Shigeki Mitsuoka

Publications (17)34.4 Total impact

• Article: Plasma RANTES, IL-10, and IL-8 levels in non--small-cell lung cancer patients treated with EGFR-TKIs.

  Kanako Umekawa, Tatsuo Kimura, Shinzoh Kudoh, Tomohiro Suzumura, Takako Oka, Misato Nagata, Shigeki Mitsuoka, Kuniomi Matsuura, Toshiyuki Nakai, Naruo Yoshimura, Yukimi Kira, Kazuto Hirata
  [show abstract] [hide abstract]
  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.
• Article: C609T Polymorphism of NADPH Quinone Oxidoreductase 1 Correlates Clinical Hematological Toxicities in Lung Cancer Patients Treated with Amrubicin.

  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
  [show abstract] [hide abstract]
  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.
• Article: Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer.

  Tomohiro Suzumura, Tatsuo Kimura, Shinzoh Kudoh, Kanako Umekawa, Misato Nagata, Kuniomi Matsuura, Hidenori Tanaka, Shigeki Mitsuoka, Naruo Yoshimura, Yukimi Kira, Toshiyuki Nakai, Kazuto Hirata
  [show abstract] [hide abstract]
  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
• Article: Prospective Assessment of Continuation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of Pemetrexed.

  Naruo Yoshimura, Kyoichi Okishio, Shigeki Mitsuoka, Tatsuo Kimura, Tomoya Kawaguchi, Masaji Kobayashi, Tomonori Hirashima, Haruko Daga, Koji Takeda, Kazuto Hirata, Shinzoh Kudoh
  [show abstract] [hide abstract]
  ABSTRACT: INTRODUCTION:: Patients with epidermal growth factor receptor (EGFR) mutation positive non-small-cell lung cancer exhibited marked response to gefitinib or erlotinib. In most cases, however, the patients showed disease progression after EGFR-tyrosine kinase inhibitor (TKI) treatment. We evaluated the efficacy and safety of pemetrexed in combination with EGFR-TKI in patients with disease progression. METHODS:: Patients with EGFR-mutant stage IIIB or IV non-small-cell lung cancer that progressed during gefitinib or erlotinib therapy were administered pemetrexed with the continuation of EGFR-TKI treatment. Pemetrexed was administered on day 1 at a dose of 500 mg/m, and EGFR-TKI was sequentially administered on days 2 to 16. This treatment was repeated every 3 weeks until disease progression. The primary endpoint was disease control rate. RESULTS:: Twenty-seven patients were enrolled in this study. The median number of treatment cycles was six. Overall response rate was 25.9% (95% confidence interval, 9.4%-42.4%) and disease control rate was 77.8% (95% confidence interval, 62.1%-93.5%). Grade 3/4 hematological toxicities were neutropenia (22.2%), leukopenia (14.8%), and anemia (7.4%). Grade 4 nonhematological toxicities were not observed. Major grade 3 nonhematological toxicities were anorexia (14.8%), infection (14.8%), and fatigue (11.1%). The median progression-free survival was 7.0 months, and median survival time was 11.4 months. No treatment-related deaths occurred. CONCLUSIONS:: Pemetrexed in combination with erlotinib or gefitinib after disease progression shows favorable response and acceptable toxicity.
  Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2012; · 4.55 Impact Factor
• Article: Comparison of adverse events of erlotinib with those of gefitinib in patients with non-small cell lung cancer: a case-control study in a Japanese population.

  Tomohiro Suzumura, Tatsuo Kimura, Shinzoh Kudoh, Kanako Umekawa, Misato Nagata, Hidenori Tanaka, Shigeki Mitsuoka, Naruo Yoshimura, Yukimi Kira, Kazuto Hirata
  [show abstract] [hide abstract]
  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.
• Article: [Carcinomatous meningitis in a post-operative patient with lung adenocarcinoma for which erlotinib was effective - a case report].

