5-fluorouracil Cardiotoxicity Research Articles

Cardiotoxicity from Capecitabine Chemotherapy: Prospective Study of Incidence at Rest and During Physical Exercise.

BackgroundPhysical activity may increase the risk of cardiotoxicity (myocardial ischemia, major arrhythmias) of 5-Fluorouracil, but this risk has never been investigated for its prodrug capecitabine.Patients and MethodsOne hundred and ninety-two consecutive patients undergoing capecitabine chemotherapy from December 1, 2010 through July 31, 2016 were prospectively evaluated. The baseline evaluation included electrocardiography (ECG) and echocardiography (2DE); a follow-up evaluation, including ECG and exercise stress testing (2DE in case of ECG abnormalities), was done after ≥10 days of treatment. Cardiotoxicity was suspected from ischemic ECG changes, new kinetic abnormalities at 2DE, Lown classification ≥2 ventricular arrhythmia, symptomatic arrhythmias, or positive stress test, and confirmed by a negative stress test after capecitabine washout.ResultsCardiotoxicity was diagnosed in 32 patients (16.7%): six at rest and 26 during exercise. All 32 patients had ECG abnormalities: ST-segment changes (24 patients), negative T-waves (2) and/or arrhythmias: ventricular arrhythmias (14 cases), supraventricular tachycardia (2), complete heart block (1). Eight patients had typical symptoms, 6 had atypical symptoms, 1 had syncope, 17 (53%) were asymptomatic. Cardiotoxicity was more common in patients with atypical symptoms during daily life (OR = 15.7) and in those on a therapeutic schedule of 5 days/week (OR = 9.44).ConclusionCapecitabine cardiotoxicity is frequent, and often elicited by physical effort. Oncologists, cardiologists, and general practitioners should be aware of this risk. Active cardiotoxicity surveillance with ECG (and echocardiogram and/or stress testing in suspected cases) during therapy is recommended.Clinical Trials registration numberCRO-2010-17.

Cardiotoxicity of 5-fluorouracil and capecitabine in Chinese patients: a prospective study

Background5-Fluorouracil (5-FU) and capecitabine-associated cardiotoxicity ranging from asymptomatic electrocardiography (ECG) abnormalities to severe myocardial infarction has been reported in a number of studies, but such cardiotoxicity in Chinese patients with malignant diseases has not been investigated to date. In the present study, we aimed to prospectively evaluate the incidence rates and clinical manifestations of 5-FU- and capecitabine-associated cardiotoxicity in cancer patients recruited from multiple centers in China.MethodsAmong the 527 patients who completed the study, 196 received 5-FU-based chemotherapy and 331 received capecitabine-based chemotherapy as either first-line or adjuvant therapy. Adverse events were reported during the treatment and up to 28 days of follow-up. Outcome measures included ECG, myocardial enzymes, cardiac troponin, brain natriuretic peptide and echocardiography. Univariate analysis and logistic regression were performed for subgroup analysis and identification of significant independent variables that are associated with cardiotoxicity of both agents.ResultsIn total, 161 of 527 patients (30.6%) experienced cardiotoxicity. The incidence rate of cardiotoxicity was 33.8% (112/331) in the capecitabine group, which was significantly higher than the rate of 25% (49/196) in the 5-FU group (P = 0.0042). 110/527 patients (20.9%) suffered arrhythmia, 105/527 (19.9%) developed ischemic changes, while only 20/527 patients (3.8%) presented heart failure and 6/527 patients (1.1%) had myocardial infarction. Pre-existing cardiac disease, hypertension, capecitabine-based chemotherapy and duration of treatment were identified as significant risk factors associated with cardiotoxicity. The odds ratio were 15.7 (prior history of cardiac disease versus no history), 1.86 (capecitabine versus 5-FU), 1.06 (5–8 versus 1–4 chemotherapy cycles) and 1.58 (hypertension versus no hypertension), respectively.ConclusionsCardiotoxicity induced by fluoropyrimidines in the Chinese population may be underestimated in clinical practice. Close monitoring of patients is recommended, especially for those patients at high risk for cardiotoxicity. Possible risk factors are duration of treatment, capecitabine-based chemotherapy, pre-existing cardiac diseases and hypertension.Trial registration This study was initiated on January 22, 2014 and has been retrospectively registered with the registration number ChiCTR1800015434

Role of Exogenous Phosphocreatine in Chemotherapy-induced Cardiomyopathy

The 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) regimen is widely used in the management of breast cancer. The common cardiotoxic effects of doxorubicin include congestive heart failure and left ventricular dysfunction, and those of cyclophosphamide include pericarditis, myocarditis, and congestive heart failure. It has been postulated that cardiotoxicity of 5-fluorouracil presents as coronary artery diseases (eg, angina). Cardiomyopathy is a common outcome following treatment with the FAC regimen. We report on a 52-year-old woman with cardiomyopathy following chemotherapy and radiation therapy. The patient did not respond well to b-blockers and angiotensin-converting enzyme inhibitors. After the addition of exogenous phosphocreatine, the patient's cardiac condition improved significantly.

Vascular Toxicities of Cancer Therapies: The Old and the New--An Evolving Avenue.

Since the late 1990s, there has been a steady decline in cancer-related mortality, in part related to the introduction of so-called targeted therapies. Intended to interfere with a specific molecular pathway, these therapies have, paradoxically, led to a number of effects off their intended cancer tissue or molecular targets. The latest examples are tyrosine kinase inhibitors targeting the Philadelphia Chromosome mutation product, which have been associated with progressive atherosclerosis and acute vascular events. In addition, agents designed to interfere with the vascular growth factor signaling pathway have vascular side effects ranging from hypertension to arterial events and cardiomyocyte toxicity. Interestingly, the risk of cardiotoxicity with drugs such as trastuzumab is predicted by preexisting cardiovascular risk factors and disease, posing the question of a vascular component to the pathophysiology. The effect on the coronary circulation has been the leading explanation for the cardiotoxicity of 5-fluorouracil and may be the underlying the mechanism of presentation of apical ballooning syndrome with various chemotherapeutic agents. Classical chemotherapeutic agents such as cisplatin, often used in combination with bleomycin and vinca alkaloids, can lead to vascular events including acute coronary thrombosis and may be associated with an increased long-term cardiovascular risk. This review is intended to provide an update on the evolving spectrum of vascular toxicities with cancer therapeutics, particularly as they pertain to clinical practice, and to the conceptualization of cardiovascular diseases, as well. Vascular toxicity with cancer therapy: the old and the new, an evolving avenue.

A mechanistic study on the cardiotoxicity of 5-fluorouracil in vitro and clinical and occupational perspectives

Fluoropyrimidines are key agents for the treatment of gastrointestinal tract adenocarcinomas. The possible cardiotoxic effects in patients and occupationally exposed workers are multifactorial and remain a puzzle to solve for investigators. In the present study, we study what cell death pathways and what doses can determine direct cardiotoxic effects of 5-fluorouracil (5-FU) and doxorubicin (DOXO) on rat cardiocytes (H9c2) and a human colon adenocarcinoma (HT-29) cell line, already reported to be sensitive to 5-FU. We have found that 5-FU induced 50% growth inhibition (IC:50) at 72h with concentrations of 400μM and 4μM on H9c2 and HT-29, respectively. Moreover, we have found that the addition of Levofolinic Acid (LF) to 5-FU potentiated the growth inhibition induced by 5-FU. The growth inhibition induced by 5-FU alone or in combination with LF in cardiocytes was paralleled by an increase of thiobarbituric acid-reactive species (Tbars) and end products of nitric oxide (NO) suggesting the increase of the oxidative stress status in cardiocytes. Interestingly, these effects were strongly potentiated by the addition of LF, a biochemical modulator of 5-FU activity.Our data suggest that agents such as 5-FU different from anthracyclines, conventionally related to the induction of cardiotoxic effects, can also induce cardiocyte damage paralleled by oxidative stress. The strategies based upon the use of scavengers could be used in order to prevent this effect.

Cardiotoxicity of 5-fluorouracil in patients with gastrointestinal cancer.

