5-Fluorouracil rechallenge after 5-fluorouracil-induced hyperammonemic encephalopathy Alice Boilève a,b , Camille Wicker b,c,d , Benjamin Verret a , Florence Leroy a , David Malka a , Mathieu Jozwiak e , Clément Pontoizeau b,c,d , Chris Ottolenghi b,c,d , Pascale De Lonlay b,c,d , Michel Ducreux a and Antoine Hollebecque a For several decades, 5-Fluorouracil (5-FU) has been the backbone of many chemotherapy regimens for various tumor types. Its most common side effects are gastrointestinal disorders, mucositis, myelosuppression, hand–foot syndrome, and rarely cardiac toxicity. More rarely, 5-FU infusion can induce hyperammonemic encephalopathy. 5-FU toxicities can be worsened by complete or partial genetic and/or phenotypic dihydropyrimidine dehydrogenase deficiency. Here, we report the case of a patient who initially developed a 5-FU-induced hyperammonemic encephalopathy after receiving FOLFIRINOX (oxaliplatin, irinotecan, folinic acid, and 5-FU) chemotherapy with bevacizumab to treat a metastatic gastrointestinal cancer of unknown primary. Thereafter, the patient was rechallenged successfully by the same chemotherapy regimen (FOLFIRINOX) for more than 6 months with a protocol consisting in a free protein diet, and administration of ammonium chelators, and Krebs and urea cycle intermediates, to prevent further hyperammonemia. We also present a review of the literature on 5-FU rechallenge after 5-FU-induced hyperammonemic encephalopathy. Anti-Cancer Drugs 30:313–317 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Anti-Cancer Drugs 2019, 30:313–317 Keywords: cancer, 5-fluorouracil, hyperammonemic encephalopathy, Krebs cycle, metabolomic disease a Medical Oncology Department, Gustave Roussy, Université Paris-Saclay, b Paris Descartes University, c Reference Center of Hereditary Métabolic Diseases, Imagine Institute, d Metabolic Biochemistry Department, Necker-Enfants Malades Hospital and e Intensive Care Unit, Bicêtre Hospital, Paris-Sud University, APHP, Le Kremlin-Bicêtre, Paris, France Correspondence to Alice Boilève, MD, Medical Oncology Department, Gustave Roussy Hospital, 114 Rue Edouard Vaillant, 94800 Villejuif, France Tel: + 33 014 211 4308; fax: + 33 014 211 5229; e-mail: alice.boileve@gmail.com Received 30 August 2018 Revised form accepted 13 November 2018 Introduction 5-Fluorouracil (5-FU)-based chemotherapy is commonly used to treat several tumor types, notably gastrointestinal, breast, and head and neck cancers, in the adjuvant or the metastatic setting. It is generally used in combination treatments, but can also be used alone. 5-FU is a pyr- imidine analog agent that interferes with DNA and RNA synthesis [1], inhibiting thymidylate synthase. Blocking thymidylate synthase activity results in reduced levels of the pyrimidine thymidine, which is a nucleoside required for DNA replication. The most common 5-FU-related side effects are gastrointestinal disorders, mucositis, myelosuppression, hand–foot syndrome, and rarely car- diac toxicity [2]. As 5-FU is metabolized by dihydropyr- imidine dehydrogenase (DPD), DPD deficiency leads to 5-FU accumulation, thus increasing its toxicity [3]. Hyperammonemic encephalopathy is a very rare and serious side effect of 5-FU infusion [4–8]. Management of further chemotherapies in patients developing 5-FU-induced hyperammonemic encephalopathy still remains a challenge for oncologists, and in most cases, 5-FU is not re-infused. Here, we report the case of a patient with a metastatic gastrointestinal cancer of unknown primitive that initially developed 5-FU-induced hyperammonemic encephalo- pathy after receiving FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and 5-FU) chemotherapy with bevacizumab. A successful rechallenge by 5-FU was performed in this patient with a partial DPD deficiency. Case report A 36-year-old woman with a gastrointestinal cancer of unknown primary with lymph nodes, lung, bone metastases, and peritoneal carcinomatosis was treated with a first line of chemotherapy including 5-FU (FOLFIRINOX– bevacizumab protocol), after confirming the presence of poorly differentiated adenocarcinoma CK7 + , CK20 + , RO/ RP - , p53 - , p16 - , PAX8 - , WT1 - , and HER2 - . Within 48 h after the initiation of 5-FU infusion, the patient developed nausea, vomiting, agitation as well as confusion, and was hospitalized in the emergency department. At admission, the neurological examination indicated no sei- zure disorder, no focal deficit, no meningeal syndrome, as well as no pyramidal or extrapyramidal syndrome, although the patient had a bilateral reactive mydriasis. In the fol- lowing hours, the patient developed a coma with a Glasgow score of 6, requiring mechanical ventilation after intubation. The cerebral computed tomography-scan and MRI did not show any hemorrhage, cerebral metastasis, stroke, or pos- terior reversible encephalopathy syndrome. The lumbar puncture was strictly normal. Biological tests indicated lactic Case report 313 0959-4973 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/CAD.0000000000000730 Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved.