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.

[Evolving 5-Fluorouracil Therapy to Achieve Enhanced Efficacy-Past and Current Efforts of Researchers].

5-fluorouracil(5-FU)therapy has advanced greatly over the past 50 years, achieving enhanced therapeutic effects and reduced adverse effects. By taking advantage of the metabolism of 5-FU, researchers have made efforts to develop prodrugs, combination drug products, and combination therapy regimens via biochemical modulation(BCM)with alteration of the drug metabolism. Examples include the advent of the prodrug tegafur(FT), followed by tegafur-uracil(UFT)and tegafurgimeracil- potassium oxonate(S-1)as combined products based on BCM. In the current standard treatment for gastrointestinal cancers, anticancer 5-FU derivatives serve as a platform for combination regimens with other cytotoxic agents or molecular- targeted drugs. To provide further improvements in anticancer therapy outcomes, novel molecular-targeted agents, immune checkpoint inhibitors, and other drugs are being developed, but 5-FU remains an attractive target that shows further potential for increased efficacy. In the future, the evolution of anticancer therapy with 5-FU derivatives is expected to continue via a variety of approaches.

Gastrointestinal toxicities of 5-fluorouracil increase the proportion of regulatory T cells in intestinal tract: advantages of alternate-day S-1 administration.

BACKGROUND: 5-Fluorouracil (5-FU), a core anticancer agent for malignancies, induces gastrointestinal (GI) toxicities. Despite recent advances in tumor immunology, it still remains unknown how GI toxicities affect antitumor immunity. S-1 is a tegafur-based oral 5-FU prodrug which has been widely introduced in Japan and other countries. The alternate-day S-1 administration has been proposed to minimize its GI and other toxicities without reducing its anticancer efficacy. METHODS: In this study, two S-1 administration regimens were compared in mice to evaluate their impact of GI toxicities on immunity. In the daily group as a standard administration model, S-1 was administered for 14 days on and 14 days off, and in the alternate-day group as a non-GI toxicity model, S-1 was administered every other day for 28 days. As well as physical findings, regulatory T cells, Th1 cells and other cells in murine lymphoid tissues were analyzed with flow cytometry. RESULTS: Only the daily group exhibited body weight loss and GI toxicities. In the daily group, a proportion of regulatory T cells in the intestinal lymphoid tissue were demonstrated to be six-fold higher than in the control without S-1, and the proportion of Th1 cells showed a decreasing trend. However, the alternate-day group exhibited almost no change in T-cell subsets. CONCLUSION: GI toxicities of 5-FU may have a negative influence on antitumor immunity due to increased proportions of regulatory T cells and decreased proportions of Th1 cells. The alternate-day S-1 administration may be a useful regimen with its minimal influence on T-cell subsets.

Usefulness of alternate-day administration of S-1 and leucovorin in a xenograft mouse model of colorectal cancer: a shorter drug-free interval leads to more efficient antitumor effects.

BACKGROUND: A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. Our present study was conducted to confirm the feasibility of alternate-day administration of S-1/LV in in vivo xenograft tumor models. METHODS: Mice were treated with S-1/LV in a daily group (2 weeks of administration followed by 2 weeks of withdrawal) or an alternate-day group (administration on alternate days for 4 weeks), then the mice were killed and the xenograft tumors were resected. We compared body weight changes, condition of feces, mucosal injury and myelosuppression and assessed adverse reactions, tumor volume, tumor growth inhibition (TGI) and expression of Ki67, TUNEL, cIAP2 and XIAP to evaluate the antitumor activity and tumor apoptosis. RESULTS: Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, some myelosuppression was also observed in the alternate-day group. The TGI in the alternate-day group was better than in the daily group, possibly resulting from apoptosis due to the suppression of cIAP2 but not XIAP. CONCLUSION: Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve high antitumor activity without severe adverse reactions, and we propose that clinical trials with this regimen should be conducted in CRC patients.

[A case of successful S-1 alternate-day administration for far-advanced remnant gastric cancer].

