Brain metastases from non-small cell lung cancer: radiation therapy in the era of targeted therapies

Abstract

A large proportion of patients with non-small cell lung cancer (NSCLC) will develop brain metastases (BM) throughout the course of their disease. Among NSCLC patients with oncogenic drivers, mainly epidermal growth-factor activating mutations and anaplastic lymphoma kinase rearrangements, the presence of BM is a common secondary localisation of disease both at the time of diagnosis and relapse. Due to a limited penetration of a wide range of drugs across the blood-brain barrier, radiotherapy is considered the cornerstone of treatment of BM. However, evidence of dramatic intracranial response rates have been reported in recent years with targeted therapies such as tyrosine kinase inhibitors (TKIs), supported by new insights in pharmacokinetics to increase TKIs cerebrospinal fluid penetration rates. In this context, the combination of brain radiotherapy and targeted therapies seems relevant, and there is a strong radiobiological rationale to harness the radiosentizing effect of the drugs. Nevertheless, to date, there is paucity of high level clinical evidence supporting the combination of brain radiotherapy and targeted therapies in NSCLC patients with BM and there are often methodological biases in reported studies, such as the lack of mutation status stratification. Moreover, among asymptomatic patients not suitable for ablative treatment, this strategy is challenged by the promising results associated with the administration of targeted therapies alone. Herein, we review the biological rationale to combine targeted therapies and brain radiotherapy for NSCLC patients with BM, report the clinical data available to date and discuss future directions to improve outcome in this group of patients.