Researcher Database

Yoshito Komatsu
Hokkaido University Hospital Cancer Center
Associate Professor

Researcher Profile and Settings

Affiliation

  • Hokkaido University Hospital Cancer Center

Job Title

  • Associate Professor

J-Global ID

Research Interests

  • 緩和ケア   支持療法   ゲノム医療   免疫チェックポイント阻害薬   薬物療法   消化器癌(腫瘍学)   Gastroenterology   Clinical Oncology   

Research Areas

  • Life sciences / Tumor diagnostics and therapeutics

Academic & Professional Experience

  • 2018/10 - Today Hokkaido University Hokkaido University Hospital
  • 2011/04 - Today Hokkaido University Hokkaido University Hospital
  • 2008/01 - 2011/03 Hokkaido University Hokkaido University Hospital
  • 2007/12 - 2008/01 Hokkaido University Hokkaido University Hospital
  • 2008 - 腫瘍センター 准教授
  • 2006 - 2007 地域医療連携センター 講師
  • 2006 - 2007 Lecturer,Community Service Network Center
  • 2007 外来治療センター 准教授
  • 2004 - 2006 北大癌診断治療学講座 腫瘍内科 助手 助手
  • 2004 - 2006 Research Associate
  • 2001 - 2004 北大病態内科学講座 第三内科 助手 助手
  • 2001 - 2004 Research Associate
  • 1998 - 2001 第三内科 研究員
  • 1998 - 2001 Researcher
  • 1993 - 1996 国立がんセンター 中央病院 薬物療法部 職員(医療系)
  • 1993 - 1996 Medical Staff

Education

  • 2001/06 - Today  Hokkaido University  Graduate School of Medicine
  • 1989/03 - Today  Tokyo Medical University
  • 1989/04 - 2001/05  Hokkaido University  School of Medicine

Association Memberships

  • 日本緩和医療学会   日本胃癌学会   米国臨床腫瘍学会   日本大腸肛門病学会   日本消化器病学会   日本癌学会   食道癌研究会   GIST研究会   欧州臨床腫瘍学会   日本内科学会   日本消化器学会   北海道食道癌研究会   北海道消化器癌化学療法研究会   American Society of Clinical Oncology   European Society for Medical Oncology   日本消化管学会   北海道癌治療研究会   

Research Activities

Published Papers

  • Yamaguchi K, Komatsu Y, Satoh T, Uetake H, Yoshino T, Nishida T, Yamazaki N, Takikawa H, Morimoto T, Chosa M, Sunaya T, Hamada Y, Muro K, Sugihara K
    The oncologist 1083-7159 2019/01 [Refereed][Not invited]
  • Denda T, Sakai D, Hamaguchi T, Sugimoto N, Ura T, Yamazaki K, Fujii H, Kajiwara T, Nakajima TE, Takahashi S, Otsu S, Komatsu Y, Nagashima F, Moriwaki T, Esaki T, Sato T, Itabashi M, Oki E, Sasaki T, Sunaga Y, Ziti-Ljajic S, Brillac C, Yoshino T
    Cancer science 1347-9032 2019/01 [Refereed][Not invited]
  • Kato K, Satoh T, Muro K, Yoshikawa T, Tamura T, Hamamoto Y, Chin K, Minashi K, Tsuda M, Yamaguchi K, Machida N, Esaki T, Goto M, Komatsu Y, Nakajima TE, Sugimoto N, Yoshida K, Oki E, Nishina T, Tsuji A, Fujii H, Kunieda K, Saitoh S, Omuro Y, Azuma M, Iwamoto Y, Taku K, Fushida S, Chen LT, Kang YK, Boku N
    Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 1436-3291 2018/12 [Refereed][Not invited]
  • Akira Sawaki, Yasuhide Yamada, Kensei Yamaguchi, Tomohiro Nishina, Toshihiko Doi, Taroh Satoh, Keisho Chin, Narikazu Boku, Yasushi Omuro, Yoshito Komatsu, Yasuo Hamamoto, Wasaburo Koizumi, Shigehira Saji, Manish A Shah, Eric Van Cutsem, Yoon-Koo Kang, Junko Iwasaki, Hiroshi Kuriki, Wataru Ohtsuka, Atsushi Ohtsu
    Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 21 (3) 429 - 438 1436-3291 2018/05 [Refereed][Not invited]
     
    BACKGROUND: AVAGAST was an international, randomized, placebo-controlled phase III study of chemotherapy with or without bevacizumab as first-line therapy for patients with advanced gastric cancer. We performed exploratory analyses to evaluate regional differences observed in the trial. METHODS: Analyses were performed in the placebo plus chemotherapy arm (intention-to-treat population). Chemotherapy was cisplatin 80 mg/m2 for six cycles plus capecitabine (1000 mg/m2 orally bid days 1-14) or 5-fluorouracil (800 mg/m2/day continuous IV infusion days 1-5) every 3 weeks until disease progression or unacceptable toxicity. RESULTS: Overall, 387 patients were assigned to placebo plus chemotherapy (eastern Europe/South America, n = 118; USA/western Europe, n = 81; Korea/other Asia, n = 94; Japan, n = 94). At baseline, poor performance status, liver metastases, and larger tumors were most frequent in eastern Europe/South America and least frequent in Japan. Patients received subsequent chemotherapy after disease progression as follows: eastern Europe/South America (14%); USA/western Europe (37%); Korea/other Asia (61%); and Japan (77%). Hazard ratios for overall survival versus USA/western Europe were 1.47 (95% CI, 1.09-1.99) for eastern Europe/South America, 0.91 (95% CI, 0.67-1.25) for Korea/other Asia, and 0.87 (95% CI, 0.64-1.19) for Japan. CONCLUSIONS: Regional differences in the healthcare environment may have contributed to the differences in overall survival observed in the AVAGAST study.
  • Hideaki Bando, Hideki Shimodaira, Kazumasa Fujitani, Atsuo Takashima, Kensei Yamaguchi, Norisuke Nakayama, Takehiro Takahashi, Eiji Oki, Mizutomo Azuma, Tomohiro Nishina, Shuichi Hironaka, Yoshito Komatsu, Kohei Shitara
    European Journal of Cancer 91 86 - 91 1879-0852 2018/03/01 [Refereed][Not invited]
     
    Background Nanoparticle albumin-bound (nab)-paclitaxel was developed to improve paclitaxel solubility and does not need premedication to avoid infusion-related reactions associated with solvent-based (sb)-paclitaxel. We conducted a phase II trial to investigate the efficacy and safety of nab-paclitaxel plus ramucirumab combination therapy for previously treated advanced gastric cancer. Patients and methods Patients with unresectable advanced gastric cancer refractory to first-line chemotherapy were administered nab-paclitaxel 100 mg/m2 intravenously on days 1, 8 and 15, plus ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary end-point was Independent Review Committee (IRC)–assessed overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), safety and quality of life (QOL). Results Forty-five patients were enrolled 43 received the study treatment. The ORR assessed by the IRC was 54.8% (90% confidence interval [CI] 41.0–68.0) and the primary end-point was met. The DCR was 92.9% (95% CI 80.5–98.5). The IRC-assessed median PFS was 7.6 months (95% CI 5.4–8.1). The median OS was not reached at the data cutoff. The main treatment-related grade 3 or 4 adverse events were decreased neutrophil count (76.7%), decreased white blood cell count (27.9%), anaemia (11.6%), decreased appetite (7.0%), febrile neutropenia (4.7%), hypertension (4.7%) and proteinuria (4.7%). No treatment-related deaths occurred. No QOL deterioration was observed during study treatment. Conclusion Nab-paclitaxel plus ramucirumab combination therapy shows promising activity and manageable toxicities and could be a useful second-line treatment option for patients with previously treated advanced gastric cancer.
  • Toshikazu Moriwaki, Shota Fukuoka, Hiroya Taniguchi, Atsuo Takashima, Yusuke Kumekawa, Takeshi Kajiwara, Kentaro Yamazaki, Taito Esaki, Chinatsu Makiyama, Tadamichi Denda, Hironaga Satake, Takeshi Suto, Naotoshi Sugimoto, Masanobu Enomoto, Toshiaki Ishikawa, Tomomi Kashiwada, Masahiko Sugiyama, Yoshito Komatsu, Hiroyuki Okuyama, Eishi Baba, Daisuke Sakai, Tomoki Watanabe, Takao Tamura, Kimihiro Yamashita, Masahiko Gosho, Yasuhiro Shimada
    Oncologist 23 (1) 7 - 15 1549-490X 2018/01/01 [Refereed][Not invited]
     
    Background: This study compared the efficacy of regorafenib and trifluridine/tipiracil (TFTD) in patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy, because despite their clinical approval, it still remains unclear which of these two drugs should be used as initial treatment. Materials and Methods: The clinical data of patients with mCRC who were treated with regorafenib or TFTD and those of drug-naive patients, between June 2014 and September 2015, were retrospectively collected from 24 institutions in Japan. Overall survival (OS) was evaluated using the Cox's proportional hazard models based on propensity score adjustment for baseline characteristics. Results: A total of 550 patients (223 patients in the regorafenib group and 327 patients in the TFTD group) met all criteria. The median OS was 7.9 months (95% confidence interval [CI], 6.8–9.2) in the regorafenib group and 7.4 months (95% CI, 6.6–8.3) in the TFTD group. The propensity score adjusted analysis showed that OS was similar between the two groups (adjusted hazard ratio [HR], 0.96 95% CI, 0.78–1.18). In the subgroup analysis, a significant interaction with age was observed. Regorafenib showed favorable survival in patients aged < 65 years (HR, 1.29 95% CI, 0.98–1.69), whereas TFTD was favored in patients aged ≥65 years (HR, 0.78 95% CI, 0.59–1.03). Conclusion: No significant difference in OS between regorafenib and TFTD was observed in patients with mCRC. Although the choice of the drug by age might affect survival, a clearly predictive biomarker to distinguish the two drugs should be identified in further studies. Implications for Practice: Previous studies of patients with metastatic colorectal cancer refractory to standard chemotherapy had demonstrated that both regorafenib and trifluridine/tipiracil could result in increased overall survival compared with placebo, but there are no head-to-head trials. This large, multicenter, observational study retrospectively compared the efficacy of regorafenib and trifluridine/tipiracil in 550 patients with metastatic colorectal cancer refractory to standard chemotherapy who had access to both drugs. Although no difference in overall survival was found between the two drugs in adjusted analysis using propensity score, regorafenib showed favorable survival in patients aged < 65 years, whereas trifluridine/tipiracil was favored in patients aged ≥65 years in the subgroup analysis.
  • Daisuke Sakai, Hyun Cheol Chung, Do-Youn Oh, Se Hoon Park, Shigenori Kadowaki, Yeul Hong Kim, Akihito Tsuji, Yoshito Komatsu, Yoon-Koo Kang, Kazunori Uenaka, Sameera R. Wijayawardana, Volker Wacheck, Xuejing Wang, Ayuko Yamamura, Toshihiko Doi
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 80 (6) 1197 - 1207 0344-5704 2017/12 [Refereed][Not invited]
     
    Purpose Mesenchymal-epithelial transition factor (MET) is expressed in gastric cancer and associated with poor clinical outcomes. We assessed activity, safety, and pharmacokinetics of emibetuzumab, a bivalent monoclonal anti-MET antibody that blocks ligand-dependent and ligand-independent MET signaling. Methods This non-randomized, single-arm, Phase 2 study enrolled Asian patients with MET diagnostic positive advanced gastric adenocarcinoma. Emibetuzumab (2000 mg, intravenous) was given on days 1 and 15 (28-day cycle). The primary endpoint was 8-week progression-free survival rate. Secondary objectives included safety, pharmacokinetics, overall survival, and change in tumor size. Results Tumors from 65 patients were immunohistochemically screened to enroll 15 MET diagnostic positive patients (23% positivity; 8 Japanese, 7 Korean; 10 male). Eight-week progression-free survival rate was 0.47 (70% CI, 0.33-0.59). Disease control rate was 40% (target lesion decreases, three patients; no complete/partial responses according to RECIST). Median overall survival was 17.1 weeks (95% CI, 6.3-not achievable). No serious emibetuzumab-related adverse events or new safety signals emerged. Grade >= 3 possibly drug-related adverse events were hyperkalemia, hyponatremia, and hyperuricemia (one each). Emibetuzumab's pharmacokinetics profile was similar to that observed previously. MET expression and clinical outcomes were not obviously associated. Conclusion Emibetuzumab was well tolerated with limited single-agent activity in advanced gastric adenocarcinoma.
  • Yasuyuki Kawamoto, Yoshito Komatsu, Satoshi Yuki, Kentaro Sawada, Tetsuhito Muranaka, Kazuaki Harada, Hiroshi Nakatsumi, Hiraku Fukushima, Atsushi Ishiguro, Masayoshi Dazai, Kazuteru Hatanaka, Michio Nakamura, Ichiro Iwanaga, Minoru Uebayashi, Susumu Sogabe, Yoshimitsu Kobayashi, Takuto Miyagishima, Kota Ono, Naoya Sakamoto, Yuh Sakata
    BMC CANCER 17 (1) 837  1471-2407 2017/12 [Refereed][Not invited]
     
    Background: In Japan, S-1 plus cisplatin (SP) regimen has become a standard therapy for patients with advanced gastric cancer. Moreover, the S-1 plus oxaliplatin regimen is now a standard treatment. Nab-paclitaxel was developed for chemotherapy of gastric cancer in Japanese clinical practice. Nab-paclitaxel, created with albumin-bound paclitaxel particles, has high transferability to tumour tissues and does not cause hypersensitivity reactions because of a different chemical composition compared with docetaxel and paclitaxel. A combination of S-1, nab-paclitaxel and oxaliplatin (which we named ` SNOW regimen') can be a promising triplet therapy for advanced gastric cancer. Although we have to pay attention to chemotherapy-induced neuropathy, we aim to investigate the recommended dose of this regimen in a phase I study. Furthermore, we will investigate its efficacy and toxicity in a phase II study. Methods: The phase I study is a dose-escalation study using a standard 3 plus 3 design, followed by expansion cohorts. The SNOW regimen involves 28-day cycles with escalated doses of nab-paclitaxel (100-175 mg/m2 on days 1 and 15) and fixed doses of oxaliplatin (65 mg/m(2) on days 1 and 15) and S-1 (80 mg/m(2)/day on day 1 to 14). The primary endpoints are assessment of dose limiting toxicities and determination of maximum tolerated dose to investigate the recommended dose in the subsequent phase II study. In the phase II study, the primary endpoint is objective response rate. Secondary endpoints are assessment of safety, progression-free survival, disease control rate, overall survival and time to treatment failure. Adverse events were monitored and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Discussion: Triplet therapies for advanced gastric cancer patients have been evaluated in clinical trials. The SNOW regimen can be a promising new triplet therapy.
  • Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Shunsuke Ohnishi, Yoshito Komatsu, Fumiyuki Sato, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Tomoe Shimazaki, Megumi Kimura, Ayaka Asano, Yoshiyuki Fujimoto, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Seiji Naganuma, Kelly A. Whelan, Hiroshi Nakagawa, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto
    CARCINOGENESIS 38 (11) 1073 - 1083 0143-3334 2017/11 [Refereed][Not invited]
     
    In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor, AZD4547, sharply diminishes CSCs via induction of mesenchym al-epithelial transition. Further experiments revealed that MAPK/Erk kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is crucial for FGF-2-mediated CSC regulation. Pharmacological inhibition of FGF receptor (FGFR)-mediated signaling via AZD4547 did not affect CSCs in Ras mutated cells, implying that Mek/Erk pathway, downstream of FGFR signaling, might be an important regulator of CSCs. Indeed, the Mek inhibitor, trametinib, efficiently suppressed ESCC CSCs even in the context of Ras mutation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Taken together, these findings indicate that FGF-2 is an essential factor regulating CSCs via Mek/Erk signaling in ESCC. Additionally, inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.
  • Toshihiko Doi, Kensei Yamaguchi, Yoshito Komatsu, Kei Muro, Tomohiro Nishina, Takako Eguchi Nakajima, Rui Tang, Hui Yang, Yilong Zhang, A. Scott Jung, Agnes Ang, Hirofumi Yasui
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 47 (11) 1002 - 1009 0368-2811 2017/11 [Refereed][Not invited]
     
