Nobel pharmacodynamics evaluation of molecular targeting agents: PHarmacokinetic/PHarmacodynamic Assessment on Malignant Effusions (PHAME)

• Project/Area Number: 23501314
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: Aichi Medical University
• Principal Investigator: KUBO Akihito 愛知医科大学, 医学部, 教授 (60416245)
• Co-Investigator(Renkei-kenkyūsha): KOU Yasuhiro 和歌山県立医科大学, 医学部, 講師 (80426519) ; FUKUOKA Junya 長崎大学, 医学部, 教授 (00324575) ; TAKADA Minoru 阪和第二泉北病院, 副院長 (20373516) ; KAWAGUCHI Tomoya 大阪市立大学, 医学部, 教授 (70254422) ; ISA Shun-Ichi 独立行政法人国立病院機構, 近畿中央胸部疾患センター臨床研究センター, 研究員 (60421913)
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 非小細胞肺癌 / 癌性胸膜炎 / 分子標的治療 / 薬力学 / 薬物動態 / FDG-PET / 化学療法 / サイトケラチン

Outline of Final Research Achievements

Objective: Pharmacokinetics (PK) / pharmacodynamics (PD) of molecular targeting agents (MTAs) in non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE) are evaluated.
Methods: MPE and blood samples are serially collected from patients with NSCLC and MPE undergoing molecular targeting therapy (MTT) and chest tube drainage, and analyzed for targeted signaling pathways. PD is also evaluated by bio-imaging using 18F-FDG-PET in NSCLC patients undergoing MTT and those undergoing cytotoxic chemotherapy (CC).
Results: MPE is a suitable condition for intensive PK/PD assessments of MTAs with less hematologic toxicities. PD evaluation using PET more clearly predicts clinical outcomes in patients undergoing MTT compared with those undergoing CC.

