Skip to main content

Advertisement

SpringerLink
Log in

Recent phase III trials of fluorouracil, irinotecan, and oxaliplatin as chemotherapy for metastatic colorectal cancer

  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Colorectal cancer is a leading cause of cancer death worldwide. Recently the results of a number of well-designed clinical trials conducted across the world have led to important advances in the management of advanced colorectal cancer. These iterative studies fostered the evolution from a standard single-agent approach using fluorouracil (5-FU) to new combination regimens including capecitabine, irinotecan, and oxaliplatin in addition to 5-FU. These developments have significantly expanded the expectations of oncologists managing the disease and the options available to individuals, leading to a likelihood of extended survival compared to previous statistics. The identification of new combination chemotherapy regimens and the integration of novel targeted therapies with cytotoxic chemotherapies are areas of active clinical investigation. In this paper selected phase III studies from around the globe that tested these new chemotherapy options and led to new standards of care and better expectations for patients with advanced colorectal cancer are reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Andre T, Louvet C, Raymond E, Tournigand C, de Gramont A (1998) 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

    Article  CAS  PubMed  Google Scholar 

  2. [Anonymous] (1992) Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 10:896

  3. [Anonymous] (1996) Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. Meta-Analysis Group in Cancer. J Natl Cancer Inst 88:252

  4. [Anonymous] (1998) Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Meta-Analysis Group in Cancer. J Clin Oncol 16:301

  5. [Anonymous] (1999) Drug-company decision to end cancer trial. Lancet 354:1045

  6. Becouarn Y, Rougier P (1998) Clinical efficacy of oxaliplatin monotherapy: phase II trials in advanced colorectal cancer. Semin Oncol 25 [2 Suppl 5]:23

  7. Becouarn Y, Ychou M, Ducreux M, Borel C, Bertheault-Cvitkovic F, Seitz JF, Nasca S, Nguyen TD, Paillot B, Raoul JL, Duffour J, Fandi A, Dupont-Andre G, Rougier P (1998) 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

    CAS  PubMed  Google Scholar 

  8. Buroker TR, O’Connell MJ, Wieand HS, Krook JE, Gerstner JB, Mailliard JA, Schaefer PL, Levitt R, Kardinal CG, Gesme DH Jr (1994) Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 12:14

    Google Scholar 

  9. Carmichael J, Popiela T, Radstone D, Falk S, Borner M, Oza A, Skovsgaard T, Munier S, Martin C (2002) Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3617

    Article  CAS  PubMed  Google Scholar 

  10. Cocconi G, Cunningham D, Van Cutsem E, Francois E, Gustavsson B, van Hazel G, Kerr D, Possinger K, Hietschold SM (1998) Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 16:2943

    CAS  PubMed  Google Scholar 

  11. Cunningham D (1998) Mature results from three large controlled studies with raltitrexed (‘Tomudex’). Br J Cancer 77 [Suppl 2]:15

  12. Cunningham D, Zalcberg JR, Rath U, Oliver I, van Cutsem E, Svensson C, Seitz JF, Harper P, Kerr D, Perez-Manga G (1996) Final results of a randomised trial comparing ‘Tomudex’ (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. “Tomudex” Colorectal Cancer Study Group. Ann Oncol 7:961

    CAS  PubMed  Google Scholar 

  13. Cunningham D, Pyrhonen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413

    Article  CAS  PubMed  Google Scholar 

  14. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Van Cutsem E (2003) Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC) (abstract 1012). Proc Am Soc Clin Oncol 22:252

    Google Scholar 

  15. Danenberg PV, Danenberg KD (1978) Effect of 5,10-methylenetetrahydrofolate on the dissociation of 5-fluoro-2′-deoxyuridylate from thymidylate synthetase: evidence for an ordered mechanism. Biochemistry 17:4018

    CAS  PubMed  Google Scholar 

  16. de Gramont A, Bosset JF, Milan C, Rougier P, Bouche O, Etienne PL, Morvan F, Louvet C, Guillot T, Francois E, Bedenne L (1997) 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

    PubMed  Google Scholar 

  17. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938

    PubMed  Google Scholar 

  18. Diaz-Rubio E, Sastre J, Zaniboni A, Labianca R, Cortes-Funes H, de Braud F, Boni C, Benavides M, Dallavalle G, Homerin M (1998) Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: a phase II multicentric study. Ann Oncol 9:105

    Article  CAS  PubMed  Google Scholar 

  19. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355:1041

    Article  CAS  PubMed  Google Scholar 

  20. Douillard JY, Hoff PM, Skillings JR, Eisenberg P, Davidson N, Harper P, Vincent MD, Lembersky BC, Thompson S, Maniero A, Benner SE (2002) Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3605

    Article  CAS  PubMed  Google Scholar 

  21. Ensminger WD (2002) Intrahepatic arterial infusion of chemotherapy: pharmacologic principles. Semin Oncol 29:119

    Article  CAS  Google Scholar 

  22. Ford HE, Cunningham D (1999) Safety of raltitrexed. Lancet 354:1824

    CAS  Google Scholar 

  23. Gamelin E, Gamelin L, Bossi L, Quasthoff S (2002) Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current management and development of preventive measures. Semin Oncol 29 [5 Suppl 15]:21

  24. Garcia-Vargas JE, Sahmoud T, Smith MP, Green S (1999) Qualitative and chronological assessment of toxicities during treatment with raltitrexed (Tomudex) in 861 patients: implications for patient management (abstract 222). Eur J Cancer 35 [Suppl 4]:S72

  25. Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Levi F (2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136

    CAS  PubMed  Google Scholar 

  26. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23

    Article  PubMed  Google Scholar 

  27. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R (2001) 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

    CAS  PubMed  Google Scholar 

  28. Hurwitz HI, Fehrenbacher T, Cartwright J, Hainsworth J, Heim W, Berlin J, Griffing S, Novotny W, Holmgren E, Kabbinavar F (2003) Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC (abstract 3646). Proc Am Soc Clin Oncol 22:3464a

    Google Scholar 

  29. Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60

    Article  PubMed  Google Scholar 

  30. Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y (1999) Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341:2039

    Article  CAS  PubMed  Google Scholar 

  31. Kemeny NE, Niedzwiecki D, Hollis R, Lenz H-J, Naughton MJ, Weeks JC, Herndon JE, Zhang K, Mayer RJ (2003) Hepatic arterial infusion (HAI) versus systemic therapy for hepatic metastases from colorectal cancer; a CALGB randomized trial of efficacy, quality of life (QOL), cost effectiveness, and molecular mark (abstract 1010). Proc Am Soc Clin Oncol 22:252

    Google Scholar 

  32. Kerr DJ, McArdle CS, Ledermann J, Taylor I, Sherlock DJ, Schlag PM, Buckels J, Mayer D, Cain D, Stephens RJ; Medical Research Council Colorectal Cancer Study Group; European Organisation for Research and Treatment of Cancer Colorectal Cancer Study Group (2003) Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet 361:368

    Article  CAS  PubMed  Google Scholar 

  33. Macdonald JS (1989) Continuous low-dose infusion of fluorouracil: is the benefit worth the cost? J Clin Oncol 7:412

    CAS  PubMed  Google Scholar 

  34. Macdonald JS, Astrow AB (2001) Adjuvant therapy of colon cancer. Semin Oncol 28:30

    Article  CAS  Google Scholar 

  35. Machover D, Diaz-Rubio E, de Gramont A, Schilf A, Gastiaburu JJ, Brienza S, Itzhaki M, Metzger G, N’Daw D, Vignoud J, Abad A, Francois E, Gamelin E, Marty M, Sastre J, Seitz JF, Ychou M (1996) 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

    CAS  Google Scholar 

  36. Mathe G, Kidani Y, Triana K, Brienza S, Ribaud P, Goldschmidt E, Ecstein E, Despax R, Musset M, Misset JL (1986) A phase I trial of trans-1-diaminocyclohexane oxalato-platinum (l-OHP). Biomed Pharmacother 40:372

    CAS  PubMed  Google Scholar 

  37. Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour MT, Cohen D, Hopwood P, Johnston C, Stephens RJ; British MRC Colorectal Cancer Working Party (2002) Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet 359:1555

    Article  CAS  PubMed  Google Scholar 

  38. Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H (1998) 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

    Article  CAS  PubMed  Google Scholar 

  39. Myers CE, Diasio R, Eliot HM, Chabner BA (1976) Pharmacokinetics of the fluoropyrimidines: implications for their clinical use. Cancer Treat Rev 3:175

