Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI
Introduction
Despite continued advances in the treatment of non-small cell lung cancer (NSCLC), central nervous system (CNS) involvement of the disease remains a grave complication conferring short duration of survival and marked deterioration in the quality of life [1]. For patients with leptomeningeal metastasis (LM), few therapeutic options are available other than palliative measures, including whole brain and/or spinal axis irradiation or intrathecal chemotherapy, which do not prolong the duration of survival [2], [3]. Poor penetration of chemotherapeutic agents beyond the blood–brain-barrier (BBB) accounts, in part, for the limitations of current treatment options.
Recently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have been developed and have been shown to have better efficacy in select subgroups of patients with NSCLC [4], [5], [6]. It has been reported that there is a high incidence of LM among responders to gefitinib in systemic disease [7], and a higher than standard dose of gefitinib is effective in the treatment of LM by overcoming the BBB [8]. In that context, we treated LM in NSCLC patients with EGFR TKIs to determine the efficacy of the drugs in CNS disease.
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Patient selection
In this retrospective study, erlotinib (150 mg/day) or higher than standard dose of gefitinib (500 mg/day and 750 mg/day) were used for the treatment of patients with NSCLC and LM at Seoul National University Hospital between January 2006 and February 2008. The inclusion criteria were as follows: the likely presence of a sensitive EGFR mutation (exon 19 deletion or exon 21 L858R) or the high probability of an EGFR mutation, as indicated by a previous objective response to an EGFR TKI or two
Patient characteristics (Table 1)
Three patients were males and 8 patients were females; the ages ranged from 34 to 73 years (median age, 58 years) at the time of diagnosis of LM, all of which were proven to be adenocarcinomas. Nine patients were never-smokers.
All of the patients had metastatic disease in the brain parenchyma at the time they were shown to have leptomeningeal involvement. Five patients had systemic disease involving more than two metastatic sites, including lung, bone, liver, adrenal glands, or spleen, in
Discussion
LM from NSCLC is a difficult disease to treat, and remains a grave entity in the clinical course of NSCLC. The duration of survival of NSLCL patients affected by LM is approximately 3 months, which is shorter than that of patients with LM from other diseases, such as breast cancer or hematologic malignancies [2], [3]. Intrathecal chemotherapy with methotrexate, cytarabine, or thiotepa has usually been used for the treatment of LM with no overt evidence of survival advantage [3]. We report
Conflict of interest
Se-Hoon Lee received expert testimony of AstraZeneca, and Seock-Ah Im received funding of AstraZeneca.
Acknowledgements
H.G. Yi and H.J. Kim equally contributed to the study.
This study was supported by grants from the Korean Health 21 R&D Project (#0412-CR01-0704-0001), and the Innovative Research Institute for Cell Therapy (A0622660) of the Republic of Korea.
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