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Erlotinib for Whole-Brain-Radiotherapy-Refractory Leptomeningeal Metastases After Gefitinib Failure in a Lung Adenocarcinoma Patient
Letters to The Editor
Erlotinib for WholeBrain-RadiotherapyRefractory Leptomeningeal Metastases After Gefitinib Failure in a Lung Adenocarcinoma Patient To the Editor: We read with interest the recent article by Morris et al.1 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 Disclosure: Nobuyuki Katakami, MD, PhD, received payment for development of educational presentations from Eli Lilly, Novartis, Taiho, Jansen, and Sanofi-Aventis. The other authors declare no conflicts of interest. Address for correspondence: Akito Hata, MD, Division of Integrated Oncology, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0704-0770
770
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.2 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.3 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.4 Low penetration of
gefitinib into the CNS is considered to be the cause of CNS resistance to gefitinib.5 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, EGFRTKIs 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. Akito Hata, MD Nobuyuki Katakami, MD, PhD Reiko Kaji, MD Shiro Fujita, MD, PhD Yukihiro Imai, MD, PhD Division of Integrated Oncology Institute of Biomedical Research and Innovation Kobe, Japan REFERENCES 1. Morris 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;7:382–385. 2. Lee 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;116:1336–1343. 3. Shingyoji 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;6:1215–1220. 4. 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. 5. Jackman 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;28:357–360.
Journal of Thoracic Oncology • Volume 7, Number 4, April 2012
Journal of Thoracic Oncology • Volume 7, Number 4, April 2012
Letters to the Editor
FIGURE 1. (A) Brain magnetic resonance image (MRI) before whole brain radiotherapy (WBRT); (B) Brain MRI 1 month after WBRT; (C) Brain MRI 1 month after the initiation of erlotinib.
Epidermal Growth Factor Receptor Mutation and Chemosensitivity To the Editor: We read with interest the recent article by Yoshimasu et al.1 which concluded that lung cancers with epidermal growth factor receptor (EGFR) mutations were less sensitive to cisplatin and docetaxel than those with wild-type EGFR based on histoculture drug response assays. As this is still a controversial issue,2,3 we would like to refer you to the results of our recent study in which we analyzed a panel of non-small cell lung carcinoma cell lines for genetic mutations; gene expression patterns; and sensitivities to cisplatin, paclitaxel, and gefitinib.4 We used a conventional cell growth inhibition assay in a 96-well format, and the results are shown in Figure 1. Our data showed that of the 40 nonsmall cell lung cancer cell lines tested, EGFR mutants (n = 6) were relatively Disclosure: The authors declare no conflicts of interest. Address for correspondence: Toshiro Niki, PhD, MD, Department of Pathology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0704-0771
resistant to cisplatin. The IC50 of EGFR mutants ranged from 2.5 to 9.5 M. Two EGFR mutants, H1650 and H1975, showed IC50 values of 2.5 and 4.0 M, respectively, and four EGFR mutants (HCC827, HCC4006, PC3, and PC14) showed IC50 values for cisplatin more than 5 M. In our assay, paclitaxel was
effective for most of the cell lines with IC50 values less than 0.1 M. However, there were four exceptional cell lines that were highly resistant to paclitaxel with IC50 values more than 10 M. Of these four cell lines, two cell lines, PC3 and PC14, harbored EGFR mutations and the other two, Calu3 and H1781,
FIGURE 1. The IC50 values of the 40 non-small cell lung cancer cell lines for cisplatin according to the driver mutations and E-cadherin mRNA levels. Cell lines with low E-cadherin mRNA are shown in blue and cell lines with high E-cadherin mRNA are shown in red. Note that cell lines mutated for EGFR, HER2, MET, and BRAF express high levels of E-cadherin mRNA and are mostly resistant to cisplatin. KRAS mutants showed distinct sensitivities to cisplatin according to E-cadherin mRNA levels. Modified from Matsubara et al.4
