Annual Report 2017

Department of Gastrointestinal Oncology

Takayuki Yoshino, Toshihiko Doi, Takashi Kojima, Kouhei Shitara, Nozomu Fuse, Hideaki Bando, Yasutoshi Kuboki, Akihito Kawazoe, Kentaro Sawada, Daisuke Kotani, Yoshiaki N

Introduction

 In 2017, approximately 850 gastrointestinal (GI) cancer patients were treated by staff oncologists and skilled residents in the Department of Gastrointestinal Oncology, which focuses on the optimal chemotherapy with or without radiation in the treatment of GI cancers.

Our team and what we do

 Inter-Divisional Tumor Board Conferences with the Surgical/Radiation Oncology Departments are held regularly to review the current treatment for each patient and to discuss further treatment strategies. Our activities for each type of GI cancer in 2017 are shown in Table 1. There are ongoing clinical trials which are consisted of 51 phase I trials including globally first-in-class (FIC), first-in-human (FIH), and investigational new drugs (INDs), 27 phase II/III clinical trials in order to approve the INDs, and 18 investigator-initiated clinical trials (IITs). In addition, young skilled residents in the early 30 years of age have become principal investigators for several IITs.

Table 1. The number of treatment cases (April 2017 - March 2018)

Research activities

1. Phase I

 Our Department has focused more on early stage clinical development of INDs. The number of patients enrolled for phase I trials has been increasing recently, especially in studies for immunomodulating agents have been increasing. Several results of phase I trials, such as DS-8201a, new HER2 ADC, TAS-120, pan-FGFR inhibitor, and TAK-931, cdc7 inhibitor were published or presented at international meetings. DS-8201a is expected to be promising therapy for HER2-

expressing tumor such as gastric cancer, and

TAS-120 is expected for FGFR2 positive gastric cancer. TAK-931 has expanded to target for colorectal and esophageal cancers.

2. Esophageal Cancer (EC)

 As in the single institutional clinical study, a phase I trial of definitive chemoprotontherapy in patients with clinical stage I/II/III esophageal carcinoma is ongoing. A phase I trial of oncolytic virus and pembrolizumab was started. A phase Ib/II study to investigate the safety, efficacy, and proof-of-concept (POC) of Anti PD-L1 antibody monotherapy following radical chemoradiotherapy in patients with inoperable locally advanced esophageal squamous cell cancer is currently being planned.

3. Gastric Cancer (GC)

 An immune monitoring study has been conducted to evaluate several immunological properties such as classification of lymphocyte, or expression of immune checkpoint in tumor infiltrating lymphocyte and PBMC before and after treatment, which will hopefully lead to personalized therapy in the field of immunotherapy. Several studies are ongoing in collaboration with pharmaceutical companies. A phase I trial of anti-CD4 depleting antibody IT1208 was completed. Other ongoing IITs include phase I of regorafenib and nivolumab, phase I of TAS-116 and nivolumab, and phase II of TAS114+S1 for gastric cancer. Phase II of lenvatinib plus pembrolizumab will be started soon.

4. Colorectal Cancer (CRC)

 Our initiative, ongoing SCRUM-Japan GI-SCREEN is the nationwide cancer genome screening project in Japanese CRC patients. Furthermore, cell free tumor DNA based NGS screening (GOZILA project) has also been started. On the basis of the screening system of GI-SCREEN, the umbrella type of IITs for metastatic CRC patients with HER2 amplifications, BRAF V600E mutation, and BRAF non-V600E mutation is ongoing. An IIT for metastatic CRC patients with MET amplification will be started soon. Clinical evaluation studies of cell-free tumor DNA-based RAS gene testing by BEAMing technology and of newly developed MSI testing kits were completed.

 We have conducted two randomized, multicenter, phase III studies called ACHIEVE and ACHIEVE-2 trial, together with other nations' collaborative groups in the U.S., UK/Australia, Italy, Greece, and France. The primary analysis of ACHIEVE study was published in the New England Journal of Medicine in 2018.

