Journal of Clinical Oncology, Vol 16, 3537-3541, Copyright © 1998 by American Society of Clinical Oncology

ARTICLES

Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. Meta-Analysis Group In Cancer

PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta- analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand- foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5- FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.

This article has been cited by other articles:

				A. D. Ricart, J. D. Berlin, K. P. Papadopoulos, S. Syed, D. W. Drolet, C. Quaratino-Baker, J. Horan, J. Chick, W. Vermeulen, A. W. Tolcher, et al. Phase I, Pharmacokinetic and Biological Correlative Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor, and Cisplatin in Patients with Solid Tumors Clin. Cancer Res., December 1, 2008; 14(23): 7947 - 7955. [Abstract] [Full Text] [PDF]

				D. Cunningham, B. Sirohi, A. Pluzanska, B. Utracka-Hutka, J. Zaluski, R. Glynne-Jones, P. Koralewski, J. Bridgewater, P. Mainwaring, H. Wasan, et al. Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer Ann. Onc., October 14, 2008; (2008) mdn638v1. [Abstract] [Full Text] [PDF]

				P. Piedbois and J. Miller Croswell Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective Statistical Methods in Medical Research, October 1, 2008; 17(5): 519 - 527. [Abstract] [PDF]

				E. Aranda, M. Valladares, M. Martinez-Villacampa, M. Benavides, A. Gomez, B. Massutti, E. Marcuello, M. Constenla, J. C. Camara, A. Carrato, et al. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study Ann. Onc., August 20, 2008; (2008) mdn557v1. [Abstract] [Full Text] [PDF]

				M. Schwab, U. M. Zanger, C. Marx, E. Schaeffeler, K. Klein, J. Dippon, R. Kerb, J. Blievernicht, J. Fischer, U. Hofmann, et al. Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group J. Clin. Oncol., May 1, 2008; 26(13): 2131 - 2138. [Abstract] [Full Text] [PDF]

				C.-H. Kohne, J. De Greve, J. T. Hartmann, I. Lang, P. Vergauwe, K. Becker, D. Braumann, E. Joosens, L. Muller, J. Janssens, et al. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015 Ann. Onc., May 1, 2008; 19(5): 920 - 926. [Abstract] [Full Text] [PDF]

				B. Glimelius, H. Sorbye, L. Balteskard, P. Bystrom, P. Pfeiffer, K. Tveit, R. Heikkila, N. Keldsen, M. Albertsson, H. Starkhammar, et al. A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer Ann. Onc., May 1, 2008; 19(5): 909 - 914. [Abstract] [Full Text] [PDF]

				J. L. Yen-Revollo, R. M. Goldberg, and H. L. McLeod Can Inhibiting Dihydropyrimidine Dehydrogenase Limit Hand-Foot Syndrome Caused by Fluoropyrimidines? Clin. Cancer Res., January 1, 2008; 14(1): 8 - 13. [Abstract] [Full Text] [PDF]

				S. M. Lichtman Pharmacology of Antineoplastic Agents for Older Patients ASCO Educational Book, January 1, 2008; 2008(1): 210 - 214. [Abstract] [Full Text] [PDF]

				M. M.Y. Tin, C.-H. Cho, K. Chan, A. E. James, and J. K.S. Ko Astragalus saponins induce growth inhibition and apoptosis in human colon cancer cells and tumor xenograft Carcinogenesis, June 1, 2007; 28(6): 1347 - 1355. [Abstract] [Full Text] [PDF]

				S. M. Lichtman, H. Wildiers, E. Chatelut, C. Steer, D. Budman, V. A. Morrison, B. Tranchand, I. Shapira, and M. Aapro International Society of Geriatric Oncology Chemotherapy Taskforce: Evaluation of Chemotherapy in Older Patients--An Analysis of the Medical Literature J. Clin. Oncol., May 10, 2007; 25(14): 1832 - 1843. [Abstract] [Full Text] [PDF]

				A.-R. Hanauske, J. Cassidy, J. Sastre, C. Bolling, R. J. Jones, A. Rakhit, S. Fettner, U. Brennscheidt, A. Feyereislova, and E. Diaz-Rubio Phase 1b Dose Escalation Study of Erlotinib in Combination with Infusional 5-Fluorouracil, Leucovorin, and Oxaliplatin in Patients with Advanced Solid Tumors Clin. Cancer Res., January 15, 2007; 13(2): 523 - 531. [Abstract] [Full Text] [PDF]

