5-FU split dose; a phase I/II and pharmacokinetic study of a different schedule of the Nordic regimen in advanced colorectal carcinoma.
OBJECTIVE
Despite more than four decades of fluoro-pyrimidine treatment in different cancers, the optimal schedule is still not known. The plasma half-life of 5-fluorouracil (5-FU) is extremely short and continuous infusion has gained popularity. In this study we explored whether repeated bolus 5-FU injections could improve the results.


METHODS
Forty-three patients with advanced gastrointestinal carcinoma, where no standard treatment was available, were included in the phase I study. The initial dose of 5-FU was 250 mg/m2 with 30 mg/m2 leucovorin, repeated three hours later. Treatments were repeated every week. Twenty-six patients were recruited in the following phase II after maximal-tolerated dose (MTD) was reached. Plasma was collected for 5-FU pharmacokinetics.


RESULTS
Diarrhoea was the dose-limiting toxicity (DLT), and was reached at 450 mg/m2. One complete and three partial responses (24%) were seen in the phase II study at 400 mg/m2. In addition, several patients had lasting subjective improvements. The treatments were well-tolerated but accumulated toxicity was seen after several months. Dose intensity was 89% after four months of treatment. A great interpatient variability was seen in 5-FU pharmacokinetics. The plasma AUC correlated with the 5-FU dose and toxicity, but not with the tumour response.


CONCLUSIONS
A split of the 5-FU push bolus injection is possible with maintained treatment activity and surprisingly high doses can be tolerated; a weekly dose intensity of 800 mg/m2 could be reached compared with 500 mg/m2 in the standard Nordic FLv schedule.
Berglund
Ake
A
Department of Oncology, Radiology and Clinical Immunology, University of Uppsala, Akademiska Sjukhuset, Uppsala, Sweden. ake.berglund@onkologi.uu.se
Carlsson
Göran
G
Gustavsson
Bengt
B
Frödin
Jan-Erik
JE
Ragnhammar
Peter
P
Glimelius
Bengt
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil