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

Freeman, Karoline; Saunders, Mark; Uthman, Olalekan A.; Taylor‐Phillips, Sian; Connock, Martin; Court, Rachel; Gurung, Tara; Sutcliffe, Paul; Clarke, Aileen

doi:10.1186/s12885-016-2581-x

Cited by 10 publications

(8 citation statements)

References 53 publications

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“…The pharmacokinetic analysis did not show a significant relationship between the AUC levels and clinical benefit rate. The median overall survival of metastatic patients was 45 months, which is among the highest survival rates of previous trials (8, 12, 17, 19, 21, 22). The lower rates of required target AUC levels and lower than required doses were not reflected in the clinical efficacy results of this study.…”

Section: Discussionmentioning

confidence: 72%

A correlation study of fluorouracil pharmacodynamics with clinical efficacy and toxicity

Esin

Telli

Yüce

et al. 2018

Tumori

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based on body surface area (BSA). However, 5-FU has a narrow therapeutic index and high variance (4). These individual differences in plasma levels depend on genetic diversity in the metabolic enzymes of 5-FU (i.e., dihydropyrimidine dehydrogenase [DPD]), as well as kinetic changes related to age, sex, body weight, and dietary differences (5, 6). Previous reports showed that inappropriate dosing is related to increased toxicity and increased rates of unresponsiveness (5, 7). Pharmacokinetic (PK) adjusted doses may overcome the problems of variability (8-11). Area under the target curve of 20-25 mg × h/L was proposed as the valid 5-FU level to achieve clinically effective and less toxic chemotherapy cycles (12-14). However, with BSA-based dosing, only 20%-30% of patients received the valid area under the curve (AUC) dose, whereas nearly 50% of patients were underdosed and 20% were overdosed (8). Gamelin et al suggested increasing the overall response rate from 18% to 33% by PK dosing (14). In this study, we prospectively investigated the clinical benefit and toxicity of 5-FU in relation to pharmacokinetic properties in advanced colorectal cancer and in the adjuvant setting.

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Section: Discussionmentioning

confidence: 72%

A correlation study of fluorouracil pharmacodynamics with clinical efficacy and toxicity

Esin

Telli

Yüce

et al. 2018

Tumori

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“…Measuring 5-FU concentrations in blood was previously difficult because of the need for specialized equipment, but since the development of new kits, relatively simple tests are available. The My5-FU assay is a nanoparticle-based immunoassay that can be run on a standard clinical laboratory automated clinical chemistry analyser, enabling high sample throughput 26 . The My5-FU assay showed equivalent performance on different analysers such as liquid chromatography-tandem mass spectrometry (LC-MS) and other clinical analyzers 27 .…”

Section: Discussionmentioning

confidence: 99%

“…The 5-FU plasma concentration was measured at three time points: immediately, after 1.5 h and after 3 h. We measured the concentrations twice for each condition and calculated the mean value. The concentrations of 5-FU were measured by photometric detection using a homogeneous competitive nanoparticle immunoassay (My5-FU; Saladax Biomedical, Bethlehem, PA, USA) and analysed on a commercial Abbott Architect C4000 biochemical analyser as described [26][27][28][30][31][32][33] . Saladax provides a stabilizer kit as a dihydropyrimidine dehydrogenase (DPD) inhibitor.…”

Section: Measurement Of 5-fu Plasma Concentrationmentioning

confidence: 99%

5-Nitrouracil stabilizes the plasma concentration values of 5-FU in colorectal cancer patients receiving capecitabine

Yoshida

Hashimoto

Miyazaki

et al. 2020

Sci Rep

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Capecitabine is selectively converted from 5′-DFUR to 5-fluorouracil (5-FU) in tumours by thymidine phosphorylase (TP). We investigated the addition of 5-nitrouracil (5-NU), a TP inhibitor, into blood samples for precise measurements of plasma 5-FU concentrations. The plasma concentration of 5-FU was measured after capecitabine administration. Two samples were obtained at 1 or 2 h after capecitabine administration and 5-NU was added to one of each pair. Samples were stored at room temperature or 4 °C and 5-FU concentrations were measured immediately or 1.5 or 3 h later. The mean plasma 5-FU concentration was significantly higher at room temperature than at 4 °C (p < 0.001). The 5-FU concentration was significantly increased in the absence of 5-NU than in the presence of 5-NU (p < 0.001). The 5-FU change in concentration was greater in the absence of 5-NU, and reached 190% of the maximum compared with baseline. A significant interaction was found between temperature and 5-NU conditions (p < 0.001). Differences between the presence or absence of 5-NU were greater at room temperature than under refrigerated conditions. 5-FU plasma concentrations after capecitabine administration varied with time, temperature, and the presence or absence of 5-NU. This indicates that plasma concentrations of 5-FU change dependent on storage conditions after blood collection. In current daily practice, the administrated dose of 5-fluorouracil (5-FU) is generally calculated based on the body surface area (BSA). However, BSA has been reported to be a poor predictor of systemic drug exposure 1-3. 5-FU is characterized by a narrow therapeutic window and strong exposure-toxicity relationship, which support the use of approaches to monitor drug administration. Several investigations have demonstrated a relationship between response and drug exposure in terms of toxicity and efficacy 4,5. Adjusting the 5-FU dose based on pharmacokinetic monitoring in patients led to a significantly improved response rate and fewer adverse events compared with patients treated with conventional 5-FU dose 6,7. Capecitabine, an oral drug that is tumour-selective fluoropyrimidines, is a key pro-drug of 5-FU used in colorectal cancer treatment 8. Capecitabine is primarily metabolized to 5′-deoxy-5-fluorocytidine (5′-DFCR) by carboxylesterase in the liver 9 ; 5′-DFCR is converted to 5′-deoxy-5-fluorouridine (5′-DFUR) by cytidine deaminase, which is predominantly present in the liver as well as in tumour tissues. In the final step, 5′-DFUR is converted to its active form, 5-FU, by thymidine phosphorylase (TP), which is present at higher concentrations in cancer than in normal tissues 10. Phase I trials have demonstrated a relationship between the occurrence of adverse events and the exposure to capecitabine metabolites 11,12. Although Cmax and area under the curve (AUC) for 5′-DFUR and α-fluoro-β-alanine were found to be predictive of dose-limiting toxicities, systemic exposure to 5-FU was poorly predicted. Furthermore, Gieschke reported that the plasma concentratio...

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“…5-Fluorouracil (5-FU) is a commonly used chemotherapeutic drug for human cancers, and its effectiveness for cancer treatment has already been veried in clinic and experiment. 7,8 Aer penetrating the cancer cells, 5-FU is transformed into two major active metabolites: FdUMP and FUTP. FdUMP interacts with thymidylate synthase (TS) and 5,10-CH 2 -FH 4 to form a covalent ternary complex, thereby inhibiting the activity of TS and DNA synthesis.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of 5-fluorouracil-treated lung cancer cells by atomic force microscopy

Jiang

et al. 2019

Anal. Methods

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

Cited by 10 publications

References 53 publications

A correlation study of fluorouracil pharmacodynamics with clinical efficacy and toxicity

A correlation study of fluorouracil pharmacodynamics with clinical efficacy and toxicity

5-Nitrouracil stabilizes the plasma concentration values of 5-FU in colorectal cancer patients receiving capecitabine

Evaluation of 5-fluorouracil-treated lung cancer cells by atomic force microscopy

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