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Department of Gastrointestinal Oncology

Takayuki Yoshino, Atsushi Ohtsu, Toshihiko Doi, Takashi Kojima, Kouhei Shitara, Hideaki Bando, Yasutoshi Kuboki, Nozomu Fuse, Ken Hatogai, Sawako Miyoshi, Shota Fukuoka

Introduction

In 2015, approximately 650 gastrointestinal (GI) cancer patients were treated by staff oncologists and skilled residents in the Department of GI Oncology, which focuses on optimal chemotherapy W/ or W/ O radiation for the treatment of GI cancers.

Routine activities

The Inter-Divisional tumor board conferences with the Surgical/Radiation Oncology Divisions are held regularly to review the current treatment for each patient and to discuss further treatment strategies. Basically, routine chemotherapy is done on an outpatient basis, and there are approximately 1,900 selected patients who need hospitalization for the purpose of planned therapy with chemotherapy or palliation. Our activities for each type of GI cancer in 2015 are shown in Table 1 (Number), Table 2 (Treatment), and Table 3 (Efficacy). There are ongoing clinical trials that consist of 45 Phase I trials including globally first-in-class (FIC), first-in-human (FIH), investigational new drugs (INDs) and 30 Phase II/III clinical trials to approve the INDs.

Research activities

Phase I

Our Department has focused more on earlystage clinical development of INDs. The number of patients enrolled for Phase I trials has been increasing recently. Importantly, the number of FIH trials and trials around the same time as Western countries is increasing. Several results of phase I trials, such as the oral pan-AKT inhibitor (MK-2206), LY2603618, a CHK1 inhibitor, in combination with gemcitabine, TAS-114, a dUTPase inhibitor in combination with S-1, and VEGF receptor/METtargeted kinase inhibitor (TAS-115), were published or presented at international meetings.

Esophageal Cancer (EC)

A prognostic or predictive biomarker study in patients who underwent surgery or received chemoradiotherapy for clinical stage I esophageal squamous cell carcinoma (JCOG0502-AI) was completed. The results of the phase I/ II trial of chemoradiotherapy with concurrent S-1 and cisplatin for clinical stage II/III esophageal carcinoma (JCOG 0604) was published. And the sub-analysis of the JCOG9907 study for the accuracy of preoperative diagnosis of lymph node metastasis and prognostic Factors in Patients Receiving Neoadjuvant 5-Fluorouracil plus Cisplatin for Advanced Esophageal Cancer were published.

Gastric Cancer (GC)

The results of a global randomized phase III trial comparing 2nd-line chemotherapy with ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) for HER2 and taxanes agents for advanced GC were presented in ASCO-GI 2016. The phase II study of adjuvant chemotherapy of S-1 plus oxaliplatin for patients with stage III gastric cancer after D2 gastrectomy was published. Several sponsored-initiated trials to evaluate molecular targeting agents as well as immune checkpoint inhibitors are currently ongoing. An investigator-initiated trial of the phase 1 trial of sulfasalazine (SSZ), which targets cancer stem-like cell fraction, plus cisplatin for CD44v gastric cancer which refractory to cisplatin finished its enrollment. Results of comprehensive molecular profiling of advanced GC using next generation sequencing and immunohistochemistry were also published, which identified several possible candidate genes that could be targets for precision medicine. Since September 2015, we have initiated an immune monitoring study to evaluate several immunological properties such as classification of lymphocyte or expression of immune checkpoint in tumor infiltrating lymphocyte and peripheral blood mononuclear cell (PBMC) before and after treatment, which will hopefully lead to personalized therapy in the field of immune therapy.

Colorectal Cancer (CRC)

We have established the SCRUM-Japan GI-SCREEN 2013-01-CRC (UMIN000016343), which is the nationwide cancer genome screening project by using the Oncomine Cancer Research Panel. We also started GI-SCREEN CRC-MSI, which is the multi-center project for screening the microsatellite instability (MSI) status of Japanese CRC patients. Based on the screening system of GI-SCREEN 2013-01-CRC, we are currently planning the investigator-initiated clinical trials for patients with BRAF non-V600E mutations, HER2 amplifications, and high tumor-infiltrating lymphocytes (TILs). The clinical evaluation study of cell-free DNA-based RAS gene testing by using BEAMing technology will soon be started.

