Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study

Liu et al. Radiation Oncology (2015) 10:118 DOI 10.1186/s13014-015-0421-9 RESEARCH Open Access Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study SongRan Liu1,2,3†, Bo Qiu1,2,3†, LiKun Chen1,2,4, Fang Wang1,2,5, Ying Liang1,2,4, PeiQiang Cai1,2,6, Li Zhang1,2,4, ZhaoLin Chen1,2,3, ShiLiang Liu1,2,3, MengZhong Liu1,2,3 and Hui Liu1,2,3* Abstract Background: Non-small cell lung cancer (NSCLC) with brain metastasis (BM) harboring an epidermal growth factor receptor (EGFR) mutation shows good response to tyrosine kinase inhibitors (TKIs). This study is to assess the appropriate timing of brain radiotherapy (RT) for asymptomatic BM in EGFR mutant NSCLC patients. Methods: There were 628 patients diagnosed with EGFR mutant NSCLC between October 2005 and December 2011. Treatment outcomes had been retrospectively evaluated in 96 patients with asymptomatic BM without prior TKI treatment. 39 patients received first-line brain RT, 23 patients received delayed brain RT, and 34 patients did not receive brain RT. Results: With a median follow-up of 26 months, the 2-year OS was 40.6 %. Univariate analyses revealed that ECOG performance status (p = 0.006), other distant metastases (p = 0.002) and first line systemic treatment (p = 0.032) were significantly associated with overall survival (OS). Multivariate analyses revealed that other sites of distant metastases (p = 0.030) were prognostic factor. The timing of brain RT was not significantly related to OS (p = 0.246). The 2-year BM progression-free survival (PFS) was 26.9 %. Brain RT as first-line therapy failed to demonstrate a significant association with BM PFS (p = 0.643). Conclusions: First-line brain RT failed to improve long-term survival in TKI-naïve EGFR mutant NSCLC patients with asymptomatic BM. Prospective studies are needed to validate these clinical findings. Keywords: Asymptomatic brain metastasis, Radiotherapy, Chemotherapy, Epidermal growth factor receptor mutation, Tyrosine kinase inhibitor * Correspondence: † Equal contributors 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China 2 Guangdong Esophogeal Cancer Research Institute, Guangzhou, China Full list of author information is available at the end of the article © 2015 Liu et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liu et al. Radiation Oncology (2015) 10:118 Background Brain metastasis (BM) is a common complication of lung cancer and is associated with poor treatment outcomes. BM is observed in approximately 25–30 % of non-small cell lung cancer (NSCLC) patients [1]. The median survival is approximately 4–11 weeks in untreated patients but can be improved by whole-brain radiation therapy (WBRT) to 3–6 months [2]. However, NSCLC has been regarded as a relatively radio-resistant malignancy, and 30 Gy WBRT may be insufficient to destroy the lesions; recent studies have suggested that the median response rate to WBRT remains approximately 25–30 % [3]. The role of chemotherapy in the treatment of brain metastasis remains controversial. Advances in the understanding of the molecular biology of tumors have led to the development of targeted agents with promising results in the treatment of NSCLC. Epidermal growth factor receptor (EGFR) mutations are associated with a significant sensitivity to EGFR tyrosine kinase inhibitors (TKI), which can significantly improve treatment outcome [4]. Recently, the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for NSCLC patients with BM has been reported [5, 6]. Moreover, several reports demonstrate that NSCLC patients with mutant EGFR and BM could also achieve favorable outcomes when treated with EGFR-TKIs as single-agent chemotherapy. Several studies have reported that TKI treatment results in high response rates (70–89 %) and increased overall survival (OS) and progression-free survival (PFS) (12.9–19.8 months and 6.6–23.3 months, respectively) in selected populations of EGFR-mutated NSCLC patients with BM [7–9]. Several studies have suggested that patients with BM harboring EGFR mutations may have higher response rates to WBRT than those with wild-type tumors [10–13]. However, unlike the EGFR-mutant primary lung tumor, 11–44 % of brain metastases exhibit resistance to TKI treatment [7, 8]. In addition, Omuro et al. [14] reported a high incidence of central nervous system (CNS) metastases during the course of a standard treatment of gefitinib, an EGFR inhibitor, despite good control of other disease sites. These results suggest that local therapy may still be important for the treatment of BM in patients with EGFR mutations. However, for EGFR-mutant NSCLC patients with asymptomatic brain metastasis who do not require urgent symptom relief, the proper treatment schedule is not well established. Therefore, we sought to gain insight from the retrospective analysis of patients treated with different combinations of irradiation/TKI therapies. Methods Acquisition of clinical data A total of 628 patients were diagnosed with adenocarcinoma of the lung harboring EGFR mutations between Page 2 of 8 October 2005 and December 2011 at the Sun Yat-Sen University Cancer Center. Treatment outcomes had been retrospectively evaluated in 96 patients with asymptomatic BM without prior TKI treatment. Before receiving treatment, each patient underwent a physical examination, laboratory tests and electrocardiograms as well as a medical history evaluation, including documentation of concomitant medications, performance status, and smoking history. Patient data included chest and upper abdomen computed tomography (CT) scans or positron emission tomography (PET) scans, bone scans, and magnetic resonance imaging (MRI) of the brain. Tumor stage was classified using the tumor/node/metastasis (TNM) system proposed by the American Joint Committee on Cancer (8th edition). T and N stage were determined on the basis of the findings of CT with or without additional fiberoptic bronchoscopy. Mediastinal lymph nodes ≥1 cm on transaxial CT images or SUV ≥ 2.5 on PET scans were considered positive. All patients were required to meet the following inclusion criteria: 1) pathologically confirmed NSCLC harboring an activating EGFR mutation; 2) documented measurable brain metastases (AJCC stage IV disease) at first diagnosis; and 3) Eastern Cooperative Oncology Group (ECOG) performance status (...truncated)