SEQUENTIAL INFUSION OF METHOTREXATE AND 5-FLUOROURACIL IN ADVANCED CANCER - PHARMACOLOGY, TOXICITY, AND RESPONSE

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  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (7) , 3354-3358
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 .mu.M MTX serum levels lasting 36 h and 1-5 .mu.M 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; 2/3 of the patients had received prior treatment with radiation therapy or chemotherapy; most of the latter treatment regimens included MTX or FUra. In 3 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 2 differences may have resulted from either the prolonged intervals of drug infusion or from metabolic interaction between the 2 drugs. During the 127 courses of treatment, nearly 1/2 of the patients experienced mild toxicity occurring after at least 1 treatment, but this toxicity was predominantly Grade I mucositis and/or diarrhea. Of the 3 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. Squenced MTX-FUra infusion by this schedule is a generally well-tolerated regimen that deserves further clinical assessment.