A 81-year-old man presented with anemia. He received a distal gastrectomy for gastric ulcer as a 40-year-old, and was also diagnosed with prostate cancer with bone metastasis as an 80-year-old. He has been undergoing treatment with anti-androgen therapy. Gastrointestinal endoscopic examination showed advanced gastric cancer, which was diagnosed as poorly differentiated adenocarcinoma. Computed tomography(CT)showed enlarged para-aortic lymph nodes. The clinical Stage was IV: cT3, N3, M1. He was treated with oral S-1 alternate-day administration of 100mg/day. The tumor in his remnant stomach shrunk in size by 3 months after beginning S-1 administration, and an endoscopic examination revealed a scar, but no cancer cells were found in a biopsy specimen of the scar tissue. Furthermore, CT scan showed that the swollen para-aortic lymph nodes were obviously reduced in size. As a result, we diagnosed this as a partial response to chemotherapy with S-1 alternate-day administration. No adverse events during the treatment were due to S-1 administration. His quality of life and poor food intake remarkably improved. S-1 alternate-day therapy demonstrated efficacy and tolerable toxicity even for a patient who was elderly and /or with poor performance status. S-1 can be managed safely on an outpatient basis without side effects for a long duration, and has been superior in terms of continuity of treatment.

Phase II trial of S-1 plus low-dose cisplatin for unresectable and recurrent gastric cancer (JFMC27-9902 Step2).

AIMS: The efficacy and the toxicity of oral fluorouracil derivative S-1 plus low-dose cisplatin in unresectable or recurrent gastric cancer were evaluated by a phase II study. METHODS: S-1 was administered orally for 28 days following 14 days' rest at 80-120 mg/body/day, depending on body surface area. During administration of S-1, cisplatin was given twice a week at the recommended dose (10 mg/m(2)), which was determined by a phase I study. Data from 34 patients in phase II and 8 patients treated with the recommended dose of cisplatin in phase I were analyzed. The primary endpoint was objective response. RESULTS: The response rate was 47.1%. The median survival time was 11.0 months and the median progression-free survival was 6.9 months. The grade 3/4 toxicities observed in 10% or more of the treated patients were neutropenia (16.7%), anemia (16.7%) and anorexia (11.9%). The serum concentration of cisplatin was 794 ± 341 ng/ml at day 25 of the first course. CONCLUSIONS: S-1 plus low-dose cisplatin may be a clinically useful regimen for unresectable or recurrent gastric cancer because of its infrequent adverse events in spite of considerable efficacy and its convenience of no hydration and no hospitalization.

Alternate-day treatment with S-1 in patients with gastric cancer: a retrospective study of strategies for reducing toxicity.

BACKGROUND: In patients with adverse events of S-1, the dose is generally reduced or the treatment cycle is shortened. Whether the therapeutic effectiveness of modified regimens is similar to that of the standard dosage remains unclear. METHODS: We retrospectively studied patients with gastric cancer who received S-1 on alternate days. RESULTS: A total of 266 patients received S-1 on alternate days. In 116 patients, S-1 was initially given at the standard dosage but was switched to alternate-day treatment because of toxicity within 28 days on average. The other 150 patients initially received alternate-day treatment because of poor general condition. In the adjuvant chemotherapy group (n = 96), the 3-year survival rate was 88% in patients with stage II, 73% in stage IIIA, and 67% in stage IIIB who underwent D2 lymph-node dissection. In the palliative surgery group (n = 96), the response rate was 13%, with a median survival time (MST) of 624 days. In patients with unresectable/recurrent disease (n = 74), the response rate was 25%, with an MST of 338 days. Among the 116 patients who initially received treatment on consecutive days, 100% had grade 1, 53% had grade 2, and 5.2% had grade 3 adverse events. When S-1 was switched to alternate-day treatment, toxicity decreased in all patients. In the 266 patients who received alternate-day treatment, 8% had grade 1, 6% had grade 2, and 0% had grade 3 adverse events. CONCLUSION: Alternate-day treatment with S-1 may have milder adverse events without compromising therapeutic effectiveness.

Development history and concept of an oral anticancer agent S-1 (TS-1): its clinical usefulness and future vistas.

