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. 2000 Jun 15;83(2):141–145. doi: 10.1054/bjoc.2000.1236

Phase II study of S-1, a novel oral fluoropyrimidine derivative, in patients with metastatic colorectal carcinoma

A Ohtsu 1, H Baba 2, Y Sakata 3, Y Mitachi 4, N Horikoshi 5, K Sugimachi 6, T Taguchi 7; for the S-1 Cooperative Colorectal Carcinoma Study Group7
PMCID: PMC2363492  PMID: 10901361

Abstract

This study set out to evaluate, in patients with metastatic colorectal carcinoma, the efficacy and toxicity of S-1, which contains tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate, based on a biochemical modulation of 5-fluorouracil (5-FU) targeted at inhibition of dihydropyrimidine dehydrogenase (DPD). Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled into the study. None of the patients had received prior chemotherapy except for adjuvant setting. S-1 was administered orally twice daily at a standard dose of 80 mg m–2day–1for 28 days followed by a 14-day rest. This agent is continued until disease progression, unaccepted toxicity, or patient refusal. Twenty-two (35%) of the 62 eligible patients achieved PR with a 95% confidence interval of 25–48%. Five of the 10 patients with a history of adjuvant chemotherapy achieved partial remission. The median survival time was 12 months. Major adverse reactions included myelosuppressive and gastrointestinal toxicities, though their incidence of grade 3 or 4 being 13% in neutropenia and less than 10% in the others. None of the 53 patients treated as outpatients required hospitalization due to adverse reactions: These results suggest that S-1 achieves similar responses to those of infusional 5-FU plus leucovorin and shows the potential of another biochemical modulation with easily manageable toxicity. © 2000 Cancer Research Campaign

