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Medline ® Abstracts for References 6,8,18,44,66,69,70,73,101,105,108-112

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

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
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
18
TI
Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study.
AU
Kosmas C, Kallistratos MS, Kopterides P, Syrios J, Skopelitis H, Mylonakis N, Karabelis A, Tsavaris N
SO
J Cancer Res Clin Oncol. 2008 Jan;134(1):75-82. Epub 2007 Jul 17.
 
BACKGROUND: Cardiotoxicity associated with 5-Fluorouracil (5FU) administration has been infrequently reported in literature, albeit various series of acute coronary syndromes have recorded a low but definite incidence of the above toxicity. In the present study, patients undergoing 5FU-based and oral capecitabine (Xeloda-based chemotherapy were tested for the potential development of cardiac-related symptoms during their administration.
PATIENTS AND METHODS: Six hundred and forty-four patients entered the study. Those experiencing any cardiac-related symptoms during 5FU infusion or oral capecitabine were subjected to ECG and serum cardiac enzymes determination. If cardiotoxicity was confirmed, 5FU infusion or oral capecitabine were interrupted, sublingual nitrates administered and cardiac monitoring initiated, while patients with>two-fold enzyme elevation were followed in a coronary care unit for at least 72 h. Cases with acute myocardial infarction were excluded from further 5FU or oral capecitabine treatment.
RESULTS: Overall 26 patients (4.03%) developed symptoms and/or ECG abnormalities due to 5FU and capecitabine. Patients with continuous 5FU infusion presented a higher incidence of cardiotoxicity [14/209; 6.7%, 95% confidence interval (CI) = 3.3-10.1%]than the remaining (7/317; 2.3%, 95% CI = 0.8-3.3%) (P<0.012). Specifically, an increased incidence of cardiac-related events was encountered in patients with continuous 24-h 5FU + LV infusion for 5 days (12.5%, 95% CI = 2.3-22.7%) rather than in patients with the same schedule without LV (5.3%, 95% CI = 1.95-8.67%) (P<0.027), as well as in patients with short 5FU + LV administration (2.4%, 95% CI = 0.9-3.9%) (P<0.019). Overall, 3/54 patients (5.5%, 95% CI = -0.6-11.1%) on oral capecitabine developed cardiac-related events. Seven out of the 20 patients suffered an acute myocardial infarction, 6 developed ischemia only, while 4 more patients had ECG consistent with coronary vasospasm and 3 with conduction disturbances, of which one subsequently died. Patients administered oral capecitabine had a similar incidence of cardiac-related events; 1/22 (4.5%) patients with advanced breast cancer and 2/32 (6.2%) with colorectal cancer.
CONCLUSIONS: The present study supports the toxic effect of 5-FU on the myocardium, which is largely schedule-dependent, whereas a low but finite risk of such toxicity has been observed with oral capecitabine. A high level of alertness is required when using fluoropyrimidines (i.v. 5FU or oral capecitabine), while their toxic effect on the coronary endothelium and myocardium merits further investigation.
AD
Department of Medicine, 2nd Division of Medical Oncology, "Metaxa" Cancer Hospital, Piraues, 21 Apolloniou Street, 16341 Athens, Greece. ckosm1@ath.forthnet.gr
PMID
44
TI
Failure of preventing 5-fluorouracil cardiotoxicity by prophylactic treatment with verapamil.
AU
Eskilsson J, Albertsson M
SO
Acta Oncol. 1990;29(8):1001.
 
The most common cardiotoxic effects of 5-fluorouracil (5-FU) are chest pain and ischemic ECG abnormalities. Coronary vasospasm may be the underlying mechanism. If so, prophylactic treatment with calcium channel blockers might have a beneficial effect. In the present study, prophylaxis with verapamil (120 mg three times daily) was given to 58 patients with esophageal or advanced head and neck carcinoma during induction chemotherapy with cisplatin and continuous infusion with 5-FU. Signs of ischemia appeared in 12% of the patients as compared to 13% in a previously studied compatible group of patients not receiving prophylaxis. The study does not support the hypothesis that prophylactic treatment with verapamil reduces the incidence of ischemia in patients undergoing 5-FU treatment. Verapamil might, however, modify the adverse cardiac effects of 5-FU by preventing supraventricular tachyarrhythmia.
AD
Department of Cardiology, University Hospital, Lund, Sweden.
PMID
66
TI
Prinzmetal's angina during 5-fluorouracil chemotherapy.
AU
Kleiman NS, Lehane DE, Geyer CE Jr, Pratt CM, Young JB
SO
Am J Med. 1987;82(3):566.
 
