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Crizotinib-induced esophageal ulceration: A novel adverse event of crizotinib
Lung Cancer 81 (2013) 495–496
Contents lists available at SciVerse ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Crizotinib-induced esophageal ulceration: A novel adverse event of crizotinib Jangchul Park a , Kimihide Yoshida a , Chiaki Kondo a , Junichi Shimizu a , Yoshitsugu Horio a , Susumu Hijioka b , Toyoaki Hida a,∗ a b
Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
a r t i c l e
i n f o
Article history: Received 26 April 2013 Received in revised form 21 June 2013 Accepted 25 June 2013
a b s t r a c t This report describes esophageal ulcer as a novel adverse event associated with crizotinib therapy. Although crizotinib is generally well tolerated, physicians should be aware of the possibility of this adverse event. © 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Non-small-cell lung cancer Anaplastic lymphoma kinase Crizotinib Ulceration Inhibitor Adverse event
1. Introduction Crizotinib, an orally active anaplastic lymphoma kinase (ALK) inhibitor, has shown marked anti-tumor activity in patients with ALK-rearranged non-small-cell lung cancer (NSCLC) [1]. Phase I, II and III studies have shown that crizotinib is well tolerated, with mild, primarily grade 1 adverse events, including visual disturbance, nausea/vomiting, diarrhea, constipation, fatigue and peripheral edema. We report the first direct evidence of novel esophageal ulcer as an adverse event associated with crizotinib. This finding may improve the management of patients receiving crizotinib. 2. Case presentation 2.1. Case one A 35-year-old woman with advanced ALK-positive NSCLC was started on treatment with crizotinib (one 250-mg capsule, twice daily). After 3 months, she reported retrosternal pain aggravated by oral intake. Upper endoscopy showed circumferential ulceration with white coating and relatively normal surrounding mucosa in the mid-esophagus (Fig. 1a). Crizotinib was discontinued, and rabeprazole (20 mg/day) was started. Histopathological
∗ Corresponding author. Tel.: +81 52 762 6111; fax: +81 52 764 2963. E-mail address: [email protected] (T. Hida). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.06.017
examination of the ulcer edge showed only acute inflammatory changes. Symptoms decreased within 1 week, and repeat endoscopy 4 weeks later showed no ulcer (Fig. 1b). The patient was restarted on one crizotinib 250-mg capsule twice daily with adequate liquid intake ingested in a standing position and has since developed no esophageal ulceration. 2.2. Case two A 36-year-old woman with advanced ALK-positive NSCLC was started on treatment with crizotinib (one 250-mg capsule, twice daily). Due to grade 3 liver dysfunction, the treatment dose was reduced to one 200-mg capsule twice daily. Two months later, the patient reported severe dysphagia and retrosternal pain, and upper endoscopy showed ulceration with a thick white coating in the mid-esophagus (Fig. 2a). Crizotinib was discontinued, and oral lansoprazole (30 mg/day) was started. Repeat endoscopy 2 weeks later showed only an esophageal ulcer scar (Fig. 2b). The patient was restarted on crizotinib one 200-mg capsule twice daily with adequate liquid intake, ingested in a standing position and has since developed no esophageal ulceration. 3. Discussion NSCLCs harboring translocations in the ALK gene have demonstrated marked sensitivity to the ALK kinase inhibitor crizotinib [1]. Crizotinib is the first clinically available ALK-TKI and competes
496
J. Park et al. / Lung Cancer 81 (2013) 495–496
Fig. 1. Endoscopic view of the esophageal lesion. (a) Circumferential ulceration of the mid-esophagus and (b) esophageal ulceration has disappeared.
Fig. 2. Endoscopic view of the esophageal lesion. (a) Ulceration of the esophagus and (b) esophageal ulceration has disappeared (only ulcer scar remains).
