Bolus Versus Continuous Infusion 5 Fu
Bolus 5-Fluorouracil as an Alternative in Patients with Cardiotoxicity Associated with Infusion 5-Fluorouracil and Capecitabine: A Case Series
Abstract
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 the four 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.
- 5-Fluorouracil
- cardiotoxicity
- bolus
- rectal cancer
- capecitabine
5-Fluorouracil (5-FU) is the third most commonly used chemotherapeutic agent worldwide for the treatment of solid malignancies, including cancer arising in the head and neck, esophagus, stomach, colon, rectum, anus and breast (1). 5-FU may be administered as a bolus injection modulated by leucovorin (LV), either weekly (Roswell regimen) or daily for five days every four weeks (Mayo Regimen), or as a continuous infusion on an outpatient basis (2). The spectrum of toxicity differs with the different schedules of administration of 5-FU and is fairly predictable based on dose, schedule and route of administration (3). When 5-FU is given as i.v. bolus by the mayo regimen at a dosage of 400-500 mg/m2 per day, the most common toxicity includes bone marrow suppression followed by diarrhea and mucositis. When 5-FU is given as i.v. bolus by the Rowell regimen at a 450-500 mg/m2, the main toxicity consists of neutropenia. On the other hand, when 5-FU is given as a continuous infusion (CIV) daily for five days at a dosage of 750-1000 mg/m2, the main toxicities include mucositis and diarrhea. By a protracted continuous infusion (PIF) given at a dose range of 200-400 mg/m2, the main side effects consist of mucositis and hand and foot syndrome (HFS). When in a hepatic artery infusion (HAI) daily for 14-21 days at a dose range of 750-1000 mg/m2, the main side-effects of 5-FU consist of mucositis and diarrhea. When given intraperitoneally for 32-124 hours in a dose of 5M, mucositis and diarrhea constitute the main adverse effects. Although there is no statistical difference in efficacy parameters, infusional 5-FU has demonstrated a better toxicity profile compared to bolus administration (4).
5-FU is combined with other agents in many regimens, such as oxaliplatin (FOLFOX; FLOX; EOF), irinotecan (FOLFIRI), and cisplatin (ECF). Infusional 5-FU is the preferred route of administration when used concomitantly with external-beam radiation therapy (5). Capecitabine, an oral pro-drug of 5-FU has also been incorporated with these combination regimens, as well as being used as a radiosensitizer (5, 6). Since capecitabine mimics an intermittent continuous infusion of 5-FU, interestingly enough when capecitabine is given for 14-21 days in a dose range of 2000-2500 mg/m2 orally, the main toxicity consists of HFS similar that observed with CIV of 5-FU.
The syndrome of cardiotoxicity has been recognized with 5-FU and capecitabine based on the increased incidence, temporal relationship, and genuine reproducibility. 5-FU is reported as being the second most common chemotherapeutic agent after anthracyclines causing cardiotoxicity (7). 5-FU cardiotoxicity ranges from asymptomatic (ECG) abnormalities to fatal myocardial infarction. We previously published the pooled analysis of all the cases published in the medical literature in which cardiotoxicity was associated with 5-FU (8). Of 305 cases, 74% of patients received 5-FU as a continuous infusion; 21% as bolus, 4% as intermediate infusion, 2.5% oral and 1% intraperitoneally. Overall, 9.2% of patients exhibiting cardiotoxicity upon 5-FU administration died. Furthermore, 19% of patients re-challenged with 5-FU died (8).
Table I.
Demographic characteristics of the patients who developed cardiotoxicity on treatment with 5-FU.
Recently, we published the first case report in the English literature where a change in the mode of 5-FU administration to bolus from infusional 5-FU- and capecitabine-induced cardiotoxicity, was found to be safe and successful (9). This triggered us to experiment with this change in other similar situations where patients with different gastrointestinal malignancies developed cardiotoxicity to CIV 5-FU or capecitabine. Here, we present a case series of an additional six patients who developed cardiotoxicity on infusional 5-FU and/or capecitabine and were challenged with bolus 5-FU for the treatment of their malignancies.
Patients and Methods
Pharmacy database was done to indicate patients for who were treated with 5-FU and/capecitabine for solid malignancy during May 2010 – Sep 2012. Review of electronic charts was performed. When a cardiac event was identified in a patient on fluoropyrimidine, paper chart was searched for details as outlined below. Every effort was made to review laboratory tests, including electrocardiogram (EKG), multigated acquisition scan (MUGA) and reports of stress test if performed. Four patients were identified from our clinic, while one patient included in this study was referred to us from another institution for a second opinion. The sixth patient was a self referred after he read an article read by us. Cardiotoxicity was defined as angina-like symptoms including chest pain, shortness of breath, palpitations, abnormal cardiac enzyme results, ischemic changes or arrhythmia on EKG, abnormal stress test or cardiac catheterization.
The data including age, sex, diagnoses, dose of fluoropyrimidine, predisposing risk factors, presenting symptoms, laboratory results on cardiac enzyme, EKGs, echocardiograms, stress tests, and cardiac catheterizations were collected. Risk factors for ischemic heart disease were smoking, diabetes, hypertension, hypercholesteremia, and family history of ischemic heart disease. Information about discontinuation of fluoropyrimidine and the response to further medical management such as patient's responses to therapies with aspirin, nitrates, beta- blockers, and calcium antagonist, were also evaluated.
Four patients were tested for polymorphic abnormality of human dihydropyrimidine dehydrogenase gene (DPYD) with TheraGuide 5-FU™ (Myriad Genetic Laboratories, Inc., Salt Lake City, UT, USA) pharmacogenetic test.
Results
The demographic characteristics of these patients are presented in Table I.
Symptoms in all six patients included substernal chest pain, chest discomfort associated with dyspnea, diaphoresis, or palpitations. All four patients with rectal cancer received concomitant radiotherapy with radio sensitizing dose of CIV 5-FU C (225 mg/m2/24) and were then challenged with capecitabine (1600 mg/m2/24) (Table II). The average time of onset of cardiac events while on 5-FU was approximately the third week of the concomitant radiochemotherapy. DPYD was normal in all four patients tested.
Patients 1, 2, 3, 4 and 6 had elevated (CPK) and/or (MB). Patients 1, 2 and 5 also had troponin levels elevated (range=0.1ng/ml-0.2 ng/ml). Among five patients who had EKG changes, patients 1 and 3 had hyper T wave in anterolateral leads, patients 2 and 4 had T wave inversion in lead III and IV, and patient 6 had ventricular tachycardia and non-specific changes.
Three patients (no. 3-5) underwent stress tests, showing no evidence of ischemic disease. Patient 6 underwent cardiac catheterization which revealed non-obstructive coronary artery disease. MUGA scan was performed in three patients (no. 1, 3 and 6) with no abnormalities observed.
Table II.
Summary of clinical and diagnostic findings and outcome
All patients had complete resolution of their symptoms after cessation of 5-FU as well as capecitabine. All patients were placed on oral aspirin 81 mg. They were prescribed sublingual nitrates for any chest pain after discharge. Two patients were started on metoprolol (25 mg bid). Another patient received aspirin of 81 mg, toporol XL (25 mg qd) and lipitor (10 mg qd).
There were no cardiac-related deaths.
Discussion
Bolus 5-FU as an alternative to infusion, in cases of cardiotoxicity, is rarely referred to in the medical literature. Based on our observation from the pooled analysis and the first case report, it gave us some level of comfort that bolus 5-FU can be an alternative for patients who have developed cardiotoxicity and have no other chemotherapeutic options (8, 9). Fortunately, we were able to treat all these patients safely with bolus 5-FU. Capecitabine was challenged in close consultation with a cardiologist but the majority of our patients developed similar symptoms, leading to cessation of the drug. Similar to 5-FU, capecitabine has been reported to cause cardiotoxicity (10, 11).
The pathogenesis of this induced cardiotoxicity is not clearly understood and may be multifactorial: coronary vasospasm, injury of the vascular endothelium, prostacyclin release by endothelial cells, or an immuno-allergic reaction (12-15). The polymorphic abnormality of DPYD is theorized as a plausible cause. Milano et al. reported one case of 5-FU-related cardiotoxicity in 19 patients with polymorphic abnormality of DPYD (5%) (16). However, none of our patients were found to have pharmacogenetic abnormalities, which allowed us to challenge the patients with capecitabine and bolus 5-FU.
Risk factors are not well-described. Previous chest radiation, cardiovascular disease and concurrent chemotherapy with other cardiotoxic agents have been reported to be risk factors. The prognostic value of pre-existing heart disease for severity of cardiotoxicity is unclear. A meta-analysis found that the prevalence of cardiac disease in patients with 5-FU cardiotoxicity did not differ significantly in an age-matched and gender-matched study (8).
The treatment for this condition is suggested to be a combination of anti-anginal drugs with the chemotherapy since there are few alternatives to 5-FU and capecitabine (17-20). In one study, seven out of 300 patients manifested cardiac toxicity after administration of 5-FU with prophylactic nitroglycerin which failed to prevent EKG changes suggestive of myocardial ischemia during repeat infusion. A similar lack of protective efficacy was seen with either nifedipine 60 mg/day, or dilfiazem 80 mg/day administered with simultaneous intravenous nitroglycerin at therapeutic doses. Eskilsson and Albertsson treated 58 patients receiving fluorouracil infusions with verapamil 120 mg three times a day. They found evidence of ischemia in 12% of patients, compared with 13% in a previously studied comparable group not receiving prophylaxis. They concluded that calcium-channel blockade does not protect against cardiotoxicity (19). A recent study however, showed protective benefit (20).
It is difficult to predict which patients will develop cardiotoxicity following 5-FU administration; therefore, caution is required in the use of 5-FU. Patients should be observed closely and 5-FU administration should be discontinued if any symptoms or signs of a cardiac event occur. In the presence of an anginal episode, it is mandatory to stop the infusion even if no EKG changes accompany chest pain because myocardial infarction can supervene even if the EKG during or after angina appears normal. Nitrates may be beneficial in the treatment of ischemic episodes. Re-challenge with 5-FU should be reserved only for patients in whom there is no reasonable alternative therapy and in the absence of other risk factors, while applying aggressive prophylaxis and close monitoring.
- Received April 27, 2013.
- Revision received June 9, 2013.
- Accepted June 10, 2013.
- Copyright © 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
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Source: https://iv.iiarjournals.org/content/27/4/531
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