S-1 in gastric cancer: a comprehensive review

The current basic and clinical studies of S-1 (TS-1^®) were reviewed. S-1 is a novel oral dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine (DIF) based on a biochemical modulation of 5-fluorouracil (5-FU); S-1 contains tegafur (FT) and two types of enzyme inhibitor; 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1?:?0.4?:?1. In pharmacokinetic studies, S-1 showed high 5-FU concentration in blood for long periods of time. In a combined analysis of two pivotal late phase II studies in gastric cancer, the overall response rate was 44.6% (45/101), and median survival time and 1-year survival rate were 244 days and 37%, respectively. A postmarketing survey was conducted, and in the interim analysis, tolerability and safety profiles were shown in 3294 patients with gastric cancer. The oral dose form and low incidence of adverse reactions permit treatment on an outpatient basis. To evaluate the survival benefit of S-1 in advanced gastric cancer, a phase III study of S-1 vs 5-FU vs cisplatin (CDDP) plus irinotecan (CPT-11) has been conducted. The effect of S-1 in adjuvant chemotherapy is also promising. Currently, a phase III study of surgery alone vs S-1 in patients with curative resection of gastric cancer is in progress. Further therapeutic benefits are expected to be gained by combining S-1 with other chemotherapeutic agents. Several preliminary results of combination phase I/II studies of S-1 with CDDP or CPT-11 have recently been obtained, and phase II studies are in progress. Thus, S-1 is currently the first candidate as the standard anticancer drug for gastric cancer. Further evaluations by well-controlled clinical trials are still needed.     

Clinical development of S-1 (TS-1) for advanced gastric cancer

The 5-FU plus cisplatin containing regimen like FP, ECF and DCF, is considered to be the most effective treatment for advanced gastric cancer in the United States, Europe, and Korea. In Japan, oral fluoropyrimidine S-1 (TS-1) is currently considered to be the first candidate as the standard drug for advanced gastric cancer. S-1 based combination therapies with other promising drugs like cisplatin, irinotecan and taxanes, are expected to yield good results. Above all, S-1+CDDP therapy showed a high efficacy and expected to be a standard therapy for advanced gastric cancer. Two large phase III studies, JCOG 9912 5-FU vs S-1 vs CPT-11 +CDDP and S-1 vs S-1+CDDP, are now on going to establish an acceptable frontline standard for patients with AGC. We therefore need to develop new agents and combination chemotherapy regimens to achieve a greater survival benefit in AGC.     

Chemotherapy for metastatic disease: review from JCOG trials

The Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group (GIOSG/JCOG) has conducted several clinical trials to establish standard chemotherapy for unresectable or recurrent gastric cancer. From the late 1980s to early 1990s, two phase II studies by JCOG evaluated oral fluoropyrimidines, and others introduced Western chemotherapy regimens. Thereafter, the first phase III study (JCOG9205), comparing 5-fluorouracil (5-FU), 5-FU plus ciplatin (CDDP) (FP), and uracil and tegafur (UFT) plus mitomycin (UFTM), could not show a survival benefit of either FP or UFTM over 5-FU alone. In the late 1990s, new active agents such as irinotecan (CPT-11) and S-1 (new oral fluoropyrimidine) showed promising results in their phase II trials. The latest phase III study (JCOG9912), comparing 5-FU, CPT-11 plus CDDP, and S-1, showed significant noninferiority of S-1 to 5-FU in overall survival, associated with a better response rate and progression-free survival and acceptable toxicities, and concluded that S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer. Simultaneously, another Japanese phase III trial comparing S-1 with S-1 plus CDDP showed a survival benefit of S-1 plus CDDP. At present, S-1 plus CDDP is recognized as standard chemotherapy for unresectable or recurrent gastric cancer, and new treatment with molecular target agents is under development.     

