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Relationship between 5‐fluorouracil (5‐FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5‐FU
Author(s) -
Gamelin Erick C.,
DanquechinDorval Etienne M.,
Dumesnil Yvan F.,
Maillart Philippe J.,
Goudier M. J.,
Burtin Pascal C.,
Delva Remy G.,
Lortholary Alain H.,
Gesta Paul H.,
Larra Francis G.
Publication year - 1996
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/(sici)1097-0142(19960201)77:3<441::aid-cncr4>3.0.co;2-n
Subject(s) - medicine , fluorouracil , toxicity , pharmacokinetics , colorectal cancer , gastroenterology , prospective cohort study , chemotherapy , oncology , cancer , pharmacology
BACKGROUND A phase II prospective trial was carried out to study the concept of 5‐fluorouracil (5‐FU) dose‐intensity in patients with advanced colorectal cancer. Forty patients were treated with 5‐FU plus leucovorin (LV), with individually increasing doses of 5‐FU. A 5‐FU pharmacokinetic follow up was performed and a relationship was sought between its metabolism and its response to treatment, and between 5‐FU's toxicity and patient survival. METHODS 5‐FU was administered weekly by 8 hour continuous infusion. The initial dose of 1000 mg/m 2 was individually increased every 3 weeks by 250 mg/m 2 steps, potentiated by 400 mg/m 2 LV. 5‐FU plasma concentrations were determined weekly by liquid chromatography. RESULTS Eighteen overall objective responses and 22 minor responses, stabilizations, or progressions (NR) were observed. 5‐FU plasma levels were significantly higher in cases of complete or partial response, whatever the dose. They reached about 2000 μg/l as early as the second dose level (1250 mg/m 2 ). Only seven patients who experienced NR reached equivalent levels after the fourth step (1750 mg/m 2 ). High 5‐FU plasma levels were predictive of an objective response and better survival (difference not significant). The acute toxicity, whatever the type, was correlated with 5‐FU levels >3000 μg/l and not with the dose. CONCLUSIONS This study shows the wide variability of 5‐FU metabolism, whatever the dose, the clear relationship between 5‐FU plasma levels, toxicity, and efficacy. This relationship points out the problem of the polymorphism of 5‐FU metabolism, the usefulness of the therapeutic range determination and the usefulness of the individual 5‐FU dose adaptation. Cancer 1996;77:441‐51.