Concurrent afatinib and stereotactic body radiotherapy in patient with oligometastatic EGFR-mutated non-small cell lung cancer: a case report and literature review

Introduction

Lung cancer is the most common malignant tumor in China and has the highest mortality rate (1). From 2012 to 2016, the five-year survival rate for patients with stage IV lung cancer was only 8% (2). Since 2013, the mortality from non-small cell lung cancer (NSCLC) has declined remarkably due to the routine use of gene tests for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations, along with targeted therapies in clinical practice (3). Patients receiving EGFR-TKIs (tyrosine kinase inhibitors) typically experience longer progression-free survival (PFS) and overall survival (OS) than those without targetable genetic mutations. However, the development of resistance to TKIs seems unavoidable, necessitating alternative therapeutic strategies. Recently, the use of stereotactic radiotherapy (SRT) to both primary tumors and metastatic sites before resistance develops has shown promising results in improving PFS and OS. Interim results from the SINDAS trial (NCT02893332) demonstrated that upfront concurrent stereotactic body radiotherapy (SBRT) combined with first-generation TKIs significantly improve the prognosis of patients with EGFR-mutated oligometastatic NSCLC (4). The more recent phase II LUNG-SORT trial (NCT04764214) demonstrated improved PFS with consolidative SBRT in metastatic NSCLC (mNSCLC) patients with oligo-residual disease after first-line treatment with third-generation EGFR-TKIs (5). While the third generation TKIs are well-recognized for their prognostic advantages over earlier generations (6,7), the second-generation TKI afatinib exhibited superior PFS compared to osimertinib (11.0 vs. 7.0 months) in patients with uncommon EGFR mutations (8). Nevertheless, the efficacy and safety of combining afatinib with SBRT remain unclear, as most existing evidence has been derived from studies involving the first- and third-generation TKIs. Meanwhile, this combined treatment has not been widely accepted due to concerns about the potentially increased risk of radiation-induced toxicity, such as radiation pneumonitis (RP), particularly when thoracic radiotherapy (RT) is administered concomitantly with TKIs (9). We present, for the first time, a case study of a stage IV NSCLC patient with both EGFR G719X and L861Q mutation. After treatment with afatinib and concurrent SBRT, has reached a long PFS and OS without any clinically significant adverse events. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-174/rc).

Case presentation

A 65-year-old female patient came to our department with a pulmonary mass in the right middle lobe. She denied any symptoms such as cough, hemoptysis, chest pain, or headache. Past history revealed no comorbidity and tobacco use. Physical examination found no positive signs with an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Chest computed tomography (CT) showed a lobulated and irregular-shaped 2.6 cm × 3.4 cm mass in the middle lobe of the right lung (Figure 1A). Brain magnetic resonance imaging (MRI) revealed a 2.3 cm × 2.5 cm metastasis with a narrow edema zone in the left frontal lobe (Figure 1B). The pulmonary mass was metabolically active with a maximum standardized uptake value (SUV) value of 9.8 as shown by Positron emission tomography-CT (PET/CT) (Figure 1C). A lung puncture biopsy was performed, and a pathological diagnosis of adenocarcinoma was confirmed (Figure 1D). Gene test revealed both 18 exon G719X (mutation abundance 15.24%) and 21 exon L861Q (mutation abundance 15.24%) in the EGFR gene at the same time. The clinical stage was cT2aN0M1b IVa according to American Joint Committee on Cancer (AJCC) 8th edition pathological staging system.

Figure 1 Imaging and pathological studies of the patient at initial diagnosis. (A) Chest CT scan (lung window) before treatment showed a 2.6 cm × 3.4 cm mass in the middle lobe of the right lung. (B) Brain MRI (T2 FLAIR) before treatment showed 2.3 cm × 2.5 cm metastasis with surrounding edema in the left frontal lobe. (C) PET/CT showed the metabolically active mass (maximum SUV value 9.8) in the right lung. (D) Hematoxylin and eosin staining of the lung biopsy (magnification, ×100). CT, computed tomography; FLAIR, fluid attenuated inversion recovery; MRI, magnetic resonance imaging; PET, positron emission tomography; SUV, standardized uptake value.

