Arrhythmias, conduction disorders and sudden cardiac death in cancer patients and survivors: expert opinion of the working groups on cardio-oncology and on electrophysiology of the hellenic cardiac society.

Introduction

The remarkable advancements in cancer therapeutics over the past decades have led to significant improvements in survival rates and transformation of many cancers into chronic conditions. Innovations such as targeted therapies, immune checkpoint inhibitors (ICIs), and Chimeric Antigen Receptor (CAR) T-cell therapies have revolutionized oncology, offering precise and effective treatment options. However, these advances come with unintended consequences, particularly the emergence of cardiotoxic effects. Cardiotoxicity, which includes heart failure (HF), ischemia, hypertension, and arrhythmias, has become an increasing concern, given the close physiological relationship between cardiovascular (CV) disease and cancer.

Arrhythmias occur more frequently in cancer patients than in the general population [ 1 – 5 ]. This is possibly due to a combination of factors, including pre-existing CV conditions, direct effects of cancer on the heart, cardiotoxicity of anti-cancer treatments, like anthracyclines, tyrosine kinase inhibitors (TKIs), and radiotherapy (RT), but also systemic inflammation, paraneoplastic syndromes, electrolyte abnormalities, polypharmacy, drug-drug interactions and autonomic dysfunction. These arrhythmias may be asymptomatic or threaten patients’ survival and quality of life. The evolving field of cardio-oncology aims to balance effective cancer treatments with strategies to minimize cardiotoxic risks, ensuring optimal outcomes for the growing population of cancer patients and survivors.

Prevalence of arrythmias in cancer patients and survivors

The incidence of arrhythmias is around 10–15% in cancer patients, depending on cancer type and treatments used [ 6 ]. Ventricular arrhythmias (VAs) are less frequent than supraventricular arrhythmias and atrial fibrillation (AF) is the most common one [ 6 ]. In a retrospective study the incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) in cancer patients with Implantable Cardioverter Defibrillators (ICDs) in the primary prevention was 39.6% and in the secondary prevention 56%. The incidence of arrhythmias was nearly 10 times higher in cancer patients, compared to patients without malignancies [ 4 ]. QTc prolongation is not rare in cancer patients ranging from 0 to 22% with classical chemotherapies and 0 to 22.7% with targeted therapies according to a recent systemic review [ 7 ]. In the same study, severe QTc prolongation (> 500 ms) was extremely rare with classical chemotherapies and between 0 and 5.2% with targeted therapies. In patients with advanced cancer on palliative care, QTc is prolonged in 20% of patients but without serious events [ 8 ]. Bradycardias and conduction disorders are rather rare in cancer patients, but their incidence depends on the anticancer treatments provided [ 9 ]. The best-known group of chemotherapeutics that are likely to cause bradycardia are anaplastic lymphoma kinase (ALK) inhibitors [ 10 ] and crizotinib, that can cause sinus bradycardia with an incidence ranging from 9% [ 11 ] to 41.9% of patients [ 10 ]. The incidence of bradycardia caused by paclitaxel varies in the literature from 0.1% to 31% [ 12 ]. Conduction disorders are not rarely induced by RT for thoracic malignancies and by myocarditis by ICIs [ 9 ]. Epidemiological data on arrhythmia prevalence specifically in cancer survivors remain limited. A very recent and important study by Sutton et al. [ 13 ], which is one of the few that explores the incidence and associated factors of arrhythmias in breast cancer survivors treated with anthracyclines and/or trastuzumab, reported that approximately 33% of survivors experienced cardiac arrhythmias. Furthermore, the researchers highlighted differences in risk patterns between racial groups and comorbid conditions such as hypertension and obesity.

Risk factors for arrhythmias in cancer patients

Arrhythmias in cancer patients result from a complex interplay of factors related to the patient, the malignancy, and the anticancer therapy itself (Fig. 1 ). Patient-related risk factors include traditional CV risk factors (CVRFs) (e.g., age, smoking, obesity, hypertension), pre-existing CV disease (such as HF or coronary artery disease), comorbidities like obstructive sleep apnea, renal, hepatic, or thyroid dysfunction, and a personal or family history of arrhythmias.

Cancer-related factors include direct myocardial infiltration by primary or secondary tumors, cardiac amyloidosis, paraneoplastic syndromes, nutritional deficiencies, and autonomic nervous system (ANS) disruption—such as with Pancoast tumors or mediastinal masses—that may promote arrhythmogenesis [ 14 ]. Therapy-related factors involve a wide spectrum of anticancer treatments (including conventional chemotherapies, targeted therapies, immunotherapies, hormonal therapies, RT and surgery) that may directly or indirectly affect the heart through variant pathophysiological mechanisms, complications and drug–drug interactions. CAR-T cell therapy and hematopoietic stem cell transplantation.

