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Pancreatic Neoplasms: HELP
Articles by Hiroyuki Isayama
Based on 91 articles published since 2010
(Why 91 articles?)
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Between 2010 and 2020, H. Isayama wrote the following 91 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial Which Is Crucial, Strengthen the Foundation or Building the Dream House? 2017

Isayama, Hiroyuki / Nakai, Yousuke / Fujisawa, Toshio. ·Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ·Gut Liver · Pubmed #28647955.

ABSTRACT: -- No abstract --

2 Review Covered versus uncovered metal stents for malignant gastric outlet obstruction: Systematic review and meta-analysis. 2017

Hamada, Tsuyoshi / Hakuta, Ryunosuke / Takahara, Naminatsu / Sasaki, Takashi / Nakai, Yousuke / Isayama, Hiroyuki / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokoyo, Japan. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA. · Department of Gastroenterology, Japanese Red Cross Medical Center, Tokoyo, Japan. · Department of Hepato-Biliary-Pancreatic Medicine, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. ·Dig Endosc · Pubmed #27997723.

ABSTRACT: BACKGROUND AND AIM: Self-expandable metal stents (SEMS) are used for non-resectable malignant gastric outlet obstruction (GOO). Studies of covered versus uncovered SEMS have yielded inconsistent results as a result of heterogeneity in design and patient population. We carried out a meta-analysis to compare covered and uncovered gastroduodenal SEMS. METHODS: Using MEDLINE, Embase, and the Cochrane database, we identified 1624 patients from 13 prospective and retrospective studies that evaluated covered and uncovered SEMS for malignant GOO and were published until October 2016. We pooled data on SEMS dysfunction, technical and clinical success, and adverse events using the fixed-effect or random-effects model. RESULTS: Compared with uncovered SEMS, covered SEMS did not show any significant difference in stent dysfunction risk (risk ratio [RR], 1.02; 95% confidence interval [CI], 0.79-1.32). A subgroup analysis of five randomized trials suggested a trend toward a lower dysfunction risk in covered SEMS (RR, 0.63; 95% CI, 0.45-0.88). Covered SEMS were associated with a lower occlusion risk (RR, 0.44; 95% CI, 0.28-0.68), but with a higher migration risk (RR, 4.28; 95% CI, 2.89-6.34). Technical and clinical success rates were comparable between the groups. Overall adverse events tended to be more frequent in covered SEMS (RR, 1.75; 95% CI, 1.09-2.83). CONCLUSIONS: Outcomes of covered and uncovered gastroduodenal SEMS were comparable, although the lower dysfunction rate of covered SEMS observed in the analysis of randomized trials needs further investigation. Antimigration mechanisms for covered SEMS and identification of patients who can achieve longer patency from uncovered SEMS would help improve the outcomes of gastroduodenal SEMS.

3 Review Progression-free survival as a surrogate for overall survival in first-line chemotherapy for advanced pancreatic cancer. 2016

Hamada, Tsuyoshi / Nakai, Yousuke / Isayama, Hiroyuki / Yasunaga, Hideo / Matsui, Hiroki / Takahara, Naminatsu / Mizuno, Suguru / Kogure, Hirofumi / Matsubara, Saburo / Yamamoto, Natsuyo / Tada, Minoru / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: hamada-tky@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: ynakai-tky@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: isayama-tky@umin.ac.jp. · Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan. Electronic address: yasunagah-tky@umin.ac.jp. · Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan. Electronic address: ptmatsui-tky@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: naminatsu.takahara@gmail.com. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: smizuno-tky@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: kogureh-tky@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: sab-tky@umin.net. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: natsuyoy-gi@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: mtada-tky@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: kkoike-tky@umin.ac.jp. ·Eur J Cancer · Pubmed #27451020.

ABSTRACT: BACKGROUND: Overall survival (OS), as the primary end-point in first-line chemotherapy trials, requires a prolonged follow-up time and may be confounded by subsequent regimens. This study aimed to evaluate the correlation between OS and surrogate end-points (progression-free survival [PFS], response rate and disease control rate), and to identify a potential surrogate for OS in advanced pancreatic cancer. METHODS: Based on an electronic search, we identified randomized controlled phase II and III trials of first-line chemotherapy for advanced pancreatic cancer. Correlation analyses were performed between surrogate end-points and OS, and between improvements in surrogates and those in OS. RESULTS: Fifty trials (II/II-III/III, 17/2/31) with 111 treatment arms were identified, and 15,906 patients were analysed. PFS was most strongly correlated with OS (correlation coefficient, 0.76). Weighted linear regression models revealed the greatest determinant coefficient of 0.84 between the hazard ratio (HR) of the experimental arms compared with the control arms of PFS and that of OS. The approximate equation was log HROS = 0.01 + 0.77 × log HRPFS, indicating that risk reduction of OS via chemotherapy would translate into a 77% risk reduction of PFS. The surrogacy of PFS for OS was robust throughout our subgroup analyses: e.g., biologic versus non-biologic regimens, locally advanced versus metastatic disease. CONCLUSIONS: The surrogacy of PFS for OS in pancreatic cancer was validated. Therefore, the use of PFS as the primary end-point in clinical trials could facilitate the early introduction of new effective chemotherapy regimens into clinical practice.

4 Review Role of endoscopic ultrasonography in pancreatic cystic neoplasms: where do we stand and where will we go? 2014

Nakai, Yousuke / Isayama, Hiroyuki / Itoi, Takao / Yamamoto, Natsuyo / Kogure, Hirofumi / Sasaki, Takashi / Hirano, Kenji / Tada, Minoru / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ·Dig Endosc · Pubmed #24219338.

