Since its discovery in the late 1950s, fluorouracil (5-FU) has been investigated in several different dosing regimens, including a daily bolus schedule for 5 consecutive days, weekly bolus schedules, and continuous infusions extending over weeks. Clinical trials have suggested the importance of constant exposure to 5-FU to obtain optimal therapeutic results. Protracted intravenous infusions appear to improve response rates and survival compared with bolus administration[3,4] and the administration of 5-FU over prolonged periods of time may also be associated with reduced toxicity.[3,5] The toxicity profile of 5-FU is schedule dependent. While stomatitis and hand-foot syndrome (palmar-plantar erythrodysesthesia) are associated with continuous or protracted infusions, neutropenia and diarrhea are the dose-limiting toxicities of bolus schedules.[3,6]
One approach to improving the activity of 5-FU has been the addition of biochemical modulators. Several modulators have been studied, including leucovorin, N-(phosphonacetyl)-L-aspartate (PALA), methotrexate, trimetrexate, and interferon alfa.
Leucovorin is the most extensively used 5-FU biochemical modulator. In a meta-analysis of nine randomized clinical trials of advanced colorectal cancer comparing 5-FU alone with 5-FU plus IV leucovorin, patients receiving 5-FU/leucovorin showed a significant improvement in response rate in comparison with patients receiving 5-FU alone. However, improvement in response rates failed to convey a significant survival advantage.
The dose and schedule of leucovorin required for the optimal modulation of 5-FU has not been clearly defined. Leucovorin doses ranging from 20 to 500 mg/m2/d have been administered on daily x 5 days, bimonthly, or weekly schedules. A low-dose leucovorin regimen (leucovorin at 20 mg/m2/d plus 5-FU at 425 mg/m2/d for 5 consecutive days administered every 4 to 5 weeks) is commonly used in the United States, both for the treatment of metastatic colorectal cancer and as adjuvant therapy. This schedule often serves as a standard regimen in phase III advanced colorectal cancer trials evaluating new agents. Another commonly used regimen is a weekly regimen (leucovorin at 500 mg/m2 plus 5-FU at 500 mg/m2 administered weekly for 6 consecutive weeks followed by a 2-week rest).
These two regimens have similar response rates and survival. The median survival of advanced colorectal cancer patients treated with these regimens is approximately 1 year. Dose-limiting (grade 3/4) toxicities of the low-dose regimen are primarily oral mucositis (24% of patients) and neutropenia (29% of patients), whereas diarrhea is the predominant toxicity of the weekly regimen (32% of patients). These regimens of 5-FU plus leucovorin have been associated with toxicity-related hospitalizations in 20% to 30% of treated patients.
Although the modulation of 5-FU by leucovorin has been suggested as a standard of care for patients with metastatic colorectal cancer, a Southwest Oncology Group (SWOG) trial suggested that a protracted infusion of 5-FU has a favorable toxicity profile and trend toward improved survival compared with six other 5-FU regimens. This trial randomly allocated 500 patients to receive one of the following treatments: 5-FU IV bolus, 5-FU plus low-dose oral leucovorin, 5-FU plus high-dose leucovorin, 5-FU continuous infusion, 5-FU 24-hour infusion, and 5-FU 24-hour infusion plus PALA. Response rates ranged between 15% and 29% with a median survival for the entire group of 14 months.
An alternative schedule of 5-FU plus leucovorin uses a bimonthly high-dose leucovorin and 5-FU regimen. The schedule, investigated by de Gramont et al, has been extensively examined in France. This bimonthly schedule was compared to the low-dose leucovorin schedule (daily x 5). The investigators observed a more favorable toxicity profile and higher response rate for the bimonthly schedule. However, no statistically significant improvement in overall survival was noted with the bimonthly schedule.
The combination of interferon alfa plus 5-FU appeared promising in phase II studies of patients with metastatic colorectal cancer.[12-14] Unfortunately, randomized phase III trials that compared the combination of 5-FU plus interferon either with 5-FU alone or 5-FU plus leucovorin concluded that interferon afforded no benefit with regard to response rates and overall survival. Toxicity in the interferon arm increased significantly.
Trimetrexate, another dihydrofolate reductase inhibitor, potentiates the cytotoxicity of 5-FU. Phase II studies demonstrated objective responses with trimetrexate in combination with high-dose leucovorin and 5-FU in patients previously treated with 5-FU chemotherapy. However, grade 3 or 4 diarrhea and hypersensitivity occurred.
Several new agents are under development for the treatment of colorectal cancer. Some of these, including oral fluoropyrimidines, oxaliplatin, and irinotecan (Camptosar, CPT-11), are reviewed herein.
