Randomized phase II study of daily and alternate-day administration of S-1 for advanced gastric cancer (JFMC43-1003).

PURPOSE: Although S-1 based chemotherapy for patients with advanced gastric cancer has generally been accepted in Japan, discontinuations of treatment have been reported due to grade 3 or more adverse events. The present randomized phase II study was conducted to test whether alternate-day administration of S-1 would be comparably efficient and reduce adverse events compared with conventional daily administration in the first-line chemotherapy for advanced gastric cancer. METHODS: 132 patients with advanced gastric cancer were randomly assigned to 1:2 ratios to receive treatment with daily at a standard dose of 80 mg/m2/day or alternate-day administration group received S-1 on 4 days a week. The primary end point was progression-free survival (PFS), and the secondary end points were safety, overall survival, time to treatment failure (TTF), disease control rate, and response rate. RESULTS: The 6-month PFS rate of the alternate-day administration group was 20.9% and failed to show significant difference from the pre-specified threshold at 15% (p = 0.117), whereas that of the daily administration group was 39.1% and significantly higher than the threshold (p = 0.001). The hazard ratio of the alternate-day administration group compared with the daily administration group was 1.753 (95% confidence interval (CI) 1.15-2.68, p = 0.010). With regard to OS, the hazard ratio of the alternate-day administration group compared with the daily administration group was 1.487 (95% CI 0.97-2.29, p = 0.072). The median TTF were 4.2 and 2.8 months in the daily and alternate-day administration group, respectively (p = 0.007). CONCLUSION: The alternate-day administration of S-1 was not recommended as the first-line therapy for patients with advanced gastric cancer.

Efficacy of a continuous venous infusion of fluorouracil and daily divided dose cisplatin as adjuvant therapy in resectable colorectal cancer: a prospective randomized trial.

PURPOSE: Daily divided dose cisplatin (DDD-P) is used as an efficient modulator of fluorouracil (5-FU), as is leucovorin (LV). We performed a randomized trial to compare the efficacy 5-FU plus DDD-P (DDD-FP) therapy with 5-FU alone in resected colorectal cancer as the adjuvant therapy. METHODS: One hundred and eighty-eight stage II or III colorectal cancer patients were enrolled. Patients were randomly assigned to receive DDD-FP (5-FU, 320 mg/ m(2), daily for 21 days; CDDP, 3.5 mg/m(2) daily for 21 days) followed by oral 5-FU (200 mg/body daily for 2 years) (DDD-FP arm) or oral 5-FU therapy (200 mg/ body daily for 2 years) exclusively (oral 5-FU arm). RESULTS: The 5-year disease-free survival (DFS) rates and the overall survival (OS) rates indicated no significant difference between the two arms. By stratified analysis, in the colon cancer patients, the DFS and the OS for the DDD-FP arm were significantly increased: 93.5% and 95.7% in the DDD-FP arm as compared with 76.9% and 82.2% in the oral 5-FU arm (P = 0.024 and P = 0.038). Regarding adverse effects, grade 3-4 toxicities were not significant in two arms. CONCLUSIONS: DDD-FP followed by oral 5-FU therapy suggested a feasible regimen for patients with resected colon cancer as the adjuvant therapy.

[The fourth report from Sapporo Tsukisamu Hospital - chemotherapy and its regimen as second choice for patients with early gastric cancer].

Surgical treatments for early gastric cancer, such as endoscopic procedures, are currently performed as standard therapy. However, when surgery is not possible due to physical or mental conditions, effective chemotherapy with minimum side effects is a second choice, although a suitable regimen has yet to be recommended. We thus retrospectively evaluated the Int FP regimen for 10 early gastric cancer patients. The results show an efficacy ratio of 100% (CR 8 cases, PR 2 cases). The two PR cases subsequently underwent surgical treatment. The 1-, 3-, and 5-year survival rates of all cases were 100%, 90% and 60%, respectively. The 1-, 3-, and 5-year survival rates of patients with chemotherapy alone were 100%, 87.5% and 50%, respectively, although none of the patients died of cancer (5-year survival rate of 100%). One out of the 8 CR cases relapsed 7 months after achieving CR. This patient then received chemotherapy with the same regimen, achieving a second CR and survived for 66 months without disease. All cases developed hematological toxicities, although they were all under grade 2 except for 2 cases which were grade 3 (decrease of WBC or Hb). Non-hematological toxicities were seen in 7 cases, all under grade 2. These results, although from a limited number of subjects, indicated that the IntFP regimen is safe and may contribute to achieving pathological CR and long-term survival of patients with early gastric cancer.

