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Medline ® Abstracts for References 5-15

of 'Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management'

5
TI
Cardiac toxicity of 5-fluorouracil: a study on 1083 patients.
AU
Labianca R, Beretta G, Clerici M, Fraschini P, Luporini G
SO
Tumori. 1982;68(6):505.
 
The possible onset of cardiotoxic manifestations during chemotherapy with 5-fluorouracil (5-FU) was evaluated in 1083 patients treated with the drug for various kinds of neoplasm. We recognized 17 cases of 5-FU cardiopathy (usually anginous crises but also myocardial infarction). The comprehensive incidence was 1.6%, with a significantly greater risk (4.5% vs 1.1%) for patients with a positive anamnesis of previous cardiopathy. On the contrary, age and combination with other antiblastic drugs had no affect on the appearance of cardiopathy. We conclude that 5-FU cardiopathy, although rare, has to be taken into account in oncologic practice, chiefly in those patients already affected with cardiac diseases.
AD
PMID
6
TI
Fluorouracil cardiotoxicity.
AU
Anand AJ
SO
Ann Pharmacother. 1994;28(3):374.
 
OBJECTIVE: To review the clinical manifestations, postulated mechanisms, and therapeutic implications of fluorouracil-induced cardiac toxicity.
DATA SOURCE: A MEDLINE search was used to identify pertinent literature.
STUDY SELECTION: Studies and case reports on fluorouracil cardiotoxicity were identified through a MEDLINE search. A manual review of bibliographies of identified articles was performed to ensure that all pertinent articles were included.
DATA EXTRACTION: Data pertaining to all aspects of fluorouracil cardiac toxicity, including pathogenesis, predisposing factors, clinical manifestations, and therapeutic implications, were evaluated.
DATA SYNTHESIS: Estimates from large series suggest a 1.6-2.3 percent incidence of clinically demonstrated cardiotoxicity. Predisposing factors include the presence of coronary artery disease and concurrent radiotherapy. Postulated mechanisms include direct myocardial ischemia, coronary spasm, or cardiotoxic impurities in fluorouracil formulation. Clinical manifestations include chest pain, nausea, diaphoresis with typical ischemic electrocardiographic (ECG) changes, relieved to normal after stopping the drug therapy. Nitrates and calcium-channel blockers do not protect against cardiotoxicity.
CONCLUSIONS: Fluorouracil cardiotoxicity may be much more common and clinically significant than previously thought. A high index of suspicion for cardiotoxicity must be maintained when the drug is administered, especially in the presence of heart disease and concomitant radiation therapy. In the presence of chest pain, it is mandatory to stop the infusion and, if possible, to replace fluorouracil with another chemotherapeutic agent.
AD
Department of Medicine, Nassau County Medical Center, East Meadow, NY 11554.
PMID
7
TI
Symptomatic cardiotoxicity with high-dose 5-fluorouracil infusion: a prospective study.
AU
Akhtar SS, Salim KP, Bano ZA
SO
Oncology. 1993;50(6):441.
 
Cardiotoxicity with 5-fluorouracil (5-FU) therapy has been reported to range from asymptomatic EKG abnormalities to fatal myocardial infarction. We report a prospective study in 100 consecutive patients receiving 5-FU infusion in combination with other chemotherapeutic agents or alone for the treatment of different malignancies with the aim of identifying patients who develop symptomatic cardiotoxicity. Patients with a history of cardiac illness, abnormal EKG or cardiac enzyme levels were excluded. Patients were observed during the total period of infusion, daily EKG was performed on asymptomatic patients, those who developed cardiotoxicity were monitored till symptom-free for 24 h. Eight patients developed symptoms suggestive of cardiotoxicity. Pain was the commonest symptom (5/8), followed by palpitation and sweating. Three patients developed EKG abnormalities and 1 went into cardiogenic shock. Time to toxicity ranged from 18 to 30 h (mean 24 +/- 3.7 h) and serial cardiac enzyme levels remained normal in all patients. The symptoms reversed immediately on cessation of the treatment in most of the patients (7/8). Time to recovery ranged from 5 to 60 min (mean 19.28 +/- 19.6 min). There was no recorded death due to toxicity. We conclude that 5-Fu infusion is associated with a significant risk of symptomatic cardiotoxicity. Concomitant chemotherapeutic agents, received by all the affected patients, may have a contributory effect too. Cardiotoxicity seems to be completely reversible, particularly in patients without underlying cardiac disease. The patients should be informed about the symptoms and the condition recognised and managed immediately.
AD
Department of Medical Oncology, SK Institute of Medical Sciences, Soura, Srinagar.
PMID
8
TI
Fluoropyrimidine-associated cardiotoxicity: revisited.
AU
Saif MW, Shah MM, Shah AR
SO
Expert Opin Drug Saf. 2009;8(2):191.
 
