Commentary

Body Surface Area–based Dosing of 5-Fluoruracil Results in Extensive Interindividual Variability in 5-Fluorouracil Exposure in Colorectal Cancer Patients on FOLFOX Regimens

This work reports a simple biotool for the determination of 5-fluorouracil (5-FU), a drug often used in chemotherapy for the treatment of certain cancers. The methodology involves an indirect competitive immunoassay performed on the surface of magnetic microbeads (MBs) and amperometric transduction at screen-printed carbon electrodes (SPCEs). In brief, free 5-FU competes with 5-FU-BSA covalently immobilized on HOOC-MBs for the limited recognition sites of a 5-FU-selective detection antibody (DAb) labeled with a secondary antibody conjugated to the peroxidase enzyme (HRP-antimIgG). Amperometric transduction was made using the H₂O₂/hydroquinone (HQ) system. The method provides analytical characteristics in terms of sensitivity (LOD of 1.0 ng mL⁻¹) and selectivity suitable with clinical usefulness and is competitive with other reported electrochemical non-biosensing detection strategies in terms of simplicity and assay time. Most interestingly, the method exhibits high accuracy in the analysis of a pharmaceutical formulation and of serum samples even from a patient with colorectal cancer (CRC) undergoing treatment with 5-FU thus showing potential for chemotherapy monitoring and personalized chemotherapy.

Rapid and simple monitoring of anticancer drug concentrations in blood is important for improving the efficacy of chemotherapeutic cancer treatment. In this study, we demonstrated the detection of 5-fluorouracil (5-FU) in human serum using a field-effect transistor (FET) biosensor with competitive adsorption between uncharged anticancer drugs and charged pseudo-targets. The target 5-FU and 5-FU-modified bovine serum albumin (BSA/5-FU) were competitively adsorbed on the FET sensor surface using antigen-antibody reaction with antigen-binding fragment (Fab) receptor. FET responses to the target 5-FU concentrations were obtained via changes in the amount of negatively charged BSA/5-FU captured by Fab molecules. In addition, the influence of serum components could be suppressed by diluting the samples with a nonionic surfactant solution. As a result, the FET biosensing system was capable of quantitatively detecting 5-FU concentrations in serum. Therefore, the semiconductor-based sensing system could enable the adjustment of anticancer drug dosages and potentially lead to improvements in anticancer drug therapy.

Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer.

Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated.

By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg·h/mL or CPT-11 AUC values below 10 mcg·h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC ≥28 mcg·h/mL [HR = 0.251, 95% CI 0.096–0.656; p = 0.005] and CPT-11 AUC <10 mcg·h/mL [HR = 0.189, 95% CI 0.073–0.486, p = 0.001].

Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma.

Body surface area (BSA)-based dosing of 5-fluorouracil (5-FU) results in marked inter-individual variability in drug levels, whereas determination of plasma 5-FU concentration and area under the curve (AUC) is a more precise dosing method but has not been integrated into clinical routine. We conducted a multicenter, prospective study to study 5-FU AUC distributions and assess clinical factors predicting therapeutic dosing in patients receiving BSA-dosed 5-FU.

Between June 2017 and January 2018, a total of 434 patients receiving continuous, infusional BSA-dosed 5-FU from 37 sites in Germany were included. Plasma 5-FU concentration and AUC were measured in venous blood samples at steady state. The primary objective was to determine 5-FU AUC distributions in relation to the target range, which is defined as 20-30 mg × h/l. The second objective was to explore clinical parameters that correlate with achievement of 5-FU AUC target range.

The primary tumor was mainly located in the gastrointestinal tract (96.3%), with colorectal cancer being the most common (71.2%) tumor entity. 5-FU was administered as monotherapy (8.1%) or as part of FOLFOX (33.2%), FOLFIRI (26.3%), or other regimens (12.4%). Treatment setting was adjuvant (31.3%) or metastatic (64.5%). The median AUC was 16 mg × h/l. Only 20.3% of patients received 5-FU treatment within the target range, whereas the majority of patients (60.6%) were underdosed and 19.1% of patients were overdosed. In the univariate logistic regression, treatment setting was the only clinical parameter that significantly correlated with achievement of the target range. Patients treated in the metastatic setting had a 2.1 (95% confidence interval 1.186-3.776, P = 0.011) higher odds to reach the target range compared with patients treated in the adjuvant setting.

The majority of patients received suboptimal doses of 5-FU using BSA dosing. Therapeutic drug monitoring of 5-FU is an option for optimized individualized cancer therapy and should be integrated into the clinical practice.

Fluoropyrimidine drugs (FP) are the backbone of many chemotherapy protocols for treating solid tumours. The rate-limiting step of fluoropyrimidine catabolism is dihydropyrimidine dehydrogenase (DPD), and deficiency in DPD activity can result in severe and even fatal toxicity. In this review, we survey the evidence-based pharmacogenetics and therapeutic recommendations regarding DPYD (the gene encoding DPD) genotyping and DPD phenotyping to prevent toxicity and optimize dosing adaptation before FP administration. The French experience of mandatory DPD-deficiency screening prior to initiating FP is discussed.

This present study used a simple aqueous chemical growth method to synthesize Al-doped ZnO (ZnO: Al) nanoneedles on ZnO seeds/glass substrates. The surface morphology and length of ZnO: Al nanostructures can suitably control by the concentration of aluminum sulfate. The surface-enhanced Raman scattering (SERS) effect of Ag sputtering durations on the ZnO: Al nanoneedles and the concentration of aluminum sulfate on the ZnO: Al/Ag heterostructures systematically investigated. The ZnO: Al/Ag heterostructures (2 mM aluminum sulfate and 60 s sputtering time) exhibited a more substantial enhancement, a lower detection limit (10⁻¹⁰ M), excellent uniformity, high reusability and stability for the SERS detection of rhodamine 6G molecule. The ZnO: Al/Ag heterostructures can also use to detect the lower concentration of melamine (10⁻⁹ M) and 5-fluorouracil (10⁻⁷ M). ZnO: Al/Ag heterostructures can provide a low-cost and straightforward manufacturing method with high enhancement, low detection limit, excellent uniformity, and reusability for the SERS applications in areas of chemical and medicine.