ABSTRACT: We increasingly encounter pancreatic cystic neoplasms (PCN) in clinical practice and the differential diagnoses vary widely from benign to malignant. There is no 'one and only' diagnostic procedure for PCN. Multiple modalities including computed tomography, magnetic resonance imaging, endoscopic retrograde cholangiopancreatography and endoscopic ultrasound (EUS) are widely used, but EUS has the advantage of anatomical proximity to the pancreas and upper gastrointestinal tract. In addition, EUS-guided fine-needle aspiration (EUS-FNA) provides both cytological evaluation and cyst fluid analysis. Although the role of EUS-FNA for PCN is established, the sensitivity of cytology is low and cyst fluid analysis is only useful for differentiation between mucinous and non-mucinous cysts. Recently, novel through-the-needle imaging under EUS-FNA, such as confocal laserendomicroscopy, is expected to attribute to a better diagnostic yield. Moreover, feasibility of cyst ablation has been reported and the role of EUS has expanded from diagnosis to treatment. However, clinical impact of cyst ablation in terms of safety, efficacy and cost-effectiveness should be validated further. In summary, EUS and EUS-guided intervention does and will play a central role in the management of PCN from surveillance to treatment, but many clinical questions remain unanswered, which warrants well-designed prospective clinical trials.

5 Review Endoscopic retrograde cholangiopancreatography for distal malignant biliary stricture. 2012

Isayama, Hiroyuki / Nakai, Yousuke / Kawakubo, Kazumichi / Kogure, Hirofumi / Hamada, Tsuyoshi / Togawa, Osamu / Sasahira, Naoki / Hirano, Kenji / Tsujino, Takeshi / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. isayama-tky@umin.ac.jp ·Gastrointest Endosc Clin N Am · Pubmed #22748244.

ABSTRACT: Endoscopic biliary stent placement is widely accepted as palliation for malignant biliary obstruction or as a treatment of benign biliary stricture. Although various biliary stent designs have become available since self-expandable metallic stents were introduced, no single ideal stent has been developed. An ideal stent should be patent until death, or surgery, in patients with resectable malignant biliary obstruction. Fewer complications, maneuverability, cost-effectiveness, and removability are also important factors. Alternatively, should we develop a novel method for biliary drainage other than biliary stenting via endoscopic retrograde cholangiopancreatography? This article reviews the current status of biliary stenting for malignant biliary obstructions.

6 Clinical Trial A phase II trial of gemcitabine, S-1 and LV combination (GSL) therapy in patients with advanced pancreatic cancer. 2019

Saito, Kei / Isayama, Hiroyuki / Nakai, Yousuke / Takahara, Naminatsu / Ishigaki, Kazunaga / Takeda, Tsuyoshi / Hakuta, Ryunosuke / Saito, Tomotaka / Uchino, Rie / Kishikawa, Takahiro / Hamada, Tsuyoshi / Mizuno, Suguru / Sasaki, Takashi / Kogure, Hirofumi / Matsubara, Saburo / Yamamoto, Natsuyo / Ijichi, Hideaki / Tateishi, Keisuke / Tada, Minoru / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan. isayama-tky@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan. isayama-tky@umin.ac.jp. ·Invest New Drugs · Pubmed #30411217.

ABSTRACT: Purpose Our previous phase I trial suggested feasibility of addition of leucovorin (LV) to S-1 and gemcitabine therapy in advanced pancreatic cancer. The aim of this phase II trial was to assess the efficacy and toxicity of gemcitabine, S-1 and LV (GSL) combination therapy for advanced pancreatic cancer. Methods Chemotherapy-naïve patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1000 mg/m2 by 30 min infusion on days 1, S-1 40 mg/m2 orally twice daily and LV 25 mg orally twice daily on days 1 to 7 every 2 weeks. Primary end point was progression free survival (PFS). Results A total of 49 patients with advanced pancreatic cancer (19 locally advanced and 30 metastatic) were enrolled. Overall response rate and disease control rate were 32.7% and 87.8%. The median PFS and overall survival (OS) were 10.8 (95% confidence interval [CI], 7.4-13.5) and 20.7 (95% CI 13.0-NA) months with 1-year survival rate of 73.4%. Major Grade 3-4 toxicities were neutropenia (22.4%) and stomatitis (14.3%). No toxicity related death was observed. Conclusions In this single center, phase II trial, gemcitabine, S-1 and LV combination therapy was tolerable and can potentially be a treatment option for advanced pancreatic cancer.

7 Clinical Trial A phase II trial of gemcitabine, S-1 and LV combination (GSL) neoadjuvant chemotherapy for patients with borderline resectable and locally advanced pancreatic cancer. 2018

Saito, Kei / Isayama, Hiroyuki / Sakamoto, Yoshihiro / Nakai, Yousuke / Ishigaki, Kazunaga / Tanaka, Mariko / Watadani, Takeyuki / Arita, Junichi / Takahara, Naminatsu / Mizuno, Suguru / Kogure, Hirofumi / Ijichi, Hideaki / Tateishi, Keisuke / Tada, Minoru / Hasegawa, Kiyoshi / Fukayama, Masashi / Kokudo, Norihiro / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan. isayama-tky@umin.ac.jp. · Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan. isayama-tky@umin.ac.jp. · Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ·Med Oncol · Pubmed #29846849.