				L. K. Mattison, J. Fourie, R. A. Desmond, A. Modak, M. W. Saif, and R. B. Diasio Increased prevalence of dihydropyrimidine dehydrogenase deficiency in african-americans compared with Caucasians. Clin. Cancer Res., September 15, 2006; 12(18): 5491 - 5495. [Abstract] [Full Text] [PDF]

				S. M Gressett, B. L Stanford, and F. Hardwicke Management of hand-foot syndrome induced by capecitabine Journal of Oncology Pharmacy Practice, September 1, 2006; 12(3): 131 - 141. [Abstract] [PDF]

				W. Ichikawa, T. Takahashi, K. Suto, Y. Sasaki, and R. Hirayama Orotate Phosphoribosyltransferase Gene Polymorphism Predicts Toxicity in Patients Treated with Bolus 5-Fluorouracil Regimen. Clin. Cancer Res., July 1, 2006; 12(13): 3928 - 3934. [Abstract] [Full Text] [PDF]

				S. A. Dobie, L.-M. Baldwin, J. A. Dominitz, B. Matthews, K. Billingsley, and W. Barlow Completion of therapy by Medicare patients with stage III colon cancer. J Natl Cancer Inst, May 3, 2006; 98(9): 610 - 619. [Abstract] [Full Text] [PDF]

				F. Vigna-Taglianti, P. Vineis, A. Liberati, and F. Faggiano Quality of systematic reviews used in guidelines for oncology practice Ann. Onc., April 1, 2006; 17(4): 691 - 701. [Abstract] [Full Text] [PDF]

				G. Beutel, H. Glen, P. Schoffski, J. Chick, S. Gill, J. Cassidy, and C. Twelves Phase I Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor in Patients with Refractory Solid Tumors Clin. Cancer Res., August 1, 2005; 11(15): 5487 - 5495. [Abstract] [Full Text] [PDF]

				J. L. Grem Screening for Dihydropyrimidine Dehydrogenase Deficiency Clin. Cancer Res., July 15, 2005; 11(14): 5067 - 5068. [Full Text] [PDF]

				J. Kortmansky, M. A. Shah, A. Kaubisch, A. Weyerbacher, S. Yi, W. Tong, R. Sowers, M. Gonen, E. O'Reilly, N. Kemeny, et al. Phase I Trial of the Cyclin-Dependent Kinase Inhibitor and Protein Kinase C Inhibitor 7-Hydroxystaurosporine in Combination With Fluorouracil in Patients With Advanced Solid Tumors J. Clin. Oncol., March 20, 2005; 23(9): 1875 - 1884. [Abstract] [Full Text] [PDF]

				Y. S. Heo, H. M. Chang, T. W. Kim, M.-H. Ryu, J.-H. Ahn, S. B. Kim, J. S. Lee, W. K. Kim, H. K. Cho, and Y.-K. Kang Hand-Foot Syndrome in Patients Treated With Capecitabine-Containing Combination Chemotherapy J. Clin. Pharmacol., October 1, 2004; 44(10): 1166 - 1172. [Abstract] [Full Text] [PDF]

				The Meta-Analysis Group in Cancer Modulation of Fluorouracil by Leucovorin in Patients With Advanced Colorectal Cancer: An Updated Meta-Analysis J. Clin. Oncol., September 15, 2004; 22(18): 3766 - 3775. [Abstract] [Full Text] [PDF]

				Q. S.-C. Chu, L. A. Hammond, G. Schwartz, L. Ochoa, S.-Y. Rha, L. Denis, K. Molpus, B. Roedig, S. P. Letrent, B. Damle, et al. Phase I and Pharmacokinetic Study of the Oral Fluoropyrimidine S-1 on a Once-Daily-for-28-Day Schedule in Patients with Advanced Malignancies Clin. Cancer Res., August 1, 2004; 10(15): 4913 - 4921. [Abstract] [Full Text] [PDF]

				J. J. Lee, T. M. Kim, S. J. Yu, D.-W. Kim, Y.-h. Joh, D.-Y. Oh, J. H. Kwon, T. Y. Kim, D. S. Heo, Y.-J. Bang, et al. Single-agent Capecitabine in Patients with Metastatic Colorectal Cancer Refractory to 5-Fluorouracil/Leucovorin Chemotherapy Jpn. J. Clin. Oncol., July 1, 2004; 34(7): 400 - 404. [Abstract] [Full Text] [PDF]

				T. A. Rich, R. C. Shepard, and S. T. Mosley Four Decades of Continuing Innovation With Fluorouracil: Current and Future Approaches to Fluorouracil Chemoradiation Therapy J. Clin. Oncol., June 1, 2004; 22(11): 2214 - 2232. [Abstract] [Full Text] [PDF]