with ATP for binding to the tyrosine kinase pocket of the enzyme, inhibiting tyrosine phosphorylation of activated ALK at nanomolar concentrations. Safety data from the expansion cohort of a phase 1 study of crizotinib suggest this drug is well tolerated, with side effects including grade 1/2 nausea (54%), diarrhea (48%), visual disturbance (41%), constipation (24%), dizziness (15%) and fatigue (10%) [2]. As far as we are aware, the patients reported here represent the first reported examples of crizotinib-associated esophageal ulcer. The clinical presentation of patients with drug-induced esophageal ulcer usually involves retrosternal pain or heartburn, odynophagia, and dysphagia. A great variety of drugs, such as antiinflammatory analgesics, doxycycline, tetracycline, clindamycin, rifampin, ascorbic acid, theophylline, warfarin and phenytoin, are associated with esophageal injuries. The injury occurs at the anatomical sites of narrowing of the esophagus or at sites of pathological narrowing. The most common site of injury has been near the level of the aortic arch, an area characterized by external compression from the arch and by a physiological reduction in the amplitude of the esophageal peristaltic wave. Generally, the risk of drug-induced esophageal ulcer increases with inadequate liquid intake or when taking the drug in a recumbent position [3]. In both patients, the crizotinib capsule was ingested with a small quantity of water while the patient was in a recumbent position, and could have caused direct esophageal mucosal injury. In addition, a lightweight capsule like crizotinib [weight, 596 mg (crizotinib, 250 mg) or 476 mg (crizotinib, 200 mg), density <1] is associated with delayed esophageal transit time when compared with a heavy capsule, and the pill may more easily
become trapped and adhere to the esophageal membrane [4]. The most important aspect of therapy is to make the correct diagnosis and then to avoid reinjury with the drug, because the prevention of esophageal ulcer is the best treatment for this disease. Our cases suggest that the amount of water and the combination of subject position and the shape and size of the capsules are important. Crizotinib is the only clinically available ALK inhibitor, and physicians should be aware of this potential adverse effect. Conflict of interest statement We declare that we have no conflicts of interest. Acknowledgements This study was supported by National Cancer Center Research and Development Funds (23-A-18) and Health and Labour Sciences Research Grants for Clinical Research for Evidence-Based Medicine from the Ministry of Health, Labour, and Welfare of Japan. References [1] Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693–703. [2] Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011–9. [3] Zografos GN, Georgiadou D, Thomas D, et al. Drug-induced esophagitis. Dis Esophagus 2009;22:633–7. [4] Hey H, Jorgensen F, Sorensen K, et al. Oesophageal transit of six commonly used tablets and capsules. Br Med J 1982;285:1717–9.
Contents lists available at SciVerse ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Crizotinib-induced esophageal ulceration: A novel adverse event of crizotinib Jangchul Park a , Kimihide Yoshida a , Chiaki Kondo a , Junichi Shimizu a , Yoshitsugu Horio a , Susumu Hijioka b , Toyoaki Hida a,∗ a b
Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
a r t i c l e
i n f o
Article history: Received 26 April 2013 Received in revised form 21 June 2013 Accepted 25 June 2013
a b s t r a c t This report describes esophageal ulcer as a novel adverse event associated with crizotinib therapy. Although crizotinib is generally well tolerated, physicians should be aware of the possibility of this adverse event. © 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Non-small-cell lung cancer Anaplastic lymphoma kinase Crizotinib Ulceration Inhibitor Adverse event
1. Introduction Crizotinib, an orally active anaplastic lymphoma kinase (ALK) inhibitor, has shown marked anti-tumor activity in patients with ALK-rearranged non-small-cell lung cancer (NSCLC) [1]. Phase I, II and III studies have shown that crizotinib is well tolerated, with mild, primarily grade 1 adverse events, including visual disturbance, nausea/vomiting, diarrhea, constipation, fatigue and peripheral edema. We report the first direct evidence of novel esophageal ulcer as an adverse event associated with crizotinib. This finding may improve the management of patients receiving crizotinib. 2. Case presentation 2.1. Case one A 35-year-old woman with advanced ALK-positive NSCLC was started on treatment with crizotinib (one 250-mg capsule, twice daily). After 3 months, she reported retrosternal pain aggravated by oral intake. Upper endoscopy showed circumferential ulceration with white coating and relatively normal surrounding mucosa in the mid-esophagus (Fig. 1a). Crizotinib was discontinued, and rabeprazole (20 mg/day) was started. Histopathological
