Fluoropyrimidines and Cardiotoxicity

• Fluoropyrimidines are a class of antimetabolite chemotherapy that includes 5-fluorouracil (5-FU) and Capecitabine. These drugs can be used in curative or palliative settings with various cancers e.g., GI, breast.
• 5-FU is administrated intravenously, typically as a bolus and an infusion (over 48 hours). The bolus may occasionally be omitted due to toxicity concerns (up-front or during subsequent cycles).
• Capecitabine is an oral pro-drug (typically given twice daily; 2 weeks on, 1 week off).

• If receiving 5-FU infusion, stop immediately (patients are often taught how to do this by their oncology team). If on capecitabine – hold the next dose.
• Assess vitals. Order troponin and ECG in all patients
• Treat symptoms with calcium channel blockers (Amlodipine 2.5-10mg, nifedipine30-120mg – based on blood pressure) and/or long-acting nitrates (isosorbide mononitrate 30-60mg vs dinitrate 5-40mg), or IV nitrates (if refractory symptoms/signs) depending on the clinical setting and access.
•  Patients with ongoing symptoms, despite the above management, should undergo angiography to rule out traditional CAD.
• An echocardiogram may be considered to assess LV systolic function and regional wall motion abnormalities, but this is normal in most patients.
• In patients with ongoing angina or severe presentation (e.g., ST elevations, ventricular arrhythmias, LV dysfunction) refractory to the above treatment, consider an antidote - uridine triacetate(given as 10g orally every 6 hours for up to 20 doses until symptoms resolve).⁵

Dihydropyrimidine dehydrogenase (DPD) testing

• DPD is an enzyme that breaks down pyrimidines. Approximately 3 to 7% of people have a DPD deficiency and can have an accumulation of fluoropyrimidines, potentially increasing the risk of cardiotoxicity.
• Testing can be done before starting 5-FU-based therapy, with a dose reduction if deficiency is identified. But this is not common practice. Also relationship between deficiency and cardiotoxicity is unclear.  

• One large retrospective study suggested younger age and fewer traditionalcardiovascular risk factors increased the risk of vasospasm².
• Ischemic heart disease increases risk of capecitabine cardiotoxicity (ORs 2.92)⁴;Pre-existing coronary artery disease (CAD increases risk of cardiotoxicity³

The diagnosis is based predominantly on history. With coronary vasospasm, most patients present with chest pain or anginal equivalents such as SOB on exertion. Temporal relationship is a key to the diagnosis:

• Usually, it occurs during or immediately after the bolus or at 24-72 hours after the end of the continuous infusion.
• Most patients (72%) present within the first cycle; 90% of patients present within the first three cycles².
• ECG and biomarkers are often normal, but some patients can have ST depressions or elevations and troponin elevation (likely reflecting more significant event)

• If receiving 5-FU infusion, stop immediately (patients are often taught how to do this by their oncology team). If on capecitabine – hold the next dose.
• Assess vitals. Order troponin and ECG in all patients
• Treat symptoms with calcium channel blockers (Amlodipine 2.5-10mg, nifedipine30-120mg – based on blood pressure) and/or long-acting nitrates (isosorbide mononitrate 30-60mg vs dinitrate 5-40mg), or IV nitrates (if refractory symptoms/signs) depending on the clinical setting and access.
•  Patients with ongoing symptoms, despite the above management, should undergo angiography to rule out traditional CAD.
• An echocardiogram may be considered to assess LV systolic function and regional wall motion abnormalities, but this is normal in most patients.
• In patients with ongoing angina or severe presentation (e.g., ST elevations, ventricular arrhythmias, LV dysfunction) refractory to the above treatment, consider an antidote - uridine triacetate(given as 10g orally every 6 hours for up to 20 doses until symptoms resolve).⁵

Dihydropyrimidine dehydrogenase (DPD) testing

• DPD is an enzyme that breaks down pyrimidines. Approximately 3 to 7% of people have a DPD deficiency and can have an accumulation of fluoropyrimidines, potentially increasing the risk of cardiotoxicity.
• Testing can be done before starting 5-FU-based therapy, with a dose reduction if deficiency is identified. But this is not common practice. Also relationship between deficiency and cardiotoxicity is unclear.  

Multidisciplinary team discussion with the oncologist is critical (i.e., is 5-FU or capecitabine the preferred oncologic agent?). From a cardiovascular perspective, if the patient had an acute myocardial infarction, rechallenge may be high risk. If objective evidence of ischemia is noted without infarction, consider rechallenging in-hospital with telemetry monitoring (5FUor capecitabine); if there is no objective ischemia, may treat as an outpatient with clear instructions to patients on reaching medical care if symptoms recur.

Re-challenge considerations

• Consider switching 5-FU from continuous infusion to bolus dose (reported with less cardiotoxic).^6,7
• Consider pre-treatment with CCB/nitrate beforerechallenging – one regimen has been suggested by Padegimas et al⁷ Whether both CCB and nitrates are needed is currently unclear¹.
• Baseline ECG and troponin to be obtained before first re-challenge; sublingual nitroglycerin or spray should be given for use in case of symptoms.
• Start CCB (nifedipine ER 30-60 mg, amlodipine 2.5-10mg, or diltiazem ER 120-420 mg) and/or isosorbide mononitrate ER (30-120 mg) 48hours before starting the drug (infusion or oral), ensuring that patient takes them in the morning every day that the drug is being given; dose adjusted according to BP/HR
• Continue CCB/nitrate every day until 48-72 hours after the last dose. Instruct patient to additionally use nitroglycerine sublingually or spray if chest pain recurs or to come to the emergency department if chest pain persists.
• Re-evaluation and medication optimization before every cycle (further dose increase may be needed if symptoms recur)
• Advise to reduce exertional activity in patients with persistent chest pain despite medications.

There are no specific long-term considerations after completion of cancer therapy unless the patient has a cardiovascular event (e.g., infarct or arrhythmia). In the latter scenario, routine cardiac follow-up should be instituted.

1. Zafar, A. et al. The efficacy and safety of cardio-protective therapy inpatients with 5-FU (Fluorouracil)-associated coronary vasospasm. PloS one 17, e0265767 (2022). https://doi.org:10.1371/journal.pone.0265767
2. Zafar, A. et al. The Incidence, Risk Factors, and Outcomes With5-Fluorouracil-Associated Coronary Vasospasm. JACC. Cardio Oncology 3,101-109 (2021). https://doi.org:10.1016/j.jaccao.2020.12.005
3. Raber, I. et al. Fluoropyrimidine-Associated Cardiotoxicity: A Retrospective Case-Control Study.Oncologist25, e606-e609 (2020). https://doi.org:10.1634/theoncologist.2019-0762
4. Dyhl-Polk, A. et al. Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity inpatients with colorectal cancer. ActaOncol59, 475-483 (2020). https://doi.org:10.1080/0284186x.2019.1711164
5. Raber, I., Frazer, M. B., Zerillo, J. A. & Asnani, A. Uridine Triacetate for Severe Fluoropyrimidine Cardiotoxicity in a Patient With Thymidylate Synthase Gene Variants. JACC.CardioOncology2, 329-332(2020). https://doi.org:10.1016/j.jaccao.2020.04.005
6. Chakrabarti, S. et al. Bolus 5-fluorouracil (5-FU) In Combination With Oxaliplatin Is Safe and Well Tolerated in Patients Who Experienced Coronary Vasospasm With Infusional 5-FU or Capecitabine. Clin Colorectal Cancer 18, 52-57(2019). https://doi.org:10.1016/j.clcc.2018.09.006
7. Padegimas, A. & Carver, J. R. How to Diagnose and Manage Patients With Fluoropyrimidine-Induced Chest Pain: A Single Center Approach. JACC. CardioOncology2, 650-654 (2020). https://doi.org:10.1016/j.jaccao.2020.06.012