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Fatal Pemetrexed-Induced Lung Injury in Patients with Advanced Mesothelioma: A Report of Two Cases
LETTERS
TO THE
EDITOR
Fatal PemetrexedInduced Lung Injury in Patients with Advanced Mesothelioma A Report of Two Cases To the Editor: Pemetrexed is an antifolate chemotherapy agent that is active in multiple tumor types including malignant mesothelioma.1 Adverse drug reactions are mild, and there have been no previous reports that pemetrexed induces fatal acute lung injury. We encountered two patients who had been given pemetrexed and developed a fatal lung injury. The first case was a 71-year-old man admitted to our hospital for evaluation of chest pain and diagnosed as sarcomatous malignant pleural mesothelioma. The patient received chemotherapy with cisplatin (60 mg/m2) and pemetrexed (500 mg/m2). However, 4 weeks after initiation of the treatment, he was dyspneic. A chest computed tomography scan demonstrated diffuse ground-glass opacities in his right lung (Figure 1). The patient’s white blood cell count was 14,800/mm3, C-reactive protein was 12.7 mg/dl, and KL-6 was 2700 U/ml (normal range: ⬍500 U/ml). No infectious, tumor-related, embolic, or cardiac causes were found after extensive workup. The patient’s clinical state deteriorated, and methylprednisolone was started at 500 mg/d. Despite the treatment, his respiratory status worsened, and he died 7 weeks after initiation of the chemotherapy. The second case was a 77-year-old man referred to our hospital for evaluation of dyspnea and diagnosed as biphasic-type malignant pleural mesothelioma. The patient received chemotherapy with carboplatin (area under the curve ⫽ 4) and Disclosure: The authors declare no conflicts of interest. Address for correspondence: Kazuma Nagata, MD, Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 4-6 Minatojima-nakamachi, Chuo-ku, Kobe 650-0046, Japan. E-mail: kazuma_n1101@ yahoo.co.jp Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0510-1714
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FIGURE 1. Computed tomography scan of the chest demonstrated diffuse ground-glass opacities in the right lung.
FIGURE 2. Computed tomography scan of the chest revealed ground-glass opacities in the left lower lobe.
pemetrexed (500 mg/m2). Three weeks after the start of the treatment, he presented with progressive exertional dyspnea. His chest computed tomography scan demonstrated ground-glass opacities in his left lower lobe (Figure 2). The patient’s white blood cell count was 16,900/mm3, C-reactive protein was 9.2 mg/dl, and KL-6 was 1236 U/ml. There were no infectious, embolic, tumor-related, or cardiac causes found after extensive workup. High-dose corticosteroid treatment was started at 500 mg/d of methylprednisolone. However, his respiratory status worsened, and he died 5 weeks after the start of chemotherapy; just before his death, the level of KL-6 was 2417 U/ml.
There is only one published report on pemetrexed-induced lung injury, but that was very mild and easily treated by corticosteroids.2 In both our cases, none of the examinations revealed evidence of embolic, tumor-related, cardiac, or infectious causes. Moreover both patients’ serum levels of KL-6 were increased remarkably. KL-6 is a high molecular weight, mucin-like glycoprotein classified as human MUC1 mucin. Serum levels of KL-6 are increased in patients with interstitial lung diseases including drug-induced pneumonitis but not in patients with bacterial pneumonia or normal control subjects.3 In both patients, there were no “candidates” that could have induced the acute interstitial pneumonitis other than the chemotherapy
Journal of Thoracic Oncology • Volume 5, Number 10, October 2010
Journal of Thoracic Oncology • Volume 5, Number 10, October 2010
drugs; neither patient had used any new drug other than the chemotherapy agents. It has been reported that platinum rarely causes acute lung injury4; so we, therefore, concluded that pemetrexed was the offender in both cases. Several risk factors have been identified regarding gefitinib; smoking habit, male sex, coexistence of interstitial pneumonia, early onset of disease, and poor performance status.5 In both our cases, many of these risk factors were found. Because the role of pemetrexed in the treatment of solid tumors continues to expand, clinicians must be aware of this possible severe pulmonary complication during the management of patients with treatment regimens that include pemetrexed. Kazuma Nagata, MD Reiko Kaji, MD Keisuke Tomii, MD Department of Respiratory Medicine Kobe City Medical Center General Hospital Chuo-ku, Kobe, Japan
REFERENCES 1. Scagliotti GV, Shin DM, Kindler HL, et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 2003;21:1556 –1561. 2. Kim HO, Lee SY, Shim JJ, et al. A case of pemetrexed-induced acute lung injury in non-small cell lung cancer. J Thorac Oncol 2010;5:401–402. 3. Ohnishi H, Yokoyama A, Yasuhara Y, et al. Circulating KL-6 levels in patients with drug induced pneumonitis. Thorax 2003;58:872–875. 4. Krauss S, Sonoda T, Solomon A. Treatment of advanced gastrointestinal cancer with 5-fluorouracil and mitomycin C. Cancer 1979;43:1598–1603. 5. Seto T, Seki N, Uematsu K, et al. Gefitinibinduced lung injury successfully treated with high-dose corticosteroids. Respirology 2006;11:113–116.