JCOG trials of systemic chemotherapy for unresectable or recurrent gastric cancer

From the late 1980s to the early 1990s, the Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group (GIOSG/JCOG) conducted several phase II studies, some of which evaluated oral fluoropyrimidines and others of which introduced Western regimens to Japanese patients. Thereafter, in the phase III study JOCG9205 comparing 5-fluorouracil (5-FU), 5-FU plus cisplatin (CDDP) (FP), and uracil and tegafur (UFT) plus mitomycin (UFTM), neither FP nor UFTM showed a survival benefit over 5-FU alone. Whereas irinotecan (CPT-11) and S-1 (new oral fluoropyrimidine) were developed with promising action against gastric cancer in the late 1990s, these agents cannot be used for patients with impaired oral intake and bowel passage caused by severe peritoneal metastasis. Sequential methotrexate (MTX) and 5-FU (MF) therapy showed substantial action against peritoneal metastasis. Thus, GIOSG/JCOG followed different treatment strategies according to the presence or absence of severe peritoneal metastasis. The phase III study JCOG9912, comparing 5-FU, CPT-11 plus CDDP, and S-1, showed a highly significant noninferiority of S-1 to 5-FU in overall survival associated with acceptable toxicities and concluded that S-1 should be considered for the standard chemotherapy for gastric cancer without severe peritoneal metastasis. For patients with severe peritoneal metastasis, the phase III study JCOG0106 compares MF to 5-FU. In that study, patient enrollment has been completed and a final analysis is planned at the end of 2008. The randomized phase II study JCOG0407 compares the best available 5-FU with weekly paclitaxel after failure in first-line chemotherapy containing 5-FU.     

Combination therapy with S-1 and irinotecan (CPT-11) for advanced or recurrent gastric cancer

S-1 and irinotecan (CPT-11) are active agents against gastric cancer. Some preclinical studies have demonstrated the theoretical background of combination therapy with S-1 and CPT-11 for gastric cancer. Based on these findings, several phase I/II studies of this combination therapy, which has been proposed as a candidate of standard treatment for advanced or recurrent gastric cancer in Japan, have been conducted. Although there were slight differences in the administration schedules of the combination therapy with S-1 and CPT-11 in these phase II studies, the response rates were more than 50%, and the median survival time (MST) exceeded 1 year. Also, good safety profiles were reported. These results warranted a further, phase III, study to define the efficacy of the combination in improving survival. In a phase III study (GC0301/TOP 002 trial), the response rate, the 1-year survival rate, and the MST in the arm with combination therapy of S-1 and CPT-11 were better than these parameters in the S-1 monotherapy arm. However, at 1.5-year follow-up, the overall survival (OS) in the combination therapy of S-1 and CPT-11 arm did not exceed that in the S-1 monotherapy arm [P = 0.23; hazard ratio (HR), 0.89]. As 22% of the patients were censored, further follow-up is needed to determine the OS with more precision. But, of note, in the SPIRITS trial, combination therapy with S-1 and cisplatin (CDDP) significantly prolonged OS compared to S-1 monotherapy (P = 0.037; HR, 0.77), suggesting that CPT-11 may not be the best partner to use in combination with S-1 at present.     

Combination therapy with S-1 and irinotecan (CPT-11) for advanced or recurrent gastric cancer

S-1 and irinotecan (CPT-11) are active agents against gastric cancer. Some preclinical studies have demonstrated the theoretical background of combination therapy with S-1 and CPT-11 for gastric cancer. Based on these findings, several phase I/II studies of this combination therapy, which has been proposed as a candidate of standard treatment for advanced or recurrent gastric cancer in Japan, have been conducted. Although there were slight differences in the administration schedules of the combination therapy with S-1 and CPT-11 in these phase II studies, the response rates were more than 50%, and the median survival time (MST) exceeded 1 year. Also, good safety profiles were reported. These results warranted a further, phase III, study to define the efficacy of the combination in improving survival. In a phase III study (GC0301/TOP 002 trial), the response rate, the 1-year survival rate, and the MST in the arm with combination therapy of S-1 and CPT-11 were better than these parameters in the S-1 monotherapy arm. However, at 1.5-year follow-up, the overall survival (OS) in the combination therapy of S-1 and CPT-11 arm did not exceed that in the S-1 monotherapy arm [P = 0.23; hazard ratio (HR), 0.89]. As 22% of the patients were censored, further follow-up is needed to determine the OS with more precision. But, of note, in the SPIRITS trial, combination therapy with S-1 and cisplatin (CDDP) significantly prolonged OS compared to S-1 monotherapy (P = 0.037; HR, 0.77), suggesting that CPT-11 may not be the best partner to use in combination with S-1 at present.     

