI dose relative to disease progression based on RECIST) and PFS2 (time of first TKI dose relative to disease progression after SBRT). The secondary endpoints were overall survival (OS) and safety.

Results

Seventy-nine patients were enrolled, including 45 patients who received SBRT for their primary tumor at the maximal response of EGFR-TKI (the preemptive RT group) and 34 patients who received SBRT for their primary tumor after the occurrence of oligoprogression (the delayed RT group). The preemptive RT group had a significantly better median PFS1 than the delayed RT group (22.3 months vs. 12.9 months, P = 0.0031). The median PFS2 in the preemptive RT and delayed RT groups were 22.3 and 28.9 months, respectively (P = 0.17). The median OS did not differ significantly between the preemptive RT group and the delayed RT group (46.6 versus 51.3 months, P = 0.54). No severe toxicities (≥ grade 3) were recorded.

Conclusion

This real-world study showed that preemptive RT to primary lung tumors is a feasible option for selected patients with EGFR-mutant non-oligometastatic NSCLC who had stable disease during first-line EGFR-TKI treatment, and that it significantly improved PFS.

Introduction

Lung cancer is one of the most common cancers, contributing to approximately one-quarter of all cancer deaths (Siegel et al. 2020). Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers, with half of the diagnosed patients already with advanced disease (Shi et al. 2017). In advanced NSCLC patients with activating epidermal growth factor receptor (EGFR) mutations, EGFR-TKI treatment has become the standard first-line treatment. This led the NSCLC treatment into a golden era with higher response rate, as well as a longer median progression-free survival (PFS) of 9–13 months compared with the classical platinum-based chemotherapy, which achieved a median overall survival (OS) of 22–30 months (Maemondo et al. 2010; Mitsudomi et al. 2010; Rosell et al. 2012; Shi et al. 2017; Zhou et al. 2011; Zhou et al. 2015). However, acquired resistance inevitably occurs in most patients after 1–2 years of TKI treatment (Camidge et al. 2014). Management after acquired resistance should depend upon the EGFR-TKI failure modes, and for those with local progression in clinical practice, continuation of EGFR-TKI treatment plus local intervention is a wise strategy (Yang et al. 2013). Indeed, local therapy combined with continuation of EGFR-TKI treatment is a promising treatment option with remarkable clinical benefits for patients with oligoprogressive disease (Yu et al. 2013).

A previous study showed that over 40% of progression events after EGFR-TKI treatment developed at the original sites (Tang et al. 2020). Based on this scenario, many studies were conducted to validate the hypothesis that NSCLC patients with oligometastases can benefit from local consolidative treatment. In a multicenter phase 2 study, local consolidative therapy for patients with oligometastatic disease after system therapy resulted in remarkably prolonged PFS and OS relative to maintenance therapy (Gomez et al. 2016; Gomez et al. 2019). A retrospective study further revealed that local consolidative therapy to all sites in the setting of EGFR-TKI treatment was a reasonable choice with improved PFS and OS (Xu et al. 2018). Additionally, two prospective studies indicated that stereotactic body radiotherapy (SBRT) for patients with oligometastatic or oligoresidual disease was safe and feasible (Chan et al. 2020; Iyengar et al. 2018).

As indicated above, emerging clinical evidence appears to favor local consolidative treatment for NSCLC patients with oligometastatic disease. However, patients with oligometastases are uncommon, and many other patients present with widespread metastases. A secondary analysis of two clinical trials clarified that aggressive radiotherapy to the primary tumors in addition to chemotherapy may prolong OS of non-oligometastatic NSCLC patients (Su et al. 2016). However, to date, evidence regarding the efficacy of local consolidative therapy for lung primary tumors in first-line EGFR-TKI-treated NSCLC patients with non-oligometastases is rare. Meanwhile, SBRT is a non-invasive local treatment that has been demonstrated to harbor high local control with acceptable adverse events and has become an effective and safe treatment choice for oligometastatic or oligoresidual NSCLC (Chan et al. 2020; Iyengar et al. 2018; Xu et al. 2018). Herein, we conducted this real-world study to determine the clinical values of preemptive SBRT to primary tumors in first-line EGFR-TKI-treated patients with non-oligometastases who had stable disease and subsequently accepted SBRT for primary tumors.