[The third report from Sapporo Tsukisamu Hospital--chemotherapy for patients with advanced gastric cancer (peritoneal dissemination, peritonitis carcinomatosa)].

Recently, it became possible to reduce the size of tumors in patients with advanced or relapsed gastric cancer by chemotherapy with the combination of several kinds of anti-cancer drugs which are all effective and allowed for use with gastric cancer patients. However, chemotherapy alone can not cure patients with advanced gastric cancer that was shown to improve median survival time (MST), compared with patients provided with the best supportive care (BSC). According to reports from Europe, US and Japan,the MST of patients with advanced gastric cancer and those with peritoneal expansion treated by chemotherapy is almost 7-12 months and 5-6 months,respectively, both of which are short and unsatisfactory. From March 2002, we started to treat patients with advanced gastric cancer (stage IV) with a new regimen; intermittent dosage of 5-FU (-->S-1), CDDP and paclitaxel utilizing the difference of cell cycle between normal and cancer cells (intermittent FP . weekly PTX). In the present study, therefore, we analyzed advanced gastric cancer patients with peritoneal expansion (9 cases, 4 with cancerous peritonitis) treated with this regimen. The results were as follows. The one-and 2-year survival rate was 55.6% and 27.8%, respectively, and the MST was 14 months. Four patients (44.4%) had hematological toxicities over grade 3. All of them had anemia (3 cases) and neutropenia (3 cases). Toxicities of thrombocytopenia were all under grade 1 and nonhematological toxicities were all under grade 2, which were clinically manageable. These results, although the sample was small, suggested that this may contribute to the extension of survival time of patients with stage IV advanced gastric cancer with peritoneal expansion.

[The second report from Sapporo Tsukisamu hospital--chemotherapy for patients with advanced colorectal cancer].

The remedy,especially recent chemotherapy,against colorectal cancer is improving median survival time (MST) of patients with Stage IV advanced colorectal cancer. According to other reports,however,it seems to be difficult to improve it longer than 20 months. In May 2002, we devised a new regimen by intermittent dosage of 5-FU (-->S-1), CDDP and paclitaxel utilizing the difference of cell cycle between normal and cancer cells, and thirteen patients with advanced colorectal cancer (Stage IV) were treated with this regimen. As a result, a satisfactory efficacy rate of 53.8%, 1-year survival rate of 69 .2%, 2-year survival rate of 53.9%, 3-year survival rate of 44.9%, 5-year survival rate of 17.9%, and MST 36 months were achieved. Five patients had hematological toxicities over grade 3 (38.5%) and most of them were anemia (3 cases) and neutropenia (5 cases). Thrombocytopenia and gastroenterological toxicity were all under grade 2. Adverse effects related to this regimen were clinically manageable. These results, although for a limited number of patients, indicated that this may contribute to the extension of survival time of patients with Stage IV advanced colorectal cancer.

[The first report from Sapporo Tsukisamu Hospital--chemotherapy and chemoradiotherapy for patients with advanced pancreatic cancer].

