Overview of cancer treatment-related cardiovascular toxicity

A closer look at the common cardiovascular conditions that can occur in people with cancer and their drug associations, as well as management considerations.
Understanding the impact of cancer treatment on cardiovascular health and the importance of optimising cardiovascular health and monitoring for cardiotoxicity has gained increasing attention to improve patient mortality and morbidity. This article will describe the common cardiovascular issues that can occur in people with cancer, outline the drug associations with these conditions and provide some management considerations for people with cancer with cardiovascular problems. 

Key points

  • Cardiovascular issues can occur at all stages of cancer treatment;
  • Understanding the interactions between different cancer treatments and cardiovascular disease is essential to ensure patient safety;
  • Identifying cardiovascular issues early and intervening promptly enables us to optimise treatment plans and improve patient mortality and morbidity;
  • A multidisciplinary management approach is necessary given the complexity of the patients, the treatments involved and the highly specialised nature of their care;
  • This is a rapidly evolving area of medicine and the development of new consensus guidelines, cardio-oncology societies, and both scientific and clinical research make it an exciting and important field to be involved in.


Therapeutic breakthroughs in the past few decades have significantly increased the life expectancy of people with cancer​​[1]​. As a result, the role that cardiovascular disease (CVD) plays in this patient cohort is now better understood. The complexities of treatment pathways and patient comorbidities has necessitated improved diagnostics and therapeutics to enable optimised cardiovascular care at all stages of cancer therapy. 

The discipline of cardio-oncology has since emerged, and aims to design and promote strategies for the prevention, diagnosis and early treatment of cardiotoxicity to improve the mortality and morbidity of people with cancer while minimising interruptions to their treatment​​[2]​. Additionally, cardio-oncology involves the diagnosis and treatment of different cardiac tumours, both primary and secondary, and the consequences of these on cardiac function​​[3]​.

The term ‘cardiotoxicity’ encompasses any clinical or subclinical cardiovascular damage and disease derived from cancer treatment, including conventional chemotherapy, small molecules and monoclonal antibodies, immunotherapy and radiotherapy​​[4,5]​. A broad spectrum of entities are included, such as myocardial dysfunction and heart failure (HF) and the development or worsening of ischaemic heart disease, arrhythmias, systemic and pulmonary arterial hypertension, valvular heart disease, myocarditis, pericardial and thromboembolic disease, and atherothrombotic phenomena, such as cerebrovascular or peripheral vascular disease​​[5]​. The main cancer therapies associated with the different subtypes of cardiotoxicity are summarised in Table 1​​[5–7]​​. 

Central to cardio-oncology is the role of the multidisciplinary team (MDT), which often comprises haemato-oncologists, surgeons, cardiologists, specialist nurses, physiologists, pharmacists and other allied healthcare professionals. Within this team, the specialist pharmacist can identify and advise on drug dosing and interactions, as well as promoting guidelines and evidence-based therapy. The specialist pharmacist can also act both as a patient advocate and a reference source for safe prescribing, ultimately aiding in the prevention, identification and management of cardiotoxicity​​[6]​.  

Although the underlying pathophysiology of cardiotoxicity is not fully understood, current antineoplastic treatments (i.e. medicines used to treat cancer) may impair the functioning of cardiomyocytes and their micro-environment through a variety of mechanisms​​[7]​. These include dysregulation of bioenergetic performance and mitochondrial dysfunction, alteration of calcium and iron homeostasis, generation of oxidative stress, apoptosis, inflammation, ischaemia, fibrosis, alteration of the contractile and electrical properties of the myocardial cell and inflammatory infiltration of the myocardium​​[7]​.

The relationship between cancer and CVD not only arises from direct damage caused by cancer treatment but also from the acceleration of pre-existing cardiac issues, often mediated by factors such as age, gender, genetics and other relevant cardiovascular risk factors, such as diabetes, hypertension, hypercholesterolaemia and smoking​​[8]​.

While there is variation in the literature on the overall prevalence of cardiotoxicity, a multicentre study published in 2020, conducted in tertiary-care hospitals in Europe involving 865 patients, revealed that around 4 out of 10 people with cancer developed some form of cardiotoxicity​​[9]​.