    To evaluate the safety (including adverse events and dose-limiting toxicities [DLTs]), tolerability, pharmacokinetics and antitumor activity of the investigational MET inhibitor rilotumumab alone in patients with advanced solid tumors (Part 1) or in combination with cisplatin plus capecitabine (CX) in patients with MET-positive advanced gastric or gastroesophageal junction cancer (Part 2) Adult patients received 10 or 20 mg/kg intravenous (IV) rilotumumab every 2 weeks (Part 1) or 15 mg/kg IV rilotumumab every 3 weeks plus 80 mg/m(2) cisplatin on Day 1 and 1000 mg/m(2) capecitabine twice daily on Days 1-14 of every 21-day cycle (Part 2). Nine patients enrolled in Part 1; 12 patients enrolled in Part 2. One DLT occurred (Grade 3 decreased appetite and stomatitis [Part 2]). Adverse events related to any treatment occurred in 17 patients (81%) and were Grade >= 3 in nine patients (43%). Rilotumumab pharmacokinetics appeared linear, and exposure was unaffected by CX. No patient who received rilotumumab monotherapy in Part 1 had a response. In Part 2, five of eight patients (63%) with measureable disease at baseline had a partial response and two patients (25%) had stable disease; median (95% CI) progression-free survival was 7.0 (2.4-15.4) months; overall survival was 18.2 (5.6-20.4) months. In combination with CX, rilotumumab appeared tolerable and showed antitumor activity in Japanese patients with MET-positive gastric/gastroesophageal junction cancer. However, owing to the results of recent Phase 3 trials of MET inhibitors (including rilotumumab), further development of rilotumumab in this setting is not being pursued. (C) The Author 2017. Published by Oxford University Press. All rights reserved.
  • Takayuki Yoshino, Hiroyuki Uetake, Katsuya Tsuchihara, Kohei Shitara, Kentaro Yamazaki, Eiji Oki, Takeo Sato, Takeshi Naitoh, Yoshito Komatsu, Takeshi Kato, Kazunori Yamanaka, Kouji Iwasaki, Jumpei Soeda, Masamitsu Hihara, Takeharu Yamanaka, Atsushi Ochiai, Kei Muro
    CLINICAL COLORECTAL CANCER 16 (2) 158 - 163 1533-0028 2017/06 [Refereed][Not invited]
     
    Background: It remains unclear whether an anti-VEGF or anti-EGFR antibody with standard doublet chemotherapy is the optimal first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC). Here we outline the PARADIGM study (NCT02394795), designed to evaluate the superiority of panitumumab over bevacizumab, in combination with oxaliplatin/5-fluorouracil/leucovorin (mFOLFOX6) in patients with RAS wild-type chemotherapy-naive mCRC. Patients and Methods: Eligible patients are aged 20 to 79 years with an ECOG performance status of 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. A total of 800 patients are to be randomly assigned (1:1 ratio) to mFOLFOX6 plus panitumumab (n = 400) or bevacizumab (n = 400) and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m(2), l-leucovorin 200 mg/m(2), and 5-fluorouracil (5-FU) I.V. 400 mg/m(2) on day 1; 5-FU continuous I.V. 2400 mg/m(2) on days 1 to 3; and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg on day 1 every 2 weeks. The primary endpoint is overall survival forming the basis to detect a hazard ratio of 0.76 with a 1-sided type I error rate of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. A comprehensive biomarker analysis (NCT02394834) using archival tumor tissue and circulating tumor DNA samples collected at different time points (pretreatment and confirmed progressive
  • Tetsuhito Muranaka, Masaki Kuwatani, Yoshito Komatsu, Kentaro Sawada, Hiroshi Nakatsumi, Yasuyuki Kawamoto, Satoshi Yuki, Yoshimasa Kubota, Kimitoshi Kubo, Shuhei Kawahata, Kazumichi Kawakubo, Hiroshi Kawakami, Naoya Sakamoto
    Journal of Gastrointestinal Oncology 8 (3) 566 - 571 2219-679X 2017/06/01 [Refereed][Not invited]
     
    Background: Irinotecan, oxaliplatin and leucovorin-modulated fluorouracil (FOLFIRINOX) and the combination regimen of gemcitabine and nanoparticle albumin-bound paclitaxel (GnP) (nab-PTX) improve the prognosis of patients with metastatic pancreatic cancer. However, no study has compared the efficacy of the two regimens. We compared retrospectively the efficacy and safety of the two regimens in patients with unresectable pancreatic cancer. Methods: Thirty-eight patients with unresectable locally advanced or metastatic pancreatic cancer received FOLFIRINOX or GnP as first-line chemotherapy between December 2013 and September 2015. In the FOLFIRINOX group, patients received 85 mg/m2 oxaliplatin followed by 180 mg/m2 irinotecan and 200 mg/m2 L-leucovorin, and by 400 mg/m2 fluorouracil as a bolus and 2,400 mg/m2 fluorouracil as a 46-h continuous infusion every 14 days. In the GnP group, patients received 125 mg/m2 nab-PTX followed by 1 g/m2, and gemcitabine on days 1, 8 and 15, repeated every 28 days. Results: Response rate was 6.3% in the FOLFIRINOX group and 40.9% in the GnP group (P=0.025). Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 3.0-4.5] in the FOLFIRINOX group and 6.5 months (95% CI, 6.2-6.9 months) in the GnP group (P=0.031). Drug toxicity in the GnP group was less than in the FOLFIRINOX group. Conclusions: Efficacy and safety of GnP compare favorably to those of FOLFIRINOX in patients with pancreatic cancer. Additional prospective trials are warranted
  • Hideyuki Hayashi, Takashi Kohno, Hideki Ueno, Nobuyoshi Hiraoka, Shunsuke Kondo, Motonobu Saito, Yoko Shimada, Hitoshi Ichikawa, Mamoru Kato, Tatsuhiro Shibata, Chigusa Morizane, Yasunari Sakamoto, Kazuaki Shimada, Yoshito Komatsu, Naoya Sakamoto, Takuji Okusaka
    PANCREAS 46 (3) 335 - 340 0885-3177 2017/03 [Refereed][Not invited]
     
    Objectives: KRAS, CDKN2A, TP53, and SMAD4 have been recognized as major driver genes in pancreatic carcinogenesis. We examined somatic mutations in 50 cancer- related genes, including the four above-mentioned driver genes, to identify genomic biomarkers for predicting the outcome of patients with pancreatic cancer. Methods: Genomic DNA was extracted from fresh-frozen specimens obtained from 100 patients with pancreatic cancer who had undergone a pancreatectomy with curative intent. The mutation profile was obtained using a single targeted deep sequencing assay performed with a nextgeneration sequencer, and the associations with clinicopathological factors were analyzed. Results: Mutations in the KRAS, CDKN2A, TP53, and SMAD4 genes were detected in 96% (96/100), 42% (42/100), 13% (13/100), and 7% (7/100) of all patients, respectively. Among the 71 patients who underwent a radical operation followed by adjuvant chemotherapy, patients with fewer mutations among the four driver genes tended to have a better outcome. A multivariate analysis using the Cox proportional hazard model showed that the presence of 0 to 2 mutated driver genes was an independent predictor of a better overall survival (hazard ratio for death, 0.20; P = 0.0040). Conclusions: The number of mutated driver genes assessed using a targeted deep sequencing assay was a promising prognostic biomarker for pancreatic cancer.
  • Takahiko Kobayashi, Junich Ishida, Yuichi Shimizu, Hiroshi Kawakami, Goki Suda, Tetsuhito Muranaka, Yoshito Komatsu, Masahiro Asaka, Naoya Sakamoto
    TUMOR BIOLOGY 39 (3) 1010428317694547  1010-4283 2017/03 [Refereed][Not invited]
     
    RNA-binding motif 5 is a putative tumor suppressor gene that modulates cell cycle arrest and apoptosis. We recently demonstrated that RNA-binding motif 5 inhibits cell growth through the p53 pathway. This study evaluated the clinical significance of RNA-binding motif 5 expression in gastric cancer and the effects of altered RNA-binding motif 5 expression on cancer biology in gastric cancer cells. RNA-binding motif 5 protein expression was evaluated by immunohistochemistry using the surgical specimens of 106 patients with gastric cancer. We analyzed the relationships of RNA-binding motif 5 expression with clinicopathological parameters and patient prognosis. We further explored the effects of RNA-binding motif 5 downregulation with short hairpin RNA on cell growth and p53 signaling in MKN45 gastric cancer cells. Immunohistochemistry revealed that RNA-binding motif 5 expression was decreased in 29 of 106 (27.4%) gastric cancer specimens. Decreased RNA-binding motif 5 expression was correlated with histological differentiation, depth of tumor infiltration, nodal metastasis, tumor-node-metastasis stage, and prognosis. RNA-binding motif 5 silencing enhanced gastric cancer cell proliferation and decreased p53 transcriptional activity in reporter gene assays. Conversely, restoration of RNA-binding motif 5 expression suppressed cell growth and recovered p53 transactivation in RNA-binding motif 5-silenced cells. Furthermore, RNA-binding motif 5 silencing reduced the messenger RNA and protein expression of the p53 target gene p21. Our results suggest that RNA-binding motif 5 downregulation is involved in gastric cancer progression and that RNA-binding motif 5 behaves as a tumor suppressor gene in gastric cancer.
  • Michio Nakamura, Atsushi Ishiguro, Tetsuhito Muranaka, Hiraku Fukushima, Satoshi Yuki, Kota Ono, Taichi Murai, Chika Matsuda, Ayane Oba, Kazufumi Itaya, Takayuki Sone, Masataka Yagisawa, Yuta Koike, Ayana Endo, Yoko Tsukuda, Yuji Ono, Takahiko Kudo, Atsushi Nagasaka, Shuji Nishikawa, Yoshito Komatsu
    ONCOLOGIST 22 (5) 592 - 600 1083-7159 2017 [Refereed][Not invited]
     
    Background. A multicenter prospective observational study evaluated the effect of gastrointestinal cancer chemotherapy with short-term periodic steroid premedication on bone metabolism. Patients and Methods. Seventy-four patients undergoing chemotherapy for gastrointestinal cancer were studied. The primary endpoints were changes in bone mineral densities (BMDs) and metabolic bone turnover 16 weeks after initiation of chemotherapy. BMDs, measured by dual-energy x-ray absorptiometry, and serum cross-linked N-telopeptides of type I collagen (sNTX), and bone alkaline phosphatase (sBAP) were assessed for evaluation of bone resorption and formation, respectively. Results. In 74.3% (55/74) of the patients, BMDs were significantly reduced at 16 weeks relative to baseline. The percent changes of BMD were 21.89% (95% confidence interval [CI], -2.67% to 21.11%: p<.0001) in the lumbar spine, -2.24% (95% CI, -3.59% to -0.89%: p=.002) in the total hip, and -2.05% (95% CI, -3.11% to -0.99%: p<.0001) in the femoral neck. Although there was no significant difference in sNTX levels during 16 weeks (p=.136), there was a significant increase in sBAP levels (p =.010). Decreased BMD was significantly linked to number of chemotherapy cycles (p=.02). There were no significant correlations between changes in BMDs and the primary site of malignancy, chemotherapy regimens, total cumulative steroid dose, steroid dose intensity, and additive steroid usage. Conclusion. Gastrointestinal cancer chemotherapy with periodic glucocorticoid premedication was associated with reduced BMD and increased sBAP levels, which were linked to number of chemotherapy cycles but independent of primary site, chemotherapy regimen, duration, and additive steroid usage.
  • Hideo Baba, Yasuhide Yamada, Daisuke Takahari, Hiroshi Matsumoto, Kazuhiro Yoshida, Masato Nakamura, Motoki Yoshida, Shigeyoshi Iwamoto, Ken Shimada, Yoshito Komatsu, Yasutsuna Sasaki, Taroh Satoh, Keiichi Takahashi, Hideyuki Mishima, Kei Muro, Masahiko Watanabe, Yuh Sakata, Satoshi Morita, Yasuhiro Shimada, Kenichi Sugihara
    ESMO open 2 (1) e000135  2017 [Refereed][Not invited]
     
    OBJECTIVE: The SOFT study previously demonstrated that S-1 and oxaliplatin (SOX) plus bevacizumab was non-inferior to l-leucovorin, fluorouracil and oxaliplatin (mFOLFOX6) plus bevacizumab in terms of the primary end point of progression-free survival (PFS) as first-line chemotherapy for metastatic colorectal cancer (mCRC). The overall survival (OS) data were immature at the time of the primary analysis. METHODS: A total of 512 patients were enrolled and randomly assigned to receive either mFOLFOX6 plus bevacizumab (5 mg/kg of bevacizumab, followed by 200 mg/m2 of l-leucovorin given simultaneously with 85 mg/m2 of oxaliplatin, followed by a 400 mg/m2 bolus of 5-FU on day 1 and then 2400 mg/m2 of 5-FU as an intravenous infusion over the course of 46 hours, every 2 weeks) or SOX plus bevacizumab (7.5 mg/kg of bevacizumab, 130 mg/m2 of oxaliplatin on day 1 and 40-60 mg of S-1 two times per day for 2 weeks, followed by a 1-week rest). The primary end point was PFS. After the primary analysis, the follow-up survey was cut-off on 30 September 2013, and the final OS data were analysed. RESULTS: With a median follow-up of 37.7 months, the median survival time (MST) was 29.7 months with mFOLFOX6 plus bevacizumab and 29.6 months with SOX plus bevacizumab (HR, 1.018; 95% CI 0.823 to 1.258). Median PFS was 11.7 months in the mFOLFOX6 plus bevacizumab group and 12.2 months in the SOX plus bevacizumab group (HR, 1.051; 95% CI 0.876 to 1.262; pnon-inferiority=0.0115). CONCLUSION: Our results reconfirmed that SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab in terms of PFS. MST did not differ between the groups. SOX plus bevacizumab is considered an effective regimen for first-line chemotherapy in patients with mCRC and can be used instead of mFOLFOX6 plus bevacizumab. TRIAL REGISTRATION NUMBER: JapicCTI-090699.
  • Van Cutsem E, Falcone A, Garcia-Carbonero R, Komatsu Y, Pastorino A, Peeters M, Shimada Y, Yamazaki K, Yoshino T, Zaniboni A, Amellal N, Kanehisa A, Winkler R, Makris L, Mayer RJ, Ohtsu A, Tabernero J
    ESMO open 2 (5) e000261  2017 [Refereed][Not invited]
  • Ralf-Dieter Hofheinz, Gael Deplanque, Yoshito Komatsu, Yoshimitsu Kobayashi, Janja Ocvirk, Patrizia Racca, Silke Guenther, Jun Zhang, Mario E. Lacouture, Aminah Jatoi
    ONCOLOGIST 21 (12) 1483 - 1491 1083-7159 2016/12 [Refereed][Not invited]
     
    Inhibition of the epidermal growth factor receptor (EGFR) is an established treatment that extends patient survival across a variety of tumor types. EGFR inhibitors fall into two main categories: anti-EGFR monoclonal antibodies, such as cetuximab and panitumumab, and first-generation tyrosine kinase inhibitors, such as afatinib, gefitinib, and erlotinib. Skin reactions are the most common EGFR inhibitor-attributable adverse event, resulting in papulopustular (acneiform) eruptions that can be painful and debilitating, and which may potentially have a negative impact on patients' quality of life and social functioning, as well as a negative impact on treatment duration. Shortened treatment duration can, in turn, compromise antineoplastic efficacy. Similarly, appropriate management of skin reactions is dependent on their accurate grading; however, conventional means for grading skin reactions are inadequate, particularly within the context of clinical trials. Treating a skin reaction only once it occurs (reactive treatment strategies) may not be the most effective management approach; instead, prophylactic approaches may be preferable. Indeed, we support the viewpoint that prophylactic management of skin reactions should be recommended for all patients treated with EGFR inhibitors. Appropriate prophylactic management could effectively reduce the severity of skin reactions in patients treated with EGFR inhibitors and therefore has the potential to directly benefit patients and improve drug adherence. Accordingly, here were view published and still-emerging data, and provide practical and evidence-based recommendations and algorithms regarding the optimal prophylactic management of EGFR inhibitor-attributable skin reactions.
  • Hideyuki Hayashi, Yoshito Komatsu, Takumi Uchida, Nobuhiko Abe, Ken Ito, Kouji Hirata, Kana Matsuda, Akira Fujinaga
    JOURNAL OF INFECTION AND CHEMOTHERAPY 22 (12) 826 - 829 1341-321X 2016/12 [Refereed][Not invited]
     
