Exploring the effectiveness and sequence of brain local treatment combined with thoracic surgery in non-small cell lung cancer patients with brain oligometastasis

Introduction

Non-small cell lung cancer (NSCLC) represents a substantial component of the global cancer burden (1), with approximately 10% of patients presenting with brain metastases at the time of diagnosis (2,3). Synchronous oligometastases are the intermediate state between localized cancer and overt distant metastases (4,5), which is defined as fewer than 3–5 metastases within a single site (6,7). An increasing number of researches have demonstrated that NSCLC patients with brain oligometastasis may benefit from aggressive local treatment of both the primary lung cancer and the metastatic sites (5,8-10).

Despite the established value of combining local brain therapy with thoracic surgery, a critical and unresolved question in real-world clinical practice pertains to the optimal sequence of these interventions. The National Comprehensive Cancer Network (NCCN) guidelines typically recommend addressing brain metastases prior to thoracic surgery (11). Nevertheless, a considerable proportion of patients still undergo resection of the lung primary tumor first in routine clinical practice (12,13). It is believed that controlling the primary lesion may decrease the risk of subsequent metastasis (12,14). Clinical practices in these circumstances are largely shaped by individual and/or institutional preferences, and there is a notable lack of large-scale real-world clinical data to identify potential beneficiaries of local radical treatment.

This study aimed to evaluate the effectiveness of local brain treatments combined with thoracic surgery in NSCLC patients with synchronous limited brain metastases. Meanwhile, we sought to provide new clinical insights into the optimal treatment sequence. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0007/rc).

Methods

Study design and participants

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (SYSUCC) (No. SL-B2025-656-01). The requirement for written informed consent was waived due to the retrospective design and the use of anonymized data. Patients diagnosed with NSCLC with synchronous brain parenchymal oligometastasis who underwent thoracic surgery at The Department of Thoracic Surgery at SYSUCC between May 2009 and December 2023 were included our analyses. The brain oligometastasis was limited as ≤3 metastases. The specific type of surgery was not restricted, including lobectomy, segmentectomy, wedge resection, and pneumonectomy. In addition, brain local treatments were defined as neurosurgical resection and stereotactic radiosurgery (SRS). Patients who received whole brain radiotherapy (WBRT) were excluded from this study. Neurological symptoms associated with brain metastases encompass both general symptoms, such as headaches, cognitive dysfunction, and gait disorders, as well as local symptoms, including hemiparesis, speech impairment, and visual field defects (15). Pulmonary function tests were conducted within one month prior to thoracic surgery. In accordance with the GOLD guidelines, forced expiratory volume in one second (FEV1) was utilized to assess the severity of ventilatory dysfunction (16).

The criteria for exclusion included: (I) pathological N3 stage of the primary lesion; (II) tumor leptomeningeal metastasis or multiple metastases in the brain parenchyma; (III) extracranial metastases or uncertain metastatic involvement; and (IV) the presence of a second primary tumor which required treatment. All enrolled patients underwent cervical, chest, and upper abdominal computed tomography (CT) and magnetic resonance imaging (MRI) of the brain. PET/CT scans or lymph node (LN) biopsies would be performed if necessary. Treatment plans were formulated by the clinician’s experience, clinical guidelines, as well as the latest results from clinical trials. Multidisciplinary expert team consultation will be conducted if necessary.

Patient grouping

In this study, the lung was designated as the primary surgical site, while the distant surgical site was restricted to the brain. Variables describing the type and timing of the three treatments (lung surgery, brain surgery, and brain SRS) were used for patient grouping. Patients who underwent brain surgery or SRS prior to lung surgery were classified into the upfront brain treatment group, whereas those who received brain local treatment subsequent to lung surgery were categorized into the subsequent brain treatment group. The timing of the lung surgery was considered the starting point for follow-up.

Clinical outcomes

The primary endpoints of this study included overall survival (OS) and progression-free survival (PFS). OS was defined as the duration from thoracic surgery to death from any cause or the follow-up deadline, while PFS was defined as the time from thoracic surgery to tumor progression, recurrence, or death. The secondary endpoints encompassed the patterns of postoperative recurrence. Locoregional recurrence was defined as recurrences within the ipsilateral thorax, including surgical margins, bronchial stump, and ipsilateral lung as well as mediastinal LN, while distant recurrence was defined as the presence of tumors found beyond the primary hemithorax, including contralateral lung, supraclavicular LN, contralateral pleura or other extrathoracic organs (17). Additionally, local tumor progression was defined as a 20% increase in the maximum diameter after treatment, compared to the smallest maximum diameter of the enhanced lesion recorded just before treatment or immediately following treatment (18).

