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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Is monitoring of plasma 5-fluorouracil levels in metastatic / advanced colorectal cancer clinically effective? A systematic review

Authors: Karoline Freeman, Mark P. Saunders, Olalekan A. Uthman, Sian Taylor-Phillips, Martin Connock, Rachel Court, Tara Gurung, Paul Sutcliffe, Aileen Clarke

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Pharmacokinetic guided dosing of 5-fluorouracil chemotherapies to bring plasma 5-fluorouracil into a desired therapeutic range may lead to fewer side effects and better patient outcomes. High performance liquid chromatography and a high throughput nanoparticle immunoassay (My5-FU) have been used in conjunction with treatment algorithms to guide dosing. The objective of this study was to assess accuracy, clinical effectiveness and safety of plasma 5-fluorouracil guided dose regimen(s) versus standard regimens based on body surface area in colorectal cancer.

Methods

We undertook a systematic review. MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; Cochrane Library; Science Citation Index and Conference Proceedings (Web of Science); and NIHR Health Technology Assessment Programme were searched from inception to January 2014. We reviewed evidence on accuracy of My5-FU for estimating plasma 5-fluorouracil and on the clinical effectiveness of pharmacokinetic dosing compared to body surface area dosing. Estimates of individual patient data for overall survival and progression-free survival were reconstructed from published studies. Survival and adverse events data were synthesised and examined for consistency across studies.

Results

My5-FU assays were found to be consistent with reference liquid chromatography tandem mass spectrometry. Comparative studies pointed to gains in overall survival and in progression-free survival with pharmacokinetic dosing, and were consistent across multiple studies.

