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Originally published as JCO Early Release 10.1200/JCO.2008.18.0158 on September 15 2008 © 2008 American Society of Clinical Oncology.
Commentary 2008: 25 or 50 Years Later?
Divisions of Medical Oncology and Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland Despite the introduction of newer agents with different mechanisms of action, fluoropyrimidines continue to be an integral component of chemotherapy for colorectal cancer (CRC). The rationale for the synthesis of fluoropyrimidines stemmed from the original observation that rat hepatomas use radiolabeled uracil more avidly than nonmalignant tissues.1 This finding suggested that the enzymatic pathways for utilization of uracil differ between malignant and normal cells and, therefore, that uracil metabolism represents a potential target for cancer treatment. Designed to circumvent the rapid degradation of fluorouracil (FU) in the intestinal wall, doxifluridine (5'-deoxy-5-fluorouridine) is a fluoropyrimidine derivative whose active component, FU, is released in the presence of uridine phosphorylase, an enzyme shown to be present at higher concentrations in malignant tissues, leading to the preferential release of FU in tumor cells.2 Twenty-five years after the publication of the promising results achieved by the Swiss Group for Clinical Cancer Research in a phase II study of doxifluridine in metastatic CRC (mCRC),3 this agent has disappeared from the armamentarium of available cytotoxic drugs. In contrast, FU remains the cornerstone of systemic therapy of CRC, although its initial development took place 50 years ago.4 Concerning the Swiss Group for Clinical Cancer Research phase II trial of doxifluridine, it is noteworthy that the objective response of 26% in patients with advanced CRC prompted the same group to carry out a phase III trial comparing FU with doxifluridine. This randomized study was prematurely terminated after the accrual of only 52 patients because of neurotoxic adverse effects and, above all, the cardiotoxicity observed in patients treated with doxifluridine.5 Neurotoxicity, but not cardiac dysfunction, had already been reported in the phase II trial.3 Therefore, one can ask the question of whether a cytotoxic agent with a similar profile would today still be studied in a phase III trial. The answer is probably not. Twenty-five years ago, phase II methodology was in its infancy, and our article reflects the situation that was prevailing at that time. We doubt that today Journal of Clinical Oncology would accept a report in which only 27 of 42 eligible patients were fully assessable for response to treatment, a fact that can lead to an undue selection of the patients considered in the final assessment. Moreover, criteria for evaluating liver and peritoneal lesions, which represented the vast majority of the measurable tumor parameters in our patients, were not stringent and were generally based on ultrasonography or clinical assessment. Today, Response Evaluation Criteria in Solid Tumors and National Cancer Institute criteria for assessing response and toxicity are standard practice. In addition, monitoring and reporting of toxicity during phase I and II trials have become much more uniform and stringent. Doxifluridine was eventually abandoned, mainly for toxicity reasons. However, that some of these toxicities were clearly defined only in the subsequent phase III trial seems less surprising today. In fact, our knowledge about the complex metabolism of fluoropyrimidines and, chiefly, of FU has increased exponentially. We now know that this metabolism is not only complex, encompassing multiple enzymatic steps, but also profoundly influenced by genetic and epigenetic variables, which can widely vary not only on an individual basis, but also on an ethnic basis.6,7 These biologic differences might, at least in part, explain why, notwithstanding the better standardization of methodology, toxicities might still widely vary in phase II trials, as has been shown in the development of many fluoropyrimidine derivatives. Twenty-five years after doxifluridine, new mechanisms of action of FU are still being proposed, such as thymidine phosphorylase as an angiogenetic factor through thymidine phosphorylase–derived 2-deoxy-D-ribose, which thus opens the potential of combining FU with