Hepatobiliary and Pancreatic Oncology Division

Introduction
The Hepatobiliary and Pancreatic Oncology Division deals with tumors originating in the liver, biliary system, or pancreas, for example, hepato-cellular carcinoma (HCC), gall bladder cancer, and pancreatic cancer (PC). As part of the multi-disciplinary care given at the National Cancer Center Hospital, we work closely with surgeons and radiologists who have special expertise in these areas. We also conduct research to study the pathophysiology of hepatobiliary and pancreatic tumors and to develop new and more effective diagnostic methods and treatments.

Routine Activities
The division consists of three 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 obser-vations of PEItreated patients, we have employed percutaneous ablation therapy as a valuable alternative to surgery for most patients with three or less HCC nodules, with size smaller than 3 cm in diameter. We also perform transcatheter arterial embolization (TAE), mainly in patients with multiple HCC nodules. Patients with locally advanced PC receive chemoradiotherapy, which has shown some survival benefit with improved symptoms such as reduction in upper abdominal pain. Chemotherapy is also provided in clinical trial setting for patients with metastatic PC.
Patients with hepatobiliary and pancreatic tumors, whether they undergo surgical or nonsurgical treatment, are all hospitalized in the Hepatobiliary and Pancreatic Ward. Case conferences are held weekly with surgeons to determine treatment strategies for these patients.Ward rounds for in-patients are made by all the staff oncologists and residents every morning and evening.

Research Activities
A phase I study of hyperfractionated radiation therapy with protracted 5-fluorouracil infusion (200 mg/ m2) was conducted to determine the maximum-tolerated dose (MTD) of radiation in patients with locally advanced PC (Ueno H, et al.). Five cohorts of patients were scheduled to receive escalating doses of hyperfractionated radiation therapy (range, 45.6 Gy to 64.8 Gy). The MTD was not reached even at the highest dose level. The median survival time was 12.2 months. We are currently planning a phase II trial of this hyperfractionated radiation therapy with protracted 5-FU infusion at a dose of 64.8 Gy.
A phase I trial was conducted to determine the MTD of gemcitabine based on the frequency of doselimiting toxicities (DLT) of weekly gemcitabine treatment (150-350 mg/m2) with concurrent radiotherapy (50.4 Gy in 28 fractions) in patients with locally advanced PC. (Ikeda M, et al.). Three of six patients at the dose of 350 mg/m2 of gemicitabine demonstrated DLT, while nine patients at doses of 150 mg/m2 and 250 mg/m2 did not demonstrate any sign of DLT. Of all 15 enrolled patients, 6 patients (40.0%) showed a partial response. The MTD of weekly gemcitabine with concurrent radiotherapy was 250 mg/m2, and this regimen may have substantial antitumor activity for patients with locally advanced PC.
Fifty patients with unresectable HCC were treated with transcatheter arterial embolization (TAE) using SMANCS (Okusaka T, et al.). Four mg SMANCS-4 ml lipiodol emulsion was injected into the hepatic artery, followed by an injection of gelatin sponge. In thirty-five patients (70%), the rate of necrotic area to whole tumor was more than 50% according to the evaluation method using lipiodol accumulation in CT. Among them, twenty-eight patients (56%) showed 100% necrosis of all tumors in CT carried out one month after treatment. The 1-year, 3-year and 5-year survival rates were 90%, 55% and 19%, respectively. TAE using SMANCS, which was well tolerated, may be an effective treatment for advanced HCC.

Clinical Trials
Fourteen clinical trials are ongoing, including one phase III trial (TAE versus intra-arterial chemo-therapy in advanced HCC patients). Five clinical trials were started in 2001: a phase I trial of NIK-333 (acyclic retinoid) in patients with HCC, a randomized double-blind placebo-controlled study of lactoferrin in patients with chronic hepatitis C, a phase I-II trial of 5-FU and gemcitabine in patients with metastatic PC, a phase II trial of CPT-11 in patients with metastatic PC, and a phase II trial of gemcitabine and CDDP in patients with metastatic PC.

S. OKADA

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