Dushinsky et al. left a great gift to human beings with the discovery of 5-fluorouracil (5-FU). Approximately 50 years have elapsed from that discovery to the development of S-1 (TS-1). The concept of developing an anticancer agent that simultaneously possesses both efficacy-enhancing and adverse reaction-reducing effects could be achieved only with a three-component combination drug. S-1 is an oral anticancer agent containing two biochemical modulators for 5-FU and tegafur (FT), a metabolically activated prodrug of 5-FU. The first modulator, 5-chloro-2,4-dihydroxypyridine (CDHP), enhances the pharmacological actions of 5-FU by potently inhibiting its degradation. The second modulator, potassium oxonate (Oxo), localizing in mucosal cells of the gastrointestinal (GI) tract after oral administration, reduces the incidence of GI toxicities by suppressing the activation of 5-FU in the GI tract. Thus, S-1 combines FT, CDHP and Oxo at a molar ratio of 1:0.4:1. In 1999-2007, S-1 was approved for the treatment of the following seven cancers: gastric, head and neck, colorectal, non-small cell lung, breast, pancreatic and biliary tract cancers. 'S-1 and low-dose cisplatin therapy' without provoking Grade 3 non-hematologic toxicities was proposed to enhance its clinical usefulness. Furthermore, 'alternate-day S-1 regimen' may improve the dosing schedule for 5-FU by utilizing its strongly time-dependent mode of action; the former is characterized by the low incidences of myelotoxicity and non-hematologic toxicities (e.g. < or =Grade 1 anorexia, fatigue, stomatitis, nausea, vomiting and taste alteration). These two approaches are considered to allow long-lasting therapy with S-1.

Combination chemotherapy of S-1 and low-dose twice-weekly cisplatin for advanced and recurrent gastric cancer in an outpatient setting: a retrospective study.

BACKGROUND: We have reported the efficacy and safety of S-1 combined with low-dose consecutive cisplatin therapy for advanced and recurrent gastric cancer, but the regimen was difficult because daily cisplatin administration was necessary. We have already confirmed that cisplatin of 6 mg/m2 twice-weekly maintained the same protein-bound Pt concentration as that of 3 mg/m2 of cisplatin daily. In the present study, the efficacy and safety of a combination of S-1 and low-dose twice-weekly cisplatin were investigated. PATIENTS AND METHODS: The participants were 32 patients treated at our hospital, and all were admitted for the first 2 weeks of therapy. S-1 at 80 mg/m2 daily was administered orally in two divided doses. Cisplatin at 6 mg/m2 was administered by intravenous drip infusion over 30 minutes on 2 days each week, day 1 and day 4. Each treatment cycle consisted of 4 weeks of drug administration followed by a 2-week drug-free period (6 weeks in total). RESULTS: A total of 146 cycles were administered, with a median of three cycles (range: 1-24) per patient. The results were rated as a complete response in 1 case, partial response in 24 cases and stable disease in 5 cases. The response rate was 78.1% (25/32) and the median survival time was 12.0 months (95% confidence interval (CI) 8.9-15.1 months). The response rate did not differ between previously treated and untreated patients. The one-year survival rate was 48.2% (95% CI 30.3-66.0%). The major adverse reactions were myelosuppression and gastrointestinal symptoms. The total incidence of grade 3 or greater adverse reactions was 15.6% (5/32). CONCLUSION: The combination of S-1 and low-dose twice-weekly cisplatin therapy appears to be highly efficacious and safe and shows promise as a useful treatment strategy, even in outpatient clinics.

A phase I study of combination therapy of the oral fluorinated pyrimidine compound S-1 with low-dose cisplatin twice-a-week administration (JFMC27-9902 Step2) in patients with advanced gastric cancer using a continual reassessment method.

OBJECTIVE: We conducted a Phase I study to evaluate the safety and efficacy of a combination of S-1 with semi-weekly low-dose cisplatin in patients with unresectable/recurrent gastric cancer to determine the recommended dose (RD) for a subsequent Phase II study. METHODS: S-1 was administered orally at 80-120 mg/body/day based on body surface area. One cycle consisted of the consecutive administration of S-1 for 28 days followed by 14 days rest. Three dose levels, 7.5, 10, and 15 mg/m(2)/day, were set for cisplatin, which was administered twice-a-week for 4 weeks followed by 2 weeks of rest in each cycle. Dose-limiting toxicity (DLT) data were continually monitored to enable decisions regarding cisplatin dose escalation and deescalation based on a new dose-finding algorithm using a continual reassessment method (CRM). The CRM target toxicity level to estimate the RD was set at 20%. RESULTS: Eight and five patients were treated at cisplatin dose levels of 10 and 15 mg/m(2)/day, respectively. Two DLTs occurred at both dose levels. On the basis of this data, the CRM estimated the RD to be 10 mg/m(2)/day of cisplatin. Three patients of eight patients treated with 10 mg/m(2)/day of cisplatin exhibited a confirmed partial response during the treatment period. CONCLUSION: For future trials examining the safety and efficacy of daily S-1 with semi-weekly cisplatin in patients with unresectable/recurrent gastric cancer, we found a cisplatin RD of 10 mg/m(2)/day.