Evaluation of Kras Gene Mutation and Copy Number in Thymic Carcinomas and Thymomas To the Editor: Compared with the more common epithelial cancers, current knowledge about the biology of thymic epithelial tumors is limited. Research has been hampered by the rarity of the tumor and
Letters to the Editor
FIGURE 1. The data for Kras gene using direct sequencing. Left, A heterozygous G to T substitution at nucleotide position 35 in exon 1 of Kras, resulting in a valine for glycine amino acid substitution at position 12 (G12V). Right, Reverse sequencing.
the lack of established cell lines and animal models. Ras family plays important roles in the regulatory processes of proliferation, differentiation, and apoptosis. A recent Caucasian report demonstrated that 1 of 38 thymoma and 1 of 7 thymic carcinoma had Kras mutations.1 Because we previously reported the EGFR copy number2 and Kras mutation3 status using quantitative polymerase chain reaction (PCR) assay in non-small cell lung cancer, we evaluated the Kras gene mutation status and Kras gene amplification, which may bring important information for the surgically treated Japanese thymic epithelial tumor patients. Thymic epithelial tumor tissues were obtained by surgical excision from 125 patients (107 thymomas and 18 thymic cancers). Kras mutation status at codon 12,13 mutation was analyzed by quantitative real-time PCR performed using LightCycler.3 Positive sample and some of the negative samples from melting analysis were directly sequenced. Using the LightCycler genotyping PCR assay, only one thymic carcinoma case was detected to have a Kras mutation. A heterozygous G to T substitution at nucleoDisclosure: The authors declare no conflicts of interest. Address for correspondence: Hidefumi Sasaki, MD, PhD, Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. E-mail: [email protected] Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0510-1715
Copyright © 2010 by the International Association for the Study of Lung Cancer
tide position 35 in exon 1 of Kras, resulting in a valine for glycine amino acid substitution at position 12 (G12V) (Figure 1). This patient was a 38-year-old woman with adenocarcinoma. She is a never smoker and had stage IVb cancer with lung metastasis. EGFR mutations were evaluated for 105 thymomas and 11 thymic carcinomas using LightCycler genotyping assay.4 However, no mutation was found within the cohort. In lung cancers, Kras mutation rate was lower in Japanese when compared with Caucasian.3 The difference between the previously published study1 and ours might be caused by the difference in ethnicity: Caucasian or Oriental. Characteristically, 70% of Kras mutations are G to T transversions,5 molecular events that are linked to exposure to tobacco smoke carcinogenesis. A previous report also showed that the mutation case from thymic carcinoma was a heterozygous G to T transversion at nucleotide position 35 in exon 1 of Kras.1 Although, in our case, the patient was a nonsmoker, other mechanisms such as passive tobacco smoking might be involved. Kras copy number was analyzed for 13 thymic cancer and 19 advanced thymoma patients by quantitative realtime PCR performed on 7500 Real Time PCR System (Applied Biosystems) by using a QuantiTect SYBR Green Kit (Qiagen, Inc., Valencia, CA).2 Only one of the 13 thymic cancer case was found to have increased Kras copy number (⬎3.0). This patient was a 76-year-old man with squamous cell carcinoma. He had stage IVb cancer with lymph node
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TO THE
EDITOR
Fatal PemetrexedInduced Lung Injury in Patients with Advanced Mesothelioma A Report of Two Cases To the Editor: Pemetrexed is an antifolate chemotherapy agent that is active in multiple tumor types including malignant mesothelioma.1 Adverse drug reactions are mild, and there have been no previous reports that pemetrexed induces fatal acute lung injury. We encountered two patients who had been given pemetrexed and developed a fatal lung injury. The first case was a 71-year-old man admitted to our hospital for evaluation of chest pain and diagnosed as sarcomatous malignant pleural mesothelioma. The patient received chemotherapy with cisplatin (60 mg/m2) and pemetrexed (500 mg/m2). However, 4 weeks after initiation of the treatment, he was dyspneic. A chest computed tomography scan demonstrated diffuse ground-glass