Statistical analyses

Baseline characteristics were assessed utilizing the Wilcoxon rank-sum test for continuous variables and either Pearson’s χ² test or Fisher exact test for categorical variables. Kaplan-Meier analysis and propensity score stratified Cox regression were used to evaluate the long-term prognosis. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated to compare OS and PFS outcomes between patients with and without brain local treatment, as well as between those who received upfront and subsequent brain treatment.

To minimize confounding bias, inverse probability of treatment weighting (IPTW) was employed to balance covariates between the groups. Variables that exhibited statistically significant differences between the two groups were identified as matching variables. All statistical analyses were performed using R version 4.5.0 (R Foundation for Statistical Computing) and SPSS version 29.0 (IBM, Armonk, New York, NY, USA). A two-sided P value of <0.05 was considered statistically significant.

Results

Baseline characteristics

A total of 198 patients diagnosed with NSCLC with synchronous brain oligometastasis were included. All the participant were underwent primary lung cancer resection surgery. Among them, 50 patients received either brain surgery or RT as the first treatment and 25 patients received brain local treatment subsequent to lung surgery. Patients in the upfront treatment group received brain local treatment from December 2010 to May 2023, with a median lung-brain treatment interval of 1.2 months. Conversely, patients in the subsequent brain treatment group underwent brain local treatment from June 2011 to January 2024, exhibiting a median lung-brain treatment interval of 8.4 months. The study diagram was shown in Figure 1.

Figure 1 Study diagram. NSCLC, non-small cell lung cancer.

Table 1 summarized the baseline information of our cohort, separated according to whether brain local treatment was performed. The median age of the groups with and without brain local therapy was 60 years (IQR, 54–65 years) and 59 years (IQR, 50–63 years). The predominant histologic type of tumors in both groups was adenocarcinoma (ADC), accounting for 83.7% in the treatment group and 84.0% in the non-treatment group. Additionally, no significant differences were observed between the two groups in terms of clinical and pathological stages.

Comparison of thoracic surgery with and without local brain treatment

In the upfront brain treatment group, the subsequent brain treatment group, and the no brain local treatment group, the median follow-up times were 62.6, 60.6, and 53.3 months, respectively. Concurrently, the median OS for the three groups was 57.4, 54.2, and 49.9 months, respectively, while the median PFS was 35.9, 37.9, and 34.5 months, respectively. Compared to patients who did not receive any brain local treatment, significantly better prognosis was observed for those who received upfront brain treatment (OS: HR, 0.52, 95% CI: 0.28–0.97, P=0.04; PFS: HR, 0.51, 95% CI: 0.32–0.84, P=0.007) and for those who received subsequent brain treatment (OS: HR, 0.50, 95% CI: 0.31–0.82, P=0.005; PFS: HR, 0.51, 95% CI: 0.35–0.74, P<0.001) (Figure 2). Similar Kaplan-Meier curve trends for OS and PFS were observed in patients with single brain metastases stratified by brain treatment group (Figure S1).

Figure 2 Kaplan-Meier curves stratified by three brain local treatment groups in terms of OS (A) and PFS (B). OS, overall survival; PFS, progression-free survival.

Subgroup analysis indicated that patients with normal lung function experienced a significant improvement in prognosis following local brain treatment (OS: HR, 0.50, 95% CI: 0.32–0.78, P=0.002; PFS: HR, 0.38, 95% CI: 0.25–0.57, P<0.001). Conversely, while patients with impaired lung function exhibited a numerical improvement in both OS and PFS after local brain treatment, these changes did not reach statistical significance. In terms of the number of brain metastatic lesions, patients with a solitary metastatic lesion derived significant benefit from local brain treatment (OS: HR, 0.46, 95% CI: 0.28–0.74, P=0.001; PFS: HR, 0.47, 95% CI: 0.31–0.71, P<0.001). In contrast, patients with ≥2 lesions did not show a significant prognosis improvement following local brain treatment. Furthermore, no significant differences were observed between groups in the analyses of neurological symptoms (Figures 3,4).

Figure 3 Subgroup analysis of the impact of brain local treatment on overall survival. ADC, adenocarcinoma; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; SCC, squamous cell carcinoma.