(HSCT) in hematological malignancies have also an arrhythmia risk due to cytokine release syndrome [ 15 ]. A thorough understanding of this multifactorial risk landscape is critical for early detection and prevention of arrhythmias in this vulnerable population.

Cancer therapeutics induced arrhythmias

Classical chemotherapies, targeted therapies, immunotherapies

Classical chemotherapies

Classical chemotherapeutics are among the earliest cancer treatments associated with arrhythmias. Anthracyclines have been associated with a broad range of arrhythmias including sinus tachycardia and bradycardia, premature atrial and ventricular complexes, supraventricular tachycardia (SVT), AF and VT [ 16 – 18 ]. They can also induce QTc prolongation and sudden cardiac death (SCD) [ 19 , 20 ].

Alkylating agents have been linked with several arrhythmias [ 18 – 20 ]. Cyclophosphamide in particular increases the risk of premature atrial and ventricular complexes, sinus tachycardia, VAs, AF and atrioventricular (AV) block [ 18 – 21 ].

In patients receiving antimetabolites, sinus tachycardia and bradycardia, premature atrial and ventricular complexes, AF and QTc prolongation have been reported, while VT or VF may be the result of myocardial ischemia induced [ 18 , 20 , 22 ].

Antimicrotubule agents have been implicated in sinus tachycardia and bradycardia, AV blocks, right and left bundle branch block, atrial flutter and AF, QTc prolongation and VT [ 18 , 20 ].

From platinum compounds, there is evidence connecting cisplatin to sinus bradycardia, SVT, AF, premature atrial and ventricular complexes, QTc prolongation and TdP [ 18 , 19 , 23 ].

In patients receiving immunomodulatory drugs (lenalidomide, thalidomide) sinus bradycardia, complete AV block and AF have been observed commonly, while VT is quite rare [ 18 , 20 ].

Histone deacetylase inhibitors present premature ventricular complexes, SVT and a dose dependent prolongation of QTc interval with the risk of TdP and SCD [ 18 – 20 ].

Arsenic trioxide, a differentiation agent, has demonstrated to induce sinus tachycardia, premature ventricular complexes, QTc prolongation, TdP and more rarely bradycardia and heart blocks [ 19 , 20 ].

Targeted therapies

Monoclonal antibodies like trastuzumab, have been correlated with increased arrhythmia risk [ 24 ]. Sinus bradycardia and tachycardia left and right bundle branch block, atrial flutter and AF are the most commonly observed, while cases of SCD have also been noted [ 20 , 24 ]. Other monoclonal antibodies, like rituximab, have been implicated in the development of SVT and AF with some cases of sinus and ventricular tachycardia, premature ventricular complexes and sinus bracycardia [ 20 ]. TKIs like ibrutinib and sorafenib, can induce the development of AF, while others like sunitinib and vandetanib QTc prolongation and TdP [ 18 , 20 ].

Immunotherapies

ICIs carry a recognized risk of CV events including arrhythmias, myocarditis, HF, vascular and pericardial toxicities [ 25 ]. Arrhythmias including sinus tachycardia, AF, complete heart block, VAs and SCD, occur more frequently if another cardiotoxic effect is present too [ 20 , 26 , 27 ]. AF, atrial flutter, VT and SVT are commonly encountered with CAR-T cell therapy [ 28 , 29 ].

Hormonal therapies

Prostate and breast cancer are among the most prevalent malignancies in men and women and in certain cases they can be treated with hormonal therapies in combination with other types of anticancer treatments. Sex hormones affect ventricular repolarization. Testosterone in men shortens QTc, similarly with progesterone in women, while estradiol prolongs QTc. Hormonal therapies, by interfering with hormone-regulated biological pathways, may alter ventricular repolarization and promote the manifestation of arrhythmias [ 30 , 31 ]. Selective estrogen receptor modulators (SERMs) (tamoxifen, raloxifene and toremifene) can cause QTc prolongation and TdP. Toremifene causes QTc prolongation that is dose- and concentration- dependent and FDA has issued a black box warning for long QT (LQT) and TdP for toremifene, while for tamoxifen similar data do not exist [ 30 ]. Special attention is needed when SERMs are combined with other drugs that prolong QTc, for example antidepressants such as serotonin reuptake inhibitors [ 32 ]. Drug-induced LQT, TdP and VAs are reported less often with Aromatase Inhibitors (AIs) compared with SERMs (4–fivefold less) [ 30 ]. On the contrary patients on AIs have a higher incidence of new-onset AF compared to patients on tamoxifen [ 33 ]. Concerning cyclin-dependent kinase (CDK) 4/6 inhibitors, there is a FDA warning only for ribociclib for LQT [ 30 ].

