Hepatobiliary and Pancreatic Oncology

Introduction
The Division of Hepatobiliary and Pancreatic Oncology deals with cancers in the liver, the biliary system, and the pancreas. Various combination therapies are often required in these tumors and the strategies of treatment are fully discussed by surgeons, radiologists and our medical oncologists. We are trying to establish new modalities of treatment and techniques in diagnosis with ultrasonography.

Routine Activities 
Abdominal ultrasonography is performed for both screening malignancies and thorough examination. We have performed contrast-enhanced ultrasound in diagnosis of liver tumors and pancreatic tumors since the clinical use of Levovist contrast agent was permitted in 1999. This contrast-enhanced ultrasound is useful for differentiating hepatocellular carcinoma (HCC), hemangioma and focal nodular hyperplasia from the other hepatic nodules. In 2002, we mainly used this technique to evaluate blood flow signals from tumor of the pancreas, and we now study these results in association with several clinicopathological factors in patients with pancreatic tumor. A total of 4,850 patients were examined by ultrasonography in 2002.
Percutaneous transhepatic biliary drainage, cholangiography and cholangioscopy are performed for patients with obstructive jaundice to improve the jaundice and examine the cause of the obstruction of the bile duct.
Percutaneous ablation therapy, including ethanol injection (PEI) or radio-frequency ablation (RFA), is indicated for HCC when the number of tumors is 3 or less and each tumor is smaller than 3 cm in diameter as standard treatment. RFA has been chosen as the first choice of the treatment for small HCC since 2000, because a wide necrotic area can be obtained by a session of the treatment and the duration of hospitalization can be shortened compared to PEI. Furthermore, we have tried RFA combined PEI at the same time in 2002. As a result, we can shorten the time of a session of the treatment. PEI is chosen when RFA is difficult to perform technically. Transcatheter arterial chemoembolization is performed for patients with advanced or recurrent HCC which is not suitable for hepatectomy or percutaneous ablation therapy.
We completed a phase II study of proton beam radiotherapy for HCC in June 2001 and we perform it as a highly advanced medical technology now. We also treat localized and larger unresectable HCC with photon radiotherapy where proton beam radiotherapy is contraindicated, such as a lesion adjacent to the intestine.
In biliary tract cancer including intra- and extra-hepatic cholangiocarcinoma (bile duct cancer), gall bladder cancer and papilla Vater cancer, we performed radiotherapy or chemotherapy according to stage of cancer. Patients with unresectable advanced bile duct cancer have been treated by radiation therapy consisting of external beam radiation therapy (EBRT) and intraluminal brachytherapy using Ir¹⁹² in a phase II study since 1999. Chemotherapy is performed as hepatic arterial infusion (HAI) or systemic chemotherapy. 5-FU is used in HAI and it is mainly applied to unresectable intrahepatic cholangiocarcinoma. Systemic chemotherapy is performed as a clinical trial or a practical treatment in patients with biliary tract cancer with distant metastases.
In pancreatic cancer, we have been treating patients with unresectable disease by gemcitabine as a key drug since it was approved by the Ministry of Health, Labor and Welfare in 2001. Patients with locally advanced pancreatic cancer receive EBRT combined with sequential gemcitabine chemotherapy, because it was reported that adverse effects were serious and full-dose of gemcitabine could not be administered in concurrent chemoradiotherapy with it. Systemic chemotherapy is performed as a clinical trial or a practical treatment for pancreatic cancer with distant metastases.


New Developments in 2002
1. Hepatic arterial infusion chemotherapy for advanced HCC
Phase I/II study of hepatic arterial infusion (HAI) with styrene maleic acid neocarzinostatin (SMANCS) alone in patients with far advanced HCC, began in 2000, has closed at a level phase I study in 2002. Because there was no responder in 12 patients when the phase I study was finished, we concluded there is no possibility of this treatment in far advanced HCC. We are preparing a next trial of HAI with 5-FU for these patients.
2. Chemoradiotherapy for locally advanced pancreatic cancer
Chemoradiotherapy using intraoperative radiotherapy followed by external beam radiotherapy and concurrent chemotherapy of 5-FU was completed in 2001. We concluded it was not superior to conventional chemoradiation therapy of EBRT and 5-FU (2002 ASCO #777, Cancer in press). We, therefore, conducted a phase I trial of hypo-fractionated radiotherapy for locally advanced PC in 2002, and it is ongoing. It is a dose escalation study of radiotherapy from 45 Gy at 15 fractions to 40 Gy at 5 fractions, followed by sequential chemotherapy with full-dose of gemcitabine. We finished the level 1, which was 45 y at 15 fractions, and it was confirmed feasible according to this protocol. We are going to the next level in 2003.
3. Randomized clinical trial of hepatectomy vs. ablation therapy for earlier stage HCC.
It has been controversial which treatment is better for earlier stage of HCC, hepatectomy and ablation therapy such as ethanol injection or radiofreaquency. This randomized clinical trial has begun as multicenter trial in October, 2002.
4. Other early clinical trials
We had 4 clinical trials as multicenter study in 2002.
A late phase II study of SM11355 (lipid-soluble platinum complex) used in transcather hepatic arterial infusion chemotherapy for unresectable HCC, is still ongoing.
A phase II study of systemic chemotherapy using gemcitabine for biliary tract cancer with distant metastases is still ongoing.
A phase II study of CPT-11 for metastatic pancreatic cancer has been ongoing since 2001 and the entry was closed in 2002. The results are in analysis. We have started a new trial of systemic chemotherapy of gemcitabine and 5-FU in December 2002, which is a phase II study.

J. FURUSE

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