Erlotinib Accumulation in Brain Metastases from Non-small Cell Lung Cancer: Visualization by Positron Emission Tomography in a Patient Harboring a Mutation in the Epidermal Growth Factor Receptor

Abstract

The Brief Report by Britta Weber et al. in this issue of the Journal of Thoracic Oncology documents accumulation of erlotinib in brain metastases in a patient with non-small cell lung cancer (NSCLC) imaged with positron emission tomography-computed tomography (PET-CT) using a novel tracer [11C]-erlotinib.1 Dynamic PET imaging showed accumulation of [11C]-erlotinib in the metastases, and this accumulation continued during the 60-minute study period, indicating binding to receptors on the tumor cells. Fused PET-magnetic resonance imaging 3 weeks after the start of treatment showed near-complete remission of brain and meningeal metastases. The marked improvement in clinical performance status observed in this patient after administration of erlotinib, a tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR), has been previously reported.2–4 Mutation analysis revealed that this patient’s tumor had a sensitizing exon 19 deletion in the EGFR gene. Metastases to the brain are common in patients with advanced NSCLC and, as reported in this study, can be associated with substantial morbidity. However, earlier detection and improved treatment options have improved survival. In this regard, the report by Weber et al. confirms the potential value of systemic therapy in the treatment of brain metastases and provides additional information that supplements recent reports concerning clinical and objective responses of brain metastases in patients with NSCLC after treatment with erlotinib or gefitinib. The authors indicate that the ability of these drugs to accumulate in brain metastases has not been previously studied. This paucity of information reflects the prevailing broader lack of understanding on drug concentrations achieved in tumors within the brain and the role of the blood-brain barrier (the continuous, nonfenestrated endothelial microvasculature of the brain parenchyma) in the resistance to systemic therapy for intracerebral tumors. Weber et al. state in their article that intravenous chemotherapy has limited therapeutic effect in the treatment of brain metastases in patients with NSCLC due to poor penetration of these drugs into brain tissue and cerebrospinal fluid. However, although observations in the treatment of brain tumors have been used to infer that the blood-brain barrier significantly decreases the efficacy of lipid insoluble chemotherapy drugs, the role of the blood-brain barrier in the resistance of intracerebral tumors to chemotherapy is unclear.5,6 In fact, the perception that the blood-brain barrier is a major factor in the resistance to chemotherapy of brain metastases may be based in part on a bias in data selection and interpretation.5,6 Limitations in the theory regarding the importance of the blood-brain barrier in brain tumor chemotherapy are widely acknowledged. While there is general consensus that most chemotherapy agents only attain comparatively low concentrations in the normal brain,