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Pancreatic Neoplasms: HELP
Articles by Takuji Okusaka
Based on 87 articles published since 2009
(Why 87 articles?)
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Between 2009 and 2019, T. Okusaka wrote the following 87 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease. 2018

Ter Veer, Emil / van Rijssen, L Bengt / Besselink, Marc G / Mali, Rosa M A / Berlin, Jordan D / Boeck, Stefan / Bonnetain, Franck / Chau, Ian / Conroy, Thierry / Van Cutsem, Eric / Deplanque, Gael / Friess, Helmut / Glimelius, Bengt / Goldstein, David / Herrmann, Richard / Labianca, Roberto / Van Laethem, Jean-Luc / Macarulla, Teresa / van der Meer, Jonathan H M / Neoptolemos, John P / Okusaka, Takuji / O'Reilly, Eileen M / Pelzer, Uwe / Philip, Philip A / van der Poel, Marcel J / Reni, Michele / Scheithauer, Werner / Siveke, Jens T / Verslype, Chris / Busch, Olivier R / Wilmink, Johanna W / van Oijen, Martijn G H / van Laarhoven, Hanneke W M. ·Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Surgery, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. · Department of Internal Medicine III, Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. · Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France. · Royal Marsden NHS Foundation Trust, London and Surrey, UK. · Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, Vandoeuvre-lès-Nancy, France. · Department of Gastroenterology and Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium. · Department of Oncology, Hôpital Riviera-Chablais, Vevey, Switzerland. · Department of Surgery, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · Nelune Cancer Centre, Prince of Wales Hospital, Prince of Wales Clinical School University of New South Wales, Randwick, NSW, Australia. · Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. · Cancer Center, ASST Papa Giovanni XXIII, Bergamo, Italy. · Department of Gastroenterology, Gastrointestinal Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. · Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA. · Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. · Department of Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI, USA. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Internal Medicine I, Medical University Vienna, Vienna, Austria. · Division of Solid Tumor Translational Oncology, West German Cancer Cancer, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. · Department of Digestive Oncology, University Hospitals Leuven, Leuven, Belgium. · Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. Electronic address: h.vanlaarhoven@amc.uva.nl. ·Lancet Oncol · Pubmed #29508762.

ABSTRACT: Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.

2 Guideline Clinical Practice Guidelines for Pancreatic Cancer 2016 From the Japan Pancreas Society: A Synopsis. 2017

Yamaguchi, Koji / Okusaka, Takuji / Shimizu, Kyoko / Furuse, Junji / Ito, Yoshinori / Hanada, Keiji / Shimosegawa, Tooru / Okazaki, Kazuichi / Anonymous7740903. ·From the *Clinic of Fukuoka Government Building, Hamanomachi Hospital, Fukuoka; †Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital; ‡Department of Gastroenterology, Tokyo Women's Medical University; §Department of Medical Oncology, Faculty of Medicine, Kyorin University; ∥Department of Radiation Oncology, National Cancer Center Hospital, Tokyo; ¶Department of Gastroenterology, JA Onomichi General Hospital, Onomichi; #Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai; and **Department of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Japan. ·Pancreas · Pubmed #28426492.

ABSTRACT: OBJECTIVES: Clinical Practice Guidelines for Pancreatic Cancer based on Evidence-Based Medicine 2006 were first published by the Japan Pancreas Society, and they were revised to Clinical Practice Guidelines for Pancreatic Cancer 2009 in July 2009 and were further revised to Clinical Practice Guidelines for Pancreatic Cancer 2013 in October 2013. These guidelines were established according to evidence-based medicine. In October 2016, the Clinical Practice Guidelines for Pancreatic Cancer were newly revised in Japanese. METHODS: In the revised version, we introduced the concepts of GRADE - grading recommendations assessment, development, and evaluation approach for better understanding of the current guidelines. RESULTS: The guidelines show algorithms for the diagnosis, treatment, and chemotherapy of pancreatic cancer and address 7 subjects: diagnosis, surgical therapy, adjuvant therapy, radiation therapy, chemotherapy, stent therapy, and palliative medicine. They include 51 clinical questions and 76 statements. There are statements corresponding to clinical questions, evidence levels, recommended strengths, and agreement rates. CONCLUSIONS: These guidelines represent the most standard clinical and practical management at this time in Japan. This is the English synopsis of the Clinical Practice Guidelines for Pancreatic Cancer 2016 in Japanese, which aims to disseminate the Japanese guidelines worldwide for the introduction of Japanese clinical management of these diseases.

3 Guideline EBM-based Clinical Guidelines for Pancreatic Cancer (2013) issued by the Japan Pancreas Society: a synopsis. 2014

Yamaguchi, Koji / Okusaka, Takuji / Shimizu, Kyoko / Furuse, Junji / Ito, Yoshinori / Hanada, Keiji / Shimosegawa, Tooru / Anonymous6910805. ·Department of Advanced Treatment of Pancreatic Diseases, School of Medicine, University of Occupational and Environmental Health, Kitakyushu yamaguch@med.uoeh-u.ac.jp. · Hepatobiliary and Pancreatic Oncology Division, National Cancer Center, Tokyo. · Department of Gastroenterology, Tokyo Women's Medical University, Tokyo. · Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, Tokyo. · Department of Radiation Oncology, National Cancer Center, Tokyo. · Department of Gastroenterology, JA Onomichi General Hospital, Onomichi. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. ·Jpn J Clin Oncol · Pubmed #25205672.

ABSTRACT: Clinical practice guidelines for pancreatic cancer based on evidence-based medicine (2006) were published by the Japan Pancreas Society (Committee for revision of clinical guidelines for pancreatic cancer) in March 2009 in Japanese, revised to Clinical Practice Guidelines for Pancreatic Cancer based on evidence-based medicine (2009) in July 2009 in Japanese and further revised to Clinical Practice Guidelines for Pancreatic Cancer (2013) in October 2013 in Japanese. These guidelines were established according to evidence-based medicine. A total of 629 papers were collected from among 4612 reports concerning pancreatic cancer listed in PubMed and Igakuchuo Zasshi between May 2007 and January 2011. This new set of guidelines was written by members of the Committee for the Revision of Clinical Practice Guidelines for Pancreatic Cancer in the Japan Pancreas Society. The guidelines provide an algorithm for the diagnosis (Fig. 1) and treatment (Fig. 2) of pancreatic cancer and address six subjects (Diagnosis, Surgery, Adjuvant therapy, Radiation therapy, Chemotherapy and stent therapy), with 35 clinical questions and 57 recommendations.

