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Table of Contents
SHORT COMMUNICATION
Year : 2021  |  Volume : 8  |  Issue : 3  |  Page : 104-108

Caution “When Rabbit Runs Turtles' Pace”: 5-fluorouracil-induced slowdown of the heart – The bradyarrhythmias


1 Department of Radiation Oncology, State Cancer Institute, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
2 Division of Cardiovascular and Thoracic Anaesthesia and Cardiac Surgical Intensive Care, Sher-i-Kashmir Institute of Medical Sciences; Department of Anaesthesiology, Pain and Critical Care, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
3 Department of Radiation Oncology, Government Medical College, Baramulla, Jammu and Kashmir, India

Date of Submission20-Oct-2020
Date of Decision27-Nov-2020
Date of Acceptance29-Nov-2020
Date of Web Publication01-Sep-2021

Correspondence Address:
Dr. Khan Talib
Faculty of Division of Cardiovascular & Thoracic Anaesthesia and Cardiac Surgical Intensive Care, Department of Anaesthesiology, Pain and Critical Care. Sher -i- Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu & Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_32_20

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  Abstract 


Background: 5-fluorouracil (5-FU) is a widely used antimetabolite drug for the treatment of a variety of cancers. It is associated with side effects and toxicities, most of which have been extensively studied. However, data related to potentially life-threatening cardiotoxicity, and especially bradyarrhythmias, are lacking in the literature. The aim is to assess potentially life-threatening bradyarrhythmias (or bradycardia) in patients on continuous 5-FU infusion. Materials and Methods: Fifty-four patients with esophageal carcinomas were included in this prospective non-randomized observational single-institution study. All of the patients underwent concurrent chemoradiation in curative settings over a period of 30 months (January 2015–June 2017). Results: Fourteen of the 54 patients developed bradycardia during continuous 5-FU infusion. Chemotherapy (CT) was stopped transiently in one of these patients and then continued uneventfully after the return of normal heart rate. The other 13 patients developed severe bradycardia, and CT was stopped completely and switched to other cardiac-safe CT protocols due to persistent bradycardia despite optimal management as per the institutional protocol. One patient died of sudden cardiac arrest during continuous 5-FU infusion. Conclusion: The persistence of life-threatening bradycardia during 5-FU infusion should prompt physicians to switch to other cardiac-safe CT protocols. Patients should be vigilantly monitored for any electrocardiography changes during continuous 5-FU infusion.

Keywords: 5-fluorouracil, bradyarrhythmias, bradycardia, cardiotoxicity, chemotherapy, esophageal carcinoma


How to cite this article:
Wani SQ, Talib K, Dar IA, Lone MM, Afroz F. Caution “When Rabbit Runs Turtles' Pace”: 5-fluorouracil-induced slowdown of the heart – The bradyarrhythmias. J Cancer Res Pract 2021;8:104-8

How to cite this URL:
Wani SQ, Talib K, Dar IA, Lone MM, Afroz F. Caution “When Rabbit Runs Turtles' Pace”: 5-fluorouracil-induced slowdown of the heart – The bradyarrhythmias. J Cancer Res Pract [serial online] 2021 [cited 2021 Oct 15];8:104-8. Available from: https://www.ejcrp.org/text.asp?2021/8/3/104/324925




  Introduction Top


Cancer chemotherapy (CT) has become more targeted, resulting in less systemic toxicity with better overall patient outcomes.[1] The cardiotoxic effects of CT and targeted drugs are ubiquitous and challenging in the field of oncology. The broad spectrum of toxicities includes ischemic, hypertensive, cardiomyopathic, and arrhythmic complications, which can be a significant challenge for clinicians treating cancer patients.[2]

5-fluorouracil (5-FU) is an antimetabolite drug which is widely used for the treatment of a variety of cancers, both in curative and metastatic settings. It is well known to induce various systemic toxicities, however robust data and comprehensive characterization are still lacking concerning fluoropyrimidine-induced cardiotoxicity, an infrequent but potentially life-threatening complication.[3]

Atrial fibrillation and ST-T changes have also frequently been reported, with chest pain being the most common presenting symptom. Cardiotoxicity due to 5-FU seems to be dosage and schedule dependent. With earlier bolus regimens, the incidence of cardiotoxicity has been reported to be 1.6%–3%. Compared to 7.6%–18% with prolonged (4–5 days) infusion regimens.[4]

Considering the life-threatening events, especially bradyarrhythmias associated with prolonged infusion of 5-FU, the aim of this study was to analyze the incidence and severity of bradycardia or mortality, if any, during the study period.