Education

 Our residents learned the latest evidence-based medicine and applied this knowledge pragmatically to enhance care for patients with GI cancers, and eventually acquire qualifications as a comprehensive GI oncologist through daily practice and direct training from our staff. Accordingly, our staff actively provides a pile of valuable opportunities to polish their skills regarding various chemotherapies, especially in collaboration with the Department of Experimental Therapeutics as well as diagnostic & therapeutic endoscopies collaborated with the Department of Gastroenterology and Endoscopy. We regularly hold tumor board meetings and frequently have numerous face-to-face opportunities 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 at the academic meeting and work on many high-impact articles in scholarly journals. To date, our department has led 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 accomplish our mission, we will provide more of the latest, cutting-edged medicine to cancer patients and foster more of the next generation of skilled GI oncologists.

2) To achieve medical innovation from 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 activity, we will establish research networks with cutting-edged researchers globally.

List of papers published in January 2017 - March 2018

Journal

 1. Doi T, Hamaguchi T, Shitara K, Iwasa S, Shimada Y, Harada M, Naito K, Hayashi N, Masada A, Ohtsu A. NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis. Cancer Chemother Pharmacol, 79:569-578, 2017

 2. Fuse N, Bando H, Chin K, Ito S, Yoshikawa T, Tsuburaya A, Terashima M, Kawashima Y, Fukunaga T, Gotoh M, Emi Y, Yoshida K, Oki E, Takahashi S, Kuriki H, Sato K, Sasako M. Adjuvant capecitabine plus oxaliplatin after D2 gastrectomy in Japanese patients with gastric cancer: a phase II study. Gastric cancer, 20:332-340, 2017

 3. Yoshino T, Uetake H, Tsuchihara K, Shitara K, Yamazaki K, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Yamanaka K, Iwasaki K, Soeda J, Hihara M, Yamanaka T, Ochiai A, Muro K. Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naive Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer. Clin Colorectal Cancer, 16:158-163, 2017

 4. Sakai D, Chung HC, Oh DY, Park SH, Kadowaki S, Kim YH, Tsuji A, Komatsu Y, Kang YK, Uenaka K, Wijayawardana SR, Wacheck V, Wang X, Yamamura A, Doi T. A non-randomized, open-label, single-arm, Phase 2 study of emibetuzumab in Asian patients with MET diagnostic positive, advanced gastric cancer. Cancer Chemother Pharmacol, 80:1197-1207, 2017

 5. Bando H, Rubinstein L, Harris P, Yoshino T, Doi T, Ohtsu A, Welch J, Takebe N. Analysis of esophagogastric cancer patients enrolled in the National Cancer Institute Cancer Therapy Evaluation Program sponsored phase 1 trials. Gastric cancer, 20:481-488, 2017

 6. Shitara K, Kim TM, Yokota T, Goto M, Satoh T, Ahn JH, Kim HS, Assadourian S, Gomez C, Harnois M, Hamauchi S, Kudo T, Doi T, Bang YJ. Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer. Oncotarget, 8:79546-79555, 2017

 7. Taniguchi H, Iwasa S, Yamazaki K, Yoshino T, Kiryu C, Naka Y, Liew EL, Sakata Y. Phase 1 study of OCV-C02, a peptide vaccine consisting of two peptide epitopes for refractory metastatic colorectal cancer. Cancer Sci, 108:1013-1021, 2017

 8. Shitara K. Chemotherapy for advanced gastric cancer: future perspective in Japan. Gastric cancer, 20:102-110, 2017

 9. Kudo T, Hamamoto Y, Kato K, Ura T, Kojima T, Tsushima T, Hironaka S, Hara H, Satoh T, Iwasa S, Muro K, Yasui H, Minashi K, Yamaguchi K, Ohtsu A, Doki Y, Kitagawa Y. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol, 18:631-639, 2017

10. Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, Mansoor W, Chung HC, Bodoky G, Shitara K, Phillips GDL, van der Horst T, Harle-Yge ML, Althaus BL, Kang YK. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol, 18:640-653, 2017