Clinical trials

Esophageal Cancer (EC)

The phase III study comparing preoperative CDDP+5-FU (CF) versus docetaxel+CF versus CF-radiation followed by esophagectomy with D2-3 lymphadenectomy for locally advanced esophageal squamous cell cancer (JCOG1109) and the phase III study comparing docetaxel, CDDP and 5-FU with CDDP and 5-FU in patients with metastatic or recurrent esophageal cancer (JCOG1314) is ongoing. A multicenter phase I study of HSP105-derived peptide vaccine for patients with advanced esophageal cancer/colorectal cancer and phase II trial of BKM120 in patients with advanced esophagus cancer is ongoing. As in the single institutional clinical study, the phase II trial of definitive chemoprotontherapy in patients with clinical stage I/II/III esophageal carcinoma is ongoing.

Gastric Cancer (GC)

The results of the GATSBY trial, which compared 2nd-line T-DM1 and taxanes agents for HER2 positive gastric cancer, was presented in ASCO-GI 2016, which could not meet its primary endpoint. The enrollment for a multicenter global trial (JACOB) of pertuzumab was completed. Multicenter global phase III trials of molecular targeting agents (ENRICH, BRIGHTER) are ongoing. Several phase 2 or 3 trials to evaluate the efficacy of an anti-PD1 antibody are also ongoing (KEYNOTE-59, 61 and 62). Several phase I or II studies of newer agents including c-MET tyrosine kinase inhibitor of MET high GC, FGFR-inhibitor for FGFR high GC as well as combination therapy of immune checkpoint inhibitors are ongoing. Several investigator-initiated trials of a multicenter phase III trial comparing DCS to cisplatin plus S-1 (JCOG 1013), a multicenter phase II trial comparing 12 months of S-1 to 6 months of S-1 as an adjuvant chemotherapy (JCOG 1104) are ongoing. After confirmation of the mode of action of SSZ as a cancer stem cell inhibitor, a phase 1 trial of SSZ in combination with cisplatin for cisplatin refractory GC patients was also conducted.

Colorectal Cancer (CRC)

The results of a global randomized phase III trial comparing TAS-102 to best supportive care (RECOURSE) were published in the New England Journal of Medicine. We have completed the phase 1b/2 trial of the novel combination of TAS-102 plus bevacizumab as an investigator-initiated trial (IIT). The patients' registration of an international phase III trial, which investigates the survival benefits of the oral multi-target kinase inhibitor nintedanib with placebo in a salvage setting (LUME-COLON 1), were finished. We are participating in two different international phase 1b/2 trials that target patients with BRAF V600E mutated CRC, of which results were reported in the ESMO World Congress on Gastrointestinal Cancer 2015. We are now recruiting the phase 1b/2 trial of the novel combination of TAS-102 plus nintedanib as an IIT. The phase II and III clinical trials of the immune checkpoint inhibitor pembrolizumab, for patients with deficiency in mismatch repair (KEYNOTE-164, KEYNOTE-177), are ongoing. We have conducted two randomized, multicenter, phase III studies called ACHIEVE and ACHIEVE-2 trials, together with other collaborative groups in the US, UK/Australia, Italy, Greece and France.

Education

Our residents learn the latest evidence-based medicine and apply this knowledge pragmatically to enhance care for patients with GI cancers, and eventually obtain qualifications as comprehensive GI oncologists through daily practice and direct training from our staff. Accordingly, our staff actively provide a wealth of valuable opportunities to polish their skills regarding various chemotherapies, especially in collaboration with the Department of Experimental Therapeutics as well as diagnostic and therapeutic endoscopies in collaboration with the Department of Digestive Endoscopy. We regularly held tumor-related board meetings and frequently have numerous face-to-face meetings with experts in different specialties. We instruct them how to conduct valuable clinical trials, how to have the chance to attend international academic conferences, and the best way to present academic meetings and work on many high-impact articles in scholarly journals. To date, our department has helped many residents to become 'true' skilled GI oncologists who play major roles at leading cancer centers across the country.

