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Maemondo M.,Miyagi Cancer Center | Inoue A.,Tohoku University | Sugawara S.,Sendai Kousei Hospital | Harada T.,Hokkaido Social Insurance Hospital | And 11 more authors.
Oncologist | Year: 2014

Background. Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapywith vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elderly NSCLC patients. Consequently, we conducted a randomized phase II study to select the proper regimen for a future phase III trial. Methods. Eligible patients were aged 70 years or older with newly diagnosed advanced NSCLC. Patients were randomly assigned either to a combination of carboplatin (area under the curve: 6 mg/mL per minute) with weekly paclitaxel (70 mg/m2) (CPregimen) or to single-agentdocetaxel (60mg/m2). The primary endpoint of this study was objective response rate. Secondary endpoints were progression-free survival, overall survival, and toxicity profile. Results. Among 83 eligible patients (41 to CP, 42 to docetaxel), the objective response rates were 54% (95% confidence interval: 39%-69%) and 24% (95% confidence interval: 11%-37%) and median progression-free survival was 6.6 months and 3.5 months in the CP arm and the docetaxel arm, respectively. Severe neutropenia, febrile neutropenia, and nausea were significantly frequent in the docetaxel arm, whereas toxicities in the CParm were generally moderate.One treatment-related death was observed in the docetaxel arm. Conclusion. The CP regimen achieved higher activity with less toxicity than single-agent docetaxel. Considering the results of this phase II trial and the IFCT-0501 trial, we have selected the CP regimen for a future phase III trial in elderly patients with advanced NSCLC. © AlphaMed Press 2014.


PubMed | Osaka National Hospital, Tsuboi Cancer Center Hospital, Kanagawa Cancer Center, Tokyo Electron and 12 more.
Type: Journal Article | Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer | Year: 2016

The purpose of this study was to evaluate the natural course of the progression of pulmonary subsolid nodules (SSNs).Eight facilities participated in this study. A total of 795 patients with 1229 SSNs were assessed for the frequency of invasive adenocarcinomas. SSNs were classified into three categories: pure ground-glass nodules (PGGNs), heterogeneous GGNs (HGGNs) (solid component detected only in lung windows), and part-solid nodules.The mean prospective follow-up period was 4.3 2.5 years. SSNs were classified at baseline as follows: 1046 PGGNs, 81 HGGNs, and 102 part-solid nodules. Among the 1046 PGGNs, 13 (1.2%) developed into HGGNs and 56 (5.4%) developed into part-solid nodules. Among the 81 HGGNs, 16 (19.8%) developed into part-solid nodules. Thus, the SSNs at the final follow-up were classified as follows: 977 PGGNs, 78 HGGNs, and 174 part-solid nodules. Of the 977 PGGNs, 35 were resected (nine minimally invasive adenocarcinomas [MIAs], 21 adenocarcinomas in situ [AIS], and five atypical adenomatous hyperplasias). Of the 78 HGGNs, seven were resected (five MIAs and two AIS). Of the 174 part-solid nodules, 49 were resected (12 invasive adenocarcinomas, 26 MIAs, 10 AIS, and one adenomatous hyperplasia). For the PGGNs, the mean period until their development into part-solid nodules was 3.8 2.0 years, whereas the mean period for the HGGNs was 2.1 2.3 years (p= 0.0004).This study revealed the frequencies and periods of development from PGGNs and HGGNs into part-solid nodules. Invasive adenocarcinomas were diagnosed only among the part-solid nodules, corresponding to 1% of all 1229 SSNs.


Watanabe T.,Fukushima Medical University | Hashimoto T.,Tsuboi Cancer Center Hospital | Sugino T.,Fukushima Medical University | Soeda S.,Fukushima Medical University | And 5 more authors.
Journal of Ovarian Research | Year: 2012

Background: A crucial step in the metastatic spread of ovarian cancer (OC) is the adhesion and implantation of tumor cells to the peritoneal mesothelium. In order to study this step in the cascade, we derived a pro-metastatic human ovarian carcinoma cell line (MFOC3) from the non-metastatic FOC3 line. Methods. Molecular profiling of the isogeneic lines identified differentially expressed genes, and investigation for a role in dissemination for specific factors was achieved by development of a co-culture adhesion assay utilizing monolayers of human mesothelial cells. Results: After murine intraperitoneal inoculation, the FOC3 cell line formed no metastases, but the MFOC3 subline formed metastases in > 80% of SCID mice. MFOC3 cells also adhered 2-3 times more avidly to mesothelial monolayers. This adhesion was inhibited by neutralizing antibodies to IL-1β and enhanced by recombinant IL-1β (p < 0.01). IL-1β induced mesothelial cell β1-integrin, and an antibody to this subunit also inhibited the adhesion of MFOC3 to mesothelial cells in vitro and significantly reduced metastases in vivo. Immunohistochemical analysis of a cohort of 96 ovarian cancer cases showed that negative IL-1β expression was significantly associated with an improved overall survival rate. Conclusions: These results suggest that a IL-1β/β1-integrin axis plays a role in ovarian tumor cell adhesion to mesothelia, a crucial step in ovarian cancer dissemination. © 2012 Watanabe et al; licensee BioMed Central Ltd.


