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Department of Hepatobiliary and Pancreatic Oncology

Masafumi Ikeda, Shuichi Mitsunaga, Izumi Ohno, Yusuke Hashimoto, Hideaki Takahashi, Kazuo Watanabe, Kumiko Umemoto

Introduction

The Department of Hepatobiliary and Pancreatic Oncology is responsible for the treatment and management of patients with hepatic, biliary, and pancreatic cancers. Our goal is to provide highquality cancer treatment with adequate palliative care, and to develop novel and effective treatments through well-designed clinical trials and research.

Routine activities

Our Department is composed of five staff oncologists and two residents, with an average of 45 beds in the hospital. We conduct clinical rounds for admitted patients every morning and evening. Most new patients with unresectable hepatobiliary and pancreatic tumors are hospitalized for the diagnosis and treatment of tumors. The treatment strategies on individual patients are discussed in weekly tumor board conferences attended by medical oncologists, surgeons, radiologists, radiation oncologists, and pharmacists. Furthermore, we are also responsible for external or endoscopic abdominal ultrasonographic examinations, endoscopic or percutaneous ultrasound-guided biopsies of abdominal masses, local ablative therapy for liver tumors, endoscopic or percutaneous biliary drainage and stenting for obstructive jaundice.

Research activities

Hepatocellular carcinoma (HCC)

Sorafenib is the only available standard of care for advanced HCC. We conducted a randomized phase II trial of sorafenib plus hepatic arterial infusion chemotherapy with cisplatin vs. sorafenib alone in patients with advanced HCC, and the combination therapy yielded favorable overall survival as compared to sorafenib alone. A further phase III trial is planned to confirm these results.

Pancreatic cancer (PC)

Gemcitabine (Gem) plus nab-paclitaxel was approved for the treatment of advanced PC in December 2014, following the approval of FOLFIRINOX in December 2014. Gem plus nabpaclitaxel has been reported to be comparable on efficacy to and more feasible on adverse events than FOLFIRINOX. In our hospital, Gem plus nabpaclitaxel has been adapted as a first line treatment of advanced PC, and it has been elucidated to have a favorable efficacy and manageable toxicities in daily practice. It should be clarified which is the better treatment in advanced PC patients: Gem plus nab-paclitaxel or FOLFIRINOX by large-scale phase III trial.

The diagnostic value of serum microRNAs on a highly sensitive microarray was found in PC and biliary tract cancer (BTC). A combination strategy of the microRNA markers has been reported to be effective in diagnosis of resectable PC. In addition, the cachexia-related factors that deteriorate during chemotherapy for PC and are associated with poor overall survival have been identified to evaluate the efficacy of the anti-cachexic treatment and to develop the newly arriving anti-cachexic treatment.

Clinical trials

Thirty-six clinical trials (sponsored: 21 trials, investigator-initiated: 15 trials) are ongoing, and eight clinical trials (sponsored: six trials, investigator-initiated: five trials) are being planned for the upcoming year. Recently, immune checkpoint inhibitors are noticed in all cancer treatment, and sponsored trials of these agents or combination therapies with these agents are increasing in this field.

HCC

A randomized phase II trial comparing sorafenib vs. observation in combination with transcatheter arterial chemoembolization (TACE) is ongoing. Some sponsored trials of sorafenib plus resminostat, sorafenib plus LY2157299, sorafenib plus BBI503 are ongoing as first line chemotherapy. As the second line setting, the enrollment of some clinical trials of nivolumab, regorafenib, ONO-7268MX1, ONO-7268MX2, and so forth, have been finished, but some clinical trials of tivantinib, ramucirumab, other immune checkpoint inhibitors, and so forth, are ongoing.

BTC

A randomized phase III trial comparing adjuvant S-1 with observation in patients with resected BTC (The Japan Clinical Oncology Group (JCOG) 1202) is ongoing. As first line chemotherapy, a randomized phase III trial comparing Gem plus S-1 with Gem plus cisplatin (JCOG1113) is ongoing, and Gem cisplatin plus nivolumab is planned. As advanced BTCs refractory to Gem, some sponsored trials of resminostat plus S-1, immune checkpoint inhibitors or these combinations are under way.

PC

A multicenter phase II trial of neoadjuvant S-1 and concurrent radiotherapy for borderline resectable PC (JASPAC05) is ongoing. A phase II trial of Gem plus Z-360 vs. Gem+Placebo, a phase I trial of Gem plus LY2157299 in chemo-naïve PC patients, a phase III trial of mixed agents of S-1 plus leucovorin (TAS-118) vs. S-1 in Gem refractory PC patients, and a phase II trial of GBS-01 in refractory PC patients to Gem-based and fluoropyrimidine-based regimen have been f inished on the enrollments. Some sponsored trials of immune check point inhibitors are planned as second line chemotherapy for advanced PC.

Education

For our residents, one-to-one training is provided on the daily practice of management of inpatients and outpatients. In addition, the residents can learn the indication, administration and management of the adverse events of all cancer treatments from local treatments to systemic chemotherapy for hepatic, biliary, and pancreatic cancer patients and the accompanied procedures to make diagnosis and drainage for obstructive jaundice. In addition, the residents can make a presentation of their research in domestic and overseas' meetings and present a paper in English under the instruction of staff physicians.

Future prospects

The prognosis of patients with hepatic, biliary, and pancreatic cancers remains bleak, and standard treatments for theses cancer is limited. In Japan, the incidences of these cancer, especially HCC and BTC, are higher than those in Western countries. Therefore, we must conduct a lot of novel and promising clinical trials and research that take the lead worldwide. And it is necessary to develop biomarker research accompanying cancer treatment in cooperation with our cancer research center and pharmaceutical companies to identify the more effective and less toxic patient subgroups.

Table 1. Number of patients Table 2. Type of procedure

List of papers published in 2015

Journal

  1. Miura T, Mitsunaga S, Ikeda M, Shimizu S, Ohno I, Takahashi H, Furuse J, Inagaki M, Higashi S, Kato H, Terao K, Ochiai A. Characterization of patients with advanced pancreatic cancer and high serum interleukin-6 levels. Pancreas, 44:756-763, 2015
  2. 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
  3. 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
  4. 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
  5. Ikeda M, Mitsunaga S, Ohno I, Hashimoto Y, Takahashi H, Watanabe K, Umemoto K, Okusaka T. Systemic chemotherapy for advanced hepatocellular carcinoma: past, present, and future. Diseases, 3:360-381, 2015
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. Matsuyama M, Ishii H, Furuse J, Ohkawa S, Maguchi H, Mizuno N, Yamaguchi T, Ioka T, Ajiki T, Ikeda M, Hakamada K, Yamamoto M, Yamaue H, Eguchi K, Ichikawa W, Miyazaki M, Ohashi Y, Sasaki Y. Phase II trial of combination therapy of gemcitabine plus anti-angiogenic vaccination of elpamotide in patients with advanced or recurrent biliary tract cancer. Invest New Drugs, 33:490-495, 2015
  15. 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
  16. 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