    CAS  PubMed  Google Scholar 

  40. Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 2:533

    Article  CAS  PubMed  Google Scholar 

  41. Pazdur R, Vincent M (1997) Raltitrexed (Tomudex) versus 5-fluorouracil and leucovorin (5-FU and LV) in patients with advanced colorectal cancer (ACC): results of a randomized, multicenter, North American trial (abstract 801). Proc Am Soc Clin Oncol 16

  42. Piedbois P, Michiels S for the Meta-Analysis Group in Cancer (2003) Survival benefit of 5FU/LV over 5FU bolus in patients with advanced colorectal cancer: an updated meta-analysis based on 2,751 patients (abstract 1180). Proc Am Soc Clin Oncol 22:294

    Google Scholar 

  43. Poon MA, O’Connell MJ, Wieand HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Mailliard JA (1991) Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9:1967

    CAS  PubMed  Google Scholar 

  44. Poon MA, O’Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK (1989) Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1407

    CAS  PubMed  Google Scholar 

  45. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Fay MP, Feuer EJ, Edwards BK (eds) (2003) SEER Cancer Statistics Review, 1975–2000. National Cancer Institute. Bethesda. http://seer.cancer.gov/csr/1975_2000

  46. Rothenberg ML, Meropol NJ, Poplin EA, Van Cutsem E, Wadler S (2001) Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 19:3801

    CAS  PubMed  Google Scholar 

  47. Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG (2003) Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21:2059

    Article  PubMed  Google Scholar 

  48. Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C (1998) Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407

    Article  CAS  PubMed  Google Scholar 

  49. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905

    Article  CAS  PubMed  Google Scholar 

  50. Saltz L, Rubin M, Hochster H, Tchekmeydian NS, Waksal H, Needle M, LoBuglio A (2001) Cetuximab (IMC-C225) plus Irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR) (abstract 7). Proc Am Soc Clin Oncol 20:7a

    Google Scholar 

  51. Saltz L, Meropol NJ, Loehrer PJ, Waksal H, Needle MN, Mayer RJ (2002) Single agent IMC-C225 (Erbitux) has activity in CPT-11-refractory colorectal cancer (CRC) that expresses the epidermal growth factor receptor (EGFR) (abstract 504). Proc Am Soc Clin Oncol 21:504a

    Google Scholar 

  52. Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura M, Nagai E, Yokoi T, Kamataki T (1996) Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res 56:3752

    CAS  PubMed  Google Scholar 

  53. Takimoto CH, Arbuck SG (2001) Topoisomerase I targeting agents: the camptothecins. In: Chabner BA, Longo DL (eds) Cancer chemotherapy and biotherapy: principles and practice. Lippincott, Williams & Wilkins, Philadelphia, p 579

  54. Tashiro T, Kawada Y, Sakurai Y, Kidani Y (1989) Antitumor activity of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane)platinum (II): new experimental data. Biomed Pharmacother 43:251

    Article  CAS  PubMed  Google Scholar 

  55. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22:229

    Article  PubMed  Google Scholar 

  56. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P; Xeloda Colorectal Cancer Study Group (2001) 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

    PubMed  Google Scholar 

  57. Van den Brande J, Schoffski P, Schellens JH, Roth AD, Duffaud F, Weigang-Kohler K, Reinke F, Wanders J, de Boer RF, Vermorken JB, Fumoleau P (2003) EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer. Br J Cancer 88:648

    Article  PubMed  Google Scholar 

  58. Zalcberg JR, Cunningham D, Van Cutsem E, Francois E, Schornagel J, Adenis A, Green M, Iveson A, Azab M, Seymour I (1996) ZD1694: a novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. Tomudex Colorectal Study Group. J Clin Oncol 14:716

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, The University of North Carolina at Chapel Hill, CB# 7305, 3009 Old Clinic Building, Chapel Hill, NC 27599-7305, USA

    Richard M. Goldberg

  2. Division of Hematology/Oncology, British Columbia Cancer Agency, Vancouver, Canada

    Sharlene Gill

Authors
  1. Richard M. Goldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sharlene Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard M. Goldberg.

Additional information

This work was presented at the 19th Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium, “State of the Arts for Digestive Organs”, 14–15 November 2003, Nagoya, Japan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goldberg, R.M., Gill, S. Recent phase III trials of fluorouracil, irinotecan, and oxaliplatin as chemotherapy for metastatic colorectal cancer. Cancer Chemother Pharmacol 54 (Suppl 1), S57–S64 (2004). https://doi.org/10.1007/s00280-004-0888-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-004-0888-9

Keywords

Search

Navigation