  Materials and Methods Top


This prospective single institutional observational non-randomized pilot study was conducted in the Department of Radiation Oncology of University Teaching and Tertiary Care Referral Hospital in a northern part of the Indian subcontinent over a period of 30 months (January 2015–June 2017).

After approval by an institutional ethics committee, 63 patients with stage II and III esophageal carcinoma, irrespective of their age, gender, and surgical status with good Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 were included in this study. Patients with a history of coronary artery disease, cardiomyopathy, arrhythmias, pre-existing infection, leukopenia, hepatobiliary disease, pregnancy, and patients who refused to consent were excluded from the study. Nine patients were excluded due to cardiac comorbidities, and the remaining 54 patients were included in the final analysis. The patients were treated either with definitive or adjuvant CCRT protocol.

Before the initiation of CCRT, Each patient was screened and evaluated by contrast enhanced computed tomography of the chest, abdomen and pelvis, and esophagogastroduodenoscopy (EGD) with biopsy for staging and histopathological confirmation. Baseline investigations included complete blood count, kidney function test, liver function test, serum electrolytes, creatinine clearance, electrocardiogram (ECG), and transthoracic echocardiogram [Table 1].
Table 1: Demographics, clinical presentation, and management of esophageal carcinoma

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The CCRT was given as continuous intravenous (IV) infusions of 5-FU and cisplatin. The IV infusion of 5-FU with a dose of 750–1000 mg/m2/day was continued over 96 h along with the infusion of cisplatin 75–100 mg/m2 over the first 3 h of day one of CT. The initial two cycles of CT were given along with radiotherapy in the first and last weeks of radiotherapy, and two more cycles of CT were planned after CCRT to complete the treatment protocol. The total dose of external beam radiotherapy was 50.4 Greys (Gys) in 25 fractions with an approximate dose of 2 Gys per fraction per day during the major part of treatment delivery.

During the course of 5-FU infusion, continuous monitoring of a), ECG for rate and rhythm abnormalities, b), digital pulse oximetry for SpO2 analysis and c), blood pressure for any BP changes was carried out for timely intervention [Figure 1]. The bradyarrhythmias were treated initially by transiently stopping the infusion of 5-FU, and if persistent, treated by IV injections of atropine ± adrenaline and CT was changed to cardiac safe CT agents.
Figure 1: Study plan depicted as flow diagram. (IEC: Institutional Ethics Committee, Ca: Carcinoma, CCRT: Concurrent chemoradiotherapy, ECG: Electrocardiogram, BP: Blood Pressure and SpO2: Oxygen Saturation measured by digital pulse oximetry)

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Injections of atropine 0.6 mg and adrenaline 1 mg (1:10000) were preloaded in syringes and kept ready to counter any bradyarrhythmias. The cardiologists and cardiac anesthetists were informed and kept in the loop if needed as a part of a code blue team. An emergency crash cart and defibrillator were also prepared to counter any adversities during infusion of the CT agents.

Statistical analysis

Data on demographics, clinical presentation, diagnostic/imaging modality, disease stage, performance status, and treatment modality were entered into a spreadsheet (Microsoft Excel) and then exported to the data editor of SPSS Version 20.0 (SPSS Inc., Chicago, Illinois, USA). Categorical variables were expressed as frequencies and percentages (%), and continuous (quantitative) variables were summarized as means and standard deviations.


  Results Top


The mean age of the patients in the study was 59.11 years (range: 25 to 75 years), including 61.11% (n = 33/54) males with a male:female ratio of 1.57:1. Regarding dwelling, 63% (n = 34/54) were from rural areas. Dysphagia was the chief complaint in all of the patients (n = 54/54) irrespective of disease stage. Disease was more common in the middle part of the esophagus (62.96%, n = 34/54), followed by the upper and lower parts. EGD was done in all patients (100%, n = 54/54) and all had biopsy-proven squamous cell carcinoma. Ultrasonography of the abdomen and pelvis was done in 46.31% (n = 25/54) of the patients, and contrast-enhanced computed tomography was done in all patients (100%, n = 54/54) for staging. Most of the patients had Stage III disease (62.96%, n = 34/54) followed by stage II (37.03%, n = 20/54). All of the patients (100%, n = 54/54) had an ECOG performance score between 0 and 1. Five patients (9.25%, n = 5/54) had upfront surgery and received CCRT with 5-FU and cisplatin in the adjuvant setting, and the other 49 patients (90.75%, n = 49/54) were not candidates for surgery, either because of patient refusal or the location of the growth and were treated with definitive CCRT [Table 1].

