Share This Article:

Measurements of 5-FU Plasma Concentrations in Patients with Gastrointestinal Cancer: 5-FU Levels Reflect the 5-FU Dose Applied

Abstract Full-Text HTML Download Download as PDF (Size:582KB) PP. 28-36
DOI: 10.4236/jct.2012.31004    5,430 Downloads   10,148 Views   Citations

ABSTRACT

Introduction: 5-Fluorouracil (5-FU) is the basis of most combination chemotherapies for gastrointestinal tumors. It is generally well tolerated, but side-effects might require dose-adjustment. As adverse events are not specific to the 5-FU component of the chemotherapy-combination, i.e. neutropenia, diarrhea or cardiotoxicity, the knowledge of 5-FU serum levels might help to attribute these side effects to the 5-FU compound. The optimal concentration-range (AUC, area under the curve) has been described to be within 20-25 mgh/l. The aim of this study was to analyse the intra- and interindividual variability of 5-FU AUC-levels in patients with 5-FU infusion therapy. Methods: 230 blood samples were obtained from 31 different gastrointestinal cancer patients (esophagus (8), stomach (10), ileum (1), colorectum (12)) treated with 5-FU-infusional regimes, based on a 24- or 48-hour AIO treatment-schedule. 5-FU plasma concentrations were measured using an immunolinked Elisa assay (Saladax 5-FU PCMTM). Intra- and interindividual differences were analysed before (0 h; n = 115), at 2 - 3 hours after the start of infusional 5-FU treatment (n = 19) (early sampling) and towards the end of the infusion (n = 96) (late sampling). Results: Early blood sampling resulted in low 5-FU plasma concentrations (541 ± 127 g/ml) due to saline prefilling (2 - 3 ml) of the Baxter pump. Blood sampling at the later time-point resulted in reproducible values (971 ± 81 ng/ml). 5-FU concentrations were dose-dependent with low intra- and interindividual variability. However, care has to be taken, as the results can be influenced by inaccurate blood sampling: too early or late sampling (when the folfusor-pump is empty), delayed centrifugation of the tube or hemolysis. Conclusions: With critical analysis of the measurements and correct performance of blood sampling, the measurement of 5-FU plasma concentrations with the immunoassay may in the future allow to optimize 5-FU dosing and to identify the cause of toxicity. Changes of 5-FU clearance in long-term therapy still have to be studied.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

M. Blaschke, J. Blumberg, U. Wegner, M. Nischwitz, G. Ramadori and S. Cameron, "Measurements of 5-FU Plasma Concentrations in Patients with Gastrointestinal Cancer: 5-FU Levels Reflect the 5-FU Dose Applied," Journal of Cancer Therapy, Vol. 3 No. 1, 2012, pp. 28-36. doi: 10.4236/jct.2012.31004.

References

[1] B. Ardalan, L. Chua, E. M. Tian, R. Reddy, K. Sridhar, P. Benedetto, et al., “A Phase II Study of Weekly 24-Hour Infusion with High-Dose Fluorouracil with Leucovorin in Colorectal Carcinoma,” Journal of Clinical Oncology, Vol. 9, No. 4, 1991, pp. 625-630.
[2] C. H. Kohne, J. Wils, M. Lorenz, P. Schoffski, R. Voigtmann, C. Bokemeyer, et al., “Randomized Phase III Study of High-Dose Fluorouracil Given as a Weekly 24-Hour Infusion with or without Leucovorin versus Bolus Fluorouracil Plus Leucovorin in Advanced Colorectal Cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952,” Journal of Clinical Oncology, Vol. 21, No. 20, 2003, pp. 3721-3728. doi:10.1200/JCO.2003.11.122
[3] A. de Gramont, A. Figer, M. Seymour, M. Homerin, A. Hmissi, J. Cassidy, et al., “Leucovorin and Fluorouracil with or without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer,” Journal of Clinical Oncology, Vol. 18, No. 16, 2000, pp. 2938-2947.
[4] F. Maindrault-Goebel, C. Louvet, T. Andre, E. Carola, J. P. Lotz, J. L. Molitor, et al., “Oxaliplatin Added to the Simplified Bimonthly Leucovorin and 5-Fluorouracil Regimen as Second-Line Therapy for Metastatic Colorectal Cancer (FOLFOX6). GERCOR,” European Journal of Cancer, Vol. 35, No. 9, 1999, pp. 1338-1342. doi:10.1016/S0959-8049(99)00149-5
[5] I. P. Popov, S. B. Jelic, M. M. Matijasevic, B. Grbic and D. R. Babic, “Mayo Regimen plus Three Different Second-Line Chemotherapy Regimens in Sequential Therapy in Patients with Advanced Colorectal Cancer (ACRC). Journal of Experimental & Clinical Cancer Research, Vol. 23, No. 3, 2004, pp. 395-401.