    When we examine a patient with symptoms of acute enteritis in the course of chemotherapy with oral fluoropyrimidines such as uracil-tegafur (often referred to as UFT), we usually suspect 5-fluorouracil-induced enterocolitis. In case of persistent clinical symptoms despite discontinuation of chemotherapy, cytomegalovirus colitis should be considered in the differential diagnosis of chemotherapy-induced enterocolitis. We herein report the case of a patient who underwent surgery for lung adenocarcinoma followed by postoperative adjuvant chemotherapy with uracil-tegafur and was diagnosed as having cytomegalovirus colitis during the therapy. In the course of chemotherapy, cytomegalovirus colitis occasionally occurs even though the patient does not experience severe myelosuppression; thus, it is necessary that we recognize its potential occurrence. (C) 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
  • Komatsu Y
    Gan to kagaku ryoho. Cancer & chemotherapy 43 (11) 1357 - 1360 0385-0684 2016/11 [Refereed][Not invited]
  • Tetsuhito Muranaka, Satoshi Yuki, Yoshito Komatsu, Kentaro Sawada, Kazuaki Harada, Yasuyuki Kawamoto, Hiroshi Nakatsumi, Naoya Sakamoto
    JOURNAL OF GASTRIC CANCER 16 (3) 177 - 181 2093-582X 2016/09 [Refereed][Not invited]
     
    Purpose: The International Organization for Standardization-5fluorouracil (FU) 10 trial found that bolus 5-FU and l-leucovorin was not inferior to S-1 in the treatment of gastric cancer (GC). Continuous 5-FU and the rapid injection of 5-FU have different anti-cancer effects. Thus, bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. Materials and Methods: We retrospectively analyzed the medical records of all patients with S-1 or capecitabine-resistant, unresectable, or recurrent GC treated with bolus 5-FU and l-leucovorin between January 2010 and December 2015 at Hokkaido University Hospital. The bolus 5-FU and l-leucovorin regimen consisted of intravenous l-leucovorin (250 mg/m(2)/2 h) and bolus 5-FU (600 mg/m(2)) administered once weekly followed by a 2-week rest period; each cycle was repeated every 8 weeks. Results: A total of 14 patients were identified. The disease control rate was 35.7%. The median progression-free survival was 1.6 months (95% confidence interval [CI], 1.3 similar to 2.0 months), and the median overall survival was 6.3 months (95% CI, 4.7 similar to 7.9 months). No patient died from treatment-related causes. The most common severe adverse event associated with bolus 5-FU and l-leucovorin was neutropenia, which occurred in 21.4% of patients. Conclusions: Bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. We are planning a multi-center prospective phase II trial to evaluate the efficacy and safety of bolus 5-FU and l-leucovorin treatment for pre-treated unresectable or recurrent GC to confirm the results of this limited, retrospective study.
  • Kohei Shitara, Kei Muro, Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, Yoshito Komatsu, Tomohiro Nishina, Kensei Yamaguchi, Yoshihiko Segawa, Yasushi Omuro, Takao Tamura, Toshihiko Doi, Seigo Yukisawa, Hirofumi Yasui, Fumio Nagashima, Masahiro Gotoh, Taito Esaki, Michael Emig, Kumari Chandrawansa, Astra M. Liepa, Hansjochen Wilke, Yukako Ichimiya, Atsushi Ohtsu
    GASTRIC CANCER 19 (3) 927 - 938 1436-3291 2016/07 [Refereed][Not invited]
     
    We evaluated the safety and efficacy of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients previously treated for advanced gastric or gastroesophageal junction adenocarcinoma in Japanese and Western subgroups from the RAINBOW trial. Patients received ramucirumab at 8 mg/kg or placebo (days 1 and 15) plus paclitaxel at 80 mg/m(2) (days 1, 8, and 15 of a 28-day cycle). End points were compared between treatment arms within Japanese (N = 140) and Western (N = 398) populations. The incidence of adverse events of grade 3 or higher was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 83.8 % vs 52.1 %; Western population, 79.1 % vs 61.9 %). Neutropenia was the commonest adverse event of grade 3 or higher, with a higher incidence for ramucirumab plus paclitaxel (Japanese population, 66.2 % vs 25.4 %; Western population, 32.1 % vs 14.7 %). The incidence of febrile neutropenia was low and was similar between treatment arms in both populations. The overall survival hazard ratio was 0.88 (95 % confidence interval, 0.60-1.28) in the Japanese population and 0.73 (95 % confidence interval, 0.58-0.91) in the Western population. The progression-free survival hazard ratio was 0.50 (95 % confidence interval, 0.35-0.73) in the Japanese population and 0.63 (95 % confidence interval, 0.51-0.79) in the Western population. The objective response rate was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 41.2 % vs 19.4 %; Western population, 26.8 % vs 13.0 %), as was the 6-month survival rate (Japanese population, 94.1 % vs 71.4 %; Western population, 66.0 % vs 49.0 %). Safety profiles of the ramucirumab plus paclitaxel arm were similar between populations, though there was a higher incidence of neutropenia in Japanese patients. Progression-free survival and objective response rate improvements were observed for ramucirumab plus paclitaxel in both populations. NCT01170663.
  • Shuichi Hironaka, Naotoshi Sugimoto, Kensei Yamaguchi, Toshikazu Moriwaki, Yoshito Komatsu, Tomohiro Nishina, Akihito Tsuji, Takako Eguchi Nakajima, Masahiro Gotoh, Nozomu Machida, Hideaki Bando, Taito Esaki, Yasunori Emi, Takashi Sekikawa, Shigemi Matsumoto, Masahiro Takeuchi, Narikazu Boku, Hideo Baba, Ichinosuke Hyodo
    LANCET ONCOLOGY 17 (1) 99 - 108 1470-2045 2016/01 [Refereed][Not invited]
     
    Background Although leucovorin enhances the efficacy of fluorouracil, the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer. Methods In this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1: 1: 1) centrally to receive S-1 plus leucovorin (S-1 40-60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m(2) on day 1, every 2 weeks), or S-1 plus cisplatin (S-1 40-60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m(2) on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635. Findings Between Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28.3-57.8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50.7-79.1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31.4-60.8]) of the 48 patients in the S-1 plus cisplatin group (Fisher's exact test, p=0.84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0.063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0.038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3-4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]). Interpretation S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway.
  • Yoshito Komatsu, Emiko Ohki, Naomi Ueno, Ai Yoshida, Yasuharu Toyoshima, Eiji Ueda, Hiroyuki Houzawa, Kanae Togo, Toshirou Nishida
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 (11) 1016 - 1022 0368-2811 2015/11 [Refereed][Not invited]
     
    Objective: This study was conducted to expand the sunitinib safety database in Japanese imatinib-resistant/-intolerant gastrointestinal stromal tumor patients. Retrospective analyses investigated common adverse events as potential prognostic markers. Methods: Four hundred and seventy patients who received sunitinib between June 2008 and November 2009 were analyzed for safety, progression-free survival and overall survival; 386 for objective response rate; 88% received sunitinib on Schedule 4/2 starting at 50 mg/day. Results: No unexpected safety issues occurred. Grade >= 3 adverse events occurred in 70%, most commonly thrombocytopenia (33%), neutropenia (22%) and leukopenia (15%). Objective response rate was 20% (95% confidence interval 16-24). Median progression-free survival was 22.4 weeks (95% confidence interval, 21.7-24.0). The overall survival rate at 24 weeks was 91% (95% confidence interval, 88-94). Higher relative dose intensity (>= 70 vs. < 70%) during the first 6 weeks and better Eastern Cooperative Oncology Group performance status (0 vs. >= 1) were associated with longer progression-free survival (24.0 vs. 20.1 weeks; P = 0.011; and 24.1 vs. 16.9 weeks; P < 0.001) and higher 24-week overall survival rate (94 vs. 83%; P < 0.001; and 96 vs. 83%; P < 0.001). Increased progression-free survival and overall survival rates were associated with specific adverse events. Cox proportional hazard modeling adjusted for relative dose intensity and performance status established hand-foot syndrome (hazard ratio = 0.636; 95% confidence interval, 0.456-0.888) and leukopenia (hazard ratio = 0.683; 95% confidence interval, 0.492-0.948) occurring within 12 weeks were significantly correlated with increased progression-free survival. Conclusion: Sunitinib showed good efficacy and tolerable safety. Factors associated with greater efficacy were relative dose intensity, performance status and specific early adverse events.
  • Osamu Maehara, Fumiyuki Sato, Mitsuteru Natsuizaka, Ayaka Asano, Yoshimasa Kubota, Jun Itoh, Seiji Tsunematsu, Katsumi Terashita, Yoko Tsukuda, Masato Nakai, Takuya Sho, Goki Suda, Kenichi Morikawa, Koji Ogawa, Makoto Chuma, Koji Nakagawa, Shunsuke Ohnishi, Yoshito Komatsu, Kelly A. Whelan, Hiroshi Nakagawa, Hiroshi Takeda, Naoya Sakamoto
    CANCER BIOLOGY & THERAPY 16 (10) 1453 - 1461 1538-4047 2015/10 [Refereed][Not invited]
     
    In hepatocellular carcinoma (HCC), there exists a highly tumorigenic subset of cells defined by high expression of CD44 and CD133 that has been reported to contain cancer stem-like cells (CSCs). Kruppel-like factor 5 (KLF5) regulates many factors involved in cell cycle, migration, inflammation, angiogenesis and stemness and has cancer-promoting effects in some cancers. While some reports have indicated that KLF5 may have important roles in regulation of CSCs, what role, if any, KLF5 plays in regulation of CSCs in HCC remains to be elucidated. Flow cytometric analysis of CD44 and CD133 in HCC cell lines revealed subpopulations of CD44(High)/CD133(High) and CD44(Low)/CD133(Low) cells. We subsequently sorted these subpopulations and identified KLF5 as a gene that is significantly upregulated in CD44(High)/CD44(High) cells via RNA sequencing using next generation sequencing technology. Moreover, KLF5 overexpression enriched the CD44(High)/CD133(High) subpopulation and, consistent with the up-regulation of CD44(High)/CD133(High) cells, KLF5 overexpressing cells were more resistant to anti-cancer drugs and displayed enhanced colony-formation capacity. By contrast, knock-down of KLF5 by siRNA diminished the CD44(High)/CD133(High) subpopulation. When KLF5 was acetylated by TGF-1, the KLF5-mediated CD44(High)/CD133(High) subpopulation enrichment was abrogated. Oppositely, ectopic expression of an acetylation-deficient KLF5 mutant further increased CD44(High)/CD133(High) subpopulations as compared to cell expressing wild-type KLF5. These findings provide novel mechanistic insight into a pivotal role for KLF5 in the regulation of CSCs in HCC.
  • Taroh Satoh, Kyung Hee Lee, Sun Young Rha, Yasutsuna Sasaki, Se Hoon Park, Yoshito Komatsu, Hirofumi Yasui, Tae-You Kim, Kensei Yamaguchi, Nozomu Fuse, Yasuhide Yamada, Takashi Ura, Si-Young Kim, Masaki Munakata, Soh Saitoh, Kazuto Nishio, Satoshi Morita, Eriko Yamamoto, Qingwei Zhang, Jung-mi Kim, Yeul Hong Kim, Yuh Sakata
    GASTRIC CANCER 18 (4) 824 - 832 1436-3291 2015/10 [Refereed][Not invited]
     
    This multicenter, randomized phase II trial was conducted to compare the efficacy and safety of nimotuzumab plus irinotecan (N-IRI) versus irinotecan alone (IRI) in patients with advanced gastric cancer (AGC) showing disease progression after previous 5-fluorouracil-based therapy.Irinotecan-naive patients (n = 82) received N-IRI (nimotuzumab 400 mg weekly plus irinotecan 150 mg/m(2) biweekly) or IRI (irinotecan 150 mg/m(2) biweekly) until disease progression. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), response rate (RR), safety, tolerability, and the correlation between efficacy and tumor epidermal growth factor receptor (EGFR) expression.Of 83 patients, 40 and 43 patients were randomly assigned to the N-IRI and IRI groups, respectively. In the N-IRI/IRI treatment group, median PFS was 73.0/85.0 days (P = 0.5668), and median OS and RR at 18 months were 250.5/232.0 days (P = 0.9778) and 18.4/10.3 %, respectively. Median PFS and OS in the EGFR 2+/3+ subgroups were 118.5/59.0 and 358.5/229.5 days, respectively. The RR was 33.3/0.0 % in the N-IRI/IRI treatment group. The incidence of grade 3 or higher adverse events was 77.5/64.3 %. No adverse events of grade 3 or higher skin rash or grade 3 or higher infusion-related reaction were reported.There was no superiority of N-IRI over IRI alone in terms of PFS in 5-fluorouracil-refractory AGC patients. However, N-IRI showed potential improvement in the EGFR 2+/3+ subgroup based on improved RR, PFS, and OS.
  • Yoshito Komatsu, Toshihiko Doi, Akira Sawaki, Tatsuo Kanda, Yasuhide Yamada, Iris Kuss, George D. Demetri, Toshirou Nishida
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 20 (5) 905 - 912 1341-9625 2015/10 [Refereed][Not invited]
     
    The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19-0.39; p < 0.0001].A subgroup analysis of Japanese patients in the GRID study was performed to compare the efficacy and safety of oral regorafenib 160 mg once daily with matching placebo, in combination with best supportive care. The primary study endpoint was progression-free survival (PFS); safety was evaluated through the incidence of adverse events (AEs).Seventeen Japanese patients were randomized to regorafenib (n = 12) or placebo (n = 5). Patient demographics were consistent with those of the overall study population. PFS was significantly longer with regorafenib than placebo (HR 0.08; 95 % CI 0.02-0.45; p = 0.000164). Centrally assessed disease control rates were 58 % and 20 % in the regorafenib and placebo groups, respectively (p = 0.080796). Treatment-related adverse events (AEs) were reported in all regorafenib-treated patients and 60 % of placebo recipients; the most frequent AE was hand-foot skin reaction (HFSR) (92 % versus 20 %, respectively).Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced GIST, consistent with the overall GRID study population. AEs, such as HFSR and maculopapular rash, were observed more frequently in Japanese patients. Although dose modification was frequently reported, only one patient with hepatic failure discontinued regorafenib because of AEs.
  • Yoshito Komatsu, Chikashi Ishioka, Ken Shimada, Yasuhide Yamada, Makio Gamoh, Atsushi Sato, Tatsuro Yamaguchi, Satoshi Yuki, Satoshi Morita, Shin Takahashi, Rei Goto, Minoru Kurihara
    BMC CANCER 15 626  1471-2407 2015/09 [Refereed][Not invited]
     
    Background: Metastatic colorectal cancer carries a poor prognosis and cannot be cured by currently available therapy. Chemotherapy designed to prolong survival and improve the quality of life (QOL) of patients is the mainstay of treatment. Standard regimens of FOLFOX/bevacizumab and CapeOX/bevacizumab can cause neurotoxicity, potentially disrupting treatment. The results of 3 phase II studies of combination therapy with S-1, irinotecan, and bevacizumab showed comparable efficacy to mFOLFOX6/bevacizumab and CapeOX/bevacizumab, without severe neurotoxicity. Therefore, the establishment and evaluation of S-1-containing irinotecan-based regimens for first-line treatment are expected to become more important.Methods: The TRICOLORE trial is a multicenter, randomized, open-label, controlled phase III study which aims to evaluate the non-inferiority of combination therapy with S-1/irinotecan/bevacizumab (a 3-week regimen [SIRB] or 4-week regimen [IRIS/bevacizumab]) to oxaliplatin-based standard treatment (mFOLFOX6/bevacizumab or CapeOX/ bevacizumab) in patients with metastatic colorectal cancer who had not previously received chemotherapy. Patients will be randomly assigned to either the control group (mFOLFOX6/bevacizumab or CapeOX/bevacizumab) or study group (SIRB or IRIS/bevacizumab). The target sample size is 450 patients. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival (OS), response rate (RR), time to treatment failure (TTF), relative dose intensity (RDI), the incidence and severity of adverse events, quality of life (QOL), quality-adjusted life years (QALY), health care costs, and relations between biomarkers and treatment response (translational research, TR).Discussion: The results of this study will provide important information that will help to improve the therapeutic strategy for metastatic colorectal cancer, and we believe that this study is very meaningful from the perspective of comparative effectiveness research.
  • Yoshito Komatsu, Kenji Okita, Satoshi Yuki, Tomohisa Furuhata, Hiraku Fukushima, Hiroyuki Masuko, Yasuyuki Kawamoto, Hiroshi Isobe, Takuto Miyagishima, Kazuaki Sasaki, Michio Nakamura, Yoshinobu Ohsaki, Junta Nakajima, Miki Tateyama, Kazunori Eto, Shinya Minami, Ryoji Yokoyama, Ichiro Iwanaga, Hitoshi Shibuya, Mineo Kudo, Koji Oba, Yasuo Takahashi
    Cancer science 106 (7) 891 - 5 1347-9032 2015/07 [Refereed][Not invited]
     
