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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rich, T. A. Articles by Mosley, S. T. Search for Related Content PubMed PubMed Citation Articles by Rich, T. A. Articles by Mosley, S. T.

Four Decades of Continuing Innovation With Fluorouracil: Current and Future Approaches to Fluorouracil Chemoradiation Therapy

From the Departments of Radiation Oncology and Internal Medicine, University of Virginia Health System, Charlottesville, VA; and Brookfield Resources, LLC, Newtown, PA.

Address reprint requests to Tyvin A. Rich, MD, FACR, Department of Radiation Oncology, University of Virginia Health System, PO Box 800383, Charlottesville, VA 22908-0383; e-mail: tar4d{at}virginia.edu

PURPOSE: Chemoradiotherapy, the combination of external radiation therapy and concurrent chemotherapy, has been the basis for the oncologic management of many patients since its development in the 1960s. Fluorouracil (FU) chemoradiotherapy has demonstrated success in several organ sites with multiple dosing schedules that now guide the selection of oral analogs of FU to provide new chemoradiotherapy options.

METHODS: This article reviews the metabolism and pharmacology of FU and the advantages of administration of FU by continuous infusion or bolus. The potential role and impact of the oral fluorouracil prodrugs UFT, S-1, BOF-A2, and capecitabine as replacements for intravenous administration are discussed. The results of recent chemoradiotherapy studies with FU from 2000 to 2003 are summarized in rectal, head and neck, esophageal, gastric, pancreatic, biliary, anal, and cervical cancers.

RESULTS: Chemoradiotherapy with FU has the potential to widen the therapeutic window by minimizing normal tissue toxicity while maintaining effective tumor toxicity. Overall, FU chemoradiotherapy maximizes local control and, for some tumor sites (such as head and neck, pancreatic, biliary, cervical, esophageal, and gastric cancers), improves survival rates. Moreover, FU chemoradiotherapy results in improved organ preservation with excellent functional outcome in several anatomic sites including head and neck cancer, anal, and rectal cancer, with improved sphincter preservation.

CONCLUSION: FU chemoradiotherapy continues to play an important role in the management of many cancer sites. During the last four decades, optimal dosing schedules have produced a therapeutic gain. The introduction of oral prodrug analogs will likely further improve the results of FU therapy in several organ systems, such as the rectum, head and neck, and esophagus.

Supported in part by a grant from Hoffmann-La Roche Inc, Nutley, NJ.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

This article has been cited by other articles:

				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]

				N. Krynetskaia, H. Xie, S. Vucetic, Z. Obradovic, and E. Krynetskiy High Mobility Group Protein B1 Is an Activator of Apoptotic Response to Antimetabolite Drugs Mol. Pharmacol., January 1, 2008; 73(1): 260 - 269. [Abstract] [Full Text] [PDF]

				C. Aschele and S. Lonardi Multidisciplinary treatment of rectal cancer: medical oncology. Ann. Onc., November 1, 2007; 18(11): 1908 - 1915. [Full Text] [PDF]

				D. S. Shewach and T. S. Lawrence Antimetabolite Radiosensitizers J. Clin. Oncol., September 10, 2007; 25(26): 4043 - 4050. [Abstract] [Full Text] [PDF]

				Q. An, P. Robins, T. Lindahl, and D. E. Barnes 5-Fluorouracil Incorporated into DNA Is Excised by the Smug1 DNA Glycosylase to Reduce Drug Cytotoxicity Cancer Res., February 1, 2007; 67(3): 940 - 945. [Abstract] [Full Text] [PDF]

				G. C. Harewood, S. Hoecht, W. Hinkelbein, J. W. Cromwell, L. T. Santiago, J. E. Marcet, G. Curigliano, G. Spitaleri, G. Zampino, J.-F. Bosset, et al. Treatment of rectal cancer. N. Engl. J. Med., December 7, 2006; 355(23): 2486 - 2486. [Full Text] [PDF]

				N. Han and S. Galandiuk Induction Chemoradiation for Rectal Cancer Arch Surg, December 1, 2006; 141(12): 1246 - 1252. [Abstract] [Full Text] [PDF]

				T. Liersch, C. Langer, B. M. Ghadimi, B. Kulle, D. E. Aust, G. B. Baretton, W. Schwabe, P. Hausler, H. Becker, and C. Jakob Lymph Node Status and TS Gene Expression Are Prognostic Markers in Stage II/III Rectal Cancer After Neoadjuvant Fluorouracil-Based Chemoradiotherapy J. Clin. Oncol., September 1, 2006; 24(25): 4062 - 4068. [Abstract] [Full Text] [PDF]

				L. Seiple, P. Jaruga, M. Dizdaroglu, and J. T. Stivers Linking uracil base excision repair and 5-fluorouracil toxicity in yeast Nucleic Acids Res., January 10, 2006; 34(1): 140 - 151. [Abstract] [Full Text] [PDF]

				A. Mueller, B. W. Schafer, S. Ferrari, M. Weibel, M. Makek, M. Hochli, and C. W. Heizmann The Calcium-binding Protein S100A2 Interacts with p53 and Modulates Its Transcriptional Activity J. Biol. Chem., August 12, 2005; 280(32): 29186 - 29193. [Abstract] [Full Text] [PDF]

				C. Aschele, M. L. Friso, S. Pucciarelli, S. Lonardi, L. Sartor, G. Fabris, E. D. L. Urso, P. Del Bianco, G. Sotti, M. Lise, et al. A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer Ann. Onc., July 1, 2005; 16(7): 1140 - 1146. [Abstract] [Full Text] [PDF]