Brain surgery in combination with tyrosine kinase inhibitor and whole brain radiotherapy for epidermal growth factor receptor-mutant non-small-cell lung cancer with brain metastases

The role of brain surgery (BS) on the survival of patients with non-small-cell lung cancer (NSCLC) and brain metastases (BM), particularly those with epidermal growth factor receptor (EGFR) mutations under tyrosine kinase inhibitors (TKIs) is yet to be defined. We aimed to investigate whether BS could improve the survival of patients in addition to the combination of TKIs and whole brain radiotherapy (WBRT). A cohort of 1394 NSCLC patients between 2011 and 2016 was retrospectively studied. One hundred patients with BM receiving TKI + RT were enrolled. Forty patients (40%) received TKI + BS + RT, and 60 patients (60%) received TKI + RT. Survival time was calculated from the date of BM diagnoses to the date of death or last follow-up. With a median follow-up of 25.6 months (95% CI, 18.6–35.7), the median survival after BM was 18.2 months (95% CI, 10.8 to 27.4) in the TKI + BS + RT group and 11.8 months (95% CI, 5.2 to18) in the TKI + RT group. Cox proportional hazards regression model for the patients with the largest BM over 1 cm showed that TKI + BS + RT group was associated with improved survival relative to TKI + RT group (HR, 0.49; 95% CI, 0.29 to 0.83; P = 0.008). BS adds significant survival benefits in addition to TKIs and WBRT, especially for patients with EGFR-mutant NSCLC and the largest BM over 1 cm.


Patients and treatment.
We sorted 1394 NSCLC patients in the data base of a tertiary university hospital and retrospectively recruited one hundred consecutive patients with pathologically proven lung adenocarcinoma who had received both WBRT and TKIs between January 1, 2011 and June 14, 2016. Their BM was diagnosed by either brain imaging or cytology. The inclusion criteria were positive EGFR mutations, the diagnosis of BM, the use of TKIs, and WBRT. The exclusion criteria were a history of malignancies other than lung cancer, prior brain irradiation, or EGFR-TKI resistance mutation, or incomplete WBRT.
All the patients underwent pretreatment workups comprising a physical examination, a history review, chest radiography, bronchoscopy with a tumor biopsy, chest computed tomography (CT), brain magnetic resonance imaging (MRI) or CT, and routine laboratory studies. The tumor stage was classified according to the seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual and Handbook 23 . All patients started taking EGFR-TKIs once the diagnosis of stage IIIB or IV lung cancer with EGFR mutation was established. Some patients received BS which was performed prior to WBRT. BS was recommended at the discretion of neuro-surgeons after discussion with each patient. All patients with or without BS had WBRT. For WBRT, three-dimensional conventional radiotherapy was done by a 2100 C/D linear accelerator (Varian Medical Systems, Palo Alto, CA). Boost plans were generated by intensity-modulated radiotherapy either with an Eclipse, version 8.6 (Varian Medical Systems Inc., Palo Alto, USA) or Hi-Art helical tomotherapy unit, version 2.2.4.1 (TomoTherapy, Inc., Madison, WI). Our RT schedule was 30 Gy in 10 fractions or 37.5 Gy in 15 fractions. Some patients had a boost to BM of 45 Gy in 10 fractions, or 45 Gy in 15 fractions. The decision whether to boost BM was made after discussion with each patient.
The following variables were collected: age, sex, stage, initial clinical Tumor and Nodal classification, extracranial metastases, histological grading, smoking history, EGFR mutation, Eastern Cooperative Oncology Group (ECOG) performance status at the time of BM, number of BM, size of largest BM, whether the patient was symptomatic from BM, mean dose of ionizing radiation delivered, name of EGFR-TKI, number of lines of TKI, mean duration of TKI use, and number of lines of chemotherapy. The date of initial cancer diagnosis, the date of BM diagnosis, RT treatments, systemic therapy, most recent follow-up, and death were documented. In addition, a disease-specific Graded Prognostic Assessment (ds-GPA) was calculated for each patient to determine whether the cohorts shared similar prognostic features 24 .
Statistical analysis. The primary end point was the survival after a diagnosis of BM was established. We calculated the survival from the date of BM diagnoses to the date of death from any cause or until the date of the last follow-up. And then we assessed the survival after a diagnosis of BM by Kaplan-Meier methods and used the log-rank test to compare time-to-event distributions. We stratified the data set and compared outcomes by t-test or chi-squared test. Besides, we performed univariate analyses and a multivariate Cox proportional hazards regression to examine all collected variables. We calculated the estimated risks of death using hazard ratios (HR) with 95% confidence intervals (CIs). The level of statistical significance was set at P < 0.05; all reported P values were two-tailed. The analyses used the SPSS software package, version 19.0 for Windows (SPSS, Chicago, IL, USA).