    The purpose of this study is to compare the efficacy of a single administration of dexamethasone (DEX) on day 1 against DEX administration on days 1-3 in combination with palonosetron (PALO), a second-generation 5-HT3 receptor antagonist, for chemotherapy-induced nausea and vomiting (CINV) in non-anthracycline and cyclophosphamide (AC) moderately-emetogenic chemotherapy (MEC). This phase III trial was conducted with a multi-center, randomized, open-label, non-inferiority design. Patients who received non-AC MEC as an initial chemotherapy were randomly assigned to either a group administered PALO (0.75 mg, i.v.) and DEX (9.9 mg, i.v.) prior to chemotherapy (study treatment group), or a group administered additional DEX (8 mg, i.v. or p.o.) on days 2-3 (control group). The primary endpoint was complete response (CR) rate. The CR rate difference was estimated by logistic regression with allocation factors as covariates. The non-inferiority margin was set at -15% (study treatment group - control group). From April 2011 to March 2013, 305 patients who received non-AC MEC were randomly allocated to one of two study groups. Overall, the CR rate was 66.2% in the study treatment group (N = 151) and 63.6% in the control group (N = 154). PALO plus DEX day 1 was non-inferior to PALO plus DEX days 1-3 (difference, 2.5%; 95% confidence interval [CI]: -7.8%-12.8%; P-value for non-inferiority test = 0.0004). There were no differences between the two groups in terms of complete control rate (64.9 vs 61.7%) and total control rate (49.7% vs 47.4%). Anti-emetic DEX administration on days 2-3 may be eliminated when used in combination with PALO in patients receiving non-AC MEC.
  • Fumiyuki Sato, Yoshimasa Kubota, Mitsuteru Natsuizaka, Osamu Maehara, Yutaka Hatanaka, Katsuji Marukawa, Katsumi Terashita, Goki Suda, Shunsuke Ohnishi, Yuichi Shimizu, Yoshito Komatsu, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Kelly A. Whelan, Hiroshi Nakagawa, Naoya Sakamoto
    CANCER BIOLOGY & THERAPY 16 (6) 933 - 940 1538-4047 2015/06 [Refereed][Not invited]
     
    There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44. A novel therapy targeting these cancer stem-like cells (CSCs) is needed to improve prognosis of ESCC. CSCs of ESCC have a mesenchymal phenotype and epithelial-mesenchymal transition (EMT) is critical to enrich and maintain CSCs. EGFR, frequently overexpressed in ESCC, has pivotal roles in EMT induced by TGF- in invasive fronts. Thus, EMT in invasive fronts of ESCC might be important for CSCs and EGFR could be a target of a novel therapy eliminating CSCs. However, effects of EGFR inhibitors on CSCs in ESCC have not been fully examined. EGFR inhibitors, erlotinib and cetuximab, significantly suppressed enrichment of CSCs via TGF-1-mediated EMT. Importantly, EGFR inhibitors sharply suppressed ZEB1 that is essential for EMT in ESCC. Further, EGFR inhibitors activated Notch1 and Notch3, leading to squamous cell differentiation. EGFR inhibition may suppress expression of ZEB1 and induce differentiation, thereby blocking EMT-mediated enrichment of CSCs. In organotypic 3D culture, a form of human tissue engineering, tumor cells in invasive nests showed high expression of CD44. Erlotinib significantly blocked invasion into the matrix and CD44 high expressing CSCs were markedly suppressed by erlotinib in organotypic 3D culture. In conclusion, EMT is a critical process for generation of CSCs and the invasive front of ESCC, where EMT occurs, might form a CSC niche in ESCC. EGFR inhibitors could suppress EMT in invasive fronts and be one therapeutic option targeting against generation of CSCs in ESCC.
  • Takayuki Yoshino, Yoshito Komatsu, Yasuhide Yamada, Kentaro Yamazaki, Akihito Tsuji, Takashi Ura, Axel Grothey, Eric Van Cutsem, Andrea Wagner, Frank Cihon, Yoko Hamada, Atsushi Ohtsu
    INVESTIGATIONAL NEW DRUGS 33 (3) 740 - 750 0167-6997 2015/06 [Refereed][Not invited]
     
    Background In the international, phase III, randomized, double-blind CORRECT trial, regorafenib significantly prolonged overall survival (OS) versus placebo in patients with metastatic colorectal cancer (mCRC) that had progressed on all standard therapies. This post hoc analysis evaluated the efficacy and safety of regorafenib in Japanese and non-Japanese subpopulations in the CORRECT trial. Methods Patients were randomized 2 : 1 to regorafenib 160 mg once daily or placebo for weeks 1-3 of each 4-week cycle. The primary endpoint was OS. Outcomes were assessed using descriptive statistics. Results One hundred Japanese and 660 non-Japanese patients were randomized to regorafenib (n = 67 and n = 438) or placebo (n = 33 and n = 222). Regorafenib had a consistent OS benefit in the Japanese and non-Japanese subpopulations, with hazard ratios of 0.81 (95 % confidence interval [CI] 0.43-1.51) and 0.77 (95 % CI 0.62-0.94), respectively. Regorafenib-associated hand-foot skin reaction, hypertension, proteinuria, thrombocytopenia, and lipase elevations occurred more frequently in the Japanese subpopulation than in the non-Japanese subpopulation, but were generally manageable. Conclusion Regorafenib appears to have comparable efficacy in Japanese and non-Japanese subpopulations, with a manageable adverse-event profile, suggesting that this agent could potentially become a standard of care in patients with mCRC.
  • Robert J. Mayer, Eric Van Cutsem, Alfredo Falcone, Takayuki Yoshino, Rocio Garcia-Carbonero, Nobuyuki Mizunuma, Kentaro Yamazaki, Yasuhiro Shimada, Josep Tabernero, Yoshito Komatsu, Alberto Sobrero, Eveline Boucher, Marc Peeters, Ben Tran, Heinz-Josef Lenz, Alberto Zaniboni, Howard Hochster, James M. Cleary, Hans Prenen, Fabio Benedetti, Hirokazu Mizuguchi, Lukas Makris, Masanobu Ito, Atsushi Ohtsu
    NEW ENGLAND JOURNAL OF MEDICINE 372 (20) 1909 - 1919 0028-4793 2015/05 [Refereed][Not invited]
     
    BACKGROUND Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients. METHODS In this double-blind study, we randomly assigned 800 patients, in a 2: 1 ratio, to receive TAS-102 or placebo. The primary end point was overall survival. RESULTS The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P<0.001). The most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. The median time to worsening performance status (a change in Eastern Cooperative Oncology Group performance status [on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing degrees of disability] from 0 or 1 to 2 or more) was 5.7 months with TAS-102 versus 4.0 months with placebo (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P<0.001). CONCLUSIONS In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival.
  • Muranaka T, Yuki S, Komatsu Y
    Nihon rinsho. Japanese journal of clinical medicine 73 Suppl 2 286 - 290 0047-1852 2015/02 [Refereed][Not invited]
  • Nakatsumi H, Komatsu Y
    Nihon rinsho. Japanese journal of clinical medicine 73 Suppl 2 380 - 383 0047-1852 2015/02 [Refereed][Not invited]
  • Masato Nakamura, Yasuhide Yamada, Kei Muro, Keiichi Takahashi, Hideo Baba, Yasutsuna Sasaki, Yoshito Komatsu, Taroh Satoh, Hideyuki Mishima, Masahiko Watanabe, Yuh Sakata, Satoshi Morita, Yasuhiro Shimada, Kenichi Sugihara
    FUTURE ONCOLOGY 11 (10) 1471 - 1478 1479-6694 2015 [Refereed][Not invited]
     
    A combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) plus bevacizumab has been widely used for the first-line chemotherapy of metastatic colorectal cancer (mCRC). S-1 is an oral fluoropyrimidine preparation that combines tegafur, a prodrug of 5-fluorouracil, with two modulators. Several studies of combination chemotherapy with oxaliplatin plus S-1 (SOX) conducted in Asia have reported promising efficacy and safety in patients with mCRC, suggesting the potential to replace mFOLFOX6. The SOFT trial (JapicCTI-090699) was a randomized Phase III trial designed to evaluate the noninferiority of SOX plus bevacizumab to mFOLFOX6 plus bevacizumab in patients with mCRC. This review summarizes the drug concept of S-1 and the results of clinical trials of S-1 and SOX in CRC and presents an overview of the SOFT trial.
  • Hirofumi Yasui, Kei Muro, Yasuhiro Shimada, Akihito Tsuji, Shinichi Sameshima, Hideo Baba, Taroh Satoh, Tadamichi Denda, Kenji Ina, Tomohiro Nishina, Kensei Yamaguchi, Taito Esaki, Shinya Tokunaga, Hiroyuki Kuwano, Narikazu Boku, Yoshito Komatsu, Masahiko Watanabe, Ichinosuke Hyodo, Satoshi Morita, Kenichi Sugihara
    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 141 (1) 153 - 160 0171-5216 2015/01 [Refereed][Not invited]
     
    The FIRIS study previously demonstrated non-inferiority of IRIS (irinotecan plus S-1) to FOLFIRI (5-fluorouracil/leucovorin with irinotecan) for progression-free survival as the second-line chemotherapy for metastatic colorectal cancer (mCRC) as the primary endpoint. The overall survival (OS) data were immature at the time of the primary analysis. Between 30 January 2006 and 29 January 2008, 426 patients with mCRC who failed in first-line chemotherapy were randomly assigned to receive either FOLFIRI or IRIS. After the primary analysis, the follow-up survey was cut off on 29 July 2010, and the final OS data were analysed. With a median follow-up of 39.2 months, the median OS was 17.4 months in the FOLFIRI group and 17.8 months in the IRIS group [hazard ratio (HR) 0.900; 95 % confidence interval (CI) 0.728-1.112]. In the pre-planned subgroup of patients who received prior chemotherapy containing oxaliplatin, the median OS was 12.7 months in the FOLFIRI group and 15.3 months in the IRIS group (HR 0.755; 95 % CI 0.580-0.983). IRIS is non-inferior to FOLFIRI for OS as second-line chemotherapy for mCRC. IRIS can be an option for second-line chemotherapy of mCRC. (ClinicalTrials.gov Number: NCT00284258).
  • Takahide Sasaki, Nozomu Fuse, Takeshi Kuwata, Shogo Nomura, Kazuhiro Kaneko, Toshihiko Doi, Takayuki Yoshino, Hiromichi Asano, Atsushi Ochiai, Yoshito Komatsu, Naoya Sakamoto, Atsushi Ohtsu
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 (1) 43 - 48 0368-2811 2015/01 [Refereed][Not invited]
     
    Objective: Increased serum human epidermal growth factor receptor 2 levels have been found in metastatic breast cancer patients and are correlated with human epidermal growth factor receptor 2 overexpression in tumor cells. However, the prevalence of serum human epidermal growth factor receptor 2 in gastric cancer patients has not been elucidated. Methods: We retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues and serum samples from 96 advanced gastric cancer patients. Human epidermal growth factor receptor 2 expression and gene amplification in tumor cells were determined by immunohistochemistry and fluorescence in situ hybridization. Serum human epidermal growth factor receptor 2 levels were measured using a chemiluminescent immunoassay. Human epidermal growth factor receptor 2 positivity in tumor cells was defined as immunohistochemistry 2+ with fluorescence in situ hybridization positive or immunohistochemistry 3+ with any fluorescence in situ hybridization results. Results: All tissue samples and serum samples were successfully measured. Nineteen patients (20%) were human epidermal growth factor receptor 2-positive in tumor cells. The median serum human epidermal growth factor receptor 2 level was 9.3 ng/ml (range, 5.0-332.4 ng/ml), and serum human epidermal growth factor receptor 2 levels were significantly separated according to human epidermal growth factor receptor 2 status in tumor cells (P < 0.0001, Wilcoxon's rank sum test); median serum human epidermal growth factor receptor 2 levels in human epidermal growth factor receptor 2-negative patients and -positive patients were 8.9 (range, 5.0-20.5) and 24.0 (range, 9.7-332.4), respectively. There were 15 serum human epidermal growth factor receptor 2-positive patients (16%) using a cutoff value of 15 ng/ml. The sensitivity and the specificity of serum human epidermal growth factor receptor 2 with respect to human epidermal growth factor receptor 2 positivity in tumor cells were 53 and 94%, respectively. Conclusions: Serum human epidermal growth factor receptor 2 measurements cannot be substituted for tissue human epidermal growth factor receptor 2 diagnosis in advanced gastric cancer patients. However, serum human epidermal growth factor receptor 2 levels are associated with human epidermal growth factor receptor 2 overexpression in tumor cells. Further investigations of clinical significance of serum human epidermal growth factor receptor 2 as a predictive marker and a therapy-monitoring marker are warranted.
  • Yoshimitsu Kobayashi, Yoshito Komatsu, Satoshi Yuki, Hiraku Fukushima, Takahide Sasaki, Ichiro Iwanaga, Minoru Uebayashi, Hiroyuki Okuda, Takaya Kusumi, Takuto Miyagishima, Susumu Sogabe, Miki Tateyama, Kazuteru Hatanaka, Yasushi Tsuji, Michio Nakamura, Jun Konno, Fumiyasu Yamamoto, Manabu Onodera, Kazuhiro Iwai, Yuh Sakata, Riichiro Abe, Koji Oba, Naoya Sakamoto
    Future oncology (London, England) 11 (4) 617 - 27 1479-6694 2015 [Refereed][Not invited]
     
    AIM: We planned a randomized, open-label trial to evaluate differences between pre-emptive and reactive skin treatment for panitumumab (Pmab)-associated skin toxicities in Japanese patients with metastatic colorectal cancer. PATIENTS & METHODS: Patients receiving third-line Pmab-containing regimens were randomized to pre-emptive or reactive treatment. The primary end point was the cumulative incidence of ≥grade 2 skin toxicities during 6 weeks. Retrospectively, a dermatologist reviewed skin toxicities, in a blinded manner. RESULTS: A total of 95 patients were enrolled (pre-emptive: 47, reactive: 48). The primary end point was achieved (21.3 and 62.5% [risk ratio: 0.34; p < 0.001], for pre-emptive and reactive treatment, respectively). A similar trend was observed in central review. CONCLUSION: Pre-emptive skin treatment could reduce the severity of Pmab-associated skin toxicities in Japanese metastatic colorectal cancer patients.
  • Hansjochen Wilke, Kei Muro, Eric Van Cutsem, Sang-Cheul Oh, Gyoergy Bodoky, Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, Oleg Lipatov, Tae-You Kim, David Cunningham, Philippe Rougier, Yoshito Komatsu, Jaffer Ajani, Michael Emig, Roberto Carlesi, David Ferry, Kumari Chandrawansa, Jonathan D. Schwartz, Atsushi Ohtsu
    LANCET ONCOLOGY 15 (11) 1224 - 1235 1470-2045 2014/10 [Refereed][Not invited]
     
    Background VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel. Methods This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase. Findings Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9.6 months [95% CI 8.5-10.8] vs 7.4 months [95% CI 6.3-8.4], hazard ratio 0.807 [95% CI 0.678-0.962]; p=0.017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]). Interpretation The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer.
  • Yoshito Komatsu, Takayuki Yoshino, Kentaro Yamazaki, Satoshi Yuki, Nozomu Machida, Takahide Sasaki, Ichinosuke Hyodo, Yutaka Yachi, Hiroshi Onuma, Atsushi Ohtsu
    INVESTIGATIONAL NEW DRUGS 32 (3) 473 - 480 0167-6997 2014/06 [Refereed][Not invited]
     