Research Products

• [Journal Article] Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small-cell lung cancer patients with an EGFR-activating mutation using picodroplet digital PCR. (2015)
  • Author(s): Watanabe M, Kawaguchi T, Isa S-I, Ando M, Tamiya A, Kubo A, Saka H, Takeo S, Adachi H, Tagawa T, Kakegawa S, Yamashita M, Kataoka K, Ichinose Y, Takeuchi Y, Sakamoto K, Matsumura A, Koh Y.
  • Journal Title: Clin Cancer Res Volume: in press Issue: 15 Pages: 3552-3560
  • DOI: 10.1158/1078-0432.ccr-14-2151
  • Peer Reviewed
• [Journal Article] Therapeutic and Preventive Antiemetic Effect of Aprepitant in Japanese Patients with Thoracic Malignancies Who Truly Need It. (2015)
  • Author(s): Ito S, Tsukiyama I, Ando M, Katakami M, Hamanaka R, Kosaka K, Matsubara A, Nishimura M, Tanaka H, Asai N, Yokoe N, Takahashi A, Baba K, Matsuura K, Yamaguchi E, Kubo A.
  • Journal Title: Support Care Cancer Volume: 23 Issue: 4 Pages: 905-12
  • DOI: 10.1007/s00520-014-2430-x
  • Peer Reviewed
• [Journal Article] Reply to G Spitzer, et al; F Zhou,et al; and B Biswas. (2015)
  • Author(s): Kawaguchi T, Ando M, Kubo A.
  • Journal Title: J Clin Oncol Volume: 33 Issue: 5 Pages: 526-7
  • DOI: 10.1200/jco.2014.58.5315
  • Peer Reviewed
• [Journal Article] The role of smoking status on the progression-free survival of non-small-cell lung cancer patients harboring activating epidermal growth factor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor: a meta-analysis of prospective randomized trials. (2015)
  • Author(s): Hasegawa Y, Ando M, Maemondo M, Yamamoto S, Isa S, Saka H, Kubo A, Kawaguchi T, Takada M, Rosell R, Kurata T, Ou SH.
  • Journal Title: The Oncologist Volume: 20 Issue: 3 Pages: 1-9
  • DOI: 10.1634/theoncologist.2014-0285
  • Peer Reviewed
• [Journal Article] Metastatic Embryonal Carcinoma Mimicking Locally Advanced Non-small Cell Lung Cancer (2015)
  • Author(s): Numanami H, Takahashi D, Takahashi E, Katsuda E, Kamei S, Naruse N, Baba K, Haniuda M, Yokoi T, Yamaguchi E, Kubo A.
  • Journal Title: Internal Medicine Volume: 54 Issue: 1 Pages: 59-61
  • DOI: 10.2169/internalmedicine.54.2884
  • NAID: 130004902986
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Long-term Complete Response in a Patient with Disseminated Pulmonary Pleomorphic Carcinoma Induced by Cisplatin and Gemcitabine (2014)
  • Author(s): Tamiya A, Asami K, Shimizu S, Matusmura A, Isa S-I, Okishio K, Kitaichi M, Atagi S, Takada M, Kawaguchi T, Kubo A.
  • Journal Title: Internal Medicine Volume: 53 Issue: 22 Pages: 2625-2628
  • DOI: 10.2169/internalmedicine.53.2637
  • NAID: 130004713245
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small cell lung cancer: Docetaxel and Erlotinib Lung cancer TriAl (DELTA). (2014)
  • Author(s): Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A.
  • Journal Title: J Clin Oncol Volume: 32 Issue: 18 Pages: 1902-8
  • DOI: 10.1200/jco.2013.52.4694
  • Peer Reviewed
• [Journal Article] Successful crizotinib re-challenge after crizotinib-induced organizing pneumonia in anaplastic lymphoma kinase-rearranged non-small cell lung cancer. (2014)
  • Author(s): Asai N, Yokoi T, Yamaguchi E, Kubo A.
  • Journal Title: Case Reports in Oncology Volume: 7 Issue: 3 Pages: 681-4
  • DOI: 10.1159/000366516
  • Peer Reviewed
• [Journal Article] Successful crizotinib re-challenge after crizotinib-induced interstitial lung disease in patients with advanced non-small cell lung cancer. (2014)
  • Author(s): Asai N, Yamaguchi E, Kubo A.
  • Journal Title: Clin Lung Cancer Volume: 15 Issue: 3 Pages: e33-e35
  • DOI: 10.1016/j.cllc.2013.12.004
  • Peer Reviewed
• [Journal Article] Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small cell lung cancer: Docetaxel and Erlotinib Lung cancer TriAl (DELTA). (2014)
  • Author(s): Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A
  • Journal Title: J Clin Oncol (in press) Volume: na
  • Peer Reviewed
• [Journal Article] Long-term complete response in a patient with disseminated pulmonary pleomorphic carcinoma induced by cisplatin and gemcitabine. (2014)
  • Author(s): Tamiya A, Asami K, Shimizu S, Matusmura A, Isa S-I, Okishio K, Kitaichi M, Atagi S, Takada M, Kawaguchi T, Kubo A
  • Journal Title: Internal Medicine (in press) Volume: na
  • NAID: 130004713245
  • Peer Reviewed
• [Journal Article] Successful crizotinib re-challenge after crizotinib-induced interstitial lung disease in patients with advanced non-small cell lung cancer. (2014)
  • Author(s): Asai N, Yamaguchi E, Kubo A
  • Journal Title: Clin Lung Cancer (in press) Volume: na
  • Peer Reviewed
• [Journal Article] Role of consolidation chemotherapy after concurrent chemo-radiotherapy in locally advanced non-small-cell lung cancer. (2014)
  • Author(s): Tsujino K, Kurata T, Kawaguchi T, Kubo A, Takada M, Ando M.
  • Journal Title: J Thorac Oncol Volume: 9 Issue: 1 Pages: e7-e8
  • DOI: 10.1097/jto.0000000000000035
  • Peer Reviewed
• [Journal Article] Human papilloma virus in non-small cell lung cancer in never smokers: A systematic review of the literature. (2014)
  • Author(s): Hasegawa Y, Ando M, Kubo A, Isa SI, Yamamoto S, Tsujino K, Kurata T, Ou SH, Takada M, Kawaguchi T
  • Journal Title: Lung Cancer Volume: 8 Issue: 1 Pages: 8-13
  • DOI: 10.1016/j.lungcan.2013.10.002
  • Peer Reviewed
