Pharmacokinetic and demographic markers of 5-fluorouracil toxicity in 181 patients on adjuvant therapy for colorectal cancer.
BACKGROUND
The relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied.


METHODS
One hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle.


RESULTS
The 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg x min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade > or =2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg x min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients.


CONCLUSIONS
A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.
Gusella
M
M
Oncology Division, Rovigo General Hospital, Rovigo, Italy. milenagusella@libero.it
Crepaldi
G
G
Barile
C
C
Bononi
A
A
Menon
D
D
Toso
S
S
Scapoli
D
D
Stievano
L
L
Ferrazzi
E
E
Grigoletto
F
F
Ferrari
M
M
Padrini
R
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003710:Demography; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil