Timing of stereotactic radiosurgery within the first-line systemic treatment in non-small cell lung cancer brain metastases: a retrospective single-center cohort study

Introduction

The treatment landscape for metastatic non-small cell lung cancer (NSCLC) has undergone remarkable advancements in recent years. The introduction of tyrosine kinase inhibitors (TKIs) such as the epidermal growth factor receptor (EGFR)-inhibitor osimertinib, the anaplastic lymphoma kinase (ALK)-inhibitor lorlatinib, and the Kirsten-rat-sarcoma (KRAS)-inhibitor sotorasib, alongside immune checkpoint inhibitors (ICIs), such as the programmed-deadth-ligand-1 (PD-L1)-inhibitor pembrolizumab, has substantially enhanced the prognosis of metastatic lung cancer patients harboring respective mutations (1-5). Notably, osimertinib has shown high efficacy in managing brain metastases due to its excellent ability to penetrate the blood-brain barrier (6).

In addition to systemic therapies, advancements in local treatments, particularly stereotactic radiosurgery (SRS), have also progressed significantly. Technical innovations enable the safe treatment of ten or even more metastases using SRS, positioning it as a less toxic alternative to whole-brain radiotherapy (WBRT) for managing this number of metastases (7,8). In the prospective controlled STEREOBRAIN trial, which compared patients receiving SRS for four to ten metastases with a matched historic WBRT cohort, a notable trend towards overall benefit was observed for SRS, demonstrating a median survival of 10.4 months compared to 7.1 months in the historic cohort (P=0.07), approaching statistical significance (9). Some other studies have suggested the feasibility of administering SRS to higher numbers of metastases, such as 15 or 20, in carefully selected patients (10-13).

The combined approach of these treatments has demonstrated advantages, likely due to a synergistic effect (14-19). Consequently, the standard practice involves the utilization of both local and systemic treatments for NSCLC brain metastases (20). One critical question, however, remains unanswered: Is it more effective to address brain metastases initially, preceding systemic treatment, or could there be greater benefit in implementing SRS on demand for non-responsive lesions subsequent to systemic treatment (16,21-25)? This retrospective study aims to analyze patients who received both, SRS/stereotactic radiotherapy (SRT) and TKI/ICI for NSCLC brain metastases. Its objective is to identify potential correlations between the timing of these treatments and the resulting outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-132/rc).

Methods

Data collection

For this monocentric retrospective analysis, the internal data base within MOSAIQ^® (Elekta, Stockholm, Sweden) was searched for patients who underwent cranial SRS/SRT in combination with ICI or TKI between 2017 and 2021. Then, patients who received ICI/TKI as their first line therapy for brain metastases were identified. Patients with prior WBRT were excluded from this study. Additionally, patients without any follow-up including imaging, were excluded as well. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The patients gave their approval as part of a broad consent at the LMU University Hospital of Munich. Due to the anonymized analysis and the retrospective nature of this study, no separate ethical approval by a review board was needed.

Radiation treatment

Brain metastases ranging from 0.3 to 2.5 cm in diameter underwent SRS with prescription doses between 18 and 20 Gy (to the 80% isodose line). Conversely, larger metastases or those positioned in critical areas were managed through multi-fraction SRT, employing a dose of 28 Gy distributed across five fractions (to the 80% isodose line). Up to ten metastases were treated simultaneously using single-isocenter dynamic arc therapy. Irregularly shaped metastases were preferably addressed utilizing volumetric arc therapy (26,27). Gross tumor volume (GTV) to planning target volume (PTV) margin was 1 mm.

Data acquisition

General patient characteristics and therapy data were obtained from the patient records, encompassing variables such as sex, age at the time of brain metastasis diagnosis, identified driver mutations, PD-L1 status, control of extracranial disease, prior radiotherapy (RT) for the primary tumor, Karnofsky performance status (KPS), count of treated brain metastases, median GTV, median PTV, use of additional chemotherapy, and subsequent systemic therapies. V10 and V12 for SRS, and V20 for SRT (volumes receiving a specific dose of more or equal than 10, 12 or 20 Gy, respectively) of the unaffected brain tissue (brain volume minus GTV), were collected as risk factors for radiation necrosis (28). Additionally, the disease specific graded prognostic assessment score (dsGPA), initial brain metastasis velocity (iBMV) score and the brain metastasis velocity (BMV) score were assessed.

iBMV=totalnumberofbrainmetastasesattimeofRTnumberofyearssinceinitialprimarycancerdiagnosis[1]

BMV=numberofnewmetastasessinceinitialRTnumberofyearssinceinitialRT[2]

Assessment of treatment-related toxicity involved grading adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Neuroradiological evaluation

Baseline cranial magnetic resonance imaging (MRI) was usually conducted no later than 2 weeks before the initiation of treatment, with follow-up assessments routinely performed every three months in most cases. Follow-up imaging was reviewed by two experienced neuroradiologists, according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria (29). Consequently, gadolinium-enhanced T1-weighted MRI was utilized to assess irradiated lesions in terms of progression, pseudoprogression, stable disease, partial response, and complete response.

Timing of SRS/SRT and ICI/TKI

This study focuses on patients who received ICIs and TKIs as first-line therapy for the brain metastases. The patients were categorized into two groups based on the timing of their cranial RT. They either received upfront SRS/SRT following ICI/TKI or underwent initial ICI/TKI treatment before initiating RT. Patients treated with ICI or TKI were analyzed separately. To analyze potential advantages of scheduling SRT/SRS with ICI/TKI, patients who underwent initial SRS/SRT were further examined in two subgroups based on whether they received concurrent or sequential ICI/TKI. The concurrent subcohort received ICI/TKI within a 2-week period after SRS/SRT. The sequential subcohort received ICI/TKI more than 2 weeks following SRS/SRT. The decision to use this 2-week timeframe was defined analogous to a comparable analysis conducted in the context of melanoma brain metastases, in which a difference between sequential and concomitant treatment was first seen when reducing the usual time frame of 4 weeks to 2 weeks, or even only 1 week (30).

Patient cohort and its subgroups

Following the database evaluation, a total of 54 patients were identified who received SRS/SRT in combination with ICI or TKI. Among them, 34 patients received ICI/TKI as their initial treatment as their first-line therapy for a total of 99 brain metastases. The latter cohort consisted of 17 (50.0%) patients for both upfront SRS/SRT and upfront TKI/ICI, each; 24 (70.6%) received SRS/SRT and ICI, and 10 (29.4%) received SRS/SRT and TKI. From the patients who received TKI (n=10), 7 (70.0%) received upfront SRS/SRT and 3 (30.0%) initial TKI treatment. Conversely, among the patients who received ICI (n=24), 10 (41.7%) patients underwent upfront SRS/SRT and 14 (58.3%) patients were initially treated with ICI. The distribution of the cohort and its subgroups is depicted in Figure 1.

Figure 1 Distribution of the patients in the (sub-)cohorts. NSCLC, non-small cell lung cancer; BM, brain metastases; RT, radiation therapy; ICI, immune checkpoint inhibitor; TKI, tyrosine kinase inhibitor; F-U, follow-up; MRI, magnet resonance imaging; WBRT, whole brain radiotherapy; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy.

