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Cardiotoxicity of 5-fluorouracil in 1350 patients with no prior history of heart disease

Bulletin du Cancer. Volume 93, Number 3, 10027-30, Mars 2006, Electronic journal of oncology

Summary

Author(s) : Panayota Tsibiribi, Jacques Descotes, Catherine Lombard-Bohas, Cécile Barel, Bernard Bui-Xuan, Majda Belkhiria, Alain Tabib, Quadiri Timour , Laboratoire de pharmacologie médicale, EA 1896, Université Claude-Bernard, 8, av. Rockefeller, 69008, Lyon, France, Centre Antipoison, Centre de pharmacovigilance, 162, av. Lacassagne, 69003, Lyon, France, Unité d’oncologie médicale, Fédération des spécialités digestives, Hôpital E. Herriot, place d’Arsonval, Lyon 69003, France, Service d’anatomie pathologique, Hôpital cardiologique, av. Doyen Lépine, 69500, Bron, France.

Summary : To show the nature and magnitude of EKG anomalies subsequent to 5-fluorouracil (5FU) administration and determine whether the onset is dependent on a pre-existing cardiovascular pathological condition. 1,350 patients were treated by 5FU between 1995 and 2000. EKG were recorded in all patients before each administration of 5FU. All cases of 5FU related cardiotoxicity were analyzed and recorded by the Lyon Pharmacovigilance Center. Clinical symptoms included chest pain in 10 patients with an infarct-like pattern in 2 (including one death), and heart failure in one. Three patients suffered from anginal pain without EKG changes and two had electrocardiographic changes without clinical symptoms. Coronary disorders resolved completely on cessation of 5FU therapy, except in one patient who died two months later of heart infarct. The patient with heart failure required specific treatment. Based on both the clinical and electrocardiographic changes, the causative role of 5FU is highly likely. The incidence of cardiotoxicity was 1.2% among these patients, which is close to previous data from the literature. These 16 case reports confirm the cardiotoxic potential of 5FU and argue for the need of a careful cardiac monitoring of 5FU treated cancer patients. The mechanism of 5FU cardiotoxicity is not elucidated. Coronary spasm is the most commonly suspected hypothesis, but further studies are warranted to seek for toxic inflammatory lesions of the myocardium (apoptosis, necrosis, fibrosis).

Keywords : cardiotoxicity, 5-fluorouracil, adverse drug reactions, mechanism, risk factors

ARTICLE

Auteur(s) : Panayota Tsibiribi¹, Jacques Descotes², Catherine Lombard-Bohas³, Cécile Barel¹, Bernard Bui-Xuan¹, Majda Belkhiria¹, Alain Tabib⁴, Quadiri Timour^1,2

¹Laboratoire de pharmacologie médicale, EA 1896, Université Claude-Bernard, 8, av. Rockefeller, 69008, Lyon, France
²Centre Antipoison, Centre de pharmacovigilance, 162, av. Lacassagne, 69003, Lyon, France
³Unité d’oncologie médicale, Fédération des spécialités digestives, Hôpital E. Herriot, place d’Arsonval, Lyon 69003, France
⁴Service d’anatomie pathologique, Hôpital cardiologique, av. Doyen Lépine, 69500, Bron, France

Cardiotoxicity is a major complication of anticancer drugs [1], including anthracyclines [2], interferon-α [3] and 5-fluorouracil (5FU) [4]. As regards 5FU, the most severe cardiac complications are heart failure [5], arrhythmia [6-8] and myocardial ischemia [9]. Typically, 5FU cardiotoxicity presents as anginal pain and/or electrocardiographic changes compatible with myocardial ischemia (elevation or depression of the ST segment, inverted T wave), either isolated or combined [10]. In addition, impairment of cardiac contractility [11, 12] and rhythmic disturbances [6-8] have been described. Even though these complications are reversible in the majority of cases after cessation of 5FU administration and symptomatic treatment, sudden death has been reported [13, 14].In this paper, 16 cases of cardiac complications associated with 5FU therapy are described in patients with cancer of the digestive tract.

Patients

Between 1995 and 2000, 1350 patients were treated with 5FU in the Digestive Cancer Medical Unit of E. Herriot Hospital, Lyon. EKG were recorded systematically prior to each 5FU infusion in all patients. Patients with digestive cancer with a clinical history of myocardial ischemia or severe coronaropathy were not treated with 5FU, but with other non cardiotoxic drugs or had palliative supportive care. During this period, all cases of cardiac toxicity associated with 5FU were reported for analysis to Lyon post-marketing drug surveillance (Pharmacovigilance) Center.