This article will describe the common cardiovascular issues related to cancer treatment, as well as outline any drug associations with these conditions and provide some practical guidance for managing people with cancer with cardiovascular problems. 

Monitoring and biomarkers

The risk stratification, diagnosis and monitoring of cardiotoxicity requires a multiparametric and multimodal approach. This should combine a thorough and detailed history and physical examination, electrocardiogram (ECG), serum biomarkers (troponin I/T, brain natriuretic peptide [BNP], and its amino-terminal fragment, NTproBNP) and advance imaging modalities (including 3D echocardiography, cardiac magnetic resonance imaging [MRI] and cardiac computerised tomography [CT])​​[10–12]​.

Although a baseline measurement of cardiac biomarkers is recommended before starting any type of antineoplastic therapy, the frequency with which these are undertaken should be individualised based on pre-determined cardiovascular risk and the proposed treatment plan​​[12]​. Although biomarkers are fundamental determinants for identifying cardiotoxicity, it is important to note that an isolated increase in a biomarker rarely justifies the interruption of cancer treatment. Instead, it emphasises the need to further investigate for the presence of cardiotoxic damage and/or underlying CVD prior to any modification of the cancer treatment plan​​[13]​​. Biomarkers used in the detection of subclinical dysfunction and monitoring during cancer treatment are listed in Table 2​​[14]​​. Recommendations regarding monitoring using biomarkers and imaging tests have been issued by different cardiology societies​​[11,12,15,16]​​. Monitoring strategies will differ depending on the type and severity of toxicity seen and local protocols. 

As such, an in-depth review of these is outside the scope of this paper; however, Byrne et al. discussed this in more detail in their review paper on cardio-oncology issues in patients with lymphoma​​[17]​. Additionally, the 2022 European Society of Cardiology (ESC) cardio-oncology guidelines provide a comprehensive approach to monitoring strategies depending on potential cardiovascular risk, drug type and toxicity, covering both imaging and biomarker strategies​[5]​.

Table 2 lists the current available and promising serum biomarkers used in the detection of cardiotoxicity and monitoring of cardiac function during cancer treatment​[12,13,18]​​.

Pharmacological approach 

Understanding of cardiotoxicity has come a long way since the original case reports on anthracycline toxicity from the 1970s​​[19,20]​. There are now a plethora of medications treating a broad spectrum of different malignancies, with the potential for causing toxicities. 

Protective strategies to reduce the risk of toxicities can be grouped into: 

  • Early identification and management of risk factors, such as diabetes, hypertension, hyperlipidaemia and smoking, to reduce the compounding effects of these conditions on cardiac function​​[10]​​;
  • Evaluating the choice of chemotherapeutic agent by highlighting those with the highest potential to cause cardiotoxicity, or considering alternative preparations (i.e. liposomal anthracyclines) for patients that have already developed cardiac complications​​[5]​;
  • The dosing strategy; for example, using a bolus as opposed to continuous infusion strategy with 5-fluorouracil is associated with lower incidence of cardiotoxicity​​[21]​​;
  • The initiation of cardioprotective therapy (CPT), which is undertaken in patients whose pre-treatment screening determined them as high risk or those having already developed toxicity during treatment​​[5]​.

These strategies are guided by monitoring of ventricular function, cardiac rhythm and analytical biomarkers such as BNP and troponin, as well as the patient’s symptoms and clinical examination findings​​[5]​.

Role of cardio-protection 

A recent meta-analysis including 17 studies (14 of them in people with breast cancer) of cardioprotective strategies in adult patients undergoing chemotherapy and neurohormonal blockade (e.g. beta blockers, Angiotensin-converting enzyme inhibitors [ACEi]/angiotension receptor blockers [ARBs] and mineralocorticoid receptor antagonists) showed that, with use of these therapies, there was a 3.96% (95% CI: 2.90% to 5.02%) reduction in left ventricular ejection fraction (LVEF) decline, estimated by weighted mean difference, compared with placebo​​[22]​​. However, significant heterogeneity was noted in the treatment effects across studies, highlighting the need for larger trials of cardioprotective strategies​​[22]​​.

