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Medline ® Abstracts for References 11,16,32,35,36,88,89

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

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
16
TI
Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study.
AU
Rezkalla S, Kloner RA, Ensley J, al-Sarraf M, Revels S, Olivenstein A, Bhasin S, Kerpel-Fronious S, Turi ZG
SO
J Clin Oncol. 1989;7(4):509.
 
Although there have been anecdotal reports of cardiac toxicity associated with fluorouracil (5-FU) therapy, this phenomenon has not been studied in a systematic fashion. We prospectively performed continuous ambulatory ECG monitoring on 25 patients undergoing 5-FU infusion for treatment of solid tumors in order to assess the incidence of ischemic ST changes. Patients were monitored for 23 +/- 4 hours before 5-FU infusion, and 98 +/- 9 hours during 5-FU infusion. Anginal episodes were rare: only one patient had angina (during 5-FU infusion). However, asymptomatic ST changes (greater than or equal to 1 mm ST deviation) were common: six of 25 patients (24%) had ST changes before 5-FU infusion v 17 (68%) during 5-FU infusion (P less than .002). The incidence of ischemic episodes per patient per hour was 0.05 +/- 0.02 prior to 5-FU infusion v 0.13 +/- 0.03 during 5-FU infusion (P less than .001); the duration of ECG changes was 0.6 +/- 0.3 minutes per patient per hour before 5-FU v 1.9 +/- 0.5 minutes per patient per hour during 5-FU (P less than .01). ECG changes were more common among patients with known coronary artery disease. There were two cases of sudden death, both of which occurred at the end of the chemotherapy course. We conclude that 5-FU infusion is associated with a significant increase in silent ST segment deviation suggestive of ischemia, particularly among patients with coronary artery disease. The mechanism and clinical significance of these ECG changes remain to be determined.
AD
Department of Medicine, Harper Hospital, Detroit, MI 48201.
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
35
TI
Evaluation of cardiotoxicity of a combined bolus plus infusional 5-fluorouracil/folinic acid treatment by echocardiography, plasma troponin I level, QT interval and dispersion in patients with gastrointestinal system cancers.
AU
Oztop I, Gencer M, Okan T, Yaren A, Altekin E, Turker S, Yilmaz U
SO
Jpn J Clin Oncol. 2004 May;34(5):262-8.
 
OBJECTIVE: To evaluate the cardiotoxicity of LV5FU2 regimen (bolus plus infusional 5-fluorouracil/folinic acid) treatment by non-invasive methods such as echocardiography, plasma troponin I (TnI) level, QT interval and QT dispersion on ECG.
METHODS: Twenty-two patients with gastrointestinal cancer who received LV5FU2 chemotherapy were evaluated prospectively during 12 cycles of chemotherapy. Plasma TnI assay and ECG recording analyses were performed before the first cycle, at 24 h, before each cycle until cycle 6 and every three cycles thereafter. The longest QT interval measurement on each recording corrected with Bazzett's formula was considered as QTmax and the difference between the QTmax and the shortest corrected QT interval was considered as QT dispersion (QTd). A complete M-mode, 2D and color Doppler echocardiogram was performed at baseline and at the first, third and sixth months of treatment.
RESULTS: Echocardiography did not show any significant change in either systolic or diastolic functions. Also, TnI measurements were found to be below detectable level in all patients and in all measurements. Meanwhile, significant prolongations of QTmax and QTd were observed as early as 24 h after first administration of chemotherapy. These events persisted and became more important over the duration of chemotherapy (P<0.05).
CONCLUSIONS: The clinical implication of these findings as predictive factors for subsequent events such as malignant arrhythmias in patients taking 5-fluorouracil-based chemotherapy need longer follow-up and further detailed evaluations.
AD
Institute of Oncology, University of Dokuz Eylul, Inciralti-Izmir, Turkey.
PMID
36
TI
Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors.
AU
Polk A, Vaage-Nilsen M, Vistisen K, Nielsen DL
SO
Cancer Treat Rev. 2013 Dec;39(8):974-84. Epub 2013 Apr 10.
 
PURPOSE: To systematically review the incidence, manifestations and predisposing factors for cardiovascular toxicity in cancer patients treated with systemic 5-fluorouracil or capecitabine.
DESIGN: We searched PubMed, EMBASE and Web of science for studies with≥20 cancer patients evaluating cardiovascular toxicity of 5-fluorouracil and capecitabine. We hand searched the reference lists of all included studies. Study selection and assessment of risk of bias were performed by two authors independently.
RESULTS: We identified 30 eligible studies (1 meta-analyses of 4 RCTs, 18 prospective and 11 retrospective). Symptomatic cardiotoxicity occurred in 0-20% of the patients treated with 5-fluorouracil and in 3-35% with capecitabine. The most common symptom was chest pain (0-18.6%) followed by palpitations (0-23.1%), dyspnoea (0-7.6%) and hypotension (0-6%). Severe clinical events such as myocardial infarction, cardiogenic shock and cardiac arrest occurred in 0-2%. Mortality rates ranged from 0 to 8%. Asymptomatic cardiac influence was demonstrated on ECG, in NT-proBNP measurements and with ultrasonic cyclic variation of integrated backscatter. Predisposing factors were mostly tested in univariate analyses. Preexisting cardiac disease was a risk factor in some studies, but there were divergent results. There was some evidence for increased cardiotoxicity during continuous infusion schedules and with concomitant cisplatin treatment. The effects of previous or current chest-radiotherapy were ambiguous.
CONCLUSION: Larger studies suggest an incidence of symptomatic cardiotoxicity of 1.2-4.3% during fluorouracil treatment, however subclinical cardiac influence are common. Possible risk factors are cardiac co-morbidity, continuous infusion schedules and concomitant cisplatin treatment, but existing evidence are of insufficient quality.
AD
Department of Cardiology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark. Electronic address: anne.polk@hotmail.com.
PMID
88
TI
Dynamic monitoring of cardio-specific markers and markers of thyroid gland function in cancer patients--a pilot study.
AU
Holubec L Jr, Topolcan O, Finek J, Salvet J, Svoboda T, Svobodova S, Mrazkova P, Ludvikova M
SO
Anticancer Res. 2007 Jul-Aug;27(4A):1883-6.
 