The remedy, especially chemotherapy, for advanced pancreatic cancer is hardly ever successful in terms of efficacy rate and survival period, because it is virtually unable to contribute to the improvement of median survival time (MST). Thus,we devised a new intermittent dosage regimen utilizing the cell cycle difference of normal GI tract, bone marrow cell and pancreatic cancer cell, making use of 5-FU (-->S-1), CDDP and paclitaxel in March 2002. Ten patients with advanced pancreatic cancer (4 in Stage IVa and 6 in Stage IVb) were treated with this new regimen. As a result, an efficacy ratio of 50.0% and a 1-year survival ratio of 60.0% were achieved. However, 2-year survival ratio of 12.0% was low, and there was no 3-year survivor. The MST was 19 months as of December 31, 2006. All of the non-hematological toxicities were under grade 2. Eight patients had hematological toxicities over grade 3 and most of them were anemia and neutropenia. Only 2 cases had thrombocytopenia. Although adverse effects related to this regimen were clinically manageable, it was difficult to improve MST of patients with advanced pancreatic cancer with chemotherapy alone including this regimen. Hence, we devised another regimen with the joint use of radiotherapy along with the same chemotherapy regimen in January 2003. Twenty patients with advanced pancreatic cancer (Stage IV) were treated with this regimen. It is presently under way, and an efficacy ratio of 35.0%, 1-year survival ratio of 86.3% and 2-year survival ratio of 64.0% were obtained by May 2005, showing that this may contribute to the extension of survival time of Stage IV pancreatic cancer patients.

[Pharmacokinetics of S-1].

S-1 is an attractive oral fluorouracil antitumor drug, which is being called "a self-rescuing drug". This novel oral fluoropyrimidine is combined with three pharmacological agents: tegafur (FT) which is a prodrug of 5-fluorouracil (5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) activity, and potassium oxonate (Oxo) which reduces gastrointestinal toxicity. Phase I and an early phase II clinical trials were performed about ten years ago, and these results had already been introduced to the Journal "Clinical Cancer Research Vol. 5, pages 2000-2005, 1999". The data of this article in this journal was referred from the results of the figures and tables based on the above trial. Most of the authors in this article have contributed on that pharmacokinetics study and published the above manuscripts. In that study, the pharmacokinetics of 5-FU, intact FT, CDHP and Oxo after administration of the standard dose of S-1 had been performed. These studies were carried out at two hospitals, Department of Surgery (Section 1) Sapporo Medical University and Chemotherapy Cancer Center, Cancer Institute Hospital and Japanese Foundation for Cancer Research (Ohtsuka). The number of patients accepted for this trial is twelve, 5 patients with gastric cancer, 4 with colorectal cancer and 3 with breast cancer. Single administration trial was referred to all patients, but consecutive administration trial was limited to ten patients. The results of plasma concentration, Cmax, Tmax, AUC0-14, and T1/2 of 5-FU, FT, CDHP, and Oxo were ascertained in details. It was a surprise that the indicated data was very similar to that of the intravenous 5-FU continuous infusion. Therefore, the low dose administration of 5-FU (FT) as S-1 may result in good antitumor effects with minimum adverse effects to the patients.

[Long-term repeatable chemotherapy for patients with advanced pancreatic cancer].

At present, the advanced pancreatic cancer is known to be one of the most resistant malignancies on chemotherapy. To improve the efficacy of chemotherapy, we shifted the aim of chemotherapy from a tumor regression to long-term survival, and sought for a repeatable regimen with little toxicity. Some of the novel (repeatable) regimens used a combination of 5-FU/S-1, CDDP and paclitaxel performed for 10 patients with advanced pancreatic cancer (4 cases of Stage IVa and 6 cases of Stage IVb). As a result, the survival ratios of one and two years were 85.7% and 22.9%, respectively. The efficacy rate was 50% (5 cases of PR and 5 cases of NC). Hematological adverse reactions over grade 3 were observed in 8 out of 10 cases, although the decrease of platelet count was observed only in 2 cases (grade 3 and 4). The majority of hematological adverse reactions over grade 3 were leukocytepenia and anemia which were easy to control safely. All of non-hematological adverse reactions were observed under grade 2 and did not disrupt the maintenance of chemotherapy.

Combination phase I trial of a novel oral fluorouracil derivative S-1 with low-dose cisplatin for unresectable and recurrent gastric cancer (JFMC27-9902).

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.