4 Review Cytotoxic chemotherapy for pancreatic neuroendocrine tumors. 2015

Okusaka, Takuji / Ueno, Hideki / Morizane, Chigusa / Kondo, Shunsuke / Sakamoto, Yasunari / Takahashi, Hideaki / Ohno, Izumi / Shimizu, Satoshi / Mitsunaga, Shuichi / Ikeda, Masafumi. ·Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. tokusaka@ncc.go.jp. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. ·J Hepatobiliary Pancreat Sci · Pubmed #25940377.

ABSTRACT: Advanced neuroendocrine tumors are incurable, and most patients will succumb to the disease. Chemotherapies with cytotoxic agents such as streptozocin, 5-fluorouracil, or temozolomide have been frequently used as drug therapies for neuroendocrine tumors. Streptozocin, which is the only approved cytotoxic agent available for the treatment of this disease in many countries, has been considered a key agent for the treatment of advanced neuroendocrine tumors based on the results of phase III studies. However, the widespread acceptance of streptozocin-based chemotherapy for this indication has been limited by concerns regarding toxicity. Recent prospective and retrospective studies showed the promising activity of a temozolomide-based regimen, although an adequate prospective controlled study defining the role of temozolomide in the treatment of neuroendocrine tumors is lacking. The promising activity of cytotoxic agents awaits confirmation; solid evidence-based recommendations and treatment decisions are needed for the optimal use of chemotherapy against this disease.

5 Review Chemotherapy for advanced poorly differentiated pancreatic neuroendocrine carcinoma. 2015

Ikeda, Masafumi / Okuyama, Hiroyuki / Takahashi, Hideaki / Ohno, Izumi / Shimizu, Satoshi / Mitsunaga, Shuichi / Kondo, Shunsuke / Morizane, Chigusa / Ueno, Hideki / Okusaka, Takuji. ·Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-56-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. masikeda@east.ncc.go.jp. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-56-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. ·J Hepatobiliary Pancreat Sci · Pubmed #25755102.

ABSTRACT: Pancreatic neuroendocrine carcinoma (P-NEC) resembles small cell lung carcinoma in its biologic and clinical features, such as rapid growth and relatively high sensitivity to platinum-based chemotherapy. And, etoposide plus cisplatin (EP) or irinotecan plus cisplatin (IP), recommended by guidelines for the treatment of small cell lung carcinoma, has also been widely used for the treatment of unresectable NEC. Both regimens have been demonstrated to show favorable efficacy and have been acknowledged as de facto standard regimens for unresectable NEC, although it remains unclear which of the two regimens might yield more favorable outcomes. Therefore, a phase III trial of EP vs. IP has been planned for unresectable gastrointestinal, hepatobiliary or pancreatic NEC by the Japan Clinical Oncology Group. For patients with unresectable NEC who are refractory or intolerant to these regimens, no standard regimens have been established. Everolimus, an mTOR inhibitor, is likely to be effective in such patients, as there have been sporadic reports of the usefulness of everolimus in the treatment of P-NEC. A multicenter phase II trial is underway to elucidate the efficacy and safety of everolimus in patients with P-NEC who are refractory or intolerant to EP or IP.

6 Review The Hepatobiliary and Pancreatic Oncology (HBPO) Group of the Japan Clinical Oncology Group (JCOG): history and future direction. 2013

Furuse, Junji / Ishii, Hiroshi / Okusaka, Takuji. ·Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, 6-20-2, Shinkawa, Mitaka, Tokyo 181-8611, Japan. jfuruse@ks.kyorin-u.ac.jp ·Jpn J Clin Oncol · Pubmed #23100604.

ABSTRACT: The Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group (JCOG) was constituted in April 2008 to develop new standard treatments for hepatobiliary and pancreatic cancer. In pancreatic cancer, the Hepatobiliary and Pancreatic Oncology Group focuses on establishing standard chemotherapy or chemoradiotherapy for unresectable locally advanced disease. The JCOG 0506 study was a Phase II study of gemcitabine alone to examine its efficacy and safety in patients with locally advanced disease. The results in survival significantly exceeded expectations, and gemcitabine monotherapy has come to be regarded as the provisional standard therapy by our group. Following JCOG 0506, the JCOG 1106 study, which is currently under investigation, is a randomized Phase II study to evaluate the efficacy of induction chemotherapy with gemcitabine in combination with S-1 chemoradiotherapy and select a candidate therapeutic agent in a Phase III study comparing with gemcitabine alone. The JCOG 0805 study was a randomized Phase II study comparing S-1 monotherapy with gemcitabine plus S-1 combination therapy for unresectable biliary tract cancer. As a result, gemcitabine plus S-1 combination therapy was considered the more promising candidate in comparison with the gemcitabine plus cisplatin combination therapy in a subsequent Phase III trial. The Hepatobiliary and Pancreatic Oncology Group is planning a Phase III study to compare gemcitabine plus S-1 combination therapy with gemcitabine plus cisplatin combination therapy (JCOG PC1113 study). No standard postoperative adjuvant treatment has been established. We plan to conduct a Phase III study to compare S-1 as adjuvant therapy after surgery with surgery alone in patients with biliary tract cancer (JCOG PC1202).

7 Review [Systemic chemotherapy and chemoradiotherapy for advanced pancreatic cancer]. 2012

Ueno, Hideki / Okusaka, Takuji. ·Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan. ·Gan To Kagaku Ryoho · Pubmed #22421761.

ABSTRACT: Currently, we are able to use S-1 with gemcitabine and erlotinib, as well as gemcitabine alone, as first-line therapy for advanced pancreatic cancer. In addition, a clinical trial of FOLFIRINOX is underway in Japan. On the other hand, chemoradiotherapy is considered to be one of the treatments of choice for locally advanced pancreatic cancer. This review summarizes current knowledge about non-surgical treatment for advanced pancreatic cancer, mainly based on the results of recent clinical trials.

8 Review [Medical treatment of pancreatic neuroendocrine tumor]. 2011

Okusaka, Takuji / Ueno, Hideki / Morizane, Chigusa / Kondo, Shunsuke / Yamaguchi, Tomohiro. ·Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital. ·Nihon Rinsho · Pubmed #21830611.

