Whole brain radiation therapy does not improve the overall survival of EGFR-mutant NSCLC patients with leptomeningeal metastasis

Leptomeningeal metastasis (LM), also termed as neoplastic meningitis, is caused by the diffusion of malignant cells to the leptomeninges and the cerebrospinal fluid (CSF) [1‐4]. Approximately 3.8% of patients with advanced NSCLC have LM at the date of diagnosis or in the course of disease. The incidence of LM in patients harboring epidermal growth factor receptor (EGFR) mutations (9.4%) is higher than that in patients with wild-type EGFR (1.7%) [5, 6]. LM often represents a terminal event of NSCLC associated with an extremely poor prognosis, and the median OS of unselected NSCLC patients varies between 3 and 6 months [6‐10].

Currently, the treatment for LM consists of using either EGFR-tyrosine kinase inhibitors (TKIs), whole brain radiation therapy (WBRT), Chemotherapy (ChT), intrathecal chemotherapy (ITC), and ventriculoperitoneal-shunt (VP-shunt) [5, 6, 8, 10‐12]. However, the survival benefits of these treatments remain poorly established. The poor permeability of chemotherapeutic or targeted agents through the blood-brain barrier (BBB) may account for the limited role of these treatments. Although WBRT is an effective treatment for patients with multiple brain metastases (BMs), its therapeutic effect in LM patients with EGFR mutations has not been evaluated fully.

Even though most previous studies have been conducted in unselected NSCLC patients, the survival data of LM in EGFR-mutant NSCLC in those studies were in shortage. Therefore, we performed a retrospective analysis of the clinical data of EGFR-mutated NSCLC patients with LM who had received treatment at our hospital from July 2014 to March 2018, aiming to evaluate whether WBRT could provide survival benefits for LM patients with EGFR mutations.

This retrospective study is a relatively large cohort of EGFR-mutant LM patients focusing on the role of WBRT in the treatment of LM. The highlight of the study is the homogeneity of all LM patients harboring EGFR mutations. Our findings showed that the administration of EGFR-TKIs and KPS ≥ 80 at the time of LM diagnosis were associated with prolonged survival. However, WBRT did not improve intracranial treatment response and survival statistically for patients selected for this study.

The survival benefit and treatment response of WBRT to NSCLC patients with LM remain debatable, especially in patients with EGFR mutations [1, 5, 6, 12, 14‐17]. A previous retrospective assessment of 52 EGFR-mutant LM patients showed that WBRT did not provide survival benefit [6]. In another retrospective cohort of 109 LM patients harboring EGFR mutations, patients who underwent WBRT for LM treatment did not achieve longer survival than those without WBRT (9.3 vs. 8.1 months; p = 0.448) [5]. Although Kuiper et al. [17] showed that WBRT could play a role in symptom control, they did not find that it influenced the survival of LM patients harboring EGFR mutations. So far, few retrospective studies have shown that WBRT could bring survival benefits to LM patients with EGFR mutations. Similarly, the survival benefit of WBRT to brain metastases is controversial. A randomized clinical trial QUARTZ showed that except for younger patients, WBRT had no significant effect on survival or quality of life in patients with brain metastases [18].

In LM, a neuraxis disease, CSF circulates dynamically through the whole compartment of the central nervous system (i.e., the intracranial and intraspinal compartments), and malignant cell diffusion affects all CSF compartments [19]. Based on the characteristics of LM, the whole craniospinal axis should be defined as target volume of radiotherapy. However, craniospinal irradiation (CSI) is rarely recommended in clinical work, because of its obvious myelotoxicity and the lack of evidence of its survival benefits [3, 20]. Subsequently, only the intracranial CSF compartment of the CNS has been irradiated in the treatment of LM with WBRT [17, 19, 21], which could account for the limited role of WBRT.