ABSTRACT: There has been a pressing need to develop optimal regimen for neoadjuvant chemotherapy (NAC) for pancreatic cancer (PC). The safety and efficacy of gemcitabine, S-1, and LV combination (GSL) therapy as NAC for borderline resectable (BR) and locally advanced (LA) PC was evaluated in this phase II study. Patients with pathologically proven BR or LA PC were enrolled and gemcitabine 1000 mg/m

8 Clinical Trial Preoperative biliary drainage using a fully covered self-expandable metallic stent for pancreatic head cancer: A prospective feasibility study. 2018

Togawa, Osamu / Isayama, Hiroyuki / Kawakami, Hiroshi / Nakai, Yousuke / Mohri, Dai / Hamada, Tsuyoshi / Kogure, Hirofumi / Kawakubo, Kazumichi / Sakamoto, Naoya / Koike, Kazuhiko / Kita, Hiroto. ·Department of Gastroenterology, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo; Department of Gastroenterology, Saitama Medical University International Medical Center, Saitama, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo; Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan. · Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. · Department of Gastroenterology, Saitama Medical University International Medical Center, Saitama; Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan. ·Saudi J Gastroenterol · Pubmed #29652026.

ABSTRACT: Background/Aims: The role of endoscopic preoperative biliary drainage (PBD) for pancreatic head cancer is controversial because of the high incidence of stent occlusion before surgery. This study was performed to evaluate the feasibility and safety of PBD using a fully covered self-expandable metallic stent (FCSEMS). Patients and Methods: This multicenter prospective study involved 26 patients treated for pancreatic head cancer with distal bile duct obstruction from April 2011 to March 2013. An FCSEMS was endoscopically placed in 24 patients. Among these, 7 patients were diagnosed with unresectable cancer, and 17 underwent surgery at a median of 18 days after FCSEMS placement. The main outcome measure was preoperative and postoperative adverse events. Results: Two adverse events (cholecystitis and insufficient resolution of jaundice) occurred between FCSEMS placement and surgery (12%). Postoperative adverse events occurred in eight patients (47%). The cumulative incidence of stent-related adverse events 4 and 8 weeks after FCSEMS placement among the 24 patients who underwent this procedure were 19%. Conclusions: PBD using an FCSEMS is feasible in patients with resectable pancreatic head cancer. Placement of an FCSEMS can be an alternative PBD technique when surgery without delay is impossible. A larger randomized controlled trial is warranted.

9 Clinical Trial Phase II study of lanreotide autogel in Japanese patients with unresectable or metastatic well-differentiated neuroendocrine tumors. 2017

Ito, Tetsuhide / Honma, Yoshitaka / Hijioka, Susumu / Kudo, Atsushi / Fukutomi, Akira / Nozaki, Akira / Kimura, Yasutoshi / Motoi, Fuyuhiko / Isayama, Hiroyuki / Komoto, Izumi / Hisamatsu, Seiichi / Nakajima, Akihiro / Shimatsu, Akira. ·Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Fukuoka Higashi-ku, Fukuoka, Japan. itopapa@med.kyushu-u.ac.jp. · Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan. · Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. · Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. · Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan. · Department of Medical Oncology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan. · Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Hospital, Sapporo, Japan. · Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan. · Gastroenterology, The University of Tokyo Hospital, Tokyo, Japan. · Department of Surgery, Kansai Electric Power Hospital, Osaka, Japan. · Pharmaceutical Research & Development Division, Teijin Pharma Limited, Tokyo, Japan. · Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto, Japan. ·Invest New Drugs · Pubmed #28470558.

ABSTRACT: Background Lanreotide is a long-acting somatostatin analog with demonstrated efficacy against enteropancreatic neuroendocrine tumor (NET) in the phase III (CLARINET) study. Materials and Methods In this single-arm study, Japanese patients with grade (G) 1/G2 NET received lanreotide (120 mg/4 weeks) for 48 weeks. Those who completed the study were enrolled in a long-term extension study. The primary endpoint was the clinical benefit rate (CBR) defined as a complete response, partial response (PR), or stable disease (SD) over 24-weeks. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and pharmacokinetics. Results Thirty-two patients were recruited at 10 sites. The full analysis set (FAS) comprised 28 patients. Primary tumors were located in pancreas (12 patients), foregut (non-pancreas, lung; 1), midgut (2), hindgut (8), and unknown (5). Four patients had gastrinoma of the functional NET, and 3 had multiple endocrine neoplasia type 1. In the FAS, 39.3% had progressive disease at baseline. The CBR at 24 weeks was 64.3% (95% confidence interval; CI: 44.1-81.4), and median PFS was 36.3 weeks (95% CI: 24.1-53.1). PR was confirmed in 1 patient at 60 weeks during the extension study (ORR: 3.6%). Frequent adverse events related to lanreotide included injection site induration (28.1%), faeces pale (18.8%), flatulence (12.5%), and diabetes mellitus (12.5%). Conclusions The efficacy and safety of lanreotide in this study indicated its usefulness as a treatment option for Japanese NET patients. TRIAL REGISTRATION: JapicCTI-132,375, JapicCTI-142,698.

