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Expert consensus guidelines and publications on therapeutic drug monitoring in oncology for 5-fluorouracil (5-FU) and busulfan.

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Therapeutic Drug Monitoring in Oncology: IATDMCT Recommendations for 5-Fluorouracil Therapy

Beumer JH, Chu E, Allegra C, et al. Clin Pharmacol Ther. 2018.


5-Fluorouracil (5-FU) is dosed by body surface area, a practice unable to reduce the interindividual variability in exposure. Endorsed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), we evaluated clinical evidence and strongly recommend TDM for the management of 5-FU therapy in patients with colorectal or head-and-neck cancer receiving common 5-FU regimens. Our systematic methodology provides a framework to evaluate published evidence in support of TDM recommendations in oncology.

Suivi thérapeutique pharmacologique du 5-fluorouracile : mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer [5-fluorouracil therapeutic drug monitoring: Update and recommendations of the STP-PT group of the SFPT and the GPCO-Unicancer]

Lemaitre F, Goirand F, Launay M, et al. Bull Cancer. 2018;105(9):790-803.

The “Suivi thérapeutique pharmacologique et personnalisation des traitements” (STP-PT) group of the “Société française de pharmacologie et de thérapeutique” (SFPT) and the “Groupe de pharmacologie clinique oncologique” (GPCO)- Unicancer, based on the latest and most up-to-date literature data, recommend the implementation of 5-FU Therapeutic Drug Monitoring in order to ensure an adequate 5-FU exposure.

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper

Wörmann B, Bokemeyer C, Burmeister T, et al. Oncol Res Treat. 2020;43(11):628-636.

This guideline was organized by the German Society of Haematology and Oncology (DGHO) with thirteen medical associations in Austria, Germany, and Switzerland. The option for 5-FU TDM is included.

Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice

Wilhelm M, Mueller L, Miller MC, et al. Clin Colorectal Cancer. 2016;15(4):381-388.

This prospective, multicenter study used the Saladax My5-FU assay for 5-FU therapeutic drug monitoring in clinical practice. The study included 75 patients with metastatic colorectal cancer. With 5-FU TDM it was possible to adjust 5-FU exposure into the target range. The incidence of severe 5-FU related toxicities were reduced compared to historical data, despite increased doses for 55% of patients.


Drug monitoring detects under- and overdosing in patients receiving 5-fluorouracil-containing chemotherapy-results of a prospective, multicenter German observational study

Li M, Mindt S, Lück A, et al. ESMO Open. 2023;8(2).

This prospective, multicenter study in Germany used the Saladax My5-FU assay to measure 5-FU plasma concentrations. As in previous studies, the majority of patients were found to be underdosed: 60.6% of 434 patients and only 20.3% of patients achieved 5-FU AUCs (Area Under the Curve) in the target range. The authors concluded that “Therapeutic drug monitoring of 5-FU is an option for optimized individualized cancer therapy and should be integrated into the clinical practice.”

Clinical Benefit of Therapeutic Drug Monitoring in Colorectal Cancer Patients Who Received Fluorouracil-Based Chemotherapy

Zhou X, Chang Y, Qian J, et al. Med Sci Monit. 2021; Jul 31;27:e929474.


BACKGROUND The impact of therapeutic drug management (TDM) on reducing toxicity and improving efficacy in colorectal cancer (CRC) patients receiving fluorouracil-based chemotherapy is still unclear. MATERIAL AND METHODS A total of 207 patients (Study Group n=54, Historical Group n=153) with metastatic colorectal cancer were enrolled. All of them received 6 administrations of the 5-FU based regimens. Initial 5-FU dosing of all patients was calculated using body surface area (BSA). In the Study Group, individual exposure during each cycle was measured using a nanoparticle immunoassay, and the 5-FU blood concentration was calculated using the area under the curve (AUC). We adjusted the 5-FU infusion dose of the next cycle based on the AUC data of the previous cycle to achieve the target of 20-30 mg×h/L. RESULTS In the fourth cycle, patients in the target concentration range (AUC mean, 26.3 mg×h/L; Median, 28 mg×h/L; Range, 14-38 mg×h/L; CV, 22.4%) accounted for 46.8% of all patients, which were more than the ones in the first cycle (P<0.001). 5-FU TDM significantly reduced the toxicity of chemotherapy and improved its efficacy. The Study Group (30/289) showed a lower percentage of severe adverse events than that in the Historical Group (185/447) (P<0.001). The incidences of complete response and partial response in the Study Group were higher than those in the Historical Group (P=0.032). CONCLUSIONS TDM in colorectal cancer can reduce toxicity, improve efficacy and clinical outcome, and can be routinely used in 5-FU-based chemotherapy.