Maemondo M.,Miyagi Cancer Center | Inoue A.,Tohoku University | Kobayashi K.,International University of Japan | Sugawara S.,Sendai Kousei Hospital | And 19 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy. METHODS: We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects. RESULTS: In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P = 0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated amino transferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. CONCLUSIONS: First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.) Copyright © 2010 Massachusetts Medical Society.


Sugiyama T.,Tochigi Cancer Center | Kasai T.,Tochigi Cancer Center | Kamiyama Y.,Tochigi Cancer Center | Mori K.,Tsuboi Cancer Center Hospital
Japanese Journal of Lung Cancer | Year: 2015

Objective. The aim of this study was to prove the antiemetic efficacy of aprepitant in patients treated with a combined regimen of pemetrexed and carboplatin. Methods. A phase II trial of a combined regimen of carboplatin (AUC 6) and pemetrexed (500 mg/m2) was conducted. The two drugs were administered on day 1 and every 3 weeks thereafter. Aprepitant was not administered during the first course but was given as an additional treatment from the second course to 14 patients who experienced grade ≥2 nausea in the first course, in order to investigate its antiemetic efficacy. Results. There were 11 male and 3 female patients, with a median age of 62 years. Four patients had a performance status (PS) of 0, and 10 had a PS of 1. All of the cases were of adenocarcinoma. During the first course, grade 2 and 3 nausea occurred in 12 and 2 patients; grade 0,1, and 2 vomiting, in 7, 6, and 1 patients; and grade 1, 2, and 3 anorexia, in 6, 6, and 2 patients, respectively. All of the cases corresponded to the delayed phase. During the second course, grade 0,1, and 2 nausea occurred in 8, 2, and 4 patients; grade 0 and 1 vomiting, in 13 and 1 patients; and grade 0, 1, and 2 anorexia, in 7, 3, and 4 patients, respectively; which indicated a significant improvement. The severity of nausea, vomiting and anorexia decreased in 11 (78.5%), 13 (92.8%); and 8 (57.1%) patients, respectively. Conclusion. Aprepitant was an effective antiemetic in patients who were treated with pemetrexed/carboplatin and could be useful in the delayed phase. © 2015 The Japan Lung Cancer Society.


Hosomi Y.,Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital | Shibuya M.,Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital | Niho S.,National Cancer Center Hospital East | Ichinose Y.,National Kyushu Cancer Center | And 9 more authors.
Anticancer Research | Year: 2011

Background: We conducted a phase II study of topotecan (Tp) with cisplatin (CDDP) in previously untreated Japanese patients with extensive-disease small cell lung cancer (ED-SCLC). Patients and Methods: In stage 1, a total of 30 patients were allocated to Tp 0.65 mg/m 2 with CDDP 60 mg/m 2 day 1 or Tp 1.00 mg/m 2 with CDDP day 5 following prophylactic granulocyte colony stimulating factor (G-CSF) from day 6. In stage 2, the selective combination in 29 patients was evaluated for response rate, toxicity and overall survival. Results: In stage 1, Tp 1.00 mg/m 2 with CDDP day 5 was selected this schedule had a better hematological profile. In stage 2, the response rate was 83%, and grade 3/4 adverse events were hematological-toxicities. The median survival time was 17.5 months and the 1 year survival rate was 79%. Conclusion: Combination of Tp and CDDP on day 5 with G-CSF support is safe and effective for previously untreated ED-SCLC Japanese patients.


Ichinose Y.,National Kyushu Cancer Center | Seto T.,National Kyushu Cancer Center | Nishiwaki Y.,National Cancer Center Hospital East | Kiura K.,Okayama University | And 5 more authors.
Japanese Journal of Clinical Oncology | Year: 2011

Objective: A single-agent topotecan has an indication for the treatment of small cell lung cancer in Japan. Previous studies demonstrated that topotecan combined with a platinum agent could provide additional antitumor efficacy. This study was to find the recommended dose of topotecan in combination with cisplatin and preferred administration sequence in untreated patients with extensive disease small cell lung cancer for Phase II study. Methods: Patients received topotecan as a 30 min infusion for 5 days in escalating doses (starting at 0.5 mg/m2/day), and cisplatin at a fixed dose of 60 mg/m2, 3 weeks cycle. This study employed the following stages: cisplatin was given before topotecan on day 1 to previously treated patients (Stage 1). After the maximum-tolerated dose level was achieved, the same schedule was applied for untreated patients (Stage 2). Subsequently, cisplatin was given after topotecan on day 5 to untreated patients (Stage 3). The recommended doses of cisplatin on day 1 and 5 schedules were estimated by considering results obtained from Stages 2 and 3, respectively. Results: A total of 34 patients were enrolled. The maximum-tolerated doses in Stages 1-3 were estimated at 0.65, 0.65, and 1.4 mg/m2, respectively. The recommended doses of cisplatin on day 1 and 5 schedules in untreated patients were determined at 0.65 and 1.0 mg/m2, respectively. The major toxicity in this combination was hematological events. Conclusions: For treatment-naive patients, the combined use of 0.65/60 mg/m2 topotecan/cisplatin with cisplatin on day 1 schedule or 1.0/60 mg/m2 topotecan/cisplatin with cisplatin on day 5 schedule is recommended for Phase II study. © The Author (2010). Published by Oxford University Press. All rights reserved.


Noro R.,Nippon Medical School | Yoshimura A.,Nippon Medical School | Yoshimura A.,Tokyo Medical University | Yamamoto K.,Nippon Medical School | And 13 more authors.
Anticancer Research | Year: 2013

Background: A phase II study was conducted in order to determine the tumor efficacy and tolerance of alternating chemotherapy for extensive-stage small cell lung cancer (ED-SCLC). Patients and Methods: Twenty patients with previously-untreated ED-SCLC were enrolled in the study. At least four courses of chemotherapy consisting of alternation of two drug combinations were given: alternating cycles of amrubicin and cisplatin with weekly administration of irinotecan and cisplatin at 3- or 4-week intervals. Results: The overall response rate was 85.0% (17/20). The median duration of overall survival and progression-free survival were 359 days and 227 days, respectively. Hematological toxicity was the main adverse event. Grade 3 or 4 neutropenia, thrombocytopenia and anemia were observed in 20 (100%), 4 (20%) and 6 (30%) patients, respectively. With regard to non-hematological adverse events, grade 3 or 4 anorexia, diarrhea, febrile neutropenia and infection were observed in 5 (25%), 2 (10%), 2 (10%) and 2 (10%) patients, respectively. No treatment-related death occurred during either regimen. Conclusion: The novel alternating non-cross-resistant chemotherapy was probably active against ED-SCLC and had acceptable toxicities. Further evaluation of this treatment for ED-SCLC in randomized phase III trials is warranted.


Kitamura K.,Nippon Medical School | Kubota K.,Nippon Medical School | Ando M.,Tsuboi Cancer Center Hospital | Takahashi S.,Nippon Medical School | And 10 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: The presence of malignant pleural effusion (MPE) indicates a poorer prognosis for patients with non-small-cell lung cancer (NSCLC) and impairs their quality of life. Because vascular endothelial growth factor (VEGF) is the key mediator MPE production, we evaluated the efficacy and safety of chemotherapy plus bevacizumab, an anti-VEGF antibody, in non-squamous NSCLC patients with MPE, especially regarding the control of pleural effusions. Methods: From November 1, 2009 to September 30, 2011, medical charts of 13 consecutive patients with MPE who received bevacizumab plus chemotherapy as the initial or secondary treatment were retrospectively analyzed. Results: Of the 13 patients, 6 did not undergo pleurodesis, 3 were unsuccessfully treated by pleurodesis, 2 had encapsulated pleural effusion, and 2 had no re-expansion of the lung. Twelve patients (92.3 %) achieved MPE control lasting >8 weeks following bevacizumab plus chemotherapy. Five of 10 patients with measurable lesions had confirmed partial responses. Of 3 patients without measurable lesions, one had confirmed CR. Median progression-free survival time without re-accumulation of MPE was 312 days. Grade 3 or 4 neutropenia, thrombocytopenia, hypertension, or proteinuria was observed in 2, 2, 1, or 1 patient, respectively. Conclusions: This is the first study to report that bevacizumab plus chemotherapy is highly effective for the management of MPE in non-squamous NSCLC patients. Prospective clinical trials are warranted to investigate the efficacy of bevacizumab for MPE. © 2012 Springer-Verlag Berlin Heidelberg.


Yoshimura A.,Nippon Medical School | Yoshimura A.,Tokyo Medical University | Noro R.,Nippon Medical School | Miyanaga A.,Nippon Medical School | And 10 more authors.
Anticancer Research | Year: 2012

Background: A phase II study was conducted to determine the tumor efficacy and tolerance of alternating chemotherapy in extensive-stage small-cell lung cancer (ED-SCLC). Patients and Methods: Thirty-six patients with previously untreated ED-SCLC were enrolled in the study. At least four courses of chemotherapy consisting of alternation of two drug combinations were given: alternating cycles of etoposide and carboplatin (EC) with weekly administration of irinotecan and cisplatin (IP) at 3- or 4-week intervals. Results: The overall response rate was 81.8%. The median duration of survival and progression-free survival were 314 days and 144 days, respectively. Hematological toxicity was the main adverse event. Grade 3 or 4 neutropenia, thrombocytopenia and anemia were observed in 69.2, 25.6 and 23.1% of the patients, respectively. Severe diarrhea (10.8%) was remarkable during the IP regimen. Conclusion: This novel alternating chemotherapy for patients with ED-SCLC showed moderate tumor efficacy and an acceptable safety profile.

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