Failure of orally administered dipyridamole to enhance the antineoplastic activity of fluorouracil in combination with leucovorin in patients with advanced colorectal cancer: a prospective randomized trial.
OBJECTIVE
A randomized trial was performed to investigate the ability of the nucleoside transport inhibitor dipyridamole (DP) to enhance the antitumor activity of fluorouracil (5-FU)/leucovorin (folinic acid [FA]).


METHODS
One hundred eighty-one untreated patients with advanced colorectal cancer were randomized to receive 5-FU 600 mg/m2 plus FA 300 mg/m2 on days 2 to 4 with or without DP 75 mg orally three times daily on days 1 to 5. Cycles were repeated every 3 weeks. Only patients with documented tumor progression before therapy were eligible. 5-FU pharmacokinetics using high-performance liquid chromatography (HPLC) were assessed in 11 nonrandomized patients receiving paired cycles with or without DP.


RESULTS
One hundred seventy-four patients were assessable for toxicity and response. There was no significant difference in toxicity, except DP-related headache in 24% of patients. An objective response rate of 15% (one complete response [CR] and 13 partial responses [PRs]) for 5-FU/FA and 13% (two CRs and nine PRs) for 5-FU/FA/DP was observed. The dose-intensity of 5-FU delivered was significantly higher (1.09- to 1.16-fold) for the DP-containing arm. Pharmacokinetic parameters of 5-FU did not differ significantly, except for a prolonged half-life (t1/2) induced by DP. The median time to progression (P = .8) and the median survival time (11.6 months for 5-FU/FA v 9.3 months for 5-FU/FA/DP; P = .14, log-rank test) were not different between treatment arms.


CONCLUSIONS
Orally administered DP did not improve the antineoplastic activity of 5-FU/FA in patients with advanced colorectal cancer when used at this dose and schedule. The observed increase in 5-FU dose-intensity for FU/FA/DP was not clinically relevant.
Köhne
C H
CH
Department of Hematology/Oncology, Hannover Medical School, Germany.
Hiddemann
W
W
Schüller
J
J
Weiss
J
J
Lohrmann
H P
HP
Schmitz-Hübner
U
U
Bodenstein
H
H
Schöber
C
C
Wilke
H
H
Grem
J
J
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D004176:Dipyridamole / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006261:Headache / Q000139:chemically induced; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
D004176:Dipyridamole; D002955:Leucovorin; D005472:Fluorouracil