Combination Phase I Trial of a Novel Oral Fluorouracil Derivative S-1 with Low-Dose Cisplatin for Unresectable and Recurrent Gastric Cancer (JFMC27–9902)

Abstract

Purpose: The Japanese Foundation for Multidisciplinary Treatment of Cancer conducted a Phase I study of a novel oral fluorouracil derivative, S-1, combined with a low dose of cisplatin in unresectable and recurrent gastric cancer.Experimental Design: S-1 was administered orally at 80 -120 mg/body/day, depending on body surface area. One course consisted of consecutive administration for 28 days followed by a rest of 14 days. Low-dose cisplatin was given i.v. on days 1-5, 8 -12, 15-19, and 22-26 of each course. The dose escalation of cisplatin began with an initial dose of 1 mg/m 2 /day as level 1 and was stepped up to 2, 3, 4, and 6 mg/m 2 /day as level 2, 3, 4, and 5, respectively. The regimen was repeated for at least two courses.Results: A total of 24 patients was entered in the study. There was no treatment-related death. At level 5, consisting of 5 evaluable patients, dose-limiting toxicity was experienced as grade 3 appetite loss in 2 patients and grade 4 neutropenia in 1 patient. The maximum-tolerated dose of cisplatin was estimated to be 6 mg/m 2 /day. We decided on a recommended dose of cisplatin of 4 mg/m 2 /day because the dosage was one level under the maximum-tolerated dose. All 3 patients at level 4 showed partial response, suggesting promising clinical efficacy with this dosage. The serum concentration of cisplatin at level 4 was 918 ؎ 92 ng/ml on day 26 of the first course.Conclusions: S-1 with low-dose cisplatin may become an effective regimen with acceptable toxicity for gastric cancer.

A randomized phase II study comparing S-1 plus weekly split-dose cisplatin with S-1 plus standard-dose cisplatin as first-line chemotherapy for advanced gastric cancer

“…The incidence of toxicities in the SWP regimen in this study was similar to or less frequent than those in previous studies of split-or low-dose cisplatin [11][12][13][14][15]. The toxicities in the SWP arm were milder than those in the SP arm, particularly with regard to general fatigue and nausea.…”

“…Administration of split-or low-dose cisplatin has been suggested to enhance the clinical efficacy of treatment, resulting in mild to moderate toxicities when added to S-1 for patients with advanced gastric cancer [11][12][13][14][15]. However, in the present study, OS in the SWP arm tended to be inferior to that in the SP arm.…”

“…Many factors, including the time commitment and transportation required, have been reported as barriers to participation in cancer-related trials [25]. These problems have been frequently reported in patient recruitment in studies of split-or low-dose cisplatin administration [14,26]. Recently, 5-FU plus oxaliplatin has been accepted as an alternative to 5-FU plus cisplatin for treatment of advanced gastric cancer based on the results of phase III studies [2,27].…”

“…A moderate to high dose of cisplatin is usually administered every 3-5 weeks to patients with advanced gastric cancer [4][5][6][7][8][9][10]; however, excessive hydration is vital to prevent renal toxicity at this dose. To reduce the necessity for excessive hydration and decrease renal toxicity, split-or low-dose cisplatin combined with S-1 has been investigated in several phase I and II studies [11][12][13][14][15] using various doses and schedules (S-1 administered at 80 mg/m 2 for 14-28 days and cisplatin infused at 10 mg/m 2 /day twice a week [11], 25 mg/m 2 /day once a week [12,13], or 4 mg/m 2 /day for 5 consecutive days/week [14]). In a phase I study, we determined the optimal split-dose of cisplatin when combined with S-1 at 70 mg/m 2 /day for 14 days every 3 weeks to be 20 mg/m 2 on days 1 and 8 [15].…”

Combination therapy with S-1 and interferon-α in hepatocellular carcinoma patients with lung metastasis

“…Following oral administration, this agent reportedly selectively accumulates in gastrointestinal tissues and suppresses the gastrointestinal toxicity induced by the phosphoribosylation of 5-FU in the gastrointestinal tract, without compromising the antitumor activity. S-1 is widely used in Japan for the treatment of several gastrointestinal malignancies, with good reported outcomes (16)(17)(18)(19).…”