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High-Dose Crizotinib for Brain Metastases Refractory to Standard-Dose Crizotinib
Case Report
High-Dose Crizotinib for Brain Metastases Refractory to Standard-Dose Crizotinib Young Hak Kim, MD, Hiroaki Ozasa, MD, Hiroki Nagai, MD, Yuichi Sakamori, MD, Hironori Yoshida, MD, Yoshitaka Yagi, MD, Takashi Nakaoku, MD, and Michiaki Mishima, MD CASE REPORT
DISCUSSION
A 41-year-old man, a former smoker (20 pack-years), was referred to Kyoto University Hospital, Kyoto, Japan, because of an abnormal chest shadow detected at an annual medical checkup. Positron emission tomography revealed multiple metastases to both the liver and bone. A biopsy of the pulmonary nodule demonstrated adenocarcinoma. Combination chemotherapy with pemetrexed and carboplatin was started, but the disease progressed after six cycles of chemotherapy. He then received multilines of chemotherapy, including gemcitabine, bevacizumab, erlotinib, TS-1, and docetaxel. Two years after the start of treatment, he developed multiple brain metastases and received whole-brain radiation therapy. At that time, molecular testing for echinoderm microtubule-associated protein like 4 (EML4)anaplastic lymphoma kinase (ALK) had just become commercially available in Japan, and his tumor demonstrated ALK rearrangement (Fig. 1). Then crizotinib was started at a dose of 250 mg twice daily. Abdominal computed tomography showed a marked decrease in the size of liver metastases, and magnetic resonance imaging of the brain demonstrated improvement of brain metastases; however, regrowth of brain metastases was detected 8 months after the start of crizotinib. Extracranial disease, including liver metastases, was under control with crizotinib. We therefore decided to increase the dose of crizotinib after a thorough discussion. At first, the dose was escalated to 750 mg/d. The dose was then escalated to 1000 mg/d after we confirmed that no new toxicities had occurred. Brain magnetic resonance imaging reassessed 2 weeks after the start of dose escalation demonstrated the striking improvement of multiple brain metastases; however, his brain diseases rapidly progressed after 1 month from the dose escalation (Fig. 2). After the dose escalation, he developed bradycardia without accompanying any symptoms. Pulse rate before and after the dose escalation were 50/minute and 39/minute, respectively.
Although it was reported that crizotinib is effective for brain metastases,1 its penetration into cerebrospinal fluid (CSF) is considered to be poor. Costa et al.2 measured the concentration of crizotinib in both CSF and plasma and reported that the CSF-to-plasma ratio of crizotinib was only 0.0026. Because of this relatively low drug exposure, the brain may be a site susceptible to progression in patients with ALK rearrangement and treated with crizotinib. A similar scenario has been observed also in patients with epidermal growth factor receptor (EGFR) mutation and treated with EGFR tyrosine kinase inhibitors, and the efficacy of high-dose gefitinib was reported in patients with EGFR mutation who developed brain metastases during treatment with a standard dose of gefitinib.3 Recently, Gandhi et al.4 reported a patient who was effectively treated with high-dose pemetrexed and high-dose crizotinib in the same situation; however, the escalated dose of crizotinib was only 100 mg/d, and the efficacy mainly seemed to be the result of pemetrexed. Therefore, we believe that this is the first case in which high-dose crizotinib was used alone for refractory brain metastases that developed during treatment with the standard dose of crizotinib. However, in this case, response duration was quite short and CSF concentration was not measured. In addition, 1000 mg/d of crizotinib is above the maximum tolerated dose. High-dose crizotinib cannot be recommended in routine clinical practice because safety data and efficacy are lacking in a prospective cohort. Further research is required in this setting.
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto, Japan. Disclosure: The authors declare no conflict of interest. Address for correspondence and reprint: Young Hak Kim, MD, PhD, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-Ku, Kyoto 606–8507, Japan. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0809-0e87
REFERENCES 1. Kaneda H, Okamoto I, Nakagawa K. Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer. J Thorac Oncol 2013;8:e32–e33. 2. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29:e443–e445. 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. Gandhi L, Drappatz J, Ramaiya NH, Otterson GA. High-dose pemetrexed in combination with high-dose crizotinib for the treatment of refractory CNS metastases in ALK-rearranged non-small-cell lung cancer. J Thorac Oncol 2013;8:e3–e5.
Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013
e85
Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013
Kim et al.
A
B
FIGURE 1. A, Fluorescent in situ hybridization showed translocation of ALK. B, Immunohistochemistry for ALK protein was strongly positive (3+). ALK, anaplastic lymphoma kinase.
A
B
C
FIGURE 2. Brain magnetic resonance imaging before and after highdose crizotinib treatment. A Before high-dose crizotinib. B, Two weeks after dose escalation. C, One month after dose escalation.