Current status and future outlooks on therapeutic drug monitoring of fluorouracil

Schmulenson E, Zimmermann N, Mikus G, Joerger M, Jaehde U. Expert Opin Drug Metab Toxicol. 2021;17(12):1407-1422.


Introduction: Therapeutic drug monitoring (TDM) of the anticancer drug fluorouracil (5FU) as a method to support dose adjustments has been researched and discussed extensively. Despite manifold evidence of the advantages of 5FU-TDM, traditional body surface area (BSA)-guided dosing is still widely applied.

Areas covered: This review covers the latest evidence on 5FU-TDM based on a literature search in PubMed between June and September 2021. It particularly highlights new approaches of implementing 5FU-TDM into precision medicine by combining TDM with pharmacogenetic testing and/or pharmacometric models. This review further discusses remaining obstacles in order to incorporate 5FU-TDM into clinical routine.

Expert opinion: New data on 5FU-TDM further strengthen the advantages compared to BSA-guided dosing as it is able to reduce pharmacokinetic variability and thereby improve treatment efficacy and safety. Interprofessional collaboration has the potential to overcome the remaining barriers for its implementation. Preemptive pharmacogenetic testing followed by 5FU-TDM can further improve 5FU exposure in a substantial proportion of patients. Developing a model framework integrating pharmacokinetics and pharmacodynamics of 5FU will be crucial to fully advance into the precision medicine era. Model applications can potentially support clinicians in dose finding before starting chemotherapy. Additionally, TDM provides further assistance in continuously improving model predictions.

Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee

Palmer J, McCune JS, Perales MA, et al. Biol Blood Marrow Transplant. 2016;22(11):1915-1925.


The Practice Guidelines Committee of the American Society of Blood or Marrow Transplantation (ASBMT) sought to develop an evidence-based review about personalizing busulfan-based conditioning. The Committee sought to grade the relevant published studies (June 1, 2008 through March 31, 2016) according to criteria set forth by the Steering Committee for Evidence Based Reviews from ASBMT. Unfortunately, the published literature was too heterogeneous and lacked adequately powered and sufficiently controlled studies for this to be feasible. Despite this observation, the continued interest in this topic led the Practice Guidelines Committee to develop a list of most frequently asked questions (FAQs) regarding personalized busulfan dosing. This “Considerations” document is a list of these FAQs and their responses, addressing topics of practical relevance to hematopoietic cell transplantation clinicians.


Automation in Busulfan Therapeutic Drug Monitoring: Evaluation of an Immunoassay on two Routine Chemistry Analyzers

Verougstraete N, Stove V, Verstraete AG, Oyaert M. Ther Drug Monit. 2022;44(2):335-339.


Background: Therapeutic drug monitoring (TDM) of busulfan is recommended for hematopoietic stem cell transplant recipients. Timely reporting of these TDM results is essential given the short administration period and the planned dose adjustments on day 2. The authors evaluated the performance of a new nanoparticle-based competitive immunoassay on two routine clinical chemistry analyzers and compared its performance to that of an in-house high-resolution mass spectrometry (HRMS) method.

Methods: The MyCare Oncology Busulfan Assay Kit (Saladax Biomedical) was applied on two routine clinical chemistry analyzers (Abbott Architect c8000 and Roche Cobas c502) with a linearity range of 187-2000 ng/mL. The study evaluation measured imprecision and accuracy, sample probe carry-over, and dilution integrity. Method comparison with liquid chromatography (LC)-HRMS was performed using samples from patients undergoing busulfan treatment.