ABSTRACT: -- No abstract --

9 Clinical Trial Efficacy and safety of sunitinib in Japanese patients with progressive, advanced/metastatic, well-differentiated, unresectable pancreatic neuroendocrine tumors: final analyses from a Phase II study. 2019

Ito, Tetsuhide / Tori, Masayuki / Hashigaki, Satoshi / Kimura, Nobuyuki / Sato, Kazuo / Ohki, Emiko / Sawaki, Akira / Okusaka, Takuji. ·Department of Hepato-Biliary-Pancreatic Medicine, Fukuoka Sanno Hospital, International University of Health and Welfare, Tokyo 814-0001, Japan. · Department of Endocrine Surgery, Osaka Police Hospital, Osaka 543-0035, Japan. · Pfizer Japan, Tokyo 151-8589, Japan. · Department of Medical Oncology, Fujita Health University, Aichi 470-1192, Japan. · Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan. ·Jpn J Clin Oncol · Pubmed #30834940.

ABSTRACT: BACKGROUND: In an interim analysis of a Phase II trial in Japanese patients with pancreatic neuroendocrine tumors (panNETs), sunitinib demonstrated antitumor activity with an objective response rate (ORR) of 50% (95% confidence interval [CI], 21-79) and a median progression-free survival (PFS) of 16.8 months (95% CI, 9.3-26.2). Here, we report the final analyses of efficacy and safety, as well as additional analyses, from this Phase II study. METHODS: This was a multicenter, open-label, Phase II trial (NCT01121562) of sunitinib in Japanese patients with panNETs. Patients received oral sunitinib 37.5 mg/day on a continuous daily dosing schedule. Dose modifications were permitted. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included ORR, PFS, overall survival (OS), safety and pharmacokinetics. RESULTS: Of 12 patients enrolled and treated, all discontinued treatment-the majority (n = 8) owing to disease progression. Most patients were male (n = 8), <65 years of age (n = 11) and had a non-functional tumor (n = 10). The median (range) number of days on drug was 323.5 (22-727). The CBR (95% CI) was 75.0% (42.8-94.5). ORR (95% CI) was 50.0% (21.1-78.9). Median (95% CI) PFS was 16.8 (9.3-26.2) months; however, median (95% CI) OS was not reached (22.0-not estimable). Most common adverse events (AEs; all-causality) were diarrhea (n = 10; 83.3%), hand-foot syndrome (n = 8; 66.7%) and hypertension (n = 8; 66.7%). CONCLUSIONS: These results support the efficacy and safety of sunitinib in Japanese patients with panNETs. Appropriate AE management through dose reduction and interruption may prolong sunitinib treatment and maximize its efficacy.

10 Clinical Trial A phase II study of modified FOLFIRINOX for chemotherapy-naïve patients with metastatic pancreatic cancer. 2018

Ozaka, Masato / Ishii, Hiroshi / Sato, Tosiya / Ueno, Makoto / Ikeda, Masafumi / Uesugi, Kazuhiro / Sata, Naohiro / Miyashita, Kouichirou / Mizuno, Nobumasa / Tsuji, Kunihiro / Okusaka, Takuji / Furuse, Junji. ·Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. masato.ozaka@jfcr.or.jp. · National Hospital Organization Shikoku Cancer Center, 160 Kou, Minami Umemoto, Matsuyama, 791-0280, Japan. · Department of Biostatistics, Kyoto University School of Public Health, Yoshida-honmachi, Sakyo-ku, Kyoto, 606-8501, Japan. · Division of Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. · Department of Surgery, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan. · Internal Medicine of Gastroenterology, Showa University Northern Yokohama Hospital, Tsudukiku, Chigasakityuo 35-1, Yokohama, Kanagawa, 224-8503, Japan. · Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan. · Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Kuratsukihigashi 2-1, Kanazawa, Ishikawa, 920-8530, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. · Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2, Shinkawa, Mitaka, Tokyo, 181-8611, Japan. ·Cancer Chemother Pharmacol · Pubmed #29633005.

ABSTRACT: BACKGROUND: We evaluated the efficacy and safety of a modified FOLFIRINOX regimen for chemotherapy-naïve patients with metastatic pancreatic cancer. METHODS: Patients with untreated metastatic pancreatic cancer (MPC) received modified FOLFIRINOX (intravenous oxaliplatin 85 mg/m RESULTS: Sixty-nine pts. were enrolled from 39 institutions in Japan. The median overall survival was 11.2 months [95% confidence interval (CI) 9.0-]. The median progression-free survival was 5.5 months (95% CI 4.1-6.7). The response rate was 37.7% (95% CI 26.3-50.2), and the disease control rate was 78.3% (95% CI 66.7-87.3). The incidence of grade 3 or higher neutropenia was 47.8%. Serious adverse events occurred in six patients (8.7%). All AE proportions were less than those in the previous Japanese full-dose phase II study. One patient died due to interstitial pneumonia related to treatment. CONCLUSION: This is the first prospective study of modified FOLFIRINOX in Asia. Modified FOLFIRINOX in this study has an improved safety profile with maintained efficacy in MPC without prophylactic pegfilgrastim.

11 Clinical Trial A randomized Phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1202, ASCOT). 2018

Nakachi, Kohei / Konishi, Masaru / Ikeda, Masafumi / Mizusawa, Junki / Eba, Junko / Okusaka, Takuji / Ishii, Hiroshi / Fukuda, Haruhiko / Furuse, Junji / Anonymous5930937. ·Department of Gastroenterology, Otaru General Hospital, Otaru. · Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa. · JCOG Data Center/Operations Office, National Cancer Center Hospital, Tokyo. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo. · Clinical Research Center, National Hospital Organization Shikoku Cancer Center, Matsuyama. · Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan. ·Jpn J Clin Oncol · Pubmed #29462482.

ABSTRACT: No standard adjuvant treatment has been established for patients with curatively resected biliary tract cancer. S-1 has been reported to show promising efficacy with mild toxicity profiles in patients with advanced biliary tract cancer, and adjuvant S-1 therapy has been demonstrated to provide survival benefit in patients with resected gastric cancer and pancreatic cancer. The aim of this open-label, multicenter, randomized Phase III trial is to confirm that adjuvant chemotherapy with S-1 would prolong overall survival in patients with resected biliary tract cancer. This study was activated in September 2013. A total of 350 patients planned to be enrolled from 36 Japanese institutions over a period of 4 years. At July 2017, the protocol was revised to increase power from 70% to 80%. Therefore, the planned total sample size is 440. The primary endpoint is overall survival. This trial is registered with the UMIN Clinical Trials Registry as UMIN000011688.