Figure 4 Subgroup analysis of the impact of brain local treatment on progression-free survival. ADC, adenocarcinoma; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; SCC, squamous cell carcinoma.

Treatment sequence of thoracic surgery and brain local therapy

In comparing the clinical characteristics of patients receiving upfront versus subsequent brain treatment (Table 2), the upfront group had a higher rate of positive neurological symptoms at the time of diagnosis compared with the subsequent group (68.0% versus 16.0%, P<0.001). Furthermore, the proportion of patients with normal pulmonary function was higher in upfront brain treatment group than those in subsequent brain treatment group (88.0% versus 72.0%, P=0.04). The proportions of patients with moderate to severe pulmonary function dysfunction, mild pulmonary function dysfunction, and normal pulmonary function were 0%, 10.34%, and 13.58%, respectively. Regarding neurological symptoms, 56.67% of patients with positive neurological symptoms at the time of diagnosis received upfront brain treatment, whereas only 4.76% of patients without neurological symptoms received upfront brain treatment (Figure S2). Additionally, 60.0% patients in upfront brain treatment group received neurosurgical resection, while 86.0% patients in subsequent brain treatment group received SRS (Table 2).

Kaplan-Meier curves indicated no significant difference in OS and PFS between patients who received upfront brain treatment and those who received subsequent brain treatment (OS: HR, 1.022; 95% CI: 0.505–2.070; P=0.95; PFS: HR, 0.928; 95% CI: 0.541–1.591; P=0.79). Based on the variables related to OS and PFS identified through univariate and multivariate Cox regression analyses (Tables S1,S2), we conducted IPTW between the groups receiving prior brain treatment and those receiving subsequent brain treatment. In the adjusted cohort, the OS curve exhibited similar trends (HR, 1.537; CI: 0.879–3.615; P=0.19). However, the PFS curve indicated that the upfront treatment group experienced significant prognostic benefits compared to the subsequent treatment group (HR, 0.167; CI: 0.012–4.226; P<0.001) (Figure S3). Subgroup analysis of prognosis between the upfront and subsequent brain treatment groups demonstrated that patients with moderately differentiated tumor derived a longer OS from brain local treatment before thoracic surgery (HR, 4.865, 95% CI: 1.348–17.563, P=0.02) (Table S3). In other subgroups, no significant differences in prognosis were observed between the two group.

Patterns of postoperative recurrence grouped by treatment sequence

We compared the differences in overall recurrence, locoregional recurrence, and distant recurrence rate between upfront and subsequent brain treatment groups (Figure 5). Among them, the postoperative brain recurrence rate in upfront brain treatment group was significantly lower than that in subsequent brain treatment group (24.0% versus 46.0%, P=0.048).

Figure 5 Rates of overall recurrence, locoregional recurrence, distant recurrence, and brain recurrence in upfront brain treatment and subsequent brain treatment subgroups.

During the follow-up period, a total of 29 cases of brain recurrence or metastatic lesion progression were observed between the two groups (Figure S4). Among these, 6 cases of brain metastasis recurrences were observed in the upfront brain treatment group. The median PFS of these patients was 14.7 months, and 2 of them dying during follow-up. In contrast, the subsequent brain treatment group, which comprised 23 patients with brain recurrence, exhibited a median PFS of 14.3 months, with 10 patients passing away during the follow-up. The median interval from upfront brain therapy to thoracic surgery was 0.9 months, while the median interval from subsequent brain therapy to thoracic surgery was 8.1 months.

Discussion

This real-world retrospective study investigated the benefit of brain local treatments and their optimal timing relative to resection of primary lung tumor for stage IV NSCLC patients with synchronous limited brain metastases. According to the American Joint Committee on Cancer’s Ninth Edition TNM staging manual (19), these patients were classified into M1b-c1 stages, which were associated with relatively poor prognosis (20,21). Recent studies have demonstrated that surgical resection of the primary lung tumor, along with brain metastasectomy, can provide a significant survival benefit for patients with synchronous NSCLC and brain metastases (12,13,22,23). Historically, WBRT was the primary treatment option for brain metastases (24). However, between 2004 and 2016, several high-quality studies were published that elevated the status of SRS in the management of patients with 1 to 4 brain metastatic lesions (25-27). Currently, surgical resection or SRS is categorized as a level 1 recommendation for the treatment of resectable brain oligometastasis (11).