Materials and methods

Patients

We retrospectively reviewed the patients with sensitive EGFR-mutant NSCLC who had non-oligometastatic disease and also received SBRT to the primary tumor between September 2012 and February 2020 at the Department of Thoracic Oncology, West China Hospital. Patients were included if they met the following inclusion criteria: pathologically diagnosed stage IV NSCLC according to the 7th or 8th edition of the American Joint Committee on Cancer (AJCC) staging manual, presented with sensitive EGFR mutation (exon 19 deletion or exon 21 L858R), aged 18 years or older, with non-oligometastatic disease (more than five metastatic lesions with transfer to more than two lesions per organ, or presented pathologically proven malignant pleural effusion, pericardial effusion, or peritoneal effusion), and accepted first-line EGFR-TKI combined with SBRT to the primary tumor. Baseline demographic characteristics such as age, sex, histology, smoking status, EGFR mutational status, type of EGFR-TKI, best response before radiotherapy, biologically effective dose (BED₁₀), metastatic sites before TKI initiation, and the use of osimertinib were abstracted. This study was approved by the Institutional Review Board of the West China Hospital of Sichuan University.

Treatment and follow-up

All patients were administered EGFR-TKIs. Based on the sequence of SBRT delivery, eligible patients were categorized into two groups: the preemptive RT group (patients had stable disease within two sequential treatment evaluations during first-line EGFR-TKI treatment, and subsequently accepted SBRT to the primary tumor) and the delayed RT group (patients received SBRT to the primary tumor after the occurrence of oligoprogression after TKI initiation). Concerning SBRT, the final decision of the dose-fractionation regimen was made by a radiotherapist based on the patient’s age, organ function, general condition, and patient’s preference. All patients who received RT had residual primary lung lesions with a maximum diameter of less than 5 cm after EGFR-TKI treatment and the residual primary lung lesions were peripheral.

Radiographic evaluation mainly included computed tomography (CT) of the chest or abdomen, which was performed every 8–12 weeks until the cut-off date (October 10, 2020) or death according to the Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoints were the progression-free survival 1 (PFS1, time of first TKI dose relative to disease progression based on RECIST), and PFS2 (time of first TKI dose relative to disease progression after SBRT). The secondary endpoints were overall survival (OS) and safety. For survival and progression, patients were censored if they did not yet have evidence of death or progression at the cut-off date. Adverse events (grade ≥ 3) were recorded according to the National Cancer Institute Common Toxicity Criteria Version 3.0. The failure patterns—which included the original failure (progressive disease only at the originally existed residual lesions), the distant failure (progressive disease only at distant new sites), and the mixed failure (progressive disease at both sites)—in the two groups were evaluated after radiotherapy by experienced oncologists (Zeng et al. 2020).

Statistical analysis

Baseline clinical data were analyzed, in which the chi-squared test was performed to compare categorical variables, while the Mann–Whitney U or independent-sample t test were performed to compare continuous variables. PFS1, OS, and PFS2 were estimated using the Kaplan–Meier method, and the distribution of survival curves was compared using log-rank tests. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were evaluated using the Cox proportional hazards model. All potential clinical factors were included in the univariate analysis, and factors with p < 0.1 in univariate analysis were further assessed by multivariate analysis. All data analyses were performed using R version 4.03 at the 0.05 significance level, and all p values were two-sided.

Results

Patients’ characteristics

In total, among the 681 patients with advanced NSCLC treated with SBRT for primary tumors, 79 were included (Fig. 1). Demographic characteristics are included in Table 1. The median age of the entire cohort was 57 years (range, 37–83 years), and 49 patients (62%) were female. In brief, 76 patients (96.2%) had histology of adenocarcinoma, 58 patients (73.4%) were non-smokers, 48 patients (60.8%) harbored exon 19 deletion mutation, and 57 patients (72.2%) had a partial response (PR) before SBRT delivery. In terms of first-line EGFR-TKI treatment, 43 patients (54.4%) received gefitinib, 22 patients (27.8%) received icotinib, 12 patients (15.2%) received erlotinib, and only two patients (2.5%) received osimertinib. The median BED₁₀ of all patients was 75 Gy (range, 40–180 Gy). Forty-eight patients (60.8%) received osimertinib as the first-line or second-line treatment. Of all 79 subjects, 41 patients (51.9%) presented with lung involvement, 36 patients (45.6%) presented with bone involvement, and 21 patients (26.6%) presented with brain involvement.