Statistical analysis

The data were analyzed using the statistical program IBM SPSS Statistics version 29.0 (IBM, Armonk, New York, USA). Descriptive statistics involved calculating both relative and absolute frequencies. Patient characteristics across all therapy groups were compared using the Fisher-Yates and Mann-Whitney tests. However, for contingency tables larger than 2×2, the Fisher-Freeman-Halton test was preferred over the Fisher-Yates test. Survival analysis was performed employing Kaplan-Meier analysis along with the log-rank test. Additionally, multiple regression was used to evaluate the impact of various variables on survival times. The survival times considered for analysis were overall survival (OS) since start of treatment (SRS/SRT or ICI/TKI, respectively) and intracranial progression-free survival (iPFS) since start of treatment (SRS/SRT or ICI/TKI, respectively). Radiation necrosis free-survival was calculated from start of SRS/SRT. A significance level of P≤0.05 was deemed statistically significant.

Results

Patient characteristics

As presented before a total of 54 patients were identified who received SRS/SRT in combination with ICI or TKI. Among them, 34 patients received ICI/TKI as their initial treatment for a total of 99 brain metastases. Within this cohort, 31 (91.2%) patients had adenocarcinoma, and 3 (8.8%) patients had squamous cell carcinoma. The group was divided, with 17 (50.0%) patients each for those receiving upfront SRS/SRT or initial TKI/ICI treatment. The distribution of patients in each cohort is illustrated in Figure 1, and specific patient characteristics are outlined in Tables 1,2.

Notably, the subgroups did not exhibit differences across various parameters except for the dsGPA score. The median dsGPA was 2.5 for upfront SRS/SRT and 2.0 for initial TKI/ICI treatment, yielding a P value of 0.07. However, when analyzed as a binary variable of the scores 0–2 and 2.5–4, the P value was 0.03. The individual components used to determine the dsGPA (such as age, Karnofsky performance score, presence of extracerebral metastases, number of brain metastases and molecular status) showed P values greater than 0.05 (see Table 2).

Upfront SRS/SRT versus initial ICI/TKI treatment

Upon comparing upfront SRS/SRT versus initial ICI/TKI treatment, no significant difference was observed OS and iPFS, in spite of a noticeable trend favoring upfront SRS/SRT in the OS curves (Figure 2, A1 and A2). Factors impacting survival were assessed in the univariate analysis and detailed in Table 3. Extracranial disease control at the time of brain metastasis diagnosis emerged as a significant influencer of OS [hazard ratio (HR) =0.378, 95% confidence interval (CI): 0.149–0.955, P=0.04]. iPFS was solely significantly influenced by the BMV score (P<0.001).

Figure 2 Kaplan-Meier curves of the OS and iPFS regarding initial ICI/TKI treatment vs. upfront SRS/SRT (A1,A2), initial ICI treatment vs. upfront SRS/SRT (B1,B2), and concurrent (within 2 weeks after RT) ICI/TKI vs. sequential (2 weeks or more after RT) ICI/TKI (C1,C2), respectively. SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy; ICI, immune checkpoint inhibition; TKI, tyrosine kinase inhibitor; OS, overall survival; iPFS, intracranial progression free survival; RT, radiation therapy.

The univariate analysis concerning RNFS, as presented in Table 4, revealed a notable impact of V10 (HR =1.193, 95% CI: 1.008–1.411, P=0.04) and V12 values (HR =1.286, 95% CI: 1.018–1.625, P=0.04) specifically for lesions that underwent single-fraction irradiation (n=89, 89.9%). The treatment order (upfront SRS/SRT vs. initial ICI/TKI treatment), however, did not show any significant impact on RNFS (HR =0.246, 95% CI: 0.027–2.254, P=0.22).

Subgroup ICI: upfront SRS/SRT vs. initial ICI treatment

In the subset of patients receiving ICI (n=24), the distribution was 10 (41.7%) patients for upfront SRS/SRT and 14 (58.4%) patients for initial ICI treatment (Table S1). With respect to specific ICI regimens 22 (91.7%) patients received pembrolizumab, the other two nivolumab and ipilimumab/nivolumab. Similar to the larger cohort, the groups only differed with regard to dsGPA (P=0.03). Kaplan-Meier analysis revealed a significantly longer OS in the upfront SRS/SRT cohort compared to initial ICI treatment (P=0.03) (Figure 2, B1 and B2).