  Masahiro Manabe, Shigeki Mitsuoka, Kanako Umekawa, Hidenori Tanaka, Tatsuo Kimura, Naruo Yoshimura, Akitoshi Takeda, Shinzoh Kudoh, Kazuto Hirata
  [show abstract] [hide abstract]
  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.
• Article: Dose Escalation and Feasibility Study of Amrubicin Combined With Cisplatin in Previously Untreated Patients With Advanced Non-small-cell Lung Cancer.

  Naruo Yoshimura, Tatsuo Kimura, Shigeki Mitsuoka, Shigenori Kyoh, Yoshihiro Tochino, Kazuhisa Asai, Yukikazu Ichimaru, Kazuto Hirata, Shinzoh Kudoh
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVES:: Cisplatin is a key drug used in the treatment of non-small-cell lung cancer (NSCLC), and amrubicin is one of the new active agents for NSCLC. The objective of this study was to determine the recommended dose (RD) of amrubicin in combination with a fixed dose of cisplatin, and to assess the toxicity profile and feasibility of this regimen. METHODS:: We conducted a dose escalation study of amrubicin and cisplatin in previously untreated patients with stage IIIB or IV NSCLC. Dose level 1 of amrubicin was 30 mg/m on days 1 to 3 and level 2 was 35 mg/m. Cisplatin was administered at a fixed dose of 80 mg/m on day 1. Chemotherapy was given in a 3-week cycle. RESULTS:: Twenty patients were enrolled. Dose-limiting toxicities were neutropenia, febrile neutropenia, thrombocytopenia, and creatinine elevation. Level 1 (30 mg/m) was determined to be the RD, and 35 mg/m exceeded the RD. In 17 patients treated with the RD, the overall response rate was 41.2% (95% confidence interval, 17.7-64.7) and the median survival time was 16.4 months (95% confidence interval, 13.1-19.5). CONCLUSIONS:: This amrubicin and cisplatin regimen may be feasible and promising against advanced NSCLC. The efficacy and safety of this regimen should be confirmed in a phase II study.
  American journal of clinical oncology 01/2012; · 2.21 Impact Factor
• Article: Clinical outcome of amrubicin therapy according to the prior chemotherapy sensitivities of extensive small cell lung cancer.

  Shigeki Mitsuoka, Shinzoh Kudoh, Tatsuo Kimura, Naruo Yoshimura, Hidenori Tanaka, Tomohiro Suzumura, Kanako Umekawa, Misato Nagata, Takako Ueda, Kazuto Hirata
  [show abstract] [hide abstract]
  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.
• Article: Reaction of plasma hepatocyte growth factor levels in non-small cell lung cancer patients treated with EGFR-TKIs.