opacities in his right lung (Figure 1). The patient’s white blood cell count was 14,800/mm3, C-reactive protein was 12.7 mg/dl, and KL-6 was 2700 U/ml (normal range: ⬍500 U/ml). No infectious, tumor-related, embolic, or cardiac causes were found after extensive workup. The patient’s clinical state deteriorated, and methylprednisolone was started at 500 mg/d. Despite the treatment, his respiratory status worsened, and he died 7 weeks after initiation of the chemotherapy. The second case was a 77-year-old man referred to our hospital for evaluation of dyspnea and diagnosed as biphasic-type malignant pleural mesothelioma. The patient received chemotherapy with carboplatin (area under the curve ⫽ 4) and Disclosure: The authors declare no conflicts of interest. Address for correspondence: Kazuma Nagata, MD, Department of Respiratory Medicine, Kobe City Medical Center General Hospital, 4-6 Minatojima-nakamachi, Chuo-ku, Kobe 650-0046, Japan. E-mail: kazuma_n1101@ yahoo.co.jp Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0510-1714
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FIGURE 1. Computed tomography scan of the chest demonstrated diffuse ground-glass opacities in the right lung.
FIGURE 2. Computed tomography scan of the chest revealed ground-glass opacities in the left lower lobe.
pemetrexed (500 mg/m2). Three weeks after the start of the treatment, he presented with progressive exertional dyspnea. His chest computed tomography scan demonstrated ground-glass opacities in his left lower lobe (Figure 2). The patient’s white blood cell count was 16,900/mm3, C-reactive protein was 9.2 mg/dl, and KL-6 was 1236 U/ml. There were no infectious, embolic, tumor-related, or cardiac causes found after extensive workup. High-dose corticosteroid treatment was started at 500 mg/d of methylprednisolone. However, his respiratory status worsened, and he died 5 weeks after the start of chemotherapy; just before his death, the level of KL-6 was 2417 U/ml.
There is only one published report on pemetrexed-induced lung injury, but that was very mild and easily treated by corticosteroids.2 In both our cases, none of the examinations revealed evidence of embolic, tumor-related, cardiac, or infectious causes. Moreover both patients’ serum levels of KL-6 were increased remarkably. KL-6 is a high molecular weight, mucin-like glycoprotein classified as human MUC1 mucin. Serum levels of KL-6 are increased in patients with interstitial lung diseases including drug-induced pneumonitis but not in patients with bacterial pneumonia or normal control subjects.3 In both patients, there were no “candidates” that could have induced the acute interstitial pneumonitis other than the chemotherapy
Journal of Thoracic Oncology • Volume 5, Number 10, October 2010
Journal of Thoracic Oncology • Volume 5, Number 10, October 2010
drugs; neither patient had used any new drug other than the chemotherapy agents. It has been reported that platinum rarely causes acute lung injury4; so we, therefore, concluded that pemetrexed was the offender in both cases. Several risk factors have been identified regarding gefitinib; smoking habit, male sex, coexistence of interstitial pneumonia, early onset of disease, and poor performance status.5 In both our cases, many of these risk factors were found. Because the role of pemetrexed in the treatment of solid tumors continues to expand, clinicians must be aware of this possible severe pulmonary complication during the management of patients with treatment regimens that include pemetrexed. Kazuma Nagata, MD Reiko Kaji, MD Keisuke Tomii, MD Department of Respiratory Medicine Kobe City Medical Center General Hospital Chuo-ku, Kobe, Japan
REFERENCES 1. Scagliotti GV, Shin DM, Kindler HL, et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 2003;21:1556 –1561. 2. Kim HO, Lee SY, Shim JJ, et al. A case of pemetrexed-induced acute lung injury in non-small cell lung cancer. J Thorac Oncol 2010;5:401–402. 3. Ohnishi H, Yokoyama A, Yasuhara Y, et al. Circulating KL-6 levels in patients with drug induced pneumonitis. Thorax 2003;58:872–875. 4. Krauss S, Sonoda T, Solomon A. Treatment of advanced gastrointestinal cancer with 5-fluorouracil and mitomycin C. Cancer 1979;43:1598–1603. 5. Seto T, Seki N, Uematsu K, et al. Gefitinibinduced lung injury successfully treated with high-dose corticosteroids. Respirology 2006;11:113–116.