Variant angina developed during intravenous 5-fluorouracil therapy in a patient without prior history of angina pectoris. Ambulatory electrocardiography demonstrated S-T segment elevation and ventricular ectopy during pain, whereas no symptoms or S-T segment changes occurred during placebo therapy. Prophylaxis with both nifedipine and diltiazem was successful in preventing recurrence. It is believed that 5-fluorouracil induced coronary vasospasm and that this was prevented by prophylactic calcium antagonist therapy. Drug-induced coronary artery spasm may be the cause of 5-fluorouracil-associated chest pain.
AD
PMID
69
TI
5-Fluorouracil-induced coronary vasospasm.
AU
Burger AJ, Mannino S
SO
Am Heart J. 1987 Aug;114(2):433-6.
 
AD
PMID
70
TI
A case of 5-fluorouracil cardiotoxicity simulating acute myocardial infarction.
AU
Mizuno Y, Hokamura Y, Kimura T, Kimura Y, Kaikita K, Yasue H
SO
Jpn Circ J. 1995 May;59(5):303-7.
 
5-Fluorouracil (5-FU) is widely used in the treatment of various solid tumors. However, 5-FU cardiotoxicity is being reported with increasing frequency. The main symptom of cardiotoxicity is chest pain at rest with ischemic electrocardiographic changes. Up until now, the underlying mechanism has been suspected to be coronary artery spasm. However, this chest pain associated with 5-FU has several characteristics that are incompatible with coronary artery spasm; eg, inefficacy of calcium-channel blocker and a slow increase in cardiac enzyme levels. We experienced a case of 5-FU-induced cardiotoxicity which showed clinical findings consistent with acute myocardial infarction. Based on the clinical findings, coronary angiography, and left ventricular angiography in a prolonged attack, we concluded that the cardiotoxicity in this case was not due to ischemia caused by coronary artery spasm.
AD
Division of Cardiology, Kumamoto Municipal Hospital, Japan.
PMID
73
TI
5-Fluorouracil cardiotoxicity: left ventricular dysfunction and effect of coronary vasodilators.
AU
Patel B, Kloner RA, Ensley J, Al-Sarraf M, Kish J, Wynne J
SO
Am J Med Sci. 1987;294(4):238.
 
Seven patients developed clinical features simulating myocardial ischemia less than 72 hours after 12 of 13 separate intravenous 5-fluorouracil administrations; 9 episodes were associated with chest pain, 3 with hypotension, 3 with ventricular tachycardia and 1 with cardiogenic shock. Left ventricular dysfunction was demonstrated by echocardiography in 5 separate episodes, 2 with interval improvement upon repeat echocardiograms. Pretreatment with nitrates and/or calcium channel blockers failed to prevent recurrence of cardiotoxicity during 5 of 6 repeat 5-fluorouracil administrations. Therapy with 5-fluorouracil is associated with cardiotoxicity simulating myocardial ischemia with left ventricular dysfunction. Pretreatment with coronary vasodilators may not prevent this phenomenon.
AD
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan.
PMID
101
TI
Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity.
AU
Cianci G, Morelli MF, Cannita K, Morese R, Ricevuto E, Di Rocco ZC, Porzio G, Lanfiuti Baldi P, Ficorella C
SO
Br J Cancer. 2003;88(10):1507.
 