Fig.1.

Flowchart of patient included NSCLC. NSCLC non-small cell lung cancer, SBRT stereotactic body radiotherapy, ALK anaplastic lymphoma kinase, EGFR epidermal growth factor receptor, TKI tyrosine kinase inhibitors

Table 1.

Baseline demographics of 79 non-oligometastatic NSCLC patients

Characteristics	No. of patients (%)
Age (year)
Mean (standard deviation)	58.4 (9.3)
Median (range)	57.0 (37.0–83.0)
Gender
Male	30 (38.0)
Female	49 (62.0)
Histology
Adenocarcinoma	76 (96.2)
Nonadenocarcinoma	3 (3.8)
Smoking status
Nonsmoker	58 (73.4)
Smoker	21 (26.6)
EGFR mutation
Exon 19 deletion	48 (60.8)
Exon 21 L858R	31 (39.2)
EGFR-TKIs
Gefitinib	43 (54.4)
Icotinib	22 (27.8)
Erlotinib	12 (15.2)
Osimertinib	2 (2.5)
Best response before radiotherapy
SD	22 (27.8)
PR	57 (72.2)
BED10
Mean (standard deviation)	85.4 (29.7)
Median (range)	75.0 (40.0–180.0)
Metastases location before treatment
Brain	21 (26.6)
Lung	41 (51.9)
Bone	36 (45.6)
Adrenal	6 (7.6)
Liver	3 (3.8)
Other*	41 (51.9)
Use of osimertinib
Yes	48 (60.8)
No	31 (39.2)

NSCLC non-small cell lung cancer, EGFR epidermal growth factor receptor, TKI tyrosine kinase inhibitor, SD stable disease, PR partial response, BED10 biologically effective dose

Other*: Pleura 30(38.0), celiac lymph node 3(3.8), cervical lymph node 2(2.5), chest wall 1(1.3), axillary lymph node 1(1.3), spleen 1(1.3), pericardium 2(2.5), diaphragm muscle 1(1.3);

Of the 79 eligible patients, 45 patients received SBRT for the primary tumor at the maximal response of EGFR-TKI (the preemptive RT group) and 34 patients received SBRT to the primary tumor after the occurrence of oligoprogression (the delayed RT group). The dose-fractionation regimen of SBRT is 30–60 Gy in 3–10 fractions (median: 48 Gy in 5 fractions) for the preemptive RT group and 20–60 Gy in 2–10 fractions (median: 49 Gy in 5 fractions) for the delayed RT group. Baseline characteristics were well balanced without a significant difference between the two groups except for EGFR mutational status and the type of EGFR-TKI (Table 2). Although there was a discrepancy of distribution between the two groups concerning EGFR mutational status and the type of EGFR-TKI, they were not independent predictive factors for PFS1, PFS2, or OS in univariate and multivariate analyses.

Table 2.