[6] A. Tomiak, M. Vincent, W. Kocha, M. Taylor, E. Winquist, B. Keith, et al., “Standard Dose (Mayo Regimen) 5-Fluorouracil and Low Dose Folinic Acid: Prohibitive Toxicity?” Amrican Journal of Clinical Oncology, Vol. 23, No. 1, 2000, pp. 94-98. doi:10.1097/00000421-200002000-00025
[7] D. Machover, E. Goldschmidt, P. Chollet, G. Metzger, J. Zittoun, J. Marquet, et al., “Treatment of Advanced Colorectal and Gastric Adenocarcinomas with 5-Fluorouracil and High-Dose Folinic Acid,” Journal of Clinical Oncology, Vol. 4, No. 5, 1986, pp. 685-696.
[8] C. Louvet, T. Andre, J. M. Tigaud, E. Gamelin, J. Y. Douillard, R. Brunet, et al., “Phase II Study of Oxaliplatin, Fluorouracil, and Folinic Acid in Locally Advanced or Metastatic Gastric Cancer Patients,” Journal of Clinical Oncology, Vol. 20, No. 23, 2002, pp. 4543-4548. doi:10.1200/JCO.2002.02.021
[9] F. Maindrault-Goebel, G. A. de, C. Louvet, T. Andre, E. Carola, M. Mabro, P. Artru, et al., “High-Dose Intensity Oxaliplatin Added to the Simplified Bimonthly Leucovorin and 5-Fluorouracil Regimen as Second-Line Therapy for Metastatic Colorectal Cancer (FOLFOX 7),” European Journal of Cancer, Vol. 37, No. 8, 2001, pp. 1000-1005. doi:10.1016/S0959-8049(01)00068-5
[10] D. Cunningham, S. Falk and D. Jackson, “Clinical and Economic Benefits of Irinotecan in Combination with 5-Fluorouracil and Folinic Acid as First Line Treatment of Metastatic Colorectal Cancer,” British Journal of Cancer, Vol. 86, No. 11, 2002, pp. 1677-1683. doi:10.1038/sj.bjc.6600204
[11] J. Y. Douillard, D. Cunningham, A. D. Roth, M. Navarro, R. D. James, P. Karasek, et al., “Irinotecan Combined with Fluorouracil Compared with Fluorouracil Alone as First-Line Treatment for Metastatic Colorectal Cancer: A Multicentre Randomised Trial,” Lancet, Vol. 355, No. 9209, 2000, pp. 1041-1047. doi:10.1016/S0140-6736(00)02034-1
[12] A. Falcone, S. Ricci, I. Brunetti, E. Pfanner, G. Allegrini, C. Barbara, et al., “Phase III trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared with Infusional Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) as First-Line Treatment for Metastatic Colorectal Cancer: The Gruppo Oncologico Nord Ovest,” Journal of Clinical Oncology, Vol. 25, No. 13, 2007, pp. 1670-1676. doi:10.1200/JCO.2006.09.0928
[13] P. Rougier, C. E. Van, E. Bajetta, N. Niederle, K. Possinger, R. Labianca, et al., “Randomised Trial of Irinotecan versus Fluorouracil by Continuous Infusion after Fluorouracil Failure in patients with Metastatic Colorectal Cancer,” Lancet, Vol. 352, No. 9138, 1998, pp. 1407-1412. doi:10.1016/S0140-6736(98)03085-2
[14] L. B. Saltz, J. V. Cox, C. Blanke, L. S. Rosen, L. Fehrenbacher, M. J. Moore, et al., “Irinotecan plus Fluorouracil and Leucovorin for Metastatic Colorectal Cancer,” The New England Journla of Medicine, Vol. 343, No. 13, 2000, pp. 905-914. doi:10.1056/NEJM200009283431302
[15] M. K. Ma and H. L. McLeod,, “Lessons learned from the irinotecan metabolic pathway,” Curr.Med.Chem., Vol. 10, No. 1, 2003, pp. 41-49. doi:10.2174/0929867033368619
[16] M. A. Jordan and L. Wilson, “Microtubules as a Target for Anticancer Drugs,” Nature Reviews Cancer, Vol. 4, No. 4, 2004, pp. 253-265. doi:10.1038/nrc1317
[17] S. Spadari, G. Pedrali-Noy, F. Focher, A. Montecucco, T. Bordoni, C. Geroni, et al., “DNA Polymerases and DNA Topoisomerases as Targets for the Development of Anti-cancer Drugs,” Anticancer Research, Vol. 6, No. 5, 1986, pp. 935-940.