• [Journal Article] Is Consolidation Chemotherapy after Concurrent Chemo-Radiotherapy Beneficial for Patients with Locally Advanced Non-Small-Cell Lung Cancer?: A Pooled Analysis of the Literature. (2013)
  • Author(s): Tsujino K, Kurata T, Yamamoto S, Kawaguchi T, Kubo A, Isa S, Hasegawa Y, Ou SH, Takada M, Ando M
  • Journal Title: J Thorac Oncol Volume: 8 Issue: 9 Pages: 1181-9
  • DOI: 10.1097/jto.0b013e3182988348
  • Peer Reviewed
• [Journal Article] Rationale and Design of the Japan Molecular Epidemiology for Lung Cancer Study (2013)
  • Author(s): Kawaguchi T, Ando M, Ito N, Isa SI, Tamiya A, Shimizu S, Saka H, Kubo A, Koh Y, Matsumura A
  • Journal Title: Clin Lung Cancer Volume: 14 Issue: 5 Pages: 596-600
  • DOI: 10.1016/j.cllc.2013.03.001
  • Peer Reviewed
• [Journal Article] Rationale and design of JME study: Japan Molecular Epidemiology for lung cancer study. (2013)
  • Author(s): Kawaguchi T
  • Journal Title: Clin Lung Cancer (in press) Volume: 未定
  • Peer Reviewed
• [Journal Article] Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors beyond progressive disease: A retrospective analysis for Japanese patients with activating EGFR mutations. (2012)
  • Author(s): Nishie K
  • Journal Title: J Thorac Oncol Volume: 7 Issue: 11 Pages: 1722-1727
  • DOI: 10.1097/jto.0b013e31826913f7
  • Peer Reviewed
• [Presentation] Updated overall survival (OS) results of randomized phase III trial of erlotinib (E) versus (v) docetaxel (D) as second or third line therapy in patients with advanced non-small cell lung cancer (NSCLC): Docetaxel and Erlotinib Lung cancer TriAl (DELTA). (2014)
  • Author(s): Ibata H, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A, Kawaguchi T.
  • Organizer: Annual Meeting of the American Society of Clinical Oncology
  • Place of Presentation: Chicago, IL, USA.
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] The role of smoking status on the progression-free survival of non-small-cell lung cancer patients harboring activating epidermal growth factor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor: a meta-analysis of prospective randomized trials. (2014)
  • Author(s): Hasegawa Y, Ando M, Maemondo M, Yamamoto S, Isa S, Saka H, Kubo A, Kawaguchi T, Takada M, Kurata T, Ou SH.
  • Organizer: Annual Meeting of the American Society of Clinical Oncology
  • Place of Presentation: Chicago, IL, USA.
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] Impacts of environmental tobacco smoke on EGFR mutations and ALK rearrangements in never smokers with non-small cell lung cancer: Analyses on a prospective multinational ETS registry. (2013)
  • Author(s): Kubo A, Ando M, Soo RA, Kawaguchi T, Ou S-HI, Ahn M-J.
  • Organizer: 15th World Conference on Lung Cancer
  • Place of Presentation: Sydney, Australia
• [Presentation] Therapeutic and preventive effects of aprepitant for chemotherapy-induced nausea and vomiting in Japanese patients with thoracic malignancies. (2013)
  • Author(s): Ito S, Tsukiyama I, Ando M, Tanahashi M, Hamanaka R, Kosaka K, Matsubara A, Nishimura M, Tanaka H, Asai N, Yokoe N, Takahashi A, Baba K, Matsuura K, Yamaguchi E, Kubo A.
  • Organizer: 15th World Conference on Lung Cancer
  • Place of Presentation: Sydney, Australia
• [Presentation] Impact of environmental tobacco smoke (ETS) on ALK rearrangements in never smokers (NS) with non-small cell lung cancer (NSCLC): Analyses on a prospective multinational ETS registry. (2013)
  • Author(s): Kubo A, Ando M, Soo RA, Kawaguchi T, Ou S-HI, Ahn M-J.
  • Organizer: Annual Meeting of the American Society of Clinical Oncology
  • Place of Presentation: Chicago, IL, USA
• [Presentation] Randomized phase III trial of erlotinib (E) versus (v) docetaxel (D) as second or third line therapy in patients with advanced non-small cell lung cancer (NSCLC) who have wild type or mutant epidermal growth factor receptor (EGFR): Docetaxel and Erlotinib Lung cancer TriAl (DELTA). (2013)
  • Author(s): Okano Y, Ando M, Asami K, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A, Kawaguchi T.
  • Organizer: Annual Meeting of the American Society of Clinical Oncology
  • Place of Presentation: Chicago, IL, USA
• [Presentation] Cytokeratin (CK) 8: the dominant type II intermediate filament protein in non-small cell lung cancer (NSCLC). (2012)
  • Author(s): Kubo A
  • Organizer: 第52回日本呼吸器学会
  • Place of Presentation: 兵庫県神戸市
• [Presentation] Early 18F-fluorodeoxyglucose-positron emission tomography predicts clinical outcome of patients with advanced non-small cell lung cancer better on gefitinib treatment than on carboplatin plus paclitaxel. (2012)
  • Author(s): Kanazu M
  • Organizer: Annual Meeting of the American Society of Clinical Oncology
  • Place of Presentation: Chicago, IL, USA
• [Presentation] Malignant pleural effusions as a model for pharmacodynamics studies. (2011)
  • Author(s): 久保昭仁
  • Organizer: Osaka Lung Cancer Expert Meeting(招待講演)
  • Place of Presentation: 大阪府堺市
• [Presentation] 非小細胞肺癌(NSCLC)の癌性胸膜炎(MPE)におけるゲフィチニブの薬力学・薬物動態・臨床第II相試験 (2011)
  • Author(s): 久保昭仁、洪 泰浩、堀 隆、伊佐俊一、福岡順也、川口知哉、安藤昌彦、岡本 勇、北市正則、安宅信二、河原正明、楠 洋子、山口悦郎、中川和彦、高田 實
  • Organizer: 第51回日本呼吸器学会学術講演会
  • Place of Presentation: 東京
• [Book] Cytokeratins - Tools in Oncology (2012)
  • Author(s): Kubo A, Kanaji N, Bandoh S, Ishii T, Fujita J, Matsunaga T, Yamaguchi E
  • Total Pages: 158
  • Publisher: InTech Co.