Results

Sixteen cases of cardiac adverse effects in cancer patients treated with 5FU were observed during this period. The main characteristics of these patients are presented in table 1( Table 1 ). These 16 patients included 12 men and 4 women, and were between 26 and 71 years old (mean age: 56.2 years). None had a clinical history of heart disease, in particular myocardial ischemia or heart failure, and the EKG performed prior to 5FU treatment did not show any abnormality. However, four patients had hypertension, including two who had type II diabetes mellitus. Another patient had type II diabetes mellitus without hypertension and one, coronary artery atheroma evidenced by coronarography. Blood pressure and glycemia were adequately controlled by standard treatment.

Myocardial ischemia was the predominant feature. Ten patients complained of angina pectoris. Two were asymptomatic, but had electrocardiographic changes indicative of myocardial ischemia. Three patients had clinical symptoms without EKG disorders. Heart failure was observed in one patient. In all cases, clinical signs and electrocardiographic changes were observed after starting 5FU therapy and all patients fully recovered after 5-FU discontinuation, except one patient who died one month later due to myocardial infarct. Recovery was also obtained after treatment in the patient with heart failure.
Table 1 Summarized data

	Age/sex	Medical history	Cancer	5FU dose	Associated treatment	Clinical symptoms	ECG changes
1	65/M	none	Oesogastric	1.7 g/d	cisplatin	none	negative T waves (V2-V6)
TD = 6.8 g
2	71/M	hypertension diabetes	Colon	1.935 g/d	folinic acid	heart failure	normal
TD = 15.5g
3	68/M	hypertension	Colon	0.77 g/d	folinic acid	anginal pain	elevated ST (V4-V6) negative T waves (V3, V4)
TD = 3.8 g
4	67/M	hypertension	Colon	0.79 g/d	folinic acid	anginal pain	elevated ST (VL, D1) abnormal T waves (V3, V4)
TD = 7.9 g
5	26/F	none	Colon	1.43 g/d	folinic acid oxaliplatin	anginal pain	negative T waves (D3)
TD = 5.63 g
6	52/F	none	Colon	0.72 g/d	folinic acid	anginal pain	normal
TD = 3.6 g
7	76/M	coronary atheroma	Pancreas	1.11 g/d	gemcitabine	myocardial infarct, death	depressed ST (V4-V6, D3, VF)
TD = 5.55 g
8	57/M	none	Colon	0.8 g/d	folinic acid	anginal pain	depressed ST
TD = 3.2 g
9	72/M	none	colon	1 g/d	folinic acid	anginal pain	depressed ST
TD = 2 g
10	76/M	phlebitis	oesogastric	?	cisplatin	anginal pain	depressed ST
11	67/M	none	colon	790 mg/d	folinic acid	anginal pain	depressed ST
TD = 3.95 g
12	69/M	hypertension diabetes mellitus	oesogastric	1.6 g/d	cisplatin	none	repolarization anomalies
TD = 8 g
13	50/M	Alcoholic cirrhosis	oesogastric	1.8 g/d	cisplatin	thoracic pain	normal
TD = 18.9 g
14	44/M	none	colon	800 mg/d	irinotecan levofolinic acid	thoracic pain	myocardial ischemia at scintigraphy
TD = 8g
15	52/F	diabetes mellitus	colon	0.19-1.2 g/d	irinotecan levofolinic acid	thoracic pain	normal
DT : 15.2 g
16	73/F	pulmonary embolism	colon	158-950 mg/d	levofolinic acid	infarct-like symptoms	elevated ST death after 1 month
TD = 7.58 g

Discussion

Because the clinical symptoms and electrocardiographic changes developed in these patients after starting 5FU treatment and ceased after 5FU discontinuation, 5FU is considered as the most likely cause of cardiac adverse events. The time course does not suggest the involvement of combined treatment when present.

Although the cardiotoxic effects of 5FU have already been described, estimates of their incidence are variable. In our oncology unit, 1,350 patients were treated with 5FU between 1995 and 2000. The incidence of 5FU related cardiotoxicity was therefore 1.2%. In a study reported by Labianca et al. of over 1000 patients, the incidence was 1.6% [15]. Other studies on smaller number of patients found an incidence between 1.2 and 18% with a mortality rate between 2.2 and 13.3%, in particular in case of symptomatic cardiopathy [16-18]. According to Meyer et al. [19], heart failure occurs in 3.5% and very often during the first course of chemotherapy.