At present, the various mechanisms involved in 5-fluorouracil (5-FU)-correlated cardiotoxicity remain to be elucidated and a universally accepted prophylaxis or treatment for this specific toxicity is not available. Although it may improve time to progression, survival and clinical benefit, a 5-FU-based regimen usually has to be discontinued if a patient experiences cardiotoxicity. Here, we describe our experience with three cases of 5-FU-associated cardiotoxicity. The angina-like pain that appeared approximately 95 h after beginning 5-FU therapy was apparently independent of the drug's administration modality. In the two patients receiving 5-FU 12-h flat continuous infusion from 22.00 to 10.00 h (5-FU 12-h c.i.) in combination with other drugs, the dose of 5-FU was reduced by 10-20% and patients received prophylactic transepidermal nitroglycerin. In the third patient, 5-FU administration modality was changed and prophylactic therapy was not given. By taking these precautions, the patients no longer complained of anginal pain and none of them discontinued chemotherapy.
AD
Department of Medical Oncology, S. Salvatore Hospital, University of L'Aquila, 67100 L'Aquila, Italy.
PMID
105
TI
Bolus 5-fluorouracil as an alternative in patients with cardiotoxicity associated with infusion 5-fluorouracil and capecitabine: a case series.
AU
Saif MW, Garcon MC, Rodriguez G, Rodriguez T
SO
In Vivo. 2013 Jul;27(4):531-4.
 
BACKGROUND: 5-Fluorouracil (5-FU) is the backbone of chemotherapy regimens approved for treatment of colorectal cancer. The incidence of cardiotoxicity associated with 5-FU ranges from 1.5% to 18%; 48% as anginal symptoms and 2% as cardiogenic shock. Cardiotoxicity is unpredictable and no alternative chemotherapeutics have been defined so far.
PATIENTS AND METHODS: We present a case series of six patients who developed cardiotoxicity on infusional fluorouracil and/or capecitabine and were challenged with bolus 5-FU for the treatment of their malignancies. Four patients were tested for polymorphic abnormality of the human dihydropyrimidine dehydrogenase gene (DPYD) with the TheraGuide 5-FU™(Myriad Genetic Laboratories, Inc., Salt Lake City, UT, USA) pharmacogenetic test.
RESULTS: Five patients were challenged with oral capecitabine that reproduced clinical and/or diagnostic concerns. All six patients tolerated bolus 5-FU either as a radiosensitizing agent or as chemotherapy without recurrence of a cardiac insult. DPYD was normal in thefour patients tested.
CONCLUSION: Cardiotoxicity induced by 5-FU seems to be schedule-dependent. Bolus 5-FU can be used in patients developing cardiotoxicity due to 5-FU infusion or capecitabine with vigilance.
AD
Section of GI Cancers and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA. wsaif@tuftsmedicalcenter.org
PMID
108
TI
Prophylaxis of 5-fluorouracil-induced coronary vasospasm with calcium channel blockers.
AU
Oleksowicz L, Bruckner HW
SO
Am J Med. 1988;85(5):750.
 
AD
Mount Sinai School of Medicine, New York, New York.
PMID
109
TI
Failure of oral nitrate and calcium channel blocker therapy to prevent 5-fluorouracil-related myocardial ischemia: a case report.
AU
Akpek G, Hartshorn KL
SO
Cancer Chemother Pharmacol. 1999;43(2):157.
 
BACKGROUND: Myocardial ischemia induced by 5-fluorouracil (5-FU) is a relatively rare, but potentially serious, occurrence. Some case reports have indicated that recurrent ischemia may be prevented if 5-FU is resumed after pretreatment with antianginal therapy.
METHODS: A 54-year old woman was diagnosed with stage IIA squamous cell carcinoma of the anus. Treatment with concurrent radiation and chemotherapy (mitomycin-C and 5-FU) was initiated with curative intent.
RESULTS: The patient had no evidence of underlying coronary artery disease based on history, physical examination or ECG. Approximately 48 h after initiation of 5-FU infusion the patient developed anginal pain associated with ECG changes compatible with ischemia. After resolution of ischemia and ruling out of myocardial infarction, coronary arteriography demonstrated normal coronary arteries. In an attempt to prevent myocardial ischemia, calcium channel blocker and nitrate therapy was started, but anginal pain with ECG change recurred when 5-FU was resumed. This necessitated selection of an alternative chemotherapy regimen.
CONCLUSIONS: Even in the presence of normal coronary arteries, antianginal therapy may not preclude the occurrence of potentially serious 5-FU induced myocardial ischemia. For patients who experience 5-FU-induced myocardial ischemia, development of alternative chemotherapy regimens should be considered.
AD
Department of Medicine, Boston Medical Center, MA, USA.
PMID
110
TI
Capecitabine-induced chest pain relieved by diltiazem.
AU
Ambrosy AP, Kunz PL, Fisher GA, Witteles RM
SO
Am J Cardiol. 2012;110(11):1623. Epub 2012 Aug 31.
 