Results: Within- and between-run coefficient of variations for both analyzers were ≤5.23% and ≤8.45%, respectively, across the busulfan concentration range. The obtained biases were ≤10.3%. Both analyzers met the acceptance criteria for sample probe carry-over and dilution integrity. Agreement between the immunoassay and LC-HRMS was high: 92% and 89% of the samples measured on Architect and Cobas, respectively, were within the ±15% limit compared to the corresponding LC-HRMS results.

Conclusions: Overall, good analytical performance and high agreement with LC-HRMS results were obtained for the immunoassay installed on both routine clinical chemistry analyzers. Therefore, this assay could be implemented as a valid alternative for LC methods in clinical laboratories on different open-channel clinical chemistry analyzers, resulting in shorter turn-around times for reporting busulfan TDM results with subsequent faster dosage adjustments.


Busulfan target exposure attainment in children undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiday therapeutic drug monitoring regimen

Bognàr T, Kingma JS, Smeijsters EH, et al. Bone Marrow Transplant. 2023;58(7):762-768.


Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all children receiving busulfan-based allogeneic hematopoietic cell transplantation. Primary outcome was the percentage of patients achieving busulfan target attainment in both TDM regimens. Secondary outcomes were the variance in busulfan exposure and day-4 clearance (Clday4) estimates between both TDM regimens and dosing day 1 and 2. In regimen d1, 84.3% (n = 91/108) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 90.9% was found (n = 30/33, not-significant). Variance of Clday4 estimate based on busulfan day 2 concentrations was significantly smaller than the variance of Clday4 estimates based on day 1 concentrations (p < 0.001). Therefore, day 1-guided TDM (pharmacometric model-based) of busulfan may be sufficient for attaining optimal target exposure, provided that subsequent TDM is carried out if required. However, performing TDM on subsequent days may be beneficial, as measurements on day 2 seemed to reduce the variance in the estimated clearance as compared to day 1 sampling.


Association between busulfan exposure and survival in patients undergoing a CD34+ selected stem cell transplantation

Tamari R, Scordo M, Kunvarjee BM, et al. Blood Adv. 2023;7(18):5225-5233.


Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). A myeloablative conditioning regimen, including busulfan, is commonly used in patients undergoing T-cell depletion (TCD) and allo-HCT, but data on optimal busulfan pharmacokinetic (PK) exposure in this setting are limited. Between 2012 and 2019, busulfan PK was performed to target an area under the curve exposure between 55 and 66 mg × h/L over 3 days using a noncompartmental analysis model. We retrospectively re-estimated busulfan exposure following the published population PK (popPK) model (2021) and correlated it with outcomes. To define optimal exposure, univariable models were performed with P splines, wherein hazard ratio (HR) plots were drawn, and thresholds were found graphically as the points at which the confidence interval crossed 1. Cox proportional hazard and competing risk models were used for analyses. 176 patients were included, with a median age of 59 years (range, 2-71). Using the popPK model, the median cumulative busulfan exposure was 63.4 mg × h/L (range, 46.3-90.7). The optimal threshold was at the upper limit of the lowest quartile (59.5 mg × h/L). 5-year overall survival (OS) with busulfan exposure ≥59.5 vs <59.5 mg × h/L was 67% (95% CI, 59-76) vs 40% (95% CI, 53-68), respectively (P = .02), and this association remained in a multivariate analyses (HR, 0.5; 95% CI, 0.29; 0.88; P = .02). In patients undergoing TCD allo-HCT, busulfan exposure is significantly associated with OS. The use of a published popPK model to optimize exposure may significantly improve the OS.


Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis

Bartelink IH, Lalmohamed A, van Reij EML, et al. Lancet Haematol. 2016;3(11):e526-e536.

Background: Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT. Added value of this study: Findings from our study showed that the way of calculating the AUC affects the optimum AUC. Validated population pharmacokinetic methods seem to be the most reliable way to calculate the AUC, allow for comparisons of busulfan AUCs between institutions, and help to facilitate prospective studies of individualized busulfan dosing strategies. A cumulative busulfan exposure of between 78 mg × h/L and 101 mg × h/L, combined with the non-alkylating drug fludarabine, predicted the highest event-free survival in children or young adults independent of indication and cell source. An increased risk of acute and chronic toxicity was noted at higher exposures, whereas an increased risk of graft rejection or disease relapse occurred at lower exposures.