[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 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.

[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.

Multicenter, randomized, open-label Phase II study comparing S-1 alternate-day oral therapy with the standard daily regimen as a first-line treatment in patients with unresectable advanced pancreatic cancer.

PURPOSE: Non-inferiority for overall survival (OS) following alternate-day treatment with the oral anticancer drug S-1 compared with standard daily treatment was assessed in Japanese patients with unresectable advanced pancreatic cancer in a multicenter, randomized, phase II study. This trial was registered at the UMIN Clinical Trials Registry (no. 000008604). METHODS: Chemotherapy-naïve patients with locally advanced or metastatic pancreatic cancer were randomly assigned 2:1 to treatment with alternate-day (twice daily on alternate days from days 1 through 42 of a 42-day cycle) or daily (twice daily on days 1 through 28 of a 42-day cycle) treatment with S-1. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), time to treatment failure, response rate, quality of life assessments, and safety. RESULTS: A total of 190 patients were enrolled, of which 185 were included in the final analysis (alternate-day: 121; daily: 64). Median OS was 9.4 for the alternate-day group and 10.4 months for the daily group [hazard ratio (HR), 1.19; 95% credible interval, 0.86 to 1.64], indicating that non-inferiority of alternate-day treatment to daily treatment was not demonstrated. Median PFS was 3.0 for the alternate-day group and 4.2 months for the daily group (HR, 1.65; 95% credible interval, 1.20-2.29). The incidence of anorexia, fatigue, neutrophils, pigmentation, and pneumonitis was lower in alternate-day treatment compared with daily treatment. CONCLUSION: S-1 for advanced pancreatic cancer should be taken daily as recommended, based on the decreased OS and PFS and marginal improvement in safety observed in the alternate-day group.

A phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) in advanced biliary tract carcinoma.

BACKGROUND: Unresectable biliary tract carcinoma is known to demonstrate a poor prognosis. We conducted a single arm phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) for advanced biliary tract malignancies basically on an outpatient basis. METHODS: Between February 1996 and September 2003, 42 patients were enrolled in this trial. LFP THERAPY: By using a total implanted CV-catheter system, 5-FU (160 mg/m2/day) was continuously infused over 24 hours for 7 consecutive days and CDDP (6 mg/m2/day) was infused for 30 minutes twice a week as one cycle. The administration schedule consisted of 4 cycles as one course. RESIST criteria (Response evaluation criteria for solid tumors) and NCI-CTC (National Cancer Institute-Common Toxicity Criteria) (ver.3.0) were used for evaluation of this therapy. The median survival time (MST) and median time to treatment failure (TTF) were calculated by the Kaplan-Meier method. RESULTS: Patients characteristics were: mean age 66.5(47-79): male 24 (54%): BDca (bile duct carcinoma) 27 GBca (Gallbladder carcinoma) 15: locally advanced 26, postoperative recurrence 16. The most common toxicity was anemia (26.2%). Neither any treatment related death nor grade 4 toxicity occurred. The median number of courses of LFP Therapy which patients could receive was two (1-14). All the patients are evaluable for effects with an over all response rates of 42.9% (95% confidence interval C.I.: 27.7-59.0) (0 CR, 18 PR, 13 NC, 11 PD). There was no significant difference regarding the anti tumor effects against both malignant neoplasms. Figure 2 Shows the BDca a longer MST and TTF than did GBca (234 vs 150, 117 vs 85, respectively), but neither difference was statistically significant.The estimated MST and median TTF were 225 and 107 days, respectively. The BDca had a longer MST and TTF than GBca (234 vs 150, 117 vs 85, respectively), but neither difference was statistically significant. CONCLUSION: LFP therapy appears to be useful modality for the clinical management of advanced biliary tract malignancy.

Potassium oxonate, an enzyme inhibitor compounded in S-1, reduces the suppression of antitumor immunity induced by 5-fluorouracil.