10 Clinical Trial Multicenter, randomized, open-label Phase II study comparing S-1 alternate-day oral therapy with the standard daily regimen as a first-line treatment in patients with unresectable advanced pancreatic cancer. 2017

Yamaue, Hiroki / Shimizu, Atsushi / Hagiwara, Yasuhiro / Sho, Masayuki / Yanagimoto, Hiroaki / Nakamori, Shoji / Ueno, Hideki / Ishii, Hiroshi / Kitano, Masayuki / Sugimori, Kazuya / Maguchi, Hiroyuki / Ohkawa, Shinichi / Imaoka, Hiroshi / Hashimoto, Daisuke / Ueda, Kazuki / Nebiki, Hiroko / Nagakawa, Tatsuya / Isayama, Hiroyuki / Yokota, Isao / Ohashi, Yasuo / Shirasaka, Tetsuhiko. ·Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, 641-8510, Japan. yamaue-h@wakayama-med.ac.jp. · Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, 641-8510, Japan. · Department of Biostatistics, School of Public Health, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. · Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan. · Department of Surgery, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, 573-1010, Japan. · Department of Surgery, Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan. · National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. · Clinical Research Center, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama City, Ehime, 791-0280, Japan. · Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. · Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, 232-0024, Japan. · Center for Gastroenterology, Teine-Keijinkai Hospital, 1-40 Maeda 1-jo 12-chome, Teine-ku, Sapporo, 006-8555, Japan. · Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan. · Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan. · Department of Gastroenterological Surgery, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. · Second Department of Internal Medicine y, Wakayama Medical University, School of Medicine, 811-1, Kimiidera, Wakayama, 641-8510, Japan. · Department of Gastroenterology, Osaka City General Hospital, 2-13-22 Miyakojima-hondori Miyakojima-ku, Osaka, 543-0021, Japan. · Department of Gastroenterology, Hokkaido P.W.F.A.C. Sapporo-Kosei General Hospital, 8-5 Kita 2 Jou Higashi, Chuo-ku, Sapporo, 060-0033, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. · Department of Biostatistics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. · Department of Integrated Science and Engineering for Sustainable Society, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo, 112-8551, Japan. · Kitasato Institute for Life Science, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. ·Cancer Chemother Pharmacol · Pubmed #28251282.

ABSTRACT: PURPOSE: Non-inferiority for overall survival (OS) following alternate-day treatment with the oral anticancer drug S-1 compared with standard daily treatment was assessed in Japanese patients with unresectable advanced pancreatic cancer in a multicenter, randomized, phase II study. This trial was registered at the UMIN Clinical Trials Registry (no. 000008604). METHODS: Chemotherapy-naïve patients with locally advanced or metastatic pancreatic cancer were randomly assigned 2:1 to treatment with alternate-day (twice daily on alternate days from days 1 through 42 of a 42-day cycle) or daily (twice daily on days 1 through 28 of a 42-day cycle) treatment with S-1. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), time to treatment failure, response rate, quality of life assessments, and safety. RESULTS: A total of 190 patients were enrolled, of which 185 were included in the final analysis (alternate-day: 121; daily: 64). Median OS was 9.4 for the alternate-day group and 10.4 months for the daily group [hazard ratio (HR), 1.19; 95% credible interval, 0.86 to 1.64], indicating that non-inferiority of alternate-day treatment to daily treatment was not demonstrated. Median PFS was 3.0 for the alternate-day group and 4.2 months for the daily group (HR, 1.65; 95% credible interval, 1.20-2.29). The incidence of anorexia, fatigue, neutrophils, pigmentation, and pneumonitis was lower in alternate-day treatment compared with daily treatment. CONCLUSION: S-1 for advanced pancreatic cancer should be taken daily as recommended, based on the decreased OS and PFS and marginal improvement in safety observed in the alternate-day group.

11 Clinical Trial Multicenter Phase II Study of Intravenous and Intraperitoneal Paclitaxel With S-1 for Pancreatic Ductal Adenocarcinoma Patients With Peritoneal Metastasis. 2017

Satoi, Sohei / Fujii, Tsutomu / Yanagimoto, Hiroaki / Motoi, Fuyuhiko / Kurata, Masanao / Takahara, Naminatsu / Yamada, Suguru / Yamamoto, Tomohisa / Mizuma, Masamichi / Honda, Goro / Isayama, Hiroyuki / Unno, Michiaki / Kodera, Yasuhiro / Ishigami, Hironori / Kon, Masanori. ·*Department of Surgery, Kansai Medical University †Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine ‡Department of Surgery, Tohoku University Graduate School of Medicine §Department of Surgery, University of Tsukuba ¶Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo ||Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital **Department of Chemotherapy, the University of Tokyo. ·Ann Surg · Pubmed #28059968.

ABSTRACT: OBJECTIVE: To evaluate the clinical efficacy and tolerability of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel combined with S-1, "an oral fluoropyrimidine derivative containing tegafur, gimestat, and otastat potassium" in chemotherapy-naive pancreatic ductal adenocarcinoma (PDAC) patients with peritoneal metastasis. BACKGROUND: PDAC patients with peritoneal metastasis (peritoneal deposits and/or positive peritoneal cytology) have an extremely poor prognosis. An effective treatment strategy remains elusive. METHODS: Paclitaxel was administered i.v. at 50 mg/m and i.p. at 20 mg/m on days 1 and 8. S-1 was administered at 80 mg/m/d for 14 consecutive days, followed by 7 days of rest. The primary endpoint was 1-year overall survival (OS) rate. The secondary endpoints were antitumor effect and safety (UMIN000009446). RESULTS: Thirty-three patients who were pathologically diagnosed with the presence of peritoneal dissemination (n = 22) and/or positive peritoneal cytology (n = 11) without other organ metastasis were enrolled. The tumor was located at the pancreatic head in 7 patients and the body/tail in 26 patients. The median survival time was 16.3 (11.47-22.57) months, and the 1-year survival rate was 62%. The response rate and disease control rate in assessable patients were 36% and 82%, respectively. OS in 8 patients who underwent conversion surgery was significantly higher than that of nonsurgical patients (n = 25, P = 0.0062). Grade 3/4 hematologic toxicities occurred in 42% of the patients and nonhematologic adverse events in 18%. One patient died of thrombosis in the superior mesenteric artery. CONCLUSIONS: This regimen has shown promising clinical efficacy with acceptable tolerability in chemotherapy-naive PDAC patients with peritoneal metastasis.

