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Medline ® Abstracts for References 8,9,32,43,59,98-100

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

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
32
TI
Capecitabine-related cardiotoxicity: recognition and management.
AU
Saif MW, Tomita M, Ledbetter L, Diasio RB
SO
J Support Oncol. 2008;6(1):41.
 
AD
Yale University School of Medicine, Section of Medical Oncology, New Haven, CT 06520, USA. wasif.saif@yale.edu
PMID
43
TI
The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy.
AU
Robben NC, Pippas AW, Moore JO
SO
Cancer. 1993;71(2):493.
 
BACKGROUND: A case of reversible cardiogenic shock linked to 5-fluorouracil (5-FU) was observed. Recognizing the increasing use of 5-FU, the authors tried to map this syndrome.
METHODS: They reviewed 134 additional case reports, retrieved information from literature searches, focused on clinical features, and discussed possible pathophysiologic findings and prevention of this syndrome.
RESULTS: Although angina and electrocardiographic changes were common and reproducible (approximately 90% each), coronary artery disease was found in a few patients. A total of 33 patients had severe left ventricular dysfunction, 28 without evidence of myocardial infarction. The symptoms were responsive to conservative management (90%).
CONCLUSIONS: Cardiac toxicity is a little known complication of 5-FU therapy, with an unknown but significant incidence. It is highly treatable.
AD
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
PMID
59
TI
Capecitabine cardiotoxicity--case reports and literature review.
AU
Manojlovic N, Babic D, Stojanovic S, Filipovic I, Radoje D
SO
Hepatogastroenterology. 2008;55(85):1249.
 
This study presents 3 case reports of patients who experienced anginous pain during treatment with capecitabine. The interruption of capecitabine and sublingual or intravenous nitroglycerine treatment lead to recovery. Rechallenge of capecitabine with dose reduction of 30% lead to repeated anginous pain in 2 patients. Treatment with capecitabine had been replaced with weekly bolus 5FU-LV, without further cardiotoxicity. The literature contains data from about 50 patients who experienced cardiotoxicity during capecitabine treatment. The most frequent manifestations of capecitabine cardiotoxicity included: anginous pain in 38/53 (71.7%), arrhythmia in 6/53 (11.3%), myocardial infarction in 6/53 (11.3%). Cardiotoxicity of capecitabine lead to death in 6/53 (11.3%) patients. Risk factors for cardiotoxicity are associated with the grade 4 and the fatal outcome of cardiotoxicity (p = 0.035, p = 0.015), but not with the symptom recurrence upon capecitabine rechallenge (p = 0.18). The combination chemotherapy regimens are associated with the grade 4 of cardiotoxicity (p = 0.048), but not with the fatal outcome (p = 0.3). Rechallenge of capecitabine lead to symptoms recurrence in 10/16 patients. Neither the dose reduction of capecitabine (p = 0.18) nor the additional medical prophylaxis (p = 0.37) were important for the outcome of capecitabine rechallenge.
AD
Clinic for Gastroenterology and Hepatology, Military Medical Academy of Serbia, Crnotravska 17, 11000 Belgrade, Serbia. nmanojlovic@ptt.yu
PMID
98
TI
Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil.
AU
Frickhofen N, Beck FJ, Jung B, Fuhr HG, Andrasch H, Sigmund M
SO
Ann Oncol. 2002;13(5):797.
 
Capecitabine is a member of a new class of oral fluoropyrimidines. It is a 5-fluorouracil (5-FU) prodrug, activated by a series of enzymes. Activation has been demonstrated to occur preferentially in tumor tissue, which may explain the favorable balance of efficacy and toxicity of this drug. Cardiotoxicity, a rare but potentially serious adverse effect of 5-FU, has not been reported for capecitabine to date. Here we report a patient who experienced a severe and prolonged acute coronary syndrome during treatment with capecitabine. He had previously developed similar symptoms during treatment with infusional 5-FU. Capecitabine should thus be considered an agent with cardiotoxic potential. This adverse effect should be specifically monitored in all patients treated with capecitabine. Patients with symptoms suggestive of cardiotoxicity during previous treatment with a fluoropyrimidine should not be treated with capecitabine.
AD
Department of Hematology/Oncology, HSK, Dr-Horst-Schmidt-Kliniken GmbH, Wiesbaden, Germany. n.frickhofen@t-online.de
PMID
99
TI
Common etiology of capecitabine and fluorouracil-induced coronary vasospasm in a colon cancer patient.
AU
Aksoy S, Karaca B, Dinçer M, Yalçin S
SO
Ann Pharmacother. 2005;39(3):573. Epub 2005 Feb 8.
 
AD
PMID
100
TI
[Cardiac toxicity of 5-fluorouracil. Review of the literature, 5 new cases].
AU
Clavel M, Siméone P, Grivet B
SO
Presse Med. 1988 Oct;17(33):1675-8.
 
The toxic effects of 5-fluorouracil - an antimitotic drug widely used in the treatment of cancer - mainly affect the digestive tract and the blood. The 5 new cases presented here may be added to the 57 cases of cardiotoxicity reported in the literature. The clinical manifestations always consist of constrictive chest pain resembling angina pectoris and associated with disorders of repolarization on electrocardiographic tracing recorded during the painful episodes. The outcome is usually favourable after discontinuation of treatment, but it may also be fatal. Reintroduction of the drug in 28 patients resulted in myocardial necrosis in 4 cases and in death due to cardiogenic shock in 4 cases. The frequency of such side-effects does not seem to be influenced by age, sex, route of administration and previous pathology including cardiovascular diseases. They usually occur at the beginning of treatment irrespective of the dose administered. The mechanism through which 5-fluorouracil exerts its cardiotoxic effects is unknown, and 3 hypothesis have been put forward: an immunoallergic reaction after a sensitization period, a coronary spasm directly induced by the drug or due to the release of a vasopressive substance, or a direct toxic effect on the myocardium and pericardium.
AD
Centre anticancéreux Léon Bérard, Lyon.
PMID