Five patients with primary colorectal adenocarcinoma or anal squamous cell carcinoma were started on a 2-weeks-on, 1-week-off capecitabine dosing regimen in addition to other chemotherapeutic agents and/or radiation. Within the first few doses, patients experienced chest pain and/or dyspnea at rest or with exertion. Acute electrocardiographic findings suggestive of ischemia were found in some cases at initial presentation, and 1 patient had troponin elevation consistent with an acute ST-segment elevation myocardial infarction. Subsequent ischemia evaluations were not suggestive of clinically significant coronary artery disease. All patients experienced immediate and sustained relief from chest pain after discontinuation of capecitabine and were able to successfully tolerate retreatment using a novel management strategy based on secondary prophylaxis with diltiazem. In conclusion, guidelines for the evaluation of and therapy for capecitabine-induced chest pain are proposed.
AD
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
PMID
111
TI
Final results of Australasian Gastrointestinal Trials Group ARCTIC study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines.
AU
Ransom D, Wilson K, Fournier M, Simes RJ, Gebski V, Yip D, Tebbutt N, Karapetis CS, Ferry D, Gordon S, Price TJ
SO
Ann Oncol. 2014 Jan;25(1):117-21. Epub 2013 Dec 2.
 
BACKGROUND: Cardiac toxicity an uncommon but serious side-effect of some fluoropyrimides. Cardiac toxicity from raltitrexed is rarely reported. With this background, we initiated this study to investigate the incidence of cardiac events in patients who had switched to raltitrexed following cardiac toxicity from fluoropyrimidines (5-fluorouracil or capecitabine).
PATIENTS AND METHODS: Pharmacy records were used to identify patients receiving raltitrexed from January 2004 till March 2012. Medical records were then reviewed to confirm the use of raltitrexed after cardiac toxicity from 5-fluorouracil or capecitabine. The primary end point was the rate of further cardiac events after commencing raltitrexed.
RESULTS: Forty-two patients were identified and the majority had colorectal cancer. Prior regimens included 5-fluorouracil±leucovorin, capecitabine alone, FOLFOX, FOLFIRI, epirubicin/cisplatin/5-fluorouracil, and capecitabine/oxaliplatin. Seven patients (17%) had bolus 5-fluorouracil regimens, 26 patients (62%) had infusion 5-fluorouracil regimens, and 9 patients (21%) had capecitabine alone or in combination. Angina was the most common cardiac toxicity from 5-fluorouracil or capecitabine and usually occurred in the first or the second cycle. Four patients after their first cardiac event continued with the same 5-fluorouracil or capecitabine regimen with the addition of nitrates and calcium antagonists but still had further cardiac events. After changing to raltitrexed, either as a single agent or a continuing combination regimen, no patients experienced further cardiac toxicity.
CONCLUSION: Raltitrexed is associated with no significant cardiac toxicity in patients who have experienced prior cardiac toxicity from 5-fluorouracil or capecitabine. Raltitrexed, alone or in combination with oxaliplatin or irinotecan, provides a safe option in terms of cardiac toxicity for such patients.
AD
Oncology Department, St John of God and Royal Perth Hospital, Perth.
PMID
112
TI
Successful Completion of Adjuvant Chemotherapy in a Patient With Colon Cancer Experiencing 5-Fluorouracil-Induced Cardiac Vasospasm.
AU
Vargo CA, Blazer M, Reardon J, Gulati M, Bekaii-Saab T
SO
Clin Colorectal Cancer. 2016 Jun;15(2):e61-3. Epub 2015 Nov 10.
 
AD
Department of Pharmacy, The James Cancer Hospital and Solove Research Institute at The Ohio State University, Columbus, OH. Electronic address: Craig.Vargo@osumc.edu.
PMID