A protracted IV infusion of 5-FU may be an optimal schedule, resulting in continuous exposure of tumor cells to active 5-FU concentrations. This delivery system requires indwelling catheters, which can lead to line infection, line slippage, or thrombosis. Oral dosing of fluoropyrimidines would circumvent this problem. The bioavailability of oral 5-FU has been demonstrated to be erratic, precluding reliable dosing by this administration route. The erratic absorption of 5-FU may be attributed to varying levels of dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract. DPD is the primary catabolic enzyme of 5-FU with an estimated 85% of an administered 5-FU dose being catabolized by this enzyme. This problem of erratic 5-FU absorption from the gastrointestinal tract was overcome by the development of 5-FU prodrugs that are well absorbed enterally and then enzymatically converted to 5-FU. A second method to circumvent inconsistent oral absorption of 5-FU is to inactivate DPD.
1. Heidelberger C, Chandler NK, Douglas H Jr: Fluorouracil pyrimidine: A new class of tumor inhibiting compounds. Nature 179:633-666, 1957.
2. Ansfield F, Klotz J, Nealon T, et al: A phase III study comparing the clinical utility of four regimens of 5-fluorouracil: A preliminary report. Cancer 39:34-40, 1977.
3. Lokich JJ, Ahlgren JD, Gullo JJ, et al: A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic Oncology Program Study. J Clin Oncol 7:425-432, 1989.
4. The 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.
5. Hansen RM, Quebbeman E, Anderson T: 5-Fluorouracil by protracted venous infusion. A review of current progress. Oncology 46:245-250, 1989.
6. Fraile RJ, Baker LH, Buroker TR, et al: Pharmacokinetics of 5-fluorouracil administered orally, by rapid intravenous and by slow infusion. Cancer Res 40:2223-2228, 1980.
7. Allegra CJ, Grem JL: Antimetabolites, in DeVita VT, Hellman S, Rosenberg SA (eds): Principles and Practice of Oncology, 5th ed, pp 432-452. Philadelphia, Lippincott-Raven, 1997.
8. Advanced Colorectal 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.
9. Buroker TR, O’Connell MJ, Wieand HS, et al: Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 12:14-20, 1994.
10. Leichman CG, Fleming TR, Muggia FM, et al: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: A Southwest Oncology Group study. J Clin Oncol 13:1303-1311, 1995.
11. de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815, 1997.
12. Wadler S, Schwartz EL, Goldman M, et al: Fluorouracil and recombinant alfa-2a-interferon: An active regimen against advanced colorectal carcinoma. J Clin Oncol 7:1769-1775, 1989.
13. Pazdur R, Ajani JA, Patt YZ, et al: Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma. J Clin Oncol 8:2027-2031, 1990.
14. Kemeny N, Younes A, Seiter K, et al: Interferon alpha-2a and 5-Fluorouracil for advanced colorectal carcinoma: Assessment of activity and toxicity. Cancer 66:2470-2475, 1990.
15. Hill M, Norman A, Cunningham D, et al: Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer. J Clin Oncol 13:1297-1302, 1995.
16. Romanini A, Li WW, Colofiore JR, et al: Leucovorin enhances cytotoxicity of trimetrexate/fluorouracil, but not methotrexate/fluorouracil, in Ccrf-Cem cells. J Natl Cancer Inst 84:1033-1038, 1992.
17. Conti JA, Kemeny N, Seiter K, et al: Trial of sequential trimetrexate, fluorouracil, and high-dose leucovorin in previously treated patients with gastrointestinal carcinoma. J Clin Oncol 12:695-700, 1994.
18. Diasio RB: Oral DPD-inhibitory fluoropyrimidine drugs. Oncology 14(suppl 9):19-23, 2000.
19. Hoff PM, Pazdur R, Benner SE, et al: UFT and leucovorin: A review of its clinical development and therapeutic potential in the oral treatment of cancer. Anti-Cancer Drugs 9:479-490, 1998.
20. 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.
21. 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.
22. Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274-1281, 1998.
23. Findlay M, Van Cutsem E, Kocha W, et al: A randomised phase II study of Xeloda (capecitabine) in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 16:227a, 1997.
24. Twelves C, Harper P, Van Cutsem E, et al: A phase III trial (SO14796) of Xeloda (capecitabine) in previously untreated advanced/metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:263a, 1999.
25. Cox JV, Pazdur R, Thibault A, et al: A phase III trial of Xeloda (capecitabine) in previously untreated advanced/metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:265a, 1999.
26. Porter DJT, Chestnut WG, Merrill BM, Spector T: Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil. J Bio Chem 267:5236-5242, 1992.
27. 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.
28. Schilsky RL, Hohneker J, Ratain MJ, et al: Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer. J Clin Oncol 16:1450-1457, 1998.
29. Mani S, Beck T, Chevlen E, et al: A phase II open-label study to evaluate a 28-day regimen of oral 5-fluorouracil (5-FU) plus 776C85 for the treatment of patients with previously untreated metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol 17:281a, 1998.
30. Butour JL, Mazard AM, Macquet JP: Kinetics of the reaction of cis-platinum compounds with DNA in vitro. Biochem & Biophys Res Commun 3:347-353, 1985.
31. Raymond E, Chaney SG, Taamma A, et al: Oxaliplatin: A review of preclinical and clinical studies. Ann Oncol 9:1053-1071, 1998.
32. Lévi F, Dogliotti L, Perpoint B, et al: A multicenter phase II trial of intensified chronotherapy with oxaliplatin (L-OHP), 5-fluorouracil (5-FU) and folinic acid (FA) in patients (pts) with previously untreated metastatic colorectal cancer (MCC). Proc Am Soc Clin Oncol 16:266a, 1997.
33. de Gramont A, Figer A, Seymour M, et al: A randomized trial of leucovorin (LV) and 5-fluorouracil (5FU) with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000.
34. de Gramont A, Figer A, Seymour M, et al: A randomized trial of leucovorin (LV) and 5-fluorouracil (5FU) with or without oxaliplatin in advanced colorectal cancer. Proc Am Soc Clin Oncol 17:257a, 1998.
35. Figer A, Louvet C, Homerin M, et al: Analysis of prognostic factors of overall survival (OS) in the randomized trial of bimonthly leucovorin and 5-fluorouracil regimen (LV5FU2) with or without oxaliplatin in advanced colorectal cancer. Proc Am Soc Clin Oncol 18:239a, 1999.
36. Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment in metastatic colorectal cancer. J Clin Oncol 18:136-147, 2000.
37. Giacchetti S, Brienza S, Focan C, et al: Contribution of second line oxaliplatin (OXA)-chronomodulated 5-fluorouracil-folinic acid (CM-5-FU-FA) and surgery to survival in metastatic colorectal cancer patients. Proc Am Soc Clin Oncol 17:273a, 1998.
38. de Gramont A, Vignoud J, Tournigand C, et al: Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 33:214-219, 1997.
39. Andre T, Louvet C, Raymond E, et al: Bimonthly high-dose leucovorin, 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastatic colorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen. Ann Oncol 9:1251-1253, 1998.
40. de Gramont A, Maindrault-Goebel F, Louvet C, et al: Evaluation of oxaliplatin dose-intensity with the bimonthly 48h leucovorin and 5-fluorouracil regimens (FOLFOX) in pretreated metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:265a, 1999.
41. Maindrault-Goebel F, de Gramont A, Louvet C, et al: High-dose oxaliplatin with the simplified 48h bimonthly leucovorin and 5-fluorouracil (5FU) regimen in pretreated metastatic colorectal cancer (FOLFOX). Proc Am Soc Clin Oncol 18:265a, 1999.
42. van Cutsem E, Szanto J, Roth A, et al: Evaluation of the addition of oxaliplatin to the same Mayo or German 5FU regimen in advanced refractory colorectal cancer. Proc Am Soc Clin Oncol 18:234a, 1999.
43. Bleiberg H, Brienza S, Gerard B, et al: Oxaliplatin combined with a high dose, 24-hour continuous 5-FU infusion and folinic acid based regimen in patients with advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol 18:241a, 1999.
44. Bécouarn Y, Ychou M, Ducreux M, et al: Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 16:2739-2744, 1998.
45. Díaz-Rubio E, Sastre J, Zaniboni A, et al: Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study. Ann Oncol 9:105-108, 1998.
46. Machover D, Diaz-Rubio E, de Gramont A, et al: Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 7:95-98, 1996.
47. Wasserman E, Kalla S, Misset JL, et al: Oxaliplatin (L-OHP) and irinotecan (CPT-11) phase I/II studies: Results in 5 FU refractory (FR) colorectal cancer (CRC) patients (pts). Proc Am Soc Clin Oncol 18:238a, 1999.
48. Kunimoto T, Nitta K, Tanaka T, et al: Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 47:5944-5947, 1987.
49. Rougier P, Bugat R, Douillard JY, et al: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997.
50. Conti JA, Kemeny NE, Saltz LB, et al: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14:709-715, 1996.
51. Pitot HC, Wender DB, O’Connell MJ, et al: Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15:2910-2919, 1997.
52. Rothenberg ML, Eckardt JR, Kuhn JG, et al: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14:1128-1135, 1996.
53. Pitot HC: US pivotal studies of irinotecan in colorectal carcinoma. Oncology 12(suppl 6):48-53, 1998.
54. Cunningham D, Pyrhönen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998.
55. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998.
56. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993.
57. Pazdur R: Irinotecan: Toward clinical end points in drug development. Oncology 12(suppl 6):13-21, 1998.
58. Durrani ASK, Benhammouda A, Gil-Delgado MA, et al: Combination of irinotecan with leucovorin and 5-FU in advanced colorectal carcinoma—A phase II study. Proc Am Soc Clin Oncol 18:282a, 1999.
59. Saltz LB, Kanowitz J, Kemeny NE, et al: Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors. J Clin Oncol 14:2959-2967, 1996.
60. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905-914, 2000.
61. Douillard JY, Cunningham D, Roth AD, et al: A randomized phase III trial comparing irinotecan (IRI) + 5FU/folinic acid (FA) to the same schedule of 5FU/FA in patients with metastatic colorectal cancer as front line chemotherapy (CT). Proc Am Soc Clin Oncol 18:233a, 1999.