∗ Corresponding author. Tel.: +81 52 762 6111; fax: +81 52 764 2963. E-mail address: [email protected] (T. Hida). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.06.017
examination of the ulcer edge showed only acute inflammatory changes. Symptoms decreased within 1 week, and repeat endoscopy 4 weeks later showed no ulcer (Fig. 1b). The patient was restarted on one crizotinib 250-mg capsule twice daily with adequate liquid intake ingested in a standing position and has since developed no esophageal ulceration. 2.2. Case two A 36-year-old woman with advanced ALK-positive NSCLC was started on treatment with crizotinib (one 250-mg capsule, twice daily). Due to grade 3 liver dysfunction, the treatment dose was reduced to one 200-mg capsule twice daily. Two months later, the patient reported severe dysphagia and retrosternal pain, and upper endoscopy showed ulceration with a thick white coating in the mid-esophagus (Fig. 2a). Crizotinib was discontinued, and oral lansoprazole (30 mg/day) was started. Repeat endoscopy 2 weeks later showed only an esophageal ulcer scar (Fig. 2b). The patient was restarted on crizotinib one 200-mg capsule twice daily with adequate liquid intake, ingested in a standing position and has since developed no esophageal ulceration. 3. Discussion NSCLCs harboring translocations in the ALK gene have demonstrated marked sensitivity to the ALK kinase inhibitor crizotinib [1]. Crizotinib is the first clinically available ALK-TKI and competes
496
J. Park et al. / Lung Cancer 81 (2013) 495–496
Fig. 1. Endoscopic view of the esophageal lesion. (a) Circumferential ulceration of the mid-esophagus and (b) esophageal ulceration has disappeared.
Fig. 2. Endoscopic view of the esophageal lesion. (a) Ulceration of the esophagus and (b) esophageal ulceration has disappeared (only ulcer scar remains).
with ATP for binding to the tyrosine kinase pocket of the enzyme, inhibiting tyrosine phosphorylation of activated ALK at nanomolar concentrations. Safety data from the expansion cohort of a phase 1 study of crizotinib suggest this drug is well tolerated, with side effects including grade 1/2 nausea (54%), diarrhea (48%), visual disturbance (41%), constipation (24%), dizziness (15%) and fatigue (10%) [2]. As far as we are aware, the patients reported here represent the first reported examples of crizotinib-associated esophageal ulcer. The clinical presentation of patients with drug-induced esophageal ulcer usually involves retrosternal pain or heartburn, odynophagia, and dysphagia. A great variety of drugs, such as antiinflammatory analgesics, doxycycline, tetracycline, clindamycin, rifampin, ascorbic acid, theophylline, warfarin and phenytoin, are associated with esophageal injuries. The injury occurs at the anatomical sites of narrowing of the esophagus or at sites of pathological narrowing. The most common site of injury has been near the level of the aortic arch, an area characterized by external compression from the arch and by a physiological reduction in the amplitude of the esophageal peristaltic wave. Generally, the risk of drug-induced esophageal ulcer increases with inadequate liquid intake or when taking the drug in a recumbent position [3]. In both patients, the crizotinib capsule was ingested with a small quantity of water while the patient was in a recumbent position, and could have caused direct esophageal mucosal injury. In addition, a lightweight capsule like crizotinib [weight, 596 mg (crizotinib, 250 mg) or 476 mg (crizotinib, 200 mg), density <1] is associated with delayed esophageal transit time when compared with a heavy capsule, and the pill may more easily
become trapped and adhere to the esophageal membrane [4]. The most important aspect of therapy is to make the correct diagnosis and then to avoid reinjury with the drug, because the prevention of esophageal ulcer is the best treatment for this disease. Our cases suggest that the amount of water and the combination of subject position and the shape and size of the capsules are important. Crizotinib is the only clinically available ALK inhibitor, and physicians should be aware of this potential adverse effect. Conflict of interest statement We declare that we have no conflicts of interest. Acknowledgements This study was supported by National Cancer Center Research and Development Funds (23-A-18) and Health and Labour Sciences Research Grants for Clinical Research for Evidence-Based Medicine from the Ministry of Health, Labour, and Welfare of Japan. References [1] Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693–703. [2] Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011–9. [3] Zografos GN, Georgiadou D, Thomas D, et al. Drug-induced esophagitis. Dis Esophagus 2009;22:633–7. [4] Hey H, Jorgensen F, Sorensen K, et al. Oesophageal transit of six commonly used tablets and capsules. Br Med J 1982;285:1717–9.