Irinotecan plus intravenous 5-fluorouracil with leucovorin is effective against gastrointestinal cancer. S-1 is an oral fluoropyrimidine derivative combining tegafur with the modulators 5-chloro-2,4-dihydroxypyrimidine (a potent dihydropyrimidine dehydrogenase inhibitor), and potassium oxonate (an orotate phosphoribosyl transferase inhibitor), in a molar ratio of 1 : 0.4 : 1. S-1 has a high response rate, of about 40%, in advanced gastric cancer. A phase I study was conducted to assess the maximum tolerated dose and the recommended dose of the combination of irinotecan and S-1.
Irinotecan was given intravenously over the course of 90 min on day 1 and S-1 was given orally from days 1 to 14 of a 21-day cycle. The dose of S-1 was 80 mg/m2 per day, given in two divided doses. The dose of irinotecan was escalated in a stepwise fashion from 100 mg/m2 (level 1; n = 3), to 125 mg/m2 (level 2; n = 3), and 150 mg/m2 (level 3; n = 6).
Dose-limiting toxicity did not occur during cycle 1, and the recommended dose for phase II studies was determined to be level 3, which was associated with grade 3 diarrhea in one patient, and with refusal to continue treatment because of prolonged fatigue in two patients. Grade 3 neutropenia developed in one of three patients at level 1 and level 2, and in two of six during cycle 1 of level 3. The recommended dose was determined to be 150 mg/m2 of irinotecan on day 1 and 80 mg/m2 per day of S-1 on days 1 to 14 of a 21-day cycle. Five of seven patients with measurable lesions had a partial response.
A combination of irinotecan and S-1 can be recommended for further phase II studies in patients with gastric cancer.
"The complex metabolism of both capecitabine and CPT-11 can thus theoretically lead to pharmacokinetic drug-drug interactions.38 In contrast, a previous phase I trial using S-1 and CPT-11 showed no change in the plasma concentrations of 5-FU, FBAL, or SN-38 as compared with the concentrations after administration of S-1 or CPT-11 alone.39 When CPT-11 is combined with S-1, it may, therefore, be safer and more convenient than a combination of capecitabine and CPT-11. "
[Show abstract][Hide abstract] ABSTRACT: Introduction:
This multicenter phase II study determined the efficacy and safety of new daily oral S-1 and weekly irinotecan (CPT-11) combination schedule in patients with previously untreated advanced or recurrent colorectal cancer.
Patients and methods:
Patients received first-line chemotherapy comprising S-1 80 mg/m2/day given on days 3 to 7, 10 to 14, and 17 to 21 and 60 mg/m2 CPT-11 administered intravenously on days 1, 8, and 15 of a 28-day cycle.
A total of 45 eligible patients were enrolled in this study. The overall response rate was 48.9%. Median progression-free survival and median overall survival was 8.1 months and 20.9 months, respectively. The rates of grade 3 or 4 toxicity were as follows: neutropenia, 8.9%; anemia, 4.4%; anorexia, 6.7%; and diarrhea, 6.7%.
This new S-1 and irinotecan combination schedule appeared to be an effective, well-tolerated, and convenient regimen in patients with advanced colorectal cancer as compared with conventional regimens such as FOLFIRI and IRIS.
Clinical Medicine Insights: Oncology 02/2013; 7:21-30. DOI:10.4137/CMO.S10769
"This drug, a novel oral fluoropyrimidine developed from a theoretical basis which combines tegafur (5-FU derivative), gimeracil, and oteracil , is now changing the course of chemotherapy for MGC in Japan , . Recent studies have shown synergistic antitumor effects of S-1 with CDDP , , PTX –, and CPT-11 –. Based on evidence from the JCOG9912 and SPIRITS trials , S-1 has now replaced 5-FU, and combination regimens including it are now widely used in the treatment of GC in Japan . "
[Show abstract][Hide abstract] ABSTRACT: Recent advances in the treatment of metastatic unresectable gastric cancers (MGC) include the development of new antitumor drugs and new regimens for their use. However, the selection of individually designed regimens by gastric cancer (GC) subtype remains problematic. Here, we investigated the clinical usefulness of programmed chemotherapy.
MGC patients were classified into three groups by clinical condition. We implemented a chemotherapy program consisting of S-1 combination regimens. Median survival time (MST) of level 1 patients was 416 days (95% CI: 313-506 days), with an overall response rate of 47%. MSTs of level 2 and 3 patients were 208 (95% CI: 153-287 days) and 95 days (95% CI: 28-136 days), respectively. Grade 3-4 toxicities were neutropenia in 12% and anorexia in 6%. All treatment- related toxicities were resolved, and no treatment-related deaths occurred.
This program provided reasonable selection of case-matching regimens and may improve the survival of patients with MGC. Further, it may represent the first clinical tool to provide efficient chemotherapy course selection for MGC. Ongoing analysis of newly developed drugs and regimens will allow the efficacy of this chemotherapy program to be improved.
PLoS ONE 06/2012; 7(6):e38652. DOI:10.1371/journal.pone.0038652 · 3.23 Impact Factor
"Basic studies have indicated that irinotecan has a multifactorial synergistic effect with the anti-tumor activity of 5-FU [24, 25]. In addition, several trials exploring combinations of S-1 and irinotecan have reported promising response rates [19, 23, 26, 27]; the dose and schedule in the present study was selected based on the lower incidence of grade 3 neutropenia and gastrointestinal toxicity evidenced from phase II studies among these trials. "
[Show abstract][Hide abstract] ABSTRACT: Irinotecan hydrochloride and S-1, an oral fluoropyrimidine, have shown antitumor activity against advanced gastric cancer as single agents in phase I/II studies. The combination of irinotecan and S-1 (IRI-S) is also active against advanced gastric cancer. This study was conducted to compare the efficacy and safety of IRI-S versus S-1 monotherapy in patients with advanced or recurrent gastric cancer.
Patients were randomly assigned to oral S-1 (80 mg/m² daily for 28 days every 6 weeks) or oral S-1 (80 mg/m² daily for 21 days every 5 weeks) plus irinotecan (80 mg/m² by intravenous infusion on days 1 and 15 every 5 weeks) (IRI-S). The primary endpoint was overall survival. Secondary endpoints included the time to treatment failure, 1- and 2-year survival rates, response rate, and safety.
The median survival time with IRI-S versus S-1 monotherapy was 12.8 versus 10.5 months (P = 0.233), time to treatment failure was 4.5 versus 3.6 months (P = 0.157), and the 1-year survival rate was 52.0 versus 44.9%, respectively. The response rate was significantly higher for IRI-S than for S-1 monotherapy (41.5 vs. 26.9%, P = 0.035). Neutropenia and diarrhea occurred more frequently with IRI-S, but were manageable. Patients treated with IRI-S received more courses of therapy at a relative dose intensity similar to that of S-1 monotherapy.
Although IRI-S achieved longer median survival than S-1 monotherapy and was well tolerated, it did not show significant superiority in this study.
Gastric Cancer 02/2011; 14(1):72-80. DOI:10.1007/s10120-011-0009-5 · 3.72 Impact Factor
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