UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Medline ® Abstracts for References 118-123

of 'Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management'

118
TI
Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study.
AU
Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, Koizumi W, Saito H, Yamaguchi K, Takiuchi H, Nasu J, Ohtsu A, Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group
SO
Lancet Oncol. 2009;10(11):1063. Epub 2009 Oct 7.
 
BACKGROUND: The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer.
METHODS: We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20-75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m(2) per day, on days 1-5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m(2), on days 1 and 15) and cisplatin (80 mg/m(2), on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m(2), twice a day, on days 1-28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350,and with UMIN-CTR, number C000000062.
FINDINGS: All randomised patients were included in the primary analysis. Median overall survival was 10.8 months (IQR 5.7-17.8) for individuals assigned fluorouracil, 12.3 months (8.1-19.5) for those allocated irinotecan plus cisplatin (hazard ratio 0.85 [95% CI 0.70-1.04]; p=0.0552), and 11.4 months (6.4-21.3) for those assigned S-1 (0.83 [0.68-1.01]; p=0.0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group.
INTERPRETATION: S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting.
AD
Shizuoka Cancer Centre, Shizuoka, Japan. n.boku@scchr.jp
PMID
119
TI
A randomised multicentre phase II trial of capecitabine vs S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer.
AU
Lee JL, Kang YK, Kang HJ, Lee KH, Zang DY, Ryoo BY, Kim JG, Park SR, Kang WK, Shin DB, Ryu MH, Chang HM, Kim TW, Baek JH, Min YJ
SO
Br J Cancer. 2008;99(4):584. Epub 2008 Jul 29.
 
This randomised multicentre phase II study was conducted to investigate the activity and safety of two oral fluoropyrimidines, capecitabine or S-1, in elderly patients with advanced gastric cancer (AGC). Elderly (>or=65 years) chemo-naive patients with AGC were randomly assigned to receive capecitabine 1250 mg m(-2) two times daily on days 1-14 every 3 weeks or S-1 40-60 mg two times daily according to body surface area on days 1-28 every 6 weeks. Ninety-six patients were enrolled and 91 patients were randomised to capecitabine (N=46) or S-1 (N=45). Overall response rate, the primary end point, was 27.2% (95% CI, 14.1-40.4, 12 of 44 assessable patients) with capecitabine and 28.9% (95% CI, 15.6-42.1, 13 of 45) with S-1. Median times to progression and overall survival in the capecitabine arm (4.7 and 9.5 months, respectively) were similar to those in the S-1 arm (4.2 and 8.2 months, respectively). The incidence of grade 3-4 granulocytopenia was 6.8% with capecitabine and 4.8% with S-1. Grade 3-4 nonhaematologic toxicities were: asthenia (9.1% with capecitabine vs 7.1% with S-1), anorexia (6.8 vs 9.5%), diarrhoea (2.3 vs 0%), and hand-foot syndrome (6.8 vs 0%). Both capecitabine and S-1 monotherapies were active and tolerable as first-line treatment for elderly patients with AGC.
AD
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea.
PMID
120
TI
An early phase II clinical study of S-1 in patients with breast cancer
AU
Taguchi T, Morimoto K, Horikoshi N, et al
SO
Jpn J Cancer Chemother. 1998;25:1035.
 
AD
121
TI
Phase II study of S-1 as first-line treatment for elderly patients over 75 years of age with advanced gastric cancer: the Tokyo Cooperative Oncology Group study.
AU
Koizumi W, Akiya T, Sato A, Sakuyama T, Sasaki E, Tomidokoro T, Hamada T, Fujimori M, Kikuchi Y, Shimada K, Mine T, Yamaguchi K, Sasaki T, Kurihara M
SO
Cancer Chemother Pharmacol. 2010 May;65(6):1093-9. Epub 2009 Aug 30.
 