Androgen deprivation Therapy (ADT) is associated with QTc prolongation, but TdP and sudden cardiac death (SCD) have rarely been reported [ 30 , 34 ]. ADT therapy and specifically abiraterone and enzalutamide are also associated with increased risk of AF [ 30 , 35 – 37 ]. Gonadotropin-releasing hormone (GnRH) agonists and antagonists consistently prolong the QTc interval by 10-20 ms and have warnings issued by the FDA for LQT [ 30 ]. In patients treated with abiraterone (a CYP17 inhibitor) and GnRH agonists, the risk of arrhythmias is increased due to abiraterone-induced hypokalemia and the inherent risks of ADT, such as LQT, TdP and AF [ 30 , 38 ]. Αpalutamide (an androgen receptor inhibitor) may also cause LQT and TdP [ 30 ].

Radiotherapy/Brachytherapy

Radiotherapy (RT) induced heart disease may appear years after therapy, with an incidence reaching 19% [ 39 , 40 ]. The risk of developing bradyarrhythmias after radiation exposure is associated with the development of fibrosis in the conduction system. Bradyarrhythmias manifest as complete heart block and sick sinus syndrome that often require the implantation of a permanent pacemaker. The rate of tachyarrhythmia development after RT, such as AF, is higher than in the general population [ 41 ]. A dose-dependent relationship between radiation dose and left atrial fibrosis has been described in patients receiving external radiation beam therapy and possibly plays a role in the occurrence of AF in irradiated patients. QTc prolongation is more frequent in patients undergoing brachytherapy [ 42 ].However, most data derive from retrospective studies without clear categorization of patients’ baseline risk, making causal inferences about RT-related arrhythmias subject to biases.

Peri-operative arrhythmias

Arrhythmias are responsible for increased morbidity and mortality in cancer patients that are scheduled for surgery [ 43 , 44 ]. Tachyarrhythmias are more common in cancer patients with AF to be the leader, especially during thoracic surgery, e.g. in lung cancer and pulmonary dissection. The incidence of post operative AF ranges between 6 and 32% in this population with a negative impact on prognosis, linked to increased hospitalization, admission in intensive care unit, and almost fourfold higher post-operative mortality [ 45 ]. Table 1 summarizes the data that is currently known regarding the risk factors for the development of post-operative AF in cancer patients [ 45 ]. Thus, it is crucial to optimize CVRFs and known CV disease prior to surgery, in accordance with the general and disease-specific recommendations.

Stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is one of the therapeutic pillars for many hematologic malignancies and disorders. Ηowever, the increased incidence of arrhythmias (9–27%) before, during and after autologous or allogeneic HSCT may obscure the optimal therapeutic effect [ 46 – 49 ]. In the early phase of HSCT, the most prevalent arrhythmias are AF, supraventricular tachycardia and atrial flutter triggered by the use of cyclophosphamide as well as melphalan, fludarabine and cytarabine which are all strong arrhythmogenics [ 50 ]. Pre-existing arrhythmias are included in calculations for the HSCT-specific comorbidity index in order to risk stratify transplant patients [ 51 ]. Patients without a history of arrhythmia who experienced one during HSCT, are likely to have poorer outcomes compared to patients who did not experience arrhythmia. Patients with a new arrhythmia after HSCT have increased risk of admission in the Intensive Care Unit, in-hospital death and a threefold increase in mortality risk within one year of transplantation [ 50 , 52 ].

Autonomic dysfunction in cancer patients

Autonomic dysfunction (AD) is the loss of normal autonomic regulation of the CV system and is more common in cancer patients than in healthy controls [ 53 ]. AD is associated with decreased parasympathetic activity manifested as an increased resting heart rate, decreased heart rate variability and abnormal heart rate recovery (1 min post peak exercise). It is also associated with decreased sympathetic nervous system activity which results in abnormal blood pressure responses and orthostatic hypotension or syncope. Various studies have demonstrated the relationship between AD and increased CV risk [ 54 – 57 ].

Different aspects of cancer treatment may result in AD. Anthracyclines, taxanes, vinca-alkaloids, platinum-based agents, head and neck Rt, and HSCT have all been related to AD [ 58 ]. Psychological stress, sleep disturbances, weight gain and loss of cardiorespiratory fitness may also contribute to AD [ 59 ]. It is hypothesized that AD promotes inflammation and endothelial dysfunction which may lead to the development of CV disease in cancer survivors [ 60 , 61 ].