BACKGROUND: The syndrome of 5-fluorouracil (5-FU)-associated cardiotoxicity remains poorly defined.
PATIENTS AND METHODS: We performed a literature review (1969 - 2007) and compiled data derived from 377 evaluable cases out of 448 reported cases.
RESULTS: Patient age ranged from 14 to 86 years. Of the patients 65% were 55 years old and the male:female ratio was 1.5:1. The most commonly treated tumors were gastrointestinal (60%), head and neck (22%) and breast (4%). Of the patients 14% had a history of heart disease whereas cardiac risk factors were found in 37%. Mode of administration included: continuous infusion (72%); bolus (22.5%); intermediate infusion (3%); oral (2%); and intraperitoneal (1 patient). The dosages of 5-FU used were<750 mg/m(2)/day (36%), 751 - 999 (16%), 1,000 (26%), 1,001 - 1,499 (4%) and 1,500 (16%). Of the patients 54% received 5-FU in combination with other chemotherapeutic agents (cisplatin 44%) whereas 51% received 5-FU alone or with leucovorin. Only 4% patients had undergone previous or concomitant radiation therapy to the mediastinum. Of cardiac incidents that happened 69% were seen during or within 72 h of the first cycle of 5-FU. Angina occurred in 45% ofpatients whereas myocardial infarction was seen in 22%, arrhythmias in 23, acute pulmonary edema in 5, cardiac arrest and pericarditis in 1.4 and heart failure in 2. Electro-cardiographic evidence of ischemia or ST-T changes were recorded in 69% of patients, but abnormal cardiac enzymes were found in only 12%. The cardiac symptoms were reproducible in 47%, including in one patient subsequently treated with 5-FU p.o. Symptoms were also elicited when the same patients were treated with lower doses or different schedules. Of the patients 68% responded to conservative anti-anginal therapy, although prophylactic coronary vasodilators had limited efficacy. Overall, 8% of patients showing cardiotoxicity on 5-FU administration died. Furthermore, 13% reexposed to 5-FU died.
CONCLUSIONS: Our review suggests that 5-FU cardiotoxicity is an infrequent but real phenomenon that is independent of dose and may be related to a continuous infusion schedule. The presence of cardiac risk factors is not predictive. Patients should be observed closely and 5-FU administration discontinued if cardiac symptoms develop. A rechallenge with 5-FU should be reserved only for those patients in whom there is no reasonable alternative therapy and should be performed in the setting of aggressive prophylaxis and close monitoring.
AD
Yale University School of Medicine, FMP 116, CT 06520, New Haven, USA. wasif.saif@yale.edu
PMID
9
TI
Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study.
AU
de Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, Canal P, Chevreau C, CarriéD, SouliéP
SO
J Clin Oncol. 1992;10(11):1795.
 
PURPOSE: A prospective clinical study was performed to determine the incidence of high-dose continuous intravenous infusion fluorouracil (5FU-CIV) cardiotoxicity.
PATIENTS AND METHODS: Three hundred sixty-seven patients who were given first-cycle high-dose 5FU-CIV were monitored for cardiac function by clinical examination, ECG, and laboratory tests. 5FU-CIV was administered during a 96- or 120-hour period at doses that ranged from 600 to 1,000 mg/m2/d. Associated drugs included cisplatin (56%), mitomycin (12.5%), folinic acid (leucovorin) (7%), and others (14%). Thirty-nine patients (10.5%) received 5FU as a single agent.
RESULTS: 5FU-induced cardiac events occurred in 28 patients (7.6%; 95% confidence interval, 4.9% to 10.3%). Nine of them had a history of cardiac disease. Primary tumors included head and neck (n = 13), gastrointestinal (n = 6), breast (n = 3), and others (n = 6). The mean onset time of cardiac symptoms was 3 days (range, 2 to 5). Inaugural symptoms included angina pectoris (n = 18), hypotension (n = 6), hypertension (n = 5), malaise (n = 4), dyspnea (n = 2),arrhythmia (n = 1), or sudden death (n = 1). At 5FU discontinuation, six patients' cardiac symptoms returned to baseline, but 21 patients experienced unstable angina (n = 8), hypotension/cardiovascular collapse (n = 11), pulmonary edema (n = 1), or sudden death (n = 4). The lethality rate was 2.2% (five sudden deaths plus three irreversible collapses). ECG showed repolarization changes (ST segment deviation; T-wave inversion) in 65% and/or diffuse microvoltage in 22% of the patients who presented with cardiac events. Echocardiography showed partial or global hypokinesia in nine of the 16 patients who were examined, and one case of prolonged akinesia. Cardiac enzymes rarely showed an increase (n = 2). In severe but reversible cases, clinical, ECG, and echographic parameters returned to baseline status within 48 hours after the drug discontinuation. A fluorine 19 nuclear magnetic resonance (19F NMR) analysis of urine was performed on 14 patients; six had cardiac symptoms and eight did not. Fluoroacetate (FAC), a known cardiotoxic compound, was detected in all cases.
CONCLUSION: In our study, the incidence of high-dose 5FU-CVI cardiotoxicity was 7.6%. The hypothesis of a toxic cardiomyopathic process requires further confirmation.
AD
Department of Medical Oncology, Centre Claudius Regaud, Toulouse, France.
PMID
10
TI
High incidence of angina pectoris in patients treated with 5-fluorouracil. A planned surveillance study with 102 patients.
AU
Wacker A, Lersch C, Scherpinski U, Reindl L, Seyfarth M
SO
Oncology. 2003;65(2):108.
 
OBJECTIVE: Angina pectoris, arrhythmic sudden death and myocardial infarction, all these cardiac events have occasionally been reported during 5-fluorouracil (5-FU) chemotherapy. Underlying mechanisms leading to these events are unknown; damage to the myocytes or vasospasms have been discussed.
METHODS: 102 consecutive and unselected patients were monitored with 12-lead ECG, echocardiography and radionuclide ventriculography prior to the first cycle of 5-FU chemotherapy and 3 months from baseline.
RESULTS: 19% of the patients developed reversible symptoms of angina pectoris during treatment which lasted up to 12 h after cessation of the infusion. Most of the 19 patients showed corresponding ECG changes. 6 out of the 19 patients with severe angina pectoris had subsequent coronary angiography. In none of these patients the coronary angiography showed coronary artery disease, but it showed low ventricular function (ejection fraction<50%) in 2 patients. The ejection fraction did not increase over time. Arrhythmias were screened for withHolter monitoring during 5-FU chemotherapy. The frequency of bradycardia and ventricular extrasystoles increased significantly (p<0.05) during treatment compared to arrhythmias in Holter monitoring 3 months later. Furthermore the Qtc time in the ECG 3 months later was significantly prolonged (p<0.05) compared to baseline values.
CONCLUSIONS: The incidence of angina pectoris in patients during 5-FU treatment seems higher than previously suspected. As myocardial ischemia can be fatal, attentiveness to these symptoms and immediate treatment are crucial.
AD
I. Medizinische Klinik und Deutsches Herzzentrum, Klinikum rechts der Isar, Technische Universität München, München, Deutschland. wacker@dhm.mhn.de
PMID
11
TI
Fluorouracil induces myocardial ischemia with increases of plasma brain natriuretic peptide and lactic acid but without dysfunction of left ventricle.
AU
Jensen SA, Hasbak P, Mortensen J, Sørensen JB
SO
J Clin Oncol. 2010;28(36):5280. Epub 2010 Nov 15.
 
PURPOSE: Fluorouracil (FU) is a cornerstone of colorectal cancer treatment; however, it has clinical and subclinical influence on the heart. This study aimed to clarify the pathophysiology, risk factors, and long-term effects of FU cardiotoxicity.
PATIENTS AND METHODS: The study prospectively accrued colorectal cancer patients (n=106) completely resected and adjuvantly treated with FU and oxaliplatin according to the FOLFOX4 regimen (infusional FU, folinic acid, and oxaliplatin). Serial measurements were made of systolic and diastolic features of the left ventricle by radionuclide ventriculography, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), lactic acid, and ECG before chemotherapy, immediately after a treatment infusion, and at follow-up 2 weeks after cessation of the intended 12 treatment courses and were further evaluated by multivariate regression analysis that included cardiovascular history and its risk factors.
RESULTS: In the entire cohort, NT-proBNP significantly increased from baseline 14.5±3.2 pmol/L (mean±standard error) to 28.3±5.3 pmol/L during FU therapy (P<.001). Nine patients (8.5%) with cardiotoxicity had significantly higher NT-proBNP of 55.3±40.8 pmol/L compared with 25.4±4.1 pmol/L in those without (P<.001). In multivariate analysis, the FU-induced rise of NT-proBNP was significantly higher in females (P<.001). Plasma lactic acid significantly increased from baseline (1.3±0.1 mmol/L to 1.8±0.1 mmol/L) during FU therapy (P<.001). Left ventricular ejection fraction at baseline of 0.66±0.01 remained unchanged at 0.65±0.01 during FU therapy and 0.66±0.01 at follow-up (P=.4).
CONCLUSION: FU therapy generally induces myocardial neuroendocrine changes with increasing plasma NT-proBNP and lactic acid but without long-term dysfunction of the left ventricle. The usability of NT-proBNP as a predictive marker for FU cardiotoxicity remains to be clarified.
AD
Rigshospitalet, Copenhagen University Hospital, and Department of Oncology 5073, University of Copenhagen, 9 Blegdamsvej, Copenhagen, DK-2100, Denmark. soren.a.jensen@mail.tele.dk
PMID
12
TI
[Histone-deacetylases inhibitors: from TSA to SAHA].
AU
Peixoto P, Lansiaux A
SO
Bull Cancer. 2006 Jan;93(1):27-36.
 
Histone-deacetylase inhibitors (HDCACi) represent a new class of antitumor agents currently in clinical development. They target a family of enzymes which catalyse histone acetylation modifications, in particular for histones H2A, H2B, H3 and H4. These proteins stabilize the nucleosome core, fundamental unity of chromatin which represents the first level of DNA nuclear compaction. The balance of histone acetylation is maintained by histone-acetyltransferases (HAT) and histone-deacetylases (HDAC) which play an important role in gene transcription. Alterations of HDACs were identified in tumor cells and contribute to the massive perturbations of gene expression in numerous tumors. HDAC inhibition leads to differentiation, cell cycle arrest and apoptosis in tumor cells. HDACi efficiently prevent tumor growth in a variety of in vivo preclinical models. Several structurally distinct classes of HDACi have entered in clinical trials and a significant antitumor activity was reported in several cases. However, a better understanding of the biological effects of this class of enzymes is mandatory for the successful development of these new antitumoral agents. In this review, are exposed the main drug candidates in clinical development. In the near future, it will be interesting to define direct relationships between specific inhibition of one or several HDAC and the subsequent HDAC-dependent antitumor effects to define a new generation of specifichistone-deacetylase inhibitors.
AD
Laboratoire de pharmacologie antitumorale, Centre Oscar-Lambret, et Unité524 Inserm, place de Verdun, 59045 Lille.
PMID
13
TI
Cardiotoxicity of 5-fluorouracil in 1350 patients with no prior history of heart disease.
AU
Tsibiribi P, Descotes J, Lombard-Bohas C, Barel C, Bui-Xuan B, Belkhiria M, Tabib A, Timour Q
SO
Bull Cancer. 2006 Mar;93(3):E27-30.
 
