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Preclinical models have shown that TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has antitumor activity in hepatocellular carcinoma (HCC). We conducted a phase I study in Japanese patients with advanced HCC to examine the pharmacokinetics, recommended dose, safety, and efficacy of TAC-101. The administered dose of TAC-101 was 10 mg/day in four patients (level 1), 20 mg/day in six (level 2), and 30 mg/day in three (level 3). There was no dose-limiting toxicity at level 1. Only one patient each had dose-limiting toxicity at level 2 (grade 2 fatigue, recovery requiring eight or more consecutive days of rest) and at level 3 (grade 3 splenic vein thrombosis). Level 3 (30 mg/day) was considered the maximum tolerated dose and 20 mg/day the recommended dose by a panel of medical experts, placing maximum emphasis on safety. The most frequent adverse events were fatigue, headache, and dermal symptoms such as rash. Pharmacokinetic parameters in Japanese patients with HCC were similar to those in patients in the United States, most of whom were Caucasian. Although no patient had a complete or partial response, the disease control rate was 38.5%. In conclusion, the recommended dose of TAC-101 for patients with HCC is 20 mg/day. TAC-101 had an acceptable toxicity profile, warranting further evaluation in clinical trials., (© 2012 Japanese Cancer Association.)

Background/aims: To clarify the efficacy and toxicity of cisplatin, epirubicin, and continuous infusion of 5-FU (CEF therapy) in patients with advanced intrahepatic cholangiocellular carcinoma (ICC)., Methodology: Chemo-naïve patients with advanced ICC were treated with cisplatin at 80 mg/m2 and epirubicin at 50 mg/m2 on day 1, and continuous infusion of 5-FU at 500 mg/m2/day on days 1 through 5. If there was no evidence of tumor progression or unacceptable toxicity, the treatment was repeated every 4 weeks, up to a maximum of 6 courses., Results: Thirty-nine patients were enrolled in this study. The median number of courses was 2 (range, 1-6). A partial response was obtained in 4 patients (10%) with a median duration of 2.3 months. Twenty-seven patients (69%) showed no change, and 7 patients (18%) had progressive disease. The median survival time was 9.1 months and the 1-year survival rate was 23%. The progression-free survival time was 5.1 months. Grade 3 to 4 adverse effects were leukocytopenia (51%), neutropenia (74%), thrombocytopenia (23%), and nausea/vomiting (10%). Most of the toxicities were reversible, but 2 patients died of neutropenic sepsis., Conclusions: CEF therapy has marginal antitumor activity against advanced ICC, although hematological toxicity is the major and most frequent toxicity.

Background: The aim of the current study was to evaluate the antitumor activity and toxicity of continuous infusion of 5-fluorouracil, mitoxantrone, and cisplatin (FMP therapy) in chemotherapy-naive patients with metastatic hepatocellular carcinoma (HCC)., Methods: Fifty-one patients with metastatic HCC who had not undergone previous systemic chemotherapy were enrolled. The therapy consisted of intravenous administration of 80 mg/m2 cisplatin and 6 mg/m2 mitoxantrone on Day 1 and continuous intravenous infusion of 450 mg/m2 5-fluorouracil per day on Days 1-5. The treatment was repeated every 4 weeks for a maximum of 6 courses with dose adjustments based on the observed toxic effects if there was no evidence of tumor progression or unacceptable toxicity., Results: Of the 51 enrolled patients, 14 (27%) achieved a partial response (95% confidence interval, 16-42%) with a median duration of 7.6 months (range, 2.3-18.4 months). Twenty-seven patients (53%) showed no change and 9 (18%) had progressive disease. The median survival time, 1-year survival rate, and median progression-free survival time for all patients were 11.6 months, 44.3%, and 4.0 months, respectively. The main Grade 3 and 4 toxicities were leukocytopenia (67%), neutropenia (71%), thrombocytopenia (27%), and elevated levels of aspartate aminotransferase (37%) and alanine aminotransferase (41%). These symptoms were generally brief and reversible, with the exception of one treatment-related death due to acute hepatic failure., Conclusions: FMP therapy had significant antitumor activity with acceptable toxicity in patients with metastatic HCC., (Copyright (c) 2005 American Cancer Society.)

