Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: A real-life evaluation in France

Guellec, Chantal Barin‐Le; Lafay-Chebassier, Claire; Ingrand, Isabelle; Tournamille, Jean-François; Boudet, Adeline; Lanoue, Mary-Christine; Défossez, Gautier; Ingrand, Pierre; Pérault‐Pochat, Marie‐Christine; Étienne-Grimaldi, Marie-Christine

doi:10.1016/j.ejca.2019.09.028

Cited by 46 publications

(36 citation statements)

References 21 publications

(25 reference statements)

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“…The European Medicines Agency now recommends testing for DPD activity for patients receiving 5FU and capecitabine 48 and some countries are moving to make testing mandatory 49 . The increased push for mandatory screening should provide impetus for other countries to invest in and develop resources to make DPD testing part of routine care in patients receiving 5FU or capecitabine, for example by adding a requirement for TDM in the product label.…”

Section: What Are the Issues Affecting Implementation?mentioning

confidence: 99%

“…The European Medicines Agency now recommends testing for DPD activity for patients receiving 5FU and capecitabine 48 and some countries are moving to make testing mandatory. 49 Published cost analysis data showing upfront DPYD genotype-guided dose individualisation results in cost saving or in worst case cost neutral outcomes could be used to support the implementation of testing in a healthcare setting. 53,54 New techniques for DPD deficiency testing that may address some of the current barriers to testing are emerging.…”

Section: Access To Dpd Deficiency Screeningmentioning

confidence: 99%

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Overcoming barriers to implementing precision dosing with 5‐fluorouracil and capecitabine

Schneider

Galettis

Martin

2021

Brit J Clinical Pharma

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Despite advances in targeted cancer therapy, the fluoropyrimidines 5-fluorouracil (5FU) and capecitabine continue to play an important role in oncology. Historically, dosing of these drugs has been based on body surface area. This approach has been demonstrated to be an imprecise way to determine the optimal dose for a patient. Evidence in the literature has demonstrated that precision dosing approaches, such as DPD enzyme activity testing and, in the case of intravenous 5FU, pharmacokineticguided dosing, can reduce toxicity and yield better patient outcomes. However, despite the evidence, there has not been uniform adoption of these approaches in the clinical setting. When a drug such as 5FU has been used clinically for many decades, it may be difficult to change clinical practice. With the aim of facilitating change of practice, issues and barriers to implementing precision dosing approaches for 5FU and capecitabine are identified and discussed with possible solutions proposed.

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Section: What Are the Issues Affecting Implementation?mentioning

confidence: 99%

Section: Access To Dpd Deficiency Screeningmentioning

confidence: 99%

Overcoming barriers to implementing precision dosing with 5‐fluorouracil and capecitabine

Schneider

Galettis

Martin

2021

Brit J Clinical Pharma

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“…The known complete lack of DPD activity is a longstanding contraindication for treatment with drugs containing FU. A recently published “real-life” study from France calculated that 76,200 patients a year receive chemotherapy with fluoropyrimidine, 1,200 of whom suffer from life-threatening toxicity, with 150 patient deaths per year [19].…”

Section: Fu-related Toxicitymentioning

confidence: 99%

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

et al. 2020

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Background: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2–1.0%. Summary: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.

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“…A recent study investigated the incidence of FP-related toxicities in France [9]. This study reported that one fifth, 14,700 out of 76,200 patients treated annually with 5-FU or Cap developed serious FP-associated adverse events (SAEs) within the first two cycles of chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…Gastrointestinal and haematological toxicities were reported as the most common SAEs (66.3%). SAEs were defined in this particular study as "any adverse event entailing hospitalisation or prolongation of hospital stay, permanent disability or invalidity, life-threatening prognosis, and death" [9]. The number of patients with a life-threatening prognosis, disability or death was estimated to be 1200 per year.…”

Section: Introductionmentioning

confidence: 99%

Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy

Hamzic¹,

Aebi²,

Joerger³

et al. 2020

Swiss Med Wkly

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Fluoropyrimidines (FPs), mainly 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Cap), remain the backbone of the treatment of many different solid tumors. Despite their broad use in clinical routine, 10-40% of patients experience severe, and in rare cases (0.2-0.5%) even lethal, FP-related toxicity in early chemotherapy cycles. Today, there is a plethora of evidence that genetic variants in the gene encoding for the 5-FU catabolising enzyme dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) are predictive of severe FP-related toxicities, and international clinical practice recommendations for DPYD genotype-guided FP dosing and therapeutic drug monitoring (TDM) are available. In spite of this strong evidence and DPYD genotyping becoming standard practice in other countries, it is has not been widely adopted in Switzerland to date. Here, we discuss current guidelines on genotypeguided FP dosing and TDM, and propose recommendations tailored to the situation in Switzerland to facilitate their clinical uptake for the further individualisation of FP chemotherapy.We recommend preemptive testing of four DPYD variants (c.1905+1G>A (rs3918290), c.1679T>G (rs55886062), c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182, c.1236G>A/HapB3)) in patients with an indication for FP-based chemotherapy, with the costs reimbursed through the compulsory health insurance in Switzerland. Carriers of these variants (6.5% in the Swiss population) have a 40-50% risk of developing severe early-onset toxicity when treated with standard FP doses. In these patients, we therefore recommend the use of a reduced starting dose, based on a dose adjustment scheme provided herein. Furthermore, we recommend the use of infusional 5-FU in patients with a DPYD risk genotype in order to enable TDM-based dose escalation. Only if the use of an infusional 5-FU regimen is not feasible should a slow titration of Cap, starting with the recommended reduced dose and basing further doses on monitoring of toxicity, be considered. Given that several studies have shown that TDM in 5-FU treatment improves not only the therapy's safety, but potentially also its efficacy, we also include detailed TDM-based dosing guidelines and discuss the pre-analytical aspects of 5-FU TDM.

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Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: A real-life evaluation in France

Cited by 46 publications

References 21 publications

Overcoming barriers to implementing precision dosing with 5‐fluorouracil and capecitabine

Overcoming barriers to implementing precision dosing with 5‐fluorouracil and capecitabine

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

Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy

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