11. Kojima T, Doi T. Immunotherapy for Esophageal Squamous Cell Carcinoma. Curr Oncol Rep, 19:33, 2017

12. Okuno T, Wakabayashi M, Kato K, Shinoda M, Katayama H, Igaki H, Tsubosa Y, Kojima T, Okabe H, Kimura Y, Kawano T, Kosugi S, Toh Y, Kato H, Nakamura K, Fukuda H, Ishikura S, Ando N, Kitagawa Y. Esophageal stenosis and the Glasgow Prognostic Score as independent factors of poor prognosis for patients with locally advanced unresectable esophageal cancer treated with chemoradiotherapy (exploratory analysis of JCOG0303). Int J Clin Oncol, 22:1042-1049, 2017

13. van Geel RMJM, Tabernero J, Elez E, Bendell JC, Spreafico A, Schuler M, Yoshino T, Delord JP, Yamada Y, Lolkema MP, Faris JE, Eskens FALM, Sharma S, Yaeger R, Lenz HJ, Wainberg ZA, Avsar E, Chatterjee A, Jaeger S, Tan E, Maharry K, Demuth T, Schellens JHM. A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer. Cancer Discov, 7:610-619, 2017

14. 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. Proxies of quality of life in metastatic colorectal cancer: analyses in the RECOURSE trial. ESMO open, 2:e000261, 2017

15. Cohn AL, Yoshino T, Heinemann V, Obermannova R, Bodoky G, Prausova J, Garcia-Carbonero R, Ciuleanu T, Garcia-Alfonso P, Portnoy DC, Van Cutsem E, Yamazaki K, Clingan PR, Polikoff J, Lonardi S, O'Brien LM, Gao L, Yang L, Ferry D, Nasroulah F, Tabernero J. Exposure-response relationship of ramucirumab in patients with advanced second-line colorectal cancer: exploratory analysis of the RAISE trial. Cancer Chemother Pharmacol, 80:599-608, 2017

16. Shitara K, Chin K, Yoshikawa T, Katai H, Terashima M, Ito S, Hirao M, Yoshida K, Oki E, Sasako M, Emi Y, Tsujinaka T. Phase II study of adjuvant chemotherapy of S-1 plus oxaliplatin for patients with stage III gastric cancer after D2 gastrectomy. Gastric Cancer, 20:175-181, 2017

17. Hatogai K, Fujii S, Kojima T, Daiko H, Nomura S, Doi T, Kitano S, Ohtsu A, Takiguchi Y, Yoshino T, Ochiai A. Large-scale comprehensive immunohistochemical biomarker analyses in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol, 143:2351-2361, 2017

18. Doi T, Fuse N, Yoshino T, Kojima T, Bando H, Miyamoto H, Kaneko M, Osada M, Ohtsu A. A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors. Cancer Chemother Pharmacol, 79:89-98, 2017

19. Kuboki Y, Nishina T, Shinozaki E, Yamazaki K, Shitara K, Okamoto W, Kajiwara T, Matsumoto T, Tsushima T, Mochizuki N, Nomura S, Doi T, Sato A, Ohtsu A, Yoshino T. TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. Lancet Oncol, 18:1172-1181, 2017

20. Bando H. The current status and problems confronted in delivering precision medicine in Japan and Europe. Curr Probl Cancer, 41:166-175, 2017

21. Yoshino T, Hyodo I, Nishina T, Narahara H, Sugimoto N, Yoshisue K, Boku N. Phase I clinical and pharmacokinetic study of S-1 plus oral leucovorin in patients with metastatic colorectal cancer. Cancer Chemother Pharmacol, 79:107-116, 2017

22. Shitara K, Takashima A, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Makari Y, Amagai K, Ueda S, Yoshida K, Shimodaira H, Nishina T, Tsuda M, Kurokawa Y, Tamura T, Sasaki Y, Morita S, Koizumi W. Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial. The lancet. Gastroenterology & hepatology, 2:277-287, 2017