Objectives: Chemoradiotherapy, which is one of the standard treatments for locally advanced pancreatic carcinoma, is considered a high-risk procedure in elderly patients. This study investigated the outcome and tolerability of this treatment in elderly patients., Methods: We reviewed our database from November 1993 to March 2003 and retrospectively examined the clinical data of patients with histologically confirmed exocrine pancreatic carcinomas that were nonresectable but confined to the pancreatic region, who were treated with protracted 5-fluorouracil infusion (200 mg/m2/day) and concurrent radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks). We evaluated the outcome of patients > or =70 years and those <70 years., Results: There were 19 patients > or =70 and 39 patients <70. On pretreatment evaluation, the elderly patients showed lower serum albumin levels, lower transaminase levels, better ECOG performance status, more frequent body weight loss and less frequent abdominal and/or back pain with the administration of morphine than the younger patients. There were no significant differences in the frequency of severe toxicity. Neither the response rate nor the incidence of treatment discontinuation differed significantly between the two groups. The median survival time was longer in the elderly patients than in the younger patients (11.3 vs. 9.5 months, p = 0.04)., Conclusions: With careful patient selection, chemoradiotherapy can be one of the treatment options for locally advanced pancreatic carcinoma in elderly patients., ((c) 2005 S. Karger AG, Basel.)

Objective: The aim of this study was to evaluate the efficacy and toxicity of S-1 in patients with metastatic pancreatic cancer., Methods: Patients were required to have a histological diagnosis of pancreatic adenocarcinoma with measurable metastatic lesions, and no prior chemotherapy. S-1 was administered orally at 40 mg/m2 twice daily for 28 days with a rest period of 14 days as one course. Administration was repeated until the appearance of disease progression or unacceptable toxicity. A pharmacokinetic study was done on day 1 in the initial 8 patients., Results: Nineteen patients were entered into this study. Four patients (21.1%) achieved a partial response with a 95% confidence interval of 6.1-45.6%. No change was noted in 10 patients (52.6%), and progressive disease in 5 patients (26.3%). The median survival time was 5.6 months with a one-year survival rate of 15.8%. The major adverse events were gastrointestinal toxicities such as nausea and anorexia, though most of them were tolerable and reversible. There were no large differences in the pharmacokinetic parameters of S-1 in patients with pancreatic cancer and those in patients with other cancers., Conclusion: S-1 is active and tolerated in patients with metastatic pancreatic cancer, which will be confirmed in the following large-scale phase II study., (Copyright (c) 2005 S. Karger AG, Basel.)

Background: To evaluate the safety and efficacy of second-line chemotherapy with docetaxel and cisplatin for non-small cell lung cancer (NSCLC), we performed a phase II study., Methods: The subjects were 25 patients with NSCLC, 75 years or younger, without organ dysfunction (performance status [PS], 0 to 2) in whom treatment with cisplatin and irinotecan had been ineffective or had been followed by recurrence or relapse. Four weeks or more after the end of the previous therapy, 60 mg/m2 of cisplatin and 60 mg/m2 of docetaxel were administered at intervals of 3 weeks., Results: Observed toxicities of grade 3 or 4 included anemia (24% of patients), leukocytopenia (48%), neutropenia (76%), thrombocytopenia (4%), hepatic dysfunction (8%), and electrolyte abnormalities (4%). However, no severe nonhematologic adverse reactions occurred. The overall response rate was 32% (95% confidence interval, 13.7-50.3). The median time to disease progression was 98 days, and the median survival time was 257 days., Conclusion: Our results suggest that cisplatin and docetaxel can be used as second-line chemotherapy against NSCLC. But further, comparative, study of this combination should be performed in patients with good PS and organ function who have responded to prior platinum-based chemotherapy.

There are a variety of tumor markers used for diagnosis of pancreatic and biliary tract cancer including carbohydrate antigens such as CA19-9, DUPAN-2, CA50 and Span-1, the carcinoembryonic antigen and pancreatic enzymes such as elastase 1. The tumor marker kinetics in serum help to predict survival in patients receiving surgical and/or non-surgical treatment. Since each of those tumor markers remains at a low sensitivity and specificity in the early stage, none are useful for detecting early cancer. In spite of the development of various diagnostic techniques, pancreas and biliary tract cancer is usually diagnosed at an incurable stage, and the 5-year survival rate is extremely low. Therefore, improvements in survival may well result from screening for early-stage pancreatic and biliary cancer. The development of tumor markers with higher sensitivity and specificity should have the highest priority.