Whole brain radiotherapy (WBRT) for leptomeningeal metastasis from NSCLC in the era of targeted therapy: a retrospective study

Patients diagnosed with LM from NSCLC at our institution were retrospectively analyzed from December 2014 to March 2019. The inclusion criteria included: (1) definitive cases with confirmed malignant cells in CSF, and/or (2) diffuse linear leptomeningeal enhancements following the gyri, sulci or ependymal surface by gadolinium-enhanced magnetic resonance imaging (MRI) scan, and (3) gene tests of EGFR mutation. We excluded patients with ALK translocation (n = 5) and those whose EGFR mutation status was unknown (n = 20). Data on the clinical characteristics of patients as well as disease-related features including radiology, histology, molecular status of EGFR mutation, and treatment regimens were reviewed. This study was approved by the Ethics Committee of Guangdong Sanjiu Brain Hospital.

Systemic therapy for patients with LM was administered according to NCCN guidelines for NSCLC including EGFR tyrosine kinase inhibitors (TKIs) for those with EGFR mutations and chemotherapy with or without bevacizumab. WBRT was implemented with either 30 Gy in 15 fractions of 2 Gy, or 36 Gy in 18 fractions of 2 Gy, delivered 5 days a week, by intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT). Five patients with concurrent brain metastasis were treated by stereotactic radiosurgery (SRS) or fractioned SRS (12–24 Gy/ 1–3 fractions) using the Novalis Tx® system. For patients with significant clinical symptoms of meningeal irritation, surgical interventions including ventriculoperitoneal (VP) shunt, external ventricular drainage (EVD), or lumbar cistern drainage (LCD) were provided especially for those with elevated intracranial pressure prior to radiotherapy. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0.

The primary endpoint of our study was median overall survival (OS) determined as the time from initial diagnosis of LM to death from any cause or censored at the date of last follow-up unless otherwise specified. The radiological signs of LM are difficult for assessment; therefore, the progression free survival and overall response rates were not calculated in this retrospective cohort. Continuous data were presented as the median (minimum-maximum). Categorical data were presented as quantities and proportions. The overall survival was estimated using the Kaplan-Meier product-limited method with ‘survival’ package [17] in R software; survival curves were compared between groups using a log-rank test. Univariable and multivariable Cox proportional hazards regression models were performed to evaluate the influence of the clinical and pathologic parameters on mortality of NSCLC patients with LM. Continuous data such as age and Karnofsky Performance Status (KPS) score were divided into two subgroups via a cut-off value using the median value of the cohort for univariable and multivariable regression modeling. Statistical analyses used R software version 3.5.1. All statistical assessments were two-sided, and P < 0.05 was considered to be statistically significant.

Eighty NSCLC patients with LM were eligible for our study and consisted of 44 males and 36 females. Baseline characteristics of all included patients are listed below (Table 1). The median age at diagnosis of LM was 53.5 (range: 30 to 78 years). Most patients had adenocarcinoma histology (73/80, 91.3%). Malignant cells were found in 55 patients from CSF while the remaining 25 patients were diagnosed with LM according to magnetic resonance imaging (MRI) findings and clinical presentations. Nineteen patients had synchronous LM when diagnosed with NSCLC while 61 patients progressed to LM after at least one line of systematic therapy. The median time from diagnosis of NSCLC to metachronous LM was17.6 month (range: 3.0 to 73.0). Forty-two (52.5%) patients had brain metastasis when diagnosed with LM. Fifty-one (63.8%) patients also had extra-central nervous system (CNS) metastasis mainly involving lung, liver, and lymph nodes (Table 2).

EGFR mutations were determined by gene panel sequencing or polymerase chain reaction (PCR)-based assays on different samples (37 from tumor tissue, 24 from CSF, 9 from both CSF and serum, 6 from serum, 3 from both tumor tissue and serum, and 1 from pleural effusion). Of these, 25 patients had EGFR exon 19 deletion, 18 had EGFR exon L858R mutation, and 1 patient had EGFR exon 20 insertion. The T790M mutations were reported in five patients. The remaining 31 patients were wild-type EGFR. Forty-six (57.5%) patients had received EGFR TKI therapy prior to the diagnosis of LM (Table 1).

