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. 2001 Apr;84(8):1023–1028. doi: 10.1054/bjoc.2001.1732

5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer

A Sobrero 1, A Guglielmi 1, M Cirillo 1, E Recaldin 1, G L Frassineti 1, C Aschele 1, A Ravaioli 1, P Testore 1, C Caroti 1, L Gallo 1, M A Pessi 1, E Cortesi 1, D Turci 1, F Grossi 1, R Labianca 1
PMCID: PMC2363863  PMID: 11308248

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 http://www.bjcancer.com

Keywords: advanced colorectal cancer, biochemical modulation, 5-fluorouracil, mitomycin-C, schedule of administration

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Selected References

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  1. Aschele C., Guglielmi A., Frassineti G. L., Milandri C., Amadori D., Labianca R., Vinci M., Tixi L., Caroti C., Ciferri E. Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a multicentric phase II study. Br J Cancer. 1998;77(2):341–346. doi: 10.1038/bjc.1998.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cunningham D., Pyrhönen S., James R. D., Punt C. J., Hickish T. F., Heikkila R., Johannesen T. B., Starkhammar H., Topham C. A., Awad L. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413–1418. doi: 10.1016/S0140-6736(98)02309-5. [DOI] [PubMed] [Google Scholar]
  3. Douillard J. Y., Cunningham D., Roth A. D., Navarro M., James R. D., Karasek P., Jandik P., Iveson T., Carmichael J., Alakl M. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041–1047. doi: 10.1016/s0140-6736(00)02034-1. [DOI] [PubMed] [Google Scholar]
  4. Giacchetti S., Perpoint B., Zidani R., Le Bail N., Faggiuolo R., Focan C., Chollet P., Llory J. F., Letourneau Y., Coudert B. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000 Jan;18(1):136–147. doi: 10.1200/JCO.2000.18.1.136. [DOI] [PubMed] [Google Scholar]
  5. Leichman C. G., Leichman L., Spears C. P., Rosen P. J., Jeffers S., Groshen S. Prolonged continuous infusion of fluorouracil with weekly bolus leucovorin: a phase II study in patients with disseminated colorectal cancer. J Natl Cancer Inst. 1993 Jan 6;85(1):41–44. doi: 10.1093/jnci/85.1.41. [DOI] [PubMed] [Google Scholar]
  6. Maindrault-Goebel F., Louvet C., André T., Carola E., Lotz J. P., Molitor J. L., Garcia M. L., Gilles-Amar V., Izrael V., Krulik M. Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer. 1999 Sep;35(9):1338–1342. doi: 10.1016/s0959-8049(99)00149-5. [DOI] [PubMed] [Google Scholar]
  7. Marsh J. C., Bertino J. R., Katz K. H., Davis C. A., Durivage H. J., Rome L. S., Richards F., 2nd, Capizzi R. L., Farber L. R., Pasquale D. N. The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer. J Clin Oncol. 1991 Mar;9(3):371–380. doi: 10.1200/JCO.1991.9.3.371. [DOI] [PubMed] [Google Scholar]
  8. Ross P., Norman A., Cunningham D., Webb A., Iveson T., Padhani A., Prendiville J., Watson M., Massey A., Popescu R. A prospective randomised trial of protracted venous infusion 5-fluorouracil with or without mitomycin C in advanced colorectal cancer. Ann Oncol. 1997 Oct;8(10):995–1001. doi: 10.1023/a:1008263516099. [DOI] [PubMed] [Google Scholar]
  9. Rougier P., Van Cutsem E., Bajetta E., Niederle N., Possinger K., Labianca R., Navarro M., Morant R., Bleiberg H., Wils J. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1407–1412. doi: 10.1016/S0140-6736(98)03085-2. [DOI] [PubMed] [Google Scholar]
  10. Sobrero A. F., Aschele C., Bertino J. R. Fluorouracil in colorectal cancer--a tale of two drugs: implications for biochemical modulation. J Clin Oncol. 1997 Jan;15(1):368–381. doi: 10.1200/JCO.1997.15.1.368. [DOI] [PubMed] [Google Scholar]
  11. Sobrero A. F., Aschele C., Guglielmi A. P., Mori A. M., Melioli G. G., Rosso R., Bertino J. R. Synergism and lack of cross-resistance between short-term and continuous exposure to fluorouracil in human colon adenocarcinoma cells. J Natl Cancer Inst. 1993 Dec 1;85(23):1937–1944. doi: 10.1093/jnci/85.23.1937. [DOI] [PubMed] [Google Scholar]
  12. Sobrero A. F., Aschele C., Guglielmi A. P., Mori A. M., Tixi L. M., Bolli E. A., Rosso R., Mammoliti S., Rollandi G. A., Bertoglio S. Schedule-selective biochemical modulation of 5-fluorouracil: a phase II study in advanced colorectal cancer. Clin Cancer Res. 1995 Sep;1(9):955–960. [PubMed] [Google Scholar]
  13. Waksal H. W. Role of an anti-epidermal growth factor receptor in treating cancer. Cancer Metastasis Rev. 1999;18(4):427–436. doi: 10.1023/a:1006302101468. [DOI] [PubMed] [Google Scholar]

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