Table 2.

Summary of medical treatments for 5-FU-related cardiotoxicity.

Effective treatment methods	Rechallenge	• Controversial - Recurrence up to 90%; death up to 13%5,14 • Avoid if possible • Individualized decision weighing risks and benefits • Patients with significant CAD who undergo revascularization: can retreat if close observation and if benefits > risks • Patients with nonsignificant CAD: avoid 5-FU if possible - if not possible and risk/benefit ratio acceptable attempt cautious challenge with BOLUS regimen6,7,109,110 - pretreat with 48 h of aspirin, CCB and long-acting nitrate - careful observation and continuous ECG monitoring - discontinue 5-FU if any symptoms/signs of cardiac event
	Use of alternative non-FU drugs	• Difficult in patients with gastrointestinal cancers when FU is an integral component of treatment • Good options in metastatic disease, i.e. for colorectal cancer: - Irinotecan alone - Irinotecan plus oxaliplatin, cetuximab or panitumumab (for patients with RAS/BRAF wild-type tumors) - Trifluridine-tipiracil, regorafenib and ramucirumab or raltitrexed alone or in combination regimens111,112 • In patients with adjuvant therapy for resected, node-positive colorectal cancer: - Global standard is oxaliplatin + FU containing regimen (also recommended for patients with node-negative disease but presumed to be at high enough risk) - In those with FU-related cardiotoxicity, trial of FU BOLUS containing regimen (Roswell Park weekly regimen)113,114 - or if patients need oxaliplatin use FLOX (FU, leucovorin and oxaliplatin) with pretreatment using antianginal therapy, empiric aspirin and close monitoring
	Use of alternative FU drugs	• UFT - Contains tefagur which is a FU prodrug, and uracil which competitively inhibits the degradation of FU - < 1% incidence of cardiotoxicity115,116 - Not available in the USA (available in Japan and other Asian and South American countries) • S-1 - Contains tefagur, gimeracil which inhibits the enzyme DPD that breaks down FU and oteracil which inhibits phosphorylation of FU - No reported cardiotoxicity to date117–119 - Not available in the USA (available in several Asian and European countries)
	Alternative treatment modalities	• Patients who are not candidates for alternative chemotherapy drugs or have limited disease could undergo locally directed therapy, e.g. surgery, radiofrequency ablation radioembolization or transarterial chemoembolization • Requires careful patient selection and evaluation of risks and benefits
Ineffective treatment methods	Dose reduction	• The dose dependence of 5-FU-related cardiotoxicity is unclear14,22,110
	Prophylactic treatment with CCB or nitrates	• Much data have shown no benefit with either CCB or nitrates3,14,100,111,120 or CCB in isolation41 • Some data have shown a benefit with prophylactic CCB69,121,122 and prophylactic nitrates110 • Overall conflicting data derived from retrospective studies and case series or reports • No randomized trial evaluating the role of CCBs or nitrates in this setting • Could be used in selected situations when they are unlikely to lead to harm
	Antidote therapy?	• Toxicity is thought to be related to metabolite FUTP - Uridine is a naturally occurring nucleoside: competes with FUTP for incorporation into RNA - Can reduce FU toxicity to normal tissues123 - Has not been studied in FU-related cardiotoxicity - Can cause phlebitis and requires central access for administration • Uridine triacetate is an oral active prodrug of uridine - Higher bioavailability - Approved by FDA in 2015 (for FU or capecitabine overdose in patients with severe/life-threatening toxicity of cardiovascular or central nervous system) - Could be used in severe toxicity124

CAD, coronary artery disease; CCB, calcium channel blocker; DPD, Dihydropyrimidine Dehydrogenase; ECG, electrocardiograph; FDA, US Food and Drug Administration; FU, fluorouracil; FUTP, 5-fluorouridine triphosphate; UFT, Uracil-tegafur.