Characteristics of preemptive radiotherapy and delayed radiotherapy groups

Characteristic no. (%)	Preemptive radiotherapy (N = 45)	Delayed radiotherapy (N = 34)	P value
Age (year)
Mean (standard deviation)	58.3 (9.2)	58.6 (9.5)	0.908
Median (range)	57.0 (43.0–79.0)	59.0 (37.0–83.0)
Gender
Male	21 (46.7)	9 (26.5)	0.067
Female	24 (53.3)	25 (73.5)
Histology
Adenocarcinoma	43 (95.6)	33 (97.1)	1.000
Nonadenocarcinoma	2 (4.4)	1 (2.9)
Smoking status
Nonsmoker	33 (73.3)	25 (73.5)	0.984
Smoker	12 (26.7)	9 (26.5)
EGFR mutation
Exon 19 deletion	33 (73.3)	15 (44.1)	0.008
Exon 21 L858R	12 (26.7)	19 (55.9)
EGFR-TKIs
Gefitinib	19 (42.2)	24 (70.6)
Icotinib	16 (35.6)	6 (17.6)	0.048
Erlotinib	8 (17.8)	4 (11.8)
Osimertinib	2 (4.4)	0 (0.0)
Best response before radiotherapy
SD	10 (22.2)	12 (35.3)	0.199
PR	35 (77.8)	22 (64.7)
BED10
Mean (standard deviation)	82.7 (24.0)	89.0 (35.9)	0.597
Median (range)	75.0 (45.0–180.0)	81.7 (40.0–180.0)
Use of osimertinib
Yes	26 (57.8)	22 (64.7)	0.532
No	19 (42.2)	12 (35.3)

EGFR epidermal growth factor receptor, TKI tyrosine kinase inhibitor, SD stable disease, PR partial response, BED10 biologically effective dose

Survival outcomes and toxicity

At the cut-off date, the median follow-up duration was 31.3 months (range, 8.6–92.3 months). The median PFS2 of the whole cohort was 24.3 months (95% CI 21.9–30.0 months), and the median OS of the entire cohort was 50.1 months (95% CI 43.9–62.4 months) (Fig. 2).

Fig. 2.

PFS2 (a) and OS (b) curves of the whole cohort. PFS progression-free survival, OS overall survival

The preemptive RT group had a significantly better PFS1 compared to the delayed RT group, with a median PFS1 of 22.3 months (95% CI 15.9–30.0 months) for the preemptive RT group versus 12.9 months (95% CI 11.3–19.9 months, P = 0.0031) for the delayed RT group (Fig. 3a). The PFS2 was 22.3 months (95% CI 15.9–30.0 months) for the preemptive RT group and 28.9 months (95% CI 22.8–41.4 months) for the delayed RT group (P = 0.17) (Fig. 3b). There were no significant differences in PFS2 between the two arms. Difference in the median OS between the preemptive RT group (46.6 months, 95% CI 38.9 months to not reach) and the delayed RT group (51.3 months, 95%CI 43.9 months to not reach) was not significant (P = 0.54) (Fig. 3c).

Fig. 3.

Kaplan–Meier plot of PFS1 (a), PFS2 (b), and OS (c) in the preemptive RT and the delayed RT group. PFS progression-free survival, OS overall survival, RT radiotherapy

With regard to adverse events, common toxicity profiles were observed during EGFR-TKI treatment, which included diarrhea, rash, aminotransferase elevation, and anemia. No severe toxicities (≥ grade 3) were recorded. No severe radiation pneumonitis or esophagitis (≥ grade 3) attributed to the integration of SBRT were observed.

Effect of clinical factors on survival

Univariate analysis was used to reveal clinical factors associated with PFS1, which were preemptive radiotherapy and histology of adenocarcinoma. Further multivariate analysis determined preemptive radiotherapy (HR: 0.46, 95% CI 0.28–0.75, P = 0.002) and histology of adenocarcinoma (HR: 0.17, 95% CI 0.05–0.56, P = 0.004) as independent prognosticators to predict longer PFS1 (Table 3). Regarding PFS2, only the histology of adenocarcinoma was selected after univariate analysis (HR: 0.13, 95% CI 0.04–0.44, P = 0.001). In univariate analysis, the use of osimertinib predicted improved OS and remained a predictive factor for better OS in an adjusted analysis (HR: 0.45, 95% CI 0.22–0.92, P = 0.029).

Table 3.

