Feasibility and Efficacy Study of Biweekly Irinotecan Combined with Oral Tegafur/Uracil in Advanced Colorectal Cancer

Masataka Ikeda, Mitsugu Sekimoto, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Masaki Mori

Department of Surgery, Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Surgery, Natinal Hospital Organization Osaka National Hospital, Osaka, Japan.

DOI: 10.4236/jct.2013.46A2002                

Abstract

Background: We evaluated the feasibility and efficacy of irinotecan (CPT-11) plus tegafur/uracil (UFT) combination chemotherapy in patients with advanced colorectal cancer. Patients and Methods: PK parameters were concurrently measured to confirm the presence of drug interactions in this treatment schedule. CPT-11 was administered intravenously at the dose of 150 mg/m² on days 1, 15. UFT was administered at the dose of 375 mg/m²/day (B.I.D.) on days 3 - 7, 10 - 14, 17 - 21, 24 - 28 repeated every 5 weeks. Results: 31 patients were enrolled. PK parameters for CPT-11, FT, 5-FU and uracil are available from 5 patients. The overall response rate was 16.1%. The median time to treatment discontinuation was 3.9 months. There was no significant difference in PK parameters of CPT-11 between day 1 and day 15 and of UFT between day 3 and day 10. Conclusion: CPT-11 plus UFT combination chemotherapy exhibited a tolerable toxicity profile with acceptable efficacy. Pharmacokinetic analysis showed that there were no drug interactions in this treatment schedule.

Keywords

Colorectal Neoplasms; Pharmacokinetics; Drug Therapy; Fluorouracil; Tegafur/Uracil; UFT

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	T. Andre, P. Colin, C. Louvet, et al., “Semimonthly versus Monthly Regimen of Fluorouracil and Leucovorin Administered for 24 or 36 Weeks as Adjuvant Therapy in Stage II and III Colon Cancer: Results of a Randomized Trial,” Journal of Clinical Oncology, Vol. 21, No. 15, 2003, pp. 2896-2903. doi:10.1200/JCO.2003.10.065
[2]	A. de Gramont, J. F. Bosset, C. Milan, et al., “Randomized Trial Comparing Monthly Low-Dose Leucovorin and Fluorouracil Bolus with Bimonthly High-Dose Leucovorin and Fluorouracil Bolus plus Continuous Infusion for Advanced Colorectal Cancer: A French Intergroup Study,” Journal of Clinical Oncology, Vol. 15, No. 2, 1997, pp. 808-815.
[3]	C. H. Kohne, J. Wils, M. Lorenz, et al., “Randomized Phase III Study of High-Dose Fluorouracil Given as a Weekly 24-Hour Infusion with or without Leucovorin Versus Bolus Fluorouracil plus Leucovorin in Advanced Colorectal Cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952,” Journal of Clinical Oncology, Vol. 21, No. 20, 2003, pp. 3721-3728. doi:10.1200/JCO.2003.11.122
[4]	G. Masci, M. Magagnoli, P. A. Zucali, et al., “Minidose Warfarin Prophylaxis for Catheter-Associated Thrombosis in Cancer Patients: Can It Be Safely Associated with Fluorouracil-Based Chemotherapy?” Journal of Clinical Oncology, Vol. 21, No. 4, 2003, pp. 736-739. doi:10.1200/JCO.2003.02.042
[5]	Y. Maehara, Y. Kakeji, S. Ohno, et al., “Scientific Basis for the Combination of Tegafur with Uracil,” Oncology (Williston Park), Vol. 11, Suppl. 10, 1997, pp. 14-21.
[6]	J. Y. Douillard, P. M. Hoff, J. R. Skillings, et al., “Multicenter Phase III Study of Uracil/Tegafur and Oral Leucovorin versus Fluorouracil and Leucovorin in Patients with Previously Untreated Metastatic Colorectal Cancer,” Journal of Clinical Oncology, Vol. 20, No. 17, 2002, pp. 3605-3616. doi:10.1200/JCO.2002.04.123
[7]	D. H. Ho, R. Pazdur, W. Covington, et al., “Comparison of 5-Fluorouracil Pharmacokinetics in Patients Receiving Continuous 5-Fluorouracil Infusion and Oral Uracil plus N1-(2’-Tetrahydrofuryl)-5-Fluorouracil,” Clinical Cancer Research, Vol. 4, No. 9, 1998, pp. 2085-2088.
[8]	P. Therasse, S. G. Arbuck, E. A. Eisenhauer, et al., “New Guidelines to Evaluate the Response to Treatment in Solid Tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada,” Journal of the National Cancer Institute, Vol. 92, No. 3, 2000, pp. 205-216. doi:10.1093/jnci/92.3.205
[9]	E. Matsushima, K. Yoshida and R. Kitamura, “Determination of S-1 (Combined Drug of Tegafur, 5-Chloro-2,4-Dihydroxypyridine and Potassium Oxonate) and 5-Fluorouracil in Human Plasma and Urine Using High-Performance Liquid Chromatography and Gas Chromatography-Negative Ion Chemical Ionization Mass Spectrometry,” Journal of Chromatography B Biomedical Sciences and Applications, Vol. 691, No. 1, 1997, pp. 95-104. doi:10.1016/S0378-4347(96)00429-X
[10]	J. Y. Douillard, D. Cunningham, A. D. Roth, et al., “Irinotecan Combined with Fluorouracil Compared with Fluorouracil Alone as First-Line Treatment FOr Metastatic Colorectal Cancer: A Multicentre Randomized Trial,” Lancet, Vol. 355, No. 9209, 2000, pp. 1041-1047. doi:10.1016/S0140-6736(00)02034-1
[11]	C. Tournigand, T. Andre, E. Achille, et al., “Folfiri Followed By FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study,” Journal of Clinical Oncology, Vol. 22, No. 2, 2004, pp. 229-237. doi:10.1200/JCO.2004.05.113
[12]	M. Malet-Martino and R. Martino, “Clinical Studies of Three oral Prodrugs of 5-Fluorouracil (Capecitabine, UFT, S-1): A Review,” Oncologist, Vol. 7, No. 4, 2002, pp. 288-323. doi:10.1634/theoncologist.7-4-288
[13]	A. Falcone, A. Di Paolo, G. Masi, et al., “Sequence Effect of Irinotecan and Fluorouracil Treatment on Pharmacokinetics and Toxicity in Chemotherapy-Naive Metastatic Colorectal Cancer Patients,” Journal of Clinical Oncology, Vol. 19, No. 15, 2001, pp. 3456-3462.
[14]	L. B. Saltz, J. Kanowitz, N. E. Kemeny, et al., “Phase I Clinical and Pharmacokinetic Study of Irinotecan, Fluorouracil, and Leucovorin in Patients with Advanced Solid Tumors,” Journal of Clinical Oncology, Vol. 14, No. 11, 1996, pp. 2959-2967.