Drug-drug interactions

Several drug-drug interactions between anticancer therapies, supportive medications and cardiological medications increase significantly the risk of arrhythmias in a variety of cases. These interactions may lead to QT prolongation, bradycardia, or other proarrhythmic effects. The most common mediators of drug-drug interactions involve the cytochrome P450 (CYP450) family of enzymes and the efflux pump P-glycoprotein (P-g) transporters, which interact with numerous drugs used in cardio-oncology, functioning as substrates, inducers, or inhibitors [ 62 ]. Some examples of important drug-drug interactions between cardiological and oncological treatments that may lead to arrhythmias are described in Table 2 , while interactions of antineoplastic therapies with antiarrhythmics are presented separately in Table 3 [ 62 , 63 ]. Supportive medications that are frequently given to cancer patients and may interact with cardiological medications by prolonging QT interval include antiemetics e.g. ondansetron, granisetron, dolasetron, antihistaminics e.g. astemizole, diphenhydramine, loratadine, terfenadine and antimicrobials e.g. azithromycin, ciprofloxacin, metronidazole [ 63 ].

Types and management of arrhythmias and conduction disorders in cancer patients

The most important arrhythmias induced by antineoplastic treatments are presented in Table 4 .

Atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmia encountered in cancer patients. AF diagnosis in patients with cancer has been associated with increased all-cause mortality with the strongest association being observed in skin cancer, melanoma, cancer of endocrine glands, bone cancer and cancer of intra-thoracic organs [ 66 , 67 ]. The increased prevalence of AF in patients with cancer may be justified by the common risk factors they share (advanced age, electrolyte imbalances, inflammation, metabolic disorders etc.) [ 68 ]. Moreover, oncological surgeries and administration of antineoplastic agents increase patients’ vulnerability to arrhythmic episodes. An incidence of up to 19% has been reported for patients with lung cancer undergoing thoracic surgery, while open surgery carried the highest risk [ 69 , 70 ]. Among anticancer drugs, ibrutinib has been associated with a high incidence of AF, ranging from 5 to 16% [ 64 , 71 ], while abiraterone, an androgen synthesis inhibitor, has been linked to an incidence of up to 10% [ 5 ]. Other categories that have been associated with an increased risk of AF include alkylating agents, antimetabolites, anthracyclines, Gonadotropin-Releasing Hormone (GnRH) antagonists, taxanes, CD20 inhibitors, CD38 inhibitors, CD52 inhibitors, ICIs, proteasome inhibitors, TKIs and immunomodulatory drugs [ 5 , 72 ].

Anticoagulation in cancer patients with AF

The basic principles of AF management in the general population, are generally followed in cancer patients too [ 73 ]. However, thromboembolic and bleeding risk significantly differ between cancer patients, depending on the cancer type and stage and their overall health status (immobility, body weight, renal function impairment, major surgeries, ulcerations etc.) [ 74 ]. Decisions on anticoagulation may be challenging under these circumstances since widely applied scoring systems, such as CHA2Ds-VAS and HASBLED, have not been extensively tested in this population. Leader et al. demonstrated that AF patients with otherwise low CHA2DS2-VASc scores of 0 to 2 and newly diagnosed cancer, experienced a significantly increased incidence of stroke, transient ischemic attack, or systemic arterial thromboembolism compared with matched controls without cancer [ 75 ]. The diagnosis of breast, prostate, colon, and lung cancer has been found to contribute similarly as age, sex, and diabetes to the hazard of stroke in CHA2Ds-VASc score [ 76 ]. The addition of Cancer (standing for the aforementioned types of cancer) as another “C” in CHA2Ds-VASc score (namely, CCHA2Ds-VASc) exhibited superior predictability than the CHA2DS2-VASc score in this population [ 76 ].

A structured approach, abbreviated by the acronym T (thrombotic risk), B (bleeding risk), I (interactions among drugs), P (patient access and preferences) has been proposed by the recent guidelines to guide clinical decisions on anticoagulation [ 5 ]. Patients with very high bleeding risk,,defined as:

active or recent major bleeding,

recent or evolving intracranial lesions or

platelet count < 25 000/μL

are not recommended to receive anticoagulation for AF.

In these patients, if the thrombotic risk is high and their life expectancy is more than one year, percutaneous left atrial appendage occlusion may be considered as an alternative option.

Selection of Anticoagulation Therapy

With the exception of patients at very high bleeding risk, anticoagulation should be strongly considered for the rest of the cancer population. However, the choice of anticoagulant regimen must be individualized, taking into account factors such as cancer type, underlying CV disease, bleeding risk, renal function, drug-drug interactions, and patient preferences.