Overall, 72.22% (n = 39/54) of the patients completed the CCRT protocol without showing any signs of adverse cardiac events (ACEs), including bradycardia, and the other 27.78% (n = 15/54) developed ACEs. Of these 15 patients, one (1.86%) showed a dip in heart rate (HR) ranging from 45 to 59 beats/min (bpm), mandating a pause in CT infusion, which was then resumed once the pulse rate returned to above 60 bpm. Thirteen patients (24.07%, n = 13/54) developed severe bradycardia with HR <45, the CT was stopped, and 0.6 mg of atropine IV bolus was given to accelerate the HR >60 bpm. The CT regimen was then changed to cardiac-safe CT protocols. One patient (1.86%) suffered a sudden cardiac arrest (asystole). The CT was stopped, cardiopulmonary resuscitation (CPR) was done, and an IV bolus of adrenaline and atropine was given; however, the patient could not be revived [Table 2] and [Figure 2].
Table 2: 5-fluorouracil-induced adverse cardiac events; incidence and its intervention

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Figure 2: Concurrent chemoradiotherapy protocol depicted as flow diagram. (CT: Chemotherapy, CCRT: Concurrent chemoradiotherapy, ECG: Electrocardiogram, BP: Blood Pressure and SpO2: Oxygen Saturation measured by digital pulse oximetry, HR: Heart rate, bpm: beats per minute, CPR: Cardiopulmonary resuscitation, IV: Intra-venous)

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  Discussion Top


The cardiotoxic effects of CT are well known.[5],[6] In particular, patients receiving 5-FU are prone to develop cardiac events during prolonged infusions, especially bradycardia.[4],[7] Most previous studies have reported a cardiotoxic event rate ranging from 0.5% to 35%.[7] The ACEs that may present during 5-FU infusion include ECG changes,[8],[9],[10] arrhythmias,[9],[10],[11],[12] chest pain,[8],[9],[10],[11],[12] myocardial infarction,[8],[11],[13] or sudden death.[9],[10],[11],[12],[13] In this study, 27.78% (n = 15/54) of the patients developed ACEs.

During continuous infusion, the patients were closely monitored for ECG changes (rate and rhythm), non-invasive blood pressure, and SpO2, and portable ECG was done whenever needed to look for any abnormalities. None of our patients had symptomatic bradycardia, and whenever the HR decreased <45 bpm, infusion of 5-FU was stopped. Similar cases of 5-FU-associated bradycardia have also been reported in other studies.[14],[15] In one of our patients who developed bradycardia, the 5-FU infusion was transiently paused, and once the HR returned to normal, the CT infusion was restarted and completed without any untoward events. Thirteen patients developed severe bradycardia (HR<45 bpm) and the CT was stopped immediately. However, as this did not improve the HR, an atropine 0.6 mg IV bolus was given to return the HR above 60 bpm. The CT infusion was tried again three hours later, but the patients again developed severe bradycardia and 5-FU infusion was stopped and changed to cardiac-safe CT regimens. One of our patients on 5-FU infusion suffered a sudden cardiac arrest (asystole) while sitting comfortably on the bed and collapsed. The alarm was raised for code blue, and advanced CPR was initiated. Endotracheal intubation was done to secure the airway for ventilation, and adrenaline and atropine were injected IV during CPR. However, the patient could not be revived despite aggressive CPR. The trends in the monitor revealed prior supraventricular tachycardia followed by asystole.

Previous studies have reported about various adverse effects, including cardiotoxic effects; however, bradycardia should be highlighted as a potentially life-threatening side effect. Whenever prolonged infusion of 5-FU is planned irrespective of the type of malignancy, patients should be monitored throughout the infusion using continuous hemodynamic monitoring, especially ECG, which is a fundamental cardiovascular diagnostic tool for monitoring HR and rhythm abnormalities which can be immediately dangerous if not treated promptly, such as severe bradycardia, new atrioventricular blocks, and fibrillation.[16]

