High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases—One with a remarkable thoracic response as well

Abstract

A considerable number of patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) develop leptomeningeal metastases. Leptomeningeal metastases are associated with deterioration of clinical symptoms and poor survival. Traditionally, treatment of metastases in the central nervous system consists of radiotherapy and less frequently, surgery. The role of systemic therapy is limited due to the blood–brain barrier inhibiting pharmacological doses to be reached in the central nervous system. Several case reports have described high-dose, pulsatile tyrosine kinase inhibitors as an effective treatment of leptomeningeal metastases, based on the hypothesis that higher concentrations in the cerebrospinal fluid can be reached by higher systemic concentrations. Here, we describe two patients with EGFR-mutated non-small cell lung cancer, with both clinical and radiological response to this high-dose, pulsatile regimen. Interestingly, one patient showed a remarkable response of intrathoracic response as well.

Introduction

EGFR-mutated NSCLC is associated with a favourable prognosis, high rate of response to EGFR-TKI's and consequently improved overall survival when compared to other subtypes of NSCLC. However, after an initial response to EGFR-TKI's, progression of disease is inevitable. A substantial number of patients develop CNS metastases, in some series up to 30%. CNS metastases are associated with disabling neurological symptoms, deterioration of performance status and poor survival. Traditionally, treatment of CNS metastases consists of radiotherapy and in selected cases, surgery. Systemic treatment is believed to have a limited role, due to the blood–brain barrier (BBB). Since EGFR TKI's are a substrate of P-glycoprotein, the BBB is preventing pharmacological dose of EGFR TKI's at standard dosing regimes to be reached in the CNS. Due to this lower drug concentration, selective pressure in the CNS is different and acquired resistance mechanisms that are often demonstrated in metastases outside the CNS are believed to be less common in CNS metastases. Hence, these metastases would still be sensitive to EGFR-TKI-treatment, if only sufficient penetration of these drugs into the CNS could be achieved. Theoretically, administering TKI's in a higher dose could achieve higher concentrations in the cerebrospinal fluid. This strategy has been applied before, with encouraging results [1], [2], [3], [4], [5], [6]. Here, we report two EGFR-mutated NSCLC-patients with leptomeningeal metastases successfully treated with high-dose, weekly erlotinib, one with a remarkable response of intrathoracic disease as well.