Neurohormonal blockade represents the cornerstone of heart failure treatment​​[23]​. This is because chronic activation of neurohormonal systems seen in the early stages of impaired cardiac function result in adaptations, which, over time, cause further deterioration to cardiovascular health​​[23]​. These include salt and water retention, arterial vasoconstriction, cardiac hypertrophy, fibrosis and apoptosis​​[23]​​. The medicines targeting this system work via different mechanisms to help preserve cardiac function​​[23]​.

In the case of anthracyclines, the use of epirubicin instead of doxorubicin has been suggested, although it is just as cardiotoxic at equipotent doses. Opting for prolonged infusion rates and the use of liposomal formulations (to reduce the maximum circulating concentrations of doxorubicin) and the concomitant use of dexrazoxane (iron chelator with cardioprotective effects through interaction with topoisomerase II) or, alternatively, using chemotherapy regimens without anthracyclines are all strategies that can infer some cardioprotection​​[24]​.

Currently, it is not recommended to start cardioprotective agents systematically in all patients with cancer​​[25]​​. Instead, a cardiovascular risk assessment should be undertaken​​[10]​. A blueprint for risk assessment depending on the treatment course being proposed can be found in the position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society, published in 2020​​[10]​. These can be subcategorised into medical cardiovascular risk factors, lifestyle cardiovascular risk factors, cardiac biomarkers, previous cardiotoxic cancer treatment and previous CVD​, with treatment being administered based on individual quantified risk and discussion with the patient​​[10]​. Recommendations on primary and secondary prevention strategies depending on risk factor scoring can be seen in the 2022 ESC cardio-oncology guidelines, with primary prevention being recommended for those at high and very high risk, which is determined by their risk assessment scores and secondary prevention strategies following standard guidelines for cardiovascular care for respective conditions​​[5]​.

Myocardial dysfunction and heart failure 

Impairment of left ventricular systolic function represents a major complication in terms of morbidity and mortality for people with cancer, and is one of the most common forms of cardiotoxicity seen in clinical practice​​[7]​

According to the latest consensus definition from the International Cardio-Oncology Society, any asymptomatic cardiac dysfunction or symptomatic heart failure (HF) attributed to cancer therapy is collectively termed cancer therapy-related cardiac dysfunction (CTRCD)​​[4,5]​. Asymptomatic CTRCD is graded based on changes in left ventricular ejection fraction (LVEF) and/or global longitudinal strain (GLS) in the absence of signs or symptoms of HF (e.g. breathlessness or peripheral oedema)​​[4,5]​

A decrease in LVEF to <40% is graded as ‘severe’, while ‘moderate’ is defined by new LVEF reduction by  ≥10 percentage points to an LVEF of 40-49% or a new LVEF reduction by <10 percentage points to an LVEF of 40–49% and either new relative decline in GLS by ≥15% from baseline or new rise in cardiac biomarkers​​[4,5]​​. ‘Mild’ asymptomatic CTRCD is defined as preserved EF (≥50%) with new relative reduction in global longitudinal strain >15%, relative to baseline and/or new rise in cardiac biomarkers​​[4,5]​​. 

Left ventricular (systolic and/or diastolic) dysfunction can be caused by various cancer therapies, including: cytotoxic chemotherapy (anthracyclines, taxanes and alkylating agents, such as cyclophosphamide, cisplatin, melphalan); molecular targeted therapies, such as human epidermal growth factor receptor (HER2) inhibitors; tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor (VEGF) or its receptor (VEGF-R), such as sunitinib or pazopanib; proteasome inhibitors; immune checkpoint inhibitors (ICIs); and radiation therapy​[7]​

Anthracyclines (e.g. doxorubicin, epirubicin, daunorubicin and idarubicin) have one of the highest incidences of CTRCD of any chemotherapeutic agent and can occur in up to 48% of patients in cumulative doses of doxorubicin at 700mg/m2​​[26]​. It induces myocardial damage that is often — but not always — dose dependent​​[26]​. Although symptomatic reductions in left ventricular ejection fraction can occur during or shortly after completion of anthracycline chemotherapy, symptoms may not develop until many years later​​[26]​

In contrast, HER2 inhibitors, such as trastuzumab, may induce early myocardial dysfunction that can be transient and dose independent, and frequently reversible when discontinued​​[15]​​. Further deleterious effects on left ventricular function are compounded when anthracyclines and HER2 therapy are combined​​[27]​​.

