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国立がん研究センター 中央病院

Home > Clincal depts. > Department of Hepatobiliary and Pancreatic Oncology

Department of Hepatobiliary and Pancreatic Oncology

Takuji Okusaka, Hideki Ueno, Chigusa Morizane, Shunsuke Kondo, Yasunari Sakamoto, Mitsuhito Sasaki

Introduction

The Department of Hepatobiliary and Pancreatic Oncology treats tumors originating from the liver, biliary system or pancreas, which include hepatocellular carcinoma (HCC), biliary tract cancer and pancreatic cancer. As part of the multi-disciplinary care given at the National Cancer Center Hospital (NCCH), we work closely with surgeons and radiologists who have expertise in these areas. We also conduct research into the pathophysiology of hepatobiliary and pancreatic tumors and seek to develop new and more effective diagnostic methods and treatments.

Routine activities

The Department consists of five staff oncologists and three to four residents. In 1990, the Division began using percutaneous ethanol injection (PEI) to treat patients with small HCCs. In 1999, radiofrequency ablation therapy (RFA) was introduced clinically as an alternative to PEI. Based on long-term observations of PEI-treated patients, we have used percutaneous ablation therapy as a valuable alternative to surgery for most patients with three or fewer HCC nodules, all of which are smaller than 3 cm in diameter. We also perform transcatheter arterial chemoembolization (TACE), mainly in patients with multiple HCC nodules. Systemic or intra-arterial chemotherapeutic regimens are indicated in advanced HCC patients for whom locoregional intervention and surgery are unsuitable or unsuccessful. In patients with unresectable pancreatic cancer or biliary tract cancer, chemotherapy is performed in clinical practice or as a clinical trial to develop active treatment. Patients with locally advanced pancreatic cancer may receive chemoradiotherapy, which has shown some clinical benefits for symptom control and survival.

Case conferences are held weekly with surgeons and radiologists to determine treatment strategies for thesepatients. Rounds and conferences for patients admitted to the division are made by all staff oncologists and residents every morning and evening.

Research activities

We conducted a phase I study of c-Met inhibitor tivantinib in Japanese patients with advanced hepatocellular carcinoma (Okusaka, Cancer Sci; 106:611-7). In this study, patients with HCC in whom sorafenib treatment has failed were enrolled to evaluate the safety, tolerability and pharmacokinetics of oral tivantinib as a single agent. The dose was escalated separately in EM and PM, from 120 mg BID to 240 mg BID, in both capsule and tablet formulations. 120 mg BID of tivantinib is recommended among Japanese patients with HCC regardless of CYP2C19 phenotype.

A phase I trial of S-1 in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer was conducted (Shoji, Morizane, Jpn J Clin Oncol; 46:132-7. We recommend gemcitabine at 800 mg/m(2)/week, cisplatin at 25 mg/m(2)/week and S-1 at 40 mg/m(2)/day during a 21-day cycle. Dose-limiting toxicities included a Grade 3 maculopapular rash, Grade 4 thrombocytopenia and consecutive administration skips of gemcitabine and cisplatin on Day 8. Five partial responses among 17 patients were observed.

We conducted are trospective review of 100 consecutive patients with pancreatic neuroendocrine neoplasms (NENs), which are rare tumors (Shiba, Morizane, Pancreatology; 16:99- 105). The 5-year survival rates of patients with NET G1, NET G2, and NEC were 91%, 69%, and 10%, respectively. Good performance status (PS), lower stage, and histopathological grade were identified as independent favorable prognostic factors.

Clinical trials

Twenty-four clinical trials are ongoing and seven are planned, including sixteen phase I or I/ II trials, eight phase II or II/III trials, and seven phase III trials such as adjuvant chemotherapy after resection versus resection alone for patients with resectable tumor, and chemotherapy with a new regimen versus standard therapy for patients with advanced tumors. Our studies are supported by the National Cancer Center Research and Development Fund (Grant No. 26-A-4), Health and Labour Sciences Research Grants (Project for Development of Innovative Research on Cancer Therapeutics -075, -080, -141) from the Japan Agency for Medical Research and Development.

Education

Our staff members are working closely with residents and chief residents to support their skill development and knowledge expansion in both clinical and research fields. We are conducting conferences daily for clinical practice and weekly for research development. The residents in our department published five papers as first authors in peer-reviewed journals in 2015, and are performing eight ongoing studies as leading researchers with assistance from staff members.

Future prospects

Our department continues providing the best and latest diagnosis, treatment and supportive care, and developing more effective methods and techniques for all patients with hepatobiliary and pancreatic cancer in this country and all over the world. Among them, conducting clinical trials with novel promising agents for this disease is considered one of the most important tasks, and establishment of cutting-edge medical treatments in this field is the most significant mission for us. To achieve our aim, we are ongoing screening for biliary cancer patients with gene-mutations in the Kanto area as the first step, and are going to expand it to a nationwide program for accrual to clinical trials for new molecular targeted agents.