In this study, the lung was designated as the primary surgical site, while the distant surgical site was restricted to the brain. Compared to patients who did not receive any brain local treatment, significantly better prognosis was observed for those who received at least one brain local treatment. Patients who received at least one type of brain local treatment exhibited a significantly better prognosis compared to those who did not receive any such treatment. A comparison of the clinical and pathological characteristics between the groups revealed a statistically significant difference solely in the number of brain lesions, indicating a strong match in characteristics between the two groups.

The NCCN guidelines for NSCLC (Version 7.2025) (11) recommend that within 3 lesions of brain metastasis were generally considered an indication for local brain therapy, which included SRS and surgical resection. In clinical trials, the criteria for bifocal treatment have included the presence of up to 3 to 5 metastatic sites (5,8,9,28). In clinical practice, lung-brain bifocal therapy was predominantly applied to patients with single brain metastases (12,23,27). This observation aligns with our findings, which indicate a significant difference in the number of lesions between the brain treatment group and the non-brain treatment group. Some studies have compared the prognosis of isolated versus multiple brain metastases, revealing that patients with multiple brain lesions generally experience poorer survival outcomes (8,9,12). In our real-world cohort, patients with isolated brain metastases derived significant benefits from local brain treatment compared to those with more than one lesions, which aligned with the conclusions drawn from previous studies (29,30).

Neurological symptoms are common clinical manifestations in patients with brain metastases from NSCLC, with the majority presenting as focal neurological dysfunction or increased intracranial pressure (31,32). Brain local treatments are regarded as the preferred management modalities for brain metastases patients exhibiting neurological symptoms (18). In this study, the comparison of clinical characteristics between patients receiving upfront and subsequent brain local therapy also demonstrated that the upfront group exhibited a higher prevalence of positive neurological symptoms at the time of diagnosis. However, no significant differences in OS and PFS were observed between the groups with and without brain local therapy in the subgroup analysis focused on neurological symptoms. A possible explanation for this finding is that the participants in our study were patients with NSCLC exhibiting brain parenchymal oligometastasis, and all neurological symptoms observed were mild to moderate focal neurological deficits, which may account for the lack of significant differences in treatment outcomes between the groups.

Bifocal treatment, which encompasses local brain treatment and thoracic surgery, is currently the recommended therapeutic regimen for NSCLC patients with brain oligometastasis, according to international guidelines and clinical trials (5,11,33-35). Although the survival benefit associated with the resection of both the primary lung tumor and the metastatic lesion has been demonstrated, the optimal patient population and the sequence of lung-brain treatments still remained unclear. In real-world clinical settings, the decision regarding a radical therapeutic regimen for stage IV NSCLC cases is significantly influenced by clinicians’ personal opinions and institutional experiences (13). Our analysis revealed that the Kaplan-Meier curves for patients receiving upfront brain treatment and those undergoing subsequent brain treatment did not demonstrate a significant difference in OS and PFS. However, after adjusting for various confounding variables using IPTW, the PFS curve indicated that the upfront treatment group experienced significant prognostic advantages compared to the subsequent treatment group. Additionally, the postoperative brain recurrence rate in the upfront group was significantly lower than that in the subsequent group. Previous recommendations have suggested that lung surgery should be performed after the complete resection of brain metastases (12,23,36). Prioritizing the management of brain metastases can alleviate neurologic deficits resulting from mass effects or perilesional edema that do not respond to medical management (13,24,37). This local control is crucial in preventing irreversible nerve damage caused by the rapid progression of brain metastases. Our results further supported the acceptability of brain local treatment prior to surgery for primary lesions as a form of pre-treatment.

Our results have some potential biases that are difficult to verify due to sample size limitation. The discrepancy can be attributed in part to the longer lung-brain treatment interval in the subsequent group, which may contribute to more progression of metastases. Additionally, the proportion of neurosurgical resection cases in upfront brain treatment cohort was higher in upfront brain treatment cohort, and neurosurgical resection surgery had relatively better effect in controlling recurrence of tumor in the brain (38-40). However, studies in recent years have also shown that SRS and brain surgery can achieve similar prognosis (41,42). Larger randomized controlled trials are needed to further investigate this issue.

Despite our meticulous efforts to collect comprehensive clinical data and address potential biases and confounding factors during the analysis, this study has several limitations. First, the sample size of this study, particularly for the group that received local brain treatment prior to thoracic surgery, was relatively small. Second, this is a retrospective study, and the findings necessitate validation in prospective studies. Consequently, these results should only be considered as supplementary evidence for optimizing treatment strategies for patients with NSCLC who have brain oligometastasis, rather than serving as a definitive guideline.

