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ABSTRACT: Small-molecule tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) pathways are used clinically for patients with non-small cell lung cancer (NSCLC). It is well established that somatic mutations in the kinase domain of the EGFR (Lynch et al. in N Engl J Med 350:2129-2139, 2004; Paez et al. in Science 304:1497-1500, 2004) are strongly associated with the tumor response and clinical outcomes in patients with NSCLC receiving EGFR-TKIs (Mitsudomi and Yatabe in Cancer Sci 98:1817-1824, 2007). Although the most common adverse events are skin rash and diarrhea, the most serious adverse effect reported is drug-related interstitial lung disease (ILD) (Inoue et al. in Lancet 361:137-139, 2003; Ando et al. in J Clin Oncol 24:2549-2556, 2006). The precise mechanism underlying the development of drug-related ILD remains unknown. Here, we describe a case of EGFR-mutant NSCLC who was rechallenged with the small-molecule EGFR antagonist erlotinib after developing gefitinib-related ILD.
Cancer Chemotherapy and Pharmacology 03/2010; 65(4):803-6. · 2.83 Impact Factor
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Susumu Arai,
Hisashi Mitsufuji, Yasuto Nishii,
Sayaka Onoda,
Shinichiro Ryuge,
Mayuko Wada,
Ken Katono,
Maiko Iwasaki,
Akira Takakura,
Sakiko Otani,
Michiko Yamamoto,
Tomoko Yanaihara,
Masanori Yokoba,
Masaru Kubota,
Masato Katagiri,
Tomoya Fukui,
Hirosuke Kobayashi,
Nobuo Yanase,
Ryuji Hataishi,
Noriyuki Masuda
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ABSTRACT: Despite the literature indicating adverse interactions between warfarin and cytotoxic agents, whether such an interaction occurs when warfarin and gefitinib are used concomitantly is unknown. We analyzed the prevalence of the concomitant use of warfarin and gefitinib, and the incidence of prothrombin time-international normalized ratio (PT-INR) alterations or adverse interactions in concomitant users of warfarin and gefitinib.
We conducted a retrospective study of patients with non-small cell lung cancer treated at the Kitasato University Hospital who received concomitant warfarin and gefitinib between September 2002 and January 2007. Medical information, including the indication for warfarin use, warfarin dosing and dosing changes, and exposure to gefitinib were collected from computerized databases and medical records.
Twelve (4.1%) of 296 patients treated with gefitinib received warfarin. PT-INR elevation occurred in 6 patients (50.0%). Two (16.7%) of the 12 patients had liver metastases. Liver dysfunction was associated with PT-INR elevation (P = 0.0100).
As there is a possibility of PT-INR abnormalities occurring during the concomitant use of gefitinib and warfarin, clinicians should be aware of this interaction. Because of the potentially severe consequences of this interaction, close monitoring of PT-INR and warfarin dose adjustment are recommended for patients receiving warfarin and gefitinib, especially during the first 2 weeks in the beginning of warfarin therapy.
International Journal of Clinical Oncology 09/2009; 14(4):332-6. · 1.41 Impact Factor
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Michiko Yamamoto,
Akinobu Kurita,
Takashi Asahara,
Akira Takakura,
Ken Katono,
Maiko Iwasaki,
Shinichiro Ryuge,
Mayuko Wada,
Sayaka Onoda,
Tomoko Yanaihara,
Masanori Yokoba,
Hisashi Mitsufuji, Yasuto Nishii,
Tomoya Fukui,
Noriyuki Masuda
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ABSTRACT: One of the dose-limiting toxicities of irinotecan (CPT-11) is delayed-onset diarrhea, which is the greatest barrier to treatment with CPT-11-containing regimens. CPT-11 is converted to its active metabolite, SN-38, which is conjugated by hepatic uridine diphosphate glucuronosyl transferase to SN-38 glucuronide (SN-38G). SN-38G, once excreted in the intestinal lumen via bile, is extensively deconjugated by bacterial beta-glucuronidase with the regeneration of SN-38 in the intestinal lumen, which may cause diarrhea. However, the metabolism of CPT-11 and its metabolites by intestinal microflora are yet to be reported. This study was carried out to investigate the microbial transformation of CPT-11 and SN-38 using an anaerobic mixed culture of rat cecal microorganisms. No reaction in the mixed cultures was observed when CPT-11 or SN-38 lactone was added to the culture medium. When CPT-11 was added to the culture broth, a significant amount of water-soluble CPT-11 was detected in the spent culture medium. In contrast, only a slight amount of SN-38 was found in the supernatant when SN-38 lactone was added to the broth. A significant quantity of SN-38 was found in the sediment. In conclusion, these results strongly suggest that SN-38 produced from SN-38G by the action of bacterial beta-glucuronidase is rapidly adsorbed by the intestinal bacterial cell walls in the sediment because of the hydrophobic and lipophilic nature of SN-38, and a small amount of SN-38 remains in the intestinal luminal fluid. Thus, we need to reconsider the role of SN-38 in the intestinal lumen in CPT-11-induced late-onset diarrhea.
Oncology Reports 11/2008; 20(4):727-30. · 1.84 Impact Factor
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ABSTRACT: A 70-year-old non-obese man with no history of cardiopulmonary disease presented 4 times to the emergency room because of sudden onset of seizure during sleep. Each time he recovered within a few hours without any medication. Nocturnal polysomnographic recording revealed severe obstructive sleep apnea syndrome (OSAS, AHI 52.4/Hr). Nasal continuous positive airway pressure (n-CPAP) therapy was performed with 10cmH2O of pressure. His symptoms of severe daytime sleepiness and seizure were diminished. CPAP was decreased from 10cmH2O to 6 cmH2O later, because the patient complained with its high pressure. He then felt daytime sleepiness and suffered seizures during sleep again, and was re-admitted to our hospital. Chest roentgenogram taken at this admission showed remarkable pulmonary edema. We found that the pulmonary edema was recognized every time on his chest roentgenogram taken when he complained seizure. In addition, subsequesnt roentgenograms also showed that the pulmonary edema was diminished soon. On the other hand, his AHI was high (24.7/hr) even when he was under 6cmH2O of n-CPAP. We concluded that incompletely treated OSAS might lead not only to pulmonary edema, but also to seizures in this patient.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 12/2006; 44(11):812-6.