Future prospects

We continue to provide the best treatment for cancer patients, the best education for residents, and aim to perform the following activities:

  1. To provide the latest, cutting-edge medicine to cancer patients and to foster the next generation of skilled GI oncologists.
  2. To achieve medical innovation in Japan, we aim to play leading roles in the clinical developments of INDs by contributing to various types of clinical trials including FIC, FIH early trials, IITs with proof-of-concept, and international clinical trials.
  3. To enhance our research activities, we will establish research networks with cutting-edge researchers in Japan as well as globally.

Table 1. Number of new patients Table 2. Treatment

List of papers published in 2015

Journal

  1. Fujii S, Fujihara A, Natori K, Abe A, Kuboki Y, Higuchi Y, Aizawa M, Kuwata T, Kinoshita T, Yasui W, Ochiai A. TEM1 expression in cancer-associated fibroblasts is correlated with a poor prognosis in patients with gastric cancer. Cancer Med, 4:1667-1678, 2015
  2. Komatsu Y, Doi T, Sawaki A, Kanda T, Yamada Y, Kuss I, Demetri GD, Nishida T. Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial. Int J Clin Oncol, 20:905-912, 2015
  3. Bando H, Takebe N. Recent innovations in the USA National Cancer Institute-sponsored investigator initiated Phase I and II anticancer drug development. Jpn J Clin Oncol, 45:1001-1006, 2015
  4. Doi T, Tamura K, Tanabe Y, Yonemori K, Yoshino T, Fuse N, Kodaira M, Bando H, Noguchi K, Shimamoto T, Ohtsu A. Phase 1 pharmacokinetic study of the oral pan-AKT inhibitor MK-2206 in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol, 76:409-416, 2015
  5. Doi T, Yoshino T, Shitara K, Matsubara N, Fuse N, Naito Y, Uenaka K, Nakamura T, Hynes SM, Lin AB. Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors. Anticancer Drugs, 26:1043-1053, 2015
  6. Kawazoe A, Shitara K, Fukuoka S, Kuboki Y, Bando H, Okamoto W, Kojima T, Fuse N, Yamanaka T, Doi T, Ohtsu A, Yoshino T. A retrospective observational study of clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations in Japanese patients with metastatic colorectal cancer. BMC Cancer, 15:258, 2015
  7. Kawazoe A, Shitara K, Fukuoka S, Noguchi M, Kuboki Y, Bando H, Okamoto W, Kojima T, Fuse N, Yoshino T, Ohtsu A, Doi T. Clinical outcomes in 66 patients with advanced gastric cancer treated in phase I trials: the NCCHE experience. Invest New Drugs, 33:664-670, 2015
  8. Yoshino T, Yamazaki K, Gotoh M, Nasroulah F, Gao L, Yoshizuka N, Ohtsu A. Safety and Pharmacokinetics of Second-line Ramucirumab plus FOLFIRI in Japanese Patients with Metastatic Colorectal Carcinoma. Anticancer Res, 35:4003-4007, 2015
  9. Yoshino T, Muro K, Yamaguchi K, Nishina T, Denda T, Kudo T, Okamoto W, Taniguchi H, Akagi K, Kajiwara T, Hironaka S, Satoh T. Clinical Validation of a Multiplex Kit for RAS Mutations in Colorectal Cancer: Results of the RASKET (RAS KEy Testing) Prospective, Multicenter Study. EBioMedicine, 2:317-323, 2015
  10. Hecht JR, Mitchell EP, Yoshino T, Welslau M, Lin X, Chow Maneval E, Paolini J, Lechuga MJ, Kretzschmar A. 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study. Cancer Manag Res, 7:165-173, 2015
  11. Kondoh C, Shitara K, Nomura M, Takahari D, Ura T, Tachibana H, Tomita N, Kodaira T, Muro K. Efficacy of palliative radiotherapy for gastric bleeding in patients with unresectable advanced gastric cancer: a retrospective cohort study. BMC Palliat Care, 14:37, 2015