Vitamin K antagonists are indisputably the anticoagulation of choice in cases of moderate to severe mitral stenosis or mechanical prosthetic valves, while they may also be considered in cases non-vitamin K antagonist anticoagulants (NOACs) have significant drug-drug interactions with the antineoplastic agents. In all other cases, the use of non-vitamin K antagonist NOACs are recommended, as in the general population, even though the supportive evidence is less strong [ 5 ] since patients with cancer were under-represented in the landmark randomized controlled trials of NOACs [ 77 – 79 ]. A pooled analysis of three post hoc studies from the ARISTOTLE [ 80 ], ROCKET AF [ 81 ] and ENGAGE AF‐TIMI 48 [ 82 ] trials comparing the use of warfarin versus NOACs in patients with and without cancer, reported similar rates of both efficacy and safety [ 83 ]. Three systematic reviews and meta-analyses have associated the use of NOACs with a significant reduction in stroke rate and lower risk of major bleeding compared to VKA in cancer patients [ 83 – 85 ]. A major limitation that should be acknowledged before prescribing anticoagulation therapy is the risk of major drug-drug interactions. Apixaban, edoxaban and rivaroxaban are all metabolized in CYP3A4. Anticancer therapies that are known to be potent inhibitors or inducers of CYP3A4, such as TKI, tamoxifen, ixazomib, can interact with NOACs leading to an increased risk of bleeding [ 86 ]. Drug-drug interactions between anticoagulation and anticancer therapy are demonstrated in Table 5 .

Rate or rhythm control management

Lastly, in cases with unoperated gastrointestinal or genitourinary cancer, severe renal dysfunction, serious gastrointestinal comorbidities, platelet count < 50.000/μL or major NOAC drug-drug interactions, parenteral anticoagulation with low molecular weight heparin (LMWH) may be preferred [ 5 ].

Rate or rhythm control management is another therapeutic decision that should be properly addressed in these patients. In cases of hemodynamic instability due to rapid AF, emergency electrical cardioversion is the intervention of choice. In all other cases, patients’ symptoms, cancer stage and prognosis are the factors that should be considered for the decision among rhythm or rate control. Antiarrhythmic drugs (AADs) are generally administered with caution in cancer patients. AADs can be proarrhythmic, especially in patients with unstable electrolyte balance. QTc prolongation and drug-drug interactions significantly limit their use in patients receiving antineoplastic therapy [ 87 ]. Dronedarone is an AAD with extensive metabolism in CYP 3A4 and P-glycoprotein systems and therefore is generally avoided. Co-administration of class IC AADs and chemotherapy with 5FU or anthracyclines is risky due to the higher risk of underlying ischemia or ventricular dysfunction. As for rate control, beta-blockers (BB) constitute the safest choice with cardioprotective properties. Possible side-effects include hypotension and bradycardia. Starting doses should be low because of the risk of increased BB concentrations in cases of drug-drug interactions. Use of non-dihydropyridine calcium channel blockers (diltiazem and verapamil) should be limited due to inhibition of CYP 3A4 metabolism which may increase toxicity of antineoplastic therapies. Digoxin, as a drug with a narrow therapeutic range and serious toxicities is generally not recommended [ 62 ]. Drug-drug interactions between AADs and anticancer therapy are demonstrated in Table 3 .

The role of catheter ablation for AF as a treatment option in cancer patients is unclear. Data from studies is extremely limited in this population [ 88 ]. The few published studies mainly included cancer survivors and not patients with active cancer. Even though the scarcity of data does not allow for drawing firm conclusions, patients with a history of cancer or active cancer may experience increased periprocedural bleeding risk [ 89 ]. As for the efficacy of catheter ablation, comparable rates of arrhythmia recurrences with the general population have been reported in the literature [ 90 , 91 ].

QTc prolongation and ventricular arrhythmias

Prolonged QTc interval is associated with an increased risk for malignant VAs and SCD. In general, QTc prolongation is defined as > 450 ms in males and > 460 ms in females.Cancer population exhibits a higher risk for QTc prolongation [ 92 ]. The Fridericia formula is the preferred one for calculations in this population since it has demonstrated less errors than other methods [ 65 ].

Etiology is commonly multifactorial and includes: chemotherapeutic agents, drug-drug interactions, electrolyte imbalances and cardiac comorbidities. Chemotherapeutic agents can impair cardiac repolarization through direct effects on ionic channels (arsenic trioxide, TKIs) or by inducing myocyte injury [ 18 ]. The list of chemotherapeutics that can lead to QTc prolongation is extensive. However, the severity of prolongation varies between agents. Aclarubicin, arsenic trioxide, glasdegib, nilotinib, oxaliplatin, pazopanib, ribociclib, sunitinib, toremifene and vandetanib carry the highest risk for arrhythmic manifestations, while agents such as afatinib, axitinib, binimetinib, bortezomib, bosutinib, carfilzomib, dabrafenib, pertuzumab, ponatinib, romidepsin, quizartinib, tamoxifen and panobinostat have been associated with a lower risk [ 5 , 7 ]. The risk of QTc prolongation is further exacerbated by the coadministration of other QT-prolonging medications, many of which are routinely used in oncology practice. These include antimicrobial agents (e.g., fluoroquinolones, ketoconazole), antiemetics, antiarrhythmics, and opioids [ 68 , 69 ]. Moreover, hepatic and renal dysfunction—frequently encountered in cancer patients—can impair drug metabolism and excretion, leading to the accumulation of QT-prolonging agents and heightened cardiotoxicity. This risk is further compounded by common oncologic complications such as electrolyte disturbances (e.g., hypokalemia, hypomagnesemia) and underlying structural heart disease, both of which can significantly increase susceptibility to arrhythmias. The aforementioned factors commonly coexist and can lead to the ‘perfect storm’ for arrhythmic manifestations [ 7 ].