PURPOSE: This prospective multicenter phase II study was carried out to investigate the efficacy, safety and pharmacokinetics of S-1 monotherapy in elderly patients over 75 years of age, with unresectable advanced or recurrent gastric cancer.
METHODS: Patients had measurable or evaluable lesions according to the Japanese Classification of Gastric Carcinoma. S-1 (25-60 mg determined by the body surface area and creatinine clearance) was given orally, twice daily. A course of treatment consisted of 4-week administration followed by a 2-week rest period, and the patients received repeated courses.
RESULTS: Thirty-three patients were enrolled. Pharmacokinetics of S-1 was studied in six patients, and the maximum plasma concentrations of respective metabolites after S-1 administration were found to be similar to those reported for younger cancer patients. The overall response rate in 33 patients was 21.2% (95% CI, 10.7-37.8%), and median progression-free survival was 3.9 months, with a median overall survival of 15.7 months. Frequently noted adverse events include leukopenia, neutropenia, anemia, anorexia, and fatigue. As for serious adverse events, relatively higher frequencies of anemia (9%) and anorexia (12%) of grade 3 severity were found, but there were no grade 4 episodes.
CONCLUSIONS: The results suggest that S-1 monotherapy is safe and useful for elderly patients with unresectable advanced or recurrent gastric cancer when the dose is selected with caution, taking into account renal function.
AD
Department of Gastroenterology and Gastrointestinal Oncology, Kitasato University School of Medicine, Kitasato University East Hospital, 2-1-1 Asamizodai, Sagamihara, Kanagawa, 228-8520, Japan. office@tcog.jp
PMID
122
TI
Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group.
AU
Koizumi W, Kurihara M, Nakano S, Hasegawa K
SO
Oncology. 2000 Apr;58(3):191-7.
 
PURPOSE: To assess the efficacy and safety of S-1, a novel oral fluoropyrimidine derivative, we conducted a multicenter late phase II study in patients with advanced gastric cancer.
PATIENTS AND METHODS: Fifty-one patients who had received no previous chemotherapy were enrolled. Fifty patients were eligible for efficacy and safety analyses. The overall response was evaluated for the 43 patients who had metastatic lesions. S-1 was administered orally after breakfast and dinner for 28 days, followed by a 14-day break. The dosages were assigned according to the patients' body surface area (BSA): BSA<1.25 m(2), 40 mg; 1.25-1.5 m(2), 50 mg, and BSA>or =1.5 m(2), 60 mg, twice daily.
RESULTS: The overall response to treatment was evaluated as partial response in 19 of the 43 patients (44%; 95% confidence interval 30-59%). The median survival time in all patients was 207 days with 1- and 2-year survival rates of 36.0 and 14.0%, respectively. Grade 3 adverse reactions included decreased hemoglobin values in 2 patients, leukopenia, neutropenia and diarrhea in 1 patient each. No other grade 4 or unexpected adverse reactions were seen.
CONCLUSIONS: S-1 is effective against advanced gastric cancer. This oral treatment is suitable for outpatients because of its mild toxicity. Further therapeutic benefits are likely to be obtained by combining S-1 with other chemotherapeutic agents.
AD
Department of Gastroenterology, East Hospital, Kitasato University, School of Medicine, Kanagawa, Japan. koizumi@med.kitasato-u.ac.jp
PMID
123
TI
Japanese nationwide post-marketing survey of S-1 in patients with advanced gastric cancer.
AU
Nagashima F, Ohtsu A, Yoshida S, Ito K
SO
Gastric Cancer. 2005;8(1):6-11.
 
BACKGROUND: It is likely that there are some discrepancies in the safety and efficacy results for anticancer agents between those shown in registration studies for approval and those shown in clinical practice after market release. The aim of this survey was to confirm the safety and efficacy of S-1 for advanced gastric cancer after market release.
METHODS: After the approval of S-1 in 1999, all patients had to be registered with the manufacturer for a post-marketing survey, according to the government recommendation. All patients were monitored for safety and survival. The data for all registered patients were updated 1 year after each registration.
RESULTS: During this survey, a total of 4177 patients with advanced gastric cancer were registered. The incidences of all adverse events and of grade 3 or worse adverse events in the 3808 patients evaluable for safety were 74.3% and 25.0%, respectively. In patients with lower creatinine clearance at baseline, the incidences of adverse reactions were higher for all grades combined, as well as for grades 3 or worse. There were 90 (2.4%) early deaths (within 30 days of the initiation of the treatment) and 5 (0.1%) deaths possibly related to the treatment. The median survival time and the 1-year survival rate for all patients evaluable for efficacy (n = 3801) were 8.3 months (95% confidence interval [CI], 8.0-8.6 months) and 33.3% (95% CI, 31.8-34.9%), respectively.
CONCLUSION: This nationwide survey confirmed that the safety and efficacy profiles of S-1 were similar to those seen in the registration study. These results have proven the utility of this post-marketing survey in assessing the reproducibility of the safety and efficacy results obtained from prior clinical studies.
AD
Division of Digestive Endoscopy/Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan.
PMID