A number of mechanisms have been proposed to explain 5FU cardiotoxicity. Many authors consider coronary spasm as the most likely mechanism resulting in angina and EKG alterations [20, 21]. However, the fact that angina associated with 5FU is often resistant to calcium antagonist drugs does not support this hypothesis [6, 8, 22, 23]. Moreover, the reintroduction of 5FU in patients with a previous adverse effect associated with 5FU did not result in coronary spasm as evidenced by coronarography [20]. The hypothesis that endothelin-1 (ET1) release could be involved [24] has never been substantiated. Another widely proposed mechanism is direct cardiotoxicity [17]. 5FU might injure the vascular endothelium, thus provoking thrombosis and the release of vasoactive substances. Cwikiel et al. [25] observed injuries of the vascular endothelium in the central ear arteries of rabbits that could result in arterial thrombosis due to platelet aggregation. In another study comparing the effects of methotrexate to those of 5FU on cultured bovine endothelial cells, 5FU, but not methotrexate was found to activate prostacyclin release by endothelial cells [26]. A reduction of antioxidant defense capacities in myocardial tissues is another hypothesis. The administration of 400 mg/kg/day of 5FU to guinea-pigs reduced the activity of the cardiac enzymes superoxide dismutase and glutathione peroxidase, and concomitantly there was an increase in the activity of catalases and malondialdehyde concentrations [27]. Interestingly, an increase in malondialdehyde concentrations is consistently observed in myocardial ischemia and this increase is prevented or reversed by calcium inhibitors [28]. A proliferation of the sarcoplasmic reticulum with vacuolizations similar to that occurring with anthracyclines was also reported with 5FU [29]. This could explain heart failure seen in one of our patients as well as in a 25 year-old patient with carcinoma of the tongue treated with 5FU [29]. In this latter patient, an endomyocardial biopsy showed the proliferation of the sarcoplasmic reticulum with numerous vacuolizations. In these two patients, no clinical or electrocardiographic signs of myocardial ischemia were observed. The possibility remains that different mechanisms may be involved either concomitantly or exclusively, but further studies are necessary to elucidate potential causative mechanism.

Another important aspect of 5FU cardiotoxicity is the role of preexisting risk factors. According to Labianca et al. [15], the global incidence of heart lesions associated with 5FU is higher in patients with a cardiac history in comparison to patients with no cardiac history (4.5 versus 1.1%). The incidence of sudden death in this population was 12.5%. As mediastinal radiotherapy is responsible for severe cardiac lesions, including death due to myocardial infarction, the risk of 5FU cardiotoxicity was logically reported to be increased in 5FU-treated patients receiving mediastinal radiotherapy [23].

In addition, 5FU cardiotoxicity was clearly shown to be dose-dependent [30, 31]. No electrocardiographic or cardiac enzyme changes were seen in 16 patients with colorectal carcinomas after receiving a low dose of 5FU (400 mg/m²/day) combined with folinic acid (20 mg/m²/day) [30]. A cumulative dose threshold for severe heart effects has been calculated between 1.5 and 7 g [6]. This estimate is based on the study of 231 patients treated with 5FU. Six patients developed severe cardiac lesions including acute cardiac ischemia, hypotension, atrio-ventricular block, bundle branch block, auricular fibrillation, tachycardia, extra-systoles and myocardial infarction. In addition, 5 of these patients had a heart failure revealed by echocardiography. The dose of 5FU ranged between 500 to 600 mg/m²/day for 5 days every 3 or 4 weeks in 201 patients, while 30 patients received infusions of higher doses (1.6 to 3 g/day every week). Symptoms in these latter patients developed during the 24 first hours of treatment. All patients were admitted to an intensive care unit and were treated with nitric derivatives, calcium antagonists, heparin and morphine. Three patients were again treated with 5FU after complete regression of their symptoms, and 2 had heart damage, one of which evolved to ventricular fibrillation. The authors concluded that the unit dose administered on one occasion rather than the cumulative dose can also constitute a risk factor, as cardiotoxicity was only observed in patients receiving 3 g/24 hours with recurrence within 24 hours. When patients were given 600 mg/m²/day for 5 days, the cumulative dose of 3 g induced less cardiac damage.

In conclusion, the 16 cases reported here and the analysis of the literature confirm the cardiotoxicity of 5FU. All of these patients had no history of cardiopathy or myocardial ischemia, and this was confirmed by EKG recordings prior to each 5FU administration. Because 2 of these 16 patients remained asymptomatic despite electrocardiographic changes, it is suggested to perform EKG recording before each 5FU administration. As no specific treatment has yet been identified, nitric derivatives and calcium inhibitors can logically be recommended.

Acknowledgements

The authors acknowledge the valuable assistance of B. Tourlière for the literature search.

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