Management of QTc prolongation in cancer patients

In comparison to the general population, in patients with cancer discontinuation of the responsible QTc prolonging drug is a difficult decision, especially in cases when the specific anti-cancer therapy is expected to be significantly beneficial for the patient. This point, together with the fact that TdP rarely occurs when QTc < 500 ms [ 93 ] supports a more flexible approach. Additionally, comorbidities—rather than QTc prolongation alone – appear to be the main determinants of cancer and CV mortality [ 94 ]. These considerations underpin the ESC guidelines recommendations, which allow for greater QTc increases in this population [ 5 ]. An increase in the QTc interval of more than 60 ms from baseline should not routinely prompt treatment modification, provided that the QTc remains < 500 ms [ 95 ].

With QTc values are ≤ 480 ms, antineoplastic therapy can be started or continued.

If 480 ms < QTc < 500 ms, all the reversible causes that may act synergistically should be sought and corrected (e.g. hypokalemia, hypocalcemia, hypomagnesaemia, hypothyroidism, adjustment of doses according to renal/hepatic metabolism and discontinuation of non-essential drugs with known effect on the QTc interval).

As long as the reversible causes have been ruled out or corrected, the management of the anti-cancer therapy depends on the symptoms, the severity of the QTc prolongation and the existence of an equally effective alternative treatment.

If the patient is asymptomatic and QTc exceeds 500 ms, temporary interruption of culprit chemotherapeutics and monitoring with daily electrocardiograms (ECGs) until normalization of the interval are recommended [ 5 ].

Asymptomatic patients with QTc between 480 ms-500 ms may continue anticancer therapy in the same or in reduced dose with close monitoring (weekly ECGs).

Patients with symptomatic VAs (TdP, sustained VAs) should immediately discontinue therapy and receive advanced cardiac life support if needed [ 5 ].

Recurrent episodes of TdP can be managed with magnesium infusion and isoproterenol or temporary pacing to maintain a high heart rate [ 96 ].

In patients with significant prolongation of the QTc interval during therapy, alternative chemotherapeutic agents should be considered.

Management decisions on QTc prolongation should be individualized according to cancer patient’s risk profile and the expected benefit derived from the antineoplastic therapies.

Conduction disorders

Atrioventricular (AV) conduction disorders and sinus bradycardia are uncommon side-effects of certain chemotherapeutic agents. AV block, as a clinical manifestation of myocarditis induced by ICIs, is the most severe form that requires hospitalization and intravenous administration of corticosteroids [ 97 ]. Under these circumstances, AV block usually resolves while in rare cases with persistent block, a permanent pacemaker may be needed [ 98 ]. Thalidomide, pomalidomide, paclitaxel and ALK inhibitors may induce sinus bradycardia that is generally well tolerated in patients without cardiac comorbidities. In case of symptoms (syncope, chronotropic incompetence) temporary discontinuation of the culprit agent is needed in order to establish a causative effect. Therapy rechallenge may be chosen in a lower dose or with an alternative agent, depending on the available choices. [ 5 , 99 ] In cancer survivors, who received RT, AV conduction disorders may become apparent several years after therapy due to myocardial fibrosis affecting the conduction system [ 100 ]. Sick sinus syndrome and AV conduction disorders are monitored and treated following the same guidelines for the general population. As for the role of cardiac resynchronization therapy, it seems to remain a valuable therapeutic option in patients with chemotherapy induced cardiomyopathy fulfilling the criteria of implantation (reduced left ventricular ejection fraction ≤ 35%, New York Heart Association class II-IV HF symptoms, and wide QRS complex) as suggested by the relevant guidelines and demonstrated in the MADIT-CHIC trial [ 101 ].