  Hidenori Tanaka, Tatsuo Kimura, Shinzoh Kudoh, Shigeki Mitsuoka, Tetsuya Watanabe, Tomohiro Suzumura, Keisei Tachibana, Masayuki Noguchi, Seiji Yano, Kazuto Hirata
  [show abstract] [hide abstract]
  ABSTRACT: Hepatocyte growth factor induces resistance to epidermal growth factor receptor tyrosine kinase inhibitors. It has been hypothesized that epidermal growth factor receptor tyrosine kinase inhibitors administration may influence the levels of plasma hepatocyte growth factor. Patients with advanced non-small cell lung cancer and relapsed after chemotherapies were eligible. Plasma hepatocyte growth factor levels were analyzed on pretreatment and post-treatment day 15 and 30. We also investigated the correlation between plasma hepatocyte growth factor levels and sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors, tissue immunoreactivity for hepatocyte growth factor and MET gene status. Thirty-one patients were enrolled. Plasma hepatocyte growth factor levels on post-treatment day 15 (630.1 ± 366.9 pg/ml) were significantly higher (p = 0.029) than the pretreatment plasma hepatocyte growth factor levels (485.9 ± 230.2 pg/ml). Plasma hepatocyte growth factor levels on the post-treatment day 30 (581.5 ± 298.1 pg/ml) tend to be higher than those before treatment (p = 0.057). Pretreatment plasma hepatocyte growth factor levels in patients with progressive disease (724.1 ± 216.4 pg/ml) were significantly higher than those in patients with stable disease (396.5 ± 148.3 pg/ml; p = 0.0008) and partial response (381.7 ± 179.0 pg/ml; p = 0.0039). The optimal pretreatment plasma hepatocyte growth factor cut-off value for diagnosis of responder was 553.5 pg/ml, and its sensitivity and specificity were 90% and 65%, respectively. Pretreatment plasma hepatocyte growth factor levels had no correlation with tissue immunoreactivities for hepatocyte growth factor, MET gene status and active EGFR mutations. Administration of epidermal growth factor receptor tyrosine kinase inhibitors significantly increased plasma hepatocyte growth factor levels. High levels of pretreatment plasma hepatocyte growth factor indicated intrinsic resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Plasma hepatocyte growth factor can serve as a useful biomarker for the early diagnosis of tumor relapse treated with epidermal growth factor receptor tyrosine kinase inhibitors.
  International Journal of Cancer 12/2010; 129(6):1410-6. · 5.44 Impact Factor
• Article: Plasma concentration of amrubicinol in plateau phase in patients treated for 3 days with amrubicin is correlated with hematological toxicities.

  Tatsuo Kimura, Shinzoh Kudoh, Shigeki Mitsuoka, Naruo Yoshimura, Hidenori Tanaka, Kazuhisa Asai, Shigenori Kyoh, Yoshihiro Tochino, Kanako Umekawa, Kazuto Hirata
  [show abstract] [hide abstract]
  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
• Article: Monitoring of chemotherapy response in malignant pleural mesothelioma using fluorodeoxyglucose positron emission tomography.

  Tatsuo Kimura, Koichi Koyama, Shinzoh Kudoh, Joji Kawabe, Naruo Yoshimura, Shigeki Mitsuoka, Susumu Shiomi, Kazuto Hirata
  [show abstract] [hide abstract]
  ABSTRACT: We report a 56-year-old man who underwent monitoring of the response to chemotherapy of malignant pleural mesothelioma (MPM). (8)F-fluoro-2-deoxy-(D)-glucose positron emission tomography (FDG-PET) and computed tomography (CT) were performed prior to chemotherapy and after the first and second courses of chemotherapy. The tumor lesion exhibited shrinkage on CT and a decrease in the standardized uptake value (SUV) max after the first course of chemotherapy, but exhibited size enlargement and an increase in SUV max after the second course of chemotherapy. These findings suggest that results of quantification of metabolic response by FDG-PET are related to the objective response as determined by CT in patients with MPM.
  Internal Medicine 02/2008; 47(23):2053-6. · 0.94 Impact Factor
• Article: Phase II study of docetaxel and carboplatin in elderly patients with advanced non-small cell lung cancer.