Treatment with ACEIs or ARBs and beta-blockers in patients with asymptomatic left ventricular systolic dysfunction (LVEF <40%) is important to help prevent progression to clinical HF and avoid adverse ventricular remodelling​​[5]​. In the presence of overt HF, it is necessary to follow the conventional treatment guidelines for HF, including the recommendations regarding the implantation of devices or indications for heart transplantation​​[28]​. Although underrepresented in pivotal clinical trials, real-world studies strongly support the use of neurohormonal blockade (including sacubitril/valsartan, beta-blockers, mineralocorticoid antagonists and ivabradine) for cardioprotection in people with cancer​[24,29]​. Experience with sodium-glucose cotransporter-2 inhibitors in this cohort is limited to in vitro and retrospective studies​​[30,31]​.

Ischaemic heart disease 

The fluoropyrimidines — particularly 5-fluorouracil and its oral prodrug, capecitabine — are the drugs most frequently associated with acute coronary ischemia and chest pain. Both have been associated with coronary vasospasm, in the presence of obstructed and unobstructed coronary arteries​​[32]​.

Treatment with platinum drugs, TKIs (particularly those that target the VEGF pathway or the BCR-ABL inhibitors), some immunomodulatory drugs used to treat multiple myeloma (e.g. thalidomide, lenalidomide and pomalidomide) and rituximab have been linked to an increased risk of arterial thrombosis or plaque rupture​​[33]​

Radiotherapy-related coronary artery disease typically affects the ostia and proximal segments of the epicardial coronary arteries (i.e. the left main and right coronary, respectively) as a result of the location of the radiation field. However, it rarely provokes an acute coronary syndrome (ACS) during cancer treatment and patients tend to present years after exposure​​[34]​​. Radiation causes direct endothelial injury and inflammation, which results in reactive oxygen species generation and cytokine production. These products cause vessel wall rupture, platelet aggregation and myofibroblast infiltration into damaged coronary intima. Over time this leads to the development of atherosclerosis (thickening or hardening of the arteries owing to plaque build-up) and stenosis (narrowing of the arteries)​​[35]​.

The same diagnostic algorithms for chest pain as in patients without cancer should be applied. However, patients with cancer frequently present with atypical chest pain symptoms, which can be masked by concurrent analgesia for cancer pain or even confused with tumoral symptoms​​[36]​. It is always advisable to individualise the antithrombotic regimen and the revascularisation strategy according to the patients’ comorbidities and life expectancy​​[36,37]​​.

In the context of ACS, the choice and duration of antiplatelet drugs should be individualised depending on the type and stage of cancer, the presence of any clotting and platelet issues, any concomitant medicines and the need for chemotherapy and/or cancer surgery after the event​​[37]​​. Additionally, it should be noted that many people with cancer exhibit a higher risk of coronary stent thrombosis owing to the prothrombotic nature of their conditions​​[37]​​.

For patients who have experienced angina while taking fluoropyrimidines, several strategies have been suggested for the prevention of new episodes, if there is no alternative cancer therapy available. These include: 

  • The administration of 5-fluorouracil as a bolus instead of continuous infusion; 
  • Pre-treatment several hours before the cycle with oral long-acting nitrates or long-acting calcium antagonists (e.g. nifedipine, diltiazem), or;
  • During the same chemotherapy cycle with intravenous infusion, under continuous ECG monitoring​​[32,37]​.

Universal prophylactic pre-treatment with antianginal vasodilators is not currently recommended as it has not been proven to diminish the risk of coronary vasospasm in randomised controlled trials​​[32]​.


The development of supraventricular tachyarrhythmias, especially atrial fibrillation (AF), is a well-known subtype of cardiotoxicity from multiple antineoplastic agents. These include anthracyclines, alkylating agents (e.g. cisplatin), antimetabolites (e.g. 5-fluorouracil, gemcitabine, clofarabine), taxanes (e.g. paclitaxel), TKIs, immunotherapy, mitoxantrone and interleukin-2 (IL-2)​​[38]​.

Ibrutinib — a TKI approved for the treatment of chronic lymphocytic leukaemia, mantle cell lymphoma and Waldenstrom’s macroglobulinemia — is associated with rates of supraventricular tachycardia and AF as high as 16% (76% in the first year, with a median onset of 3.0 to 3.8 months)​​[39,40]​. Supraventricular arrhythmias are also a frequent complication (8–10%) of hematopoietic stem cell transplants (particularly when melphalan is used as part of the conditioning regimen) and of the novel chimeric antigen receptor T cell (CAR-T) therapies​​[38,41]​.

The management of AF in oncological patients has the same objectives as in the general population and it is recommended to follow the available embolic (CHA2DS2VASc) and haemorrhagic (HAS-BLED) risk scales, although both scores have not been prospectively validated in people with cancer and, as such, do not consider cancer-specific risk bleeding features, such as intracranial metastasis, severe thrombocytopenia or actively bleeding high-risk malignancies​​[38,39,42]​

It is recommended to prioritise the use of direct-acting oral anticoagulants (DOACs) or low-molecular- weight heparins over vitamin-K antagonists, although drug–drug interactions with certain cancer therapeutics, such as ibrutinib and dabigatran, should be considered and reviewed with specialist pharmacists​​[6,38]​​. 

In ibrutinib-induced AF, it is recommended to avoid dabigatran, calcium channel blockers, digoxin or amiodarone owing to their intrinsic inhibition of P-glycoprotein, which can lead to supratherapeutic levels of these medicines​​[17]​.

Sinus bradycardia is a frequent adverse effect of classical antineoplastic therapies (e.g. paclitaxel and thalidomide), although in most cases the patient is asymptomatic​​[43]​. The incidence is variable, depending on the agent, but can occur, for example, in up to 40% of patients taking thalidomide​​[38]​. Pazopanib and anaplastic lymphoma kinase inhibitors, such as alectinib or crizotinib, stand out among the targeted therapies that are most associated with sinus bradycardia​[44]​. Immunotherapy is also known to cause bradycardia in a more malignant form via atrioventricular block​​[45]​. In all these cases, judicious use of compounding drugs, such as beta-blockers, calcium antagonists, digoxin and amiodarone, is recommended. Reducing the dose, or even interrupting these medicines temporarily may be necessary. In refractory or emergent cases, pacing may be advised​​[38,43]​.

Prolongation of QT interval

Antineoplastic treatments may contribute to other electrocardiographic changes, such as QTc interval prolongation. This is important owing to the association between prolongation of the QTc interval and the risk of ventricular arrhythmias, such as polymorphic ventricular tachycardia, otherwise known as torsades de pointes​[5]​. It should be noted that the Fridericia formula (QT/3√RR) is considered the most appropriate for calculating QTc in the cancer population​​[5]​.

QT interval prolongation (QTcF > 500ms) can result both from direct inhibition of ionic channels and through interference with intracellular signalling cascades, such as the PI-3K pathway​​[46]​. The highest incidence of QT interval prolongation is seen with arsenic trioxide treatment (up to 40% of cases) and with TKIs (including ceritinib, crizotinib, dasatinib, gliteritinib, nilotinib, lapatinib, sorafenib, sunitinib, vemurafenib and vandetanib). Histone deacetylase inhibitors (e.g. panobinostat or vorinostat), inhibitors of cyclin-dependent kinases CDK4 and CDK6 (e.g. ribociclib) and antimetabolites also have a non-negligible risk of 1–10%​​[38,43]​.

Performing a baseline ECG and periodic monitoring of the QTc interval in people with cancer receiving anticancer therapies associated with a risk of QT prolongation is mandatory; however, the risk of developing malignant ventricular arrhythmias in the form of polymorphic ventricular tachycardia (torsades de pointes) is generally low. Arrhythmic complications are generally observed when the QT interval is greater than 500ms or when an increase of more than 60ms from baseline occurs​​[38,47]​.