689 Background: 5-fluorouracil (5-FU) is a agent of chemotherapy that has been associated with cardiotoxicity infrequently. The reports shown incidence of clinically apparent 5-FU cardiotoxicity in 1.6% for patients receiving 5-FU alone or in combination with another agents. Methods: We investigated the clinical characteristics of 5-FU cardiotoxicity in patients with gastrointestinal cancer treated in instituto nacional de enfermedades neoplasicas (INEN) Lima - Peru between October 2009 and October 2010. Results: Between October 2009 and October 2010, were evaluated 240 cases with gastrointestinal cancer treated with 5-FU alone or plus combinations with another chemotherapy agent, 8 cases (3.3%) had cardiotoxicity. 37.5 % had history of cardiovascular disease, 3 patients had a history of hypertension and 1 patient diabetes mellitus plus hypertension. 50% (4 patients ) had normal EKG prior to treatment, 25% (2 patients) had no EKG, In 12.5% (1patient) had sinus tachycardia and another patient had ventricular extrasystoles were detected. After chemotherapy infusion 75% (6) had changes in the EKG. In 8 patients was observed as the main symptom chest pain with radiation to left arm or upper back, without elevated cardiac enzymes. 87.5% (7 patients ) had symptoms after 6 pm. And the duration of symptoms was 48 hours in 62.5% (5 patients), 12.5% (1patient ) in 24 hours and 6 hours in 12.5% (1 patient). One patient died of acute heart failure and had history of hypertension and diabetes mellitus and received the combination cisplatin - 5-FU. Conclusions: The eight cases reports confirm the potential cardiotoxicity of 5-FU and argues the need for cardiovascular assessment by a specialist before the start of treatment in addition to cardiac monitoring in patients during treatment, especially in patients with risk factors especially in the first cycle, women and at night. The mechanism of 5-FU cardiotoxicity is not fully elucidated. Coronary spasm is the most accepted hypothesis.

5-Fluorouracil-induced coronary vasospasm

Cardiotoxicity due to 5-fluorouracil involves rare and life-threatening cardiotoxic events occurring in less than 1% of the patients. We describe a case of coronary vasospasm due to parenteral 5-fluorouracil, which did not recur with oral capecitabine. We also give a brief review of the cardiotoxicity of 5-fluorouracil, its treatment and prevention.

Réversibilité d'un état de choc cardiogénique sous 5-fluorouracil

5-fluorouracil, an antimetabolite agent, has been widely used since 1957 for treatement of varied types of cancer such as gastro-intestinal, pancreas, breast, lung, head and neck malignancies. Cardiotoxicity of 5-fluorouracil is rare and was first described in 1975. It can induce severe complications and involve vital prognosis in the short term. These complications are less known by cardiologists than medical oncologists. The following clinical case represents a potentially serious and rare case of completely reversible cardiogenic shock in a patient with a colo-rectal cancer. A better knowledge of these complications could reduce cases of death by an earlier diagnosis, and a better evaluation of patients with high cardiotoxicity risk.

Noninvasive evaluation of cardiotoxicity of 5-fluorouracil and low doses of folinic acid: A one-year follow-up study

To conduct a serial evaluation of the cardiac effects of antineoplastic therapy with 5-fluorouracil (5-FU) and low-dose folinic acid. Sixteen patients with colon-rectal carcinoma, without cardiac disease, treated with 400 mg/ m2/die of 5-FU and 20 mg/m2/die of folinic acid for five days, once a month, for six months. Parameters evaluated: blood pressure, ECG, two-dimensional and digitized M-mode echocardiograms before and after the first and fifth drug administrations of the first cycle, after the fifth drug administration of the sixth cycle and six months after the treatment. Blood pressure, heart rate, left ventricular (LV) diameter and LV mass index did not change; all of the patients showed a decrease in the peak shortening rate of the LV diameter index of systolic function, and of the peak lengthening rate of the LV diameter and peak thinning rate of LV posterior wall, indexes of diastolic function, with abnormal values in 11 patients at the end of treatment LV wall motion remained normal in all; two patients developed transient T wave inversion without chest pain and with normal cardiac enzymes and myocardial scintigraphy during dypiridamole stress test. Six months after the treatment all indexes of LV systolic and diastolic function had returned within the normal limits and were similar to pre-treatment values. 5-FU and low-dose folinic acid treatment induced a decrease of LV systolic function and an impairment of diastolic function, that developed without symptoms and were transient and reversible.