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Copyright © 2013 by the International Association for the Study of Lung Cancer
High-Dose Crizotinib for Brain Metastases Refractory to Standard-Dose Crizotinib Young Hak Kim, MD, Hiroaki Ozasa, MD, Hiroki Nagai, MD, Yuichi Sakamori, MD, Hironori Yoshida, MD, Yoshitaka Yagi, MD, Takashi Nakaoku, MD, and Michiaki Mishima, MD CASE REPORT
DISCUSSION
A 41-year-old man, a former smoker (20 pack-years), was referred to Kyoto University Hospital, Kyoto, Japan, because of an abnormal chest shadow detected at an annual medical checkup. Positron emission tomography revealed multiple metastases to both the liver and bone. A biopsy of the pulmonary nodule demonstrated adenocarcinoma. Combination chemotherapy with pemetrexed and carboplatin was started, but the disease progressed after six cycles of chemotherapy. He then received multilines of chemotherapy, including gemcitabine, bevacizumab, erlotinib, TS-1, and docetaxel. Two years after the start of treatment, he developed multiple brain metastases and received whole-brain radiation therapy. At that time, molecular testing for echinoderm microtubule-associated protein like 4 (EML4)anaplastic lymphoma kinase (ALK) had just become commercially available in Japan, and his tumor demonstrated ALK rearrangement (Fig. 1). Then crizotinib was started at a dose of 250 mg twice daily. Abdominal computed tomography showed a marked decrease in the size of liver metastases, and magnetic resonance imaging of the brain demonstrated improvement of brain metastases; however, regrowth of brain metastases was detected 8 months after the start of crizotinib. Extracranial disease, including liver metastases, was under control with crizotinib. We therefore decided to increase the dose of crizotinib after a thorough discussion. At first, the dose was escalated to 750 mg/d. The dose was then escalated to 1000 mg/d after we confirmed that no new toxicities had occurred. Brain magnetic resonance imaging reassessed 2 weeks after the start of dose escalation demonstrated the striking improvement of multiple brain metastases; however, his brain diseases rapidly progressed after 1 month from the dose escalation (Fig. 2). After the dose escalation, he developed bradycardia without accompanying any symptoms. Pulse rate before and after the dose escalation were 50/minute and 39/minute, respectively.
Although it was reported that crizotinib is effective for brain metastases,1 its penetration into cerebrospinal fluid (CSF) is considered to be poor. Costa et al.2 measured the concentration of crizotinib in both CSF and plasma and reported that the CSF-to-plasma ratio of crizotinib was only 0.0026. Because of this relatively low drug exposure, the brain may be a site susceptible to progression in patients with ALK rearrangement and treated with crizotinib. A similar scenario has been observed also in patients with epidermal growth factor receptor (EGFR) mutation and treated with EGFR tyrosine kinase inhibitors, and the efficacy of high-dose gefitinib was reported in patients with EGFR mutation who developed brain metastases during treatment with a standard dose of gefitinib.3 Recently, Gandhi et al.4 reported a patient who was effectively treated with high-dose pemetrexed and high-dose crizotinib in the same situation; however, the escalated dose of crizotinib was only 100 mg/d, and the efficacy mainly seemed to be the result of pemetrexed. Therefore, we believe that this is the first case in which high-dose crizotinib was used alone for refractory brain metastases that developed during treatment with the standard dose of crizotinib. However, in this case, response duration was quite short and CSF concentration was not measured. In addition, 1000 mg/d of crizotinib is above the maximum tolerated dose. High-dose crizotinib cannot be recommended in routine clinical practice because safety data and efficacy are lacking in a prospective cohort. Further research is required in this setting.
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Sakyo-Ku, Kyoto, Japan. Disclosure: The authors declare no conflict of interest. Address for correspondence and reprint: Young Hak Kim, MD, PhD, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-Ku, Kyoto 606–8507, Japan. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0809-0e87
REFERENCES 1. Kaneda H, Okamoto I, Nakagawa K. Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer. J Thorac Oncol 2013;8:e32–e33. 2. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29:e443–e445. 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. Gandhi L, Drappatz J, Ramaiya NH, Otterson GA. High-dose pemetrexed in combination with high-dose crizotinib for the treatment of refractory CNS metastases in ALK-rearranged non-small-cell lung cancer. J Thorac Oncol 2013;8:e3–e5.
Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013
e85
Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013
Kim et al.
A
B
FIGURE 1. A, Fluorescent in situ hybridization showed translocation of ALK. B, Immunohistochemistry for ALK protein was strongly positive (3+). ALK, anaplastic lymphoma kinase.
A
B
C
FIGURE 2. Brain magnetic resonance imaging before and after highdose crizotinib treatment. A Before high-dose crizotinib. B, Two weeks after dose escalation. C, One month after dose escalation.
e86
Copyright © 2013 by the International Association for the Study of Lung Cancer