				E. Diaz-Rubio New Chemotherapeutic Advances in Pancreatic, Colorectal, and Gastric Cancers Oncologist, June 1, 2004; 9(3): 282 - 294. [Abstract] [Full Text] [PDF]

				L. K. Mattison, H. Ezzeldin, M. Carpenter, A. Modak, M. R. Johnson, and R. B. Diasio Rapid Identification of Dihydropyrimidine Dehydrogenase Deficiency by Using a Novel 2-13C-Uracil Breath Test Clin. Cancer Res., April 15, 2004; 10(8): 2652 - 2658. [Abstract] [Full Text] [PDF]

				K. Patel, D. A. Anthoney, A. M. Crellin, D. Sebag-Montefiore, J. Messruther, and M. T. Seymour Weekly 5-fluorouracil and leucovorin: achieving lower toxicity with higher dose-intensity in adjuvant chemotherapy after colorectal cancer resection Ann. Onc., April 1, 2004; 15(4): 568 - 573. [Abstract] [Full Text] [PDF]

				P. Gilbar Palmar-plantar erythrodysesthesia Journal of Oncology Pharmacy Practice, December 1, 2003; 9(4): 137 - 150. [Abstract] [PDF]

				J. E Mortimer, M. K. Lauman, B. Tan, C. L Dempsey, A. C Shillington, and K. S Hutchins Pyridoxine treatment and prevention of hand-and-foot syndrome in patients receiving capecitabine Journal of Oncology Pharmacy Practice, December 1, 2003; 9(4): 161 - 166. [Abstract] [PDF]

				A. B. P. van Kuilenburg, R. Meinsma, B. A. Zonnenberg, L. Zoetekouw, F. Baas, K. Matsuda, N. Tamaki, and A. H. van Gennip Dihydropyrimidinase Deficiency and Severe 5-Fluorouracil Toxicity Clin. Cancer Res., October 1, 2003; 9(12): 4363 - 4367. [Abstract] [Full Text] [PDF]

				S. Sadahiro, T. Suzuki, K. Ishikawa, Y. Tanaka, T. Masuda, T. Nakamura, S. Yasuda, H. Makuuchi, and C. Murayama Pharmacokinetics of 5-Fluorouracil Following Hepatic Intra-arterial Infusion in a VX2 Hepatic Metastasis Model Jpn. J. Clin. Oncol., August 1, 2003; 33(8): 377 - 381. [Abstract] [Full Text] [PDF]

				T. Andre, P. Colin, C. Louvet, E. Gamelin, O. Bouche, E. Achille, N. Colbert, C. Boaziz, P. Piedbois, N. Tubiana-Mathieu, 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 J. Clin. Oncol., August 1, 2003; 21(15): 2896 - 2903. [Abstract] [Full Text] [PDF]

				H. Ezzeldin, M. R. Johnson, Y. Okamoto, and R. Diasio Denaturing High Performance Liquid Chromatography Analysis of the DPYD Gene in Patients with Lethal 5-Fluorouracil Toxicity Clin. Cancer Res., August 1, 2003; 9(8): 3021 - 3028. [Abstract] [Full Text] [PDF]

				M. Ychou, T. Conroy, J. F. Seitz, S. Gourgou, A. Hua, D. Mery-Mignard, and A. Kramar An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/ 5-fluorouracil every 2 weeks in patients with advanced solid tumors Ann. Onc., March 1, 2003; 14(3): 481 - 489. [Abstract] [Full Text] [PDF]

				P. Rougier, D. Lepille, J. Bennouna, A. Marre, M. Ducreux, L. Mignot, A. Hua, and D. Mery-Mignard Antitumour activity of three second-line treatment combinations in patients with metastatic colorectal cancer after optimal 5-FU regimen failure: a randomised, multicentre phase II study Ann. Onc., October 1, 2002; 13(10): 1558 - 1567. [Abstract] [Full Text] [PDF]

				M. Malet-Martino and R. Martino Clinical Studies of Three Oral Prodrugs of 5-Fluorouracil (Capecitabine, UFT, S-1): A Review Oncologist, August 1, 2002; 7(4): 288 - 323. [Abstract] [Full Text] [PDF]

				N. Maisey, I. Chau, D. Cunningham, A. Norman, M. Seymour, T. Hickish, T. Iveson, M. O'Brien, N. Tebbutt, A. Harrington, et al. Multicenter Randomized Phase III Trial Comparing Protracted Venous Infusion (PVI) Fluorouracil (5-FU) With PVI 5-FU Plus Mitomycin in Inoperable Pancreatic Cancer J. Clin. Oncol., July 15, 2002; 20(14): 3130 - 3136. [Abstract] [Full Text] [PDF]