Conclusions

Brain local therapy has the potential to prolong OS and PFS in NSCLC patients with brain oligometastasis receiving thoracic surgery, especially recommended for those with a solitary metastatic lesion and normal lung function. Upfront brain treatment was associated with lower postoperative brain recurrence rate compared to subsequent brain therapy, making it advisable as a pre-treatment for patients who would eventually receive resection of the primary lung cancer.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0007/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0007/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0007/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0007/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (SYSUCC) (No. SL-B2025-656-01). The requirement for written informed consent was waived due to the retrospective design and the use of anonymized data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. Waqar SN, Samson PP, Robinson CG, et al. Non-small-cell Lung Cancer With Brain Metastasis at Presentation. Clin Lung Cancer 2018;19:e373-9. [Crossref] [PubMed]
3. Sacks P, Rahman M. Epidemiology of Brain Metastases. Neurosurg Clin N Am 2020;31:481-8. [Crossref] [PubMed]
4. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8-10. [Crossref] [PubMed]
5. De Ruysscher D, Wanders R, Hendriks LE, et al. Progression-Free Survival and Overall Survival Beyond 5 Years of NSCLC Patients With Synchronous Oligometastases Treated in a Prospective Phase II Trial (NCT 01282450). J Thorac Oncol 2018;13:1958-61. [Crossref] [PubMed]
6. Rashdan S, Iyengar P, Minna JD, et al. Narrative review: molecular and genetic profiling of oligometastatic non-small cell lung cancer. Transl Lung Cancer Res 2021;10:3351-68. [Crossref] [PubMed]
7. Chen YH, Ho UC, Kuo LT. Oligometastatic Disease in Non-Small-Cell Lung Cancer: An Update. Cancers (Basel) 2022;14:1350. [Crossref] [PubMed]
8. Gomez DR, Tang C, Zhang J, et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol 2019;37:1558-65.
9. Suzuki K, Shiono S, Hasumi T, et al. Clinical significance of bifocal treatment for synchronous brain metastasis in T1-2 non-small-cell lung cancers: JNETS0301. Gen Thorac Cardiovasc Surg 2021;69:967-75. [Crossref] [PubMed]
10. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2018;4:e173501. [Crossref] [PubMed]
11. Riely GJ, Wood DE, Aisner DL, et al. NCCN Guidelines® Insights: Non-Small Cell Lung Cancer, Version 7.2025. J Natl Compr Canc Netw 2025;23:354-62. [Crossref] [PubMed]
12. Kumar A, Kumar S, Potter AL, et al. Surgical management of non-small cell lung cancer with limited metastatic disease involving only the brain. J Thorac Cardiovasc Surg 2024;167:466-477.e2. [Crossref] [PubMed]
13. He X, Yin S, Liu H, et al. Upfront Brain Treatments Followed by Lung Surgery Improves Survival for Stage IV Non-small Cell Lung Cancer Patients With Brain Metastases: A Large Cohort Analysis. Front Surg 2021;8:649531. [Crossref] [PubMed]
14. Ulusan A, Elma B, Danaci HZK, et al. Impact of metastasectomy on survival in patients with oligometastatic stage 4a lung cancer: a retrospective analysis. Updates Surg 2025;77:937-45. [Crossref] [PubMed]
15. Okuno T, Isobe T, Tsubata Y. Current pharmacologic treatment of brain metastasis in non-small cell lung cancer. Clin Exp Metastasis 2024;41:549-65. [Crossref] [PubMed]
16. Mirza S, Clay RD, Koslow MA, et al. COPD Guidelines: A Review of the 2018 GOLD Report. Mayo Clin Proc 2018;93:1488-502. [Crossref] [PubMed]
17. Li H, Pezeshkian F, Xie Y, et al. Lung cancer recurrence after neoadjuvant immunotherapy. J Thorac Cardiovasc Surg 2025;170:852-863.e6. [Crossref] [PubMed]
18. Liu Q, Yin Q, Dong Y, et al. Microsurgery vs. radiosurgery for the treatment of multiple metastases in the brain: a retrospective cohort study. Cancer Biol Med 2021;19:884-92.
19. Fong KM, Rosenthal A, Giroux DJ, et al. The International Association for the Study of Lung Cancer Staging Project for Lung Cancer: Proposals for the Revision of the M Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2024;19:786-802.