Table 1. Primary tumor Table 2. Treatment

List of papers published in 2015

Journal

  1. Okusaka T, Ueno H, Ikeda M, Mitsunaga S, Ozaka M, Ishii H, Yokosuka O, Ooka Y, Yoshimoto R, Yanagihara Y, Okita K. A Phase 1 and pharmacological trial of OPB-31121, a STAT3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatol Res, 45:1283-1291, 2015
  2. Honda K, Kobayashi M, Okusaka T, Rinaudo JA, Huang Y, Marsh T, Sanada M, Sasajima Y, Nakamori S, Shimahara M, Ueno T, Tsuchida A, Sata N, Ioka T, Yasunami Y, Kosuge T, Miura N, Kamita M, Sakamoto T, Shoji H, Jung G, Srivastava S, Yamada T. Plasma biomarker for detection of early stage pancreatic cancer and risk factors for pancreatic malignancy using antibodies for apolipoprotein-AII isoforms. Sci Rep, 5:15921, 2015
  3. Takai E, Totoki Y, Nakamura H, Morizane C, Nara S, Hama N, Suzuki M, Furukawa E, Kato M, Hayashi H, Kohno T, Ueno H, Shimada K, Okusaka T, Nakagama H, Shibata T, Yachida S. Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer. Sci Rep, 5:18425, 2015
  4. Ito T, Igarashi H, Nakamura K, Sasano H, Okusaka T, Takano K, Komoto I, Tanaka M, Imamura M, Jensen RT, Takayanagi R, Shimatsu A. Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis. J Gastroenterol, 50:58-64, 2015
  5. Okita K, Izumi N, Matsui O, Tanaka K, Kaneko S, Moriwaki H, Ikeda K, Osaki Y, Numata K, Nakachi K, Kokudo N, Imanaka K, Nishiguchi S, Okusaka T, Nishigaki Y, Shiomi S, Kudo M, Ido K, Karino Y, Hayashi N, Ohashi Y, Makuuchi M, Kumada H, Peretinoin Study Group. Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study. J Gastroenterol, 50:191- 202, 2015
  6. Grenader T, Nash S, Plotkin Y, Furuse J, Mizuno N, Okusaka T, Wasan H, Valle J, Bridgewater J. Derived neutrophil lymphocyte ratio may predict benefit from cisplatin in the advanced biliary cancer: the ABC-02 and BT-22 studies. Ann Oncol, 26:1910-1916, 2015
  7. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J, Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD, Kudo M, REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double- blind, multicentre, phase 3 trial. Lancet Oncol, 16:859-870, 2015
  8. Mori M, Shimizu C, Ogawa A, Okusaka T, Yoshida S, Morita T. A National Survey to Systematically Identify Factors Associated With Oncologists' Attitudes Toward End-of-Life Discussions: What Determines Timing of End-of-Life Discussions? Oncologist, 20:1304-1311, 2015
  9. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, Hama N, Hosoda F, Urushidate T, Ohashi S, Hiraoka N, Ojima H, Shimada K, Okusaka T, Kosuge T, Miyagawa S, Shibata T. Genomic spectra of biliary tract cancer. Nat Genet, 47:1003- 1010, 2015
  10. Miyazaki M, Yoshitomi H, Miyakawa S, Uesaka K, Unno M, Endo I, Ota T, Ohtsuka M, Kinoshita H, Shimada K, Shimizu H, Tabata M, Chijiiwa K, Nagino M, Hirano S, Wakai T, Wada K, Isayama H, Iasayama H, Okusaka T, Tsuyuguchi T, Fujita N, Furuse J, Yamao K, Murakami K, Yamazaki H, Kijima H, Nakanuma Y, Yoshida M, Takayashiki T, Takada T. Clinical practice guidelines for the management of biliary tract cancers 2015: the 2nd English edition. J Hepatobiliary Pancreat Sci, 22:249-273, 2015
  11. Ikeda M, Okuyama H, Takahashi H, Ohno I, Shimizu S, Mitsunaga S, Kondo S, Morizane C, Ueno H, Okusaka T. Chemotherapy for advanced poorly differentiated pancreatic neuroendocrine carcinoma. J Hepatobiliary Pancreat Sci, 22:623-627, 2015
  12. Watanabe T, Ueno H, Watabe Y, Hiraoka N, Morizane C, Itami J, Okusaka T, Miura N, Kakizaki T, Kakuya T, Kamita M, Tsuchida A, Nagakawa Y, Wilber H, Yamada T, Honda K. ACTN4 copy number increase as a predictive biomarker for chemoradiotherapy of locally advanced pancreatic cancer. Br J Cancer, 112:704-713, 2015
  13. Kondo S, Shiba S, Udagawa R, Ryushima Y, Yano M, Uehara T, Asanabe M, Tamura K, Hashimoto J. Assessment of adverse events via a telephone consultation service for cancer patients receiving ambulatory chemotherapy. BMC Res Notes, 8:315, 2015
