Table 1.

Studies of FP-related cardiovascular toxicities

Incidence of cardiotoxicity according to chemotherapy regimens
Author	Primary cancer	Chemotherapy regimen	Number of patients	Overall 5-FU-induced cardiotoxicity incidence (N)	Signs and symptoms	Timing of onset
Jin et al. [19]	Gastric cancer	5-FU-containing regimens	129	29.5% (38)	Chest pain	Not reported
					Heart failure
					Atrial fibrillation
					Acute myocardial infarction
					Sinus arrhythmia
					Palpitation
					Ventricular premature beat
					Atrioventricular block
					QT interval prolongation
					Abnormal ST and T waves
Kwakman et al. [20]	Colorectal cancer	Capecitabine	1973	5.9% (117)	Cardiac ischemia	Note reported
		CAPIRI			Arrhythmia
		CAPOX			Chest pain
		CAPOX bevacizumab			Heart failure
					Cardiac death
Turan et al. [21]	Colorectal cancer	5-FU-containing regimens	32	12.5% (4)	Angina	During the first hours of continuous 5-FU infusion
	Gastric cancer				ECG changes	Just after minute after the bolus 5-FU administration
	Pancreatic cancer
	Head and neck cancer
Płońska-Gościniak et al. [22]	Colorectal cancer	LF1	25	unknown	Prolonged QT interval	Not reported
		XELOX			Worsening in left ventricular
		Capecitabine			Functional parameters by tissue
		FOLFIRI			Doppler
Polk et al. [23]	Breast cancer	Capecitabine	452	4.9% (22)	Chest pain	In the first cycle: 50% (11)
					Dyspnea	In the second cycle: 18% (4)
					Palpitations	In the third cycle: 14% (3)
					Atrial fibrillation	In the fourth cycle: 4.5% (1)
					ST deviations
					Negative or fluctuating T-waves
					Cardiac arrest
Lestuzzi et al. [10]	Gastric cancer	5-FU-continuous infusion	228	10.3% (37)	Angina	Not reported
	Head and neck cancer	TCF			ECG changes
	Colorectal cancer	CDDP 5-FU (±  RT)
		FOLFOX
		FOLFIRI
Jensen et al. [7]	Colorectal cancer	FOLFOX4	106	8.5% (9)	Angina	Not reported
Khan et al. [24]	Unknown	5-FU-containing regimens	301	19.93% (60)	Angina	Not reported
					Bradycardia
					Ventricular tachycardia
					Sudden death
					Cardiac arrest
Koca et al. [25]	Gastric cancer	Capecitabine mono	52	34.6% (18)	New-onset cardiovascular symptoms	1 h - 24 days
	Colorectal cancer	Capecitabine containing regimens		11.5% (6)	New-onset physical sigins
	Breast cancer			32.6% (17)	New-onset ECG signs
Salepci et al. [26]	Gastric cancer	5-FU-containing regimens	31	unknown	Decrease in mean brachial artery diameter	Immediately after first 5-FU treatment
	Colorectal cancer
Kosmas et al. [13]	Colorectal cancer	Capecitabine	644	4.03% (26)	Angina	Not reported
	Breast cancer	LV5-FU2			Palpitations
	Head and neck cancer	CDDP 5-FU			Sudden death
		MMC 5-FU			ECG changes
Yilmaz et al. [27]	Colorectal cancer	LV5-FU2	27	7.4% (2)	Angina	Not reported
	Gastric cancer				Decrease in mean heart rate
	Esophageal cancer				Increase in the number and complexity of premature complexes
Holubec et al. [28]	Colorectal cancer	De Gramont regimen	42	unknown	Laboratory signs of coronary	Not reported
		FOLFIRI			Ischemia
					Laboratory signs of heart failure
Tsibiribi et al. [29]	Colorectal cancer	5-FU	1350	1.2% (16)	Angina	Not reported
	Gastric cancer				Heart failure
	Oesophageal cancer				ECG changes
	Pancreatic cancer
Jensen et al. [30]	Colorectal cancer	Capecitabine	668	4.3% (29)	Angina	Capecitabine (XELOX): median 4 days (min: 2 days - max: 15 days)
	Gastric cancer	XELOX			Heart failure	5-FU Mayo: median 5 days (min: 3 days - max: 7 days)
		TCX				De Gramont regimen, FOLFOX4: median 3 days (min: 2 days - max: 6 days)
		De Gramont regimen
		5-FU Mayo
		FOLFOX4
Tsavaris et al. [31]	Colorectal cancer	5-FU-containing regimens	522	3.8% (20)	Acute myocardial infarction	Not reported
	Head and neck cancer				Ischemia
Ceyhan et al. [32]	Colorectal cancer	HD-LV5-FU	37	5.4% (2)	Transthoracic echocardiography and cyclic variation of integrated backscatter (CVIBS)	CVIBS: significantly decreased at the 48th hour of treatment
	Gastric cancer
	Head and neck cancer
	Breast cancer
Ng et al. [33]	Colorectal cancer	XELOX	153	6.5% (10)	Angina	Median cycle1 dayto (min: cycle1 day4-max: cycle4)
					Sudden death
					Heart failure
Meydan et al. [34]	Gastrointestinal	De Gramont regimen	231	3.9% (9)	Acute coronary syndrome	1–16 days
	Breast cancer				Congestive heart failure
	Head and neck cancer				Atrial fibrillation
Barutca et al. [35]	Gastrointestinal	5-FU-containing regimens	28	0.0% (0)		Not reported
Oztop et al. [36]	Gastrointestinal	LV5-FU2	22	Clinically evident cardiac event: 0.0% (0) QT interval prolongation: unknown	QT interval prolongation	QT interval prolongation: as early as 24 h
Sudhoff et al. [37]	Gastrointestinal	5-FU-containing regimens	30	unknown	Contraction brachial artery	Not reported
	Lung cancer
	Lymphoma
	Head and neck cancer
Wacker et al. [12]	Gastrointestinal	5-FU-containing regimens	102	18.6% (19)	Angina	Within 24 h
	Head and neck cancer
Van Cutsem et al. [38]	Colorectal cancer	5-FU (593)	1425	3.2% (46)	Chest pain	Not reported
	Breast cancer	Capecitabine (832)			Sudden death
					Heart failure
Balloni et al. [39]	Colorectal cancer	5-FU-containing regimens	25	8.0% (2)	Tachycardia	Not reported

CAPIRI: capecitabine + irinotecan; CAPOX, XELOX: capecitabine + oxaliplatin; CDDP 5-FU: cisplatin +5-FU; De Gramont regimen: leucovorin + 5-FU IV bolus and 5-FU continuous IV infusion; FOLFIRI: irinotecan + leucovorin +5-FU IV bolus and 5-FU continuous IV infusion; FOLFOX: oxaliplatin + leucovorin + 5-FU IV bolus and 5-FU continuous IV infusion, HD-LV5-FU: high-dose leucovorin + 5-FU. LF1: leucovorin + 5-FU; LV5-FU2: leucovorin + 5-FU IV bolus and 5-FU continuous IV infusion; MMC 5-FU: mitomycin + 5-FU; TCX: capecitabine + carboplatin + docetaxel; TPF: docetaxel + cisplatin + 5-FU; 5-FU Mayo: isovorin + 5-FU