Subgroup TKI: upfront SRS/SRT vs. initial TKI treatment

For the subset of patients receiving TKI (n=10), the distribution was 7 (70.0%) patients for upfront SRS/SRT and 3 (30.0%) patients for initial TKI treatment (Table S2). Three (30.0%) patients received afatinib, 4 (40.0%) osimertinib, 2 (20.0%) crizotinib and 1 (10.0%) gefitinib. The cohorts did not significantly differ from each other. Kaplan-Meier analysis, however, failed to show any significant differences concerning OS and iPFS (P=0.15 and P=0.09, respectively) (Figure S1A,S1B).

Subgroup upfront SRS/SRT: concurrent vs. sequential ICI/TKI treatment

When looking at all patients receiving upfront SRS/SRT (n=17), 10 (58.8%) patients received ICI/TKI concurrently within 2 weeks after SRS/SRT, and 7 (41.2%) patients sequentially more than 2 weeks after SRS/SRT (Table S3). The analysis unveiled significantly improved OS and iPFS in the sequential cohort compared to the concurrent cohort (P=0.009 and P=0.03, respectively) (Figure 2, C1 and C2). Unfortunately, conducting separate analyses for ICI and TKI was not feasible due to the limited number of patients in each subgroup.

Discussion

Despite the advancements in systemic treatments that directly target specific cancer mutations, local therapies such as surgery and RT remain integral, particularly in the management of oligometastatic disease. Several trials have highlighted the benefits of improved PFS and/or OS by incorporating focal SRS/SRT alongside systemic treatments for oligometastatic NSCLC (31-33). Due to the high efficacy of EGFR-targeted TKI, the question remains, whether TKI can replace SRS/SRT in patients with EGFR-mutated NSCLC or if patients benefit more from the combination of SRS/SRT and TKI. A retrospective trial by Magnuson et al. analyzing 351 patients with EGFR-mutant NSCLC brain metastases treated with TKI demonstrated improved OS when receiving upfront SRS compared to initial TKI treatment and SRS or WBRT at progression (46 vs. 25 months, HR 0.39, P<0.001) (15). When looking at extracranial metastases, a recently published trial by Wang et al. involving 133 patients with oligometastatic EGFR-mutated NSCLC (without brain metastases) receiving first-line TKI found that those who received upfront focal SRS/SRT to all tumor sites exhibited significantly enhanced OS (25.5 vs. 17.4 months, P<0.001) and PFS (20.2 vs. 12.5 months, P=0.001) (34). These findings indicate that SRS/SRT influences outcomes even when combined with highly effective systemic treatments like EGFR inhibitors. However, the impact of SRS/SRT in patients receiving the newest generation of EGFR inhibitors, such as osimertinib, remains unclear. Addressing this uncertainty, the NORTHSTAR trial (NCT03410043) aims to investigate the role of SRS/SRT in patients receiving osimertinib, shedding light on its potential impact in this specific treatment context.

In our analysis, upfront SRS/SRT demonstrated a significantly improved OS in the cohort receiving ICI. This finding aligns with another retrospective study by Yu et al., indicating that delayed SRS/SRT resulted in poorer OS compared to upfront or concomitant SRS/SRT: within a cohort of 73 NSCLC patients with brain metastases treated with ICI were associated with shorter OS when receiving delayed RT (P=0.003) administration; in a meta-analysis with 254 from four studies parallelly done in the same article, improved OS was shown for concurrent vs. delayed RT (HR =0.44, P<0.03) and upfront vs. delayed RT (HR =0.32, P<0.01) (17). Guo et al. also reported comparable results: while analyzing 461 patients with NSCLC brain metastases receiving ICI, patients with upfront RT showed longer OS (25.4 vs. 14.6 months, HR =0.52, P=0.04) (35). The fact that in our study OS is significantly different, but iPFS is not, may appear peculiar at first glance, yet it is a common occurrence in trials involving ICI or TKI: Hess et al. specifically analyzed this phenomenon in 192 studies with biological or targeted agents, and concluded that this is not a result of poor study design, but suggested it may be due to still unknown complex mechanisms of action of the biological or targeted agents (36).

