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

C. H. Kohne, W. Hiddemann, J. Schuller, J. Weiss, H. P. Lohrmann, U. Schmitz- Hubner, H. Bodenstein, C. Schober, H. Wilke, J. Grem, H. J. Schmoll

Research output: Contribution to journalArticle

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Abstract

Purpose: 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]). Patients and 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 (t( 1/2 )) 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1201-1208
Number of pages8
JournalJournal of Clinical Oncology
Volume13
Issue number5
DOIs
StatePublished - Jan 1 1995

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Dipyridamole
Leucovorin
Fluorouracil
Antineoplastic Agents
Colorectal Neoplasms
Pharmacokinetics
Nucleosides
Headache
Half-Life
Appointments and Schedules
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Kohne, C. H.; Hiddemann, W.; Schuller, J.; Weiss, J.; Lohrmann, H. P.; Schmitz- Hubner, U.; Bodenstein, H.; Schober, C.; Wilke, H.; Grem, J.; Schmoll, H. J.

In: Journal of Clinical Oncology, Vol. 13, No. 5, 01.01.1995, p. 1201-1208.

Research output: Contribution to journalArticle

Kohne, C. H. ; Hiddemann, W. ; Schuller, J. ; Weiss, J. ; Lohrmann, H. P. ; Schmitz- Hubner, U. ; Bodenstein, H. ; Schober, C. ; Wilke, H. ; Grem, J. ; Schmoll, H. J. / 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. In: Journal of Clinical Oncology. 1995 ; Vol. 13, No. 5. pp. 1201-1208.
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abstract = "Purpose: 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]). Patients and 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 (t( 1/2 )) 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. Conclusion: 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.",
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T1 - Failure of orally administered dipyridamole to enhance the antineoplastic activity of fluorouracil in combination with leucovorin in patients with advanced colorectal cancer

T2 - A prospective randomized trial

AU - Kohne, C. H.

AU - Hiddemann, W.

AU - Schuller, J.

AU - Weiss, J.

AU - Lohrmann, H. P.

AU - Schmitz- Hubner, U.

AU - Bodenstein, H.

AU - Schober, C.

AU - Wilke, H.

AU - Grem, J.

AU - Schmoll, H. J.

PY - 1995/1/1

Y1 - 1995/1/1

N2 - Purpose: 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]). Patients and 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 (t( 1/2 )) 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. Conclusion: 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.

AB - Purpose: 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]). Patients and 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 (t( 1/2 )) 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. Conclusion: 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.

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