Results
There were 147 patients with EGFR-mutant NSCLC and BM, regardless of the treatment. One hundred patients out of 1394 patients in the lung cancer data base were identified after applying the aforementioned inclusion and exclusion criteria (Fig. 1). The clinical characteristics, divided by whether they had BS (TKI + BS + RT group vs TKI + RT group) were sum up in Table 1. All patients had both EGFR-TKI and WBRT. The mean age of this retrospective cohort was 60 ± 10 years ± standard deviation (SD), 96 patients (96%) had an ECOG performance status less than 2, and 78% were symptomatic from their BM. Forty patients (40%) received BS (TKI + BS + RT group), and 60 patients (60%) did not. Patients who received BS were more likely to have BM larger than 1 cm (90% in the TKI + BS + RT group and 60% in the TKI + RT group; P = 0.001). Patients who received BS were more likely to have EGFR mutation in exon 19 (60% in the TKI + BS + RT group and 36.7% in the TKI + RT group; P = 0.022) and were less likely to have EGFR mutation in exon 21 (27.5% in the TKI + BS + RT group and 48.3% in the TKI + RT group; P = 0.037). One patient has EGFR mutation in both exon 19 and 21. There was no significant difference in terms of age, gender, stage, initial clinical Tumor and Nodal classification, extracranial metastases, histological grading, smoking history, ECOG performance status at the time of BM, number of BM, whether the patient was symptomatic from BM, mean RT dose, number of lines of TKI, mean duration of TKI use, ds-GPA and number of lines of chemotherapy (all P > 0.05; Table 1).
All patients started having EGFR-TKI (afatinib, erlotinib, gefitinib or osimertinib) once the diagnosis of stage IIIB or IV lung cancer with EGFR mutation was established. Twelve patients had afatinib; 57 patients had erlotinib; 64 patients had gefitinib; and 5 patients had osimertinib. Thirty-seven (37%) patients had more than one line of TKIs due to disease progression or intolerance of side effect. The median duration of TKIs use was 14.4 months (95% CI, 10.7 to 17.9). The median duration of TKIs use was 14 months (95% CI, 8.3 to 18.3) in the TKI + BS + RT group and 14.4 months (95% CI, 9.6 to 19) in the TKI + RT group. The mean duration of TKIs use were 18 ± 14 months and 20 ± 18.5 months for patients with and without BS respectively (P = 0.585).
After a median follow-up of 25.6 months (95% CI 18.6 to 35.7), the median survival after BM was 15.1 months (95% CI, 11.3 to 19.4) for the 100 patients in this study. The median survival after BM was 11.2 months (95% CI, 8.3 to 14.2) for the 147 patients irrespective of treatment. Specifically, the median survival after BM was 18.2 months (95% CI, 10.8 to 27.4) in the TKI + BS + RT group and 11.8 months (95% CI, 5.2 to18) in the TKI + RT group. The mean survival after BM were 21.9 ± 14.8 months and 15.6 ± 14.5 months for patients with and without BS respectively (P = 0.026).
BM size. In order to identify potential differences in the benefits of BS in patients by the size of largest BM, we selected 72 patients with the largest BM larger than 1 cm. Thirty-six (50%) patients had BS. Cox regression analysis revealed that BS was a strong favorable prognostic factor for longer survival (HR, 0.5; 95% CI, 0.3 to 0.84; P = 0.008; Fig. 3). In Table 3, after controlling for significant covariables in a multivariable model, the TKI + BS + RT group was associated with improved OS relative to the TKI + RT group (HR, 0.49; 95% CI, 0.29 to 0.83; P = 0.008). Clinical nodal classification 0-1 relative to 2-3 (HR, 2.23; 95% CI, 1.27 to 3.92; P = 0.005) and the use of erlotinib (HR, 0.49; 95% CI, 0.29 to 0.85; P = 0.011) were also beneficial.
EGFR mutation. In order to identify potential differences in the benefits of BS in patients with EGFR mutation, we selected 85 patients with mutation in exon 19 or 21 or both. Thirty-four (40%) patients had BS. Cox regression analysis revealed that female, BS and single BM were favorable prognostic factors for longer survival (Table 4). However, after controlling for significant covariables in a multivariable model, the TKI + BS + RT group was not associated with improved OS relative to the TKI + RT group (HR, 0.66; 95% CI, 0.4 to 1.11; P = 0.116). Female (HR, 0.47; 95% CI, 0.28 to 0.78; P = 0.004) and single BM relative to more than 3 BM (HR, 2.41; 95% CI, 1.16 to 5; P = 0.018) were two independent favorable prognostic factors.  Table 1. Patient and treatment characteristics. Abbreviations: BS: brain surgery; EGFR: epidermal growth factor receptor; RT: radiation therapy; TKI: tyrosine kinase inhibitor; ECOG: Eastern Cooperative Oncology Group; BM: brain metastasis; dsGPA: disease-specific Graded Prognostic Assessment.

