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© 2001 American Society for Clinical Oncology
Oral Versus Intravenous Fluoropyrimidines for Advanced Colorectal Cancer: By Either Route, It’s All the SameDana-Farber Cancer Institute, Boston, MA MORE THAN 40 YEARS after its development, fluorouracil (5-FU) remains the chemotherapeutic mainstay for the management of patients with advanced colorectal cancer.1 Approximately 15% to 20% of patients treated with 5-FU experience an objective response, and such responding patients are believed to have a more prolonged survival than similar individuals who do not experience objective benefit from treatment. Debate persists regarding the optimal dose schedule for 5-FU administration. A "loading" regimen (intravenous [IV] bolus administration on 5 consecutive days every 4 to 5 weeks) or a weekly regimen (IV bolus treatment every week) is most commonly used in the United States, whereas a prolonged IV infusion schedule has become more popular in Europe. Several controlled trials and even a meta-analysis have suggested that the infusion approach, which is more costly and inconvenient, results in a higher response rate than bolus treatment; differences in overall survival, however, have been negligible.2 An additional meta-analysis has documented a distinctly different toxicity profile between the loading schedule of bolus administration and the continuous-infusion approach. Neutropenia seems to be far more common when the loading schedule is utilized, clinically significant palmar-plantar erythema ("hand and foot" syndrome) is more frequent when continuous-infusion therapy is given, and the likelihood of diarrhea and other nonhematologic toxicities appears in equal frequency when the two treatment programs have been compared.3 Various pharmacologic strategies have been undertaken to biologically enhance the activity of 5-FU. The most widely accepted of these approaches focuses on the use of 5-FU in combination with leucovorin. Laboratory studies have shown that increasing the intracellular pool of reduced folate through pretreatment with leucovorin enhances the binding of 5-FU to its target enzyme, thymidylate synthase, thereby providing a greater inhibition of DNA synthesis. Several dose schedules of 5-FU/leucovorin have been examined, with the leucovorin having been added to loading bolus, weekly bolus, and continuous-infusion regimens. None of these schedules has been shown to be therapeutically superior to the others. However, the loading bolus program results in a significantly higher rate of neutropenia and stomatitis than does the weekly bolus regimen, which, in turn, leads to a somewhat greater frequency of diarrhea.4 A meta-analysis of nine randomized trials comparing 5-FU/leucovorin treatment with 5-FU alone in previously untreated patients with advanced colorectal cancer, using various dose schedules of both the 5-FU and the leucovorin, revealed an increase in the probability of response when leucovorin was added to 5-FU but little effect on overall survival.5 During the 1990s, 5-FU/leucovorin became accepted as the standard treatment for patients with advanced colon cancer. In recent years, several new approaches to the treatment of colorectal cancer have undergone examination. These include the introduction of two novel cytotoxic compounds, irinotecan and oxaliplatin, each of which has been examined alone and in combination with 5-FU/leucovorin. Another strategy that has received attention has been the development of several oral forms of fluoropyrimidines, offering an alternative route of administration to intravenous 5-FU. When 5-FU was initially synthesized, it was given either by parenteral or oral routes. The use of oral 5-FU fell into disfavor with the publication in 1975 of a double-blind, placebo-controlled, randomized study which showed IV 5-FU to be more effective than oral 5-FU.6 Pharmacokinetic plasma assays suggested this superiority to be due, in large part, to the variable absorption of the oral 5-FU by the intestine. The gastrointestinal mucosa contains dihydropyrimidine dehydrogenase (DPD), one of the enzymes that catabolize 5-FU. It seems that individuals who have greater concentrations of DPD in their intestinal mucosa inactivate more of the 5-FU, which leads to lower plasma drug concentrations. Strategies that have been developed to overcome this erratic oral absorption of 5-FU include the coadministration of oral 5-FU with drugs that inhibit the action of DPD and the oral administration of prodrugs of 5-FU that are absorbed intact and are metabolically activated after intestinal absorption has occurred.7 Three of these compounds have been individually compared with loading bolus IV 5-FU/leucovorin in prospectively randomized clinical trials as initial therapy for patients with metastatic colorectal cancer (Table 1).