  12. Kotaka M, Yoshino T, Oba K, Shinozaki K, Touyama T, Manaka D, Matsui T, Ishigure K, Hasegawa J, Inoue K, Goto K, Sakamoto J, Saji S, Ohtsu A, Watanabe T. Initial safety report on the tolerability of modified FOLFOX6 as adjuvant therapy in patients with curatively resected stage II or III colon cancer (JFMC41-1001-C2: JOIN trial). Cancer Chemother Pharmacol, 76:75-84, 2015
  13. Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A, RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med, 372:1909-1919, 2015
  14. Oh DY, Doi T, Shirao K, Lee KW, Park SR, Chen Y, Yang L, Valota O, Bang YJ. Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer. Cancer Res Treat, 47:687-696, 2015
  15. Saito T, Kondo C, Shitara K, Ito Y, Saito N, Ikehara Y, Yatabe Y, Yamamichi K, Tanaka H, Nakanishi H. Comparison of intratumoral heterogeneity of HER2 expression between primary tumor and multiple organ metastases in gastric cancer: Clinicopathological study of three autopsy cases and one resected case. Pathol Int, 65:309-317, 2015
  16. Satake H, Yano T, Muto M, Minashi K, Yoda Y, Kojima T, Oono Y, Ikematsu H, Aoyama I, Morita S, Miyamoto S, Fujii S, Yoshizawa A, Ochiai A, Hayashi R, Kaneko K. Clinical outcome after endoscopic resection for superficial pharyngeal squamous cell carcinoma invading the subepithelial layer. Endoscopy, 47:11-18, 2015
  17. Tabernero J, Lenz HJ, Siena S, Sobrero A, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Yoshino T, Goldberg RM, Sargent DJ, Wagner A, Laurent D, Teufel M, Jeffers M, Grothey A, Van Cutsem E. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol, 16:937-948, 2015
  18. Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F, RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after firstline therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol, 16:499-508, 2015
  19. Takahashi H, Kaniwa N, Saito Y, Sai K, Hamaguchi T, Shirao K, Shimada Y, Matsumura Y, Ohtsu A, Yoshino T, Doi T, Takahashi A, Odaka Y, Okuyama M, Sawada J, Sakamoto H, Yoshida T. Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method. BMC Cancer, 15:718, 2015
  20. Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, Yang SX, Ivy SP. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol, 12:445-464, 2015
  21. Taniguchi H, Yamazaki K, Yoshino T, Muro K, Yatabe Y, Watanabe T, Ebi H, Ochiai A, Baba E, Tsuchihara K, Japanese Society of Medical Oncology. Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients. Cancer Sci, 106:324-327, 2015
  22. Ueda S, Satoh T, Gotoh M, Gao L, Doi T. A phase ib study of safety and pharmacokinetics of ramucirumab in combination with paclitaxel in patients with advanced gastric adenocarcinomas. Oncologist, 20:493-494, 2015
  23. Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, Kakimi K, Nishikawa H, Udono H, Oka M, Ueda R, Nakayama E. Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients. Clin Cancer Res, 21:4327-4336, 2015
  24. Yoshida M, Muro K, Tsuji A, Hamamoto Y, Yoshino T, Yoshida K, Shirao K, Miyata Y, Takahari D, Takahashi T, Ohtsu A. Combination chemotherapy with bevacizumab and S-1 for elderly patients with metastatic colorectal cancer (BASIC trial). Eur J Cancer, 51:935-941, 2015
  25. Nishio M, Horiike A, Nokihara H, Horinouchi H, Nakamichi S, Wakui H, Ohyanagi F, Kudo K, Yanagitani N, Takahashi S, Kuboki Y, Yamamoto N, Yamada Y, Abe M, Tahata T, Tamura T. Phase I study of the anti-MET antibody onartuzumab in patients with solid tumors and MET-positive lung cancer. Invest New Drugs, 33:632-640, 2015
  26. Yoshino T, Komatsu Y, Yamada Y, Yamazaki K, Tsuji A, Ura T, Grothey A, Van Cutsem E, Wagner A, Cihon F, Hamada Y, Ohtsu A. Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations. Invest New Drugs, 33:740-750, 2015