				S. J. Cohen, C. G. Leichman, G. Yeslow, M. Beard, A. Proefrock, B. Roedig, B. Damle, S. P. Letrent, A. P. DeCillis, and N. J. Meropol Phase I and Pharmacokinetic Study of Once Daily Oral Administration of S-1 in Patients with Advanced Cancer Clin. Cancer Res., July 1, 2002; 8(7): 2116 - 2122. [Abstract] [Full Text] [PDF]

				E. Diaz-Rubio, T. R. J. Evans, J. Tabernero, J. Cassidy, J. Sastre, M. Eatock, D. Bisset, P. Regueiro, and J. Baselga Capecitabine (Xeloda(R)) in combination with oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors Ann. Onc., April 1, 2002; 13(4): 558 - 565. [Abstract] [Full Text] [PDF]

				J. A. Sloan, R. M. Goldberg, D. J. Sargent, D. Vargas-Chanes, S. Nair, S. S. Cha, P. J. Novotny, M. A. Poon, M. J. O'Connell, and C. L. Loprinzi Women Experience Greater Toxicity With Fluorouracil-Based Chemotherapy for Colorectal Cancer J. Clin. Oncol., March 15, 2002; 20(6): 1491 - 1498. [Abstract] [Full Text] [PDF]

				R. J. Mayer Oral Versus Intravenous Fluoropyrimidines for Advanced Colorectal Cancer: By Either Route, It's All the Same J. Clin. Oncol., November 1, 2001; 19(21): 4093 - 4096. [Full Text] [PDF]

				P. M. Hoff, J. Cassidy, and H.-J. Schmoll The Evolution of Fluoropyrimidine Therapy: From Intravenous to Oral Oncologist, August 1, 2001; 6(2008): 3 - 11. [Abstract] [Full Text] [PDF]

				P. M. Hoff, R. Ansari, G. Batist, J. Cox, W. Kocha, M. Kuperminc, J. Maroun, D. Walde, C. Weaver, E. Harrison, et al. Comparison of Oral Capecitabine Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Treatment in 605 Patients With Metastatic Colorectal Cancer: Results of a Randomized Phase III Study J. Clin. Oncol., April 15, 2001; 19(8): 2282 - 2292. [Abstract] [Full Text] [PDF]

				D. C. Hodgson, C. S. Fuchs, and J. Z. Ayanian Impact of Patient and Provider Characteristics on the Treatment and Outcomes of Colorectal Cancer J Natl Cancer Inst, April 4, 2001; 93(7): 501 - 515. [Abstract] [Full Text] [PDF]

				S. A. Elasmar, E. D. Saad, and P. M. Hoff Case Report: Hand-Foot Syndrome Induced by the Oral Fluoropyrimidine S-1 Jpn. J. Clin. Oncol., April 1, 2001; 31(4): 172 - 174. [Abstract] [Full Text] [PDF]

				M. Lotem, A. Hubert, O. Lyass, M. A. Goldenhersh, A. Ingber, T. Peretz, and A. Gabizon Skin Toxic Effects of Polyethylene Glycol-Coated Liposomal Doxorubicin Arch Dermatol, December 1, 2000; 136(12): 1475 - 1480. [Abstract] [Full Text] [PDF]

				A. B. P. van Kuilenburg, J. Haasjes, D. J. Richel, L. Zoetekouw, H. Van Lenthe, R. A. De Abreu, J. G. Maring, P. Vreken, and A. H. van Gennip Clinical Implications of Dihydropyrimidine Dehydrogenase (DPD) Deficiency in Patients with Severe 5-Fluorouracil-associated Toxicity: Identification of New Mutations in the DPD Gene Clin. Cancer Res., December 1, 2000; 6(12): 4705 - 4712. [Abstract] [Full Text]

				J. Nemunaitis, R. Eager, T. Twaddell, A. Corey, K. Sekar, K. Tkaczuk, J. Thompson, P. M. Hoff, and R. Pazdur Phase I Assessment of the Pharmacokinetics, Metabolism, and Safety of Emitefur in Patients With Refractory Solid Tumors J. Clin. Oncol., October 19, 2000; 18(19): 3423 - 3434. [Abstract] [Full Text] [PDF]

				J. A. Sloan, C. L. Loprinzi, P. J. Novotny, S. Okuno, S. Nair, and D. L. Barton Sex Differences in Fluorouracil-Induced Stomatitis J. Clin. Oncol., January 14, 2000; 18(2): 412 - 412. [Abstract] [Full Text] [PDF]