23. Yoshino T, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu T, Portnoy DC, Kim TW, Hsu Y, Ferry D, Nasroulah F, Tabernero J. Baseline carcinoembryonic antigen as a predictive factor of ramucirumab efficacy in RAISE, a second-line metastatic colorectal carcinoma phase III trial. Eur J Cancer, 78:61-69, 2017

24. Hatogai K, Fujii S, Kojima T, Daiko H, Doi T, Ohtsu A, Ochiai A, Takiguchi Y, Yoshino T. Concordance between PIK3CA mutations in endoscopic biopsy and surgically resected specimens of esophageal squamous cell carcinoma. BMC Cancer, 17:36, 2017

25. Shitara K. RAINFALL before RAINBOW-an illusion or reality? Translational gastroenterology and hepatology, 2:26, 2017

26. Kumabe A, Zenda S, Motegi A, Onozawa M, Nakamura N, Kojima T, Daiko H, Shigematsu N, Akimoto T. Long-term Clinical Results of Concurrent Chemoradiotherapy for Patients with Cervical Esophageal Squamous Cell Carcinoma. Anticancer Res, 37:5039-5044, 2017

27. Shitara K, Doi T, Nagano O, Fukutani M, Hasegawa H, Nomura S, Sato A, Kuwata T, Asai K, Einaga Y, Tsuchihashi K, Suina K, Maeda Y, Saya H, Ohtsu A. Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407). Gastric cancer, 20:1004-1009, 2017

28. Shitara K, Doi T, Nagano O, Imamura CK, Ozeki T, Ishii Y, Tsuchihashi K, Takahashi S, Nakajima TE, Hironaka S, Fukutani M, Hasegawa H, Nomura S, Sato A, Einaga Y, Kuwata T, Saya H, Ohtsu A. Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205). Gastric Cancer, 20:341-349, 2017

29. Kawazoe A, Kuwata T, Kuboki Y, Shitara K, Nagatsuma AK, Aizawa M, Yoshino T, Doi T, Ohtsu A, Ochiai A. Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein-Barr virus status in a large cohort of gastric cancer patients. Gastric Cancer, 20:407-415, 2017

30. Uemura H, Matsubara N, Kinuya S, Hosono M, Yajima Y, Doi T. Safety and efficacy of radium-223 dichloride in Japanese patients with castration-resistant prostate cancer and bone metastases. Int J Clin Oncol, 22:954-963, 2017

31. Hyman DM, Smyth LM, Donoghue MTA, Westin SN, Bedard PL, Dean EJ, Bando H, El-Khoueiry AB, Perez-Fidalgo JA, Mita A, Schellens JHM, Chang MT, Reichel JB, Bouvier N, Selcuklu SD, Soumerai TE, Torrisi J, Erinjeri JP, Ambrose H, Barrett JC, Dougherty B, Foxley A, Lindemann JPO, McEwen R, Pass M, Schiavon G, Berger MF, Chandarlapaty S, Solit DB, Banerji U, Baselga J, Taylor BS. AKT Inhibition in Solid Tumors With AKT1 Mutations. J Clin Oncol, 35:2251-2259, 2017

32. Nakamura Y, Hattori N, Iida N, Yamashita S, Mori A, Kimura K, Yoshino T, Ushijima T. Targeting of super-enhancers and mutant BRAF can suppress growth of BRAF-mutant colon cancer cells via repression of MAPK signaling pathway. Cancer Lett, 402:100-109, 2017

33. Kataoka K, Kinoshita T, Moehler M, Mauer M, Shitara K, Wagner AD, Schrauwen S, Yoshikawa T, Roviello F, Tokunaga M, Boku N, Ducreux M, Terashima M, Lordick F. Current management of liver metastases from gastric cancer: what is common practice? New challenge of EORTC and JCOG. Gastric cancer, 20:904-912, 2017