Combination therapy with S-1 and CDDP for head and neck cancer

The combination with cisplatin (CDDP) and 5-FU is considered the first choice chemotherapy for squamous cell carcinoma of the head and neck (HNSCC). S-1, a modulation of tegafur developed in Japan, is an active agent for HNSCC. Some clinical phase I/II studies about the combination with CDDP and S-1 have been reported. The combination showed a good response rate of 67.6% for advanced and recurrent HNSCC in our clinical phase I/II study. The regimens of S-1 combined with carboplatin or nedaplatin have also been reported. Regimens containing S-1 appear to have been effective for HNSCC. Multi-institutional phase II studies with a large sample size are needed in the future. The compliance for patients is better than a 5-FU injection because S-1 is orally administrated. The adverse effect, especially for bone mallow toxicity, is equal or upgraded compared with a 5-FU injection. The efficacy and adverse effects of CDDP plus S-1 should be studied in carefully designed phase II/III trials. S-1 will be one of the key drugs for HNSCC in the future.     

The current evidence of S-1 and irinotecan hydrochloride combination chemotherapy with tri-weekly schedule

A combination therapy of irinotecan hydrochloride (CPT-11) with continuous intravenous infusions of (infusional) 5-fluorouracil (5-FU) and Leucovorin (LV) is often used to treat advanced colorectal cancer. However, recent concerns on safety and convenience have prompted the development of new oral fluoropyrimidine derivatives which improved regimens. Yamada et al conducted a phase I study to assess the maximum tolerated dose and recommended dose of S-1 combined with CPT-11. The study recommended that 150 mg/m2 of CPT-11 be given on day 1 and 80 mg/m2 of S-1 daily on days 1 to 14 every 3 weeks. Recently, several phase I/II studies assessed the efficacy and safety of the combined therapy with S-1 and CPT-11 in patients with advanced colorectal cancer. Some of the studies which were ongoing assessed a tri-weekly schedule regimen. Our results showed that S-1 plus CPT-11 was very effective, with a response rate of 63% and PFS of 8 months. Toxicity was generally mild and manageable on an outpatient basis. The current evidence showed that a combination of S-1 and CPT-11 was more convenient and easier to administer than a combination of CPT-11 plus infusional 5-FU and LV. It will be essential to prove that the combination of S-1 plus CPT-11 can replace the combination of infusional 5-FU and LV plus CPT-11 without negatively affecting efficacy and toxicity.     

Clinical development of S-1 plus cisplatin therapy as first-line treatment for advanced gastric cancer

We reviewed the clinical development of S-1 and S-1 plus cisplatin (CDDP) therapy for advanced gastric cancer (AGC). S-1 is an active oral fluoropyrimidine in patients with AGC. Phase I/II clinical trials of S-1 plus CDDP for AGC have yielded high response rates and the agents were well tolerated. On the basis of these phase I/II studies, we performed a randomized phase III study comparing S-1 plus CDDP with S-1 alone in patients with AGC. In the S-1 plus CDDP group, S-1 was given orally, twice daily for 3 consecutive weeks, and 60 mg/m² CDDP was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. In the S-1 alone group, S-1 was given orally, twice daily for 4 consecutive weeks, followed by 2 weeks of rest, within a 6-week cycle. Median overall survival was significantly longer in the S-1 plus CDDP group (13.0 months) than in the S-1 alone group (11.0 months; P = 0.04). Progression-free survival was significantly longer in the S-1 plus CDDP group (median, 6.0 months vs 4.0 months; P < 0.0001) and the response rate was also significantly higher (54.0% vs 31.1%; P = 0.002). There were more grade 3 or 4 adverse events, including leukopenia, neutropenia, anemia, nausea, and anorexia in the S-1 plus CDDP group, but the events were manageable. No treatment-related deaths were observed. As a result of this study, S-1 plus CDDP therapy has become a standard first-line treatment for AGC in Japan.     

Relationship between expression of vascular endothelial growth factor in tumor tissue from gastric cancers and chemotherapy effects: comparison between S-1 alone and the combination of S-1 plus CDDP

BACKGROUND: We have reported that vascular endothelial growth factor (VEGF) expression in gastric cancers might be a selective marker between 5-fluorouracil (5-FU) and a combination of 5-FU plus cisplatin (CDDP). In this study, the relationship between VEGF expression and effects of S-1 with and without CDDP is investigated. METHODS: The subjects were 44 patients treated with S-1 (40 mg/m2, twice daily, days 1-28, repeated every 6 weeks) and 24 patients treated with S-1 plus CDDP (S-1 40 mg/m2, twice daily, days 1-21, CDDP, 60 or 70 mg/m2, day 8, repeated every 5 weeks). VEGF expression in pretreatment endoscopic biopsy samples was assessed immunohistochemically. RESULTS: Median survival times (MST) of the patients treated with S-1 and S-1 plus CDDP were 344 and 388 days. Among evaluable patients, the response rates of patients with VEGF (+) and (-) tumors to S-1 were 40% (6/15) and 54% (13/24), and to S-1 plus CDDP, 79% (15/19) and 80% (4/5). While the survival of patients with VEGF (-) tumors was slightly longer than those with VEGF (+) tumors in the S-1 group (MST, 425 versus 308 days, P = 0.42), patients with VEGF (+) tumors survived remarkably longer than those with VEGF (-) tumors in the S-1 plus CDDP group (MST, 570 versus 333 days, P = 0.19). CONCLUSION: Similarly to our previous study, it is suggested that the effects of adding CDDP to S-1 might be more remarkable in gastric cancer patients with VEGF (+) tumors than in those with VEGF (-) tumors. These results should be confirmed in a large phase III study.     

Clinical development of S-1 plus cisplatin therapy as first-line treatment for advanced gastric cancer

We reviewed the clinical development of S-1 and S-1 plus cisplatin (CDDP) therapy for advanced gastric cancer (AGC). S-1 is an active oral fluoropyrimidine in patients with AGC. Phase I/II clinical trials of S-1 plus CDDP for AGC have yielded high response rates and the agents were well tolerated. On the basis of these phase I/II studies, we performed a randomized phase III study comparing S-1 plus CDDP with S-1 alone in patients with AGC. In the S-1 plus CDDP group, S-1 was given orally, twice daily for 3 consecutive weeks, and 60 mg/m² CDDP was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. In the S-1 alone group, S-1 was given orally, twice daily for 4 consecutive weeks, followed by 2 weeks of rest, within a 6-week cycle. Median overall survival was significantly longer in the S-1 plus CDDP group (13.0 months) than in the S-1 alone group (11.0 months; P = 0.04). Progression-free survival was significantly longer in the S-1 plus CDDP group (median, 6.0 months vs 4.0 months; P < 0.0001) and the response rate was also significantly higher (54.0% vs 31.1%; P = 0.002). There were more grade 3 or 4 adverse events, including leukopenia, neutropenia, anemia, nausea, and anorexia in the S-1 plus CDDP group, but the events were manageable. No treatment-related deaths were observed. As a result of this study, S-1 plus CDDP therapy has become a standard first-line treatment for AGC in Japan.     

Progress in chemotherapy for colorectal cancer

Among colorectal cancer patients with recurrent or metastatic sites, survival was significantly prolonged for a group undergoing LV/5-FU therapy based on biochemical modulation compared with a group receiving no chemotherapy (best supportive care). LV/5-FU combination therapy is recognized as the standard therapy for colorectal cancer, but recently LV/5-FU plus oxaliplatin and LV/5-FU plus CPT-11 have appeared to be more effective than LV/5-FU in some randomized studies. Capecitabine, UFT/LV and S-1 are new oral drugs that are at least comparable to LV/5-FU in antitumor activity, but superior in tolerability, which benefits the patients' quality of life, especially elderly patients with colorectal cancer. Clinical combination studies using CDDP or CPT-11 with these oral drugs are now being performed. Much is expected of these drugs.     

Chemotherapy for metastatic gastric cancer in Japan

Until the 1990s, there were no chemotherapy regimens with old-generation anticancer agents showing a survival benefit over 5-fluorouracil (FU) alone, and standard chemotherapy for metastatic gastric cancer had not been established. In the late 1990s, several new active agents were developed and some phase III trials with these agents were conducted; the new agent S-1 showed noninferiority to 5-FU in these trials. S-1 plus cisplatin is the first doublet chemotherapy to have shown a survival benefit over monotherapy with S-1. It has been demonstrated that capecitabine and oxaliplatin (OHP) can replace 5-FU and cisplatin (CDDP), offering more convenient treatment options. Thus, combination chemotherapy with an oral fluoropyrimidine (S-1 or capecitabine) and platinum (CDDP or OHP) has been recognized as standard chemotherapy for metastatic gastric cancer all over the world. However, it can be said that none of these new combination chemotherapies have shown remarkable progress from 5-FU plus cisplatin regimens. It is expected that triplet chemotherapy with a taxane; the use of molecular targeting agents; and the establishment of treatment strategies including second line chemotherapy, will lead to remarkable progress in personalized medicine in the near future.     

Efficacy of low-dose CDDP and CPT-11 for patients with intestinal type of gastric adenocarcinoma

BACKGROUND: Preclinical studies have shown that irinotecan (CPT-11) and cisplatin (CDDP) can act synergistically. Several chemotherapy regimens combining CPT-11 and CDDP for advanced gastric cancer have been reported to demonstrate high response rates and high incidence of severe toxicity. PURPOSE: We conducted a combination chemotherapy regimen of low-dose CDDP and CPT-11 to prolong the time to progression with less toxicity. PATIENTS AND METHODS: Seven patients with histologically-confirmed intestinal type of gastric adenocarcinoma were enrolled in this study. All patients were male, and their age at diagnosis ranged from 52 to 76 with a mean age of 64.8. Six patients received combination chemotherapy with CPT-11 and CDDP after the gastrectomy (stage I b: 1, II : 3, III b: 1, IV: 1). Only chemotherapy was administered in one patient because of a far advanced primary lesion and metastatic tumors. Low-dose CDDP (20 mg/body) and CPT-11 (65 mg/m(2)) were administered intravenously once every two weeks. RESULTS: The overall response rate was 43% including 1 complete response and 2 partial responses. One patient had grade 3 myelosuppression. Other adverse reactions were mild. CONCLUSION: The combination of low-dose CDDP and CPT-11 has mild therapeutic toxicities and may achieve a prolonged median survival time in patients with intestinal- type gastric adenocarcinoma.     

Combination chemotherapy with S-1 and carboplatin for head and neck cancers

Chemotherapy plays an important role in the treatment of head and neck cancer (HNC) patients with recurrent and/or metastatic unresectable disease. The standard regimen for HNC has been a combination of cisplatin (CDDP) and 5-fluorouracil (5-FU). We planned to develop a new outpatient regimen that could be carried out safely and had an antitumor activity equivalent to the regimen of CDDP plus 5-FU. For this purpose, we selected a combination of S-1 and carboplatin. The overall response rate of 40.9% in this study was almost equivalent to the study previously reported on 5-FU plus CDDP. This regimen of S-1 plus carboplatin has the possibility of yielding tumor responses equivalent to a conventional regimen of 5-FU combined with CDDP in patients with recurrent and/or metastatic head and neck carcinoma as a second-line palliative chemotherapy.     