  14. Okusaka T, Ueno H, Morizane C, Kondo S, Sakamoto Y, Takahashi H, Ohno I, Shimizu S, Mitsunaga S, Ikeda M. Cytotoxic chemotherapy for pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci, 22:628-633, 2015
  15. Takahashi H, Ikeda M, Kumada T, Osaki Y, Kondo S, Kusumoto S, Ohkawa K, Nadano S, Furuse J, Kudo M, Ito K, Yokoyama M, Okusaka T, Shimoyama M, Mizokami M. Multicenter cooperative case survey of hepatitis B virus reactivation by chemotherapeutic agents. Hepatol Res, 45:1220-1227, 2015
  16. Okusaka T, Ikeda M, Fukutomi A, Ioka T, Furuse J, Ohkawa S, Isayama H, Boku N. Response to Y. Sasaki et al.: Is repeating FOLFIRINOX in the original dosage and treatment schedule tolerable in Japanese patients with pancreatic cancer? Cancer Sci, 106:1101-1102, 2015
  17. Murakami H, Ikeda M, Okusaka T, Inaba Y, Iguchi H, Yagawa K, Yamamoto N. A Phase I study of MEDI-575, a PDGFRα monoclonal antibody, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol, 76:631-639, 2015
  18. Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, Moore MJ, Peeters M, Bodoky G, Ikeda M, Melichar B, Nemecek R, Ohkawa S, Świeboda-Sadlej A, Tjulandin SA, Van Cutsem E, Loberg R, Haddad V, Gansert JL, Bach BA, Carrato A. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol, 26:921- 927, 2015
  19. Ohkawa S, Okusaka T, Isayama H, Fukutomi A, Yamaguchi K, Ikeda M, Funakoshi A, Nagase M, Hamamoto Y, Nakamori S, Tsuchiya Y, Baba H, Ishii H, Omuro Y, Sho M, Matsumoto S, Yamada N, Yanagimoto H, Unno M, Ichikawa Y, Takahashi S, Watanabe G, Wakabayashi G, Egawa N, Tsuda M, Hosotani R, Hamada C, Hyodo I. Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer. Br J Cancer, 112:1428-1434, 2015
  20. Yamaue H, Tsunoda T, Tani M, Miyazawa M, Yamao K, Mizuno N, Okusaka T, Ueno H, Boku N, Fukutomi A, Ishii H, Ohkawa S, Furukawa M, Maguchi H, Ikeda M, Togashi Y, Nishio K, Ohashi Y. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study. Cancer Sci, 106:883-890, 2015
  21. Okusaka T, Aramaki T, Inaba Y, Nakamura S, Morimoto M, Moriguchi M, Sato T, Ikawa Y, Ikeda M, Furuse J. Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma: Distinctive pharmacokinetic profiles from other solid tumors. Cancer Sci, 106:611-617, 2015
  22. Shinohara A, Ikeda M, Okuyama H, Kobayashi M, Funazaki H, Mitsunaga S, Shimizu S, Ohno I, Takahashi H, Ichida Y, Takahashi K, Okusaka T, Saitoh S. Efficacy of prophylactic minocycline treatment for skin toxicities induced by erlotinib plus gemcitabine in patients with advanced pancreatic cancer: a retrospective study. Am J Clin Dermatol, 16:221-229, 2015
  23. Okusaka T, Ueno H, Ikeda M, Mitsunaga S, Ozaka M, Ishii H, Yokosuka O, Ooka Y, Yoshimoto R, Yanagihara Y, Okita K. Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatol Res, 45:1283-1291, 2015
  24. Ioka T, Okusaka T, Ohkawa S, Boku N, Sawaki A, Fujii Y, Kamei Y, Takahashi S, Namazu K, Umeyama Y, Bycott P, Furuse J. Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial. Jpn J Clin Oncol, 45:439-448, 2015
  25. Okita K, Izumi N, Ikeda K, Osaki Y, Numata K, Ikeda M, Kokudo N, Imanaka K, Nishiguchi S, Kondo S, Nishigaki Y, Shiomi S, Ueshima K, Isoda N, Karino Y, Kudo M, Tanaka K, Kaneko S, Moriwaki H, Makuuchi M, Okusaka T, Hayashi N, Ohashi Y, Kumada H, Peretinoin Study Group. Survey of survival among patients with hepatitis C virus-related hepatocellular carcinoma treated with peretinoin, an acyclic retinoid, after the completion of a randomized, placebo-controlled trial. J Gastroenterol, 50:667-674, 2015
  26. Okuyama H, Ikeda M, Kuwahara A, Takahashi H, Ohno I, Shimizu S, Mitsunaga S, Senda S, Okusaka T. Prognostic factors in patients with hepatocellular carcinoma refractory or intolerant to sorafenib. Oncology, 88:241-246, 2015
  27. Aoki T, Kokudo N, Komoto I, Takaori K, Kimura W, Sano K, Takamoto T, Hashimoto T, Okusaka T, Morizane C, Ito T, Imamura M. Streptozocin chemotherapy for advanced/metastatic well-differentiated neuroendocrine tumors: an analysis of a multi-center survey in Japan. J Gastroenterol, 50:769-775, 2015