To date, the treatment of advanced NSCLC patients with BM remains a significant clinical challenge. Therapeutic modalities for controlling BM include WBRT, SRS, surgery, and chemotherapy, but the efficacy of these treatments remains poor. The use of first-line EGFR-TKI therapy for patients with metastatic EGFR-mutant lung adenocarcinoma is based upon a randomized trial demonstrating improved PFS compared to standard chemotherapy.19

For patients with mutations like the exon 19 deletion and the exon 21 L858R mutation, EGFR-TKIs are recommended as a first-line treatment. In our study, although we found that patients with the exon 19 deletion had a longer median OS than patients with the exon 21 L858R mutation (not reached vs 23.2 months), this difference was not statistically significant (P=0.031). This result suggested that these 2 mutations are different to some extent. Recent studies also reported that patients with the exon 19 deletion and the exon 21 L858R mutation have different survival outcomes in response to EGFR-TKIs and chemotherapy.20–22 EGFR-TKI treatment was demonstrated to be more effective in patients with the exon 19 deletion than in patients with the exon 21 L858R mutation.20,21 In contrast, in a meta-analysis by Lee et al,20 patients who were not treated with EGFR-TKIs were randomly assigned to chemotherapy, and patients with the exon 21 L858R mutation had a statistically significantly longer PFS than those with the exon 19 deletion. These findings suggest that the difference in the prognosis between patients with the exon 19 deletion and the exon 21 L858R mutation might be related to the efficacy of the EGFR-TKIs.23

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There was no improvement in the OS of patients who received upfront RT compared with deferral RT group in our study (28.0 vs 26.5 months, P=0.74), which varies from many previous studies. A systematic review and meta-analysis of 12 studies found that, compared with upfront erlotinib alone, upfront cranial RT (SRS or WBRT) followed by erlotinib improved the OS and intracranial PFS in patients with EGFR-mutant NSCLC who developed BM.17 Another multi-institutional analysis by Magnuson et al6 also demonstrated that the use of upfront EGFR-TKI and deferral of RT associated with inferior OS in patients with EGFR-mutant NSCLC who developed BM. In addition, SRS followed by EGFR-TKI associated with the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT.24 However, a recent Phase III trial (BRAIN) showed that icotinib was associated with a significantly longer intracranial PFS than that of whole-brain irradiation plus chemotherapy, indicating that icotinib might be a better first-line therapeutic option for this patient population. We assume that our conclusion may be due to factors such as small sample size and the nonrandomized nature of the study. However, further randomized controlled trials are needed to examine the correlation between the timing of RT interval and OS and to define the optimal timing of RT.

In our study, due to the limitation of the period that patients were treated and the limitation of the medical insurance policy, more than half of the patients received chemotherapy as first-line treatment. We compared the OS of the first-line chemotherapy group and the first-line EGFR-TKI group and found no statistically significant difference (P=0.50). The OS of the chemotherapy group was somewhat better than the EGFR-TKI group (28.0 vs 23.2 months). Barlesi et al8 previously demonstrated that pemetrexed-based chemotherapy has a great activity as well as a good safety profile in managing the NSCLC patients with inoperable BM. Thus, the patients who we enrolled were limited to those who had received pemetrexed treatment. Ten randomized controlled trials showed that there was no significant difference in the OS between first-line TKI treatment and first-line chemotherapy. For iPFS, the first-line chemotherapy group showed a longer iPFS than that of the EGFR-TKI group (17.78 vs 13.00 months, P=0.590). This result is possibly because most patients of the chemotherapy group received upfront RT in our study, which could efficiently prolong the PFS. And the EGFR-TKI group may show clinical resistance after the use of the first-generation EGFR-TKIs. The responses of first-generation EGFR-TKIs typically last for 6–12 months before resistance develops, which is coincide with our results.15

There are many limitations in the current study. First, we used a retrospective design, and due to the variety of exclusion factors, there may have been bias in choosing patients for enrollment. Therefore, the results reported here are not entirely representative of a large sample population. Second, the sample size of this study was quite small, which may have affected its statistical power. Third, based on the baseline clinical characteristics of the patients, the treatment groups were not homogeneous. Fourth, the choice for treatment was not random because it was determined by the willingness of both the physicians and the patients, which may have led to deviations between the 2 treatment groups. Fifth, patients enrolled in our study were not tested for the EGFR status after the progression of EGFR-TKIs, and so the acquired mutations were unknown and the next generation of EGFR-TKIs was not applied. Finally, follow-up data on toxicities, cognitive impairment, and quality of life were lacking, and we were therefore unable to analyze these factors.