[18] J. Bertino, M. Fleisher, J. H. Beumer, E. Chu, A. diPaolo, C. Eng, et al., “Highlights from: 5-Fluorouracil Drug Management Pharmacokinetics and Pharmacogenomics Work-shop; Orlando, Florida; January 2007,” Clinical Colorectal Cancer, Vol. 6, No. 6, 2007, pp. 407-422. doi:10.1016/S1533-0028(11)70480-7
[19] E. Gamelin, R. Delva, J. Jacob, Y. Merrouche, J. L. Raoul, D. Pezet, et al., “Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-Up Compared with Conventional Dosage: Results of a Multicenter Randomized Trial of Patients with Metastatic Colorectal Cancer,” Journal of Clinical Oncology, Vol. 26, No. 13, 2008, pp. 2099-2105. doi:10.1200/JCO.2007.13.3934
[20] O. Capitain, M. Boisdron-Celle, A. L. Poirier, S. Abadie-Lacourtoisie, A. Morel and E. Gamelin,, “The Influence of Fluorouracil Outcome Parameters on Tolerance and Efficacy in Patients with Advanced Colorectal Cancer,” The Pharmacogenomics Journal, Vol. 8, No. 4, 2008, pp. 256-267. doi:10.1038/sj.tpj.6500476
[21] E. Bandres, R. Zarate, N. Ramirez, A. Abajo, N. Bitarte and J. Gariia-Foncillas, “Pharmacogenomics in Colorectal Cancer: The First Step for Individualized-Therapy,” World Journal of Gastroenterology, Vol. 13, No. 44, 2007, pp. 5888-5901.
[22] A. Beck, M. C. Etienne, S. Cheradame, J. L. Fischel, P. Formento, N. Renee, et al., “A Role for Dihydropyrimidine Dehydrogenase and Thymidylate Synthase in Tumour Sensitivity to Fluorouracil,” European Journal of Cancer, Vol. 30, No. 10, 1994, pp. 1517-1522. doi:10.1016/0959-8049(94)00216-R
[23] G. Bocci, C. Barbara, F. Vannozzi, P. A. Di, A. Melosi, G. Barsanti, et al., “A Pharmacokinetic-Based Test to Prevent Severe 5-Fluorouracil Toxicity,” Clinical Pharmacology & Therapeutics, Vol. 80, No. 4, 2006, pp. 384-395. doi:10.1016/j.clpt.2006.06.007
[24] B. E. Harris, J. T. Carpenter and R. B. Diasio, “Severe 5-Fluorouracil Toxicity Secondary to Dihydropyrimidine Dehydrogenase Deficiency. A Potentially More Common Pharmacogenetic Syndrome,” Cancer, Vol. 68, No. 3, 1991, pp. 499-501. doi:10.1002/1097-0142(19910801)68:3<499::AID-CNCR2820680309>3.0.CO;2-F
[25] H. Bleiberg, N. Kemeny, P. Rougier and H. Wilke, “Colorectal Cancer: A Clinical Guide to Therapy,” Martin Dunitz, London, 2002, pp. 419-429.
[26] C. Erlichman, S. Fine and T. Elhakim, “Plasma Pharmacokinetics of 5-FU Given by Continuous Infusion with Allopurinol,” Cancer Treatment Reports, Vol. 70, No. 7, 1986, pp. 903-904.
[27] M. Kawai, J. Rosenfeld, P. McCulloch and B. L. Hillcoat, “Letter: Blood Levels of 5-Fluorouracil during Intravenous Infusion,” British Journal of Cancer, Vol. 33, No. 3, 1976, pp. 346-347. doi:10.1038/bjc.1976.51
[28] J. G. Wagner, J. W. Gyves, P. L. Stetson, S. C. Walker-Andrews, I. S. Wollner, M. K. Cochran et al., “Steady-State Nonlinear Pharmacokinetics of 5-Fluorouracil during Hepatic Arterial and Intravenous Infusions in Cancer Patients,” Cancer Resarch, Vol. 46, No. 3, 1986, pp. 1499-1506.