Thirty-eight (47.5%) patients received WBRT out of a total of 30–36 Gy/15–18 fractions. Stereotactic radiosurgery was implemented in 5 patients for the treatment of concurrent brain metastasis. Sixteen patients underwent surgical interventions including 6 VP shunts, 7 external ventricle drainage cases, and 3 lumbar cistern drainages. With respect to systematic therapy after diagnosis of LM, 25 patients received osimertinib, 22 patients received first- or second-generation EGFR TKI (including gefitinib in 12 patients, erlotinib in 4, icotinib in 5, and afatinib in 1 patients). Two patients received gefitinib followed by osimertinib; 36 patients were given platinum-based chemotherapy, and 9 of them were supplemented with bevacizumab (Table 2).

The median follow-up time was 8.6 months (range: 1 to 28.4 months); 47 patients died within this period, 29 patients were still alive, and 4 were lost to follow-up. The median OS after diagnosis of LM was 8.0 months (95% confidence interval [CI]: 4.4 to 11.6 months), and one-year OS was 39.4% (Fig. 1a). Subgroup analysis revealed that the median OS for EGFR-mutated patients was 12.6 months (95% CI: 3.0 to 22.2 months), which was significantly longer than those with wild-type EGFR LM patients (4.1 months, 95% CI: 2.8 to 5.4 months, P < 0.001) (Fig. 1b). Patients who received EGFR TKI were identified to have a better OS than non-TKI treatment (11.1 vs. 2.5 months, P < 0.001).

We next asked whether age at diagnosis of LM has an impact on survival and prognosis; subgroup analysis indicated that younger age (< 53.5 yrs.) appeared to gain a favorable OS versus older ones (≥53.5 yrs.) (12.6 vs. 6.1 months, P = 0.041) (Fig. 1c). No significant difference was found in OS with reference to sex, KPS score, Glasgow Coma Scale (GCS) score, concurrent brain metastasis, chemotherapy, and bevacizumab therapy (Table 3). Multivariate analysis showed that EGFR mutations (P = 0.013, HR 0.39, 95% CI: 0.186 to 0.820) and younger age (P = 0.025, HR 0.492, 95% CI: 0.265 to 0.915) were still independent prognostic factors that predicted better survival (Table 3).

To study the therapeutic effects of WBRT, the OS of patients who received WBRT (WBRT group, n = 38) were evaluated versus those without WBRT (non-WBRT group, n = 42). Although no significant difference in OS was found between two arms (P = 0.051), the median OS of WBRT group was numerically doubled compared to non-WBRT group (11.4 vs. 5.0 months). (Fig. 2a). We next explored the consequences of WBRT in LM patients with different mutation backgrounds via sub-group analysis. For patients harboring EGFR mutations, no survival benefits were observed with WBRT treatment by univariate analysis (WBRT vs. non-WBRT: P = 0.49, HR 0.73, 95%CI 0.297 to 1.794) (Fig. 2b). Interestingly, with respect to patients with wild-type EGFR, the survival advantages of WBRT was exceptionally established (median OS: 8.0 vs. 2.1 months, P = 0.002, HR 0.229, 95%CI 0.083 to 0.632) (Fig. 2c). Multivariate analysis consistently showed that WBRT (P = 0.025) and younger age (P = 0.048) were independent prognostic factors that predicted favorable overall survival in patients with wild-type EGFR (Table 4).

Two patients in WBRT group suspended irradiation due to worsening headache, both of them completed irradiation after decompression surgery were conducted. Other WBRT related toxicities including grade 1 to 2 nausea/vomiting in 7 patients, grade 1 transient headache in 5 patients, grade 1 radiation dermatitis in 3 patients and grade 1 hearing impaired in 1 patient.