Leptomeningeal Metastases in Non-Small Cell Lung Cancer Patients with an Epidermal Growth Factor Receptor Mutation

Abstract

ABSTRACT Aim: Leptomeningeal metastasis (LM) is considered to be a devastating complication of non-small cell lung cancer (NSCLC). As overall survival (OS) is prolonged in NSCLC patients with an activating epidermal growth factor receptor mutation (EGFR+), especially when treated with targeted therapy, LM may have become more prevalent in this patient group. Currently, there is no standard treatment for EGFR+ NSCLC patients with LM and prognosis is unknown. Methods: The medical records of 229 patients who were diagnosed with EGFR+ NSCLC between July 2002 and January 2014 in 7 hospitals were retrospectively reviewed for diagnosis of LM (by MRI and/or positive cytology of cerebrospinal fluid). Information on symptoms, treatment, progression-free survival (PFS) and OS was collected. OS was estimated by Kaplan-Meier method, differences were determined by log-rank test. Results: 19 patients with LM were identified. Patient characteristics are described in table 1. All but 1 patient had yet progressed on 1st line EGFR TKI-treatment and median PFS on first TKI-treatment was 9.5 months (95% Confidence Interval (CI) 8.0 – 11.0). Median time from diagnosis of advanced-stage NSCLC to diagnosis of LM was 12.3 months (95% CI 7.4 – 17.2). At time of analysis, 4 patients were alive and median time from diagnosis of LM to death or last date of follow-up was 5.7 months (95% CI 0.0 – 14.2). 1-year survival was 26.3%. Median OS of patients who received high dose EGFR-TKI (i.e. 1500 mg erlotinib weekly) after diagnosis of LM (n = 8) was 5.7 months (95% CI 0.0 – 14.8) compared to 4.6 months (95% CI 0.0 – 13.0) in patients (n = 11) who were treated otherwise (P = 0.888). Patient characteristics Patients (N = 19) Median age at time of 1st diagnosis of NSCLC Years 48.1 (range 29.2 - 75.2) No. of patients Percentage (%) Gender Male 8 42.1 Female 11 57.9 Histology Adenocarcinoma 19 100.0 Performance score PS 0 11 57.9 PS 1 5 26.3 PS 2 3 15.8 Mutation EGFR-exon 18 2 10.5 EGFR-exon 19 14 73.7 EGFR-exon 21 3 15.8 Diagnosis LM MRI 14 73.7 Cytology 1 5.3 MRI + cytology 4 21.1 Treatment at time when LM was diagnosed TKI 11 57.9 Chemo 3 15.8 TKI + chemo 2 10.5 No treatment 3 15.8 Systemic treatment started at time of diagnosis of LM Continuation of TKI 6 31.6 Continuation of TKI + chemo 1 5.3 High-dose TKI 3 15.8 High-dose TKI + chemo 5 26.3 TKI-switch 1 5.3 Start TKI-treatment 2 10.5 No treatment 1 5.3 Radiotherapy started at time of diagnosis of LM WBRT 5 26.3 Radiotherapy (thoracic/lumbal) 3 15.8 None 11* 57.9 * 8 of these patients started high-dose TKI, 1 patient started standard-dose TKI, 1 patient died 5 days after diagnosis of LM and in 1 patient standard-dose TKI was continued. Abbreviations: NSCLC: non-small cell lung cancer. PS: performance score. EGFR: Epidermal growth factor receptor. LM: leptomeningeal metastases. TKI: tyrosine kinase inhibitor. WBRT: whole brain radiotherapy. Chemo: chemotherapy. Conclusions: Although LM is generally thought to be a fatal complication of NSCLC, in this cohort 26.3% of EGFR+ NSCLC patients was alive 1 year after diagnosis of LM. In this retrospective, multi-center study, there was no statistical significant advantage for patients who received high dose EGFR TKI. Further investigation for optimal treatment of LM in EGFR+ NSCLC patients is warranted. Disclosure: A.C. Dingemans: Advisory boards for Roche and Astra Zeneca. All other authors have declared no conflicts of interest.