Conclusions

Although our analyses are encouraging, uncertainties remain because evidence is mainly from outmoded 5-fluorouracil regimens; a randomised controlled trial is urgently needed to investigate new dose adjustment methods in modern treatment regimens.
Appendix
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Literature
1.
Mansouri D, McMillan DC, Grant Y, Crighton EM, Horgan PG. The impact of age, sex and socioeconomic deprivation on outcomes in a colorectal cancer screening programme. PLoS One. 2013;8(6):e66063.CrossRefPubMedPubMedCentral
2.
Gellad ZP, Provenzale D. Colorectal Cancer: National and International Perspective on the bBurden of disease and Public Health Impact. Gastroenterology. 2010;138:2177–90.CrossRefPubMed
3.
Office for National Statistics (ONS). Mortality Statistics: Deaths registered in 2010, England and Wales. London: ONS; 2011.
4.
Northern Ireland Statistics and Research Agency (NISRA). Registrar General Annual Report 2011. Belfast: NISRA; 2012.
5.
6.
Moynihan T, Hansen R, Anderson T, Quebbeman E, Beatty P, Ausman R, Ritch P, Chitambar C, Vukelich M. Continuous 5-Fluorouracil Infusion in Advanced Gastric Carcinoma. Am J Clin Oncol. 1988;11(4):461–4.CrossRefPubMed
7.
Pelusi J. Capecitabine versus 5-FU in metastatic colorectal cancer: Considerations for treatment decision-making. Commun Oncol. 2006;3(1):19–27.CrossRef
8.
Bertino J, Gamelin E, Milano G. Highlights from: 5-Fluorouracil drug management pharmacokinetics and pharmacogenomics workshop: Orlando, Florida; January 2007–5-Fluorouracil drug management: Pharmacokinetics and pharmacogenomics workshop meeting summary. Clin Colorectal Cancer. 2007;6(6):407–22.CrossRef
9.
Harris BE, Song R, Soong SJ, Diasio RB. 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;50(1):197–201.PubMed
10.
Di Paolo A, Danesi R, Falcone A, Cionini L, Vannozzi F, Masi G, Allegrini G, Mini E, Bocci G, Conte PF, et al. Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients. Ann Oncol. 2001;12(9):1301–6.CrossRefPubMed
11.
van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, Van Lenthe H, De Abreu RA, Maring JG, Vreken P, van Gennip AH. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res. 2000;6(12):4705–12.PubMed
12.
Ezzeldin H, Diasio R. Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clin Colorectal Cancer. 2004;4(3):181–9.CrossRefPubMed
13.
Gamelin E, Boisdron-Celle M. Dose monitoring of 5-fluorouracil in patients with colorectal or head and neck cancer-status of the art. Crit Rev Oncol Hematol. 1999;30(1):71–9.CrossRefPubMed
14.
Salamone SJ, Li Y, Courtney J, Harney R, Lundell G, Stocker D. 5-Fluorouracil determination in plasma by rapid nanoparticle immunoassay; Highlights from: 5-Fluorouracil Drug Management Pharmacokinetics and Pharmacogenomics Workshop; Orlando, Florida; January 2007. Clin Colorectal Cancer. 2007;6(6):419–20.
15.
Beumer JH, Boisdron-Celle M, Clarke W, Courtney JB, Egorin MJ, Gamelin E, Harney RL, Hammett-Stabler C, Lepp S, Li Y, et al. Multicenter evaluation of a novel nanoparticle immunoassay for 5-fluorouracil on the olympus AU400 analyzer. Ther Drug Monit. 2009;31(6):688–94.PubMed
16.
Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377–84.CrossRefPubMedPubMedCentral
17.
Guyot P, Ades A, Ouwens M, Welton N. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12(1):9.CrossRefPubMedPubMedCentral
18.
Wan X, Peng L, Li Y. A review and comparison of methods for recreating individual patient data from published Kaplan-Meier survival curves for economic evaluations: a simulation study. PLoS One. 2015;10(3):e0121353.CrossRefPubMedPubMedCentral
19.
Crowther MJ, Lambert PC. A general framework for parametric survival analysis. Stat Med. 2014;33(30):5280–97.CrossRefPubMed
20.
Davies A, Briggs A, Schneider J, Levy A, Ebeid O, Wagner S, Kotapati S, Ramsey S. The ends justify the mean: outcome measures for estimating the value of new cancer therapies. Health Outcomes Res Med. 2012;3(1):e25–36.CrossRef
21.
Harris R, Bradburn M, Deeks J, Harbord R, Altman D, Sterne J. metan: fixed- and random-effects meta-analysis. Stata J. 2008;8(1):3–28.
22.
Boisdron-Celle M, Craipeau M, Brienza S, Delva R, Guerin-Meyer V, Cvitkovic E, Gamelin E. Influence of oxaliplatin on 5-fluorouracil plasma clearance and clinical consequences. Cancer Chemother Pharmacol. 2002;49(3):235–43.CrossRefPubMed
23.
Capitain O, Boisdron-Celle M, Poirier AL, Abadie-Lacourtoisie S, Morel A, Gamelin E. The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer. Pharmacogenomics J. 2008;8(4):256–67.CrossRefPubMed
24.