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 mostcommonly suspected hypothesis, but further studies are warranted to seek for toxic inflammatory lesions of the myocardium (apoptosis, necrosis, fibrosis).
AD
Laboratoire de pharmacologie médicale, EA 1896, UniversitéClaude-Bernard, 8, av. Rockefeller, 69008, Lyon, France.
PMID
14
TI
Effort myocardial ischemia during chemotherapy with 5-fluorouracil: an underestimated risk.
AU
Lestuzzi C, Vaccher E, Talamini R, Lleshi A, Meneguzzo N, Viel E, Scalone S, Tartuferi L, Buonadonna A, Ejiofor L, Schmoll HJ
SO
Ann Oncol. 2014 May;25(5):1059-64. Epub 2014 Feb 20.
 
BACKGROUND: Effort-induced myocardial ischemia (EMI) has been seldom described. Aims of our study were (A) to evaluate the prevalence of EMI during long-lasting 5-FU infusion; (B) to identify possible risk factors of EMI during 5-FU infusion.
PATIENTS AND METHODS: For the purpose (A), we prospectively evaluated a group of patients undergoing in-hospital continuous infusion (c.i.) of 5-FU. Patients with rest ischemia were excluded. Among 358 consecutive patients, 21 (5.9%) had rest ischemia; 109 could not perform a stress test. The remaining 228 patients underwent a treadmill stress test (TST) after>46 h of 5-FU infusion. For the purpose (B), we compared the characteristics of patients with EMI (including 3 previously described in a 2001 paper) with those without EMI.
RESULTS: Among 228 patients, 16 (6.9%) had EMI. These 16 had a second TST after stopping 5-FU: in 14, it was negative, 2 patients with coronary artery disease had milder ischemia. The whole group of 231 (including 3 described in a previous paper) patients undergoing TST included 148 males and 83 females, with mean age of 57.5. Cardiovascular riskfactors were present in 178 of them. Eight patients had ischemic heart disease. Among 19 patients with EMI, 7 had angina, 12 silent ischemia. ST segment at ECG was elevated in 10 patients, depressed in 9. Comparing the group with toxicity and the one without, the only significant difference was the complaint of atypical symptoms at rest before the TST. No difference was observed as regards: chemotherapy schedule (chronic c.i. in 49, 5 days in 178, FOLFOX type in 12), coronary risk factors or heart disease.
CONCLUSIONS: EMI is as frequent as rest ischemia during 5-FU infusion. Patients undergoing 5-FU continuous infusions should be adviced to avoid unusual efforts, to refer any cardiac symptom, and should be investigated for EMI.
AD
Cardiology Unit.
PMID
15
TI
Symptomatic cardiotoxicity associated with 5-fluorouracil.
AU
Meyer CC, Calis KA, Burke LB, Walawander CA, Grasela TH
SO
Pharmacotherapy. 1997 Jul-Aug;17(4):729-36.
 
A prospective cohort study was conducted in 35 hospitals with oncology units to determine the incidence of symptomatic cardiotoxicity in patients receiving continuous infusions of 5-fluorouracil (5-FU), and to identify risk factors that could contribute to the development of 5-FU-associated cardiotoxicity. A sample of 483 patients [197 (41%) women, overall average age +/- SD 60.9 +/- 11.9 yrs]were followed for one cycle of 5-FU infusion. Thirty-eight (7.9%) patients had abrupt termination of the infusion. There were 9 (1.9%) cases of suspected or documented cardiotoxic events. Cardiotoxicity occurred in 7 (3.35%) of 209 patients receiving their first course of 5-FU and in 2 (0.73%) other patients (p=0.044). Based on univariate analysis, the following patient groups were at elevated risk of cardiotoxicity: those with preexisting cardiac disease (RR=6.83, p=0.0023); patients receiving calcium channel blockers (RR=4.75, p=0.014); those receiving nitrates (RR=9.18, p=0.007); and patients receiving concomitant etoposide (RR=10.32, p=0.022). Patients with underlying cardiac disease require close monitoring while receiving continuous infusions of 5-FU. They should be observed for signs and symptoms of cardiotoxicity, and vital signs should be measured frequently. Continued reporting of 5-FU-associated cardiotoxicity is necessary to identify other patients at risk.
AD
Drug Information Center, Division of Pharmacy Practice, University of Missouri-Kansas City, USA.
PMID