    Background Efatutazone, a novel oral highly-selective peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, has demonstrated some inhibitory effects on disease stabilization in patients with metastatic colorectal cancer (mCRC) enrolled in previous phase I studies. Here, we evaluate the safety and pharmacokinetics of efatutazone combined with FOLFIRI (5-fluorouracil, levo-leucovorin, and irinotecan) as second-line chemotherapy in Japanese patients with mCRC. Methods Dose-limiting toxicities (DLTs) were evaluated at 2 efatutazone dose levels of 0.25 and 0.50 mg (the recommended dose [RD] of efatutazone monotherapy) twice daily in combination with FOLFIRI in a 3-9 patient cohort. Furthermore, tolerability at the RD level was assessed in additional patients, up to 12 in total. Blood samples for pharmacokinetics and biomarkers and tumor samples for archival tissues were collected from all patients. Results Fifteen patients (0.25 mg, 3; 0.5 mg, 12) were enrolled. No DLTs were observed. Most patients experienced weight increase (100 %) and edema (80.0 %), which were manageable with diuretics. Common grade 3/4 toxicities were neutropenia (93.3 %), leukopenia (46.7 %), and anemia (33.3 %). Stable disease was observed in 8 of the 14 patients evaluable for tumor response. The plasma adiponectin levels increased over time and increased dose. No clear relationship was detected between treatment efficacies and plasma levels of adiponectin as well as the expression levels of PPAR gamma and the retinoid X receptor in tumor tissues. Conclusions Efatutazone combined with FOLFIRI demonstrates an acceptable safety profile and evidence of disease stabilization in Japanese patients with mCRC. The RD for efatutazone monotherapy can be used in combination with FOLFIRI.
  • Akira Sawaki, Tatsuo Kanda, Yoshito Komatsu, Toshirou Nishida
    GASTROENTEROLOGY RESEARCH AND PRACTICE 2014 342986  1687-6121 2014 [Refereed][Not invited]
     
    Purpose. This retrospective, nonrandomized study investigated the effect of imatinib rechallenge plus best supportive care (BSC) on overall survival after imatinib and sunitinib treatment for patients with locally advanced or metastatic gastrointestinal stromal tumor (GIST). Methods. Twenty-six patients who had previously been exposed to both imatinib and sunitinib were enrolled in this study. The treatment regimen was BSC with or without imatinib, based on the patient's choice after discussion with his or her physician. The primary endpoint was overall survival, and secondary endpoints were time to treatment failure, clinical response rate assessed by Choi criteria, and safety. Results. Fourteen patients were treated with imatinib plus BSC and 12 received BSC alone. Median overall survival was greatly improved for the imatinib group, although differences were not significant (22 months for imatinib plus BSC versus 4 months for BSC; P = 0.058). Three patients (21%) had a clinical response in the imatinib group, and one had a clinical response in the BSC alone group. Imatinib was well tolerated. Conclusions. Rechallenge with imatinib may be associated with improvement in overall survival without deteriorating performance status in patients who failed imatinib and sunitinib. A prospective study should be considered to confirm the efficacy of rechallenge with imatinib.
  • Komatsu Y, Harada K, Fukushima H, Yuki S
    Nihon rinsho. Japanese journal of clinical medicine 1 72 (1) 120 - 126 0047-1852 2014/01 [Refereed][Not invited]
  • Yasuhide Yamada, Daisuke Takahari, Hiroshi Matsumoto, Hideo Baba, Masato Nakamura, Kazuhiro Yoshida, Motoki Yoshida, Shigeyoshi Iwamoto, Ken Shimada, Yoshito Komatsu, Yasutsuna Sasaki, Taroh Satoh, Keiichi Takahashi, Hideyuki Mishima, Kei Muro, Masahiko Watanabe, Yuh Sakata, Satoshi Morita, Yasuhiro Shimada, Kenichi Sugihara
    LANCET ONCOLOGY 14 (13) 1278 - 1286 1470-2045 2013/12 [Refereed][Not invited]
     
    Background Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer.Methods We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20-80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m(2) oxaliplatin, 200 mg/m(2) l-leucovorin, 400 mg/m(2) bolus fluorouracil, and 2400 mg/m(2) infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7.5 mg/kg intravenous infusion of bevacizumab and 130 mg/m(2) intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (>= 20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699.Findings Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11.5 months (95% CI 10.7-13.2) in the group assigned to mFOLFOX6 plus bevacizumab and 11.7 months (10.7-12.9) in the group assigned to SOX plus bevacizumab (HR 1.04, 95% CI 0.86-1.27; less than non-inferiority margin of 1.33, p(non-inferiority) = 0.014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0.0029) and neutropenia (84 [34%] vs 22 [9%]; p<0.0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0.019) and diarrhoea (23 [9%] vs seven [3%]; p=0.0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab).Interpretation SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations.
  • Taroh Satoh, Hirofumi Yasui, Kei Muro, Yoshito Komatsu, Shinichi Sameshima, Kensei Yamaguchi, Kenichi Sugihara
    Anticancer Research 33 (9) 3845 - 3854 0250-7005 2013/09 [Refereed][Not invited]
     
    Background: We evaluated the pharmacokinetics of irinotecan (CPT-11) and its metabolites in patients with metastatic colorectal cancer receiving the combination of CPT-11/S-1 (IRIS) or 5-fluorouracil (5-FU)/l-leucovorin (LV)/CPT-11 (FOLFIRI) regimens in the FIRIS trial. Patients and Methods: Serum CPT-11, SN-38 (an active metabolite of CPT-11), and SN-38-glucuronide concentrations were compared between the IRIS and FOLFIRI regimens, and between days 1 and 15 of administration. Correlations between pharmacokinetic data and incidence of neutropenia and diarrhea were also assessed. Results: There were no significant differences in the pharmacokinetics of CPT-11 or its metabolites between days 1 and 15. SN-38 concentrations were correlated with the occurrence of neutropenia, which was significantly more frequent in the FOLFIRI group than in the IRIS group. Conclusion: No alterations in CPT-11 pharmacokinetics after repeated IRIS or FOLFIRI administration were observed. Neutropenia was more frequent in the FOLFIRI group than in the IRIS group because exposure to SN-38 was greater in the former group.
  • Kensei Yamaguchi, Akira Sawaki, Toshihiko Doi, Taroh Satoh, Yasuhide Yamada, Yasushi Omuro, Tomohiro Nishina, Narikazu Boku, Keisho Chin, Yasuo Hamamoto, Hiroya Takiuchi, Yoshito Komatsu, Shigehira Saji, Wasaburo Koizumi, Yoshinori Miyata, Atsushi Sato, Eishi Baba, Takao Tamura, Takashi Abe, Atsushi Ohtsu
    GASTRIC CANCER 16 (2) 175 - 182 1436-3291 2013/04 [Refereed][Not invited]
     
    Capecitabine plus cisplatin (XP) is recognized as one of the global standard first-line chemotherapy regimens for patients with metastatic gastric cancer (mGC). Recent multinational phase III trials in mGC have been conducted with XP as the control arm, although no data on XP in Japanese patients with mGC have been published to date. The AVAGAST (XP +/- A bevacizumab in mGC) and ToGA (XP +/- A trastuzumab in human epidermal growth factor receptor 2 [HER2]-positive mGC) studies were the first two global studies including Japanese mGC patients. The aim of this analysis was to investigate the efficacy and safety of XP in Japanese mGC patients, using AVAGAST and ToGA subgroup data.Efficacy and safety analyses were carried out in Japanese patients with mGC receiving XP alone, based on results from the AVAGAST and ToGA studies. There were differences in the target populations between the two studies; for example, the ToGA study limited patients to those with HER2-positive tumors; therefore, efficacy was evaluated separately.Ninety-four Japanese patients in the AVAGAST study and 50 in the ToGA study received XP alone. Median overall and progression-free survivals were 14.2 and 5.7 months, respectively, in the AVAGAST study, and 17.7 and 5.6 months, respectively, in the ToGA study. Overall response rates were 49.2 % in the AVAGAST and 58.5 % in the ToGA study. Adverse events were generally mild; the most common grade 3/4 events were neutropenia, anemia, anorexia, and nausea.XP is effective and well tolerated in Japanese patients with mGC, and could be one of the standard regimens for the first-line treatment in this cohort.
  • Kohei Shitara, Satoshi Yuki, Kentaro Yamazaki, Yoichi Naito, Hiraku Fukushima, Yoshito Komatsu, Hirofumi Yasui, Toshimi Takano, Kei Muro
    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 139 (4) 595 - 603 0171-5216 2013/04 [Refereed][Not invited]
     
    Five prognostic factors had been previously identified in patients with metastatic colorectal cancer (MCRC) who received irinotecan-based second-line chemotherapy. Patients were classified into three prognostic groups based on significant differences in median overall survival (OS). This study is conducted to validate this classification in an external validation cohort. This retrospective study included 193 patients of an external validation cohort who received irinotecan-based second-line chemotherapy after first-line oxaliplatin-based chemotherapy, with or without bevacizumab at three institutions. Three of the five predefined factors (poorly differentiated adenocarcinoma, LDH a parts per thousand yen400 IU/L, progression-free survival of first-line therapy < 6 months) remained highly significant in the validation cohort, although two (performance status 2 and peritoneal metastasis) were associated with borderline significance. The distribution of the three prognostic groups (low risk = no factors, intermediate risk = 1 factor, high risk = 2 or more factors) was low risk (n = 68; 35 %), intermediate risk (n = 80; 41 %), and high risk (n = 45; 23 %). The median OS of each group were 19.8, 11.0, and 7.9 months, respectively, with significant differences between groups, as found in the previous cohort. The previous prognostic classification of patients with MCRC who received irinotecan-based second-line chemotherapy was validated in another independent cohort. Validation in prospective studies is warranted.
  • Tatsuo Kanda, Toshirou Nishida, Norihito Wada, Osamu Kobayashi, Masakazu Yamamoto, Akira Sawaki, Narikazu Boku, Masato Koseki, Toshihiko Doi, Yasushi Toh, Yoshihiro Kakeji, Toshiro Sugiyama, Yoshito Komatsu, Shojiro Kikuchi, Kyoji Ogoshi, Hitoshi Katai, Kazuhito Miyachi, Seiichi Hirota, Atsushi Ohtsu
    International Journal of Clinical Oncology 18 (1) 38 - 45 1341-9625 2013/02 [Refereed][Not invited]
     
    Background: Imatinib mesylate, a small-molecule tyrosine kinase inhibitor, is currently used for adjuvant therapy of patients who have undergone resection of high-risk gastrointestinal stromal tumors (GISTs). There are no data concerning the efficacy and safety of postoperative adjuvant therapy with imatinib for Japanese or East Asian patients with GIST. Methods: A single-arm, open-label, multicenter trial was conducted in 17 hospitals in Japan. The eligibility criteria included histologically proven primary high-risk GISTs with macroscopic complete resection. Patients were treated with imatinib at a dose of 400 mg/day for 1 year after surgery. The primary endpoint was recurrence-free survival as assessed by Kaplan-Meier analysis. The secondary endpoints were overall survival and safety. This study was registered with ClinicalTrials.gov, number NCT00171977. Results: A total of 64 patients were enrolled between September 2004 and July 2006. The median age of the patients was 59.5 years. Forty-nine (76.6%) patients completed the 1-year treatment, whereas 15 (23.4%) patients did not complete the treatment owing to recurrence, toxicities, and consent withdrawal. At the median follow-up period of 109 weeks, 20 patients had recurrence. The 3-year recurrence rate was 42.7% (95% confidence interval 29.2-56.3%), which exceeded the expected recurrence rate in this trial. The recurrence-free and overall survival rates at 2 years were 71.1 and 93.7%, respectively. The most frequent adverse drug reaction of any grade was eyelid edema (48.4%), followed by neutropenia (40.6%), leukopenia (39.1%), nausea (39.1%), rash (37.5%), and peripheral edema (37.5%), most of which were mild and manageable. Conclusions: Adjuvant therapy with imatinib at 400 mg/day for 1 year is well tolerated by Japanese patients and possibly reduces the risk of early recurrence of high-risk GISTs. © 2011 Japan Society of Clinical Oncology.
  • Sachi Morita, Satoshi Oizumi, Hironobu Minami, Koichi Kitagawa, Yoshito Komatsu, Yutaka Fujiwara, Megumi Inada, Satoshi Yuki, Naomi Kiyota, Ayako Mitsuma, Masataka Sawaki, Hiromi Tanii, Junko Kimura, Yuichi Ando
    INVESTIGATIONAL NEW DRUGS 30 (5) 1950 - 1957 0167-6997 2012/10 [Refereed][Not invited]
     
    Panobinostat (LBH589) is a potent pan-histone deacetylase inhibitor. As a result of promising preclinical data, Phase I and II clinical trials of intravenous and oral panobinostat have been conducted in patients with a wide variety of hematologic and solid tumors. This is the first report of a phase I study to evaluate intravenous panobinostat given on days 1 and 8 of a 21-day cycle in patients with solid tumors. The primary objective was to characterize the safety and tolerability of panobinostat by evaluating the occurrence of dose-limiting toxicity (DLT) and determining the maximum tolerated dose (MTD) in Japanese patients with advanced solid tumors. Secondary objectives included characterizing the pharmacokinetics and assessing antitumor activity. Fourteen patients were assigned to three dose levels (Cohort 1: 10 mg/m(2) [three patients], Cohort 2: 15 mg/m(2) [three patients], Cohort 3: 20 mg/m(2) [eight patients]), according to a standard "3 + 3" design. One patient who received 20 mg/m(2) had a DLT (grade 3 elevation of gamma-glutamyl transpeptidase for > 7 days). Thrombocytopenia was observed in all patients (grade 3 or 4 in 8), the severity of which was dependent on the dose and platelet count at baseline. The thrombocytopenia rapidly resolved within 8 days. Plasma panobinostat levels increased dose dependently, without clinically significant drug accumulation. Stable disease for a parts per thousand yen4 months was observed in six patients; however, there were no complete or partial responses. It is feasible to conclude that 20 mg/m(2) was the MTD and recommend as the starting dose for phase II clinical trials.
  • Takayuki Yoshino, Nobuyuki Mizunuma, Kentaro Yamazaki, Tomohiro Nishina, Yoshito Komatsu, Hideo Baba, Akihito Tsuji, Kensei Yamaguchi, Kei Muro, Naotoshi Sugimoto, Yasushi Tsuji, Toshikazu Moriwaki, Taito Esaki, Chikuma Hamada, Takanori Tanase, Atsushi Ohtsu
    LANCET ONCOLOGY 13 (10) 993 - 1001 1470-2045 2012/10 [Refereed][Not invited]
     
    Background Treatments that confer survival benefit are needed in patients with heavily pretreated metastatic colorectal cancer. The aim of this trial was to investigate the efficacy and safety of TAS-102-a novel oral nucleoside antitumour agent. Methods Between August 25, 2009, and April 12, 2010, we undertook a multicentre, double-blind, randomised, placebo-controlled phase 2 trial in Japan. Eligible patients were 20 years or older; had confirmed colorectal adenocarcinoma; had a treatment history of two or more regimens of standard chemotherapy; and were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin. Patients had to be able to take oral drugs; have measurable lesions; have an Eastern Cooperative Oncology Group performance status of between 0 and 2; and have adequate bone-marrow, hepatic, and renal functions within 7 days of enrolment. Patients were randomly assigned (2: 1) to either TAS-102 (35 mg/m(2) given orally twice a day in a 28-day cycle [2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period]) or placebo; all patients received best supportive care. Randomisation was done with minimisation methods, with performance status as the allocation factor. The randomisation sequence was generated with a validated computer system by an independent team from the trial sponsor. Investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety analyses were done in the per-protocol population. The study is in progress and is registered with Japan Pharmaceutical Information Center, number JapicCTI-090880. Findings 112 patients allocated to TAS-102 and 57 allocated to placebo made up the intention-to-treat population. Median follow-up was 11.3 months (IQR 10.7-14.0). Median overall survival was 9.0 months (95% CI 7.3-11.3) in the TAS-102 group and 6.6 months (4.9-8.0) in the placebo group (hazard ratio for death 0.56, 80% CI 0.44-0.71, 95% CI 0.39-0.81; p=0.0011). 57 (50%) of 113 patients given TAS-102 in the safety population had neutropenia of grade 3 or 4, 32 (28%) leucopenia, and 19 (17%) anaemia. No patient given placebo had grade 3 or worse neutropenia or leucopenia; three (5%) of 57 had grade 3 or worse anaemia. Serious adverse events occurred in 21 (19%) patients in the TAS-102 group and in five (9%) in the placebo group. No treatment-related deaths occurred. Interpretation TAS-102 has promising efficacy and a manageable safety profile in patients with metastatic colorectal cancer who are refractory or intolerant to standard chemotherapies.
  • Yoshito Komatsu, Satoshi Yuki, Susumu Sogabe, Hiraku Fukushima, Hiroshi Nakatsumi, Yoshimitsu Kobayashi, Ichiro Iwanaga, Michio Nakamura, Kazuteru Hatanaka, Takuto Miyagishima, Mineo Kudo, Masaki Munakata, Takashi Meguro, Miki Tateyama, Yuh Sakata
    ACTA ONCOLOGICA 51 (7) 867 - 872 0284-186X 2012/09 [Refereed][Not invited]
     
