Lethal toxicities after capecitabine intake in a previously 5-FU-treated patient: why dose matters with dihydropryimidine dehydrogenase deficiency
| Autor: | L'Houcine Ouafik, Crescent C Gbeto, Catherine Roche, Bruno Lacarelle, Sylvie Quaranta, Thierry Allegre, Sophie Nahon, Roxane Mari, Raphaelle Fanciullino, Caroline Solas, Joseph Ciccolini |
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| Přispěvatelé: | Centre Hospitalier d'Aix en Provence [Aix-en-Provence] (CHIAP ), Laboratoire de Biologie médicale, AP-HM, Assistance Publique - Hôpitaux de Marseille (APHM), Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Pharmacocinétique Toxicocinétique - [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM), Service Hématologie et Médecine Interne, Centre Hospitalier du Pays d'Aix, Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE) |
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_specialty
Antimetabolites Antineoplastic Dihydropyrimidine Dehydrogenase Deficiency [SDV.CAN]Life Sciences [q-bio]/Cancer Breast Neoplasms Vinorelbine Gastroenterology Capecitabine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Genetics Medicine Humans Dosing ComputingMilieux_MISCELLANEOUS Dihydrouracil Dehydrogenase (NADP) 030304 developmental biology Pharmacology 0303 health sciences business.industry Dihydrouracil Middle Aged medicine.disease Metastatic breast cancer 3. Good health chemistry 030220 oncology & carcinogenesis Toxicity Molecular Medicine DPYD Female Fluorouracil business Pharmacogenetics medicine.drug |
| Zdroj: | Pharmacogenomics Pharmacogenomics, Future Medicine, 2019, 20 (13), pp.931-938. ⟨10.2217/pgs-2019-0028⟩ Pharmacogenomics, 2019, 20 (13), pp.931-938. ⟨10.2217/pgs-2019-0028⟩ |
| ISSN: | 1744-8042 1462-2416 |
| DOI: | 10.2217/pgs-2019-0028⟩ |
| Popis: | Dihydropryimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome associated with severe or lethal toxicities with oral capecitabine. Usually, patients with history of 5-FU-based therapy with no signs for life-threatening toxicities are considered as not DPD-deficient individuals who can be safely treated next with capecitabine if required. Here we describe the case of a woman originally treated with standard FEC100 protocol for metastatic breast cancer with little severe toxicities but grade-3 mucosities that were quickly resolved by symptomatic treatment. When switched to capecitabine + vinorelbine combo, extremely severe toxicities with fatal outcome were unexpectedly observed. Pharmacogenetic investigations were performed on cytidine deaminase and DPYD, and showed that this patient was heterozygous for the 2846A>T mutation on the DPYD gene. DPD phenotyping (i.e., uracil plasma levels >250 ng/ml, dihydrouracil/uracil ratio 2 5-FU) and capecitabine (i.e., 2250 mg daily) could explain why initial 5-FU-based protocol did not lead to life-threatening toxicities, whereas capecitabine rapidly triggered toxic death. Overall, this case report suggests that any toxicity, even when not life threatening, should be considered as a warning signal for possible underlying profound DPD deficiency syndrome, especially with low-dose protocols. |
| Databáze: | OpenAIRE |
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