Multiple additional factors may contribute to QT interval prolongation in people with cancer, including chemotherapy, electrolyte disturbances (loss of potassium and magnesium ions from chemotherapy-related vomiting and diarrhoea), concomitant use of other drugs that prolong the QT interval (such as antiemetics, H2-blockers, proton pump inhibitors, antimicrobial agents or antipsychotics), underlying CVD, older age and female gender​​[47]​.


Myocarditis (i.e. inflammation of the heart muscle) is defined using a combination of clinical, electrocardiographic, biomarker, imaging and tissue pathology findings. Major (definite cardiac MRI findings according to the modified Lake Louise criteria) and minor (clinical syndrome, arrhythmias, decrease in ejection fraction, regional wall motion abnormalities, abnormal troponin) criteria aid a clinical diagnosis​​[4]​. Prognosis and management varies depending on the underlying aetiology. Subsequent decisions to rechallenge, if necessary, following myocarditis treatment needs to be discussed by the MDT and the patient, who would need to be appropriately counselled regarding the risks and benefits.

ICIs are known to cause myocarditis with an incidence ranging from 0.09% and 1.00%​​[48]​​. However, this is probably an underdiagnosed entity owing to the wide spectrum of possible clinical presentations, the difficulty of its diagnosis, and the lack of awareness of this complication​​[45]​​. The risk of ICI-associated myocarditis is higher with combination therapy (anti-CTLA-4 and anti-PD1 therapy) than in monotherapy. It usually occurs within the first three months after starting treatment and varies from an asymptomatic increase in troponin to sudden cardiac death (fulminant myocarditis)​[48]​. Normal ECG or normal troponin values do not rule out the presence of myocarditis owing to immunotherapy. Echocardiography is often unremarkable, with LVEF normal in >50% of cases in the initial evaluation and thus should be complemented by cardiovascular MRI​​[49]​. The gold standard for the diagnosis of myocarditis continues to be endomyocardial biopsy (according to the Dallas criteria), but this is invasive and there is a risk of a false negative diagnosis when a representative sample is not obtained​​[45]​​.

The current management of ICI-associated myocarditis implies in all cases the interruption of immunotherapy, hemodynamic support if needed (vasoactive drugs or with mechanical circulatory support) and the administration of corticosteroids (0.5–1.0g of methylprednisolone for three to five days followed by a weight-adjusted taper of prednisone [1.5 mg/kg] under close monitoring) with analytical markers and imaging tests. In corticosteroid-refractory cases, favourable experiences have been reported with mycophenolate, anti-CD52 monoclonal antibodies, plasmapheresis, abatacept (CTL4 agonist, cytotoxic T-lymphocyte–associated antigen 4), anti-thymocyte globulin and infliximab. Additionally, prolonged immunosuppressive therapy with steroid-sparing agents can be considered​​[41]​​.

Cases of haemorrhagic myopericarditis with cyclophosphamide have also been reported, with ominous prognosis. This is a rare complication and associated with higher doses of this medicine, such as those seen with bone marrow transplant patients​​[17]​.

Pericardial disease 

The pericardial involvement seen in cardio-oncology patients ranges from an asymptomatic small pericardial effusion to symptomatic myocarditis/pericarditis — which can be further classified as acute, subacute-chronic, constrictive — and cardiac tamponade (a life-threatening condition requiring immediate intervention whereby pericardial fluid inhibits the hearts ability to pump). The occurrence of pericardial effusion is associated with thoracic radiation therapy and drugs, such as anthracyclines, cyclophosphamide, cytarabine, bleomycin, all-trans retinoic acid and immunotherapy​​[50]​​. Acute pericarditis is rare (although it is the most frequent presentation of acute radiotherapy toxicity) and its management is similar to that of patients without cancer (e.g. non-steroidal anti-inflammatory drugs and colchicine in the absence of contraindications and pericardial drainage in the case of tamponade). 7–20% of patients develop chronic pericarditis after completion of radiotherapy. This results in pericardial constriction, which restricts ventricular filling and manifests clinically as a spectrum of heart failure symptoms. Management is with diuretics and beta blockers, and, in some cases, pericardectomy​[51]​.