Cardiotoxicity related to 5-FU administration is a poorly understood but relatively common clinical entity that deserves special consideration in view of its potential morbidity and mortality. Patients with pre-existing cardiovascular disease receiving continuous infusions of 5-FU, as opposed to a bolus-based regimen, may be at increased risk. The precise mechanism of cardiotoxicity from fluoropyrimidines remains unclear; however, several mechanisms have been proposed, including coronary artery vasospasm, direct toxicity to the myocardium, endothelial dysfunction, and a hypercoagulable state causing thrombosis.[7],[17] The clinical manifestations may include angina pectoris, myocardial infarction, cardiomyopathy, myocarditis, pericarditis, and sudden cardiac death. The ECG changes may include supraventricular tachycardia, ventricular tachycardia, Q-Tc prolongation, and ST-T abnormalities.[17]

The incidence of 5-FU-related cardiotoxicity may be higher, as this study was conducted in only one cohort with esophagus malignancies. Razkella et al. also reported that the asymptomatic ECG change rate may be as high as 88%.[10] Holubec et al. demonstrated a rise in the cardio-specific markers brain natriuretic peptide and troponin I in all of their patients who received 5-FU irrespective of the CT cycle as a marker of cardiac injury.[18]


  Conclusion Top


This pilot study showed an association between 5-FU infusion and bradycardia, and further larger randomized trials are warranted to establish the correlations. It is very important to stress that cardiotoxicity related to the prolonged infusion of 5-FU may provoke life-threatening events, as seen in this study. Furthermore, when planning 5-FU infusions, patients should be vigilantly monitored in high dependency units in CT suites for any ECG abnormalities to allow for timely interventions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Bonita R, Pradhan R. Cardiovascular toxicities of cancer chemotherapy. Semin Oncol 2013;40:156-67.  Back to cited text no. 1
    
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Babiker HM, McBride A, Newton M, Boehmer LM, Drucker AG, Gowan M, et al. Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system. Crit Rev Oncol Hematol 2018;126:186-200.  Back to cited text no. 2
    
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Depetris I, Marino D, Bonzano A, Cagnazzo C, Filippi R, Aglietta M, et al. Fluoropyrimidine-induced cardiotoxicity. Crit Rev Oncol Hematol 2018;124:1-10.  Back to cited text no. 3
    
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Pottage A, Holt S, Ludgate S, Langlands AO. Fluorouracil cardiotoxicity. Br Med J 1978;1:547.  Back to cited text no. 8
    
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Eskilsson J, Albertsson M, Mercke C. Adverse cardiac effects during induction chemotherapy treatment with cis-platin and 5-fluorouracil. Radiother Oncol 1988;13:41-6.  Back to cited text no. 9
    
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Rezkalla S, Kloner RA, Ensley J, al-Sarraf M, Revels S, Olivenstein A, et al. Continuous ambulatory ECG monitoring during fluorouracil therapy: A prospective study. J Clin Oncol 1989;7:509-14.  Back to cited text no. 10
    
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Schöber C, Papageorgiou E, Harstrick A, Bokemeyer C, Mügge A, Stahl M, et al. Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer. Cancer 1993;72:2242-7.  Back to cited text no. 11
    
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Khan MA, Masood N, Husain N, Bokemeyer C, Mügge A, Stahl M. A retrospective study of cardiotoxicities induced by 5-fluouracil (5-FU) and 5-FU based chemotherapy regimens in Pakistani adult cancer patients at Shaukat Khanum Memorial Cancer Hospital & Research Center. J Pak Med Assoc 2012;62:430-4.  Back to cited text no. 12
    
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de Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: A prospective clinical study. J Clin Oncol 1992;10:1795-801.  Back to cited text no. 13
    
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Hafeez I, Lone A, Beig JR, Alai MS, Dar I, Tramboo N. Effect of 5-fluorouracil on sinoatrial node and conduction system of heart. Int J Adv Med 2017;4:184-7.  Back to cited text no. 14
    
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Aziz SA, Ahmad M, Bhat GM. 5-fluorouracil induced bradycardia? is an autonomic imbalance. JK Pract 1995;2:189-90.  Back to cited text no. 15
    
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Khan T, Mir SY, Wani SQ. Discovering substitutes to the conventional lead positions of three-lead electrocardiogram monitoring. Ann Card Anaesth 2019;22:236-8.  Back to cited text no. 16
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Yuan C, Parekh H, Allegra C, George TJ, Starr JS. 5-FU induced cardiotoxicity: Case series and review of the literature. Cardiooncology 2019;5:13.  Back to cited text no. 17
    
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Holubec L Jr., Topolcan O, Finek J, Salvet J, Svoboda T, Svobodova S, et al. Dynamic monitoring of cardio-specific markers and markers of thyroid gland function in cancer patients – A pilot study. Anticancer Res 2007;27:1883-6.  Back to cited text no. 18
    


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