CNS metastases in non-small-cell lung cancer: current role of EGFR-TKI therapy and future perspectives.

A considerable proportion of non-small-cell lung cancer (NSCLC) patients will develop central nervous system (CNS) metastases throughout the course of their disease and these manifestations cause significant morbidity and mortality. Accordingly, novel therapies with high efficacy and low toxicity are needed for NSCLC-related CNS metastases. In NSCLC patients with activating epidermal growth factor receptor gene (EGFR) mutations EGFR-specific tyrosine kinase inhibitors (TKI) represent effective and well tolerated modes of therapy, however, it has been unclear whether these drugs are also able to cross the blood-brain-barrier (BBB) and cause remission of CNS metastases. Recent studies suggest that this might indeed be the case and intracerebral response rates of 70-80% in molecularly selected patients are considerably higher compared to what would be expected for standard approaches like systemic chemotherapy and whole brain radiation therapy. Limitations in the application of EGFR-TKI may arise from genetic heterogeneity between the primary tumor and CNS metastases. Accordingly, the acquisition of repeated biopsies from all relevant metastatic sites, including the CNS, may be necessary to guide therapeutic decisions. However, even in EGFR-wildtype patients EGFR-TKI seem to represent a valuable second line therapy with response rates of about 10%. Application of EGFR-TKI in a "pulsative" pattern may help to overcome insufficient delivery of TKI to the cerebro-spinal fluid and may further increase response rates and time until progression. In the future, combination of EGFR-TKI with radiation or chemotherapy and/or incorporation of next-generation TKI should be evaluated regarding their potential for further optimizing therapy of NSCLC patients with CNS metastases.