[29] P. A. Di, M. Lencioni, F. Amatori, D. S. Di, G. Bocci, C. Orlandini, et al., “5-Fluorouracil Pharmacokinetics Predicts Disease-Free Survival in Patients Administered Adjuvant Chemotherapy for Colorectal Cancer,” Clin Cancer Resarch, Vol. 14, No. 9, 2008, pp. 2749-2755. doi:10.1158/1078-0432.CCR-07-1529
[30] B. L. Hillcoat, P. B. McCulloch, A. T. Figueredo, M. H. Ehsan and J. M. Rosenfeld, “Clinical Response and Plasma Levels of 5-Fluorouracil in Patients with Colonic Cancer Treated by Drug Infusion,” British Journal of Cancer, Vol. 38, No. 6, 1978, pp. 719-724. doi:10.1038/bjc.1978.278
[31] D. I. Jodrell, M. Stewart, R. Aird, G. Knowles, A. Bowman, L. Wall et al., “5-fluorouracil Steady State Pharmacokinetics and Outcome in Patients Receiving Protracted venous Infusion for Advanced Colorectal Cancer,” British Journal of Cancer, Vol. 84, No. 5, 2001, pp. 600-603. doi:10.1054/bjoc.2000.1664
[32] E. Gamelin and M. Boisdron-Celle, “Dose Monitoring of 5-Fluorouracil in Patients with Colorectal or Head and Neck Cancer—Status of the Art,” Critical Reviews in Oncology/Hematology, Vol. 30, No. 1, 1999, pp. 71-79. doi:10.1016/S1040-8428(98)00036-5
[33] G. Milano, M. C. Etienne, E. Cassuto-Viguier, A. Thyss, J. Santini, M. Frenay, et al., “Influence of Sex and Age on Fluorouracil Clearance,” Journal of Clinical Oncology, Vol. 10, No. 7, 1992, pp. 1171-1175.
[34] M. W. Saif, A. Choma, S. J. Salamone and E. Chu, “Pharmacokinetically Guided Dose Adjustment of 5-Fluorouracil: A Rational Approach to Improving Therapeutic Outcomes,” Jouranl of the National Cancer Institure, Vol. 101, No. 22, 2009, pp. 1543-1552. doi:10.1093/jnci/djp328
[35] J. H. Beumer, M. Boisdron-Celle, W. Clarke, J. B. Courtney, M. J. Egorin, E. Gamelin, et al., “Multicenter Evaluation of a Novel Nanoparticle Immunoassay for 5-Fluorouracil on the Olympus AU400 Analyzer,” Therapeutic Drug Monitoring, Vol. 31, No. 6, 2009, pp. 688-694.
[36] M. Ychou, W. Hohenberger, S. Thezenas, M. Navarro, J. Maurel, C. Bokemeyer, et al., “A Randomized Phase III Study Comparing Adjuvant 5-Fluorouracil/Folinic Acid with FOLFIRI In Patients Following Complete Resection of Liver Metastases from Colorectal Cancer,” Annuls of Oncology, Vol. 20, No. 12, 2009, pp. 1964-1970. doi:10.1093/annonc/mdp236
[37] E. Gamelin, M. Bosdron-Celle, V. Guerin-Meyer, A. Poirier, V. Berger and A. Morel, “5-FU Dose Monitoring and Prevention of Oxaliplatin-Induced Neurotoxicity in FOLFOX 4 Regimen: Results of a Phase II Study,” Proceedings of American Society of Clinical Oncology, Chicago, 30 May-3 June 2008.
[38] E. Gamelin, O. Capitain, A. Morel, D. Luet, V. Guierin-Meyer and M. Boisdron-Celle, “Comparison of Two Patient Cohorts Treated in Parallel for Advanced Colorectal Cancer with a Simplified FOLFOX 4 Regimen with or without 5-FU Therapeutic Dose Management,” Proceedings of American Society of Clinical Oncology, Orlando, 29 May-2 June 2009.
[39] J. L. Grem, N. McAtee, S. M. Steinberg, J. M. Hamilton, R. F. Murphy, J. Drake, et al., “A Phase I Study of Continuous Infusion 5-Fluorouracil plus Calcium Leucovorin in Combination with N-(phosphonacetyl)-L-aspartate in Metastatic Gastrointestinal Adenocarcinoma,” Cancer Research, Vol. 53, No. 20, 1993, pp. 4828-4836.
