Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer: Pharmacology, toxicity, and response

C. Benz, M. DeGregorio, S. Saks, N. Sambol, W. Holleran, R. Ignoffo, B. Lewis, E. Cadman

Research output: Contribution to journalArticle

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Abstract

Preclinical studies have suggested that synergistic antitumor toxicity occurs when methotrexate (MTX) is administered prior to 5-fluorouracil (FUra). A protocol of sequenced, overlapping infusions of MTX and FUra was designed to achieve 5 μM MTX serum levels lasting 36 h and 1 to 5 μM FUra levels lasting 24 h, with leucovorin started at the end of the MTX infusion. Thirty-nine patients with metastatic neoplasms received a total of 127 treatment courses; two-thirds of the patients had received prior treatment with radiation therapy or chemotherapy; most of the latter treatment regimens included MTX or FUra. In three patients, the duration of FUra infusion was prolonged up to 72 h to determine the toxic limits of therapy. Blood samples were collected during treatment courses to estimate the half-lives and total-body clearances of MTX and FUra. The initial serum half-lives and total-body clearances of both MTX and FUra appeared within the range of reported normal values. The terminal half-life of MTX appeared less than previously reported values, and there appeared to be a substantial delay in achieving a FUra steady-state concentration; these two differences may have resulted from either the prolonged intervals of drug infusion or from metabolic interaction between the two drugs. During the 127 courses of treatment, nearly one-half of the patients experienced mild toxicity occurring after at least one treatment, but this toxicity was predominantly Grade I mucositis and/or diarrhea. Of the three patients who received extended intervals of FUra infusion, none was able to tolerate more than 48 h of FUra without developing mucositis. Thirty-four patients were evaluable for response; no one experienced a complete response, but 11 (32%) patients had either a partial or minimal response. Adenocarcinomas as a group, arising from the lung, gut, breast, and unknown site, appeared to respond best. Sequenced MTX-FUra infusion by this schedule is a generally well-tolerated regimen that deserves further clinical assessment.

Original languageEnglish (US)
Pages (from-to)3354-3358
Number of pages5
JournalCancer Research
Volume45
Issue number7
StatePublished - 1985

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Methotrexate
Fluorouracil
Pharmacology
Neoplasms
Mucositis
Therapeutics
Leucovorin
Poisons
Serum
Pharmaceutical Preparations
Half-Life
Diarrhea
Appointments and Schedules
Reference Values
Adenocarcinoma
Breast
Radiotherapy
Drug Therapy
Lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Benz, C., DeGregorio, M., Saks, S., Sambol, N., Holleran, W., Ignoffo, R., ... Cadman, E. (1985). Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer: Pharmacology, toxicity, and response. Cancer Research, 45(7), 3354-3358.

Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer : Pharmacology, toxicity, and response. / Benz, C.; DeGregorio, M.; Saks, S.; Sambol, N.; Holleran, W.; Ignoffo, R.; Lewis, B.; Cadman, E.

In: Cancer Research, Vol. 45, No. 7, 1985, p. 3354-3358.

Research output: Contribution to journalArticle

Benz, C, DeGregorio, M, Saks, S, Sambol, N, Holleran, W, Ignoffo, R, Lewis, B & Cadman, E 1985, 'Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer: Pharmacology, toxicity, and response', Cancer Research, vol. 45, no. 7, pp. 3354-3358.
Benz C, DeGregorio M, Saks S, Sambol N, Holleran W, Ignoffo R et al. Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer: Pharmacology, toxicity, and response. Cancer Research. 1985;45(7):3354-3358.
Benz, C. ; DeGregorio, M. ; Saks, S. ; Sambol, N. ; Holleran, W. ; Ignoffo, R. ; Lewis, B. ; Cadman, E. / Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer : Pharmacology, toxicity, and response. In: Cancer Research. 1985 ; Vol. 45, No. 7. pp. 3354-3358.
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