Given that 80% of the patients in the subgroup receiving TKI had EGFR mutations, it’s plausible to assume that the substantial response of EGFR inhibitors on brain metastases might have minimized the impact of SRS in first-line treatment, consequently impacting the timing as well. It would be intriguing to investigate whether the timing of SRS holds significance in non-EGFR-positive brain metastases treated with TKIs, but due to the limited representation of only two patients, this analysis couldn’t be conducted in this cohort. Regarding the comparison between concurrent and sequential application of systemic treatment with RT, patients appeared to benefit more from sequential application, as concurrent treatment of systemic treatment may have a certain impact on toxicity, as it was recently suggested in a study regarding SRS and ipilimumab/nivolumab in melanoma brain metastases (30), a reason herefore may the higher treatment morbidity. However, due to the minimal incidence of radiation necrosis in our study (only one patient in this subgroup), this aspect couldn’t be thoroughly analyzed.

In summary, our study suggests that upfront SRS/SRT may lead to a survival advantage to NSCLC patients undergoing ICI treatment with very low additional treatment toxicity. However, for patients with mutations susceptible to TKIs, the benefits of upfront SRS/SRT appear less pronounced. In these cases, salvage SRS/SRT targeted to persistent or progressing metastases might be sufficient. It is important to note the clear limitations of our study, primarily its retrospective nature and the limited number of patients, which posed challenges in analyzing subgroups comprehensively. Specifically, for the analysis of the TKI cohort, a larger patient cohort would be necessary to draw more definitive conclusions. Besides, the low number of squamous cell carcinoma and relatively high number of EGFR positive patients does not make this cohort representative for all patients. Additionally, a selection bias is very likely due to the fact that patients with a good systemic and intracranial response might not have been treated with SRS/SRT afterwards, and thus were not taken into account in this analysis. Therefore, there is a pressing need for a randomized trial specifically investigating the optimal timing of SRS/SRT in these patient cohorts, which would offer more conclusive and robust insights into treatment strategies.

Conclusions

In this small retrospective cohort, patients treated with ICI (mainly pembrolizumab) and SRS/SRT as first-line treatment for brain metastases of NSCLC, upfront SRS/SRT followed by ICI lead to significantly prolonged OS than initial ICI treatment followed by SRS/SRT. While the difference between patients treated with upfront SRS/SRT and patients initially treated with TKI was not significant, the number of patients in this subcohort was too small to make any meaningful conclusions. Despite of the inherent limitations of this single-center retrospective study, timing of SRS/SRT within multimodal approach for NSCLC brain metastases seems to have a considerable impact on the patients’ outcome.

Acknowledgments

Preliminary data have been presented on the national conference of the German Society of Radiation Oncology (DEGRO) and the international conference of the European Society of Radiation Oncology (ESTRO).

Funding: The study was supported by Open Access Publication Fund of the University of Tübingen.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-132/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-132/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-132/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-132/coif). R.B. received Open Access Fund from University of Tübingen, and received honoraria from NovoCure for participating in invited meetings of specialized centers. C.B. received grants or contracts not related to this manuscript from Viewray, Brainlab and Elekta, and received support for attending meetings and/or travel from BMS, Roche, Merck, AstraZeneca and Viewray. F.M. received an unrestricted Research Institutional Grant from AstraZeneca, received honoraria from AstraZeneca, Novartis, Roche, Lilly, Elekta and Brainlab, and serves in the advisory board of AstraZeneca and Novartis. M.N. received payments from Brainlab and AstraZeneca for speaking services. The other 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 (as revised in 2013). The patients gave their approval as part of a broad consent at the LMU University Hospital of Munich. Due to the anonymized analysis and the retrospective nature of this study, no separate ethical approval by a review board was needed.

