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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e3181d899bb
Letters to the Editor

High-dose Erlotinib for Refractory Brain Metastases in a Patient with Relapsed Non-small Cell Lung Cancer

Hata, Akito MD; Kaji, Reiko MD; Fujita, Shiro MD, PhD; Katakami, Nobuyuki MD, PhD

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Division of Integrated Oncology; Institute of Biomedical Research and Innovation; Kobe, Japan

Disclosure: The authors declare no conflicts of interest.

Address for correspondence: Nobuyuki Katakami, MD, PhD, Division of Integrated Oncology, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, 650-0047 Kobe, Japan. E-mail:

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To the Editor:

We read with great interest the recent article by Katayama et al.1 on the efficacy of erlotinib for intracranial metastases in patients who had shown a good response to gefitinib. Even if a substantial response is obtained with erlotinib as a readministration of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), the progression-free interval is usually not long enough. We present herein a patient with multiple brain metastases whose lesions were refractory to previous standard-dose EGFR-TKI therapies and whole brain radiotherapy (WBRT). Nevertheless, her brain metastases showed a remarkable response to “high-dose” erlotinib therapy.

A 52-year-old woman without a history of smoking presented with productive cough and progressive dyspnea. The computed tomography scan revealed bilateral pleural effusion, bilateral innumerable intrapulmonary nodules, and pericardial effusion. Multiple brain lesions compatible with metastatic tumors were found with magnetic resonance imaging (MRI) of the brain. Cytologic examination of the pleural fluid revealed adenocarcinoma, and the patient was diagnosed with metastatic non-small cell lung cancer (NSCLC). Simultaneously, a sensitive EGFR mutation (exon 18 G719A) was identified based on analysis of the malignant effusion. After chest-tube drainage, gefitinib was administered, and a partial response was achieved for approximately 1 year. After disease progression on gefitinib, the patient was consecutively treated with several chemotherapy regimens. During the course of therapy, the brain metastases became symptomatic, and she underwent WBRT (total of 30 Gy). In the spring of 2009, erlotinib was administered, and disease stability was obtained for 4 months, followed by a progression of brain metastases with complaints of gait disturbance and dysarthria. Elrotinib was changed to pemetrexed as the sixth-line treatment. Nevertheless, 2 weeks after initiation of the agent, her symptoms further deteriorated. The brain MRI and body computed tomography scan showed a further progression of brain metastases (Figure 1A), despite stable extracranial lesions. WBRT had already been performed and, considering her heavy treatment history, cytotoxic agents seemed to be ineffective for the brain metastases. Moreover, the standard dosage of erlotinib had failed to improve brain lesions several weeks before. Therefore, we decided to administer “high-dose erlotinib.” Erlotinib was given on alternating days at a dose of 300 mg/d. Two weeks after the initiation of high-dose erlotinib, both her clinical symptoms and findings of brain MRI improved. Regarding adverse events, a grade 1 rash was observed. Since high-dose erlotinib was initiated, her clinical symptoms and findings of brain MRI (Figure 1B) have remained stable for 6 months.

Figure 1
Figure 1
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WBRT is commonly used as the primary approach for multiple brain metastases in the treatment of NSCLC. The efficacy of cytotoxic agents for brain metastases is considered to be modest and limited because of the blood brain barrier. Several authors have recently reported the utility of small molecule EGFR-TKIs for brain metastases from NSCLC, especially in patients with EGFR mutations.2 Nevertheless, after the failure of WBRT and the standard dose of EGFR-TKIs, there has until now been almost no other approach to controlling brain metastases. In this case, we adopted high-dose erlotinib to treat such refractory central nervous system (CNS) metastases. Two recent reports have already demonstrated the efficacy of high-dose EGFR-TKIs for refractory CNS metastases.3,4 In both reports, after failure of standard-dose EGFR-TKIs for CNS metastases, high-dose EGFR-TKIs were administered, and intracranial lesions showed a response. These responses suggest that the CNS metastases remained sensitive to high-dose EGFR-TKIs and that the higher dose led to higher CNS penetration of the drugs. High-dose EGFR-TKIs will contribute to the treatment of refractory CNS metastases after the failure of WBRT and the standard-dose EGFR-TKIs treatment. Further prospective trials regarding high-dose EGFR-TKIs are warranted for such patients.

Akito Hata, MD

Reiko Kaji, MD

Shiro Fujita, MD, PhD

Nobuyuki Katakami, MD, PhD

Division of Integrated Oncology

Institute of Biomedical Research and Innovation

Kobe, Japan

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1. Katayama 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;4:1415–1419.

2. Benedetti G, Latini L, Galetta D, et al. Epidermal growth factor receptor exon 19 deletions predict complete regression of multiple intracranial metastases in two cases of non-small cell lung cancer treated with erlotinib. J Thorac Oncol 2009;4:936–937.

3. Jackman DM, Holmes AJ, Lindeman N, et al. 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 2006;24:4517–4520.

4. Dhruva N, Socinski MA. Carcinomatous meningitis in non-small-cell lung cancer: response to high-dose erlotinib. J Clin Oncol 2009;27:e31–e32.

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Note to the readership

The letter that was intended by the authors to follow “High-dose Erlotinib for Refractory Brain Metastases in a Patient with Relapsed Non-small Cell Lung Cancer,” which appears in the current issue of the journal, has been published in a previous issue. This letter, “Does the Addition of Vascular Endothelial Growth Factor Inhibitors to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Overcome T790M Acquired Resistance?,” can be found in the February 2011 issue of the Journal.

Hata A, Kaji R, Fujita S, Katakami N: Does the Addition of Vascular Endothelial Growth Factor Inhibitors to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Overcome T790M Acquired Resistance? J Thorac Oncol 2011;6:404. View Full Text | PubMed

Cited By:

This article has been cited 5 time(s).

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Clinical Lung Cancer
Cerebrospinal Fluid Concentrations of Gefitinib in Patients With Lung Adenocarcinoma
Zhao, J; Chen, MJ; Zhong, W; Zhang, L; Li, LY; Xiao, Y; Nie, LG; Hu, P; Wang, MZ
Clinical Lung Cancer, 14(2): 188-193.
International Journal of Cancer
The theoretical foundation and research progress for WBRT combined with erlotinib for the treatment of multiple brain metastases in patients with lung adenocarcinoma
Zhuang, HQ; Wang, J; Zhao, LJ; Yuan, ZY; Wang, P
International Journal of Cancer, 133(): 2277-2283.
Lung Cancer
High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases-One with a remarkable thoracic response as well
Kuiper, JL; Smit, EF
Lung Cancer, 80(1): 102-105.
Journal of Neuro-Oncology
EGFR mutation status in brain metastases of non-small cell lung carcinoma
Burel-Vandenbos, F; Ambrosetti, D; Coutts, M; Pedeutour, F
Journal of Neuro-Oncology, 111(1): 1-10.
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© 2011International Association for the Study of Lung Cancer


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