12 Clinical Trial A randomized phase II study of gemcitabine plus Z-360, a CCK2 receptor-selective antagonist, in patients with metastatic pancreatic cancer as compared with gemcitabine plus placebo. 2017

Ueno, Makoto / Li, Chung Pin / Ikeda, Masafumi / Ishii, Hiroshi / Mizuno, Nobumasa / Yamaguchi, Taketo / Ioka, Tatsuya / Oh, Do Youn / Ichikawa, Wataru / Okusaka, Takuji / Matsuyama, Yutaka / Arai, Daichi / Chen, Li Tzong / Park, Young Suk / Furuse, Junji. ·Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-ku, Yokohama-shi, Kanagawa, 241-8515, Japan. uenom@kcch.jp. · Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shin-Pai Road, Taipei, 11217, Taiwan. · School of Medicine, National Yang-Ming University, 155, Section 2, Linong Street, Taipei, 112, Taiwan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan. · Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan. · Department of Gastroenterology, Clinical Research Center, National Hospital Organization Shikoku Cancer Center, 160, Kou, Minamiumemoto-machi, Matsuyama-shi, Ehime, 791-0280, Japan. · Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan. · Department of Gastroenterology, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba-shi, Chiba, 260-8717, Japan. · Department of Gastrointestinal Cancer Screening and Surveillance, Osaka Medical Center for Cancer and Cardiovascular Disease, 3-3 Nakamichi 1-Chome, Higashinari-ku, Osaka, 537-8511, Japan. · Department of Gastrointestinal Cancer Screening and Surveillance, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka, 541-8567, Japan. · Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea. · Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa, 227-8501, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. · Department of Biostatistics, School of Public Health, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. · Division of Clinical Research 3, ZERIA Pharmaceutical Co., Ltd., 10-11, Nihonbashi Kobuna-cho, Chuo-ku, Tokyo, 103-8351, Japan. · National Institute of Cancer Research, National Health Research Institutes, 367, Sheng-Li Rd., North District, 70456, Tainan, Taiwan. · Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea. · Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan. ·Cancer Chemother Pharmacol · Pubmed #28634650.

ABSTRACT: BACKGROUND: We investigated the efficacy and safety of 60, 120, or 240 mg of Z-360, which is a highly potent cholecystokinin2-receptor-selective antagonist, combined with gemcitabine in patients with metastatic pancreatic cancer. METHODS: Patients were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups. Patients received 1000 mg/m RESULTS: The median OS was 1.3 months longer in the GZ 60 mg group compared with the Gem group (8.5 vs. 7.2 months) and the risk of death was reduced by 19% compared with the Gem group, although there were no statistically significant differences. The study treatments were well tolerated. CONCLUSIONS: In this Phase II study, no statistically significant differences between the GZ groups and Gem group were detected in any analysis. However, Z-360 in dose of 60 mg tends to improve OS in patients with metastatic pancreatic cancer with low toxic effect. Further exploratory trials with other agents such as gemcitabine plus nab-paclitaxel might be beneficial.

13 Clinical Trial Updated results from GEST study: a randomized, three-arm phase III study for advanced pancreatic cancer. 2017

Okusaka, Takuji / Miyakawa, H / Fujii, H / Nakamori, S / Satoh, T / Hamamoto, Y / Ito, T / Maguchi, H / Matsumoto, S / Ueno, H / Ioka, T / Boku, N / Egawa, S / Hatori, T / Furuse, J / Mizumoto, K / Ohkawa, S / Yamaguchi, T / Yamao, K / Funakoshi, A / Chen, J S / Cheng, A L / Sato, A / Ohashi, Y / Tanaka, M / Anonymous450897. ·Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. tokusaka@ncc.go.jp. · Division of Biliopancreatology, Sapporo Kosei General Hospital, Sapporo, Japan. · Division of Clinical Oncology, Jichi Medical University, Tochigi, Japan. · Hepato-Biliary-Pancreatic Surgery, Osaka National Hospital, Osaka, Japan. · Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Japan. · Keio Cancer Center, Keio University Hospital, Tokyo, Japan. · Department of Medicine and Bioreguratory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan. · Department of Medical Oncology, Kyoto University Hospital, Kyoto, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. · Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan. · Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan. · Department of Surgery, Tohoku University, Sendai, Japan. · Department of Surgery and Digestive Diseases Center, International University of Health and Welfare Mita Hospital, Tokyo, Japan. · Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan. · Kyushu University Hospital Cancer Center, Fukuoka, Japan. · Division of Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Yokohama, Japan. · Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan. · Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. · Division of Pancreatology, Fukuoka Sanno Hospital, Fukuoka, Japan. · Division of Hematology-Oncology, Linkou Chang Gung Memorial Hospital and Chang Gung University, Tao-Yuan, Taiwan, Republic of China. · Department of Oncology, National Taiwan University Hospital, and National Taiwan University Cancer Center, Taipei, Taiwan, Republic of China. · Department of Medical Oncology, Hirosaki University Graduate School of Medicine, Aomori, Japan. · Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan. · Department of Surgery, Shimonoseki City Hospital, Shimonoseki, Japan. ·J Cancer Res Clin Oncol · Pubmed #28210843.

ABSTRACT: PURPOSE: The GEST study showed non-inferiority of S-1 but not superiority of gemcitabine plus S-1 (GS) to gemcitabine alone for overall survival with the data by the cut-off date of 31st July in 2010 for chemo-naïve patients with advanced pancreatic cancer. We considered it important to determine whether S-1 maintains non-inferiority after a long-term follow-up in the GEST study and to obtain a firm positive conclusion. In addition, it may be an interesting challenge to explore the efficacious profile of GS in the long-term follow-up study. Using the data from the follow-up period, background and efficacy in patients from Taiwan and Japan, as well as the rates of tumor shrinkage in locally advanced and metastatic patients (Waterfall plot) were also analyzed. METHODS: The results of the primary analysis were reconfirmed, and subset analysis of overall survival and progression-free survival was performed based on the overall survival data updated by the cut-off date of 31st July in 2011. RESULTS: The median follow-up period was 29.8 months, and 795 deaths occurred (95.6%). The median overall survival was 8.8 months for gemcitabine, 9.7 months for S-1 (hazard ratio [HR], 0.96; 97.5% confidence interval [CI], 0.79-1.17), and 9.9 months for GS (HR 0.91; 97.5% CI 0.75-1.11). In patients with performance status (PS) 0, the median overall survival was 9.8 months for gemcitabine, 10.9 months for S-1, and 10.5 months for GS. In patients with PS 1, the median overall survival was 6.2 months for gemcitabine, 6.3 months for S-1, and 9.6 months for GS. CONCLUSION: Our survey reconfirmed the non-inferiority of S-1 to gemcitabine and showed S-1 can be used as one of the standard treatment options for advanced pancreatic cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00498225.