LM is more common in NSCLC patients harboring EGFR mutations, especially in patients after effective EGFR-TKI treatment [5, 9]. In our study, 23 of 30 developed LM during treatment with EGFR-TKI. After the diagnosis of LM, the 36 patients who received EGFR-TKIs achieved significantly longer iPFS_LM and OS_LM than patients who did not (median iPFS_LM 3.9 vs. 2.7 months, p = 0.019; median OS_LM 10 vs. 3.3 months, p = 0.002), and these findings are consistent with those from previous studies [5, 6, 22, 23]. Li et al. [5] showed that patients who received EGFR-TKIs after LM diagnosis had significantly longer survival compared with those who did not (10.0 vs. 3.3 months; p < 0.001). Another retrospective study [6] also reported that EGFR-TKI therapy was an independent predictor of longer survival in 75 EGFR-mutated NSCLC patients with LM. Overall, EGFR-TKIs exhibited good efficacy for EGFR-mutant NSCLC patients with LM.

Currently, there is no sufficient evidence to suggest that the combination of EGFR-TKIs and WBRT has a better survival benefit than EGFR-TKIs alone in EGFR-mutant NSCLC patients with LM. However, research on brain metastasis has shown that EGFR-TKIs plus WBRT has a higher response rate and significant improvement in survival, compared with EGFR-TKIs alone in the treatment of BM from EGFR-mutant NSCLC patients [24‐27]. Borghetti et al. [28] also confirmed that radiation therapy combined with TKI is a safe and well-tolerated therapy for metastatic NSCLC patients with EGFR- or ALK- mutations. In this study, the addition of WBRT to EGFR-TKIs did not lead to any survival benefit in EGFR-mutant LM patients when compared with patients who received only EGFR-TKIs (median OS_LM 13.6 vs. 15 months; p = 0.381). This result is similar to the findings from 33 patients treated with both WBRT and EGFR-TKIs in a previous investigation who did not survive longer than those who received only EGFR-TKIs (median 9.7 vs. 10.1 months; p = 0.778, 3). To patients with EGFR-mutant LM, EGFR-TKIs alone could be the better treatment option, with further clinical studies required to certify the hypothesis.

Different EGFR-TKIs options have provided promising outcomes in the treatment of LM form NSCLC. Erlotinib reportedly could be more effective than gefitinib in the treatment of LM in NSCLC patients [29]. Compared to gefitinib, erlotinib has shown higher CSF concentrations (28.7 vs. 3.7 ng/mL, p = 0.0008) and penetration rates (2.77 vs. 1.13%, p < 0.0001) [30]. Afatinib and icotinib have also shown efficacy on LM from NSCLC with EGFR mutation [31, 32]. Osimertinib (AZD9291) is a third-generation EGFR-TKI targeting sensitized EGFR mutations and acquired EGFR T790 M resistance mutations [33]. The therapy exhibited a better BBB penetration than the other EGFR-TKIs (gefitinib, rociletinib, or afatinib) [34]. The preliminary results from the phase I BLOOM study (NCT02228369) demonstrated that high-dose osimertinib (160 mg daily) showed encouraging activity and manageable tolerability in pretreated EGFR-mutant NSCLC patients with LM confirmed by CSF cytology [35]. In another study, 20 EGFR-mutant LM patients treated with osimertinib had an OS of 18.0 months [36], whereas, OS was only 3.1 months in a cohort of 32 LM patients treated with first- and second-generation EGFR-TKIs [16]. Osimertinib appears to be more effective than the first- and second-generation EGFR-TKIs. However, the use of osimertinib in the treatment of EGFR-mutant LM has not been approved yet, and further randomized clinical studies are needed to confirm its prowess.

This study, despite its mixed findings, also has several limitations. Firstly, the retrospective design and small sample size affected its statistical power. Moreover, the data were obtained retrospectively from medical records, and there may have been biasing in patient selection. Secondly, the intracranial therapeutic response was not evaluated using CSF parameters. Therefore, our conclusions should be interpreted cautiously.

In conclusion, our study revealed that EGFR-TKIs seems to have an excellent control of LM in NSCLC patients with EGFR mutations even if WBRT is not delivered; on the other hand, WBRT seems to positively influence the survival of these patients even if it does not get the statistical significance. Probably, WBRT could be omitted in asymptomatic patients when EGFR-TKIs are available for LM, thus further avoiding the side effects of WBRT.