A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

O'Byrne, Kenneth J., Philip, P. A., Propper, D. J., Braybrooke, J. P., Saunders, M. P., Bates, N. P., Taylor, M. A., Madigan, D., Ganesan, T. S., Talbot, D. C., & Harris, A. L. (1999) A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma. Annals of Oncology, 10(8), pp. 981-983.

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Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU.

Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours.

Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another.

Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

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ID Code: 65289
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after 12 months
Additional URLs:
Keywords: 5-fluorouracil, Chemotherapy, Colorectal cancer, Folinic acid, Hydroxyurea, Modulation, deoxyribonucleotide, DNA, floxuridine phosphate, fluorouracil, ribonucleotide reductase, adult, aged, anemia, article, bolus injection, cancer combination chemotherapy, cancer survival, clinical article, clinical trial, colorectal carcinoma, continuous infusion, diarrhea, dose calculation, drug megadose, female, human, intravenous drug administration, male, metastasis, neutropenia, phase 2 clinical trial, priority journal, treatment outcome, treatment planning, Adenocarcinoma, Antineoplastic Combined Chemotherapy Protocols, Colorectal Neoplasms, Disease-Free Survival, Dose-Response Relationship, Drug, Humans, Infusions, Intravenous, Leucovorin, Middle Aged, Nucleic Acid Synthesis Inhibitors, Prognosis, Survival Rate
DOI: 10.1023/A:1008330302535
ISSN: 0923-7534
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 1999 Oxford University Press
Deposited On: 11 Dec 2013 02:18
Last Modified: 27 Jan 2015 04:48

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