12 Clinical Trial Intravenous and intraperitoneal paclitaxel with S-1 for treatment of refractory pancreatic cancer with malignant ascites. 2016

Takahara, Naminatsu / Isayama, Hiroyuki / Nakai, Yousuke / Ishigami, Hironori / Satoi, Sohei / Mizuno, Suguru / Kogure, Hirofumi / Matsubara, Saburo / Yamamoto, Natsuyo / Yamaguchi, Hironori / Tada, Minoru / Kitayama, Joji / Watanabe, Toshiaki / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. isayama-tky@umin.ac.jp. · Department of Chemotherapy, The University of Tokyo, Tokyo, Japan. · Department of Surgery, Kansai Medical University, Osaka, Japan. · Department of Surgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan. · Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan. ·Invest New Drugs · Pubmed #27339809.

ABSTRACT: CLINICAL TRIAL REGISTRATION NUMBER: UMIN000005306).

13 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.

14 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.

15 Clinical Trial A phase I trial of gemcitabine, S-1 and LV combination (GSL) therapy in advanced pancreatic cancer. 2014

Nakai, Yousuke / Isayama, Hiroyuki / Saito, Kei / Sasaki, Takashi / Takahara, Naminatsu / Hamada, Tsuyoshi / Mizuno, Suguru / Miyabayashi, Koji / Yamamoto, Keisuke / Mohri, Dai / Kogure, Hirofumi / Yamamoto, Natsuyo / Hirano, Kenji / Ijichi, Hideaki / Tateishi, Keisuke / Tada, Minoru / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan. ·Cancer Chemother Pharmacol · Pubmed #25143299.

ABSTRACT: PURPOSE: In our previous randomized controlled trial, the addition of S-1 to gemcitabine for advanced pancreatic cancer did not prolong overall survival (OS) significantly, despite its higher response rate and longer progression-free survival (PFS). Leucovorin is known to enhance efficacy of S-1, and we conducted this phase I trial of combination therapy of gemcitabine, S-1 and leucovorin (GSL). METHODS: Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Gemcitabine was administered at an escalating dose of 600, 800 and 1,000 mg/m(2) over 30 min on day 1, and oral S-1 at a dose of 40 mg/m(2) twice daily and oral leucovorin at a dose of 25 mg twice daily on days 1-7, every 2 weeks. A standard "3 + 3" phase I dose escalation design was utilized. RESULTS: Fifteen patients were enrolled across three dose levels. Three patients developed DLTs: two patients in level 1 (grade 3 anorexia in 1 and grade 3 anorexia, stomatitis and diarrhea in 1) and one patient in level 2 (grade 3 deep vein thrombosis). No DLT was observed in level 3. Response rate and the disease control rate were 33 and 93 %, respectively. The median PFS and OS were 5.4 and 16.6 months. Ten of 12 patients (83 %) with elevated CA19-9 at baseline had a ≥ 50 % decline. CONCLUSIONS: RD of gemcitabine in GSL was determined as 1,000 mg/m(2). GSL was well tolerable and showed promising results in advanced pancreatic cancer.

16 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.

17 Clinical Trial Intravenous and intraperitoneal paclitaxel with S-1 for refractory pancreatic cancer with malignant ascites: an interim analysis. 2014

Takahara, Naminatsu / Isayama, Hiroyuki / Nakai, Yousuke / Sasaki, Takashi / Ishigami, Hironori / Yamashita, Hiroharu / Yamaguchi, Hironori / Hamada, Tsuyoshi / Uchino, Rie / Mizuno, Suguru / Miyabayashi, Koji / Mohri, Dai / Kawakubo, Kazumichi / Kogure, Hirofumi / Yamamoto, Natsuyo / Sasahira, Naoki / Hirano, Kenji / Ijichi, Hideaki / Tateishi, Keisuke / Tada, Minoru / Kitayama, Joji / Watanabe, Toshiaki / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, , Bunkyo-ku, Tokyo, 113-8655, Japan. ·J Gastrointest Cancer · Pubmed #24676891.

ABSTRACT: OBJECTIVES: Here, we reported an interim analysis of feasibility and safety in the first 10 cases of 30 cases in a phase II trial of intravenous and intraperitoneal paclitaxel combined with S-1 for gemcitabine-refractory pancreatic cancer with malignant ascites. METHODS: Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8 every 3 weeks, and S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7-day rest. RESULTS: Between April 2011 and February 2012, ten patients were enrolled. A partial response was achieved in two patients (20%) and a disease control rate of 50%. The median time to progression and overall survival were 2.1 and 3.4 months, respectively. Malignant ascites was completely resolved in two patients (20%). Major grade 3/4 adverse events were myelosuppression including neutropenia (50%) and catheter-related infection (10%). CONCLUSIONS: This novel combination chemotherapy was feasible and showed promising results in pancreatic cancer patients with malignant ascites (clinical trial registration number: UMIN000005306).

18 Clinical Trial A multicenter phase II trial of gemcitabine and candesartan combination therapy in patients with advanced pancreatic cancer: GECA2. 2013

Nakai, Yousuke / Isayama, Hiroyuki / Ijichi, Hideaki / Sasaki, Takashi / Takahara, Naminatsu / Ito, Yukiko / Matsubara, Saburo / Uchino, Rie / Yagioka, Hiroshi / Arizumi, Toshihiko / Hamada, Tsuyoshi / Miyabayashi, Koji / Mizuno, Suguru / Yamamoto, Keisuke / Kogure, Hirofumi / Yamamoto, Natsuyo / Hirano, Kenji / Sasahira, Naoki / Tateishi, Keisuke / Tada, Minoru / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, Japan, 113-8655. ·Invest New Drugs · Pubmed #23690239.