Copyright © 2012 by the International Association for the Study of Lung Cancer
771
Erlotinib for WholeBrain-RadiotherapyRefractory Leptomeningeal Metastases After Gefitinib Failure in a Lung Adenocarcinoma Patient To the Editor: We read with interest the recent article by Morris et al.1 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 Disclosure: Nobuyuki Katakami, MD, PhD, received payment for development of educational presentations from Eli Lilly, Novartis, Taiho, Jansen, and Sanofi-Aventis. The other authors declare no conflicts of interest. Address for correspondence: Akito Hata, MD, Division of Integrated Oncology, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0704-0770
770
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.2 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.3 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.4 Low penetration of
gefitinib into the CNS is considered to be the cause of CNS resistance to gefitinib.5 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, EGFRTKIs 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. Akito Hata, MD Nobuyuki Katakami, MD, PhD Reiko Kaji, MD Shiro Fujita, MD, PhD Yukihiro Imai, MD, PhD Division of Integrated Oncology Institute of Biomedical Research and Innovation Kobe, Japan REFERENCES 1. Morris 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;7:382–385. 2. Lee 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;116:1336–1343. 3. Shingyoji 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;6:1215–1220. 4. 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. 5. Jackman 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;28:357–360.
Journal of Thoracic Oncology • Volume 7, Number 4, April 2012
Journal of Thoracic Oncology • Volume 7, Number 4, April 2012
Letters to the Editor
FIGURE 1. (A) Brain magnetic resonance image (MRI) before whole brain radiotherapy (WBRT); (B) Brain MRI 1 month after WBRT; (C) Brain MRI 1 month after the initiation of erlotinib.
Epidermal Growth Factor Receptor Mutation and Chemosensitivity To the Editor: We read with interest the recent article by Yoshimasu et al.1 which concluded that lung cancers with epidermal growth factor receptor (EGFR) mutations were less sensitive to cisplatin and docetaxel than those with wild-type EGFR based on histoculture drug response assays. As this is still a controversial issue,2,3 we would like to refer you to the results of our recent study in which we analyzed a panel of non-small cell lung carcinoma cell lines for genetic mutations; gene expression patterns; and sensitivities to cisplatin, paclitaxel, and gefitinib.4 We used a conventional cell growth inhibition assay in a 96-well format, and the results are shown in Figure 1. Our data showed that of the 40 nonsmall cell lung cancer cell lines tested, EGFR mutants (n = 6) were relatively Disclosure: The authors declare no conflicts of interest. Address for correspondence: Toshiro Niki, PhD, MD, Department of Pathology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0704-0771
resistant to cisplatin. The IC50 of EGFR mutants ranged from 2.5 to 9.5 M. Two EGFR mutants, H1650 and H1975, showed IC50 values of 2.5 and 4.0 M, respectively, and four EGFR mutants (HCC827, HCC4006, PC3, and PC14) showed IC50 values for cisplatin more than 5 M. In our assay, paclitaxel was
effective for most of the cell lines with IC50 values less than 0.1 M. However, there were four exceptional cell lines that were highly resistant to paclitaxel with IC50 values more than 10 M. Of these four cell lines, two cell lines, PC3 and PC14, harbored EGFR mutations and the other two, Calu3 and H1781,
FIGURE 1. The IC50 values of the 40 non-small cell lung cancer cell lines for cisplatin according to the driver mutations and E-cadherin mRNA levels. Cell lines with low E-cadherin mRNA are shown in blue and cell lines with high E-cadherin mRNA are shown in red. Note that cell lines mutated for EGFR, HER2, MET, and BRAF express high levels of E-cadherin mRNA and are mostly resistant to cisplatin. KRAS mutants showed distinct sensitivities to cisplatin according to E-cadherin mRNA levels. Modified from Matsubara et al.4
Copyright © 2012 by the International Association for the Study of Lung Cancer
771