14 Clinical Trial Identification of IGFBP2 and IGFBP3 As Compensatory Biomarkers for CA19-9 in Early-Stage Pancreatic Cancer Using a Combination of Antibody-Based and LC-MS/MS-Based Proteomics. 2016

Yoneyama, Toshihiro / Ohtsuki, Sumio / Honda, Kazufumi / Kobayashi, Makoto / Iwasaki, Motoki / Uchida, Yasuo / Okusaka, Takuji / Nakamori, Shoji / Shimahara, Masashi / Ueno, Takaaki / Tsuchida, Akihiko / Sata, Naohiro / Ioka, Tatsuya / Yasunami, Yohichi / Kosuge, Tomoo / Kaneda, Takashi / Kato, Takao / Yagihara, Kazuhiro / Fujita, Shigeyuki / Huang, Wilber / Yamada, Tesshi / Tachikawa, Masanori / Terasaki, Tetsuya. ·Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. · Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. · Japan Agency for Medical Research and Development (AMED) CREST, Tokyo, Japan. · Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan. · Division of Epidemiology, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Departments of Hepato-Biliary-Pancreatic Surgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan. · Department of Oral Surgery, Osaka Medical College, Osaka, Japan. · Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan. · Department of Surgery, Jichi Medical University, Tochigi, Japan. · Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan. · Islet Institute, Fukuoka University, Fukuoka, Japan. · Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan. · Department of Radiology, Nihon University School of Dentistry at Matsudo, Chiba, Japan. · Department of Oral Implant, Nihon University School of Dentistry at Matsudo, Chiba, Japan. · Department of Oral Surgery, Saitama Cancer Center, Saitama, Japan. · Department of Oral and Maxillofacial Surgery, Wakayama Medical University, Wakayama, Japan. · Abnova, Taipei City, Taiwan. ·PLoS One · Pubmed #27579675.

ABSTRACT: Pancreatic cancer is one of the most lethal tumors, and reliable detection of early-stage pancreatic cancer and risk diseases for pancreatic cancer is essential to improve the prognosis. As 260 genes were previously reported to be upregulated in invasive ductal adenocarcinoma of pancreas (IDACP) cells, quantification of the corresponding proteins in plasma might be useful for IDACP diagnosis. Therefore, the purpose of the present study was to identify plasma biomarkers for early detection of IDACP by using two proteomics strategies: antibody-based proteomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics. Among the 260 genes, we focused on 130 encoded proteins with known function for which antibodies were available. Twenty-three proteins showed values of the area under the curve (AUC) of more than 0.8 in receiver operating characteristic (ROC) analysis of reverse-phase protein array (RPPA) data of IDACP patients compared with healthy controls, and these proteins were selected as biomarker candidates. We then used our high-throughput selected reaction monitoring or multiple reaction monitoring (SRM/MRM) methodology, together with an automated sample preparation system, micro LC and auto analysis system, to quantify these candidate proteins in plasma from healthy controls and IDACP patients on a large scale. The results revealed that insulin-like growth factor-binding protein (IGFBP)2 and IGFBP3 have the ability to discriminate IDACP patients at an early stage from healthy controls, and IGFBP2 appeared to be increased in risk diseases of pancreatic malignancy, such as intraductal papillary mucinous neoplasms (IPMNs). Furthermore, diagnosis of IDACP using the combination of carbohydrate antigen 19-9 (CA19-9), IGFBP2 and IGFBP3 is significantly more effective than CA19-9 alone. This suggests that IGFBP2 and IGFBP3 may serve as compensatory biomarkers for CA19-9. Early diagnosis with this marker combination may improve the prognosis of IDACP patients.

15 Clinical Trial Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer. 2016

Kobayashi, Satoshi / Ueno, Makoto / Hara, Hiroki / Irie, Kuniyasu / Goda, Yoshihiro / Moriya, Satoshi / Tezuka, Shun / Tanaka, Masao / Okusaka, Takuji / Ohkawa, Shinichi / Morimoto, Manabu. ·Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama City, Japan. ·Oncology · Pubmed #27303788.

ABSTRACT: OBJECTIVE: In this subanalysis of a phase III trial using three categorized doses of S-1, the influence of the actual doses on safety and efficacy was evaluated. METHODS: We compared the efficacy and safety of the S-1 or gemcitabine plus S-1 combination (GS) arm between the top 10% group and the bottom 10% group according to the initial doses of S-1: ≥77.6 versus ≤65.9 mg/m2/day (n = 28 vs. 28) in the S-1 arm, and ≥65.1 versus ≤53.8 mg/m2/day (n = 27 vs. 28) in the GS arm. RESULTS: Overall and progression-free survival were not significantly different between these two groups: hazard ratios of 0.818 and 0.761 with p values of 0.498 and 0.330 in the S-1 arm, and hazard ratios of 0.836 and 0.759 with p values of 0.557 and 0.323 in the GS arm, respectively. Incidences of grade 3-4 hematological toxicities were significantly higher in the top 10% group than in the bottom 10% group: 42.9 versus 14.3 and 85.2 versus 57.1%, with p values of 0.037 and 0.037 in the S-1 and the GS combination arm, respectively. CONCLUSIONS: Higher actual doses of S-1 were associated with a higher incidence of hematological toxicity even in the same dose setting.

16 Clinical Trial A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer. 2016

Ueno, M / Okusaka, T / Omuro, Y / Isayama, H / Fukutomi, A / Ikeda, M / Mizuno, N / Fukuzawa, K / Furukawa, M / Iguchi, H / Sugimori, K / Furuse, J / Shimada, K / Ioka, T / Nakamori, S / Baba, H / Komatsu, Y / Takeuchi, M / Hyodo, I / Boku, N. ·Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama uenom@kcch.jp. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo. · Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo. · Department of Gastroenterology, The University of Tokyo, Graduate School of Medicine, Tokyo. · Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa. · Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya. · Department of Surgery, Oita Red Cross Hospital, Oita. · Department of Gastroenterology, National Kyushu Cancer Center, Fukuoka. · Department of Gastroenterology, National Hospital Organization Shikoku Cancer Center, Matsuyama. · Gastroenterological Center, Yokohama City University Medical Center, Yokohama. · Department of Medical Oncology, Kyorin University School of Medicine, Tokyo. · Department of Medical Oncology, Saitama Medical University International Medical Center, Saitama. · Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka. · Hepato-biliary-pancreatic Surgery, National Hospital Organization Osaka National Hospital, Osaka. · Department of Gastroenterological Surgery, Kumamoto University, Kumamoto. · Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo. · Department of Clinical Medicine (Biostatistics and Pharmaceutical Medicine), Kitasato University School of Pharmacy, Tokyo. · Division of Gastroenterology, University of Tsukuba, Tsukuba. · Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Japan. ·Ann Oncol · Pubmed #26681680.

ABSTRACT: BACKGROUND: We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC). PATIENTS AND METHODS: Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS). RESULTS: Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37-0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54-1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47-1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group. CONCLUSION: The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting. CLINICAL TRIALS NUMBER: Japan Pharmaceutical Information Center: JapicCTI-111554.

17 Clinical Trial Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer. 2015

Takai, Erina / Totoki, Yasushi / Nakamura, Hiromi / Morizane, Chigusa / Nara, Satoshi / Hama, Natsuko / Suzuki, Masami / Furukawa, Eisaku / Kato, Mamoru / Hayashi, Hideyuki / Kohno, Takashi / Ueno, Hideki / Shimada, Kazuaki / Okusaka, Takuji / Nakagama, Hitoshi / Shibata, Tatsuhiro / Yachida, Shinichi. ·Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 1040045, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo 1040045, Japan. · Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo 1040045, Japan. · Department of Bioinformatics, National Cancer Center Research Institute, Tokyo 1040045, Japan. · Division of Genome Biology, National Cancer Center Research Institute, Tokyo 1040045, Japan. · Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tokyo 1040045, Japan. · Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan. ·Sci Rep · Pubmed #26669280.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect and monitor molecular characteristics of tumors. In the present study, we determined the mutational status of KRAS in plasma cfDNA using multiplex picoliter-droplet digital PCR in 259 patients with PDAC. We constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA and matched germline DNA samples in 48 patients who had ≥1% mutant allele frequencies of KRAS in plasma cfDNA. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2%) examined by targeted deep sequencing of cfDNA. We also analyzed somatic copy number alterations based on the targeted sequencing data using our in-house algorithm, and potentially targetable amplifications were detected. Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients.

18 Clinical Trial Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer. 2015

Ohkawa, S / Okusaka, T / Isayama, H / Fukutomi, A / Yamaguchi, K / Ikeda, M / Funakoshi, A / Nagase, M / Hamamoto, Y / Nakamori, S / Tsuchiya, Y / Baba, H / Ishii, H / Omuro, Y / Sho, M / Matsumoto, S / Yamada, N / Yanagimoto, H / Unno, M / Ichikawa, Y / Takahashi, S / Watanabe, G / Wakabayashi, G / Egawa, N / Tsuda, M / Hosotani, R / Hamada, C / Hyodo, I. ·Department of Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-ku, Yokohama, Kanagawa 241-8515, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. · Department of Gastroenterology, Graduate School of Medicine, University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. · Department of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho Sunto-gun, Shizuoka 411-8777, Japan. · Department of Gastroenterology, Saitama Cancer Center, 780, Komuro, Inamachi, Kitaadachi-gun, Saitama 362-0806, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. · Department of Gastroenterology, National Hospital Organization Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka 811-1395, Japan. · Department of Chemotherapy, Japanese Red Cross Nagoya Daiichi Hospital, 15-1, Michishita-cho, Nakamura-ku, Nagoya, Aichi 453-8511, Japan. · Department of Internal Medicine, Keio University Hospital, 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. · Department of Hepatobiliary-Pancreatic Surgery, Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka 540-0006, Japan. · Department of Surgery, Niigata Cancer Center, 2-15-3, Kawagishi-cho, Chuo-ku, Niigata 951-8566, Japan. · Department of Digestive Surgery, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556, Japan. · Department of Gastroenterology, Cancer Institute Hospital of JFCR, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan. · Department of Chemotherapy, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. · Department of Surgery, Nara Medical University Hospital, 840, Shijo-cho, Kashihara, Nara 634-8522, Japan. · Department of Clinical Oncology, Kyoto University Hospital, 54, Kawahara-cho, Shogoin, Sakyo-ku Kyoto 606-8507, Japan. · Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan. · Department of Surgery, Kansai Medical University Hirakata Hospital, 2-3-1, Shinmachi, Hirakata, Osaka 573-1191, Japan. · Department of Hepatobiliary-Pancreatic Surgery, Tohoku University Hospital, 1-1, Seiryomachi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. · Department of Gastroenterological Surgery, Yokohama City University Hospital, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. · Department of Clinical Oncology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. · Department of Digestive Surgery, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo 105-8470, Japan. · Department of Surgery, Iwate Medical University Hospital, 19-1, Uchimaru, Morioka, Iwate 020-8505, Japan. · Department of Internal Medicine, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1, Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan. · Department of Gastroenterological Oncology, Hyogo Cancer Center, 13-70, Kitaoji-cho, Akashi, Hyogo, 673-8558, Japan. · Department of Surgery, Kobe City Medical Center General Hospital, 2-1-1, Minatojimanakamachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. · Department of Management Science, Tokyo University of Science, 1-3, Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan. · Department of Gastroenterology, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8577, Japan. ·Br J Cancer · Pubmed #25880004.

ABSTRACT: BACKGROUND: This randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer. METHODS: Patients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day(-1) based on body surface area (BSA), orally, days 1-28, every 6 weeks) or SOX (S-1 80/100/120 mg day(-1) based on BSA, orally, days 1-14, plus oxaliplatin 100 mg m(-2), intravenously, day 1, every 3 weeks). The primary end point was PFS. RESULTS: Between January 2009 and July 2010, 271 patients were randomly allocated to either S-1 (n=135) or SOX (n=136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65-1.08; stratified log-rank test P=0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79-1.34; stratified log-rank test P=0.82). The response rate (RR) was 11.5% vs 20.9% (P=0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%). CONCLUSIONS: Although SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.