ABSTRACT: BACKGROUND: Our retrospective study and phase I trial of gemcitabine and candesartan combination therapy suggested the inhibition of renin-angiotensin system potentially has a role in the treatment of advanced pancreatic cancer. The aim of this multicenter phase II trial was to assess the efficacy and toxicity of gemcitabine and candesartan combination therapy for advanced pancreatic cancer. METHODS: Chemotherapy-naive patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1,000 mg/m(2) over 30 min on days 1, 8, and 15 and oral candesartan at a dose of 16 mg in normotensive patients, and 8 mg initially in hypertensive patients, with dose escalation to 16 mg allowed, from days 1 to 28, repeated every 4 weeks. RESULTS: A total of 35 patients with advanced pancreatic cancer were enrolled. Overall response rate and disease control rate were 11.4 % and 62.9 %. The median PFS and OS were 4.3 and 9.1 months with 1-year survival rate of 34.2 %. The median PFS was significantly longer in patients receiving 16 mg compared with 8 mg of candesartan (4.6 vs. 3.5 months, p=0.031). Major severe toxicities were neutropenia (23 %), leukopenia (17 %) and thrombocytopenia (11 %). Grade 2 hypotension was observed in 3 patients (9 %) and candesartan was discontinued in 2 patients due to hypotension. Conclusions In this multicenter phase 2 trial, gemcitabine and candesartan combination therapy was tolerable but failed to demonstrate activity against advanced pancreatic cancer. (UMIN CTR: UMIN000005580).

19 Clinical Trial Uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene (UGT1A1) polymorphisms are associated with toxicity and efficacy in irinotecan monotherapy for refractory pancreatic cancer. 2013

Takahara, Naminatsu / Nakai, Yousuke / Isayama, Hiroyuki / Sasaki, Takashi / Satoh, Yumiko / Takai, Daiya / Hamada, Tsuyoshi / Uchino, Rie / Mizuno, Suguru / Miyabayashi, Koji / Mohri, Dai / Kawakubo, Kazumichi / Kogure, Hirofumi / Yamamoto, Natsuyo / Sasahira, Naoki / Hirano, Kenji / Ijichi, Hideaki / Tada, Minoru / Yatomi, Yutaka / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ·Cancer Chemother Pharmacol · Pubmed #23053265.

ABSTRACT: PURPOSE: The aim of this study was to evaluate the efficacy and safety of irinotecan monotherapy in patients with advanced pancreatic cancer (APC). METHODS: Patients with APC refractory to gemcitabine and S-1 were included. Irinotecan (100 mg/m(2)) was administered on days 1, 8, and 15 every 4 weeks until disease progression or unacceptable toxicity was observed. The relationship between uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene (UGT1A1) polymorphisms and clinical outcomes was evaluated. RESULTS: Between January 2007 and December 2011, 231 cycles were delivered in 56 patients. Irinotecan was administered as second-line chemotherapy in 35.7% of patients and as third-line chemotherapy or later in 64.3%. A partial response was achieved in two (3.6%) and stable disease in 23 patients (41.0%), giving a disease control rate of 44.6%. The median time to progression (TTP) and overall survival (OS) were 2.9 (95% confidence interval [CI] 1.8-3.5) months and 5.3 (95% CI 4.5-6.8) months, respectively. Median survival from the first-line chemotherapy was 19.5 (95% CI 15.3-23.8) months. Major grade 3/4 adverse events included neutropenia (28.6%), anemia (12.5%), and anorexia (10.7%). Patients with *6 and/or *28 allele(s) (n = 15) were associated with grade 3/4 neutropenia and anorexia but showed longer TTP (5.3 vs. 1.8 months; p = 0.05), and OS (8.0 vs. 4.8 months; p = 0.09) than those without *6 and/or *28 (n = 29). CONCLUSIONS: Salvage chemotherapy with irinotecan was moderately effective and well-tolerated in patients with APC refractory to gemcitabine and S-1. UGT1A1 polymorphisms were associated with toxicity and efficacy.

20 Clinical Trial A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study. 2012

Nakai, Y / Isayama, H / Sasaki, T / Sasahira, N / Tsujino, T / Toda, N / Kogure, H / Matsubara, S / Ito, Y / Togawa, O / Arizumi, T / Hirano, K / Tada, M / Omata, M / Koike, K. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan. ·Br J Cancer · Pubmed #22555398.

ABSTRACT: BACKGROUND: This randomised phase II trial compared gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer. METHODS: Patients were randomly assigned to 4-week treatment with gemcitabine alone (1000, mg m(-2) gemcitabine by 30-min infusion on days 1, 8, and 15) or gemcitabine and S-1 combination therapy (1000, mg m(-2) gemcitabine by 30-min infusion on days 1 and 15 and 40 mg m(-2) S-1 orally twice daily on days 1-15). The primary end point was progression-free survival (PFS). RESULTS: Between July 2006 and February 2009, 106 patients were enrolled. The PFS in gemcitabine and S-1 combination arm was significantly longer than in gemcitabine arm (5.4 vs 3.6 months), with a hazard ratio of 0.64 (P=0.036). Overall survival (OS) for gemcitabine and S-1 combination was longer than that for gemcitabine monotherapy (13.5 vs 8.8 months), with a hazard ratio of 0.72 (P=0.104). Overall, grade 3 or 4 adverse events were similar in both arms. CONCLUSION: Gemcitabine and S-1 combination therapy demonstrated longer PFS in advanced pancreatic cancer. Improved OS duration of 4.7 months was found for gemcitabine and S-1 combination therapy, though this was not statistically significant.