Evaluation of Kras Gene Mutation and Copy Number in Thymic Carcinomas and Thymomas To the Editor: Compared with the more common epithelial cancers, current knowledge about the biology of thymic epithelial tumors is limited. Research has been hampered by the rarity of the tumor and
Letters to the Editor
FIGURE 1. The data for Kras gene using direct sequencing. Left, A heterozygous G to T substitution at nucleotide position 35 in exon 1 of Kras, resulting in a valine for glycine amino acid substitution at position 12 (G12V). Right, Reverse sequencing.
the lack of established cell lines and animal models. Ras family plays important roles in the regulatory processes of proliferation, differentiation, and apoptosis. A recent Caucasian report demonstrated that 1 of 38 thymoma and 1 of 7 thymic carcinoma had Kras mutations.1 Because we previously reported the EGFR copy number2 and Kras mutation3 status using quantitative polymerase chain reaction (PCR) assay in non-small cell lung cancer, we evaluated the Kras gene mutation status and Kras gene amplification, which may bring important information for the surgically treated Japanese thymic epithelial tumor patients. Thymic epithelial tumor tissues were obtained by surgical excision from 125 patients (107 thymomas and 18 thymic cancers). Kras mutation status at codon 12,13 mutation was analyzed by quantitative real-time PCR performed using LightCycler.3 Positive sample and some of the negative samples from melting analysis were directly sequenced. Using the LightCycler genotyping PCR assay, only one thymic carcinoma case was detected to have a Kras mutation. A heterozygous G to T substitution at nucleoDisclosure: The authors declare no conflicts of interest. Address for correspondence: Hidefumi Sasaki, MD, PhD, Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. E-mail: [email protected] Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0510-1715
Copyright © 2010 by the International Association for the Study of Lung Cancer
tide position 35 in exon 1 of Kras, resulting in a valine for glycine amino acid substitution at position 12 (G12V) (Figure 1). This patient was a 38-year-old woman with adenocarcinoma. She is a never smoker and had stage IVb cancer with lung metastasis. EGFR mutations were evaluated for 105 thymomas and 11 thymic carcinomas using LightCycler genotyping assay.4 However, no mutation was found within the cohort. In lung cancers, Kras mutation rate was lower in Japanese when compared with Caucasian.3 The difference between the previously published study1 and ours might be caused by the difference in ethnicity: Caucasian or Oriental. Characteristically, 70% of Kras mutations are G to T transversions,5 molecular events that are linked to exposure to tobacco smoke carcinogenesis. A previous report also showed that the mutation case from thymic carcinoma was a heterozygous G to T transversion at nucleotide position 35 in exon 1 of Kras.1 Although, in our case, the patient was a nonsmoker, other mechanisms such as passive tobacco smoking might be involved. Kras copy number was analyzed for 13 thymic cancer and 19 advanced thymoma patients by quantitative realtime PCR performed on 7500 Real Time PCR System (Applied Biosystems) by using a QuantiTect SYBR Green Kit (Qiagen, Inc., Valencia, CA).2 Only one of the 13 thymic cancer case was found to have increased Kras copy number (⬎3.0). This patient was a 76-year-old man with squamous cell carcinoma. He had stage IVb cancer with lymph node
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