  Naruo Yoshimura, Shinzoh Kudoh, Tatsuo Kimura, Shigeki Mitsuoka, Shigenori Kyoh, Yoshihiro Tochino, Kazuhisa Asai, Toyoki Kodama, Yukikazu Ichimaru, Takashi Yana, Kazuto Hirata
  [show abstract] [hide abstract]
  ABSTRACT: Mainly single-agent chemotherapy has been considered as standard treatment for elderly patients with non-small cell lung cancer (NSCLC). Docetaxel monotherapy is regarded as a standard treatment for elderly patients with advanced NSCLC, and recent subset analyses have suggested that platinum-based chemotherapy can be safely used in the elderly. This phase II study was conducted to evaluate the efficacy and safety of docetaxel and carboplatin in elderly patients with advanced NSCLC. Patients enrolled in this study had stage IIIB or IV NSCLC with measurable disease, no prior chemotherapy, Eastern Cooperative Oncology Group performance status of 0-2, and were 70 years or older. Treatment consisted of docetaxel at a dose of 60 mg/m(2) and carboplatin at area under the curve of 5 mg/ml/min on day 1 every 3 weeks. From October 2003 to April 2006, 30 patients were enrolled. One complete response and 13 partial responses were observed, for an overall response rate of 46.7% (95% confidence interval: 28.8-64.6%). Median progression-free survival and overall survival periods were 4.4 months and 9.9 months, respectively. One-year survival rate was 43.3%. Major grade 3 and 4 hematological toxicities included neutropenia (86.7%), leucopenia (80.0%) and febrile neutropenia (16.7%). Major grade 3 nonhematological toxicities were anorexia (30.0%) and diarrhea (13.3%). There were no grade 4 nonhematological toxicities or treatment-related deaths. Docetaxel combined with carboplatin was an active treatment with manageable toxicity for the treatment of elderly patients with chemotherapy-naive NSCLC.
  Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2008; 4(3):371-5. · 4.55 Impact Factor
• Article: Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative and inhibitor of tubulin polymerization, which was administered to patients with advanced solid tumors on days 1 and 8 in 3-week courses.

  Kenji Tamura, Kazuhiko Nakagawa, Takayasu Kurata, Taroh Satoh, Toshiji Nogami, Koji Takeda, Shigeki Mitsuoka, Naruo Yoshimura, Shinzoh Kudoh, Shunichi Negoro, Masahiro Fukuoka
  [show abstract] [hide abstract]
  ABSTRACT: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of TZT-1027 (soblidotin), a dolastatin 10 analogue, in Japanese patients with advanced solid tumors when administered on days 1 and 8 in 3-week courses. Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and also met the following criteria: prior chemotherapy < or = 2 regimens, Eastern Cooperative Oncology Group (ECOG) performance status < or = 1, and acceptable organ function. The MTD was defined as the highest dose at which no more than one of six patients experienced a DLT during course 1. Pharmacokinetic samples were collected in courses 1 and 2. Eighteen patients were enrolled in the present study. Three doses (1.5, 1.65, and 1.8 mg/m(2)) were evaluated. Neutropenia was the principal DLT at doses of 1.65 and 1.8 mg/m(2). In addition, one patient also experienced grade 3 pneumonia with neutropenia, and another patient experienced grade 3 constipation, neuropathy, grade 4 neutropenia, and hyponatremia as DLTs at 1.65 mg/m(2). Phlebitis, the most frequent nonhematological toxicity, was improved by administration of additional saline after TZT-1027 administration. The MTD was 1.5 mg/m(2), at which DLT was not observed in a total of nine patients. The pharmacokinetic profile did not differ from that for the European population. One patient with metastatic esophageal cancer achieved partial response, and each of two patients with non-small cell lung cancer had a minor response. When TZT-1027 was administered on days 1 and 8 in 3-week courses to Japanese patients, the MTD was 1.5 mg/m(2) and was lower than the value of 2.4 mg/m(2) in European patients. However, antitumor activity was observed at low doses. TZT-1027 was tolerated well at the MTD, without grade 3 nonhematological toxicities or neutropenia up to grade 2. TZT-1027 is a promising new tubulin polymerization inhibitor that requires further investigation in phase II studies.
  Cancer Chemotherapy and Pharmacology 07/2007; 60(2):285-93. · 2.83 Impact Factor
• Article: Smoking history and prior surgical resection predict sensitivity to gefitinib in advanced non-small-cell lung cancer.