    Background. In Japan, a study comparing the effectiveness and safety of irinotecan plus S-1 (IRIS) with those of a combination of 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line treatment in patients with advanced or recurrent colorectal cancer demonstrated that IRIS was non-inferior to FOLFIRI. We previously reported that IRIS is also effective as first-line treatment. Patients and methods. Eligibility criteria included inoperable recurrent colorectal cancer with a confirmed diagnosis of adenocarcinoma, age >= 20 years, and no history of prior chemotherapy. S-1 (40-60 mg twice daily) was given orally on Days 1 to 14, and irinotecan (100 mg/m(2)) and bevacizumab (5 mg/kg) were given intravenously on Days 1 and 15 of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included overall response (OR), progression-free survival (PFS), and overall survival (OS). Results. A total of 52 eligible patients were enrolled from October 2007 through March 2009. In safety analysis, the incidences of grade 3 or 4 adverse reactions were as follows: neutropenia, 27%; hypertension, 21%; and diarrhea, 17%. The overall response rate was 57.7%. Median progression-free survival was 16.7 months. Conclusion. IRIS plus bevacizumab is a well-tolerated, highly effective chemotherapeutic regimen that is easy to administer.
  • Yasushi Tsuji, Taroh Satoh, Akihito Tsuji, Kei Muro, Motoki Yoshida, Tomohiro Nishina, Michitaka Nagase, Yoshito Komatsu, Takeshi Kato, Yoshinori Miyata, Naoko Mizutani, Satoshi Hashigaki, Maria Jose Lechuga, Tadamichi Denda
    CANCER SCIENCE 103 (8) 1502 - 1507 1347-9032 2012/08 [Refereed][Not invited]
     
    This phase II, open-label, single-arm study investigated sunitinib + FOLFIRI in Japanese patients with treatment-naive unresectable/metastatic colorectal cancer. Patients received i.v. FOLFIRI (levo-leucovorin 200 mg/m2 + irinotecan 180 mg/m2, followed by 5-fluorouracil 400 mg/m2 bolus then 2400 mg/m2 46-h infusion) every 2 weeks, and oral sunitinib 37.5 mg/day on Schedule 4/2 (4 weeks on, 2 weeks off), until disease progression or treatment withdrawal. Progression-free survival (PFS) was the primary endpoint, with a target median of 10.8 months (35% improvement over FOLFIRI alone). Seventy-one patients started a median of 3 (range 111) sunitinib cycles (median relative dose intensity, <60%). The median PFS was 6.7 months (95% confidence interval, 4.79.2) by independent review, 7.2 months (95% confidence interval, 5.49.5) by investigator assessment. Objective response rate (complete responses + partial responses) was 36.6% (independent review) and 42.3% (investigator assessment). Clinical benefit rate (complete responses + partial responses + stable disease) was 83.1% (independent review) and 88.7% (investigator assessment). Common all-causality, any-grade, adverse events were: neutropenia and leukopenia (both 97.2%); thrombocytopenia (84.5%); diarrhea and nausea (both 78.9%); decreased appetite (74.6%); and fatigue (66.2%). Neutropenia (96%) was the most frequent grade 3/4 adverse event. This study was closed early due to findings from a concurrent phase III study of sunitinib + FOLFIRI in non-Japanese patients with metastatic colorectal cancer. In conclusion, the median PFS for sunitinib + FOLFIRI in Japanese patients was shorter than the 10.8 month target, indicating that sunitinib did not add to the antitumor activity of FOLFIRI. This study was registered with (NCT00668863). (Cancer Sci 2012; 103: 15021507)
  • Kohei Shitara, Satoshi Yuki, Motoki Yoshida, Daisuke Takahari, Setsuo Utsunomiya, Tomoya Yokota, Yozo Sato, Yoshitaka Inaba, Masahiro Tajika, Hiroki Kawai, Hidekazu Yamaura, Mina Kato, Kentaro Yamazaki, Yoshito Komatsu, Kei Muro
    INVESTIGATIONAL NEW DRUGS 30 (2) 787 - 793 0167-6997 2012/04 [Refereed][Not invited]
     
    The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with every second week cetuximab and irinotecan in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with wild-type KRAS metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. Cetuximab was administered at 500 mg/m(2) biweekly with irinotecan. The primary endpoint was response rate. The pharmacokinetics of cetuximab was also evaluated in 5 patients. From May 2009 to February 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 patients who were treated with biweekly cetuximab plus irinotecan, partial response was observed in 9 patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7%-49.4%) and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95% CI, 57.7%-90.0%). The median progression-free survival was 5.3 months and median overall survival was 10.8 months. Grade 3 skin toxicity was observed in 3 patients (10.0%) and one treatment related death due to pneumonia was observed. Combination chemotherapy with biweekly cetuximab and irinotecan was effective for pretreated metastatic colorectal cancer with wild-type KRAS.
  • Hiroshi Nakatsumi, Yoshito Komatsu, Satoshi Yuki, Susumu Sogabe, Miki Tateyama, Shuichi Muto, Mineo Kudo, Kanji Kato, Takuto Miyagishima, Minoru Uebayashi, Takashi Meguro, Koji Oba, Masahiro Asaka
    Chemotherapy 58 (6) 439 - 44 0009-3157 2012 [Refereed][Not invited]
     
    BACKGROUND: Indisetron is a serotonin (5-hydroxytryptamine type 3) receptor antagonist that also antagonizes 5-hydroxytryptamine type 4 receptors. We designed a pilot study in order to explore the optimal dosing period for indisetron during modified FOLFOX6 (mFOLFOX6). PATIENTS AND METHODS: Forty-two chemotherapy-naive patients with advanced colorectal cancer scheduled to receive mFOLFOX6 were randomly assigned to either a 1- or 3-day indisetron regimen arm. The primary endpoint was complete protection from vomiting. RESULTS: Proportions of patients with complete protection from vomiting were 85.7% [95% confidence interval (CI) 63.7-97.0] with the 3-day regimen and 81.0% (95% CI 58.1-94.6) with the 1-day regimen. Proportions of patients with complete protection from nausea were 47.6% in each arm (95% CI 25.7-70.2). No rescue therapy rates were 66.7% (95% CI 43.0-85.4) versus 57.1% (95% CI 34.0-78.2). No severe adverse events were observed in either arm. CONCLUSION: Both 1- and 3-day indisetron regimens were feasible for preventing nausea and vomiting induced by mFOLFOX6.
  • Kohei Shitara, Takashi Ura, Keitaro Matsuo, Daisuke Takahari, Tomoya Yokota, Satoshi Yuki, Motoki Yoshida, Setsuo Utsunomiya, Yozo Sato, Hidekazu Yamaura, Mina Kato, Yoshitaka Inaba, Masahiro Tajika, Hiroki Kawai, Kentaro Yamazaki, Yoshito Komatsu, Kei Muro
    EUROPEAN JOURNAL OF CANCER 47 (18) 2673 - 2680 0959-8049 2011/12 [Refereed][Not invited]
     
    The aim of this study was to evaluate the association of sensitivity to previous irinotecan-based chemotherapy with efficacy of cetuximab plus irinotecan therapy in metastatic colorectal cancer (MCRC) patients with wild-type KRAS. We analysed a pooled data set consisting of data from 87 MCRC patients from two previous phase II studies (n = 60) and a group given off-protocol treatment (n = 27) following irinotecan-, oxaliplatin-, and fluoropyrimidine-based chemotherapy. Overall objective response rate to cetuximab plus irinotecan was 28.7%, median progression-free survival (PFS) was 5.3 months, and median overall survival was 12.2 months. Objective response rate did not significantly differ between patients with a favourable response to previous irinotecan (n = 23), stable disease (n = 38), or progressive disease (n = 26), with observed rates of 29.2%, 31.6%, and 23.1%, respectively. Additionally, the non-parametric Spearman rank correlation coefficients (rho) between the PFS of previous irinotecan-based chemotherapy and that of cetuximab plus irinotecan were quite low (rho = 0.067 and 0.057 in patients with previous irinotecan as first- and second-line therapies, respectively). Although exploratory nature and small sample size may be limitations of this study, these findings indicate that the efficacy of irinotecan plus cetuximab in MCRC patients with wild-type KRAS did not differ by previous sensitivity to irinotecan. (C) 2011 Elsevier Ltd. All rights reserved.
  • Ken Kato, Kei Muro, Keiko Minashi, Atsushi Ohtsu, Satoshi Ishikura, Narikazu Boku, Hiroya Takiuchi, Yoshito Komatsu, Yoshinori Miyata, Haruhiko Fukuda
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 81 (3) 684 - 690 0360-3016 2011/11 [Refereed][Not invited]
     
    Purpose: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC). Patients and Methods: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m(2)/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m(2)) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-week break. Responders received two courses of 5-FU (800 mg/m(2)/day) on Days 1-5 and CDDP (80 mg/m(2)) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years. Results: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46(62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths. Conclusions: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity. (C) 2011 Elsevier Inc.
  • Akira Sawaki, Toshirou Nishida, Toshihiko Doi, Yasuhide Yamada, Yoshito Komatsu, Tatsuo Kanda, Yoshihiro Kakeji, Yusuke Onozawa, Makoto Yamasaki, Atsushi Ohtsu
    CANCER 117 (20) 4633 - 4641 0008-543X 2011/10 [Refereed][Not invited]
     
    BACKGROUND: Patients with gastrointestinal stromal tumors (GISTs) resistant to both imatinib and sunitinib have a poor prognosis and few therapeutic options. In this study, the efficacy and safety of nilotinib (AMN107) as a third-line therapy for patients with GISTs was evaluated. METHODS: A single-arm, open-label trial was conducted in 8 Japanese hospitals. The key eligibility criteria included resistance or intolerance to both imatinib and sunitinib treatment. The primary endpoint was disease control rate, defined as the percentage of patients with complete response, partial response (PR), or stable disease (SD) lasting 24 weeks or longer. RESULTS: Thirty-five patients were enrolled and treated with nilotinib 400 mg twice daily, which generally was well tolerated. Disease control rate at Week 24 was 29% (90% confidence interval, 16.4%-43.6%). The median progression-free survival was 113 days, and the median overall survival was 310 days. The objective response rate was 3%, comprising 1 PR in a patient with a GIST possessing both a KIT exon 11 mutation, and an imatinib-resistant and sunitinib-resistant KIT exon 17 mutation. Twenty-three (66%) patients had SD (>= 6 weeks) as the best response. CONCLUSIONS: These results suggest that nilotinib is generally well tolerated and has encouraging antitumor activity in patients with GIST who failed both imatinib and sunitinib. Cancer 2011;117:4633-41. (C) 2011 American Cancer Society.
  • Yoshito Komatsu, Yutaka Takahashi, Yutaka Kimura, Hisashi Oda, Yusuke Tajima, Shigeyuki Tamura, Jo Sakurai, Takehiro Wakasugi, Shigeru Tatebe, Masahiro Takahashi, Yuh Sakata, Masaki Kitajima, Junichi Sakamoto, Shigetoyo Saji
    ANTI-CANCER DRUGS 22 (6) 576 - 583 0959-4973 2011/07 [Refereed][Not invited]
     
    The pharmacokinetics of irinotecan vary markedly between individuals. This study sought to compare tailored irinotecan and S-1 therapy with S-1 monotherapy for the treatment of patients with advanced/recurrent gastric cancer. Patients with advanced/recurrent gastric cancer were randomized to receive tailored irinotecan and S-1 (arm A) therapy or S-1 therapy alone (arm B). Arm A received S-1 (80-120 mg/m(2)/day) for 14 days, with irinotecan on days 1 and 15. The initial irinotecan dose of 75 mg/m(2) (level 0) was adjusted for toxicity during an earlier course. In arm B, S-1 (80-120 mg/day) was administered alone for 28 days, followed by 14 days without therapy. Ninety-five patients were randomized (48 patients to arm A and 47 patients to arm B). The response rate of the primary tumor (Japanese criteria) was 25.0% in arm A (12 of 48 patients) and 14.9% in arm B (seven of 47 patients), whereas the response rates according to Response Evaluation Criteria In Solid Tumors were 27.8% (10 of 36) versus 21.9% (seven of 32). Hematological toxicity, anorexia, and diarrhea were significantly more common in arm A, but both arms had similar grades 3-4 toxicities. These findings suggest the usefulness of tailored irinotecan and S-1 therapy for gastric cancer. Anti-Cancer Drugs 22:576-583 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
  • Susumu Sogabe, Yoshito Komatsu, Satoshi Yuki, Takaya Kusumi, Kazuteru Hatanaka, Michio Nakamura, Takashi Kato, Takuto Miyagishima, Ayumu Hosokawa, Ichiro Iwanaga, Yuh Sakata, Masahiro Asaka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 (4) 490 - 497 0368-2811 2011/04 [Refereed][Not invited]
     
    Objective: After approval of bevacizumab in Japan, post-marketing surveillance studies reported on safety. However, few reports have shown the efficacy of bevacizumab as used in daily practice. We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients in daily practice. Methods: All unresectable metastatic colorectal cancer patients who began receiving bevacizumab in participating facilities from June 2007 to October 2008 were retrospectively analyzed for safety and efficacy. Adverse events were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events. Response Evaluation in Solid Tumors criteria, version 1.0, was used for the tumor response rate. Results: A total of 212 patients from 17 institutions were assessed. Grade 3 or higher adverse events related to bevacizumab included gastrointestinal perforation in 3, thrombosis in 7, hypertension in 30 and gastrointestinal bleeding in 2. Response rates were 62.5, 30.1 and 11.8% overall among patients receiving bevacizumab as first-, second-and third-line or greater therapy. Median progression-free survival was 14.4 [95% confidence interval (CI): 10.8-18.1], 7.8 (95% CI: 6.5-9.1) and 6.0 (95% CI: 4.6-7.3) months, and median overall survival was 32.5 (95% CI: 24.6-40.3), 16.4 (95% CI: 14.4-18.5) and 11.8 (95% CI: 8.6-15.0) months, respectively. Conclusions: The general cohort of patients in HGCSG0801 showed a similar efficacy and safety profile of bevacizumab as seen in clinical trials. Although the sample size was small and there were several study limitations, these results suggest that colorectal cancer patients in Japan might safely receive and benefit from bevacizumab in combination with chemotherapy in daily practice, as is seen in patients in other countries.
  • Nakatsumi H, Yuki S, Kobayashi Y, Komatsu Y
    Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 3 585 - 588 0047-1852 2011/04 [Refereed][Not invited]
  • Susumu Sogabe, Satoshi Yuki, Hironobu Takano, Yoshimitsu Kobayashi, Hiroshi Nakatsumi, Takahide Sasaki, Yasuyuki Kawamoto, Hiraku Fukushima, Ichiro Iwanaga, Yasuko Uehata, Yoshito Komatsu, Masahiro Asaka
    Japanese Journal of Cancer and Chemotherapy 38 (8) 1375 - 1377 0385-0684 2011 [Refereed][Not invited]
     
    A 40-year-old woman visited our hospital with adenocaricinoma of the sigmoid colon with multiple liver metastases and ovarian metastasis. Because of a stenosis of the primary tumor, she underwent a colostomy before chemotherapy. 5-fluorouracil and irinotecan and leucovorin (FOLFIRI) was selected as first-line chemotherapy. At the start of chemotherapy, just after the end of irinotecan and leucovorin administration, the patient developed dysarthria. There were no neurological abnormalities or hematological abnormalities. The treatment was temporarily discontinued, and the dysarthria completely disappeared within 90 minutes. 5-fluorouracil was administered after the disappearance of dysarthria. Within 60 minutes of the administration of irinotecan and leucovorin at the second chemotherapy treatment, the patient developed dysarthria again. The patient had no neurological or hematological abnormalities. Magnetic resonance imaging (MRI) showed no abnormalities. The treatment was stopped and dysarthria disappeared within 60 minutes as it did the first time. At each time, no treatment for dysarthria was performed. This patient refused to continue irinotecan because of dysarthria. Therefore, chemotherapy without irinotecan was continued for the third time onward. In the previous literature, 8 cases of dysarthria caused by irinotecan were reported as a rare toxicity. In all cases, dysarthria was temporary and reversible. Because the mechanism of dysarthria is unclear, specific treatment and precaution for dysarthria is not recommended. Since dysarthria is reversible, however, irinotecan might be continued until progression.
  • Atsushi Sato, Toshihiko Doi, Narikazu Boku, Ken Kato, Yoshito Komatsu, Kensei Yamaguchi, Kei Muro, Yasuo Hamamoto, Wasaburo Koizumi, Nobuyuki Mizunuma, Hiroya Takiuchi
    Japanese Journal of Cancer and Chemotherapy 38 (4) 561 - 569 0385-0684 2011 [Refereed][Not invited]
     
    FOLFOX plus Bevacizumab (BEV) is one of the current standard treatments for unresectable colorectal cancer. In Europe and the United States, XELOX is a regimen which replaced 5-FU/LV of FOLFOX with capecitabine (XEL), an oral prodrug of fluorouracil. Benefits of XELOX and FOLFOX are reported to be the same in Europe and the United States. XELOX+BEV is recommended as a treatment option in various guidelines. However, the safety and effectiveness data were from overseas, and unconfirmed in Japan. Therefore, we carried out a JO19380 study to evaluate the effectiveness and safety of XELOX+BEV on Japanese patients in a domestic phase I / II clinical trial. A total of 64 patients were registered in this study. The response rate was 72%, the progression free survival was 11 months, and the median survival time was 27.4 months with XELOX+ BEV. The common grade 3/4 toxicities were sensory neurotoxicity (17%) and neutropenia (16%). The effectiveness and safety equivalents of overseas reports were confirmed in Japanese patients. They suggested that XELOX+BEV has the potential to becom one of the standard treatments for unresectable colorectal cancer in Japan. In the trial, long-term disease control with XEL+BEV was reported in patients who discontinued oxaliplatin because of adverse events. Continuous treatment with XEL+BEV after XELOX+BEV is considered to be a significant first-line therapy for colorectal cancer based on that report.
  • Yoshito Komatsu, Satoshi Yuki, Susumu Sogabe, Hiraku Fukushima, Ichiro Iwanaga, Mineo Kudo, Miki Tateyama, Takashi Meguro, Minoru Uebayashi, Akiyoshi Saga, Yuh Sakata, Masahiro Asaka
    ONCOLOGY 80 (1-2) 70 - 75 0030-2414 2011 [Refereed][Not invited]
     
    Objectives: This phase II study was designed to evaluate the efficacy and safety of oral fluoropyrimidine S-1 plus irinotecan (IRIS regimen) in patients with previously untreated metastatic colorectal cancer. Methods: The response rate was the primary endpoint. Safety, progression-free survival time, and median survival time were secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer. Irinotecan was administered at a dose of 100 mg/m(2) (on days 1 and 15). S-1 (40 mg/m2) was administered for 2 weeks (on days 1 to 14) and followed by a 2-week rest. Results: Forty patients were enrolled. Four patients had grade 4 neutropenia, and six patients had grade 3 diarrhea. No other serious hematologic or nonhematologic adverse reactions occurred, and all patients received IRIS safely on an outpatient basis. The response rate was 52.5% (95% confidence interval [CI], 36.1-68.5%). Median progression-free survival was 8.6 months (95% CI, 5.3-11.9), and median survival time was 23.4 months (95% CI, 15.9-30.8). Conclusions: IRIS produced a high response rate and could be given safely. IRIS may become a first-line treatment for inoperable or recurrent advanced colorectal cancer. Copyright (C) 2011 S. Karger AG, Basel
  • Kuniaki Shirao, Toshirou Nishida, Toshihiko Doi, Yoshito Komatsu, Kei Muro, Yinhua Li, Eiji Ueda, Atsushi Ohtsu
    INVESTIGATIONAL NEW DRUGS 28 (6) 866 - 875 0167-6997 2010/12 [Refereed][Not invited]
     
    Purpose: To establish a recommended sunitinib dosing schedule in Japanese patients with imatinib-resistant/intolerant gastrointestinal stromal tumor (GIST) and to evaluate the efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of sunitinib using this schedule. Patients and methods: In the phase I part of this open-label phase I/II trial, Japanese GIST patients received 25, 50, or 75 mg/day of sunitinib on Schedule 4/2 (4 weeks on treatment; 2 weeks off treatment) following imatinib failure. In phase II, patients received the recommended (maximum tolerated) dose on this schedule; the primary endpoint was clinical benefit rate (CBR; percent objective responses or stable disease [SD] a parts per thousand yen22 weeks). Additional efficacy, safety, pharmacokinetic, and biomarker analyses were performed. Results: In phase I (12 patients), the recommended dose was determined to be 50 mg/day. Sunitinib pharmacokinetics were similar to those observed in studies with Western patients. In the phase II part (36 patients), the CBR was 39% (95% CI: 23-57%; 11% partial responses, 28% SD a parts per thousand yen22 weeks). The most common treatment-related non-hematologic adverse events (AEs) were hand-foot syndrome (86%) and fatigue (67%). A trend towards a correlation between decreases from baseline in plasma soluble KIT levels and improved CB was found. Conclusions: The pharmacokinetics observed and clinical outcomes achieved in Japanese GIST patients on sunitinib (50 mg/day, Schedule 4/2) after imatinib failure appeared similar to those of Western patients in previous sunitinib trials. Although some serious AEs were observed, AEs were generally manageable using dose interruption/modification and/or standard medical treatments.
  • Kei Muro, Narikazu Boku, Yasuhiro Shimada, Akihito Tsuji, Shinichi Sameshima, Hideo Baba, Taroh Satoh, Tadamichi Denda, Kenji Ina, Tomohiro Nishina, Kensei Yamaguchi, Hiroya Takiuchi, Taito Esaki, Shinya Tokunaga, Hiroyuki Kuwano, Yoshito Komatsu, Masahiko Watanabe, Ichinosuke Hyodo, Satoshi Morita, Kenichi Sugihara
    LANCET ONCOLOGY 11 (9) 853 - 860 1470-2045 2010/09 [Refereed][Not invited]
     
    Background Fluorouracil and folinic acid with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are widely used as first-line or second-line chemotherapy for metastatic colorectal cancer. However, infusional fluorouracil-based regimens, requiring continuous infusion and implantation of an intravenous port system, are inconvenient. We therefore planned an open-label randomised controlled trial to verify the non-inferiority of irinotecan plus oral S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; IRIS) to FOLFIRI as second-line chemotherapy for metastatic colorectal cancer. Methods Between Jan 30,2006, and Jan 29,2008,426 patients with metastatic colorectal cancer needing second-line chemotherapy from 40 institutions in Japan were randomly assigned by a computer-based minimisation method to receive either FOLFIRI (n=213) or IRIS (n=213). In the FOLFIRI group, patients received folinic acid (200 mg/m(2)) and irinotecan (150 mg/m2) and then a bolus injection of fluorouracil (400 mg/m2) on day 1 and a continuous infusion of fluorouracil (2400 mg/m2) over 46 h, repeated every 2 weeks. In the IRIS group, patients received irinotecan (125 mg/m2) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was progression-free survival, with a non-inferiority margin of 1.333. Statistical analysis was on the basis of initially randomised participants. This study is registered with ClinicalTrials.gov, number NCT00284258. Findings All randomised patients were included in the primary analysis. After a median follow-up of 12.9 months (IQR 11.5-18.2), median progression-free survival was 5.1 months in the FOLFIRI group and 5.8 months in the IRIS group (hazard ratio 1-077,95% CI 0.879-1.319, non-inferiority test p=0.039). The most common grade three or four adverse drug reactions were neutropenia (110 [52.1%] of 211 patients in the FOLFIRI group and 76 [36.2%] of 210 patients in the IRIS group; p=0.0012), leucopenia (33 [15.6%] in the FOLFIRI group and 38 [18.1%] in the IRIS group; p=0.5178), and diarrhoea (ten [47%] in the FOLFIRI group and 43 [20.5%] in the IRIS group; p<0.0001). One treatment-related death from hypotension due to shock was reported in the FOLFIRI group within 28 days after the end of treatment; no treatment-related deaths were reported in the IRIS group. Interpretation Progression-free survival with IRIS is not inferior to that with FOLFIRI in patients receiving secondline chemotherapy for metastatic colorectal cancer. Treatment with IRIS could be an additional therapeutic option for second-line chemotherapy in metastatic colorectal cancer.
  • Yoshito Komatsu, Satoshi Yuki, Nozomu Fuse, Takashi Kato, Takuto Miyagishima, Mineo Kudo, Yasuyuki Kunieda, Miki Tateyama, Osamu Wakahama, Takashi Meguro, Yuh Sakata, Masahiro Asaka
    ADVANCES IN THERAPY 27 (7) 483 - 492 0741-238X 2010/07 [Refereed][Not invited]
     
    Background: Irinotecan and S-1, an oral fluoropyrimidine composed of tegafur, gimeracil, and oteracil potassium, have demonstrated antitumor activity against advanced gastric cancer. We performed a phase 1/2 study to determine the recommended dose, antitumor activity, and safety of a combination of S-1 and irinotecan in patients with advanced gastric cancer. Methods: Patients with previously untreated advanced gastric cancer were enrolled. Patients received irinotecan intravenously on days 1 and 15 plus oral S-1 twice daily on days 1-14 of a 28-day cycle. In the phase 1 part, the dose of irinotecan was escalated from 100 mg/m(2) to 125 mg/m(2) and then to 150 mg/m(2). Results: A total of 24 patients were enrolled. Overall, the median number of treatment cycles per patient was 5.9, and 92% of the patients completed at least two cycles. The overall response rate was 54.2% (13 of 24). The response rates in differentiated and undifferentiated cancer were 56.3% (nine of 16) and 50.0% (four of eight), respectively. Median survival time was 581 days. The maximum tolerated dose of irinotecan was not reached at the highest level. However, grade 4 neutropenia occurred at 125 mg/m(2). We concluded that the recommended dose of irinotecan for the present regimen was 125 mg/m(2). Conclusion: Treatment with S-1+irinotecan is considered effective in patients with advanced gastric cancer who have not previously received chemotherapy. A combination of irinotecan and S-1 was well tolerated in patients with advanced gastric cancer and could be given on an outpatient basis.
  • Akira Sawaki, Yasuhide Yamada, Yoshito Komatsu, Tatsuo Kanda, Toshihiko Doi, Masato Koseki, Hideo Baba, Yu-Nien Sun, Koji Murakami, Toshirou Nishida
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 65 (5) 961 - 967 0344-5704 2010/04 [Refereed][Not invited]
     
    Motesanib (AMG 706) is a multitargeted anticancer agent with an inhibitory action on the human vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and the cellular stem-cell factor receptor (KIT). The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate.All patients had experienced progression or relapse while undergoing with imatinib as 400 mg/day or higher. The patients were administered 125 mg of motesanib once daily. The primary endpoint was overall response. Efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumor, and safety was assessed according to the Common Terminology Criteria for Adverse Events (version 3).Of 35 enrolled and treated patients, no patient showed a complete response, and one patient showed a partial response (PR). Seven had stable disease (SD) for at least 24 months, two of whom continued to have SD for more than 2 years. The median progression-free survival time was 16.1 weeks. Motesanib was well tolerated; commonly reported treatment-related adverse events were hypertension, diarrhea, and fatigue. Anemia was the only hematological toxicity that was reported.One patient showed PR, and seven patients showed SD more than 24 weeks. Motesanib was found to be safe and well tolerated. The observed toxicities were consistent with Phase I study findings.
  • Toshihiko Doi, Kei Muro, Narikazu Boku, Yasuhide Yamada, Tomohiro Nishina, Hiroya Takiuchi, Yoshito Komatsu, Yasuo Hamamoto, Nobutsugu Ohno, Yoshie Fujita, Matthew Robson, Atsushi Ohtsu
    JOURNAL OF CLINICAL ONCOLOGY 28 (11) 1904 - 1910 0732-183X 2010/04 [Refereed][Not invited]
     
    PurposeEverolimus, an oral inhibitor of the mammalian target of rapamycin, has shown antitumor activity in gastric cancer in preclinical and phase I studies. This phase II study evaluated the efficacy and safety of everolimus in pretreated patients with advanced gastric cancer.Patients and MethodsPatients with advanced gastric cancer who experienced progression despite prior chemotherapy received everolimus 10 mg orally daily until disease progression or study discontinuation. The primary end point was disease control rate (DCR; ie, complete response, partial response, or stable disease). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.ResultsFifty-three patients were assessable (median age, 63 years; 51% and 49% received one or two prior chemotherapy regimens, respectively). Although no complete or partial response was obtained, a decrease in tumor size from baseline was observed in 45% of patients by central review. The DCR was 56.0% (95% CI, 41.3% to 70.0%); median PFS was 2.7 months (95% CI, 1.6 to 3.0 months). At a median follow-up time of 9.6 months, median OS was 10.1 months (95% Cl, 6.5 to 12.1 months). Common grade 3 or 4 adverse events included anemia, hyponatremia, increased gamma-glutamyltransferase, and lymphopenia. Grade 1 or 2 pneumonitis was reported in eight patients (15.1%).ConclusionEverolimus monotherapy resulted in a promising DCR in patients with previously treated advanced gastric cancer. Adverse events are consistent with the reported safety profile of everolimus. These results warrant further evaluation in patients with advanced gastric cancer.
  • Shouko Ono, Mototsugu Kato, Kikuko Takagi, Junichi Kodaira, Kanako Kubota, Yoshihiro Matsuno, Yoshito Komatsu, Masahiro Asaka
    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 25 (4) 804 - 809 0815-9319 2010/04 [Refereed][Not invited]
     
    Background and Aim: According to a few recent reports on the long-term clinical outcome of gastric marginal zone B-cell mucosa associated lymphoid tissue lymphoma (MALT lymphoma); localized gastric MALT lymphoma generally has a favorable prognosis. However, the risk of metachronous gastric cancer has not been evaluated. In this study, we analyzed long-term outcomes of localized gastric MALT lymphoma including the incidence of metachronous gastric cancer. Methods: Between April 1996 and May 2008, 60 patients (31 men and 29 women; mean age 58.1 years) with localized gastric MALT lymphoma (stage I and II1 according to Lugano classification) were analyzed retrospectively. Results: Forty-eight patients (82.6%) achieved complete remission by eradication therapy. Radiation therapy was conducted on eight patients as second-line treatment, and all of them achieved remission. The median follow-up period was 76 months (range, 12-157 months). One patient had local relapse after remission for 5 years and three patients developed early gastric cancer without recurrence of lymphoma (5%). All of the three gastric cancers appeared in the same areas where MALT lymphoma had been eradicated. Conclusion: Eradication therapy and radiation therapy for localized gastric MALT lymphoma have a favorable long-term outcome, though regular follow-up endoscopy should be performed for detecting metachronous early gastric cancer.
  • Susumu Sogabe, Satoshi Yuki, Tomofumi Takagi, Takuji Miyazaki, Hironobu Takano, Yasuyuki Kawamoto, Hiroshi Nakatsumi, Takahide Sasaki, Ichiro Iwanaga, Yasuko Uehata, Masahiro Asaka, Yoshito Komatsu
    Japanese Journal of Cancer and Chemotherapy 37 (3) 535 - 538 0385-0684 2010/03/06 [Refereed][Not invited]
     
    A 51-year-old man was referred to our hospital with adenocarcinoma of sigmoid colon with multiple lymph node metastasis. At the time of admission, he had dyspnea, and computed tomography (CT) showed typical signs of lymphangitis carcinomatosa of the lung. Combination of mFOLFOX6 and bevacizumab was started. After start of the therapy, CT revealed an improvement in lymphangitis carcinomatosa. 8 months later, the tumor assessment became progressive disease. FOLFIRI was started as the second-line chemotherapy, but the patient did not respond. Then, dyspnea emerged again, and CT indicated the lymphangitis carcinomatosa had become worse. So as the third-line chemotherapy, combination of irinotecan and cetuximab was started. Dyspnea immediately disappeared, and CT showed an improvement of lymphangitis carcinomatosa. In the previous literature, malignant tumor cases which accompany lymphangitis carcinomatosa might always have a poor course. Our case dramatically responded to the chemotherapy including molecular targeting drug and showed a long survival. So we conclude that aggressive chemotherapy including a molecular targeting drug may be recommended in a case of colorectal cancer which accompanies lymphangitis carcinomatosa of the lung.
  • Satoshi Yuuki, Yoshito Komatsu, Nozomu Fuse, Takashi Kato, Takuto Miyagishima, Mineo Kudo, Masao Watanabe, Miki Tateyama, Yasuyuki Kunieda, Osamu Wakahama, Yu Sakata, Masahiro Asaka
    CLINICAL DRUG INVESTIGATION 30 (4) 243 - 249 1173-2563 2010 [Refereed][Not invited]
     
    Background: Combined therapy with irinotecan/fluorouracil/levoleucovorin (calcium levofolinate) [IFL] has lost its position as the standard regimen for metastatic colorectal cancer because its toxicity and effectiveness have become controversial. Objective: To (i) identify the optimal regimen for IFL therapy in terms of irinotecan dosage, and (ii) determine the maximum tolerated dose and efficacy of the modified-IFL regimen in patients with histologically confirmed advanced colorectal cancer. Methods: In a phase I study, nine patients with advanced colorectal cancer received IFL treatment modified such that irinotecan was administered every 2 weeks, as opposed to the more toxic once-weekly administration. The study evaluated three escalating dose levels of irinotecan (100, 125 and 150 mg/m(2)). Each treatment cycle consisted of irinotecan on days I and 15; fluorouracil 600 mg/m(2) on days 1, 8, 15 and 22; and levoleucovorin 250 mg/m(2) on days 1, 8, 15 and 22. Data from the phase I study were used to determine the recommended dose of irinotecan for the phase II study. The latter study evaluated the effectiveness (overall response rate, median time to disease progression and median survival time) and tolerability of this modified-IFL therapy as ambulatory treatment in 22 patients with advanced colorectal cancer. Results: The dose-limiting toxicity of irinotecan was grade 3 neutropenia, which occurred in three patients at dose level 2 (125 mg/m(2)); furthermore, a fourth patient developed grade 4 neutropenia at this dose level. Therefore, 125 mg/m(2) was considered to be the maximum tolerated dose, and the dose of irinotecan for the phase 11 study was set at 100 mg/m(2). Fourteen patients achieved partial response using this modified-IFL regimen, and the overall response rate was 63.6% (95% CI 43.5, 83.7). The median time to progression was 197 days (range 111-283 days) and the median survival time was 414 days (95% CI 116, 712). Toxicities were acceptable and manageable. Conclusions: Modified-IFL therapy is a practical, effective and tolerable option for ambulatory treatment of advanced colorectal cancer.
  • Yoshito Komatsu, Susumu Sogabe, Yasuyuki Kawamoto, Ichiro Iwanaga, Yasuko Uehata, Satoshi Yuki, Masahiro Asaka
    Japanese Journal of Cancer and Chemotherapy 36 (5) 721 - 725 0385-0684 2009 [Refereed][Not invited]
     
    For the current metastatic colorectal cancer, FOLFIRI or FOLFOX is chosen as first-line chemotherapy. Second-line irinotecan-based chemotherapy is commonly used after first-line oxaliplatin-based chemotherapy. Of course, FOLFOX becomes the second-line if FOLFIRI becomes primary therapy. It is important that these regimens combine molecular targetting agents such as Bevacizumab or Cetuximab. The addition of these new agents offers a chance to further enhance the activity of conventional chemotherapy.
  • Kohei Shitara, Yoshito Komatsu, Satoshi Yuki, Masaki Munakata, Osamu Muto, Sen Shimaya, Yuh Sakata
    ONCOLOGY 75 (1-2) 67 - 70 0030-2414 2008 [Refereed][Not invited]
     
    Objective: The aim of this study was to evaluate the efficacy and safety of a combination regimen using irinotecan plus S-1 in patients with metastatic pancreatic cancer. Methods: Based on the results of our previous phase I/II study in patients with gastric and colorectal cancer, we initiated a regimen with irinotecan at 100 mg/m(2) on days 1 and 15 and S-1 at 80 mg/m(2) starting at day 1 for 14 consecutive days, followed by a 14-day rest period. This treatment was repeated every 28 days. Results: From November 2003 to December 2006, a total of 16 patients were enrolled. All patients presented with metastatic disease. Six patients had received prior gemcitabine. The median number of treatment cycles was 4 (range 1-16) and the response rate was 43.7% (95% confidence interval 19.5-68.1). The median time to progression was 4.9 months, and the median survival time was 11.3 months. Grade 3-4 neutropenia developed in 5 of 16 patients and grade 3 diarrhea in 1 patient. Conclusions: The combination of irinotecan and S-1 is feasible and promising for pancreatic cancer. Further evaluation of this combination chemotherapy is required. Copyright (C) 2008 S. Karger AG, Basel.
  • Motosugu Kato, Masahiro Asaka, Shouko Ono, Manabu Nakagawa, Souichi Nakagawa, Yuichi Shimizu, Makoto Chuma, Hiroshi Kawakami, Yoshito Komatsu, Shuhei Hige, Hiroshi Takeda
    JOURNAL OF GASTROENTEROLOGY 42 16 - 20 0944-1174 2007/01 [Refereed][Not invited]
     
    Because most gastric cancers develop from a background of Helicobacter pylori-infected gastric mucosa, H. pylori plays an important role in gastric carcinogenesis. Therefore, eradication of H. pylori may inhibit the incidence of gastric cancers. In experimental studies, H. pylori eradication has proved to act as a prophylaxis against gastric cancer. However, the results of recent randomized controlled studies are absolutely contradictory. In Japan, mucosal gastric cancer is usually resected by endoscopic treatment. As only a small part of the gastric mucosa is resected, secondary gastric cancer after endoscopic resection of the primary gastric cancer often develops at another site in the stomach. A nonrandomized Japanese study involving 132 early gastric cancer patients reported that eradication of H. pylori after endoscopic resection tended to reduce the development of secondary gastric cancer. Also, a retrospective multicenter survey indicated that the incidence rate of secondary gastric cancer in H. pytori-eradicated patients was about one-third that among patients in the noneradication group. We conducted a large-scale multicenter randomized trial to confirm the effect of H. pylori eradication on secondary and residual gastric cancer after endoscopic resection. This study was begun in 2003 and is ongoing at present. Diagnosis of a new carcinoma at another site of the stomach is defined as the primary end point, and recurrence of tumors at the resection site as a secondary end point. A total of 542 subjects have been enrolled in the study. This study will have the statistical power to demonstrate whether H. pylori eradication decreases the incidence and recurrence of gastric cancer.
  • Komatsu Y, Yuki S, Miyagishima T, Asaka M
    Gan to kagaku ryoho. Cancer & chemotherapy 33 Suppl 1 75 - 78 0385-0684 2006/06 [Refereed][Not invited]
  • Komatsu Y, Yuki S, Tateyama M, Kudo M, Asaka M
    Gan to kagaku ryoho. Cancer & chemotherapy 33 Suppl 1 131 - 134 0385-0684 2006/06 [Refereed][Not invited]
  • Kensei Yamaguchi, Tomotaka Shimamura, Yoshito Komatsu, Akinori Takagane, Takashi Yoshioka, Soh Saitoh, Masaki Munakata, Yu Sakata, Tsukasa Sato, Tatsuhiro Arai, Hiroshi Saitoh
    Gastric Cancer 9 (1) 36 - 43 1436-3291 2006/02 [Refereed][Not invited]
     
    Background. Both paclitaxel (TXL) and cisplatin (CDDP) show efficacy against gastric cancer. The aim of this phase I-II study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity and efficacy of combination chemotherapy with these two agents. Methods. Nineteen patients entered the phase I part of the study, and 21 patients entered the phase II part. TXL infusions were administered on days 1 and 15, with a fixed 3mg/m 2 dose of CDDP. Results. In the phase I part of the study, we determined dose level 5, which represented a TXL dose of 18mg/m2, with CDDP 3mg/m2, to be the MTD. The recommended dose (RD) was level 4, with a TXL dose of 16mg/m2 with CDDP, 3mg/m2. In the phase II part of the study, the response rate was 25.0% five patients had a partial response, seven had stable disease, 6 had progressive disease, and 2 were not evaluable. Grade 3 or 4 neutropenia was the most common adverse event and occurred in 65% of the patients. During treatment, 25% of the patients received granulocyte colony-stimulating factor, but febrile neutropenia was not shown in any of the patients. Major nonhematological toxicities were nausea/vomiting, anorexia, fatigue, alopecia, and sensory neuropathy. Adverse reactions of grade 3 or 4 were shown by two patients, one with anorexia (5%) and the other with sensory neuropathy (5%). Conclusion. The RD was determined to be TXL 14mg/m2, with CDDP 3mg/m2. © 2006 by International and Japanese Gastric Cancer Association.
  • Y Komatsu, S Yuuki, N Fuse, M Takei, T Kato, T Miyagishima, M Kudo, Y Kunieda, M Tateyama, O Wakahama, T Meguro, H Ohizumi, M Watanabe, H Akita, Y Sakata, M Asaka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 35 (2) 88 - 89 0368-2811 2005/02 [Refereed][Not invited]
     
    We have previously reported on phase I/II studies of irinotecan plus S-1 therapy for advanced gastric cancer. Based on the safety and efficacy data that were obtained, this phase 11 study was planned to assess the efficacy of irinotecan plus S-1 for patients with advanced colorectral cancer. A total of 40 patients are enrolled at 13 medical institutions. The objective of this study was to establish a useful chemotherapy regimen for an out-patient setting.
  • Y Shimizu, M Kato, J Yamamoto, S Nakagawa, Y Komatsu, H Tsukagoshi, M Fujita, M Hosokawa, M Asaka
    GASTROINTESTINAL ENDOSCOPY 60 (4) 636 - 639 0016-5107 2004/10 [Refereed][Not invited]
     
    Background. With increasing use of EMR for early stage esophageal carcinoma, the number of cases of iatrogenic esophageal perforation is likely to increase. This study evaluated the results of endoscopic clip application for treatment of perforations caused by EMR in patients with esophageal carcinoma. Methods: Among 185 patients who underwent EMR for esophageal carcinoma, esophageal perforation occurred in 3 patients (1.6%). Metallic clips were immediately applied endoscopically to close the perforations. Observations: All 3 patients were observed closely and were managed conservatively (intravenous hyperalimentation, antibiotics) after closure of the perforation. They were discharged without any further serious complication. Conclusions: When esophageal perforation caused by EMR is immediately recognized, endoscopic application of metallic clips is appropriate therapy. However, patients must be carefully monitored for the development of generalized mediastinitis.
  • Y Takahashi, J Sakamoto, T Takeuchi, M Mai, T Kubota, M Kitajima, Y Tanigawara, Y Komatsu, T Toge, S Saji
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 34 (6) 342 - 345 0368-2811 2004/06 [Refereed][Not invited]
     
    A randomized phase II clinical trial has been designed and started in the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) to select the better regimen between tailored CPT-11 + S-1 and the standard S-1 treatment for advanced or recurrent gastric cancer as the first line chemotherapy. Selection of the better treatment for general clinical practice in this clinical trial will lead to a more precise assignment of a promising regimen for a future phase III randomized trial, placing continuous 5-FU infusion as the reference arm. In this trial, subsidiary pharmacokinetic analysis for the tailored dose arm is also proposed. In order to continue chemotherapy for a long time and to obtain longer survival, our study design for the tailored therapy could be exploited, especially in the field of general clinical practice.
  • Kato M, Nakagawa S, Shimizu Y, Yuki S, Fuse N, Takei M, Furukawa S, Perez-Aldana LA, Rinan Z, Komatsu Y, Saito N, Takeda H, Sugiyama T, Asaka M
    Nihon rinsho. Japanese journal of clinical medicine 3 62 (3) 470 - 476 0047-1852 2004/03 [Refereed][Not invited]
  • T Ohkawara, M Kato, S Nakagawa, M Nakamura, M Takei, Y Komatsu, Y Shimizu, H Takeda, T Sugiyama, M Asaka
    GASTROINTESTINAL ENDOSCOPY 57 (4) 599 - 602 0016-5107 2003/04 [Refereed][Not invited]
  • Kato M, Shimizu Y, Kobayashi T, Komatsu Y, Takeda H, Sugiyama T, Asaka M
    Nihon rinsho. Japanese journal of clinical medicine 1 61 (1) 72 - 78 0047-1852 2003/01 [Refereed][Not invited]
  • T Kato, Y Komatsu, E Tsukamoto, M Takei, T Takei, F Yamamoto, Y Kuge, M Asaka, N Tamaki
    CLINICAL NUCLEAR MEDICINE 27 (5) 376 - 377 0363-9762 2002/05 [Refereed][Not invited]
     
    Menetrier's disease is a rare disorder that is characterized by significant hypertrophy of the gastric mucosa accompanied by hypoproteinemia caused by the loss of proteins from the gastric mucosa. To the authors' knowledge, the F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) findings of Menetrier's disease have not been reported. They present F-18 FDG-PET images of a patient with Menetrier's disease that show intense accumulation of F-18 FDG in the stomach that is likely to indicate a malignant disease of the stomach.
  • Komatsu Y
    [Hokkaido igaku zasshi] The Hokkaido journal of medical science 2 77 (2) 185 - 192 0367-6102 2002/03 [Refereed][Not invited]
  • Kato M, Shimizu Y, Komatsu Y, Takeda H, Sugiyama T, Asaka M
    Nihon rinsho. Japanese journal of clinical medicine 60 Suppl 2 397 - 402 0047-1852 2002/02 [Refereed][Not invited]
  • T Mizushima, T Sugiyama, T Kobayashi, Y Komatsu, J Ishizuka, M Kato, M Asaka
    HELICOBACTER 7 (1) 22 - 29 1083-4389 2002/02 [Refereed][Not invited]
     
    Background. The cag pathogenicity, island (cag PAI) is a major virulence factor. The ability of Helicobacter pylori to adhere to gastric epithelial cells is an important initial step for virulence. The aim of this study was to evaluate the relationship between genetic variations of cag PAI in Japanese clinical isolates and the ability of H. pylori to adhere to gastric epithelial cells. Materials and Methods. The polymerase chain reaction and Southern blot analysis were used to verify the presence or absence of cagA, cagE, cagG, cagI and cagM in the cag PAI in 236 Japanese clinical isolates. The ability of H. pylori to adhere to KATOIII cells was examined by flow cytometry. Results. Seven (3.0%) cag PAI partial-deleted strains were found in 236 clinical isolates, and these strains showed three patterns in the deleted region within the cag PAL All of the cagG-deleted strains showed decreased adherence to KATOIII cells, in comparison with cagG-positive strains. These strains had abolished IL-8 induction despite the presence of cagE, which is essential for IL-8 induction. Conclusions. Our results suggest that cagG or surrounding genes in the cag PAI has a function related to adhesion to epithelial cells.
  • Kato M, Shimizu Y, Nakagawa S, Kodaira J, Takei M, Furukawa S, Yamamoto F, Takano M, Nagasako T, Nakaya H, Kato T, Oda H, Okawara T, Mizushima T, Komatsu Y, Takeda H, Sugiyama T, Asaka M
    Nihon rinsho. Japanese journal of clinical medicine 60 Suppl 2 491 - 496 0047-1852 2002/02 [Refereed][Not invited]

Books etc

Works

  • 『CPT-11を用いた消化器癌化学療法』
    2002
  • 札幌薬剤師会学術講演会『消化器癌に対する薬物療法』
    2002

MISC

Awards & Honors

  • 2009/10 日本癌治療学会 優秀園演題賞
     
    受賞者: 小松 嘉人
  • 2003/10 17th Asia Pacific Cancer Conference Best Poster AWARD
     
    受賞者: KOMATSU Yoshito

Research Grants & Projects

  • 消化器癌の化学療法 固形癌の化学療法
  • GI oncology Cancer Chemotherapy Clinical Study

Educational Activities

Teaching Experience

  • 医学総論
    開講年度 : 2019
    課程区分 : 博士後期課程
    開講学部 : 医学研究科


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