Valvular heart disease 

Radiation-induced valvular changes have been described in around 3–13% of patients treated with radiotherapy​​[52]​​. As with radiation induced coronary disease and pericarditis, these effects are directly related to the location and dose of radiotherapy given​​[17]​. As such, the improved safety protocols for radiotherapy seen today compared with the 1970s, should result in a precipitous reduction in radiotherapy-induced cardiotoxic presentations over the coming years​​[51]​.

Radiotherapy to the mediastinum damages the valvular endocardium, causing fibrotic thickening, dystrophic valvular calcification and valvular retraction leading to stenosis and/or regurgitation​​[53]​. The degree of involvement is related to the time elapsed since radiotherapy and the accumulated dose​[53]​. Thickening and calcification of the mitral-aortic junction is an almost pathognomonic marker of previous chest irradiation​​[53]​​. The most frequently implicated valves are those of the left heart, in the form of aortic stenosis and mitral regurgitation​​[53]​. It often takes many years for patients to develop clinically significant valvular dysfunction​​[53]​. Treatment recommendations are similar to those for the general population, although radiotherapy increases the odds of surgical complications and valve repair is less likely to be successful​​[54]​.

Arterial hypertension  

The diagnostic threshold for hypertension in patients with malignancy or following cancer therapy is ³130/80 mmHg for those with high CV risk, otherwise ³140/90 mmHg according to the 2022 ESC cardio-oncology guidelines​​[5]​. Hypertension is the most frequent cardiac comorbidity in patients with cancer​​[55]​. This can either be as a consequence of the cancer itself or as a result of cancer treatments with antineoplastic therapies causing hypertension via a number of different mechanisms, including endothelial dysfunction and decreased nitric oxide bioavailability​​[55]​. This occurs with proteasome inhibitors (e.g. carfilzomib) and angiogenesis inhibitors (e.g. anti-VEGF agents, especially bevacizumab as well as sunitinib or sorafenib)​​[5]​

Hypertension is the most common cardiovascular adverse event reported with BRAF-MEK inhibitors, and the incidence is higher with combination therapy​​[56]​. The increase in blood pressure may be observed in the first few days after commencing treatment.  

It has been suggested that hypertension associated with anti-VEGF treatment might represent a marker of tumour response​​[57]​. This is because the effects of anti-VEGF on tumour vasculature and arterial vasculature occur via alterations in endothelial function​​[57]​. Since arterial endothelial dysfunction can cause hypertension, it has been proposed that this could serve as a surrogate marker for anti-VEGF activity on tumour endothelium​​[57]​. Importantly, controlling hypertension in this patient cohort does not reduce therapeutic efficacy​​[58]​. Optimally controlled blood pressure is important and this prevents cardiovascular complications and treatment interruption​​[5]​.   

ACE inhibitors, ARBs and beta-blockers are the first-line drugs for managing hypertension in this patient cohort, given the protective effect they have towards left ventricular function. In uncontrolled cases, the addition of a calcium-antagonist, such as amlodipine, and an aldosterone antagonist (e.g. spironolactone or eplerenone), is recommended​​[59]​​. Cancer therapy causing severe hypertension (³180/110) should be evaluated by the MDT, with treatment being deferred or held until blood pressures values are controlled <160/100 mmHg. At this point, treatment can be restarted with consideration for dose reduction or alternative treatment lines if the risks are felt to outweigh the benefits​​[5]​.

Pulmonary hypertension 

Pulmonary hypertension in patient with cancer is a rare complication with an extensive list of etiologies. These include chronic thromboembolic pulmonary hypertension, pulmonary hypertension from other arterial obstructions (i.e. direct compression or invasion of pulmonary vasculature from the malignancy), unclear or multifactorial mechanisms and the cancer therapy itself​​[60]​. It usually appears months or years after exposure to antineoplastic agents (e.g. TKIs, such as dasatinib and proteosome inhibitors) and can be reversible upon discontinuation of treatment​​[60]​. Cyclophosphamide and other alkylating agents can cause severe pulmonary hypertension in the form of pulmonary veno-occlusive disease. The diagnostic and therapeutic recommendations for pulmonary hypertension in patients with cancer are the same as established guidelines and right heart catheterisation may be required in selected cases​​[50,60]​.