rapamycin analogs as antiangiogenics.8 What has definitely changed in the last 25 years is the outcome of patients with CRC, in both the adjuvant and metastatic setting. However, this improvement has not been achieved through a more rational use of FU or as a result of the development of better fluoropyrimidine derivatives. All of the modifications of the FU schedules, including different routes of administration and the attempt to increase the efficacy of FU through potentiating agents (folinic acid, methotrexate, and interferons), were unable to significantly improve the survival of patients with mCRC. It was only when combination therapies were developed by adding new cytotoxic drugs (irinotecan and oxaliplatin) to FU that results became significantly better. A further improvement was then achieved by the addition of biologic agents, such as bevacizumab and cetuximab. However, costs of systemic treatment of CRC have increased tremendously.9 Whether the addition of the new biologic agents is cost effective in all patients with mCRC is still being debated and is creating a major confrontation between pharmaceutical companies and the British National Institute for Health and Clinical Excellence (NICE).10 It is to be hoped that, through a better definition of validated predictive biomarkers, it will soon be possible to select those patients who are more likely to derive benefit from such agents. The convenience and quality of life for patients have further improved after the introduction of oral fluoropyrimidines such as capecitabine, a compound that was mainly developed to mimic continuous infusion of FU. Today, capecitabine, as a single agent or in combination, is the recognized oral fluoropyrimidine of first choice in the systemic treatment of CRC, both in the adjuvant setting11 and in advanced disease.12 Therefore, in summary, we believe that after 25 years, even after 50 years, fluoropyrimidines do not represent an old story. New chapters remain to be written, mainly as a result of a better understanding of the metabolism of this important family of anticancer agents as well as our continuously expanding understanding of the biology of CRC. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Cristiana Sessa, Franco Cavalli Manuscript writing: Piercarlo Saletti, Cristiana Sessa Final approval of manuscript: Piercarlo Saletti, Cristiana Sessa, Franco Cavalli
NOTES published online ahead of print at www.jco.org on September 15, 2008 REFERENCES 1. Rutman RJ, Cantarow A, Paschkis KE: Studies in 2-acetylaminofluorene carcinogenesis: III. The utilization of uracil-2-C14 by preneoplastic rat liver and rat hepatoma. Cancer Res 14:119-123, 1954 2. Armstrong RD, Diasio RB: Selective activation of 5'-deoxy-5-fluorouridine by tumor cells as a basis for an improved therapeutic index. Cancer Res 41:4891-4894, 1981 3. Abele R, Alberto P, Kaplan S, et al: Phase II study of doxifluridine in advanced colorectal adenocarcinoma. J Clin Oncol 1:750-754, 1983[Abstract] 4. Heidelberger C, Chaudhuri NK, Danneberg P, et al: Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 179:663-666, 1957[CrossRef][Medline] 5. Alberto P, Mermillod B, Germano G, et al: A randomized comparison of doxifluridine and fluorouracil in colorectal carcinoma. Eur J Cancer Clin Oncol 24:559-563, 1988[CrossRef][Medline] 6. Ezzeldin HH, Diasio RB: Predicting fluorouracil toxicity: Can we finally do it? J Clin Oncol 26:2080-2118, 2008 7. Haller DG, Cassidy J, Clarke SJ, et al: Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol 26:2118-2123, 2008 8. Seeliger H, Guba M, Koehl GE, et al: Blockage of 2-deoxy-D-ribose-induced angiogenesis with rapamycin counteracts a thymidine phosphorylase-based escape mechanism available for colon cancer under 5-fluorouracil therapy. Clin Cancer Res 10:1843-1852, 2004 9. Schrag D: The price tag on progress: Chemotherapy for colorectal cancer. N Engl J Med 351:317-319, 2004 10. Jack A: Tensions grow over cancer treatments. http://www.ft.com/cms/s/0/fc9fa62a-42e4-11dd-81d0-0000779fd2ac.html?nclick_check=1 11. Twelves C, Wong A, Nowacki MP, et al: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696-2704, 2005 12. Saletti P, Cavalli F: Metastatic colorectal cancer. Cancer Treat Rev 32:557-571, 2006[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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