S-1 is an oral formulation combining tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. We examined whether Oxo reduces the immunosuppression induced by 5-fluorouracil (5-FU) in the rat. The body weight of rats treated with S-1 (FT + CDHP + Oxo) for seven consecutive days was significantly higher than that of rats treated with a combination of FT plus CDHP (FT + CDHP) for a similar period. The number of peripheral leukocytes was significantly higher in the S-1-treated rats (S-1 group) than that in the FT + CDHP-treated rats (FT + CDHP group). There was no apparent difference between the two treated groups in phenotypic changes of CD3-, CD45-, CD4-, or CD8-positive cells from the spleen or mesenteric lymph nodes. However, the natural killer activities of both spleen cells and mesenteric lymph node cells were significantly higher in the S-1 group than in the FT + CDHP group. Interleukin (IL)-2 production by spleen cells stimulated with concanavalin A was significantly lower in the FT + CDHP group than in the S-1 group. Although IL-2 production by mesenteric lymph node cells in the S-1 group was lower than that in untreated rats, it was higher than that in the FT + CDHP group. These findings suggest that Oxo in S-1 may reduce the suppression of antitumor immunity induced by 5-FU.

[Timeline from discovery of 5-FU to development of an oral anticancer agent S-1 and its drug concept].

C. Heidelberger et al left great gifts to us. Approximately 50 years have elapsed since their discovery of 5-FU in 1957 before eventually elucidating the mechanisms by which the drug exerts its pharmacological actions and provokes its adverse reactions. Namely, 5-FU is a typical antimetabolite with strong time dependency, and continuous venous infusion(CVI) is considered to be its optimal regimen. The following facts may be mentioned to explain why such a long period of time has been spent to reach this level of research: 1) 5-FU, when administered to the living individual, is mostly inactivated by hepatic catabolic enzymes without delay and is then excreted in the urine, thus making it difficult to precisely analyze the relationship of blood 5-FU concentrations with concentration persistence, anticancer activity, and adverse reactions; and 2) unlike other anticancer agents, an antimetabolite 5-FU separately generates metabolites which show anticancer activity and adverse reactions, as well as metabolites which show adverse reactions only. For the last 30 years, we paid attention especially to 5-FU among chemotherapeutic agents for cancer and have sought for a long-lasting therapeutic modality which maintains quality of life of the patient and patient compliance by considering the balancing between its effects and adverse reactions. Consequently, we concretized an innovative therapeutic drug, TS-1 (S-1). We have a long history of research before developing S-1, which is represented by a series of investigations consisting in the developments of Futrafur (FT)--an oral anticancer agent of a 5-FU derivative (prodrug)-in 1970 subsequent to the above discovery of 5-FU, of UFT(FT: Ura=1 : 4) in 1976, and of S-1 in 1999. To date, we took the initiative in the world to devise S-1, the first self-rescuing concept(SRC)-based anticancer agent with dual actions, i.e., enhancement of pharmacological actions of 5-FU and reduction of its adverse reactions, by making use of the biochemical and enzymological properties of 5-FU and by combining FT, which is gradually converted to 5-FU in the body, with a 5-FU's effect-enhancing substance and a 5-FU's adverse reaction-reducing substance. S-1 is an oral anticancer agent in capsule, in which the following 2 modulators for 5-FU are combined to FT: one is CDHP(5-chloro-2,4-dihydroxypyridine) which increases blood concentrations and enhances pharmacological actions of 5-FU by potently inhibiting the degradation of 5-FU; and another is Oxo(potassium oxonate) which is localized in the mucosa of the gastrointestinal (GI) tract after oral administration and reduces GI toxicities provoked by 5-FU. S-1 is an oral anticancer agent in which these 3 components, FT, CDHP, and Oxo, are combined at a molar ratio of 1 : 0.4 : 1. Our conception to develop an SRC-based therapeutic drug and the preclinical concepts validated by numerous basic studies were demonstrated also in the clinical trials. In January 1999, S-1 was approved for the treatment of advanced and recurrent gastric cancers through the priority review system. From 2001 to 2005, S-1 was approved for the treatment of head and neck cancer, colon cancer, non-small cell lung cancer, and breast cancer. S-1 has been applied to acquire its expanded indications for the treatment of pancreatic cancer and biliary tract cancer. We are confident that the combined regimen of S-1 with other anticancer agents and with other therapeutic modalities will contribute to the routine medical practice of cancer treatment in the future.

[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.

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.