Figure 2.
Cox regression comparing survival after the diagnosis of brain metastasis in epidermal growth factor receptor-mutant non-small-cell lung cancer patients under tyrosine kinase inhibitors treated with and without brain surgery for brain metastases before whole-brain radiation therapy.

Discussion
The mainstay of treatment for BM consisted of surgical resection, RT, or a combination of these modalities. A prospective randomized study showed that patients with cancer and a single BM who received BS plus RT lived longer 25 . A further study showed that BS followed by consolidative WBRT was better than BS alone for local control 26 . RT is commonly used following BS since local recurrence occurs in more than 50% of patients 27 . In two randomized trials, postoperative adjuvant WBRT reduced the incidence of local recurrence by half 27,28 . Twenty years ago, additional postoperative WBRT with 30Gy for patients with single BM was reported (BS + WBRT: median OS 13 months; BS only: median OS 8 months). In addition, the rate of cerebral recurrence was distinctly higher in the non-WBRT group 29 .
Toffart et al. concluded that the survival of NSCLC with synchronous solitary M1 was more similar to stage III than other stage IV NSCLC and advocated for BS 30 . In this large retrospective study of 4832 patients, 64% of patients had BM. Operation conducted at both primary and metastatic sites (HR 0.35, 95% CI: 0.19 to 0.65) was an independent prognostic factor for longer survival. For accessible tumors with diameter of more than 3 cm, BS still carries the advantages of obtaining histological diagnosis, providing immediate symptomatic relief by removal of local mass effect and source of edema, and decreasing the length of steroid use 21 .
At the time of the studies of Patchell et al., however, EGFR-TKIs were not available 25,28 . In the era of EGFR mutations and TKIs, we seek to compare survival trends that are likely to be attributable to combined treatment, especially BS plus TKIs and WBRT. We investigated one hundred patients who received TKIs as a first-line therapy for advanced EGFR-mutant NSCLC in a tertiary cancer center. Because the administration of EGFR-TKI has limited penetration across BBB, combined RT would provide better outcome 31 . According to Burel-Vandenbos et al., BM occurring during the course of TKI, despite good control of extracranial disease, is possibly due to insufficient concentration of TKI in cerebral spinal fluid 32 although raising TKI doses might increase the possibility of drug intolerance. Soon et al. conducted a meta-analysis from 2008 to July 2014, and reported there was a better 2-year OS (HR 1.33, 95% CI 1.00-1.77; P = 0.05) for patients with upfront WBRT compared with TKI alone 33 .
However, NSCLC is a radioresistant malignancy and 30 Gy of WBRT may not be sufficient to sterilize the metastatic brain lesions 32 , therefore combination therapy is required. We hypothesized that BS would be beneficial prior to WBRT. After controlling for significant covariables in a multivariable model, EGFR mutation in exon 19 (HR, 0.83; 95% CI, 0.51 to 1.35; P = 0.461) or the TKI + BS + RT group was not associated with improved survival relative to the TKI + RT group (HR, 0.69; 95% CI, 0.43 to 1.12; P = 0.134). However, for the 72 patients with the largest BM over 1 cm, multivariate analysis showed that the TKI + BS + RT group was associated with improved survival relative to the TKI + RT group (HR, 0.49; 95% CI, 0.29 to 0.83; P = 0.008). For the majority of the patients with EGFR mutation in exon 19 or 21, Female and single BM relative to more than 3 BM were two strong independent favorable prognostic factors.
The present study demonstrated the advantage of BS, especially for patients with stage IV EGFR-mutant NSCLC who had the largest BM over 1 cm. To the best of our knowledge, this is the first study to confirm the advantage from combination therapy of TKI + BS + RT. Until recently, there was no prospective randomized trial regarding the addition of BS to TKIs and WBRT. Cox regression comparing survival after the diagnosis of brain metastasis in epidermal growth factor receptor-mutant non-small-cell lung cancer patients under tyrosine kinase inhibitors with a size of the largest brain metastasis over 1 cm treated with and without brain surgery for brain metastases before whole-brain radiation therapy.   Table 4. For patients with EGFR mutation in exon 19 or exon 21: univariate and multivariate Cox regression analyses of covariables associated with survival after the diagnosis of brain metastasis. Abbreviations: EGFR: epidermal growth factor receptor; RT: radiation therapy; TKI: tyrosine kinase inhibitor; ECOG: Eastern Cooperative Oncology Group; dsGPA: disease-specific Graded Prognostic Assessment.