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Kanako Umekawa,
Tatsuo Kimura,
Shinzoh Kudoh,
Tomohiro Suzumura,
Takako Oka,
Misato Nagata,
Shigeki Mitsuoka,
Kuniomi Matsuura,
Toshiyuki Nakai,
Naruo Yoshimura,
Yukimi Kira,
Kazuto Hirata
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ABSTRACT: BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), routinely used to treat advanced non-small-cell lung cancer (NSCLC) patients with activated EGFR mutations, are associated with excellent response and improved performance status. Recently, pro-inflammatory cytokines, such as regulated upon activation normal T cell expressed and secreted (RANTES), interleukin (IL)-10 and IL-8 have been proposed as mediators of cancer development. EGFR-TKIs have been found to affect this network of pro-inflammatory cytokines. METHODS: EGFR-TKIs (erlotinib, 150 mg/day; and gefitinib, 250 mg/day) were administered once per day. Treatment was continued until disease progressed or the patient developed intolerable symptoms of toxicity, or withdrew his/her consent for study participation. The treatment was a part of standard care. We investigated the correlation between plasma pro-inflammatory cytokines (including plasma RANTES, IL-10, and IL-8) levels and clinical outcomes following EGFR-TKI treatment in lung cancer patients. Pro-inflammatory cytokine levels were evaluated at diagnosis and on treatment day 30 after the first administration of EGFR-TKIs. RESULTS: Overall, 33 patients were enrolled. Plasma pro-inflammatory cytokine levels were determined for all patients at diagnosis. Plasma samples from 26 patients were obtained on treatment day 30. High level of RANTES at diagnosis was associated with severe general fatigue (P = .026). Low level of RANTES at diagnosis was significantly associated with long-term survival (P = .0032). Percent decrease change of IL-10 was associated with severity of rash (P = .037). The plasma IL-8 level on treatment day 30 (median, 5.48 pg/mL; range, 0.49--26.13 pg/mL) was significantly lower than the level at diagnosis (median 10.45 pg/mL; 3.04--54.86 pg/mL; P = .021). CONCLUSIONS: These results suggest that EGFR-TKIs may suppress systemic inflammation and promote tumor shrinkage. The network of pro-inflammatory cytokines was affected by EGFR-TKI treatment for NSCLC. In addition, the clinical outcomes of EGFR-TKI treatment were influenced by the status of the plasma pro-inflammatory cytokines at diagnosis.
BMC Research Notes 04/2013; 6(1):139.
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Misato Nagata,
Tatsuo Kimura,
Tomohiro Suzumura,
Yukimi Kira,
Toshiyuki Nakai, Kanako Umekawa,
Hidenori Tanaka,
Kuniomi Matsuura,
Shigeki Mitsuoka,
Naruo Yoshimura,
Takako Oka,
Shinzoh Kudoh,
Kazuto Hirata
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ABSTRACT: Amrubicin hydrochloride (AMR) is a key agent for lung cancer. NADPH quinone oxidoreductase 1 (NQO1) metabolizes the quinone structures contained in both amrubicin (AMR) and amrubicinol (AMR-OH). We hypothesized that 1 C609T polymorphism may affect AMR-related pharmacokinetics and clinical outcomes.
Patients received AMR doses of 30 or 40 mg/m/day on days 1-3. Plasma sampling was performed 24 hours after the first and third AMR injections. Concentrations of AMR and AMR-OH were determined by HPLC and the 1 C609T polymorphism was assayed by RT-PCR.
A total of 35 patients were enrolled. At a dose of 40 mg/m, the T/T genotype exhibited a tendency toward a relationship with decrease concentrations of AMR-OH on days 2 and 4. The genotype also showed a significant decrease of hematological toxicities ( < 0.05).
1 C609T polymorphism had a tendency of correlation with the plasma concentrations of AMR-OH, and thereby had significant correlations with hematologic toxicities.
Clinical Medicine Insights: Oncology 01/2013; 7:31-9.