Univariable and multivariable analysis of clinical factors associated with PFS1 and OS

PFS1
	Univariable analysis			Multivariable analysis
Variable	HR	95% CI	P	HR	95% CI	P
Gender (male vs. female)	1.15	0.71–1.86	0.580
Age	0.99	0.96–1.02	0.462
Histology (adenocarcinoma vs. nonadenocarcinoma)	0.23	0.07–0.75	0.015	0.17	0.05–0.56	0.004
Smoking status (smoker vs. nonsmoker)	1.55	0.91–2.64	0.105
EGFR mutation (exon 19 deletion vs. exon 21 L858R)	1.09	0.67–1.79	0.722
EGFR-TKIs (gefitinib vs. others)	0.76	0.47–1.25	0.283
Best response before radiotherapy (PR vs. SD)	0.88	0.52–1.49	0.639
Preemptive Radiotherapy (yes vs. no)	0.49	0.30–0.80	0.004	0.46	0.28–0.75	0.002

OS
	Univariable analysis			Multivariable analysis
Variable	HR	95% CI	P	HR	95% CI	P
Gender (male vs. female)	1.77	0.86–3.67	0.122
Age	1.01	0.96–1.05	0.808
Histology (adenocarcinoma vs. nonadenocarcinoma)	0.16	0.02–1.27	0.082	0.14	0.02–1.19	0.071
Smoking status (smoker vs. nonsmoker)	1.57	0.74–3.31	0.239
EGFR mutation (exon 19 deletion vs. exon 21 L858R)	1.05	0.50–2.20	0.893
EGFR-TKIs (gefitinib vs. others)	0.63	0.30–1.30	0.208
Best response before radiotherapy (PR vs. SD)	1.15	0.51–2.60	0.729
Preemptive Radiotherapy (yes vs. no)	1.27	0.60–2.69	0.540
BED10	0.99	0.98–1.00	0.132
Use of Osimertinib (yes vs. no)	0.45	0.22–0.93	0.032	0.45	0.22–0.92	0.029

PFS1 progression-free survival 1, OS overall survival, HR hazard ratio, 95%CI 95% confidence interval, EGFR epidermal growth factor receptor, TKI tyrosine kinase inhibitor, SD stable disease, PR partial response, BED10 biologically effective dose

Patterns of treatment failure after RT intervention

Overall, 73.3% (33/45) of the patients in the preemptive RT group and 85.3% (29/34) of the patients in the delayed RT group had disease progression. In the preemptive RT group, 9 (27.3%) patients had original failure, 11 (33.3%) had distant failure, and 13 (39.4%) had mixed failure. In the delayed RT group, 13 (44.8%) had original failure, 7 (24.1%) had distant failure, and 9 (31.0%) had mixed failure. The distribution of the failure pattern was not significantly different between the groups. (P = 0.351). Additionally, the common sites of disease progression in the preemptive RT group were lung (44.4%), bone (13.3%), brain (20.0%), liver (4.4%), adrenal gland (2.2%), lymph node (6.7%), and pleura (11.1%). The failure sites in the delayed RT group were lung (47.1%), bone (20.6%), brain (23.5%), liver (8.8%), adrenal gland (11.8%), lymph node (8.8%), pleura (11.8%), and kidney (2.9%).

Discussion

To the best of our knowledge, this is the first study to investigate the real-world utilization and efficacy of SBRT to the primary lesions in selected EGFR-mutant NSCLC patients with the non-oligometastatic disease during first-line EGFR-TKI treatment. We found that SBRT for primary lesions plus first-line EGFR-TKIs may provide durable first-line EGFR-TKI exposure for selected non-oligometastatic NSCLC patients with EGFR sensitizing mutations. The progression pattern in most EGFR-TKI-treated NSCLC is observed in the primary site of the disease, which also supports the inclusion of thoracic SBRT into the treatment of selected NSCLC patients in the setting of first-line EGFR-TKI (Al-Halabi et al. 2015; Patel et al. 2017; Tang et al. 2020).