  Kuniomi Matsuura, Shinzoh Kudoh, Naruo Yoshimura, Tatsuo Kimura, Shigeki Mitsuoka, Kazuto Hirata, Junichi Yoshikawa, Hiroshi Iwao
  [show abstract] [hide abstract]
  ABSTRACT: Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase, and induces radiographic regression and symptomatic improvement in patients with non-small cell lung cancer (NSCLC). Phase II trials suggested female sex and adenocarcinoma were associated with response, never smoking history and adenocarcinoma were associated with survival. We attempted to identify additional clinical features associated with response and survival. We reviewed medical records and imaging studies of all 68 NSCLC patients treated by gefitinib monotherapy in our institution. We identified patients experiencing disease control and compared their clinical features with those of other patients. We considered partial response, stable disease or incomplete response and stable disease to be evidence of disease control. Univariate and multivariate analysis were performed to determine predictive and prognostic factors associated with disease control and survival. Of 68 patients, 20 (29.4%) experienced disease control. Variables identified as significant for disease control with gefitinib included never smoking history (p=0.0128) and history of curative surgical resection (p=0.0007) on multivariate analysis. Variables identified as significant for overall survival included never smoking history (p=0.0128), history of curative surgical resection (p=0.0007), and performance status (PS) of 0 and 1 (p=0.0001) on multivariate analysis. Our findings suggest that never smoking history and history of curative surgical resection are key factors for disease control and prognostic factors in patients with NSCLC treated with gefitinib.
  Osaka city medical journal 07/2006; 52(1):1-8.
• Article: EKB-569, a new irreversible epidermal growth factor receptor tyrosine kinase inhibitor, with clinical activity in patients with non-small cell lung cancer with acquired resistance to gefitinib.

  Naruo Yoshimura, Shinzoh Kudoh, Tatsuo Kimura, Shigeki Mitsuoka, Kuniomi Matsuura, Kazuto Hirata, Kaoru Matsui, Shunichi Negoro, Kazuhiko Nakagawa, Masahiro Fukuoka
  [show abstract] [hide abstract]
  ABSTRACT: EKB-569 is a potent, low molecular weight, selective, and irreversible inhibitor of epidermal growth factor receptor (EGFR) that is being developed as an anticancer agent. A phase 1, dose-escalation study was conducted in Japanese patients. EKB-569 was administered orally, once daily, in 28-day cycles, to patients with advanced-stage malignancies known to overexpress EGFR. Two patients with advanced non-small cell lung cancer with EGFR mutations and acquired gefitinib resistance from the phase 1 study are described in detail. Case #1 is a 63-year-old man with smoking history. He received treatment from 4 March 2004. Because he had no severe adverse events, a total of 10 courses of therapy were completed through December 16. Grade 2 skin rash and ALT elevation, and grade 1 diarrhea and nail changes developed. A chest CT scan on 4 August 2003 revealed multiple pulmonary metastases that had decreased in size. Case #2 is a 49-year-old woman with no smoking history. She received therapy from 9 February 2004. She received a total of five courses of the therapy until 22 June 2004. Grade 3 nausea and vomiting and grade 1 diarrhea and dry skin developed. A chest CT scan on March 3 revealed multiple pulmonary metastases that had decreased in size. A brain MRI on March 4 showed that multiple brain metastases also had decreased in size. Based on RECIST criteria, they had stable disease but radiographic tumor regression was observed.
  Lung Cancer 04/2006; 51(3):363-8. · 3.43 Impact Factor
• Article: A phase II study of continuous concurrent thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non-small cell lung cancer.