19 Clinical Trial Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study. 2015

Yamaue, Hiroki / Tsunoda, Takuya / Tani, Masaji / Miyazawa, Motoki / Yamao, Kenji / Mizuno, Nobumasa / Okusaka, Takuji / Ueno, Hideki / Boku, Narikazu / Fukutomi, Akira / Ishii, Hiroshi / Ohkawa, Shinichi / Furukawa, Masayuki / Maguchi, Hiroyuki / Ikeda, Masafumi / Togashi, Yosuke / Nishio, Kazuto / Ohashi, Yasuo. ·Second Department of Surgery Wakayama Medical University, Wakayama, Japan. · Department of Gastroenterology Aichi Cancer Center Hospital, Aichi, Japan. · Hepatobiliary and Pancreatic Oncology Division National Cancer Center Hospital, Tokyo, Japan. · Department of Gastroenterology Shizuoka Cancer Center, Shizuoka, Japan. · Hepatobiliary and Pancreatic Division Cancer Institute Hospital, Tokyo, Japan. · Hepatobiliary and Pancreatic Medical Oncology Division Kanagawa Cancer Center Hospital, Kanagawa, Japan. · Department of Gastroenterology National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. · Center for Gastroenterology Teine-Keijinkai Hospital, Hokkaido, Japan. · Division of Hepatobiliary and Pancreatic Oncology National Cancer Center Hospital East, Chiba, Japan. · Dept Genome Biology Kinki University School of Medicine, Osaka, Japan. · Department of Integrated Science and Engineering for Sustainable society Chuo University, Tokyo, Japan. ·Cancer Sci · Pubmed #25867139.

ABSTRACT: Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival.

20 Clinical Trial Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial. 2015

Ioka, Tatsuya / Okusaka, Takuji / Ohkawa, Shinichi / Boku, Narikazu / Sawaki, Akira / Fujii, Yosuke / Kamei, Yoichi / Takahashi, Satori / Namazu, Katsushi / Umeyama, Yoshiko / Bycott, Paul / Furuse, Junji. ·Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka ioka-ta@mc.pref.osaka.jp. · Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo. · Department of Gastroenterology, Kanagawa Cancer Center, Kanagawa. · Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka. · Department of Clinical Oncology, Kawasaki Medical School, Okayama. · Pfizer Japan Inc., Tokyo, Japan. · Pfizer Oncology, San Diego, CA, USA. · Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan. ·Jpn J Clin Oncol · Pubmed #25647781.

ABSTRACT: OBJECTIVE: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3. This analysis compared efficacy and safety of axitinib plus gemcitabine in patients with advanced pancreatic cancer from Japan, North America and the European Union, enrolled in a randomized Phase III study. METHODS: Patients (n = 632), stratified by disease extent, were randomly assigned (1:1) to receive axitinib/gemcitabine or placebo/gemcitabine. Axitinib was administered at a starting dose of 5 mg orally twice daily and gemcitabine at 1000 mg/m(2) once weekly for 3 weeks in 4 week cycles. Primary endpoint was overall survival. RESULTS: Among Japanese patients, median overall survival was not estimable (95% confidence interval, 7.4 months-not estimable) with axitinib/gemcitabine (n = 58) and 9.9 months (95% confidence interval, 7.4-10.5) with placebo/gemcitabine (n = 56) (hazard ratio 1.093 [95% confidence interval, 0.525-2.274]). Median survival follow-up (range) was 5.1 months (0.02-12.3) with axitinib/gemcitabine vs. 5.4 months (1.8-10.5) with placebo/gemcitabine. Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union. Common adverse events with axitinib/gemcitabine in Japanese patients were fatigue, anorexia, dysphonia, nausea and decreased platelet count. Axitinib safety profile was generally similar in patients from the three regions, although there were differences in incidence of some adverse events. An exploratory analysis did not show any correlation between axitinib/gemcitabine-related hypertension and overall survival. CONCLUSIONS: Axitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions.

21 Clinical Trial A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. 2015

Fuchs, C S / Azevedo, S / Okusaka, T / Van Laethem, J-L / Lipton, L R / Riess, H / Szczylik, C / Moore, M J / Peeters, M / Bodoky, G / Ikeda, M / Melichar, B / Nemecek, R / Ohkawa, S / Świeboda-Sadlej, A / Tjulandin, S A / Van Cutsem, E / Loberg, R / Haddad, V / Gansert, J L / Bach, B A / Carrato, A. ·Department of Medical Oncology/Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston, USA charles_fuchs@dfci.harvard.edu. · Oncology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium. · Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, Australia. · Department of Hematology, Oncology, and Tumor Immunology, Charité University, Berlin, Germany. · Department of Oncology, Military Institute of Health Services, Warsaw, Poland. · Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Department of Oncology, Antwerp University Hospital, Edegum, Belgium. · Department of Oncology, St László Hospital, Budapest, Hungary. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. · Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc. · Department of Oncology, Masaryk University Medical School and Masaryk Memorial Cancer Institute, Brno, Czech Republic. · Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan. · Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland. · Department of Clinical Pharmacology and Chemotherapy, Russian Cancer Research Center, Moscow, Russia. · Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium. · Medical Sciences, Amgen Inc., Thousand Oaks, USA. · Global Biostatistical Science, Amgen Ltd, Cambridge, UK. · Global Development, Thousand Oaks. · Development Oncology Therapeutics, Amgen Inc., Thousand Oaks, USA. · Medical Oncology Department, University Hospital Ramon y Cajal, Madrid, Spain. ·Ann Oncol · Pubmed #25609246.

ABSTRACT: BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

22 Clinical Trial Phase II study of FOLFIRINOX for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer. 2014

Okusaka, Takuji / Ikeda, Masafumi / Fukutomi, Akira / Ioka, Tatsuya / Furuse, Junji / Ohkawa, Shinichi / Isayama, Hiroyuki / Boku, Narikazu. ·Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. ·Cancer Sci · Pubmed #25117729.

ABSTRACT: The FOLFIRINOX combination of chemotherapy drugs had not been fully evaluated for Japanese pancreatic cancer patients. Therefore, we carried out a phase II study to examine the efficacy and safety of FOLFIRINOX in chemotherapy-naïve Japanese patients with metastatic pancreatic cancer. FOLFIRINOX (i.v. infusion of 85 mg/m(2) oxaliplatin, 180 mg/m(2) irinotecan, and 200 mg/m(2) l-leucovorin, followed by a bolus of 400 mg/m(2) fluorouracil and a 46-h continuous infusion of 2400 mg/m(2) fluorouracil) was given every 2 weeks. The primary endpoint was the response rate. The 36 enrolled patients received a median of eight (range, 1-25) treatment cycles. The response rate was 38.9% (95% confidence interval [CI], 23.1-56.5); median overall survival, 10.7 months (95% CI, 6.9-13.2); and median progression-free survival, 5.6 months (95% CI, 3.0-7.8). Major grade 3 or 4 toxicities included neutropenia (77.8%), febrile neutropenia (22.2%), thrombocytopenia (11.1%), anemia (11.1%), anorexia (11.1%), diarrhea (8.3%), nausea (8.3%), elevated alanine aminotransferase levels (8.3%), and peripheral sensory neuropathy (5.6%). Febrile neutropenia occurred only during the first cycle. There were no treatment-related deaths. FOLFIRINOX can be a standard regimen showing favorable efficacy and acceptable toxicity profile in chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.

