Feasibility of 5-fluorouracil pharmacokinetic monitoring using the My-5FU PCM™ system in a quaternary oncology centre
- 121 Downloads
5-Fluorouracil (5FU) drug exposure correlates with treatment response and toxicity in cancer patients. Dosing is based upon body surface area which does not correlate with 5FU pharmacokinetics (PK)/pharmacodynamics. Therapeutic drug monitoring has enabled real-time 5FU dose adjustments: reducing toxicity with increased efficacy. The aim of this study was to assess feasibility of a 5FU monitoring service utilising a commercial kit in a quaternary cancer centre and to compare PK parameters to previously published studies.
Cancer patients receiving continuous infusional (CI) 5FU with ECOG PS 0–2, and adequate organ function, were eligible. Patients had blood samples taken at t = 0, mid infusion (if feasible) then 2 h pre infusion end. 5FU levels were measured using a commercial kit (My-5FU PCM™). A feasibility questionnaire was completed by trial nurses and toxicity data were recorded at baseline and at the commencement of the next cycle. 5FU pharmacokinetic exposure parameters were calculated.
Twenty patients (12 male; 8 female), median age 62, (range 37–71) had samples taken. Twenty (100%) feasibility forms were available for assessment. Blood samples were taken at 51/69 (74%) specified time points. Ease of sample processing was recorded as easy in all 20 patients. Patient compliance with scheduled visits was 18/20 (90%). One form noted other difficulties with predicting end of infusion time. 19/20 patients had blood samples analysed. Mean measured 5FU AUC (0-Tlast) for 5FU 1 g/m2 with platinum: 35.8 h mg/L (range 28.56–44.26), mean Css 372.2 µg/L (range 297.5–461.0); 5FU 600 mg/m2 with platinum: 12.42 h mg/L (range 6.91–18.29), mean Css 111.0 µg/L (72.0–190.5) and 5FU 2400 mg/m2 as part of FOLFOX ± bevacizumab: 14.75 h mg/L (range 6.74–22.93), mean Css 320.70 µg/L (range 146.5–498.5). One patient had grade 4 neutropenia and one patient without PK parameters experienced febrile neutropenia (grade 4 neutropenia). Mucositis was observed in two patients: [5FU/platinum (1), grade 1, FOXFOX ± bevacizumab (1) grade 1]. Diarrhoea was reported in three patients [5FU/platinum (2) grade 1–2, FOXFOX ± bevacizumab (1) grade 1].
Therapeutic 5FU drug monitoring was feasible using commercial kits and analysers and hence warrants development as a routine standard of care in cancer patients. The variability in the 5FU exposure parameters is consistent with other studies using the My 5FU PCM kit.
KeywordsFluorouracil Pharmacokinetics Drug monitoring Feasibility
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institution and the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Conflict of interest
The authors declare that they have no conflict of interest.
- 11.Fety R, Rolland F, Barberi-Heyob M, Hardouin A, Campion L, Conroy T et al (1998) Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinomas. Clin Cancer Res 4(9):2039–2045PubMedGoogle Scholar
- 16.Harris BE, Song R, Soong SJ, Diasio RB (1990) 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 50(1):197–201PubMedGoogle Scholar
- 19.Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U et al (2015) Clinical relevance of DPYD variants c.1679T > G, c.1236G > A/HapB3, and c.1601G > A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol 16(16):1639–1650CrossRefGoogle Scholar
- 24.van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, Van Lenthe H, De Abreu RA et al (2000) 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 6(12):4705–4712PubMedGoogle Scholar
- 32.Gamelin E, Boisdron-Celle M, Delva R, Regimbeau C, Cailleux P, Alleaume C et al (1998) 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 16(4):1470–1478CrossRefGoogle Scholar
- 33.Ychou M, Duffour J, Pinguet F, Kramar A, Joulia J, Topart D et al (1998) Individual 5FU-dose adaptation schedule using bimonthly pharmacokinetically modulated LV5FU2 regimen: a feasibility study in patients with advanced colorectal cancer. Anticancer Res 19(3B):2229–2235Google Scholar
- 34.Ychou M, Duffour J, Kramar A, Debrigode C, Gourgou S, Bressolle F et al (2003) 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 52(4):282–290CrossRefGoogle Scholar
- 37.Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D et al (2008) 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 26(13):2099–2105CrossRefGoogle Scholar
- 38.Capitain O, Asevoaia A, Boisdron-Celle M, Poirier A-L, Morel A, Gamelin E (2012) 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 11(4):263–267CrossRefGoogle Scholar
- 39.Kline CLB, Schiccitano A, Zhu J, Beachler C, Sheikh H, Harvey HA et al (2014) 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 13(2):119–126CrossRefGoogle Scholar
- 40.Saam J, Critchfield GC, Hamilton SA, Roa BB, Wenstrup RJ, Kaldate RR (2011) 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 10(3):203–206CrossRefGoogle Scholar
- 41.Denda T, Kanda M, Morita Y, Kim HM, Kashiwada T, Matsuda C et al (2016) Pharmacokinetic dose adjustment of 5-FU in modified FOLFOX7 plus bevacizumab for metastatic colorectal cancer in Japanese patients: a-JUST phase II clinical trial. Cancer Chemother Pharmacol 78(6):1253–1261CrossRefGoogle Scholar
- 44.Braiteh FS, Salamone SJ, Li Y, Courtney JB, Duda M, Diamond S et al (2014) Pharmacokinetic (PK)-guided optimization of 5-fluorouracil (5FU) exposure in colorectal cancer (CRC) patients: US-based clinical practices experience. J Clin Oncol 32(15 suppl):3574Google Scholar
- 56.Gamelin EC, Danquechin-Dorval EM, Dumesnil YF, Maillart PJ, Goudier M, Burtin PC et al (1996) Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU. Cancer 77(3):441–451CrossRefGoogle Scholar
- 60.Freeman K, Connock M, Cummins E, Gurung T, Taylor-Phillips S, Court R et al (2015) Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion. Health Technol Assess (Winch Engl) 19(91):1CrossRefGoogle Scholar
- 61.ClinicalTrials.gov Study comparing optimized 5-FU dosing and standard dosing in metastatic colorectal cancer patients treated with FOLFOX6 (PROFUSE)Google Scholar