Sudden cardiac death in cancer patients

Sudden cardiac death (SCD) is rare in cancer patients receiving anticancer therapy, primarily from VAs either due to cancer therapy related cardiac dysfunction (CTRCD) or mainly due to QTc prolongation [ 102 ]. The probability of SCD the first 6 months of anticancer treatment is 0.6% [ 103 ]. This risk is higher in patients younger than 74 years old, with a history of congestive HF and lung cancer [ 103 ]. In cancer patients, the causes of SCD differ from those in the general population. Ischemic events are less common,. [ 104 ], while non-ischemic cardiomyopathy is a more frequent cause [ 105 ]. FDA has released black box warnings for some chemotherapeutics after their approval and 11% of them is about SCD [ 106 ]. Several anticancer treatments have been associated with QTc prolongation and VAs and less with SCD, including BTK inhibitors, TKIs, anthracyclines,arsenic trioxide, 5FU, capecitabine, gemcitabine, interferons, nilotinib, romidepsin, bortezomib, carfilzomib, rituximab and hormonal therapies (more rarely) [ 7 , 14 , 19 , 20 , 30 , 107 ]. BTK inhibitors (ibrutinib, acalabrutinib and zanubrutinib) may lead to increased risk of VAs and SCD, independently of QT lengthening [ 108 ]. Cetuximab and necitumumab carry a black box warning for SCD [ 20 , 109 ]. Vandetanib and nilotinib also carries a black box warning for increased risk of QTc prolongation, TdP, and SCD [ 20 ].

However, the outcome of resuscitation in cancer patients with SCD treated in hospital is not different from that of non-cancer patients, highlighting that cancer should not be a rebuttable factor to the initiation of resuscitation or intensive care therapies in the context of SCD [ 105 ]. In more detail, among hospitalized patients with solid tumors and SCD survival to discharge is higher than in patients with hematologic malignancies. Furthermore, patients who underwent initial arrest outside of an intensive care unit, were more likely to survive and be discharged than patients who experienced initial arrest in the intensive care unit. Surprisingly, patients with an unexpected arrest had a higher rate of survival than did patients whose arrest followed gradual unrelenting deterioration [ 110 ].

Cardiological assessment of cancer patients

Pre-treatment screening of cancer patients

Before initiating cancer therapy, a baseline comprehensive cardiologic evaluation should be performed to assess both the risk of CTRCD and the risk of arrhythmias (Fig. 2 ). This includes a detailed medical history focusing on any pre-existing CV condition, family history of arrhythmias and any previous exposure to cardiotoxic treatments. A baseline ECG is essential in the assessment of all cancer patients scheduled to receive cardiotoxic agents, in order to identify any pre-existing arrhythmias, conduction abnormalities or QTc prolongation that could be exacerbated by cancer treatment [ 5 ]. An echocardiographic study can assess cardiac structure and function and global longitudinal strain, providing a baseline for future comparisons [ 5 ].Cardiac magnetic resonance or computed tomography imaging may be considered when structural heart disease is suspected but not adequately visualized on echocardiography.. Blood tests to evaluate thyroid, kidney and liver function and electrolyte levels (potassium, magnesium, calcium) are crucial as imbalances can predispose patients to arrhythmias. In addition, QTc-prolonging drugs (antiarrhythmics, antibiotics, antifungals, psychoactive drugs, antidepressants, antipsychotics, antiemetics, antihistaminics) should be taken into account.

Monitoring during treatment

During treatment with potentially cardiotoxic agents, an expert consultation with a cardiologist with specific expertise in managing arrhythmias in cancer treatment would be beneficial for at-risk cancer patients. Regular ECG monitoring is recommended to detect early signs of myocardial injury and arrhythmias. The frequency of monitoring depends on the specific drugs used and the patient’s baseline arrhythmia risk. In high-risk patients, ECG may be performed at every cycle of chemotherapy (Table 6 ). Awareness of the possible arrhythmic effects of each therapeutic intervention is of great value as personalized assessment is necessary. More specifically, in patients treated with Vascular Endothelial Growth Factor inhibitors, QTc monitoring is recommended every month for the first three months and in stable patients afterwards, every 3 to 6 months [ 5 , 111 ]. In patients receiving second generation BCR-ABL TKI, especially nilotinib, QTc measurement is recommended at baseline and at 2 and 4 weeks after therapy initiation [ 112 ]. Every dose increase in QTc prolonging treatment should be accompanied by regular QTc monitoring. During treatment with these agents, drugs with synergic effect on the QT interval should be avoided or administered with caution under monitoring. Proper electrolyte management (K + > 4.0 mmol/L, Mg 2+ > 2.0 mg/dL and normal values of corrected Ca 2+ ) should be ensured.

Patient’s education about the signs and symptoms of arrhythmias (palpitations, dizziness, shortness of breath, and chest pain), as well as self-monitoring are vital. Encouraging the use of home monitoring devices such as portable ECG monitors can help in early detection of recurrent arrhythmias. Patients should be advised on lifestyle changes that can help manage arrhythmias, including diet, exercise, and avoiding substances such as caffeinated drinks or grapefruit juice that can exacerbate arrhythmias [ 6 , 39 , 113 ].