23 Clinical Trial Safety, tolerability, pharmacokinetics and antitumor activity of ganitumab, an investigational fully human monoclonal antibody to insulin-like growth factor type 1 receptor, combined with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer: a phase 1b study. 2014

Okusaka, Takuji / Ikeda, Masafumi / Fukutomi, Akira / Kobayashi, Yoshikazu / Shibayama, Kazuhiro / Takubo, Takatoshi / Gansert, Jennifer. ·*National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. tokusaka@ncc.go.jp. ·Jpn J Clin Oncol · Pubmed #24782485.

ABSTRACT: OBJECTIVE: Previous Phase 1 studies have shown the acceptable safety profile of ganitumab-a fully human monoclonal antibody to insulin-like growth factor Type 1 receptor-in patients with advanced solid tumors. However, ganitumab 20 mg/kg in combination with gemcitabine had not been administered to patients with metastatic pancreatic cancer. To evaluate the safety, tolerability, pharmacokinetics and antitumor activity of ganitumab 20 mg/kg combined with gemcitabine 1000 mg/m(2) as first-line therapy in patients with metastatic pancreatic cancer, we conducted a Phase 1b study. METHODS: Eligible patients were adults with previously untreated metastatic adenocarcinoma of the pancreas. Patients received gemcitabine 1000 mg/m(2) on Days 1, 8 and 15 plus ganitumab 20 mg/kg on Days 1 and 15 of each 28-day cycle. Gemcitabine was administered intravenously over 30-60 min. Ganitumab was administered intravenously over 60 min after completing gemcitabine infusion. RESULTS: Six patients were enrolled and received the study treatment. All patients had thrombocytopenia and leukopenia. Other most common adverse events were neutropenia and nausea. One patient had a dose-limiting toxicity defined as Grade 3 neutropenia with fever. Exposure to ganitumab 20 mg/kg was not affected by the administration of gemcitabine. No apparent pharmacokinetic drug-drug interaction was observed. No anti-ganitumab antibodies were detected. Five patients had a measurable tumor region at baseline. Of these, four patients had a best response of stable disease. CONCLUSIONS: Ganitumab 20 mg/kg combined with gemcitabine 1000 mg/m(2) was tolerable and showed an acceptable safety profile in patients with untreated metastatic pancreatic cancer.

24 Clinical Trial Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. 2013

Ueno, Hideki / Ioka, Tatsuya / Ikeda, Masafumi / Ohkawa, Shinichi / Yanagimoto, Hiroaki / Boku, Narikazu / Fukutomi, Akira / Sugimori, Kazuya / Baba, Hideo / Yamao, Kenji / Shimamura, Tomotaka / Sho, Masayuki / Kitano, Masayuki / Cheng, Ann-Lii / Mizumoto, Kazuhiro / Chen, Jen-Shi / Furuse, Junji / Funakoshi, Akihiro / Hatori, Takashi / Yamaguchi, Taketo / Egawa, Shinichi / Sato, Atsushi / Ohashi, Yasuo / Okusaka, Takuji / Tanaka, Masao. ·Taiho Pharmaceutical, Tokyo, Japan. ·J Clin Oncol · Pubmed #23547081.

ABSTRACT: PURPOSE: The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival. PATIENTS AND METHODS: The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m(2) on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle). RESULTS: In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P < .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group. CONCLUSION: Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer.

25 Clinical Trial Phase II study of sunitinib in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumor. 2013

Ito, Tetsuhide / Okusaka, Takuji / Nishida, Toshirou / Yamao, Kenji / Igarashi, Hisato / Morizane, Chigusa / Kondo, Shunsuke / Mizuno, Nobumasa / Hara, Kazuo / Sawaki, Akira / Hashigaki, Satoshi / Kimura, Nobuyuki / Murakami, Mami / Ohki, Emiko / Chao, Richard C / Imamura, Masayuki. ·Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, Japan, itopapa@intmed3.med.kyushu-u.ac.jp. ·Invest New Drugs · Pubmed #23269537.

ABSTRACT: BACKGROUND: Pancreatic neuroendocrine tumors (NETs) are rare but are frequently diagnosed at advanced stages and require systemic therapy. PATIENTS AND METHODS: This multicenter, open-label, phase II study evaluated sunitinib in Japanese patients with well-differentiated pancreatic NET. Patients received sunitinib 37.5 mg/day on a continuous daily dosing (CDD) schedule. The primary endpoint was clinical benefit rate (CBR; percentage of complete responses [CRs] plus partial responses [PRs] plus stable disease [SD] ≥ 24 weeks). Secondary endpoints included objective response rate (ORR), tumor shrinkage, progression-free survival (PFS) probability, safety, pharmacokinetics, and biomarkers. RESULTS: Twelve patients received treatment. The CBR was 75 % (95 % confidence interval [CI], 43-94) and included 6 patients with a PR and 3 with SD. The ORR was 50 % (95 % CI, 21-79). PFS probability was 91 % (95 % CI, 54-99) at 6 months and 71 % (95 % CI, 34-90) at 12 months. Commonly reported treatment-emergent (all-causality), any-grade adverse events included diarrhea (n=10), hand-foot syndrome and hypertension (both n=8), fatigue and headache (both n=7), and neutropenia (n=6). No deaths on study were reported; one death due to disease progression occurred >28 days after end of treatment. Sunitinib on a CDD schedule resulted in sustained drug concentrations without accumulation across cycles. Tumor responses in all 12 patients did not appear to correlate with decreases in chromogranin A levels. CONCLUSIONS: Sunitinib 37.5 mg/day on a CDD schedule demonstrated antitumor activity in Japanese patients with unresectable, well-differentiated pancreatic NET. Commonly reported adverse events were consistent with the known safety profile of sunitinib.

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