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Abstract
Colorectal cancer (CRC) treatment can be limited to surgical resection for low stages of the disease while subsequent chemotherapy is the preferred treatment for the higher-stage disease. This chemotherapy relies heavily on fluoropyrimidine: 5-fluorouracil (5-FU) and capecitabine, a role played for decades. Fluoropyrimidine-linked treatment can present important and even lethal toxic events at the cardiac level like acute coronary syndrome, arrhythmias, and death.The production of these toxic events depends on the capacity of a subject to metabolize the fluoropyrimidines adequately, and this depends on the activity of the enzyme dihydropyrimidine dehydrogenase (DPD). Any change that affects the quantity or quality of this enzyme will compromise its capacity to metabolize the fluoropyrimidines. The resultant abnormal enzyme activity exposes the patient to continuously high levels of the chemotherapeutic agent or its catabolites. Consequently, the patient becomes more susceptible to pyrimidine-linked toxic adverse events.Genetic testing of patients for potential decreased DPD activity before subjecting them to fluoropyrimidine-based chemotherapy will help identify subjects at greater risk of increased cardiotoxicities, the possibility of prompt intervention, should these appear, and a multidisciplinary strategy aimed at managing these cases. Potential cases of cardiotoxicity in CRC patients, candidates to fluoropyrimidine toxicities, can be anticipated by pretreatment screening of DPD activity. Pretreatment screening will reduce many hospitalizations with a consequent decrease in costs both to the patients and the healthcare system.This review article will examine the 5-FU linked cardiotoxicity, known correlated risk factors, clinical manifestations, management strategy, and the role of genetic testing in identifying high-risk patients.
Highlights
BackgroundPatients with advanced colorectal cancer (CRC) need to undergo adjuvant or neoadjuvant chemotherapy with fluoropyrimidines like 5-fluorouracil (5-FU), a cytotoxic antineoplastic, and antimetabolite chemotherapeutic agents
Colorectal cancer (CRC) treatment can be limited to surgical resection for low stages of the disease while subsequent chemotherapy is the preferred treatment for the higher-stage disease
Fluoropyrimidine-linked treatment can present important and even lethal toxic events at the cardiac level like acute coronary syndrome, arrhythmias, and death. The production of these toxic events depends on the capacity of a subject to metabolize the fluoropyrimidines adequately, and this depends on the activity of the enzyme dihydropyrimidine dehydrogenase (DPD)
Summary
Patients with advanced colorectal cancer (CRC) need to undergo adjuvant or neoadjuvant chemotherapy with fluoropyrimidines like 5-fluorouracil (5-FU), a cytotoxic antineoplastic, and antimetabolite chemotherapeutic agents. When used with levamisole after surgery, it has contributed to a significant decrease of risks of relapse of stage III CRC by 41% in three years after surgery [28,29] Notwithstanding their immense beneficial effects, the use of fluoropyrimidines can cause critical adverse reactions in various organs, which may put the life of the patient in danger. Some centers implement a protocol based on the screening for these variants associated with the DPYD before starting fluoropyrimidine therapy and eventually adjusting the doses of the medication if these variants are present [7] Besides genotyping, another technique that can permit the identification of DPD deficiency is evaluating its action in the peripheral mononuclear cell (PBMC), which is the phenotypical expression of the enzyme [38]. Table created with data from Conti et al [10]
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