Cattel L, La Grotta G, Infante L, Passera R, Arpicco S, Brusa P, Bumma C. Pharmacokinetic study of oxaliplatin iv chronomodulated infusion combined with 5-fluorouracil iv continuous infusion in the treatment of advanced colorectal cancer. Farmaco. 2003;58(12):1333–8.CrossRefPubMed
25.
Duffour J, Roca L, Bressolle F, Abderrahim AG, Poujol S, Pinguet F, Ychou M. Clinical impact of intesified 5-Fluorouracil-based chemotherapy using a prospective pharmacokinetically-guided dosing approach: comparative study in elderly and non-elderly patients with metastatic colorectal cancer. J Chemother. 2010;22(3):179–85.CrossRefPubMed
26.
Findlay MPN, Raynaud F, Cunningham D, Iveson A, Collins DJ, Leach MO. Measurement of plasma 5-fluorouracil by high-performance liquid chromatography with comparison of results to tissue drug levels observed using in vivo 19 F magnetic resonance spectroscopy in patients on a protracted venous infusion with or without interferon-alpha. Ann Oncol. 1996;7(1):47–53.CrossRefPubMed
27.
Gamelin EC, Danquechin-Dorval EM, Dumesnil YF, Maillart PJ, Goudier MJ, Burtin PC, Delva RG, Lortholary AH, Gesta PH, Larra FG. Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU. Cancer. 1996;77(3):441–51.CrossRefPubMed
28.
Gamelin E, Boisdron-Celle M, Delva R, Regimbeau C, Cailleux PE, Alleaume C, Maillet ML, Goudier MJ, Sire M, Person-Joly MC, et al. 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;16(4):1470–8.PubMed
29.
Ho YF, Lu WC, Chen RRL, Cheng AL, Yeh KH. Phase I, pharmacokinetic, and bone marrow drug-level studies of trimonthly 48-h infusion of high-dose 5-fluorouracil and leucovorin in patients with metastatic colorectal cancers. Anti-Cancer Drugs. 2011;22(3):290–8.CrossRefPubMed
30.
Jodrell DI, Stewart M, Aird R, Knowles G, Bowman A, Wall L, Cummings J, McLean C. 5-Fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer. Br J Cancer. 2001;84(5):600–3.CrossRefPubMedPubMedCentral
31.
Kline CL, Sheikh HS, Scicchitano A, Gingrich R, Beachler C, Finnberg NK, Liao J, Sivik J, El-Deiry WS. Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients. Cancer Biol Ther. 2011;12(7):557–68.CrossRefPubMed
32.
Metzger G, Massari C, Etienne MC, Comisso M, Brienza S, Touitou Y, Milano G, Bastian G, Misset JL, Levi F. Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in patients with cancer. Clin Pharmacol Ther. 1994;56(2):190–201.CrossRefPubMed
33.
Milano G, Roman P, Khater R, Frenay M, Renee N, Namer M. Dose versus pharmacokinetics for predicting tolerance to 5-day continuous infusion of 5-FU. Int J Cancer. 1988;41(4):537–41.CrossRefPubMed
34.
Stremetzne S, Streit M, Kreuser ED, Schunack W, Jaehde U. Pharmacokinetic and pharmacodynamic comparison of two doses of calcium folinate combined with continuous fluorouracil infusion in patients with advanced colorectal cancer. Pharm World Sci. 1999;21(4):184–9.CrossRefPubMed
35.
Ychou M, Duffour J, Pinguet F, Kramar A, Joulia JM, Topart D, Bressolle F. Individual 5FU-dose adaptation schedule using bimonthly pharmacokinetically modulated LV5FU2 regimen: A feasibility study in patients with advanced colorectal cancer. Anticancer Res. 1999;19(3 B):2229–35.PubMed
36.
Ychou M, Duffour J, Kramar A, Debrigode C, Gourgou S, Bressolle F, Pinguet F. Individual 5-FU dose adaptation in metastatic colorectal cancer: Results of a phase II study using a bimonthly pharmacokinetically intensified LV5FU2 regimen. Cancer Chemother Pharmacol. 2003;52(4):282–90.CrossRefPubMed
37.
Yoshida T, Araki E, Iigo M, Fujii T, Shimada Y, Saito D, Tajiri H, Yamaguchi H, Yoshida S, Yoshino M, et al. Clinical significance of monitoring serum levels of 5-fluorouracil by continuous infusion in patients with advanced colonic cancer. Cancer Chemother Pharmacol. 1990;26(5):352–4.CrossRefPubMed
38.
Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M. 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. J Clin Oncol. 2008;26(13):2099–105.CrossRefPubMed
39.
Capitain O, Asevoaia A, Boisdron-Celle M, Poirier AL, Morel A, Gamelin E. Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: A phase II, proof-of-concept study. Clin Colorectal Cancer. 2012;11(4):263–7.CrossRefPubMed
40.
Kline CLB, Schiccitano A, Zhu J, Beachler C, Sheikh H, Harvey HA, MacKley HB, McKenna K, Staveley-O’Carroll K, Poritz L, et al. Personalized dosing via pharmacokinetic monitoring of 5-fluorouracil might reduce toxicity in early- or late-stage colorectal cancer patients treated with infusional 5-fluorouracil-based chemotherapy regimens. Clin Colorectal Cancer. 2014;13(2):119–26.CrossRefPubMed
41.
Buchel B, Sistonen J, Joerger M, Aebi Y, Schurch S, Largiader CR. Comparative evaluation of the My5-FU immunoassay and LC-MS/MS in monitoring the 5-fluorouracil plasma levels in cancer patients. Clin Chem Lab Med. 2013;51(8):1681–8.CrossRefPubMed
42.
Makihara K, Mishima H, Azuma S, Matsuyama K, Komori K, Hasegawa H, Yasui M, Ikenaga M, Tsujinaka T. A pilot study of pharmacokinetically guided dose management of capecitabine in CRC patients. J Clin Oncol. 2012;30(4 SUPPL):510.
43.
Kaldate RR, Haregewoin A, Grier CE, Hamilton SA, McLeod HL. Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6. Oncologist. 2012;17(3):296–302.CrossRefPubMedPubMedCentral
44.
Gamelin E, Boisdron-Celle M. Individual dose adjustment in cancer chemotherapy. [French] L’adaptation individuelle de posologie en chimiotherapie anticancereuse. Rev Med Interne. 1996;17(7):529–33.CrossRefPubMed
45.
Kohne CH, Wils J, Lorenz M, Schoffski P, Voigtmann R, Bokemeyer C, Lutz M, Kleeberg C, Ridwelski K, Souchon R, 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. J Clin Oncol. 2003;21(20):3721–8.CrossRefPubMed
46.
Köhne C-H, van Cutsem E, Wils J, Bokemeyer C, El-Serafi M, Lutz MP, Lorenz M, Reichardt P, Rückle-Lanz H, Frickhofen N, et al. Phase III Study of Weekly High-Dose Infusional Fluorouracil Plus Folinic Acid With or Without Irinotecan in Patients With Metastatic Colorectal Cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005;23(22):4856–65.CrossRefPubMed
47.
Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, Smith DB, Shepherd S, Maraveyas A, Ferry DR, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370(9582):143–52.CrossRefPubMed
48.
Cunningham D, Sirohi B, Pluzanska A, Utracka-Hutka B, Zaluski J, Glynne-Jones R, Koralewski P, Bridgewater J, Mainwaring P, Wasan H, et al. Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer. Ann Oncol. 2009;20(2):244–50.CrossRefPubMed
49.
Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, et al. FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. J Clin Oncol. 2004;22(2):229–37.CrossRefPubMed
50.
Ducreux M, Bennouna J, Hebbar M, Ychou M, Lledo G, Conroy T, Adenis A, Faroux R, Rebischung C, Bergougnoux L, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer. 2011;128(3):682–90.CrossRefPubMed
51.
Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, et al. Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab As First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study. J Clin Oncol. 2008;26(21):3523–9.CrossRefPubMed
52.
Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011;12(7):642–53.CrossRefPubMedPubMedCentral
53.
Patel JN, O’Neil BH, Deal AM, Ibrahim JG, Sherrill GB, Olajide OA, Atluri PM, Inzerillo JJ, Chay CH, McLeod HL, et al. A community-based multicenter trial of pharmacokinetically guided 5-fluorouracil dosing for personalized colorectal cancer therapy. Oncologist. 2014;19(9):959–65.CrossRefPubMedPubMedCentral
54.
Saam J, Critchfield GC, Hamilton SA, Roa BB, Wenstrup RJ, Kaldate RR. Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens. Clin Colorectal Cancer. 2011;10(3):203–6.CrossRefPubMed
55.
Saif MW, Choma A, Salamone SJ, Chu E. Pharmacokinetically guided dose adjustment of 5-fluorouracil: A rational approach to improving therapeutic outcomes. J Natl Cancer Inst. 2009;101(22):1543–52.CrossRefPubMed
56.
Romero RZ, Morales R, Garcia F, Huarriz M, Bandres E, De la Haba J, Gomez A, Aranda E, Garcia-Foncillas J. Potential application of GSTT1-null genotype in predicting toxicity associated to 5-fluouracil irinotecan and leucovorin regimen in advanced stage colorectal cancer patients. Oncol Rep. 2006;16(3):497–503.PubMed
57.
Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D, Catalano V, Ficarelli R, Maltese P, Bisonni R, et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol. 2007;25(10):1247–54.CrossRefPubMed
58.
Boige V, Mendiboure J, Pignon JP, Loriot MA, Castaing M, Barrois M, Malka D, Tregouet DA, Bouche O, Le Corre D, et al. Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05. J Clin Oncol. 2010;28(15):2556–64.CrossRefPubMed
59.
Goldstein DA, Chen Q, Ayer T, Howard DH, Lipscomb J, Harvey RD, El-Rayes BF, Flowers CR. Cost effectiveness analysis of pharmacokinetically-guided 5-fluorouracil in folfox chemotherapy for metastatic colorectal cancer. Clin Colorectal Cancer. 2014;13(4):219–25.CrossRefPubMed
60.
Metadata
Title
Is monitoring of plasma 5-fluorouracil levels in metastatic / advanced colorectal cancer clinically effective? A systematic review
Authors
Karoline Freeman
Mark P. Saunders
Olalekan A. Uthman
Sian Taylor-Phillips
Martin Connock
Rachel Court
Tara Gurung
Paul Sutcliffe
Aileen Clarke
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2581-x

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