BACKGROUND: With the increased effectiveness of anticancer therapy, much more attention is being paid to the monitoring of the side-effects of chemotherapy, which often constitute a limiting factor in anticancer therapy. In this pilot study, the results of our monitoring of changes in cardio-specific markers and thyroid gland parameters in patients with colorectal carcinoma in the course of adjuvant and palliative chemotherapy are presented.
PATIENTS AND METHODS: A total of 42 patients with colorectal carcinoma were monitored (median age 52 years, range 34-82 years); in these patients a post-operative adjuvant or palliative chemotherapy was applied (de Gramont's or FOLFIRI regimen). In all of these patients, the cardio-specific markers brain natriuretic peptide (BNP) and troponin I were assessed, as well as markers of thyroid gland function, TSH and FT4.
RESULTS: In the course of chemotherapy, more than half of the patients showed laboratory signs of coronary ischemia; in 6 of these (14%) coronary ischemia was manifested with troponin I levels above 0.3 microg/L. Twenty patients (48%) had laboratory signs of heart failure in the course of adjuvant or palliative chemotherapy. A more frequent incidence of elevated cardio-specific enzymes was observed in continual regimens than in bolus application of fluorouracil. Reduced TSH values were observed in the course of chemotherapy in 9 patients (21%), without changes in FT4 values. An increase in TSH values was observed in 4 patients (10%), again without changes in FT4 values.
CONCLUSION: The pilot study demonstrated that in patients undergoing treatment for colorectal carcinoma by adjuvant or palliative chemotherapy on the basis of 5-fluorouracil, it is advisable to check for possible cardiotoxicity and simultaneously to monitor thyroid gland functions. This systematic monitoring may improve the quality of life in cancer patients.
AD
Departments of Oncology, University Hospital and Medical Faculty Pilsen, Charles University Prague, Czech Republic. holubec@fnplzen.cz
PMID
89
TI
5-Fluorouracil induces arterial vasoconstrictions but does not increase angiotensin II levels.
AU
Salepci T, Seker M, Uyarel H, Gumus M, Bilici A, Ustaalioğlu BB, Oztürk A, Sonmez B, Orcun A, Ozates M, Irmak R, Yaylaci M
SO
Med Oncol. 2010 Jun;27(2):416-20. Epub 2009 May 5.
 
Because the mechanisms of 5-Fluorouracil (5-FU) cardiotoxicity have not yet been completely identified, prophylactic options are not available. To our knowledge, there are no published data investigating the use of angiotensin converting enzyme (ACE) inhibitors for 5-Fluorouracil-associated cardiotoxicity. In this study, we aimed to evaluate the influence of 5-FU administration on the diameter of the brachial artery and the levels of angiotensin II. The patients were administered bolus 5-FU/leucovorin in the study group. Angiotensin II and troponin T assays, complete blood cell counts, hepatic and renal function tests were analyzed in five consecutive blood samples in the initiation, just after termination, and on 24, 48, and 72 h after termination of the regimen. Pre- and post-treatment angiotensin II and troponin T assays, complete blood cell counts, hepatic and renal function tests were also analyzed in the control group. Brachial arterial diameters were measured and recorded in all patients before and after the treatment. A total of 59 patients were included in this study. Thirty one out of 59 patients (52.5%) were in the 5-FU study group and the remaining 28 patients (47.5%) were in the control group. Basal and post-treatment brachial artery diameters in the 5-FU study group were 0.436 +/- 0.51 and 0.423 +/- 0.50 cm, respectively (P = 0.001). The corresponding values in the controls were 0.3954 +/- 0.50 and 0.3957 +/- 0.49 cm, basal and post-treatment, respectively (P = 0.979). Angiotensin II levels were not changed significantly at serial measurements (P = 0.496). Moreover, the corresponding measurements were not statistically different in both two groups treated with and without 5-FU (P = 0.372). The pathophysiology of 5-FU-induced cardiac toxicity has not yet been elucidated. In the present study, 5-FU-associated vasoconstriction was not dependent on angiotensin II levels, thus we suggest that the prophylactic administration of ACE inhibitors cannot prevent cardiotoxicity in these patients. The underlying mechanisms of cardiotoxicity related to 5-FU might be multifactorial; nevertheless, further prospective investigation for the toxic effects of fluoropyrimidines on the coronary endothelium and myocardium are needed.
AD
Department of Medical Oncology, Dr Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey.
PMID