20. Sperduto PW, De B, Li J, et al. Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases: Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors. Int J Radiat Oncol Biol Phys 2022;114:60-74. [Crossref] [PubMed]
21. Zhu Y, He D, Hou Z, et al. Clinical Features, Molecular Biology, and the Metastatic Microenvironment in Lung Cancer Brain Metastases: Implications for Treatment Decisions. Adv Sci (Weinh) 2025;12:e02626. [Crossref] [PubMed]
22. Paek SH, Audu PB, Sperling MR, et al. Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery 2005;56:1021-34; discussion 1021-34.
23. Louie AV, Rodrigues G, Yaremko B, et al. Management and prognosis in synchronous solitary resected brain metastasis from non-small-cell lung cancer. Clin Lung Cancer 2009;10:174-9. [Crossref] [PubMed]
24. Pikis S, Protopapa M, Mantziaris G, et al. Stereotactic radiosurgery for brain metastases. Adv Cancer Res 2025;165:115-143. [Crossref] [PubMed]
25. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004;363:1665-72. [Crossref] [PubMed]
26. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006;295:2483-91. [Crossref] [PubMed]
27. Brown PD, Jaeckle K, Ballman KV, et al. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA 2016;316:401-9. [Crossref] [PubMed]
28. Gomez DR, Blumenschein GR Jr, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol 2016;17:1672-82. [Crossref] [PubMed]
29. Fuchs J, Früh M, Papachristofilou A, et al. Resection of isolated brain metastases in non-small cell lung cancer (NSCLC) patients - evaluation of outcome and prognostic factors: A retrospective multicenter study. PLoS One 2021;16:e0253601. [Crossref] [PubMed]
30. Alsousli M, Maire CL, Piffko A, et al. Altered CD4 T cell response in oligometatastic non-small cell lung cancer brain metastasis. Acta Neuropathol Commun 2025;13:95. [Crossref] [PubMed]
31. Malhotra J, Mambetsariev I, Gilmore G, et al. Targeting CNS Metastases in Non-Small Cell Lung Cancer With Evolving Approaches Using Molecular Markers: A Review. JAMA Oncol 2025;11:60-9. [Crossref] [PubMed]
32. Lamba N, Wen PY, Aizer AA. Epidemiology of brain metastases and leptomeningeal disease. Neuro Oncol 2021;23:1447-56. [Crossref] [PubMed]
33. De Ruysscher D, Wanders R, van Baardwijk A, et al. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct01282450). J Thorac Oncol 2012;7:1547-55. [Crossref] [PubMed]
34. Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29:iv192-237. [Crossref] [PubMed]
35. Vogelbaum MA, Brown PD, Messersmith H, et al. Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. J Clin Oncol 2022;40:492-516. [Crossref] [PubMed]
36. Bonnette P, Puyo P, Gabriel C, et al. Surgical management of non-small cell lung cancer with synchronous brain metastases. Chest 2001;119:1469-75. [Crossref] [PubMed]
37. Schiff D, Messersmith H, Brastianos PK, et al. Radiation Therapy for Brain Metastases: ASCO Guideline Endorsement of ASTRO Guideline. J Clin Oncol 2022;40:2271-6. [Crossref] [PubMed]
38. Muacevic A, Wowra B, Siefert A, et al. Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial. J Neurooncol 2008;87:299-307. [Crossref] [PubMed]
39. Roos DE, Smith JG, Stephens SW. Radiosurgery versus surgery, both with adjuvant whole brain radiotherapy, for solitary brain metastases: a randomised controlled trial. Clin Oncol (R Coll Radiol) 2011;23:646-51. [Crossref] [PubMed]
40. Schöggl A, Kitz K, Reddy M, et al. Defining the role of stereotactic radiosurgery versus microsurgery in the treatment of single brain metastases. Acta Neurochir (Wien) 2000;142:621-6. [Crossref] [PubMed]
41. González L, Castro S, Villa E, et al. Surgical resection versus stereotactic radiosurgery on local recurrence and survival for patients with a single brain metastasis: a systematic review and meta-analysis. Br J Neurosurg 2021;35:703-13. [Crossref] [PubMed]
42. Bougie E, Masson-Côté L, Mathieu D. Comparison Between Surgical Resection and Stereotactic Radiosurgery in Patients with a Single Brain Metastasis from Non-Small Cell Lung Cancer. World Neurosurg 2015;83:900-6. [Crossref] [PubMed]