THE TRIS FORMULATION OF FLUOROURACIL IS MORE CARDIOTOXIC THAN THE SODIUM-SALT FORMULATIONS

The cardiotoxicity of 5-fluorouracil (FU) was attributed to degradation compounds present in the injected vials, fluoroacetaldehyde (Facet) and fluoromalonaldehydic acid (FMald). FU-NaOH vials were much less cardiotoxic than FU-Tris vials on the isolated perfused rabbit heart model since Facet and FMald are stored in stable depot forms in FU-Tris vials whereas, in FU-NaOH vials, they are extensively transformed. Cardiotoxic fluoroacetate (FAG), coming from Facet metabolization, was found in urine of patients, with a ratio FAC /FU catabolites 10-30 fold lower in patients treated with FU-NaOH than in those treated with FU-Tris.

Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer.

Cardiotoxicity related to the widely used cytotoxic compound 5-fluorouracil (5-FU) is rare compared with the frequency observed with the use of anthracyclines. More effective protocols incorporating active biomodulatory compounds like folinic acid (FA) or combination chemotherapy change type and severity of toxicity as well. The objective of the current study was to assess cardiotoxicity of the combination 5-FU and folinic acid. The authors' multicenter experience with 390 patients treated for advanced gastrointestinal cancer with intermediate-dose folinic acid and 5-FU was reviewed. The overall risk of cardiotoxicity was 3%, which is not significantly higher than that reported with 5-FU alone. Eight of 53 patients with a history of cardiac disease reported cardiac symptoms (15.1%), compared with 5 of 337 patients (1.5%) with a no history of cardiac disease. Median time to symptoms was 3 days (range, 2-6). Nine patients had symptoms resembling myocardial ischemia, one patient died due to assumed myocardial infarction related closely to fluorouracil treatment, four patients had supraventricular arrhythmia, and one patient had congestive heart failure. A history of cardiac disease was the only risk factor associated with cardiotoxicity. Relapses were frequent on reinstitution of therapy despite cardiac symptoms in the preceding cycle. Therapeutically or prophylactically administered nitrates had no significant effect. Physicians should be aware of the cardiotoxic properties of active fluorouracil treatment. The combination of 5-FU and leucovorin does not differ from single-agent therapy in frequency or type of cardiotoxicity. Close monitoring of patients is mandatory, especially for those patients at high risk for cardiac side effects. Treatment should be discontinued if coronary symptoms develop, because neither effective treatment nor prophylaxis exists for such symptoms.

Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug

The cardiotoxicity of 5-fluorouracil (FU) was attributed to impurities present in the injected vials. One of these impurities was identified as fluoroacetaldehyde which is metabolised by isolated perfused rabbit hearts into fluoroacetate (FAC), a highly cardiotoxic compound. FAC was also detected in the urine of patients treated with FU. These impurities were found to be degradation products of FU that are formed in the basic medium employed to dissolve this compound. To avoid chemical degradation of this antineoplastic drug, the solution of FU that will be injected should be prepared immediately before use.

A comparative study on the cardiotoxicity of 5-fluorouracil and ftorafur in rabbits.

Intravenous administration of 5-FU 15 mg/kg significantly lowered the blood pressure 17 hours after, while ftorafur 20 mg/kg did not alter the pressure. Ftorafur 60 mg/kg significantly lowered the pressure 17 hours after the drug administration. In a large number of rabbits treated with 5-FU 15 mg/kg or ftorafur 60 mg/kg, the ventricular fibrillation spontaneously produced within 17 hours after the treatment. Adrenaline 5-50 μg/kg was injected into an ear vein in a stepwise manner, to assess whether or not the drug would induce a ventricular fibrillation. Pretreatment with 5-FU 15 mg/kg sensitized the ventricle to adrenaline-induced ventricular fibrillation, while ftorafur 20 and 60 mg/kg did not. The time required to produce ventricular fibrillation after a large dose (200 μg/kg) of ouabain was significantly shorter in 5-FU 15 mg/kg and ftorafur 60 mg/kg treated (17 hours before) groups than in the control group, while in the ftorafur 20 mg/kg treated group, the time was much the same as seen in the control group. These findings indicate that the cardiotoxicity of ftorafur in rabbits may be weaker than that of 5-FU.