A superior median PFS and OS were observed with the preemptive radiotherapy arm relative to the historical data of EGFR-TKI monotherapy (22.3 months versus 9–13 months and 46.6 months versus 22–30 months, respectively). Additionally, we found the superiority of preemptive SBRT to the primary lung lesion plus EGFR-TKI over EGFR-TKI monotherapy in terms of PFS1, and the magnitude of survival benefit was remarkable, mainly due to SBRT delivery (22.3 vs. 12.9 months, P = 0.0031, HR = 0.46). However, this research cannot conclude whether the administration of preemptive SBRT can provide any benefits in terms of the patients’ OS and quality of life. Previous studies have clarified the potential value of local consolidative therapy for NSCLC patients who had oligometastatic disease (Gomez et al. 2016; Gomez et al. 2019; Hu et al. 2019; Xu et al. 2018). Recently, in the SINDAS trial, which is an ongoing multicenter phase III clinical trial, the interim result suggested that upfront SBRT to all sites combined with first-line EGFR-TKI significantly improved PFS and OS for oligometastatic NSCLC by 7.7 months and 8.1 months, respectively (NCT02893332) (Wang and Zeng 2020). Meanwhile, prospective small sample size research conducted by Chan also identified the feasibility of preemptive SBRT in oligoresidual NSCLC (Chan et al. 2020). A recent study found that over 20% of patients develop oligoresidual disease after osimertinib initiation at the time of maximal response, and stated that such patients may benefit from consolidative SBRT delivery (Guo et al. 2020). In a retrospective study, those authors indicated that local consolidative therapy could achieve better local control and PFS for osimertinib-treated NSCLC patients with limited residual metastatic lesions (≤ 5) (NR vs 12.8 months, P = 0.01) (Zeng et al. 2020). However, as with most of studies mentioned, there are still a number of issues that need to be addressed when patients with oligometastatic or oligoresidual disease are treated with radiotherapy. The use of local consolidative therapy as a treatment modality for primary lung tumors has previously been proven feasible (Blake-Cerda et al. 2020; Xu et al. 2018). Furthermore, the occurrence of TKI-resistant clones at the primary tumor site with subsequent distant progression resulted in disease progression (Basler et al. 2017). Given this, upfront SBRT to lung primary tumors might be an effective treatment choice that could eradicate potential TKI-resistant clones and postpone progression. Our real-world study, for the first time, showed that preemptive SBRT for primary lung lesions at the maximal response of first-line EGFR-TKI might defer disease progression and achieve longer PFS with tolerable adverse events for selected non-oligometastatic NSCLC patients. Further prospective studies are needed to explore the efficacy and safety of upfront SBRT for primary tumors of non-oligometastatic NSCLC at the maximal response to first-line EGFR-TKIs.

We also calculated the survival benefits from delayed SBRT to primary lung lesions after the occurrence of oligoprogression. We found that delayed SBRT for primary lung lesions plus the continuation of EGFR-TKI for selected patients with oligoprogression effectively prolonged survival and deferred subsequent osimertinib or chemotherapy exposure (28.9 months versus 9–13 months and 51.3 months versus 22–30 months, respectively). Some retrospective series supported the treatment strategy of the integration of local therapy with the continuation of EGFR-TKIs in the setting of oligoprogression (Chan et al. 2017; Xu et al. 2019; Yu et al. 2013). Yu et al. conducted a study on 18 NSCLC patients with acquired resistance who were treated with elective local therapy (Yu et al. 2013). Patients who received local therapy achieved a median time to progression of 10 months, a median time to change in systemic therapy of 22 months, and a median OS of 41 months. The above studies are consistent with our findings, and our results also showed the benefits of local therapy for selected patients for whom oligoprogression was treated with EGFR-TKI.

Owing to the recent comprehensive recognition of the clinical value of local consolidative therapy, there are currently only a few studies that have reported whether the survival benefits obtained from preemptive RT are in line with delayed RT. For most advanced NSCLC patients during first-line treatment, the advantage of upfront RT was to delay progression, thereby also postponing the advent of further treatment. We consider the use of preemptive SBRT better than salvage SBRT, which was supported by a retrospective multi-institutional analysis (Magnuson et al. 2017). This multi-institutional analysis indicated that upfront stereotactic radiosurgery resulted in the longest OS compared to upfront whole-brain radiotherapy and EGFR-TKI for NSCLC with brain metastases (47 versus 31 or 25 months, P < 0.001). They also implied that delayed radiotherapy was associated with inferior OS in patients who presented with brain metastases. However, our real-world data suggested that preemptive SBRT delivery does not show a benefit in OS and PFS2 relative to delayed SBRT delivery (46.6 versus 51.3 months and 22.3 versus 28.9 months, P > 0.05). One of the main reasons why there is a numerically longer PFS2 and OS provided by SBRT to the primary lesion may be because, for the patients in the delayed radiotherapy group, there were those with oligoprogression who had a relatively more satisfactory prognosis (Chan et al. 2017; Xu et al. 2019) that were included into that group that may have skewed the numbers. Nevertheless, approximately only 15–40% of NSCLC patients with disease progression develop oligoprogression (Basler et al. 2017) which indicates that there are over 50% of patients with disease progression that do not have the opportunity for thoracic RT except for RT with the intent to alleviate symptoms. The primary advantage of preemptive RT in patients with non-oligometastases is that it may bring survival benefits to selected patients. This implies that the integration of preemptive SBRT and EGFR-TKI remains a promising option for selected patients with non-oligometastases. In future research, we will further explore whether, compared with delayed RT, preemptive RT would give more patients the opportunity to receive thoracic RT. Furthermore, whether preemptive RT could achieve better quality of life has not been studied. This might be evaluated with the EORTC QLQ 30 and LC14 modules in further prospective studies.

Other than the usual limitations of any real world, retrospective study, which include selection bias in a study performed in a single center, we acknowledge other limitations. First, no details about mild or moderate adverse events (grade < 3) were reported, as we could only obtain detailed information from electronic records which only sufficiently recorded severe toxicities (grade ≥ 3). Apart from this, the best RT technology for selected patients with non-oligometastatic NSCLC treated with first-line EGFR-TKIs is yet to be defined; whether SBRT is more effective than conventional RT is unknown. It is worth exploring in further studies. It is noteworthy that patients in the delayed RT group can be considered as patients who did not receive preemptive SBRT in the study. Although selective bias existed, baseline characteristics were well balanced between the two groups, and univariate and multivariate analyses were performed to reduce the influence of confounding factors on the results. Our study found that patients who are suitable for SBRT, administration of preemptive SBRT can significantly prolong PFS (PFS1: 22.3 months vs. 12.9 months, P = 0.0031). Our current research is unable to conclude whether OS can provide any benefits; this issue needs to be further explored in future studies. Besides, patients with non-oligometastatic NSCLC treated with first-line EGFR-TKIs who are suitable for preemptive RT combined with TKI are not well defined. The main objective of our retrospective study was to determine the value of SBRT to the primary lung lesion for selected patients; hence, we reviewed the patients from the RT database. Despite limitations, it is beneficial for selected patients. Future studies will focus on the local treatment of patients who are unable to accept SBRT. Moreover, patients with non-oligometastatic NSCLC are a heterogeneous population; incorporation of preemptive RT into the primary tumor as a part of the holistic treatment strategy needs to be considered carefully. The response to EGFR-TKI, performance status, and organ functions are important factors in deciding whether to proceed with RT in clinical practice. For selected patients, preemptive RT combined with TKIs is safe and feasible. Finally, the sample size was relatively small, and further randomized clinical trials are needed.

This real-world study showed that preemptive RT for the primary tumor was a feasible option for selected patients with EGFR-mutant non-oligometastatic NSCLC who had stable disease during first-line EGFR-TKI treatment; significant improvement was noted only in terms of PFS in these patients who underwent preemptive RT.

Author contribution

HW: data curation, formal analysis, investigation, visualization, original draft; XZ: conceptualization, data curation, investigation, review and editing; HY: methodology, formal analysis, resources, software; YG: project administration, resources, validation; JW: resources, validation; YX: resources, validation; LZ: resources, validation; JX: resources, validation; BZ: resources, validation; YZ: resources, validation; JZ: resources, validation; FP: resources, validation; MH: resources, validation, supervision; YLu: resources, project administration, supervision; YLiu: conceptualization, project administration, resources, supervision, review and editing.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of the West China Hospital of Sichuan University.

Data availability

The authors ensure transparency and availability of data.

Code availability

R version 4.03 software was used and measurement data.