  27. Geva R, Vecchione L, Kalogeras KT, Jensen BV, Lenz HJ, Yoshino T, Paez D, Montagut C, Souglakos J, Cappuzzo F, Cervantes A, Frattini M, Fountzilas G, Johansen JS, Høgdall EV, Zhang W, Yang D, Yamazaki K, Nishina T, Papamichael D, Vincenzi B, Macarulla T, Loupakis F, De Schutter J, Spindler KL, Pfeiffer P, Ciardiello F, Piessevaux H, Tejpar S. FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study. Gut, 64:921-928, 2015
  28. Nagatsuma AK, Aizawa M, Kuwata T, Doi T, Ohtsu A, Fujii H, Ochiai A. Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer, 18:227-238, 2015
  29. Nishida Y, Kuwata T, Nitta H, Dennis E, Aizawa M, Kinoshita T, Ohtsu A, Ochiai A. A novel gene-protein assay for evaluating HER2 status in gastric cancer: simultaneous analyses of HER2 protein overexpression and gene amplification reveal intratumoral heterogeneity. Gastric Cancer, 18:458-466, 2015
  30. Osera S, Yano T, Odagaki T, Oono Y, Ikematsu H, Ohtsu A, Kaneko K. Peritonitis related to percutaneous endoscopic gastrostomy using the direct method for cancer patients. Surg Endosc, 29:2941-2946, 2015
  31. Satoh T, Lee KH, Rha SY, Sasaki Y, Park SH, Komatsu Y, Yasui H, Kim TY, Yamaguchi K, Fuse N, Yamada Y, Ura T, Kim SY, Munakata M, Saitoh S, Nishio K, Morita S, Yamamoto E, Zhang Q, Kim JM, Kim YH, Sakata Y. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer. Gastric Cancer, 18:824-832, 2015
  32. Shitara K, Ohtsu A. Ramucirumab for gastric cancer. Expert Rev Gastroenterol Hepatol, 9:133-139, 2015
  33. Sasaki T, Fuse N, Kuwata T, Nomura S, Kaneko K, Doi T, Yoshino T, Asano H, Ochiai A, Komatsu Y, Sakamoto N, Ohtsu A. Serum HER2 levels and HER2 status in tumor cells in advanced gastric cancer patients. Jpn J Clin Oncol, 45:43-48, 2015
  34. Watanabe T, Itabashi M, Shimada Y, Tanaka S, Ito Y, Ajioka Y, Hamaguchi T, Hyodo I, Igarashi M, Ishida H, Ishihara S, Ishiguro M, Kanemitsu Y, Kokudo N, Muro K, Ochiai A, Oguchi M, Ohkura Y, Saito Y, Sakai Y, Ueno H, Yoshino T, Boku N, Fujimori T, Koinuma N, Morita T, Nishimura G, Sakata Y, Takahashi K, Tsuruta O, Yamaguchi T, Yoshida M, Yamaguchi N, Kotake K, Sugihara K, Japanese Society for Cancer of the Colon and Rectum. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. Int J Clin Oncol, 20:207-239, 2015
  35. Doi T, Yoshino T, Fuse N, Boku N, Yamazaki K, Koizumi W, Shimada K, Takinishi Y, Ohtsu A. Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients with advanced colorectal cancer. Invest New Drugs, 33:1068-1077, 2015
  36. Nishina T, Kato T, Yamazaki K, Yoshino T, Miyata Y, Esaki T, Moriwaki T, Boku N, Hyodo I. A phase II study of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA) in patients with unresectable metastatic colorectal cancer. Cancer Chemother Pharmacol, 76:547-553, 2015
  37. Kataoka K, Tokunaga M, Mizusawa J, Machida N, Katayama H, Shitara K, Tomita T, Nakamura K, Boku N, Sano T, Terashima M, Sasako M, Stomach Cancer Study Group/Japan Clinical Oncology Group. A randomized Phase II trial of systemic chemotherapy with and without trastuzumab followed by surgery in HER2-positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301 (Trigger Study). Jpn J Clin Oncol, 45:1082-1086, 2015
  38. Mizutani T, Tanaka M, Eba J, Mizusawa J, Fukuda H, Hanaoka N, Takeuchi M, Aoyama I, Kojima T, Takizawa K, Ono H, Muto M, Gastrointestinal Endoscopy Study Group of the Japan Clinical Oncology Group (JCOG). A Phase III study of oral steroid administration versus local steroid injection therapy for the prevention of esophageal stricture after endoscopic submucosal dissection (JCOG1217, Steroid EESD P3). Jpn J Clin Oncol, 45:1087-1090, 2015