Erlotinib for Whole-Brain-Radiotherapy-Refractory Leptomeningeal Metastases After Gefitinib Failure in a Lung Adenocarcinoma Patient

Abstract

We read with interest the recent article by Morris et al.1Morris PG Reiner AS Szenberg OR et al.Leptomeningeal Metastasis from Non-small Cell Lung Cancer: Survival and the Impact of Whole Brain Radiotherapy.J Thorac Oncol. 2012; 7: 382-385Crossref PubMed Scopus (194) Google Scholar on the negative impact of whole brain radiotherapy (WBRT) for leptomeningeal metastases (LM). WBRT is commonly performed as the first choice for diffuse-type brain metastases. However, WBRT is occasionally ineffective, especially in cases combined with LM. We experienced a case with an epidermal growth factor receptor (EGFR)-sensitive mutation in which WBRT-refractory central nervous system (CNS) metastases markedly responded to erlotinib after gefitinib failure, and herein present the case. A 66-year-old woman was referred to our institution, diagnosed with metastatic adenocarcinoma of the lung. Initially, a chest computed tomography showed multiple pulmonary metastases and pleural and pericardial effusions. Drainage of the pleural and pericardial effusions was performed, and cytological examination of the pericardial effusion revealed adenocarcinoma cells. A point mutation in exon 21 (L858R) was detected in the EGFR mutational analysis. Her performance status (Eastern Cooperative Oncology Group) was 2, and we administered gefitinib as the first-line therapy. Remarkable response was confirmed, and the effusions mostly disappeared. Although the response continued for 18 months, she complained of gait disturbance during gefitinib therapy. Brain magnetic resonance imaging (MRI) showed multiple brain metastases (Figure 1A). We withdrew gefitinib and administered WBRT. After WBRT, her symptoms and MRI findings further deteriorated (Figure 1B). We suspected that these brain metastases were complicated by LM. Cerebrospinal fluid (CSF) cytology did not reveal malignant cells, but an L858R mutation (without T790M) was detected by EGFR mutational analysis. We then initiated erlotinib as the second-line therapy. A month after erlotinib initiation, neurological symptoms and brain MRI findings dramatically improved (Figure 1C). Two months later, she was transferred to another hospital near her home. A high frequency of CNS relapse has been suggested in EGFR-tyrosine kinase inhibitor (TKI) treatment periods.2Lee YJ Choi HJ Kim SK et al.Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer.Cancer. 2010; 116: 1336-1343Crossref PubMed Scopus (92) Google Scholar Treatments for CNS relapse are therefore important after EGFR-TKI failure. Although WBRT is frequently performed for diffuse types of brain metastases, even during EGFR-TKI therapy, WBRT is not always effective. If WBRT is not effective for diffuse types of brain metastases, we should assume these metastases are complicated by LM. We suspected LM after WBRT failure, and LM was definitively diagnosed via the detection of an EGFR mutation in the CSF, despite the absence of cytological confirmation. Shingyoji et al.3Shingyoji M Kageyama H Sakaida T et al.Detection of epithelial growth factor receptor mutations in cerebrospinal fluid from patients with lung adenocarcinoma suspected of neoplastic meningitis.J Thorac Oncol. 2011; 6: 1215-1220Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar have demonstrated EGFR mutational analysis is useful in diagnosing LM. In their study, EGFR mutations were detected in five (31%) of 16 patients with negative CSF cytology. A highly sensitive polymerase chain reaction technique can detect DNA fragments in the CSF despite negative CSF cytology. Several reports have demonstrated erlotinib efficacy after gefitinib failure for CNS metastases, especially in combination with LM.4Katayama T Shimizu J Suda K et al.Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib.J Thorac Oncol. 2009; 4: 1415-1419Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar Low penetration of gefitinib into the CNS is considered to be the cause of CNS resistance to gefitinib.5Jackman D Pao W Riely GJ et al.Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.J Clin Oncol. 2010; 28: 357-360Crossref PubMed Scopus (678) Google Scholar However, erlotinib has a higher concentration in the CNS, and thus was extremely effective for LM after gefitinib failure, as demonstrated in our present case. Our present case showed a lack of WBRT effectiveness for LM. Furthermore, Morris et al. have demonstrated that survival was not improved by WBRT for LM. They also suggested the importance of EGFR-TKIs for patients with LM harboring EGFR mutations. In such patients, EGFR-TKIs should be administered before WBRT. Additionally, erlotinib should be administered before WBRT, especially in such patients after gefitinib failure. Further studies are warranted to confirm our observation.