Keywords: metastatic colorectal carcinoma, tegafur, CDHP, S-1

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Selected References

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  1. Baccanari D. P., Davis S. T., Knick V. C., Spector T. 5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11064–11068. doi: 10.1073/pnas.90.23.11064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. DeMario M. D., Ratain M. J. Oral chemotherapy: rationale and future directions. J Clin Oncol. 1998 Jul;16(7):2557–2567. doi: 10.1200/JCO.1998.16.7.2557. [DOI] [PubMed] [Google Scholar]
  3. Diasio R. B., Beavers T. L., Carpenter J. T. Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Invest. 1988 Jan;81(1):47–51. doi: 10.1172/JCI113308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Etienne M. C., Chéradame S., Fischel J. L., Formento P., Dassonville O., Renée N., Schneider M., Thyss A., Demard F., Milano G. Response to fluorouracil therapy in cancer patients: the role of tumoral dihydropyrimidine dehydrogenase activity. J Clin Oncol. 1995 Jul;13(7):1663–1670. doi: 10.1200/JCO.1995.13.7.1663. [DOI] [PubMed] [Google Scholar]
  5. Harris B. E., Song R., Soong S. J., Diasio R. B. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res. 1990 Jan 1;50(1):197–201. [PubMed] [Google Scholar]
  6. Heggie G. D., Sommadossi J. P., Cross D. S., Huster W. J., Diasio R. B. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res. 1987 Apr 15;47(8):2203–2206. [PubMed] [Google Scholar]
  7. Houghton J. A., Houghton P. J., Wooten R. S. Mechanism of induction of gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorouridine, and 5-fluoro-2'-deoxyuridine. Cancer Res. 1979 Jul;39(7 Pt 1):2406–2413. [PubMed] [Google Scholar]
  8. Ikenaka K., Shirasaka T., Kitano S., Fujii S. Effect of uracil on metabolism of 5-fluorouracil in vitro. Gan. 1979 Jun;70(3):353–359. [PubMed] [Google Scholar]
  9. Leichman C. G., Fleming T. R., Muggia F. M., Tangen C. M., Ardalan B., Doroshow J. H., Meyers F. J., Holcombe R. F., Weiss G. R., Mangalik A. Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol. 1995 Jun;13(6):1303–1311. doi: 10.1200/JCO.1995.13.6.1303. [DOI] [PubMed] [Google Scholar]
  10. Liu G., Franssen E., Fitch M. I., Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997 Jan;15(1):110–115. doi: 10.1200/JCO.1997.15.1.110. [DOI] [PubMed] [Google Scholar]
  11. Lévi F., Misset J. L., Brienza S., Adam R., Metzger G., Itzakhi M., Caussanel J. P., Kunstlinger F., Lecouturier S., Descorps-Declère A. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer. Cancer. 1992 Feb 15;69(4):893–900. doi: 10.1002/1097-0142(19920215)69:4<893::aid-cncr2820690410>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  12. Malik S. T., Talbot D., Clarke P. I., Osborne R., Reznek R., Wrigley P. F., Slevin M. L. Phase II trial of UFT in advanced colorectal and gastric cancer. Br J Cancer. 1990 Dec;62(6):1023–1025. doi: 10.1038/bjc.1990.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Pazdur R., Lassere Y., Rhodes V., Ajani J. A., Sugarman S. M., Patt Y. Z., Jones D. V., Jr, Markowitz A. B., Abbruzzese J. L., Bready B. Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol. 1994 Nov;12(11):2296–2300. doi: 10.1200/JCO.1994.12.11.2296. [DOI] [PubMed] [Google Scholar]
  14. Poon M. A., O'Connell M. J., Moertel C. G., Wieand H. S., Cullinan S. A., Everson L. K., Krook J. E., Mailliard J. A., Laurie J. A., Tschetter L. K. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407–1418. doi: 10.1200/JCO.1989.7.10.1407. [DOI] [PubMed] [Google Scholar]
  15. Sakata Y., Ohtsu A., Horikoshi N., Sugimachi K., Mitachi Y., Taguchi T. Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer. 1998 Oct;34(11):1715–1720. doi: 10.1016/s0959-8049(98)00211-1. [DOI] [PubMed] [Google Scholar]
  16. Shirasaka T., Nakano K., Takechi T., Satake H., Uchida J., Fujioka A., Saito H., Okabe H., Oyama K., Takeda S. Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res. 1996 Jun 1;56(11):2602–2606. [PubMed] [Google Scholar]
  17. Shirasaka T., Shimamoto Y., Fukushima M. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res. 1993 Sep 1;53(17):4004–4009. [PubMed] [Google Scholar]
  18. Sugimachi K., Maehara Y., Horikoshi N., Shimada Y., Sakata Y., Mitachi Y., Taguchi T. An early phase II study of oral S-1, a newly developed 5-fluorouracil derivative for advanced and recurrent gastrointestinal cancers. The S-1 Gastrointestinal Cancer Study Group. Oncology. 1999 Oct;57(3):202–210. doi: 10.1159/000012032. [DOI] [PubMed] [Google Scholar]
  19. Taguchi T., Inuyama Y., Kanamaru R., Hasegawa K., Akazawa S., Niitani H., Furue H., Kurihara M., Ota K., Suga S. [Phase I study of S-1. S-1 Study Group]. Gan To Kagaku Ryoho. 1997 Dec;24(15):2253–2264. [PubMed] [Google Scholar]
  20. Takechi T., Nakano K., Uchida J., Mita A., Toko K., Takeda S., Unemi N., Shirasaka T. Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother Pharmacol. 1997;39(3):205–211. doi: 10.1007/s002800050561. [DOI] [PubMed] [Google Scholar]
  21. Takiuchi H., Ajani J. A. Uracil-tegafur in gastric carcinoma: a comprehensive review. J Clin Oncol. 1998 Aug;16(8):2877–2885. doi: 10.1200/JCO.1998.16.8.2877. [DOI] [PubMed] [Google Scholar]
  22. Tatsumi K., Fukushima M., Shirasaka T., Fujii S. Inhibitory effects of pyrimidine, barbituric acid and pyridine derivatives on 5-fluorouracil degradation in rat liver extracts. Jpn J Cancer Res. 1987 Jul;78(7):748–755. [PubMed] [Google Scholar]
  23. Tuchman M., Stoeckeler J. S., Kiang D. T., O'Dea R. F., Ramnaraine M. L., Mirkin B. L. Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity. N Engl J Med. 1985 Jul 25;313(4):245–249. doi: 10.1056/NEJM198507253130407. [DOI] [PubMed] [Google Scholar]

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