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. 2001 Mar;84(5):600–603. doi: 10.1054/bjoc.2000.1664

5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer

D I Jodrell 1, M Stewart 1, R Aird 1, G Knowles 1, A Bowman 2, L Wall 1, J Cummings, C McLean 2
PMCID: PMC2363784  PMID: 11237378

Abstract

PVI 5FU gives increased response rates and reduced toxicity when compared to bolus 5FU (J Clin Oncol 1989, 425–432). PVI 5FU administration was reported to give highly variable (>1000-fold) plasma 5FU concentrations at steady state (FU Css) which correlated with toxicity (Ann Oncol 1996, 47–53); but only 19 patients were studied. Therefore, we performed a study of PVI 5FU in 61 patients with advanced colorectal cancer to assess the variability (inter- and intra-subject) in 5FU Css associated with PVI 5FU (300 mg m−2day−1) and to attempt to correlate pharmacodynamic end-points (anti-tumour activity, toxicity) with 5FU Css as a prelude to ‘exposure-guided’ 5FU administration. All 5FU sampling was performed between 10 am and noon. PVI 5FU administration continued to 26 weeks in patients with disease improvement or stabilization. The response rate was 26% (33% stable disease) and median survival was 11 months. Hand–foot syndrome was the most common dose limiting toxicity. Variability in 5FU 300 Css was considerably less than previously reported; 94 ± 25 ng ml−1(CV = 27%). No relationships were demonstrated between subject mean 5FU 300 Css and PD end-points such as response, mucositis, diarrhoea and hand–foot syndrome. The lack of correlation suggests that measurement of 5FU concentrations should not be used to individualize dosing in patients receiving PVI 5FU for advanced colorectal cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: protracted infusion 5FU, 5FU pharmacokinetics, colorectal cancer

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Selected References

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  1. Diasio R. B., Lu Z. Dihydropyrimidine dehydrogenase activity and fluorouracil chemotherapy. J Clin Oncol. 1994 Nov;12(11):2239–2242. doi: 10.1200/JCO.1994.12.11.2239. [DOI] [PubMed] [Google Scholar]
  2. Etienne M. C., Milano G., Lagrange J. L., Bajard F., François E., Thyss A., Schneider M., Renée N., Fety R. Marked fluctuations in drug plasma concentrations caused by use of portable pumps for fluorouracil continuous infusion. J Natl Cancer Inst. 1993 Jun 16;85(12):1005–1007. doi: 10.1093/jnci/85.12.1005. [DOI] [PubMed] [Google Scholar]
  3. Findlay M. P., Raynaud F., Cunningham D., Iveson A., Collins D. J., Leach M. O. Measurement of plasma 5-fluorouracil by high-performance liquid chromatography with comparison of results to tissue drug levels observed using in vivo 19F magnetic resonance spectroscopy in patients on a protracted venous infusion with or without interferon-alpha. Ann Oncol. 1996 Jan;7(1):47–53. doi: 10.1093/oxfordjournals.annonc.a010476. [DOI] [PubMed] [Google Scholar]
  4. Fleming R. A., Milano G., Thyss A., Etienne M. C., Renée N., Schneider M., Demard F. Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res. 1992 May 15;52(10):2899–2902. [PubMed] [Google Scholar]
  5. Gamelin E., Boisdron-Celle M., Delva R., Regimbeau C., Cailleux P. E., Alleaume C., Maillet M. L., Goudier M. J., Sire M., Person-Joly M. C. Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients. J Clin Oncol. 1998 Apr;16(4):1470–1478. doi: 10.1200/JCO.1998.16.4.1470. [DOI] [PubMed] [Google Scholar]
  6. Harris B. E., Carpenter J. T., Diasio R. B. Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome. Cancer. 1991 Aug 1;68(3):499–501. doi: 10.1002/1097-0142(19910801)68:3<499::aid-cncr2820680309>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  7. Harris B. E., Song R., Soong S. J., Diasio R. B. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res. 1990 Jan 1;50(1):197–201. [PubMed] [Google Scholar]
  8. Lokich J. J., Ahlgren J. D., Gullo J. J., Philips J. A., Fryer J. G. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989 Apr;7(4):425–432. doi: 10.1200/JCO.1989.7.4.425. [DOI] [PubMed] [Google Scholar]
  9. Lu Z., Zhang R., Diasio R. B. Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res. 1993 Nov 15;53(22):5433–5438. [PubMed] [Google Scholar]
  10. McMurrough J., McLeod H. L. Analysis of the dihydropyrimidine dehydrogenase polymorphism in a British population. Br J Clin Pharmacol. 1996 May;41(5):425–427. doi: 10.1046/j.1365-2125.1996.34212.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Santini J., Milano G., Thyss A., Renee N., Viens P., Ayela P., Schneider M., Demard F. 5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer. Br J Cancer. 1989 Feb;59(2):287–290. doi: 10.1038/bjc.1989.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Seymour M. T., Patel N., Johnston A., Joel S. P., Slevin M. L. Lack of effect of interferon alpha 2a upon fluorouracil pharmacokinetics. Br J Cancer. 1994 Oct;70(4):724–728. doi: 10.1038/bjc.1994.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Vokes E. E., Mick R., Kies M. S., Dolan M. E., Malone D., Athanasiadis I., Haraf D. J., Kozloff M., Weichselbaum R. R., Ratain M. J. Pharmacodynamics of fluorouracil-based induction chemotherapy in advanced head and neck cancer. J Clin Oncol. 1996 May;14(5):1663–1671. doi: 10.1200/JCO.1996.14.5.1663. [DOI] [PubMed] [Google Scholar]

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