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Tomohiro Suzumura,
Tatsuo Kimura,
Shinzoh Kudoh, Kanako Umekawa,
Misato Nagata,
Kuniomi Matsuura,
Hidenori Tanaka,
Shigeki Mitsuoka,
Naruo Yoshimura,
Yukimi Kira,
Toshiyuki Nakai,
Kazuto Hirata
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ABSTRACT: BACKGROUND: Rash, liver dysfunction, and diarrhea are known major adverse events associated with erlotinib and gefitinib. However, clinical trials with gefitinib have reported different proportions of adverse events compared to trials with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib but not erlotinib. It has been hypothesized that CYP2D6 phenotypes may be implicated in different adverse events associated with gefitinib and erlotinib therapies. METHODS: The frequency of each adverse event was evaluated during the period in which the patients received gefitinib or erlotinib therapy. CYP2D6 phenotypes were determined by analysis of CYP2D6 genotypes using real-time polymerase chain reaction techniques, which can detect single-nucleotide polymorphisms. The CYP2D6 phenotypes were categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of the adverse events associated with each factor, including CYP2D6 activities and treatment types. RESULTS: A total of 232 patients received gefitinib therapy, and 86 received erlotinib therapy. Reduced function of CYP2D6 was associated with an increased risk of rash of grade 2 or more (OR, 0.44; 95% confidence interval [CI], 0.21--0.94; *p = 0.03), but not diarrhea >= grade 2 (OR, 0.49; 95% CI, 0.17--1.51; *p = 0.20) or liver dysfunction >= grade 2 (OR, 1.08; 95% CI, 0.52--2.34; *p = 0.84) in the gefitinib cohort. No associations were observed between any adverse events in the erlotinib cohort and CYP2D6 phenotypes (rash: OR, 1.77; 95% CI, 0.54--6.41; *p = 0.35/diarrhea: OR, 1.08; 95% CI, 0.21--7.43; *p = 0.93/liver dysfunction: OR, 0.93; 95% CI, 0.20--5.07; *p = 0.93). CONCLUSIONS: The frequency of rash was significantly higher in patients with reduced CYP2D6 activity who treated with gefitinib compared to patients with functional CYP2D6. CYP2D6 phenotypes are a risk factor for the development of rash in response to gefitinib therapy.
BMC Cancer 12/2012; 12(1):568. · 3.01 Impact Factor
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ABSTRACT: Rash, liver dysfunction, and diarrhea are known as adverse events of erlotinib and gefitinib. However, clinical trials with gefitinib have reported different adverse events compared to those with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib and not of erlotinib. It has been hypothesized that gefitinib therapy results in different adverse events compared to erlotinib therapy.
The frequency of each adverse event was evaluated in a case-control study on Japanese patients who were treated with gefitinib or erlotinib. The CYP2D6 phenotype was categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of adverse events with each factor, including CYP2D6 activities as well as treatment types.
A total of 112 patients received gefitinib therapy, 74 patients received erlotinib therapy, and 17 patients received erlotinib and gefitinib sequentially. The OR of developing rash with gefitinib versus erlotinib treatment was 0.38 (95% confidence interval [CI], 0.15-0.86). The OR of developing diarrhea with gefitinib versus erlotinib treatment was 0.46 (95% CI, 0.22-0.94). The OR of developing liver dysfunction with gefitinib versus erlotinib treatment was 3.30 (95% CI, 1.59-7.22). Reduced function of CYP2D6 was not associated with an increased risk of any adverse events in both gefitinib and erlotinib cohorts.
Erlotinib had higher rate of rash and diarrhea than gefitinib. Liver dysfunction occurred significantly more often in the gefitinib group than in the erlotinib group.
Osaka city medical journal 06/2012; 58(1):25-34.
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ABSTRACT: A 53-year-old female was admitted to our hospital complaining of disturbance of consciousness and hallucinations. About one year and 5 months ago she had adenocarcinoma of the lung, which was treated with surgery and chemotherapy. Computed tomography and magnetic resonance imaging revealed that her lung cancer had relapsed as caricinomatous meningitis and multiple lung metastases. She was treated with erlotinib, which rapidly resulted in disappearance of her symptoms. She still continues to receive erlotinib therapy without suffering from evident relapse 7 months after the initiation of the treatment.
Gan to kagaku ryoho. Cancer & chemotherapy 04/2012; 39(4):633-5.
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ABSTRACT: Amrubicin (AMR) is an active agent for relapsed small cell lung cancer (SCLC). However, the activity of AMR in refractory relapsed patients is controversial. The objective of this retrospective analysis was to evaluate the efficacy and safety of AMR as second-line chemotherapy in SCLC, especially refractory relapsed SCLC.
Between July 2003 and February 2009, a total of 27 patients were treated with AMR at a dosage of 40 mg x m(-2) x day(-1) on days 1-3 every 3 weeks. Safety was assessable for all patients. Efficacy was evaluated in 26 patients (one patient was not assessable for response), in 12 patients with chemotherapy-sensitive relapse and 14 patients with chemotherapy-refractory relapse. Sensitive relapse means that a first-line response lasted more than 90 days. Refractory relapse means that either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days.
Thirteen patients (50%, 95% CI, 31% to 69%) had partial response, including 6 (50%) of the 12 patients with chemotherapy-sensitive relapse and 7 (50%) of 14 patients with chemotherapy-refractory relapse. Median survival times of patients with chemotherapy-sensitive and -refractory relapse were 9.7 months and 8.4 months, respectively, showing significant difference (p = 0.0337). Adverse events were observed in all 27 patients. Grade 3 and 4 neutropenia was seen in 8 patients (29.6%) and 15 patients (55.5%), respectively. Grade 3 and 4 thrombocytopenia occurred in 10 patients (37.0%) and 2 patients (7.4%). Non-hematologic toxicities were generally mild, except for febrile neutropenia. Febrile neutropenia was seen in 6 patients (22.2%). No treatment-related deaths occurred.
AMR is an active agent for the treatment of relapsed SCLC, especially chemotherapy-refractory relapse SCLC, with predictable and manageable toxicities.
Osaka city medical journal 12/2011; 57(2):59-66.
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ABSTRACT: Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-aminoanthracycline derivative. The time-concentration profile of AMR-OH exhibits a continuous long plateau slope in the terminal phase. To determine the relationships between the steady-state plasma concentration of AMR-OH and treatment effects and toxicities associated with AMR therapy, we carried out a pharmacokinetic/pharmacodynamic study in patients treated with AMR alone or the combination of AMR+cisplatin (CDDP). AMR was given at a dose of 30 or 40 mg/m(2) on days 1-3. Plasma samples were collected 24 h after the third injection (day 4). Plasma concentrations of AMR-OH or total CDDP were determined by a high-performance liquid chromatography or an atomic absorption spectrometry. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid E(max) model. A total of 35 patients were enrolled. Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (P=0.018, P=0.012, and P=0.025, respectively). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (P=0.081). The plasma concentration of AMR-OH on day 4 was positively correlated with dANC in the group of all patients, as well as in patients treated with AMR alone and in patients coadministered with CDDP. In conclusion, the plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. The assessment of plasma concentration of AMR-OH at one timepoint might enable the prediction of hematological toxicities.
Anti-cancer drugs 05/2009; 20(6):513-8. · 2.23 Impact Factor
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ABSTRACT: A 31-year-old man was referred to our hospital for further investigation of a pulmonary shadow in July, 2004. Chest X-ray and CT films revealed an ill-defined nodule in the right middle lung field. Because the specimens of transbronchial lung biopsy were not diagnostic, video-assisted thoracoscopic surgery was performed. The pathologic diagnosis of the resected lung was lymphomatoid granulomatosis/angiocentric immunoproliferative lesion (LYG/AIL), grade I. Adjuvant therapy was not performed. There has been no evidence of recurrence during the 2-year postoperative follow-up period.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 02/2008; 46(1):50-4.
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ABSTRACT: A 77-year-old man was given emergency admission because of fever and dyspnea in October, 2005. He had been treated with Sai-rei-to, a herbal drug, for tinnitus. Laboratory data showed high values of C-reactive protein and liver dysfunction. Chest X-ray and CT films revealed ground-glass attenuation in both lung fields. Bronchoalveolar lavage showed an increase in number of lymphocytes and the lymphocyte-stimulation test was positive for Sai-rei-to. Based on the above findings, we diagnosed this case as Sai-rei-to-induced pneumonitis. The patient recovered after discontinuation of Sai-rei-to and corticosteroid therapy.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 12/2006; 44(11):833-7.
