Abstract
We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m2), modulated by MTX (24 h earlier, 200 mg/m2) were alternated with a 3-week continuous infusion of FU (200 mg/m2daily), modulated by LV (20 mg/m2weekly bolus). Mito, 7 mg/m2, was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28–46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III–IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents. © 2001 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Aschele C, Guglielmi A, Frassineti GL, Milandri C, Amadori D, Labianca R, Vinci M, Tixi L, Caroti C, Ciferri E, Verdi E, Rosso R and Sobrero A (1998) Schedule selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a multicentric phase II study. British J Cancer 77: 341–346
Bergsland E, Hurwitz H, Fehrenbacher L, Meropol MJ, Novotny WF, Gaudreault J, Lieberman G and Kabbinavar F (2000) A randomized phase II trial comparing rhuMAb VEGF (recombinant humanized monoclonal antibody to vascular endothelial cell growth factor) plus 5-fluorouracil/leucovorin (FU/LV) to FU/LV alone in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 19: 936
Cunningham D, Pyrrhonen S, James RD, Punt CJA, Hickih TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C and 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: 1413–1418
Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L and Rougier P (2000) Irinotecan combined with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355: 1041–1047
Giachetti 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 and Lévi 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: 136–147
Kaplan E and Meier P (1958) Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457–458
Leichman CG, Leichman L and Spears CP (1993) Prolonged infusion of fluorouracil with weekly bolus leucovorin: a phase II study in patients with disseminated colorectal cancer. J Natl Cancer Inst 85: 41–44
Maindrault-Goebel F, Louvet C, Andre T, Carola E, Lotz JP, Molitor JL, Garcia ML, Gilles-Amar V, Izrael V, Krulik M and de Gramont A (1999) Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer 35: 1338–1342
Mantel M (1963) Chi-square tests with one degree of freedom: extensions of the Mantel-Haenszel procedure. J Am Stat Assoc 58: 690–700
Marsh JC, Bertino JR, Katz KH, Davis CA, Durivage HJ, Rome LS, Richards IIF, Capizzi RL, Farber LR, Pasquale DN, Stuart R, Koletsky AJ, Makuch R and O’Hollaren K (1991) The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer. J Clin Oncol 9: 371–380
Reid T, Galanis E, Abbruzzese J, Sze D, Romel L, Hatfield M, Rubin J and Kirn D (2000) Hepatic artery infusion of onyx-015, a selectively-replicanting adenovirus in combination with 5-FU/leucovorin for gastrointestinal carcinoma metastatic to the liver. Proc Am Soc Clin Oncol 19: 953
Rosen PJ, Amado R, Hecht JR, Chang D, Mulay M, Parson M, Laxa B, Brown J, Cropp G, Hannah A and Rosen L (2000) A phase I/II study of SU5416 in combination with 5-FU/leucovorin in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 19: 5D
Ross P, Norman A, Cunningham D, Webb A, Iveson T, Padhani A, Prendiville J, Watson M, Massey A, Popescu R and Oates J (1997) A prospective randomized trial of protracted venous infusion fluorouracil with or without mitomycin C in advanced colorectal cancer. Annals Oncol 8: 995–1001
Rougier P, Van Custem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Hérait P and Jacques C (1998) Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352: 1407–1412
Saltz JB, Douillard J, Pirotta N, Awad L, Elfring GL, Gruia G, Locker PK, Alakl M, Knight RD and Miller LL (2000) Combined analysis of two phase III randomized trials comparing irinotecan, fluorouracil, leucovorin vs fluororuacil alone as first-line therapy of previously untreated metastatic colorectal cancer. Proc Am Soc Clin Oncol 19: 938
Sobrero A, Aschele C, Guglielmi A, Mori AM, Melioli GG, Rosso R and Bertino JR (1993) Synergism and lack of cross-resistance between short-term and continuous exposure to fluorouracil in human colon adenocarcinoma cells. J Natl Cancer Inst 85: 1937–1944
Sobrero A, Aschele C, Guglielmi A, Mori AM, Tixi L, Bolli E, Rosso R, Mammoliti S, Bertoglio S, Rollandi G, Bruzzi P and Bertino JR (1995) Schedule-selective biochemical modulation of 5-fluorouracil: a phase II study in advanced colorectal cancer. Clin Cancer Res 1: 955–960
Sobrero AF, Aschele C and Bertino JR (1997) Fluorouracil in colorectal cancer: a tale of two drugs. Implications for biochemical modulation. J Clin Oncol 15: 368–381
Sobrero A, Zaniboni A, Frassineti GL, Aschele C, Guglielmi A, Giuliani R, Ravaioli A, Lanfranco C, Caroti C, Arnoldi E, Barni S, Gallo L, Pessi MA, Turci D, Cortesi E, Grossi F, Frontini L, Piazza E, Bruzzi P and Labianca R (2000) Schedule specific biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a randomized study. Annals of Oncol 11: 1–8
Waksal HW (1999) Role of an anti-epidermal growth factor receptor in treating cancer. Cancer Metastasis Rev 18: 427–436
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Sobrero, A., Guglielmi, A., Cirillo, M. et al. 5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer. Br J Cancer 84, 1023–1028 (2001). https://doi.org/10.1054/bjoc.2001.1732
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1054/bjoc.2001.1732
Keywords
This article is cited by
-
Phase II study of a triplet regimen in advanced colorectal cancer using methotrexate, oxaliplatin and 5-fluorouracil
British Journal of Cancer (2004)
-
Protracted infusional 5-fluorouracil plus high-dose folinic acid combined with bolus mitomycin C in patients with gastrointestinal cancer: a phase I/II dose escalation study
British Journal of Cancer (2003)