21 Clinical Trial Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1. 2012

Nakai, Yousuke / Isayama, Hiroyuki / Ijichi, Hideaki / Sasaki, Takashi / Kogure, Hirofumi / Yagioka, Hiroshi / Miyabayashi, Koji / Mizuno, Suguru / Yamamoto, Keisuke / Mouri, Dai / Kawakubo, Kazumichi / Yamamoto, Natsuyo / Hirano, Kenji / Sasahira, Naoki / Tateishi, Keisuke / Tada, Minoru / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ·Cancer Sci · Pubmed #22515232.

ABSTRACT: Our retrospective study showed inhibition of the renin-angiotensin system was associated with better outcomes in patients with advanced pancreatic cancer receiving gemcitabine. The primary objective of this phase I study was to determine the recommended dose of candesartan in combination with gemcitabine in normotensive patients with advanced pancreatic cancer. Candesartan was given orally at an escalating dose (4, 8, 16, and 32 mg) q.d. daily, and gemcitabine was given 1000 mg/m(2) 30 min i.v. on days 1, 8, and 15, repeated every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicities, grade 2 hypotension, abnormal creatinine or potassium, and grade 3 or 4 other non-hematological toxicities. A standard "3+3" phase I dose-escalation design was used. A total of 14 patients (candesartan 4 mg, three patients; 8 mg, three patients; 16 mg, six patients; 32 mg, two patients) were enrolled. One of six patients at 16 mg showed DLT of grade 4 neutropenia and two of two patients at 32 mg showed DLT of grade 2 hypotension. Response rate and disease control rate were 0% and 79%, respectively. Progression-free survival and overall survival were 7.6 and 22.9 months, respectively. Candesartan 16 mg is the recommended dose in combination with gemcitabine in the treatment of advanced pancreatic cancer. (UMIN CTR: UMIN000002152).

22 Clinical Trial Management of malignant gastric outlet obstruction with a modified triple-layer covered metal stent. 2012

Isayama, Hiroyuki / Sasaki, Takashi / Nakai, Yousuke / Togawa, Osamu / Kogure, Hirofumi / Sasahira, Naoki / Yashima, Yoko / Kawakubo, Kazumichi / Ito, Yukiko / Hirano, Kenji / Tsujino, Takeshi / Toda, Nobuo / Tada, Minoru / Omata, Masao / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ·Gastrointest Endosc · Pubmed #22284092.

ABSTRACT: BACKGROUND: A high incidence of migration with covered metal stents has been reported in malignant gastric outlet obstruction (GOO). A newly modified, partially covered, triple-layer nitinol stent was developed that has a longer uncovered portion (5-15 mm) to prevent stent migration. OBJECTIVE: To estimate the efficacy and safety of the modified covered, triple-layer metal stent. DESIGN: Multicenter, prospective cohort study. SETTING: Three tertiary referral centers. PATIENTS: Fifty consecutive patients (26 with pancreatic carcinoma, 14 with gastric carcinoma, 9 with cholangiocarcinoma, 1 with a metastatic node) who presented with symptomatic unresectable malignant GOO between April 2007 and March 2010. INTERVENTIONS: Endoscopic placement of the modified covered, triple-layer metal stent. MAIN OUTCOME MEASUREMENTS: The primary endpoint was to improve the GOO scoring system (GOOSS) score. Secondary endpoints were success rate, patency, and complications. RESULTS: The median GOOSS score improved significantly (P < .0001) after stenting (from 0 to 3). The technical and clinical success rates were 100% and 90%, respectively. Stent occlusion by tumor overgrowth or ingrowth at the uncovered portion developed in 5 patients (10%). Asymptomatic stent migration occurred in 3 patients (6%) receiving chemotherapy at 95, 230, and 553 days after stent placement, but these patients tolerated solid food 68, 260, and 142 days after stent migration, respectively. Other complications occurred in 1 patient with insufficient expansion, cholangitis, and pancreatitis. No procedure-related deaths occurred. LIMITATIONS: A single-arm study in tertiary-care centers. CONCLUSIONS: The modified covered, triple-layer metal stent was effective and safe for managing malignant GOO and can prevent tumor ingrowth and stent migration. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000004566.).

23 Clinical Trial Gemcitabine and oxaliplatin combination chemotherapy for patients with refractory pancreatic cancer. 2011

Isayama, Hiroyuki / Nakai, Yousuke / Yamamoto, Keisuke / Sasaki, Takashi / Mizuno, Suguru / Yagioka, Hiroshi / Yashima, Yoko / Kawakubo, Kazumichi / Kogure, Hirofumi / Arizumi, Toshihiko / Togawa, Osamu / Ito, Yukiko / Matsubara, Saburo / Yamamoto, Natsuyo / Sasahira, Naoki / Hirano, Kenji / Tsujino, Takeshi / Tada, Minoru / Omata, Masao / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. isayama-tky@umin.ac.jp ·Oncology · Pubmed #21677453.