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. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 2020;382:41-50. [Crossref] [PubMed]
2. Solomon BJ, Bauer TM, Mok TSK, et al. Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study. Lancet Respir Med 2023;11:354-66. [Crossref] [PubMed]
3. de Langen AJ, Johnson ML, Mazieres J, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial. Lancet 2023;401:733-46. [Crossref] [PubMed]
4. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 2020;38:1505-17. [Crossref] [PubMed]
5. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25. [Crossref] [PubMed]
6. Park S, Lee MH, Seong M, et al. A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann Oncol 2020;31:1397-404. [Crossref] [PubMed]
7. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014;15:387-95. [Crossref] [PubMed]
8. Bodensohn R, Kaempfel AL, Fleischmann DF, et al. Simultaneous stereotactic radiosurgery of multiple brain metastases using single-isocenter dynamic conformal arc therapy: a prospective monocentric registry trial. Strahlenther Onkol 2021;197:601-13. [Crossref] [PubMed]
9. Bodensohn R, Kaempfel AL, Boulesteix AL, et al. Stereotactic radiosurgery versus whole-brain radiotherapy in patients with 4-10 brain metastases: A nonrandomized controlled trial. Radiother Oncol 2023;186:109744. [Crossref] [PubMed]
10. Yamamoto M, Higuchi Y, Sato Y, et al. Stereotactic Radiosurgery for Patients with 10 or More Brain Metastases. Prog Neurol Surg 2019;34:110-24. [Crossref] [PubMed]
11. Yamamoto M, Sato Y, Higuchi Y, et al. A Cohort Study of Stereotactic Radiosurgery Results for Patients With 5 to 15 Versus 2 to 4 Brain Metastatic Tumors. Adv Radiat Oncol 2020;5:358-68. [Crossref] [PubMed]
12. Yamamoto M, Serizawa T, Sato Y, et al. Stereotactic Radiosurgery Results for Patients with 5-10 versus 11-20 Brain Metastases: A Retrospective Cohort Study Combining 2 Databases Totaling 2319 Patients. World Neurosurg 2021;146:e479-91. [Crossref] [PubMed]
13. Mizuno T, Takada K, Hasegawa T, et al. Comparison between stereotactic radiosurgery and whole-brain radiotherapy for 10-20 brain metastases from non-small cell lung cancer. Mol Clin Oncol 2019;10:560-6. [Crossref] [PubMed]
14. Zhao Y, Li S, Yang X, et al. Overall survival benefit of osimertinib and clinical value of upfront cranial local therapy in untreated EGFR-mutant nonsmall cell lung cancer with brain metastasis. Int J Cancer 2022;150:1318-28. [Crossref] [PubMed]
15. Magnuson WJ, Lester-Coll NH, Wu AJ, et al. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. J Clin Oncol 2017;35:1070-7. [Crossref] [PubMed]
16. Yu F, Ni J, Zeng W, et al. Clinical Value of Upfront Cranial Radiation Therapy in Osimertinib-Treated Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer With Brain Metastases. Int J Radiat Oncol Biol Phys 2021;111:804-15. [Crossref] [PubMed]
17. Yu Y, Chen H, Tian Z, et al. Improved survival outcome with not-delayed radiotherapy and immediate PD-1/PD-L1 inhibitor for non-small-cell lung cancer patients with brain metastases. J Neurooncol 2023;165:127-37. [Crossref] [PubMed]
18. Yang Y, Deng L, Yang Y, et al. Efficacy and Safety of Combined Brain Radiotherapy and Immunotherapy in Non-Small-Cell Lung Cancer With Brain Metastases: A Systematic Review and Meta-Analysis. Clin Lung Cancer 2022;23:95-107. [Crossref] [PubMed]