34. Arnold D, Fuchs CS, Tabernero J, Ohtsu A, Zhu AX, Garon EB, Mackey JR, Paz-Ares L, Baron AD, Okusaka T, Yoshino T, Yoon HH, Das M, Ferry D, Zhang Y, Lin Y, Binder P, Sashegyi A, Chau I. Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann Oncol, 28:2932-2942, 2017

35. Shinozaki E, Yoshino T, Yamazaki K, Muro K, Yamaguchi K, Nishina T, Yuki S, Shitara K, Bando H, Mimaki S, Nakai C, Matsushima K, Suzuki Y, Akagi K, Yamanaka T, Nomura S, Fujii S, Esumi H, Sugiyama M, Nishida N, Mizokami M, Koh Y, Abe Y, Ohtsu A, Tsuchihara K. Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study. Br J Cancer, 117:1450-1458, 2017

36. Fukuoka S, Kojima T, Koga Y, Yamauchi M, Komatsu M, Komatsuzaki R, Sasaki H, Yasunaga M, Matsumura Y, Doi T, Ohtsu A. Preclinical efficacy of Sym004, novel anti-EGFR antibody mixture, in esophageal squamous cell carcinoma cell lines. Oncotarget, 8:11020-11029, 2017

37. Doi T, Yamaguchi K, Komatsu Y, Muro K, Nishina T, Nakajima TE, Tang R, Yang H, Zhang Y, Jung AS, Ang A, Yasui H. A Phase 1/1b tolerability study of rilotumumab alone or in combination with cisplatin and capecitabine in Japanese patients with gastric cancer. Jpn J Clin Oncol, 47:1002-1009, 2017

38. Fukuoka S, Shitara K, Noguchi M, Kawazoe A, Kuboki Y, Bando H, Okamoto W, Kojima T, Doi T, Ohtsu A, Yoshino T. Prophylactic Use of Oral Dexamethasone to Alleviate Fatigue During Regorafenib Treatment for Patients With Metastatic Colorectal Cancer. Clin Colorectal Cancer, 16:e39-e44, 2017

39. Tanase T, Hamada C, Yoshino T, Ohtsu A. A Proposal for Progression-Free Survival Assessment in Patients with Early Progressive Cancer. Anticancer Res, 37:5851-5855, 2017

40. Nagata K, Endo S, Honda T, Yasuda T, Hirayama M, Takahashi S, Kato T, Horita S, Furuya K, Kasai K, Matsumoto H, Kimura Y, Utano K, Sugimoto H, Kato H, Yamada R, Yamamichi J, Shimamoto T, Ryu Y, Matsui O, Kondo H, Doi A, Abe T, Yamano H-O, Takeuchi K, Hanai H, Saida Y, Fukuda K, Nappi J, Yoshida H. Accuracy of CT Colonography for Detection of Polypoid and Nonpolypoid Neoplasia by Gastroenterologists and Radiologists: A Nationwide Multicenter Study in Japan. Am J Gastroenterol, 112:163-171, 2017

41. Yasui H, Go N, Yang H, Amore BM, Jung AS, Doi T. A Phase 1 study evaluating AMG 337 in Asian patients with advanced solid tumors. Jpn J Clin Oncol, 47:772-776, 2017

42. Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, Shimizu C, Shimoi T, Kuboki Y, Matsubara N, Kitano A, Jikoh T, Lee C, Fujisaki Y, Ogitani Y, Yver A, Tamura K. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol, 18:1512-1522, 2017

43. Yoshino T, Hsu Y, Nasroulah F. Response to Letter to the Editor, 'Pharmacokinetics partly explains the relationship between CEA level and survival of colorectal cancer patients treated with ramucirumab,' by Ibrahim et al. Eur J Cancer, 92:121-122, 2018

44. Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. N Engl J Med, 378:1177-1188, 2018