[40] J. M. Kirkwood, W. Ensminger, A. Rosowsky, N. Papathanasopoulos and E. Frei III, “Comparison of Pharmacokinetics of 5-Fluorouracil and 5-Fluorouracil with Concurrent Thymidine Infusions in a Phase I Trial,” Cancer Resaerch, Vol. 40, No. 1, 1980, pp. 107-113.
[41] M. Ychou, J. Duffour, A. Kramar, C. Debrigode, S. Gourgou, F. Bressolle, et al., “Individual 5-FU Dose Adaptation in Metastatic Colorectal Cancer: Results of a Phase II Study Using a Bimonthly Pharmacokinetically Intensified LV5FU2 Regimen,” Cancer Chemotherapy and Pharmacology, Vol. 52, No. 4, 2003, pp. 282-290. doi:10.1093/annonc/mdp236
[42] M. Blaschke, S. Cameron, K. Emami, J. Blumberg, U. Wegner, M. Nischwitz et al., “Measurement of 5-FU Plasma Levels in Patients with Advanced Cancer: Correct Approach to Practical Procedures Is Essential,” International Journal of Clinical Pharmacology, Therapy, Vol. 49, No. 1, 2011, pp. 83-85.
[43] J. Saam, G. C. Critchfield, S. A. Hamilton, B. B. Roa, R. J. Wenstrup and R. R. Kaldate, “Body Surface Area-Based Dosing of 5-Fluoruracil Results in Extensive Interindividual Variability in 5-Fluorouracil Exposure in Colorectal Cancer Patients on FOLFOX Regimens,” Clinical Colorectal Cancer, Vol. 10, No. 3, 2011, pp. 203-206. doi:10.1016/j.clcc.2011.03.015
[44] C. M. Walko and H. L. McLeod, “Will We Ever Be Ready for Blood Level-Guided Therapy?” Journal of Clinical Oncology, Vol. 26, No. 13, 2008, pp. 2078-2079. doi:10.1200/JCO.2007.14.9609
[45] D. L. Trump, M. J. Egorin, A. Forrest, J. K. Willson, S. Remick and K. D. Tutsch, “Pharmacokinetic and Pharmacodynamic Analysis of Fluorouracil during 72-Hour Continuous Infusion with and without Dipyridamole,” Journal of Clinical Oncology, Vol. 9, No. 11, 1991, pp. 2027-2035.
[46] J. L. Grem, L. K. Yee, B. Schuler, J. M. Hamilton, A. P. Chen, C. Chabuk, et al., “N-(phosphonacetyl)-L-aspartate and Calcium Leucovorin Modulation of Fluorouracil Administered by Constant Rate and circadian Pattern of Infusion over 72 Hours in Metastatic Gastrointestinal Adenocarcinoma,” Annals of Oncology, Vol. 12, No. 11, 2001, pp. 1581-1587. doi:10.1023/A:1013185125186
[47] M. Ducreux, D. Malka, J. Mendiboure, P. L. Etienne, P. Texereau, D. Auby, et al., “Sequential versus Combination Chemotherapy for the Treatment of Advanced Colorectal Cancer (FFCD 2000-05): An Open-Label, Randomised, Phase 3 Trial,” The Lancet Oncology, Vol. 12, No. 11, 2011, pp. 1032-1044. doi:10.1016/S1470-2045(11)70199-1
[48] M. Koopman, N. F. Antonini, J. Douma, J. Wals, A. H. Honkoop, F. L. Erdkamp, et al., “Sequential versus Combination Chemotherapy with Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer (CAIRO): A Phase III Randomised Controlled Trial,” Lancet, Vol. 370, No. 9582, 2007, pp. 135-142. doi:10.1016/S0140-6736(07)61086-1
[49] M. Seymour, “Sequential Chemotherapy for Colorectal Cancer,” The Lancet Oncology, Vol. 12, No. 11, 2011, pp. 987-988. doi:10.1016/S1470-2045(11)70233-9
[50] M. T. Seymour and C. J. A. Punt, “Sequential Chemotherapy for Advanced Colorectal Cancer: Should We Ever Start with a Sincgle Cytotoxic Agent?” Current Colorectal Cancer Reports, Vol. 4, No. 3, 2009, pp. 130-138. doi:10.1007/s11888-008-0022-1

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.