This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by O’Dwyer, P. J. Articles by Benson, A. B. Search for Related Content PubMed PubMed Citation Articles by O’Dwyer, P. J. Articles by Benson, A. B., III

Fluorouracil Modulation in Colorectal Cancer: Lack of Improvement With N -Phosphonoacetyl- l -Aspartic Acid or Oral Leucovorin or Interferon, But Enhanced Therapeutic Index With Weekly 24-Hour Infusion Schedule—An Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study

From the University of Pennsylvania Cancer Center, Philadelphia, PA; Eastern Cooperative Oncology Group and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Dartmouth-Hitchcock Medical Center, Hanover, NH; Cleveland Metropolitan General Hospital, OH; Montefiore Medical Center, Bronx; Roswell Park Memorial Institute, Buffalo, NY; Fox Chase Cancer Center, Philadelphia, PA; and Northwestern University, Chicago, IL.

Address reprint requests to Peter J. O’Dwyer, MD, University of Pennsylvania Cancer Center, 51 N 39th St, MAB 103, Philadelphia, PA 19104; email: podwyer{at}mail.med.upenn.edu

PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer.

PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m² by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m² day l, 5-FU 2,600 mg/m² by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m² with oral leucovorin (LV) 125 mg/m² hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m² with intravenous (IV) LV 600 mg/m², weekly; arm E, 5-FU 750 mg/m²/d IV by continuous infusion for 5 days, then 750 mg/m² weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years.

RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P < .001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly.

CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.

This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, MD) and supported in part by Public Health Service grant nos. CA15488, CA23318, CA14548, CACA14958, CA27525, CA17145, CA31946, CA37027, CA66636, and CA21115 from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services.

The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

This article has been cited by other articles:

				L. Shen, P. J. Catalano, A. B. Benson III, P. O'Dwyer, S. R. Hamilton, and J.-P. J. Issa Association between DNA Methylation and Shortened Survival in Patients with Advanced Colorectal Cancer Treated with 5-Fluorouracil Based Chemotherapy Clin. Cancer Res., October 15, 2007; 13(20): 6093 - 6098. [Abstract] [Full Text] [PDF]

				P. A. Tang, S. M. Bentzen, E. X. Chen, and L. L. Siu Surrogate End Points for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis From 39 Randomized Controlled Trials of First-Line Chemotherapy J. Clin. Oncol., October 10, 2007; 25(29): 4562 - 4568. [Abstract] [Full Text] [PDF]

				O. Tredan, C. M. Galmarini, K. Patel, and I. F. Tannock Drug Resistance and the Solid Tumor Microenvironment J Natl Cancer Inst, October 3, 2007; 99(19): 1441 - 1454. [Abstract] [Full Text] [PDF]

				S. R. Smalley, J. K. Benedetti, S. K. Williamson, J. M. Robertson, N. C. Estes, T. Maher, B. Fisher, T. A. Rich, J. A. Martenson, J. W. Kugler, et al. Phase III Trial of Fluorouracil-Based Chemotherapy Regimens Plus Radiotherapy in Postoperative Adjuvant Rectal Cancer: GI INT 0144 J. Clin. Oncol., August 1, 2006; 24(22): 3542 - 3547. [Abstract] [Full Text] [PDF]

				C. Leonetti, M. Scarsella, G. Zupi, W. Zoli, D. Amadori, L. Medri, F. Fabbri, M. Rosetti, P. Ulivi, L. Cecconetto, et al. Efficacy of a nitric oxide-releasing nonsteroidal anti-inflammatory drug and cytotoxic drugs in human colon cancer cell lines in vitro and xenografts. Mol. Cancer Ther., April 1, 2006; 5(4): 919 - 926. [Abstract] [Full Text] [PDF]

				H. Kelly and R. M. Goldberg Systemic Therapy for Metastatic Colorectal Cancer: Current Options, Current Evidence J. Clin. Oncol., July 10, 2005; 23(20): 4553 - 4560. [Abstract] [Full Text] [PDF]

				A. Venook Critical Evaluation of Current Treatments in Metastatic Colorectal Cancer Oncologist, April 1, 2005; 10(4): 250 - 261. [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]

				C-H. Kohne, J. Wils, M. Lorenz, P. Schoffski, R. Voigtmann, C. Bokemeyer, M. Lutz, U. Kleeberg, K. Ridwelski, R. Souchon, 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 J. Clin. Oncol., October 15, 2003; 21(20): 3721 - 3728. [Abstract] [Full Text] [PDF]

				P. G. Johnston, A. B. Benson III, P. Catalano, M. S. Rao, P. J. O'Dwyer, and C. J. Allegra Thymidylate Synthase Protein Expression in Primary Colorectal Cancer: Lack of Correlation With Outcome and Response to Fluorouracil in Metastatic Disease Sites J. Clin. Oncol., March 1, 2003; 21(5): 815 - 819. [Abstract] [Full Text] [PDF]

				P. Nadella, C. Shapiro, G. A. Otterson, M. Hauger, S. Erdal, E. Kraut, S. Clinton, M. Shah, M. Stanek, P. Monk, et al. Pharmacobiologically Based Scheduling of Capecitabine and Docetaxel Results in Antitumor Activity in Resistant Human Malignancies J. Clin. Oncol., June 1, 2002; 20(11): 2616 - 2623. [Abstract] [Full Text] [PDF]

				J. S. Macdonald Vive La Difference: Sex and Fluorouracil Toxicity J. Clin. Oncol., March 15, 2002; 20(6): 1439 - 1441. [Full Text] [PDF]