Although surgery currently remains the only potentially curative treatment for hepatobiliary and pancreatic cancers, a definitive diagnosis is usually made at an advanced unresectable stage of the disease in most patients. Therefore, clinical trials have been conducted to identify more promising non-surgical treatments for patients with metastatic or locally advanced disease.
Sorafenib, an oral multikinase inhibitor targeting Raf kinase and receptor tyrosine kinases, is the first agent that has been shown to confer a survival benefit, with the promise of becoming a standard treatment, in patients with advanced hepatocellular carcinoma (HCC) in western countries. In Japan, a phase I clinical study was conducted in 27 advanced HCC patients to confirm the pharmacokinetics (PK) and safety of sorafenib, since it was expected that the underlying liver disorders might affect the PK of the drug. The results revealed no significant PK differences between patients with Child-Pugh class A and B disease. The most common adverse events were an increase in lipase and amylase, rash, desquamation, diarrhea, and hand-foot skin reactions. It was therefore recommended that sorafenib should be administered continuously at a daily dose of 800 mg/day b.i.d. (43). Another phase I/II trial of combined mitoxantrone and uracil/tegafur therapy was conducted to determine the recommended dose and clarify efficacy and safety. A total of 25 patients were enrolled in the study. The response rate and median progression-free survival were determined to be 5.3% and 2.5 months, respectively; the most commonly encountered toxicities were grade 3-4 leukopenia (15.8%) and neutropenia (10.5%). Although this regimen was generally well-tolerated, it appeared to have little activity against advanced HCC. Thus, to enhance the treatment efficacy of chemotherapy, development of other chemotherapeutic regimens is required. Combined administration of sorafenib and hepatic arterial infusion with cisplatin has been designed for the treatment of advanced HCC, and a phase I trial is scheduled to begin in 2009.
Most of the clinical chemotherapy trials that have been conducted to date for biliary tract cancer (BTC) have been phase II trials, and no standard chemotherapy has so far been established. A multicenter phase II study was conducted to evaluate the antitumor effect and safety of S-1 in previously untreated patients with advanced BTC (44). Of the 41 patients enrolled, complete response was achieved in 1 patient (2.5%) and partial response in 13 patients (32.5%), and the overall objective response rate was 35.0%. Moreover, the overall median survival was 9.4 months, and the median time-to-progression was 3.7 months. Grade 3 or 4 toxicities included fatigue (7.5%), anorexia (7.5%) and elevation of serum total bilirubin (7.5%). Thus, significant antitumor activity with a mild toxicity profile was observed. Based on this promising result, S-1 was approved for BTC treatment in 2007. Gemcitabine and S-1 are currently available clinically for BTC treatment in Japan. Comparative trials of regimens based on these drugs should be conducted in the future.
Following the approval of gemcitabine in 2001, S-1 was approved for pancreatic cancer (PC) treatment in 2006 based on the results of phase II studies conducted in Japan. Both drugs are currently available for PC treatment in Japan; however, there is as yet no evidence as to which of the following regimens might be the most effective in PC patients: gemcitabine alone, S-1 alone, or a combination of the two. A large randomized controlled trial of 3 treatment arms is currently under way in Japan and Taiwan.
Gemcitabine monotherapy has been recognized as the standard first-line therapy for advanced PC; however, no standard regimen is currently available for the treatment of these cases after disease progression. On the other hand, the efficacy and toxicity of S-1 were evaluated in a phase II study for gemcitabine-refractory metastatic PC. In the 40 evaluable patients, the response rate, median progression-free survival and overall survival were 21%, 2.0 months and 4.5 months, respectively. Most of the adverse reactions were well-tolerated and reversible. Thus, S-1 as monotherapy exhibited marginal antitumor activity with tolerable toxicity in patients with gemcitabine-refractory metastatic PC.
In patients with locally advanced PC, chemoradiotherapy has shown some survival benefits and the potential to improve symptoms such as abdominal pain. However, most of these chemoradiotherapy-treated patients eventually developed disease progression with metastasis. Thus, the development of effective systemic chemotherapy is required. Gemcitabine plus S-1 chemotherapy has been shown to yield a high tumor response rate in cases of advanced PC. An early phase II study was previously conducted in Japan to examine the efficacy of gemcitabine plus S-1 therapy followed by chemoradiotherapy in patients with locally advanced PC. Twenty patients were enrolled, and the induction chemotherapy of gemcitabine plus S-1 could be completed in 18 patients. Among all the evaluable patients, 2 showed disease progression (general deterioration) during the induction chemotherapy, while 5 (25%) showed partial response. Laparotomy with curative intent was undertaken in 4 patients, and R0 resection could be accomplished in 3. A pathological complete response was observed in 1 of these patients. The progression-free survival rate at 6 months was 70% (14/20, 95% CI: 45.7-88.1%). The median overall survival period was 11.0 months (95% CI: 5.4-16.5 months). Another clinical trial of S-1 chemoradiotherapy for locally advanced PC is currently ongoing. Other treatment strategies against locally advanced PC will be planned based on the results.
The following trials were completed in 2008:
● M. Ikeda
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