In cases where patients exhibit symptoms suggestive of arrhythmias, 24-h Holter monitoring may be suggested to detect transient arrhythmic events that could be missed by an ECG. For patients presented with symptomatic VAs, a complete evaluation for CV side-effects as well as discontinuation or dose reduction of the responsible drug is needed. On the contrary, self-terminating VAs in asymptomatic patients require discontinuation of anticancer therapy only for cases where concomitant persistent ECG abnormalities exist or additional CV toxicity has been established [ 12 ].

Monitoring cardiac biomarkers such as troponin levels can provide additional information regarding myocardial injury that may predispose patients to arrhythmias. Regular assessment of these biomarkers can help in identifying patients at risk for developing serious cardiac complications and guide adjustments in their treatment regimen to mitigate further damage [ 114 – 116 ].

Monitoring after treatment

Anticancer therapies may induce CV effects (coronary artery disease, left ventricular systolic dysfunction, peripheral artery disease, valvular heart disease, pericardial constriction) several years after their administration (late-effects) [ 101 , 102 ]. As a consequence, patients who have successfully completed cancer treatment should be re-assessed at the end of anticancer therapies in order to define their surveillance plan. The decision is based on four major criteria: the baseline arrhythmia risk prior to therapies, the type of the received anticancer therapy, the diagnosis of any CV toxicity during treatment and at the end of it [ 12 ].

Focusing on the arrhythmic manifestations in cancer survivors, conduction disorders, new-onset supraventricular or ventricular arrhythmias and symptoms of AD are among the possible late-effects of anticancer therapies [ 12 , 101 , 102 ]. Thoracic RT, especially when increased doses were administered (> 25 Gy mean heart dose), is a major risk factor for late arrhythmic events due to the induction of myocardial fibrosis [ 12 , 103 – 105 ]. Cancer survivors who present with sick sinus syndrome, AV conduction disorders or VA during the follow-up period are managed according to the guidelines for the general population, as no dedicated recommendations for this population exist [ 76 , 106 ].

Conclusion

Arrhythmias are relatively common in cancer patients, with AF being the most frequently observed. The development of arrhythmias is influenced by patient-related factors, the underlying malignancy, and the effects of antineoplastic therapies. Assessment of the arrhythmogenic risk alongside cardiotoxicity risk is essential both before and during cancer treatment to facilitate the safe and uninterrupted completion of cancer therapy, reducing morbidity and mortality at the same time. Furthermore, the current lack of clinical trials specifically addressing arrhythmia prevention and management in cancer patients represents a significant gap in the field. Future efforts should prioritize the development of cardio-oncology registries and prospective multicenter studies to better characterize arrhythmic risk and guide evidence-based interventions both for prevention but also for treatment of the induced arrhythmias. This evolving field also calls for collaborative care models that integrate oncologists, cardiologists, and electrophysiologists to optimize CV outcomes across the cancer continuum.

Abbreviations

Antiarrhythmic drugs

Autonomic dysfunction

Androgen deprivation Therapy

Atrial fibrillation

Aromatase Inhibitors

Anaplastic lymphoma kinase

Autonomic nervous system

Atrioventricular

Beta blockers

Chimeric antigen receptor

Cancer therapy related cardiac dysfunction

Cardiovascular

Cardiovascular risk factors

Direct Oral Anticoagulants

Electrocardiogram

Epidermal growth factor receptor

Gonadotropin-Releasing Hormone

Human epidermal growth factor receptor 2

Heart failure

Hematopoietic stem cell transplantation

Implantable Cardioverter Defibrillators

Immune checkpoint inhibitors

Low molecular weight heparin

Non-vitamin K antagonist anticoagulants

Radiotherapy induced heart disease

Radiotherapy

Sudden cardiac death

Selective estrogen receptor modulators

Supraventricular tachycardia

Torsades de Pointes

Tyrosine kinase inhibitors

Ventricular arrhythmias

Vascular endothelial growth factor

Ventricular fibrillation

Ventricular tachycardia

5-Fluoruracil

Authors’ contributions

All authors wrote different sections in the manuscript. All authors reviewed the manuscript. K.K., O. K. and K.P.L. prepared figures and tables.

Funding

This study has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 945175 CARDIOCARE — H2020-SC1-BHC-2018-2020/H2020-SC1-2020-Two-Stage-RTD.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

(applicable for both human and/or animal studies. Ethical committees, Internal Review Boards and guidelines followed must be named. When applicable, additional headings with statements on consent to participate and consent to publish are also required).

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

8/22/2025

Following the article's publication, an error was found in the Funding section. This has been corrected.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.