First-line TKI target therapy with afatinib 40 mg once a day has been administered since April 30, 2020. One month later, a thorax CT scan and brain MRI were repeated and revealed partial remission of both the lung tumor and brain metastasis (Figure S1A). Because the patient preferred a non-surgical treatment, we administrated hypofractionated SRT to the brain metastasis with 30 Gy in 5 fractions, 6 Gy/fraction/day (Figure S1B). One month after RT, the brain tumor showed a minor increase in size while no neurological symptoms were reported (Figure S1C). We considered this change might be a treatment effect of radiation instead of progression.

Seven months later, the patient gradually developed a headache. The brain MRI revealed that the metastasis grew from 1.5 cm × 1.4 cm to 2.1 cm × 1.8 cm (Figure S2A). Meanwhile, the right pulmonary tumor remained unchanged as shown by the subsequent thorax CT scans. Considering that the patient was going through a symptomatic intracranial oligo-progression, surgical resection was performed followed by a postoperative SRT thereafter (Figure S2B-S2F). Due to the large resection cavity volume (46 cc) and the previous irradiation history of this brain lesion, the constraints of the organs at risk could not be met if treated with a high-dose regimen of SRT. To achieve tolerable toxicity and an acceptable local control, a relatively low dose regimen of SRT, 25 Gy in 5 fractions over 1 week, was applied to this patient. The gene test of the resected brain metastasis remained the same as the initial lung tumor with both exon 18 G719X (mutation abundance 5.8%) and exon 21 L861Q (mutation abundance 6.5%) in the EGFR gene. Seven months later, the patient received a concurrent afatinib with SBRT with 50 Gy/5 fractions, 10 Gy/fraction/day, to the primary lung tumor (conformity index =0.98, gradient index =3.17, homogeneity index =1.48; lung V5 =17.52%, lung V20 =4.58%, lung V30 =2.59%, Dmean =412 cGy, V12 =241.03 cc) (Figure 2). Three months after completion of thorax RT, a grade 1 RP was detected during a routine follow-up chest CT scan (Figure S3). Up to January 2023, the patient was still alive, continued to use afatinib with good tolerance, and remained a stable disease.

Figure 2 SBRT plan of right lung and timeline of treatment. (A-C) Isodose curve (A: axial, B: sagital, C: transverse). (D) Dose volume histogram (red: PTV, blue: heart, orange: lungs, yellow: esophagus, green: chest wall, purple: spinal cord). (E) Timeline of treatment. ADC, adenocarcinoma; PR, partial response; SD, stable disease; SBRT, stereotactic body radiotherapy; SRT, stereotactic radiotherapy.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

We reported a case of an oligometastatic NSCLC patient with both the EGFR G719X and L861Q mutations. Following first-line targeted therapy with afatinib combined with concurrent SRT to the brain metastasis and primary lung tumor, the patient achieved a PFS of 24 months and OS of 32 months. These outcomes are longer than the previously reported median PFS (8.2–13.8 months) and OS (12.1–26.9 months) of stage IIIb–IV NSCLC patients with EGFR G719X/L861Q mutations treated with afatinib (10). Furthermore, the patient showed good tolerance during the concurrent treatment of afatinib and SRT/SBRT. To our knowledge, this is the first case study of concurrent second-generation TKI afatinib and SBRT for EGFR-mutated NSCLC.

Retrospective studies and phase II randomized clinical trials (RCTs) have shown that local consolidative surgical resection and RT offer additional prognostic benefits for oligometastatic NSCLC patients beyond effective systemic treatment. This includes EGFR-mutated patients who are on target therapy (11-14). Despite high response rates, acquired resistance to TKIs is unavoidable for these patients. A real-world study found that 76.2% of disease progression occurred in original oligo-residual lesions in patients who did not receive local consolidative therapy before osimertinib treatment failed (15). Therefore, instead of being used as a salvage treatment after local progression on TKIs, upfront or consolidative local RT could suppress potentially resistant clones while still controlling sensitive clones which have not developed resistance yet (16). As early as 2011, a prospective study first uncovered the favorable outcomes of concurrent treatment with gefitinib or erlotinib and thoracic RT in mNSCLC patients (17). In recent years, several investigations have analyzed the efficacy and safety of concurrent treatment with TKIs and local RT, primarily focusing on mNSCLC (Table 1) (4,5,14,17-20). In a single-arm phase II study published in 2019, patients with mNSCLC received concurrent erlotinib/gefitinib and conventionally fractionated thoracic RT (14). The 1-year PFS rate (57.1%) and median PFS (13 months) were numerically higher than those observed in the ENSURE study, where patients receiving erlotinib monotherapy had a 1-year PFS rate of 43% and a median PFS of 11.0 months (21). Compared to conventionally fractionated or hypofractionated RT, SBRT demonstrates superior efficacy and safety, along with a shorter treatment duration. This approach reduces the risk of disease flare cause by discontinuing TKIs and minimizes the overlap of thoracic RT with simultaneous TKI treatment (22,23). Consequently, SBRT is being increasingly used as a local therapy for mNSCLC (24). Subsequent clinical trials have shown that EGFR-TKIs combined with concurrent SBRT to metastases and primary tumor significantly improved PFS and OS in EGFR-mutated oligometastatic NSCLC compared to TKI alone (4,5,18). This finding is supported by retrospective studies that noted a more marked survival benefit from local consolidative treatment to all residual diseases (19,20). For patients with synchronous brain metastasis, the role and timing of brain RT have been debated (25-27), especially since third-generation TKIs have notably improved intracranial control (28). A recent real-world study showed that combining TKIs with brain RT as first-line treatment leads to prolonged intracranial PFS compared to TKIs alone (16.0 vs. 9.0 months, P<0.001) (29). Retrospective analysis has revealed that upfront craniocerebral RT improves both OS and PFS in osimertinib-treated patients with oligo-brain metastases (30). The ongoing NCT03769103 and completed NCT03497767 phase II trials are both designed to compare the use of osimertinib with and without stereotactic radiosurgery (SRS) in patients with brain metastasis.

Afatinib is now widely used in mNSCLC patients harboring uncommon EGFR mutations, thanks to the efforts of LUX-LUNG 2/3/6 studies (10). Despite its unique advantages for this patient group, the clinical efficacy and safety of combining afatinib with concurrent local RT have not been thoroughly examined, as most patients in previous studies and ongoing clinical trials (NCT05089916, NCT03667820, NCT06014827) have received first- or third-generation TKIs (4,5,18,31). In 2014, Akin Atmaca et al. reported a case of concurrent afatinib and conventional fractionated thoracic RT to relieve upper vena cava compression, leading to a partial response of the irradiated tumor and pulmonary metastases (32). Eze et al. reported a case of concomitant afatinib and whole brain radiotherapy (WBRT) in a NSCLC patient with EGFR 19del mutation, resulting in near-complete regression of neurological symptoms (33). Both cases did not report any clinically significant toxicities.

Pneumonitis has been a major obstacle limiting the application of concurrent thoracic RT and TKI treatment (22,34-38) (Table 2). While the toxicities associated with concurrent TKIs and SBRT are generally tolerable, RP and skin rash caused by target therapies are the most common severe adverse events (Table 1). Compared to conventionally fractionated thoracic RT, SBRT is associated with a lower risk of RP (6.7% with grade ≥2, 0.4% with grade 3 RP) (39). For the present case, we chose SRT rather than WBRT as the initial consolidative therapy for brain metastasis, as WBRT can result in cognitive deterioration, especially among long-term survivors. Previous studies have also found that WBRT fails to provide OS or intracranial PFS benefits (25,40). However, it has been reported that patients on TKIs have an elevated risk of radiation cerebral necrosis after stereotactic radiosurgery than those who are not on TKIs (41).

We speculated that this new mode of concurrent afatinib and SBRT may offer a promising strategy to further prolong PFS and OS in mNSCLC patients with uncommon EGFR mutations. Our case is the first one to demonstrate the efficacy and safety of concurrent thoracic SBRT and afatinib, as far as we know. Nonetheless, we acknowledge the limitations of our treatment strategy. The patient failed to receive an upfront surgical resection of the brain metastasis out of personal preference, which may preclude the risk of late onset brain necrosis potentially induced by the re-irradiation of brain.

Conclusions

We present the first case of a patient who, after concurrent treatment with the second-generation TKI afatinib and thoracic SBRT, has achieved a sustainable PFS of 24 months and OS of 32 months with good tolerance. Due to the scarcity of clinical data, the exact response rate, long-term survival outcome, and toxicity profile of this combined therapy remain to be further clarified. Moreover, a large-scale randomized control study is also needed to determine the optimal time for adding SBRT to afatinib treatment.

Acknowledgments

We would like to thank the researchers and study participants for their contributions.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-174/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-174/prf

Funding: The current study was supported by grants from the Basic Scientific Research Project for Central Universities (No. 2023CDJYGRH-YB01 to D.T.; No. 2023CDJYGRH-ZD01 to W.Z.) and the National Clinical Key Specialty Construction Program.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-174/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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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. Qiu H, Cao S, Xu R. Cancer incidence, mortality, and burden in China: a time-trend analysis and comparison with the United States and United Kingdom based on the global epidemiological data released in 2020. Cancer Commun (Lond) 2021;41:1037-48. [Crossref] [PubMed]
2. Luo YH, Chiu CH, Scott Kuo CH, et al. Lung Cancer in Republic of China. J Thorac Oncol 2021;16:519-27. [Crossref] [PubMed]
3. Howlader N, Forjaz G, Mooradian MJ, et al. The Effect of Advances in Lung-Cancer Treatment on Population Mortality. N Engl J Med 2020;383:640-9. [Crossref] [PubMed]
4. 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. Erratum in: J Natl Cancer Inst 2023;115:773. [Crossref] [PubMed]
5. Zhou Y, Peng L, Liang F, et al. Safety and efficacy of consolidative stereotactic radiotherapy for oligo-residual EGFR-mutant non-small cell lung cancer after first-line third-generation EGFR-tyrosine kinase inhibitors: a single-arm, phase 2 trial. EClinicalMedicine 2024;76:102853. [Crossref] [PubMed]
6. Cheng Y, He Y, Li W, et al. Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study. Target Oncol 2021;16:165-76. [Crossref] [PubMed]
7. Vaid AK, Gupta A, Momi G. Overall survival in stage IV EGFR mutation‑positive NSCLC: Comparing first‑, second‑ and third‑generation EGFR‑TKIs Int J Oncol 2021;58:171-84. (Review). [Crossref] [PubMed]
8. Wang C, Zhao K, Hu S, et al. Clinical Outcomes of Afatinib Versus Osimertinib in Patients With Non-Small Cell Lung Cancer With Uncommon EGFR Mutations: A Pooled Analysis. Oncologist 2023;28:e397-405. [Crossref] [PubMed]
9. Meng Y, Sun H, Wang S, et al. Treatment-Related Pneumonitis of EGFR Tyrosine Kinase Inhibitors Plus Thoracic Radiation Therapy in Patients With Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Int J Radiat Oncol Biol Phys 2024;118:415-26. [Crossref] [PubMed]
10. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 2015;16:830-8. [Crossref] [PubMed]
11. 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]
12. 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]
13. Wu Y, Verma V, Liang F, et al. Local Consolidative Therapy Versus Systemic Therapy Alone for Metastatic Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Int J Radiat Oncol Biol Phys 2022;114:635-44. [Crossref] [PubMed]
14. Zheng L, Wang Y, Xu Z, et al. Concurrent EGFR-TKI and Thoracic Radiotherapy as First-Line Treatment for Stage IV Non-Small Cell Lung Cancer Harboring EGFR Active Mutations. Oncologist 2019;24:1031-e612. [Crossref] [PubMed]
15. Zeng Y, Ni J, Yu F, et al. The value of local consolidative therapy in Osimertinib-treated non-small cell lung cancer with oligo-residual disease. Radiat Oncol 2020;15:207. [Crossref] [PubMed]
16. Chaft JE, Oxnard GR, Sima CS, et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res 2011;17:6298-303. [Crossref] [PubMed]
17. Wang J, Xia TY, Wang YJ, et al. Prospective study of epidermal growth factor receptor tyrosine kinase inhibitors concurrent with individualized radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e59-65. [Crossref] [PubMed]
18. Peng P, Gong J, Zhang Y, et al. EGFR-TKIs plus stereotactic body radiation therapy (SBRT) for stage IV Non-small cell lung cancer (NSCLC): A prospective, multicenter, randomized, controlled phase II study. Radiother Oncol 2023;184:109681. [Crossref] [PubMed]
19. Borghetti P, Bonù ML, Giubbolini R, et al. Concomitant radiotherapy and TKI in metastatic EGFR- or ALK-mutated non-small cell lung cancer: a multicentric analysis on behalf of AIRO lung cancer study group. Radiol Med 2019;124:662-70. [Crossref] [PubMed]
20. Xu Q, Zhou F, Liu H, et al. Consolidative Local Ablative Therapy Improves the Survival of Patients With Synchronous Oligometastatic NSCLC Harboring EGFR Activating Mutation Treated With First-Line EGFR-TKIs. J Thorac Oncol 2018;13:1383-92. [Crossref] [PubMed]
21. Wu YL, Zhou C, Lu S, et al. Erlotinib versus gemcitabine/cisplatin in Chinese patients with EGFR mutation-positive advanced non-small-cell lung cancer: Crossover extension and post-hoc analysis of the ENSURE study. Lung Cancer 2019;130:18-24. [Crossref] [PubMed]
22. Jia W, Gao Q, Wang M, et al. Overlap time is an independent risk factor of radiation pneumonitis for patients treated with simultaneous EGFR-TKI and thoracic radiotherapy. Radiat Oncol 2021;16:41. [Crossref] [PubMed]
23. Takahashi T, Umeguchi H, Tateishi A, et al. Disease flare of leptomeningeal metastases without radiological and cytological findings after the discontinuation of osimertinib. Lung Cancer 2021;151:1-4. [Crossref] [PubMed]
24. Das A, Giuliani M, Bezjak A. Radiotherapy for Lung Metastases: Conventional to Stereotactic Body Radiation Therapy. Semin Radiat Oncol 2023;33:172-80. [Crossref] [PubMed]
25. Jiang T, Su C, Li X, et al. EGFR TKIs plus WBRT Demonstrated No Survival Benefit Other Than That of TKIs Alone in Patients with NSCLC and EGFR Mutation and Brain Metastases. J Thorac Oncol 2016;11:1718-28. [Crossref] [PubMed]
26. Magnuson WJ, Yeung JT, Guillod PD, et al. Impact of Deferring Radiation Therapy in Patients With Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Develop Brain Metastases. Int J Radiat Oncol Biol Phys 2016;95:673-9. [Crossref] [PubMed]
27. Jung HA, Park S, Lee SH, et al. The Role of Brain Radiotherapy before First-Line Afatinib Therapy, Compared to Gefitinib or Erlotinib, in Patients with EGFR-Mutant Non-Small Cell Lung Cancer. Cancer Res Treat 2023;55:479-87. [Crossref] [PubMed]
28. Colclough N, Chen K, Johnström P, et al. Preclinical Comparison of the Blood-brain barrier Permeability of Osimertinib with Other EGFR TKIs. Clin Cancer Res 2021;27:189-201. [Crossref] [PubMed]
29. Tong Y, Wan X, Yin C, et al. In-depth exploration of the focus issues of TKI combined with radiotherapy for EGFR-mutant lung adenocarcinoma patients with brain metastasis: a systematic analysis based on literature metrology, meta-analysis, and real-world observational data. BMC Cancer 2024;24:1305. [Crossref] [PubMed]
30. Zhou J, Zhou Y, Sun Y, et al. The efficacy of upfront craniocerebral radiotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors in patients with epidermal growth factor receptor-positive non-small cell lung cancer with brain metastases. Front Oncol 2024;13:1259880. [Crossref] [PubMed]
31. Rashdan S, Sampath S, Iyengar P, et al. Safety and efficacy of osimertinib plus consolidative stereotactic ablative radiation (SABR) in advanced EGFR mutant non-small cell lung cancer (NSCLC): Results from a multi-center phase II trial. J Clin Oncol 2024;42:8518. [Crossref]
32. Atmaca A, Al-Batran SE, Allgäuer M, et al. Afatinib with concurrent radiotherapy in a patient with metastatic non-small cell lung cancer. Oncol Res Treat 2014;37:262-5. [Crossref] [PubMed]
33. Eze C, Hegemann NS, Roengvoraphoj O, et al. Concurrent Afatinib and Whole-Brain Radiotherapy in Exon 19-del-EGFR Mutant Lung Adenocarcinoma: A Case Report and Mini Review of the Literature. Front Oncol 2017;7:88. [Crossref] [PubMed]
34. Jia W, Guo H, Jing W, et al. An especially high rate of radiation pneumonitis observed in patients treated with thoracic radiotherapy and simultaneous osimertinib. Radiother Oncol 2020;152:96-100. [Crossref] [PubMed]
35. Xu K, Liang J, Zhang T, et al. Clinical outcomes and radiation pneumonitis after concurrent EGFR-tyrosine kinase inhibitors and radiotherapy for unresectable stage III non-small cell lung cancer. Thorac Cancer 2021;12:814-23. [Crossref] [PubMed]
36. Akamatsu H, Murakami H, Harada H, et al. Gefitinib With Concurrent Thoracic Radiotherapy in Unresectable Locally Advanced NSCLC With EGFR Mutation; West Japan Oncology Group 6911L. J Thorac Oncol 2021;16:1745-52. [Crossref] [PubMed]
37. Yang X, Mei T, Yu M, et al. Symptomatic Radiation Pneumonitis in NSCLC Patients Receiving EGFR-TKIs and Concurrent Once-daily Thoracic Radiotherapy: Predicting the Value of Clinical and Dose-volume Histogram Parameters. Zhongguo Fei Ai Za Zhi 2022;25:409-19. [PubMed]
38. Banla LI, Tzeng A, Baillieul JP, et al. Pneumonitis in Patients Receiving Thoracic Radiotherapy and Osimertinib: A Multi-Institutional Study. JTO Clin Res Rep 2023;4:100559. [Crossref] [PubMed]
39. Saha A, Beasley M, Hatton N, et al. Clinical and dosimetric predictors of radiation pneumonitis in early-stage lung cancer treated with Stereotactic Ablative radiotherapy (SABR) - An analysis of UK's largest cohort of lung SABR patients. Radiother Oncol 2021;156:153-9. [Crossref] [PubMed]
40. Palmer JD, Klamer BG, Ballman KV, et al. Association of Long-term Outcomes With Stereotactic Radiosurgery vs. Whole-Brain Radiotherapy for Resected Brain Metastasis: A Secondary Analysis of The N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group) Randomized Clinical Trial. JAMA Oncol 2022;8:1809-15. [Crossref] [PubMed]
41. Zhuang H, Tao L, Wang X, et al. Tyrosine Kinase Inhibitor Resistance Increased the Risk of Cerebral Radiation Necrosis After Stereotactic Radiosurgery in Brain Metastases of Non-small-Cell Lung Cancer: A Multi-Institutional Retrospective Case-Control Study. Front Oncol 2020;10:12. [Crossref] [PubMed]