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

doi:10.1016/j.lungcan.2008.10.016

Lung Cancer

Volume 65, Issue 1, July 2009, Pages 80-84

https://doi.org/10.1016/j.lungcan.2008.10.016 Get rights and content

Abstract

The purpose of this study was to demonstrate the beneficial effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of leptomeningeal metastasis (LM) for a select group of non-small cell lung cancer (NSCLC) patients who had a sensitive EGFR mutation or good predictive clinical factors for EGFR TKI treatment. Eleven patients with NSCLC and LM were treated with a standard dose of erlotinib (n = 9), or higher than standard dose of gefitinib followed by erlotinib (n = 2). They were treated with various therapies including whole brain radiotherapy or intrathecal chemotherapy for CNS lesion previously and concurrently with EGFR TKI. Nine of 11 patients showed overt improvement in ECOG performance status. Six patients were alive >6 months, and 2 additional patients were alive 2.5+ and 4.4+ months with clinical improvement. Two patients showed responses to higher than standard dose of gefitinib. The median overall survival was not reached. In conclusion, EGFR TKIs are effective in the treatment of LM from NSCLC when patients were selected properly.

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.

Section snippets

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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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

Abstract

Introduction

Section snippets

Patient selection

Patient characteristics (Table 1)

Discussion

Conflict of interest

Acknowledgements

Lung Cancer

Ann Oncol

Brain metastases in locally advanced nonsmall cell lung carcinoma after multimodality treatment: risk factors analysis

Cancer

Neoplastic meningitis

J Clin Oncol

Comparison of intrathecal chemotherapy for leptomeningeal carcinomatosis of a solid tumor: methotrexate alone versus methotrexate in combination with cytosine arabinoside and hydrocortisone

Jpn J Clin Oncol

Epidermal growth factor receptor mutations in lung cancer

Nat Rev Cancer

EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib

Proc Natl Acad Sci USA

Predictive and prognostic Impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib

J Clin Oncol

High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib

Cancer

Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib

J Clin Oncol