Original article Gemcitabine-induced atrial fibrillation

Annals of Oncology 11: 479-481, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Gemcitabine-induced atrial fibrillation: A hitherto unreported manifestation of drug toxicity D. Santini,1 G. Tonini,1 A. Abbate,2 S. Di Cosimo,1 G. Gravante,1 B.Vincenzi,1 C. Campisi,3 G. Patti2 & G. Di Sciascio2 1

Division ofOncology and 2 Department of Cardiovascular Sciences, Campus Bio-Medico University, 3 National Council ofResearch, Rome, Italy

prolapse and complete right bundle branch block. During the arrhythmia episodes no other precipitating factors were Background: Gemcitabine is an antimetabolic drug for solid reported. The close temporal relationship of the arrhythmia to tumors. Altough its pharmacokinetics as well as its side-effects drug administration and the recurrence of arrhythmia upon are well known, paroxysmal atrial fibrillation associated to the rechallenge allowed to hypothesize an intrinsic pro-arrhythmic effect of gemcitabine or its metabolite 2',2'-difluorodeoxyadministration of this drug has not yet been described. Patients and methods: We describe the case of a 78-year-old uridine. Conclusions: The occurrence of atrial fibrillation during the man with pancreatic adenocarcinoma who presented repeated paroxysmal atrial fibrillation episodes 18-24 hours after every administration of gemcitabine may be considered as a cardiac gemcitabine infusion which resolved with antiarrhythmic arrhythmia drug-related toxicity. This side-effect of gemcitadrugs. This clinical history was positive for a remote brief bine infusion is a previously unreported sign of drug toxicity; episode of atrialfibrillation,which resolved spontaneously, and therefore, a high level of awareness to this problem is warthe patient had no predisposing factors for supraventricular ranted when this drug is administered. arrhythmias (systemic hypertension, diabetes or coronary artery disease). Key words: cardiac toxicity, gemcitabine, paroxysmal atrial Results: Cardiac work-up revealed only a mild mitral-valve fibrillation Summary

Gemcitabine (2',2'-difluorodeoxycytidine, dFdC) appears to be a safe and effective new antimetabolic drug for the treatment of solid tumors. It is an analogue of deoxycytidine and differs from ara-C by two fluorine atoms in position 2' of the deoxyribose, which reduce inactivation by deaminase and allow a remarkable efficacy against a wider spectrum of solid tumors [1-3]. Gemcitabine is a highly liposoluble molecule and intracellular incorporation appears to be mediated by trans-membrane diffusion. Blood concentrations are 9- to 20-fold higher than 3-phosphate citarabine and they are due both to efficient phosphorylation and slow clearance [4]. Pharmacokinetics depend on infusion modality [5]. Studies on gemcitabine administered with the usual schedule (i.e., 30 minutes weekly infusion) revealed a short plasma half-life (8 minutes), a biphasic elimination rate with half-time rates of 3.9 hours (tV4 alfa) and 16 hours (t'A beta) and a primary urinary metabolite, the deamination product difluorodeoxyuridine (dFdU) [6]. Clearance and distribution volumes of central and peripheral compartments are influenced by age, gender, infusion length and body surface area [7]. Extensive data from early phase I trials demonstrated relevant schedule-dependent differences in gemcitabine

toxicity. Daily infusion producesflu-likesymptoms (fever, malaise and headache) and idiosyncratic episodes of severe hypertension in selected cases. Twice a week administration was associated with severe thrombocytopenia [8]. A weekly dose - once a week for three weeks followed by a seven days interruption - provides a combination of the highest dose-intensity and the lowest incidence of acceptable toxicity [8]. Phase II studies show that dose-limiting toxicity of such schedule is neutropenia and trombocytopenia. Flu-like symptoms are experienced in a small percentage of patients and are of short duration. Peripheral edema is rare and not due to cardiac, hepatic or renal failure, but to transient water retention [9]. Cardiac side effects after gemcitabine infusion are rare: a small percentage of patients developed ventricular tachiarrhythmias with grade 1, 2, 3 and 4 severity in 1.4%, 0.7%, 0.2% and 0%, respectively, cardiac dysfunction with reduction of left ventricular ejection fraction with grade 1, 3 and 4 severity in 0.9%, 0.7% and 0.2%, respectively, and exsudative pericarditis with grade 1 in 0.2% [6]. We report for the first time a case of a 78-year-old man with pancreatic cancer who developed repeated episodes of paroxysmal atrial fibrillation after gemcitabine infusion.

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Introduction

480 Case history

Discussion This is the first report of recurrent atrial fibrillation probably due to cardiac toxicity of the cytotoxic agent gemcitabine. This arrhythmia occurs more frequently in subjects older than 70 years; it is usually benign in prognosis but potentially lethal and often associated with complications (risk of systemic embolism, precipitation of myocardial ischemia in patients with pre-existing coronary artery disease, impairment of cardiac function in presence of chronic heart failure) and persistent disabilities. In our case all episodes of atrial fibrillation were closely related in time to treatment with gemcitabine: they occurred 18-24 hours after the drug infusion and recurred upon rechallenge. However, risk factors for atrial fibrillation were present in the patient's history: advanced age and a previous episode of atrial fibrillation (albeit remote and not documented, six years previously) may constitute a predisposing factor to supraventricular arrhythmias [10]. There are sporadic reports of pro-arrhythmic cardiac toxicity during gemcitabine use [11] and ventricular arrhythmia [12] and sporadic asymptomatic brady-arrhythmias, but no atrial fibrillation [6] has been reported. A case of a severe cardio-pulmonary toxicity (ARDS and atrial fibrillation) after gemcitabine infusion has been recently described [13] and the authors suggested an inflammatory pathogenetic mechanism mediated by cytokine release resulting in myofibroblasts proliferation and collagen deposits. However, this patient had ARDS and developed a further episode of atrial fibrillation unrelated to gemcitabine infusion. Gemcitabine has a double mechanism of drug clearance, urinary and hepatic and a product of gemcitabine de-amination (2',2'-difluorodeoxyuridine, dFdU) has a half-life of approximately 18-24 hours [6]. The precipitating role of this metabolite is strongly suspected since arrhythmic episodes occurred 18-24 hours after gemcitabine infusion and no other predisposing clinical factors, such as electrolyte imbalance, water retention, neuro-autonomic dysfunction, thyrotoxicosis or subclinical hyperthyroidism, pulmonary embolism, hypertensive crisis were involved. The use of corticosteroids has not previously been associated with an increased risk for atrial fibrillation, while pre-treatment with the anti-H2 antagonist ranitidine warrants further discussion. This drug may cause sinus node dysfunction, specially when administered by infusion in a susceptible patient [14], but such complication is rare and sporadic; even if we recognize a concomitant causing role of ranitidine, a direct effect of gemcitabine seems more likely as a cause for the arrhythmia since no episodes occurred when this drug was discontinued and anti-H2 antagonists were continued. However, a combined effect of these two


A 78-year-old man was referred to our institution on March 1998 because of a diagnosis of adenocarcinoma of the pancreas. His clinical history was positive for a brief episode of suspected atrial fibrillation in 1992 that resolved spontaneously; at that time a diagnosis of mild mitral-valve prolapse with mild valve regurgitation and complete right bundle branch block was made. Clinical history was negative for arterial hypertension, diabetes or coronary artery disease. On admission he complained of epigastric pain radiating to the right hypochondrium, marked weight loss and anorexia. There were no other pathological signs on physical examination and relevant comorbidity was excluded. A CT scan showed a 4 cm pancreatic mass with areas of necrosis and hemorrhages. The mass infiltrated the portal vein, superior mesenteric artery and vein at 1 cm from the celiac axis; there was no lymph-node enlargement; the serum CA 19-9 value was 237 U/ml (normal values < 35 U/ml). A biopsy showed a well differentiated ductal pancreatic adenocarcinoma. Gemcitabine chemotherapy was initiated on June 1998, weekly for three weeks every 28 days; he was also treated with ranitidine and tropisetron. After the first cycle he had G3 neutropenia and Gl thrombocytopenia; he also developed dyspnea and chest discomfort and a diagnosis of atrial fibrillation with moderate ventricular response was made, beginning 24 hours after the infusion of the first cycle of cytotoxic therapy. He was successfully treated with propafenone (300 mg i.v.). During the arrhythmic episode his blood pressure was normal (125/70 mmHg), the patient was afebrile and no signs of water retention or electrolyte imbalance were evident. He was discharged without cardiac therapy. Seven days later another episode of transient atrial fibrillation occurred 18 hours after the administration of the second dose of gemcitabine. The relation between the drug infusion and the acute onset of the supraventricular arrhythmia seemed likely and prophylaxis was started with oral propafenone (450 mg daily) and digoxin (0.125 mg daily). On September 1998 the mass was found to be enlarged to 5 cm, with extension to the splenic vein and the duct of Wirsung; his serum CA 19-9 was increased to 1224 U/ml, but the patient was considered to be a 'responder' for Net Clinical Benefit. On October and November 1998 a second and third gemcitabine cycle was administered at lower doses, dividing the weekly dose into two administrations. Despite prophylactic antiarrhythmic treatment, further episodes of paroxysmal atrial fibrillation occurred in four other instances following gemcitabine administration (each 18-22 hours after the infusion). No other precipitating causes were found and the patient had no signs of multi-system failure. After nine administrations of gemcitabine, reevaluation showed an unchanged extension of pancreatic mass, a reduction of serum Ca 19-9 level to 436 U/ml, and an appreciable clinical benefit. The treatment was discontinued. On April 1999 a restaging of the disease showed a progression of the pancreatic mass, and it was

decided to treat the patient with local radiotherapy (45 Gy) and infusion of 5-fluorouracil (5-FU), corticosteroids and anti-H2 antagonists. No further episodes of atrial fibrillation occurred at 12 months follow-up.

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15. 16. 17. 18. 19. 20.

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In conclusion, the administration of gemcitabine may be associated with atrialfibrillation.The pathophysiology of cardiac rhythm disturbance during treatment with gemcitabine remains to be established. Careful cardiac monitoring of patients with a high risk for cardiac arrhythmias seems warranted.

Received 9 December 1999; accepted 24 February 2000.

References

Correspondence to: D. Santini, MD Universita Campus Bio-Medico Via Emilio Longoni, 83 00155 Rome Italy E-mail: [email protected]

1. Heinemann V, Hertel LW, Grindey GB, Pluckett W. Comparison of the cellular pharmacokinetics and toxicity of 2l,21-difluoro-


drugs cannot completely be excluded, as previously suggested for paclitaxel-related cardiac toxicity [15]. Mitralvalve prolapse, although it may cause cardiac irritability, has probably no causative role for atrial fibrillation in our patient, since the risk for cardiac arrhythmias in patients with prolapse is not higher than in the general population [16]. Cardiac arrhythmias represent a possible side-effect of several cytotoxic drugs [17]. Anthracyclines, are associated with cardiac toxicity and brady- or tachyarrhythmias [17]. Sinus bradycardia is the most frequent cardiac side-effect of paclitaxel administration [15], while 5-FU [18], cisplatin and etoposide [19] are mostly associated with atrial fibrillation. The pathophysiology of chemically-induced rhythm dysfunctions by cytotoxic agents remains to be clarified. The hypotheses are multiple and include direct and indirect effects. The sinus node may be influenced by several stimuli, and a hyperstimulation of the parasympathic as well as of the sympathic system may cause abnormal function of the sinus node, lack of beatto-beat rate variability and abnormal intra-supraventricular or atrio-ventricular conduction [20]. Increased histamine release by tissue histiocytes has also been associated with cardiac abnormalities. The histaminereceptors Hi are present in the cardiac tissue and may cause cardiac contractile depression, sinus bradycardia, rhythm dysfunctions and a concomitant use of anti-H2 antagonists may increase H] effects [14]. Electrolyte imbalance is a possible cause of atrial fibrillation when cytotoxic tubular kidney lesions may cause cation (K + , Mg ++ ) depletion and subsequent lowering of cardiac arrhythmia threshold [10]. Among gemcitabine's sideeffects neither neuro-autonomic dysfunction or hypersensitivity to histamine release have been reported. Moreover, our patient had no signs of cardiac autonomic disturbance or increased histamine release; electrolyte serum levels were always in the normal range and renal impairment was not observed. A direct toxic effect by gemcitabine or its metabolite 2',2'-difluorodeoxyuridine on the sinus node and/or supraventricular conduction system seems therefore more likely. Eccipients (mannitol and sodium acetate) in the gemcitabine-cloridrate preparation appear innocuous on cardiac rhythm.