  Shinji Atagi, Masaaki Kawahara, Shigeto Hosoe, Mitsumasa Ogawara, Tomoya Kawaguchi, Kyoichi Okishio, Nobuyuki Naka, Toshihiko Sunami, Shigeki Mitsuoka, Masanori Akira
  [show abstract] [hide abstract]
  ABSTRACT: The split-course concurrent thoracic radiation therapy (TRT) and full-dose chemotherapy for unresectable stage III non-small cell lung cancer (NSCLC) has produced promising results by comparison with the sequential approach. Instead of split-course radiation, we conducted a phase II study to investigate the feasibility of continuous concurrent TRT and chemotherapy. Twenty-two patients with unresectable NSCLC were enrolled onto a phase II study of continuous concurrent radiotherapy and chemotherapy. Treatment consisted of two courses of cisplatin (80 mg/m(2) on days 1 and 29), vindesine (3 mg/m(2) on days 1, 8, 29 and 36), and mitomycin (8 mg/m(2) on days 1 and 29). TRT began on day 2 at a dose of 60 Gy (2 Gy per fraction and 5 fractions per week for a total of 30 fractions). Of 22 patients assessable for response, none achieved a CR and 17 (77.3%) achieved a PR with an overall response rate of 77.3% (95% confidence interval, 54.6-92.2%). Grade 3 or 4 leukopenia was observed in 5/13 (81.8%) patients. Six patients (27.3%) experienced > or = grade 3 thrombocytopenia. Non-hematological toxicity was relatively mild. The overall median survival time was 19.0 months and the 1- and 2-year survival rates were 84.8 and 34.5%, respectively. It was possible to administer two courses of chemotherapy in 18 patients (81.8%) as planned. Nineteen (86.4%) of the 22 patients received the planned 60 Gy radiation. It seems to be difficult to administer the planned treatment without any interruption for the majority of patients. However, in the selected patients who completed the 60 Gy TRT, nearly half of the patients completed TRT without interruption. This combination regimen is considered to be feasible on condition that the stopping rule of the treatment is followed. We recommend administering radiotherapy continuously as far as possible.
  Lung Cancer 04/2002; 36(1):105-11. · 3.43 Impact Factor
• Article: A feasibility study of paclitaxel 225 mg/m(2) and carboplatin AUC = 6 in untreated advanced non-small cell lung cancer patients in Japan.

  Mitsumasa Ogawara, Masaaki Kawahara, Shigeto Hosoe, Shinji Atagi, Tomoya Kawaguchi, Kyoichi Okishio, Nobuyuki Naka, Toshihiko Sunami, Shigeki Mitsuoka, Koji Inoue, Hiroyuki Haryu, Tsutomu Yoneda, Hideki Origasa
  [show abstract] [hide abstract]
  ABSTRACT: The combination of paclitaxel (225 mg/m(2), 3 h infusion) and carboplatin [area under the curve (AUC) 6 mg/ml x min] is used widely for non-small cell lung cancer in the USA and is one of the standard regimens in the Southwest Oncology Group. In Japan, however, the upper limit of the approved dose for single-use paclitaxel is 210 mg/m(2) and the optimum dose of this agent in combination with carboplatin has not yet been established. This study was designated to determine whether the paclitaxel dose of 225 mg/m(2 ) plus carboplatin (AUC = 6) is tolerable for Japanese patients with untreated advanced non-small cell lung cancer. Ten patients were enrolled between October 1999 and June 2000 and all of these patients were evaluable for toxicity. Chemotherapy consisted of carboplatin (AUC = 6 mg/ml x min) and 225 mg/m(2 )of paclitaxel on day 1 every 3 weeks. Neutropenia was the major toxicity and grade 4 neutropenia was observed in seven of the 10 patients (70%), but febrile neutropenia was not observed. Grade 4 anemia as a dose-limiting toxicity was observed in two patients. This was due to gastric ulcer bleeding in both patients. Only one patient experienced grade 3 peripheral neuropathy. No grade 3 or more myalgia or arthralgia was reported. Overall, 44 courses of chemotherapy were administered in 10 patients. Partial responses were observed in six of the 10 patients (60%). Median survival time was 7.7 months. Paclitaxel at 225 mg/m(2) in a 3 h infusion and carboplatin AUC = 6 appears to be tolerable in Japanese patients with untreated advanced non-small cell lung cancer.
  Japanese Journal of Clinical Oncology 03/2002; 32(2):48-53. · 1.78 Impact Factor