Venous and arterial thrombosis 

Venous thromboembolic disease (VTE), defined as deep vein thrombosis (DVT) and/or pulmonary embolism (PE), is significantly more frequent in onco-haematological patients (four to seven times higher than the general population), with a high risk of recurrence of 12% per year​[33]​​. The factors associated with VTE include age, hereditary pre-disposition, extension and type of tumour (most frequent in cancer of the pancreas, ovary, lung, stomach, kidney, lymphomas and multiple myeloma) and those undergoing active treatment with bevacizumab, TKI, 5-fluorouracil, cisplatin, tamoxifen, and immunomodulators such as thalidomide, lenalidomide, or pomalidomide​​[33,50]​. Patients with multiple myeloma treated with immunomodulators in combination with other drugs, such as doxorubicin, exhibit a risk of VTE greater than 20% and in these cases the prophylactic use of low-molecular-weight heparin or aspirin monotherapy should be considered​​[61]​.

Management of VTE in people with cancer may initially involve low-molecular-weight heparin or unfractionated heparin for five to ten days, subsequently followed by long-term anticoagulation with low-molecular-weight heparin, edoxaban or rivaroxaban for at least six months​​[61]​. These are suggested over vitamin-K antagonists because of improved efficacy​​[61]​​. Anticoagulation beyond six months needs to be continually reviewed to ensure that the benefits still outweigh the risks. Treatment at this stage should be offered to those with either metastatic disease or receiving ongoing chemotherapy​​[61]​.

Patients with active cancer, particularly those with advanced disease or cancer types such as lung, colorectal and gastric cancer, are also associated with an elevated short-term risk of arterial thromboembolism (in the form of myocardial infarction, acute stroke or acute lower limb ischaemia). The risk factors for arterial thrombosis include age, smoking, hypertension, and diabetes as well as certain chemotherapeutic agents, including platinum-based drugs, anti-VEGF and TKIs​​[61,62]​. Treatment of arterial thrombosis depends on the anatomy involved and often involves a combination of antiplatelets, such as aspirin and clopidogrel, vascular intervention and, in the case of acute stroke, thrombolysis​​[61,62]​.

Cytokine release syndrome 

Cytokine release syndrome (CRS) is a state of immune hyperactivation with hyperproduction of proinflammatory cytokines (such as IL-6, IL-10, interferon-g, granulocyte-macrophage colony-stimulating factor) and increased vascular permeability. This can cause hypotension, tachycardia, prolongation of the QTc interval and, in the most severe cases, depression of systolic ventricular function, arrhythmias, shock and death​​[41,63,64]​​. CAR-T cell infusions can produce both direct cardiotoxicity (through cross-reactivity with proteins in healthy tissues that resemble the targeted antigen) and indirect toxicity through CRS​​[63]​. Other treatments associated with CRS include immune checkpoint inhibitors and bispecific T cell engaging (BiTE) single chain antibody constructs​​[65]​. In addition to supportive treatment with IV fluids, biological therapies, monoclonal antibodies and therapies directed against IL-6 (tocilizumab) are the treatments of choice for CRS​​[41,63]​.


Cardio-oncology has emerged as an integral component of care for people with cancer. The concept of cardiotoxicity is very broad and ultimately encompasses all potential cardiovascular conditions. A multiparametric approach — by means of a detailed history and examination, alongside advanced cardiac imaging and cardiac biomarkers — helps to stratify risk, and identify and treat cardiovascular issues that occur during and following cancer treatment. 

This process should be individualised for each patient, depending on the causative agent, underlying malignancy and type of toxicity seen. As such, the role of the MDT is integral in the safe and effective management of these patients. 

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The Pharmaceutical Journal, PJ, December 2022, Vol 309, No 7968;309(7968)::DOI:10.1211/PJ.2022.1.168548

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