19. Enright TL, Witt JS, Burr AR, et al. Combined Immunotherapy and Stereotactic Radiotherapy Improves Neurologic Outcomes in Patients with Non-small-cell Lung Cancer Brain Metastases. Clin Lung Cancer 2021;22:110-9. [Crossref] [PubMed]
20. Le Rhun E, Guckenberger M, Smits M, et al. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol 2021;32:1332-47. [Crossref] [PubMed]
21. Bodensohn R, Niyazi M. Response to the letters to the editor of S. Benkhaled et al. and C.H. Rim regarding the article "Stereotactic radiosurgery versus whole-brain radiotherapy in patients with 4-10 brain metastases: A nonrandomized controlled trial" by Bodensohn et al. Radiother Oncol 2023;189:109888. [Crossref] [PubMed]
22. Benkhaled S, Jullian N, Collen C. Letter to the editor regarding the article “Stereotactic radiosurgery versus whole-brain radiotherapy in patients with 4–10 brain metastases: A non-randomized controlled trial” by Bodensohn et al. Radiother Oncol 2023; [Crossref]
23. Minniti G, Le Rhun E. Should radiotherapy be considered for the initial treatment of brain metastases? Lancet Oncol 2022;23:205-6. [Crossref] [PubMed]
24. Zhai X, Li W, Li J, et al. Therapeutic effect of osimertinib plus cranial radiotherapy compared to osimertinib alone in NSCLC patients with EGFR-activating mutations and brain metastases: a retrospective study. Radiat Oncol 2021;16:233. [Crossref] [PubMed]
25. Merkin RD, Chiang VL, Goldberg SB. Management of patients with brain metastases from NSCLC without a genetic driver alteration: upfront radiotherapy or immunotherapy? Ther Adv Med Oncol 2023;15:17588359231175438. [Crossref] [PubMed]
26. Hofmaier J, Bodensohn R, Garny S, et al. Single isocenter stereotactic radiosurgery for patients with multiple brain metastases: dosimetric comparison of VMAT and a dedicated DCAT planning tool. Radiat Oncol 2019;14:103. [Crossref] [PubMed]
27. Bodensohn R, Maier SH, Belka C, et al. Stereotactic Radiosurgery of Multiple Brain Metastases: A Review of Treatment Techniques. Cancers (Basel) 2023;15:5404. [Crossref] [PubMed]
28. Minniti G, Clarke E, Lanzetta G, et al. Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol 2011;6:48. [Crossref] [PubMed]
29. Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 2015;16:e270-8. [Crossref] [PubMed]
30. Bodensohn R, Werner S, Reis J, et al. Stereotactic radiosurgery and combined immune checkpoint therapy with ipilimumab and nivolumab in patients with melanoma brain metastases: A retrospective monocentric toxicity analysis. Clin Transl Radiat Oncol 2023;39:100573. [Crossref] [PubMed]
31. 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. [Crossref] [PubMed]
32. 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]
33. Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol 2020;38:2830-8. [Crossref] [PubMed]
34. Wang XS, Bai YF, Verma V, et al. Randomized Trial of First-Line Tyrosine Kinase Inhibitor With or Without Radiotherapy for Synchronous Oligometastatic EGFR-Mutated Non-Small Cell Lung Cancer. J Natl Cancer Inst 2023;115:742-8. [Crossref] [PubMed]
35. Guo T, Chu L, Chu X, et al. Brain metastases, patterns of intracranial progression, and the clinical value of upfront cranial radiotherapy in patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors. Transl Lung Cancer Res 2022;11:173-87. [Crossref] [PubMed]
36. Hess LM, Brnabic A, Mason O, et al. Relationship between Progression-free Survival and Overall Survival in Randomized Clinical Trials of Targeted and Biologic Agents in Oncology. J Cancer 2019;10:3717-27. [Crossref] [PubMed]