ABSTRACT: OBJECTIVE: The aim of this study was to investigate the effect of gemcitabine and oxaliplatin combination chemotherapy on refractory pancreatic cancer. METHODS: Patients with advanced pancreatic cancer refractory to gemcitabine and S-1 were treated with gemcitabine 1,000 mg/m² over 30 min and oxaliplatin 85 mg/m² over 120 min on days 1 and 15. Treatment was repeated every 4 weeks and tumor response was assessed every two cycles by RECIST version 1.0. RESULTS: Twenty-two patients with pathologically confirmed pancreatic cancer were enrolled. The treatment was administered as a second-line chemotherapy in eighteen patients (82%) and as a third-line chemotherapy in four patients (18%). Tumor response did not occur in any of the cases. Thirteen patients demonstrated stable diseases, and the disease control rate was 59%. Median overall survival and time to progression were 6.8 months (95% CI, 2.8-11.5) and 2.6 months (95% CI, 1.5-3.8), respectively. Median overall survival from the first-line chemotherapy was 22.7 months (95% CI, 14.8-24.4). The major grade 3/4 adverse events included neutropenia (14%), anorexia (23%), and peripheral neuropathy (14%). CONCLUSIONS: Gemcitabine and oxaliplatin combination chemotherapy was tolerable but had limited activity in patients with advanced pancreatic cancer in a refractory setting.

24 Clinical Trial Impact of S-1 in patients with gemcitabine-refractory pancreatic cancer in Japan. 2010

Nakai, Yousuke / Isayama, Hiroyuki / Sasaki, Takashi / Sasahira, Naoki / Kogure, Hirofumi / Hirano, Kenji / Tsujino, Takeshi / Ijichi, Hideaki / Tateishi, Keisuke / Tada, Minoru / Omata, Masao / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan. ·Jpn J Clin Oncol · Pubmed #20462979.

ABSTRACT: OBJECTIVE: We investigated the impact of S-1 on the prognosis of patients with gemcitabine-refractory pancreatic cancer. METHODS: A total of 108 patients with gemcitabine-refractory pancreatic cancer were divided by the time of S-1 introduction in our institution: 47 patients who experienced progressive disease before February 2005 (pre-S-1 group) and 61 patients showed progressive disease after February 2005 (post-S-1 group). Introduction rates of second-line chemotherapy and survival were compared. Prognostic factors for residual survival were analyzed using the Cox proportional hazards model. RESULTS: Introduction rates of second-line chemotherapy were 12.8% in the pre-S-1 group and 45.9% in the post-S-1 group. Second-line chemotherapy was administered to 34 patients: 29 using S-1, 4 using 5-fluorouracil-based chemoradiation and 1 using 5-fluorouracil. The objective response rate, progression-free survival and overall survival for second-line chemotherapy with S-1 were 17.2%, 2.5 and 7.7 months, respectively. By the introduction of S-1 in our institution, residual survival was prolonged from 3.1 months in the pre-S-1 group to 6.7 months in the post-S-1 group (P < 0.001). Overall survival from the initiation of gemcitabine was 8.8 months in the pre-S-1 group and 11.3 months in the post-S-1 group (P = 0.013). Multivariate analysis identified the post-S-1 group (hazard ratio, 0.43; P = 0.001), gender, performance status, liver metastasis, and lactate dehydrogenase and C-reactive protein levels at progressive disease for gemcitabine to be prognostic factors for residual survival. CONCLUSIONS: The introduction of S-1 might improve the prognosis of patients with gemcitabine-refractory pancreatic cancer.

25 Article Prevalence Rate and Predictive Factors of Pancreatic Diseases in Cases with Pancreatic Duct Dilatation: A Cross-sectional Study of a Large, Healthy Japanese Population. 2020

Fujisawa, Toshio / Isayama, Hiroyuki / Gunji, Toshiaki / Sato, Hajime / Matsuhashi, Nobuyuki. ·Department of Gastroenterology, Juntendo University School of Medicine, Japan. · Department of Gastroenterology, NTT Medical Center Tokyo, Japan. · Center for Preventive Medicine, NTT Medical Center Tokyo, Japan. · Department of Health Policy and Technology Assessment, National Institute of Public Health, Japan. ·Intern Med · Pubmed #31813913.

ABSTRACT: Objectives To clarify the significance of ultrasonographically recorded pancreatic duct dilatation. Methods Various parameters predicting pancreatic disease were evaluated in relation to pancreatic duct dilatation using data from medical checkups of healthy examinees. Results Records of 281,384 subjects were analyzed. Pancreatic duct dilatation (≥3 mm) was determined ultrasonographically in 524 patients (0.19%). Subsequent detailed examinations revealed the presence of pancreatic disease in 24.8% of these patients, including pancreatic cysts (15.6%) and chronic pancreatitis (4.9%). Pancreatic cancer was found in 6 cases (1.3%). Predictive factors of pancreatic diseases in examinees with pancreatic duct dilatation were investigated, and the diameter of the pancreatic duct (p<0.001) and HbA1c (p=0.003) were identified by a multivariate analysis. The diameter of the pancreatic duct (p<0.013), HbA1c (p=0.009), and body mass index (p=0.032) were identified as predictive factors in pancreatic cancer. The diameter of the pancreatic duct (p<0.001), age (p=0.006), and bilirubin (p=0.020) in pancreatic cyst as well as the diameter of the pancreatic duct (p<0.001), white blood cells (p=0.022), HbA1c (p=0.033), and alkaline phosphatase (p=0.043) in chronic pancreatitis were also identified. In patients with pancreatic duct dilatation, the optimal cut-off values were 3.5 mm and 6.1% for the pancreatic duct diameter and age, respectively, based on a receiver operating characteristic analysis. Conclusion In cases with ultrasonography-determined pancreatic duct dilatation, subsequent detailed examinations of the pancreas were necessary because of the high-prevalence rate of 24.8%. In particular, marked pancreatic duct dilatation (≥3.5 mm) and elevated HbA1c (≥6.1%) strongly suggest the presence of pancreatic diseases.

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