Safe administration of S-1 after 5-fluorouracil-induced cardiotoxicity in a patient with colorectal cancer

Franck, Caspar; Malfertheiner, Peter; Venerito, Marino

doi:10.1136/bcr-2016-219162

Cited by 11 publications

(7 citation statements)

References 9 publications

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“…We believe that this patient did not develop cardiac toxicity on S-1 due to the fact that gimeracil is a highly active reversible DPD inhibitor; DPD inhibition by gimeracil results in significantly reduced levels of cardiotoxic catabolites of 5-FU, hence resulting in less cardiotoxicity. This is further supported by clinical experience with the use of S-1 in CRC patients with previous 5-FU-or capecitabine-induced cardiotoxicity [33,34].…”

Section: Discussionmentioning

confidence: 81%

Safety and Efficacy of s-MOX Regimen in Patients with Colorectal Cancer Who Developed Cardiotoxicity Following Fluoropyrimidine Administration: A Case Series

et al. 2020

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Background: Fluoropyrimidines compose the backbone of regimens to treat many common solid tumors, including gastrointestinal (GI), breast and head/neck. As we continue to use these agents routinely, recognition of rare but real toxicities, such as cardiotoxicity, has also improved. The treatment options for patients who have encountered fluoropyrimidine-induced cardiotoxicity are limited as many anti-angiogenic drugs also pose a cardiac risk. Patients and Methods:We present a case series of three patients who developed cardiotoxicity in the form of anginal-like symptoms, EKG changes and elevated cardiac enzymes on infusional 5-FU or capecitabine and were subsequently treated with the s-MOX (simplified-mitomycin-oxaliplatin) regimen for their metastatic colorectal cancer (mCRC). All three patients were tested for polymorphic abnormality of DYPD and TYMS.Results: All three patients were treated with s-MOX consisting of mitomycin-C 7 mg/m 2 on day 1 and oxaliplatin 85 mg/m 2 on days 1 and 15 (1 cycle = 28 days) after they encountered cardiotoxicity to 5-FU and/or capecitabine. None of these patients developed any cardiotoxicity on s-MOX. Overall, the MOX regimen was well tolerated. The most common toxicities included < 2 grade peripheral neuropathy, nausea, vomiting, thrombocytopenia, and anemia. Grade > 3 toxicities included neutropenia (10%), thrombocytopenia (33%), vomiting (8%), and peripheral neuropathy (30%). DYPD gene was normal in all patients and TYMS was abnormal (2R/2R) in one patient. Conclusion:This is the first case series that reports the safety and feasibility of s-MOX in patients with mCRC who developed cardiac toxicity to 5-FU or capecitabine. The s-MOX regimen may provide an alternative treatment option for patients who either develop fluoropyrimidine-related cardiotoxicity or who have abnormalities in the DYPD gene.

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Section: Discussionmentioning

confidence: 81%

Safety and Efficacy of s-MOX Regimen in Patients with Colorectal Cancer Who Developed Cardiotoxicity Following Fluoropyrimidine Administration: A Case Series

et al. 2020

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“…Nonetheless, the pathogenesis of cardiotoxicity caused by 5-FU is not clear. Actually, unchanged 5-FU elimination only represents 5–10% of the administered dose [32] and the inhibition of dihydropyrimidine dehydrogenase has been reported to be protective against the 5-FU-inflicted cardiotoxicity in humans [34,70] and in animal models [71]. Another in vitro study using keratocytes with high thymidine phosphorylase activity also showed higher 5-FU toxicity when compared to FBAL [72].…”

Section: Discussionmentioning

confidence: 99%

The Main Metabolites of Fluorouracil + Adriamycin + Cyclophosphamide (FAC) Are Not Major Contributors to FAC Toxicity in H9c2 Cardiac Differentiated Cells

et al. 2019

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In the clinical practice, the combination of 5-fluorouracil (5-FU) + Adriamycin (also known as doxorubicin, DOX) + cyclophosphamide (CYA) (known as FAC) is used to treat breast cancer. The FAC therapy, however, carries some serious risks, namely potential cardiotoxic effects, although the mechanisms are still unclear. In the present study, the role of the main metabolites regarding FAC-induced cardiotoxicity was assessed at clinical relevant concentrations. Seven-day differentiated H9c2 cells were exposed for 48 h to the main metabolites of FAC, namely the metabolite of 5-FU, α-fluoro-β-alanine (FBAL, 50 or 100 μM), of DOX, doxorubicinol (DOXOL, 0.2 or 1 μM), and of CYA, acrolein (ACRO, 1 or 10 μM), as well as to their combination. The parent drugs (5-FU 50 μM, DOX 1 μM, and CYA 50 μM) were also tested isolated or in combination with the metabolites. Putative cytotoxicity was evaluated through phase contrast microscopy, Hoechst staining, membrane mitochondrial potential, and by two cytotoxicity assays: the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and the neutral red (NR) lysosomal incorporation. The metabolite DOXOL was more toxic than FBAL and ACRO in the MTT and NR assays. When in combination, neither FBAL nor ACRO increased DOXOL-induced cytotoxicity. No nuclear condensation was observed for any of the tested combinations; however, a significant mitochondrial potential depolarization after FBAL 100 μM + DOXOL 1 μM + ACRO 10 μM or FBAL 100 μM + DOXOL 1 μM exposure was seen at 48 h. When tested alone DOX 1 μM was more cytotoxic than all the parent drugs and metabolites in both the cytotoxicity assays performed. These results demonstrated that DOXOL was the most toxic of all the metabolites tested; nonetheless, the metabolites do not seem to be the major contributors to FAC-induced cardiotoxicity in this cardiac model.

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“…The management is symptomatic, while re-challenge does not seem an attractive and safe option (25). S-1, an oral fluoropyrimidine, consisting of tegafur, a 5-FU prodrug, oteracil potassium and gimeracil, which inhibits the degradation of 5-FU by DPD inhibition, can be possibly administered safely after capecitabine or 5-FU induced cardiotoxicity according to a limited number of case reports (38).…”

Section: Capecitabinementioning

confidence: 99%

Cardiovascular complications of metastatic colorectal cancer treatment

Keramida¹,

Charalampopoulos²,

Filippiadis³

et al. 2019

J. Gastrointest. Oncol

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Colorectal cancer (CRC) burdenCRC is one of the most prevailing malignancies, being the third most commonly occurring cancer in men, and the second in women (1,2), making up about 10% of all cancer cases (3). It is the fourth highest cause of cancer death (1).Its incidence increases with increasing age (4). It is more prevalent in developed countries, where more than 65% of cases are found (3). The global burden of CRC is expected to increase by 60% to more than 2.2 million new cases and 1.1 million cancer deaths by 2030 (1).

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Safe administration of S-1 after 5-fluorouracil-induced cardiotoxicity in a patient with colorectal cancer

Cited by 11 publications

References 9 publications

Safety and Efficacy of s-MOX Regimen in Patients with Colorectal Cancer Who Developed Cardiotoxicity Following Fluoropyrimidine Administration: A Case Series

Safety and Efficacy of s-MOX Regimen in Patients with Colorectal Cancer Who Developed Cardiotoxicity Following Fluoropyrimidine Administration: A Case Series

The Main Metabolites of Fluorouracil + Adriamycin + Cyclophosphamide (FAC) Are Not Major Contributors to FAC Toxicity in H9c2 Cardiac Differentiated Cells

Cardiovascular complications of metastatic colorectal cancer treatment

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