UFT is a combination of uracil and tegafur (a prodrug of 5-FU) in a fixed molar ratio of 4:1.8 Uracil is a normal substrate for DPD and competitively blocks the actions of this enzyme, allowing tegafur absorption and the availability of biologically active plasma concentrations of 5-FU. UFT has usually been administered with oral leucovorin. UFT with leucovorin has been compared with parenteral 5-FU/leucovorin (loading bolus schedules) in two randomized studies involving 3809 and 81610 patients. The trials demonstrated similar efficacy between the oral and parenteral regimens in regard to objective response rates, median time to tumor progression, and median overall survival. Parenteral 5-FU/leucovorin was associated with a greater likelihood of severe (grades 3 and 4) neutropenia and stomatitis, but this difference was influenced by the toxicity profile of the loading bolus schedule that was selected for these clinical trials. UFT/leucovorin is also being compared with parenteral 5-FU/leucovorin (weekly bolus schedule) in an adjuvant trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP C-06); accrual to this study has been completed, but results are not yet available. Eniluracil is a direct inhibitor of DPD.11 The compound, given orally together with oral 5-FU, has been compared with parenteral 5-FU/leucovorin (loading bolus schedule) in two randomized studies of 53112 and 96413 patients. Once again, the oral treatment program resulted in an outcome therapeutically indistinguishable from that of the parenteral 5-FU/leucovorin, but it led to a decreased likelihood of myelosuppression and stomatitis. Because, in part, the trends in response rate and overall survival did not favor the oral drug, eniluracil has been withdrawn by its manufacturer from further study. The best developed example of a 5-FU prodrug that can be absorbed intact through the gastrointestinal mucosa is capecitabine, a fluoropyrimidine carbonate that is converted to 5-FU through three enzymatic steps.14 Capecitabine is absorbed intact and is initially metabolized in the liver by carboxylesterase to 5-deoxy-5 fluorocytosine. It is then metabolized to doxifluridine by cytidine deaminase, an enzyme that is expressed in higher concentrations in liver and tumor than normal tissue. Doxifluridine is then converted to 5-FU by the enzyme thymidine phosphorylase, which is also found in higher concentrations in tumors than in normal tissue. The daily administration of capecitabine has been associated with the "hand and foot" syndrome similar to that observed with continuous-infusion IV 5-FU.3 Capecitabine, given for 14 consecutive days at a dose of 2,500 mg/m2 twice daily for 14 consecutive days every 3 weeks, was compared with parenteral 5-FU/leucovorin (IV loading schedule) in a randomized trial involving 605 patients from North, Central, and South America performed by Hoff et al, the results of which were published in the April 15, 2001, issue of the Journal of Clinical Oncology,15 and in a similarly designed study including 602 patients from Europe, Israel, Australia, New Zealand, and Taiwan, conducted by van Cutsem et al, the data from which appear in the this issue of the Journal.16 In apparent contrast to the phase III trails assessing UFT9,10 and eniluracil,11,12 the investigators conducting the capecitabine trials recruited independent review committees, presumably to provide a more objective assessment of response to treatment than might emerge from the treating investigators. The response rates reported by both investigators and the independent review committee have been published. In the study of Hoff et al,15 both favor capecitabine over IV 5-FU/leucovorin (investigators: 24.8% v 15.5%; independent review committee: 25.8% v 11.6%), whereas in the trial of van Cutsem et al,16 capecitabine had an advantage over IV 5-FU/leucovorin only when investigators (26.6% v 17.9%) but not the independent review committee (18.9% v 15.0%) assessed response. More importantly, both trials demonstrated statistical equivalency between the oral and parenteral therapy in regard to median duration of response, median time to tumor progression, and median overall survival, thereby questioning the clinical value of the "objective response" criterion. The two trials reported similar toxicity patterns, with 16% to 18% of the capecitabine-treated patients experiencing grade 3 hand and foot syndrome and 13.3% to 16.0% of the IV 5-FU/leucovorin patients having grade 3 to 4 stomatitis. The authors of both studies conclude by stating that capecitabine provides "at least equivalence," "a favorable benefit-risk ratio," and greater "patient preference," making it an acceptable replacement for IV bolus 5-FU/leucovorin. What can we learn from these data evaluating oral fluoropyrimidines in general, and capecitabine in particular, in the treatment of patients with advanced colorectal cancer? As is evident from Table 1, all three compounds (UFT, eniluracil, and capecitabine) have demonstrated therapeutic efficacy, which indicates that the drug development efforts to overcome the effect of DPD on intestinal absorption have been successful. Despite an apparent difference in the response rate in the capecitabine study of Hoff et al,15 the data demonstrate equivalency between the oral and parenteral approaches. That being the case, the future value for capecitabine (the only oral fluoropyrimidine yet approved commercially in the United States for the treatment of metastatic colorectal cancer) and future oral drugs will rest on documentation of enhanced tolerance, decreased toxicity, patient convenience, or diminished costs. Although, in theory, capecitabine may fulfill all these criteria, it is somewhat premature to draw such conclusions at the present time (as have the authors of the two capecitabine trials). The choice of IV loading bolus 5-FU/leucovorin as the parenteral comparison regimen, which was apparently mandated by regulatory agencies, resulted in a far higher rate of stomatitis and myelosuppression than was observed with any of the oral compounds (or, for that matter, would have been the case had the investigators chosen the IV weekly bolus or the infusion program as the parenteral comparison regimen). During the past several years in North America, there has been general acceptance that the loading bolus program is too toxic. The three most recent North American adjuvant studies in colon cancer, in which IV 5-FU/leucovorin has been compared with UFT (NSABP C-06), irinotecan (Intergroup C89803), or oxaliplatin (NSABP C-07), have each used the weekly bolus 5-FU/leucovorin schedule. Consequently, it is inappropriate to conclude that capecitabine has a favorable benefit-risk ratio to any IV 5-FU/leucovorin regimen—only to the IV loading bolus 5-FU/leucovorin program. Given its toxicity profile (ie, hand and foot syndrome), it does seem that capecitabine acts biologically in a manner similar to continuous-infusion IV 5-FU. Although capecitabine can be considered to be a potential alternative to continuous-infusion 5-FU, in the absence of data, it is too soon to assume that the two treatment strategies are equivalent in terms of therapeutic outcome and tolerance. Clinical studies combining capecitabine with irinotecan, oxaliplatin, and radiation therapy are in progress. It is also too early to predict whether capecitabine and other oral fluoropyrimidines will eventually replace parenteral 5-FU treatment. An advantage of the oral route is its potential for greater patient convenience and comfort; patients take pills at home rather than an IV injection in a physician’s office. Uncertain, however, is patients’ compliance in using oral medications that may be associated with toxic effects. In theory, the use of oral fluoropyrimidines should be less costly than IV treatment. However, such an economic advantage has not yet been shown because drugs such as capecitabine are relatively expensive and regular visits to physicians’ offices will undoubtedly continue if fluoropyrimidine is combined with other drugs, such as irinotecan or oxaliplatin, which to date can only be administered in a parenteral manner. As can be seen from Table 1, the best outcome that can be anticipated for the oral fluoropyrimidines is equivalency to parenteral 5-FU; these oral agents do not enhance the probability of response or the duration of survival that can be achieved through the use of 5-FU. Although the necessary assessments of treatment-related quality of life and cost efficacy for oral fluoropyrimidines should continue, we must not lose sight of the greater importance of identifying and examining newer forms of cytotoxic, biologic, or molecular therapy that hold far greater promise of enhancing the ultimate outcome for patients with advanced colorectal cancer. REFERENCES 1. Mayer RJ: Newer cytotoxic agents for advanced colon cancer. ASCO Educational Book Spring : 625-630, 2000
2.
Meta-Analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16: 301-308, 1998 3. Meta-Analysis Group in Cancer: Toxicity of fluorouracil in patients with advanced colorectal cancer: Effect of administration schedule and prognostic factors. J Clin Oncol 16: 3537-3541, 1998[Abstract] 4. Haller DG, Catalano PJ, Macdonald JS, et al: Fluorouracil (FU), leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon cancer: Five-year final report of INT-0089. Proc Am Soc Clin Oncol 17: 256a, 1998 (abstr 982) 5. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 10: 896-903, 1992[Abstract] 6. Hahn RG, Moertel CG, Schutt AJ, et al: A double-blind comparison of intensive course 5-fluorouracil by oral vs. intravenous route in the treatment of colorectal carcinoma. Cancer 35: 1031-1035, 1975[Medline] 7. Meropol NJ: Oral fluoropyrimidines in the treatment of colorectal cancer. Eur J Cancer 34: 1509-1513, 1998 8. Sulkes A, Benner SE, Canetta RM: Uracil-ftorafur: An oral fluoropyrimidine active in colorectal cancer. J Clin Oncol 16: 3461-3475, 1998[Abstract] 9. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of ORZEL (oral uracil/tegafur (UFT) plus leucovorin (LV)) versus parenteral 5-fluorouracil (5-FU) plus LV in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 18: 264a, 1999 (abstr 1015) 10. Pazdur R, Douillard J-Y, Skillings JR, et al: Multicenter phase III study of 5-fluorouracil (5-FU) or UFT in combination with leucovorin (LV) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 18: 263a, 1999 (abstr 1009) 11. Baker SD, Khor SP, Adjei AA, et al: Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. J Clin Oncol 14: 3085-3096, 1996[Abstract] 12. Van Cutsem E, Sorensen J, Cassidy J, et al: International phase III study of oral eniluracil (EU) plus 5-fluorouracil (5-FU) versus intravenous (IV) 5-FU plus leucovorin (LV) in the treatment of advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol 20: 131a, 2001 (abstr 522) 13. Levin J, Schilsky R, Burris H, et al: North American phase III study of oral eniluracil (EU) plus oral 5-fluorouracil (5-FU) versus intravenous (IV) 5-FU plus leucovorin (LV) in the treatment of advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol 20: 132a, 2001 (abstr 523) 14. Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumors by enzymes concentrated in human liver and cancer tissues. Eur J Cancer 34: 1274-1281, 1998
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Hoff PM, Ansari R, Batist G, 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 19: 2282-2292, 2001
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Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19: 4097-4106, 2001
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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