Hepatobiliary & Pancreatic Oncology

Introduction

Currently, surgery remains the only potentially curative treatment for hepatobiliary and pancreatic cancers; however, most patients are found to have an unresectable advanced stage of the disease. Therefore, clinical trials have been conducted to identify more promising nonsurgical treatments for patients with distant metastases or locally advanced disease.

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies in Japan, and most patients with HCC have chronic liver disease, particularly liver cirrhosis associated with hepatitis C virus infection. Despite the success of local therapeutic modalities, such as surgery, ablation, and transcatheter arterial chemoembolization (TACE), many patients develop cancer recurrence or progression after treatment (53). In 2007, various randomized controlled trials (RCTs) of adjuvant chemotherapeutic agents for HCC patients who have undergone surgery, ablation, and TACE have been conducted in a multicenter setting. On the other hand, systemic chemotherapy should be administered to patients with advanced HCC where local treatment is not indicated but a standard systemic therapy has not been established yet. Our Division has conducted clinical trials of chemotherapy and immunotherapy for advanced HCC.

Biliary Tract Cancer

Most of the clinical trials of chemotherapy conducted thus far have been phase II trials for biliary tract cancer (BTC), and no standard chemotherapy has been established yet. To clarify the impact of systemic chemotherapy on BTC, the overall survival (OS) in patients who were treated with systemic chemotherapy or best supportive care (BSC) was analyzed in a multicenter observational study (54) on 304 patients. The median OS of patients on BSC was 3.12 months and that of patients on chemotherapy was 7.38 months, with a significant difference between their survival times (p = 0.0001). regarding the survival in each chemotherapeutic regimen, the adjusted hazard ratio for gemcitabine in the cox regression model was 0.53 (95% CI, 0.34–0.82) and the hazard ratio for the CDDP-based regimen was 0.49 (95% CI, 0.36–0.99).
By the end of 2007, gemcitabine and S-1 were available for treating BTC in routine clinical practice in Japan. A comparative trial between the regimens including them should be conducted in the future.

Pancreatic Carcinoma

Gemcitabine was approved for treating pancreatic cancers in 2001; subsequently, S-1 was approved for treating pancreatic cancers in 2006 based on the results of phase II studies in Japan. Out of the 40 patients with metastases in a late phase II study, 15 patients showed partial responses, yielding an objective response rate of 37.5%, and the median OS was 8.8 months (42). Furthermore, the combination of gemcitabi and S-1 was investigated in an effort to improve the survival of patients with unresectable pancreatic cancer. Both gemcitabine and S-1 are currently available in Japan for treating pancreatic cancer; however, there is no evidence regarding the most effective treatment regimen—out of gemcitabine, S-1, or their combination—in patients with unresectable pancreatic cancer. A large RCT of the 3 arms is currently in progress in Japan and Taiwan.
Despite these promising chemotherapeutic regimens, some patients show rapid deterioration of general condition after failure of first-line chemotherapy. Therefore, the prognosis and prognostic factors in patients who are refractory to gemcitabine were investigated to identify the appropriate candidates for second-line chemotherapy (55). The results of the multivariate analysis revealed that the performance status (PS), serum C-reactive protein (CRP) level, and peritoneal dissemination were the most important prognostic factors in these patients. The median OS in approximately 40% of the patients in the good prognosis group as classified on the basis of the above results (patients with PS 0–1, no peritoneal dissemination, and CRP <5.0 mg/dl) was 3.4 months, and these patients could be good candidates for second-line chemotherapy (55).
Various chemoradiotherapeutic regimens have been investigated in an effort to improve the survival of patients having unresectable pancreatic cancer without distant metastases, i.e., locally advanced disease (56, 57). Based on the perspective that hypofractionated radiotherapy could shorten the treatment duration and that full-dose gemcitabine chemotherapy as a part of sequential chemoradiotherapy can be started as early as possible, a phase I study of this regimen was conducted. In this study, 3 patients received radiotherapy of 45 Gy in 15 fractions (Level 1), and 6 patients received 40 Gy in 8 fractions (Level 2). All patients in Level 2 developed grade 3 nausea, vomiting, and anorexia. Hypofractionated radiotherapy of 40 Gy administered in 5.0-Gy fractions was found to be unacceptable in patients with locally advanced pancreatic cancer. On the other hand, concurrent radiotherapy with S-1 therapy as an alternative to 5-FU infusion may result in more efficient treatment and improve the quality of life of such patients. A phase I trial was conducted to determine the maximum tolerated dose of S-1 with concurrent radiotherapy in patients with locally advanced pancreatic cancer (57). This regimen was found to be well tolerated, and the recommended dose of S-1 with 50.4 Gy of concurrent radiotherapy was 80 mg/m2/day. The median progression-free survival time was very good, i.e., 8.9 months, and a multiinstitutional phase II trial of this regimen has just been completed in 2007.

Clinical Trials

The following trials were completed in 2007.
1. A phase I/II study of S-1 for advanced HCC (multicenter trial); registration trial.
2. A phase I/II study of systemic chemotherapy with UFT + mitoxantrone for advanced HCC (multicenter trial).
3. A phase II study of HAI with CDDP for HCC with portal vein tumor thrombus (multicenter trial).
4. A placebo-controlled randomized phase III study of NIK333 as adjuvant therapy after curative treatment including surgery and ablation therapy for HCC (multicenter trial); registration trial.
5. A randomized phase II study of gemcitabine vs. CDDP + gemcitabine for unresectable biliary tract cancer (multicenter study); registration trial.
6. A phase II study of gemcitabine alone for locally advanced disease (multicenter trial); JCOG study.
7. A phase II study of S-1 + concurrent chemoradiotherapy for locally advanced disease (multicenter trial).

● J. Furuse ●

Table of Contents