A case of S-1-resistant resected advanced gastric cancer with para-aortic lymph node recurrence responding to bi-weekly CPT-11 and CDDP

A 64-year-old man with advanced gastric cancer who underwent a curative total gastrectomy(LM, Less, Type 3, 70×55 mm, por1>tub2>sig, pT3(ss), med, INF b, ly3, v3, pN3b(41/61), pPM0, pDM0, pT3N3bM0, Stage III B)followed by adjuvant chemotherapy(paclitaxel+S-1)a year ago, revealed an increasing level of serum CEA and para-aortic lymphnode (#16b1)recurrence on abdominal CT. He was given chemotherapy with low-dose weekday CDDP+S-1 for the recurrence, after which he failed to respond. Thereafter, he received 2nd-line chemotherapy with bi-weekly CPT-11+CDDP as a S-1- refractory regimen. 3 courses of the regimen reduced the serum CEA level accompanied by grade 3 of anemia. After recovery from the adverse event, another 4 courses at a 20% lower dosage for safety were administered. Complete response to the lymphnode was ensured on the abdominal CT with a reduced serum CEA level into the normal range. The patient has no signs of recurrence and has survived in fair condition for more than 5 years after the surgery. The combination treatment of biweekly CPT-11+CDDP can be a worthwhile regimen for patient with S-1-refractory recurrence of the resected advanced gastric cancer.     

Irinotecan plus oral S-1 in patients with advanced colorectal cancer--biweekly IRIS regimen

We planned to conduct a phase II clinical study of combination therapy with CPT-11 and S-1. The antitumor effect was the primary endpoint, while the safety, progression-free survival time, and median survival time were the secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer aged 20-75 years. Based on the results of our previous phase I/II study in patients with gastric cancer, the dosage was established in consideration of safety for outpatient therapy. CPT-11 was administered at a dose of 100 mg/m2 (on days 1 and 15) as an intravenous infusion over 90 minutes, and oral S-1 (40 mg/m2) was administered after breakfast and dinner and then withdrawn for 2 weeks. No other serious adverse reactions occurred (either hematological or non-hematological), and all patients could receive therapy safely on an outpatient basis. Interim analysis suggested excellent results, with a response rate of 50%. Combination therapy with CPT-11 and S-1 achieved a high response rate and could be given safely. These findings suggest that the therapy has potential as first-line treatment for inoperable advanced recurrent colorectal cancer.     

Combination chemotherapy of TS-1 +cisplatin for inoperable gastric cancer

There is no chemotherapy considered to be standard treatment for advanced gastric cancer worldwide, and there is no consensus as to whether combination or single agent therapy is preferred. In the phase I portion, a dose-escalation study of cisplatin (CDDP) combined with TS-1, new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). TS-1 was given orally at 40 mg/m2 bid for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg/m2, depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg/m2, because 33.3% of patients (2/6) developed DLTs; mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg/m2. In the phase II portion, 19 patients including 6 patients of the RD phase I portion were evaluated. The median administered courses was 4 (range: 1-8). The incidence of haematological and non-haematological toxicities (> or = grade 3) was 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95%) confidence interval: 54.9 (90.6%), and the median survival days were 383. This regimen is considered to be active against AGC with acceptable toxicity. In addition, currently, a randomized phase III study (JCOG 9912) for AGC patients not treated previously with chemotherapy is underway in Japan. It compares three arms: 5-FU alone, TS-1 alone and CPT-11 with CDDP therapy. We also initiated a randomized phase III study comparing TS-1 alone, and with CDDP for AGC. From those two phase III studies, we may be able to evaluate the clinical benefit of TS-1 in combination with CDDP versus TS-1 single, or 5-FU combined with CDDP therapy in terms of survival benefits and improving the QOL for AGC patients.