45. Watanabe T, Muro K, Ajioka Y, Hashiguchi Y, Ito Y, Saito Y, Hamaguchi T, Ishida H, Ishiguro M, Ishihara S, Kanemitsu Y, Kawano H, Kinugasa Y, Kokudo N, Murofushi K, Nakajima T, Oka S, Sakai Y, Tsuji A, Uehara K, Ueno H, Yamazaki K, Yoshida M, Yoshino T, Boku N, Fujimori T, Itabashi M, Koinuma N, Morita T, Nishimura G, Sakata Y, Shimada Y, Takahashi K, Tanaka S, Tsuruta O, Yamaguchi T, Yamaguchi N, Tanaka T, Kotake K, Sugihara K. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer. Int J Clin Oncol, 23:1-34, 2018

46. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2016 for the Clinical Practice of Hereditary Colorectal Cancer (Translated Version). J Anus Rectum Colon, 2:S1-S51, 2018

47. Shitara K, Kadowaki S, Nishina T, Sakai D, Yoshikawa R, Piao Y, Ozeki A, Inoue K, Gritli I, Muro K. Safety, pharmacokinetic, and clinical activity profiles of ramucirumab in combination with three platinum/fluoropyrimidine doublets in Japanese patients with chemotherapy-naive metastatic gastric/gastroesophageal junction cancer. Gastric Cancer, 21:106-113, 2018

48. Imbe K, Nagata N, Hisada Y, Takasaki Y, Sekine K, Mishima S, Kawazoe A, Tajima T, Shimbo T, Yanase M, Akiyama J, Fujimoto K, Uemura N. Validation of the American Gastroenterological Association guidelines on management of intraductal papillary mucinous neoplasms: more than 5 years of follow-up. Eur Radiol, 28:170-178, 2018

49. Doi T, Hewes B, Kakizume T, Tajima T, Ishikawa N, Yamada Y. Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors. Cancer Sci, 109:193-198, 2018

50. Doi T, Piha-Paul SA, Jalal SI, Saraf S, Lunceford J, Koshiji M, Bennouna J. Safety and Antitumor Activity of the Anti-Programmed Death-1 Antibody Pembrolizumab in Patients With Advanced Esophageal Carcinoma. J Clin Oncol, 36:61-67, 2018

51. Yoshino T, Arnold D, Taniguchi H, Pentheroudakis G, Yamazaki K, Xu RH, Kim TW, Ismail F, Tan IB, Yeh KH, Grothey A, Zhang S, Ahn JB, Mastura MY, Chong D, Chen LT, Kopetz S, Eguchi-Nakajima T, Ebi H, Ohtsu A, Cervantes A, Muro K, Tabernero J, Minami H, Ciardiello F, Douillard JY. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol, 29:44-70, 2018

52. Falcone A, Ohtsu A, Van Cutsem E, Mayer RJ, Buscaglia M, Bendell JC, Kopetz S, Bebeau P, Yoshino T. Integrated safety summary for trifluridine/tipiracil (TAS-102). Anticancer Drugs, 29:89-96, 2018

53. Tabernero J, Hozak RR, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Prausova J, Muro K, Siegel RW, Konrad RJ, Ouyang H, Melemed SA, Ferry D, Nasroulah F, Van Cutsem E. Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. Ann Oncol, 29:602-609, 2018

54. Kotani H, Adachi Y, Kitai H, Tomida S, Bando H, Faber AC, Yoshino T, Voon DC, Yano S, Ebi H. Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers. Oncogene, 37:1775-1787, 2018

55. Bando H, Shimodaira H, Fujitani K, Takashima A, Yamaguchi K, Nakayama N, Takahashi T, Oki E, Azuma M, Nishina T, Hironaka S, Komatsu Y, Shitara K. A phase II study of nab-paclitaxel in combination with ramucirumab in patients with previously treated advanced gastric cancer. Eur J Cancer, 91:86-91, 2018

56. Matsumoto H, Kawazoe A, Shimada K, Fukuoka S, Kuboki Y, Bando H, Kojima T, Ohtsu A, Yoshino T, Doi T, Shitara K. A retrospective study of the safety and efficacy of paclitaxel plus ramucirumab in patients with advanced or recurrent gastric cancer with ascites. BMC Cancer, 18:120, 2018