Cardiovascular health: an important component of cancer survivorship

Shared risk factors

Shared biological mechanisms

Insights into the biology of cancer and CVD suggest several shared pathological mechanisms, including inflammation and oxidative stress, with emerging evidence of a possible bidirectional relationship (figure 1).50 Oxidative modification of lipids, with ensuing endothelial dysfunction and increased leucocyte–endothelial adhesion, is a key early step in atheroma development.51 Alterations in cell signalling, DNA damage and upregulation of inflammatory pathways in the presence of oxidative stress also appear to promote tumourigenesis and influence cancer evolution.52 Chronic inflammation may promote tumourigenesis via modulation of several important pathways including provision of growth stimuli, transcriptional change, epigenetic alterations and epithelial to mesenchymal transition.53 Furthermore, a growing body of evidence suggests complex platelet–tumour interactions assist in producing a favourable environment for tumour progression, invasion and metastasis.54 In vivo markers of platelet activation have also been associated with all-cause, CV and cancer mortality.55

Over the past two decades, inflammation has been implicated at each step of atherogenesis, although the causal link has been debated.56 57 Inflammatory mediators are elevated in heart failure, and C reactive protein (CRP) is associated with increased risk of CV events and the development of heart failure.58–60 Clinical evidence that reducing inflammation can reduce CV events was reported in the CANTOS trial (NCT01327846). Canakinumab, a monoclonal antibody against interleukin-1β, at 300 mg, 150 mg and 50 mg, was compared with placebo in 10 061 participants with a history of myocardial infarction and elevated high-sensitivity CRP. Interestingly, only the 150 mg evaluation met the prespecified significance threshold for reducing CV events (hazard ratio (HR) 0.85, 95% CI: 0.74 to 0.98; p=0.021).61 Canakinumab use was, however, associated with an increased risk of fatal infections and thrombocytopenia without any significant difference in haemorrhage risk.61 Exploratory analyses also found a reduced incidence of lung cancer and cancer mortality with canakinumab.62 However, subsequent phase III trials of canakinumab in locally advanced and metastatic non-small cell lung cancer failed to reach their primary outcome measure of prolonging OS.63

Several studies have observed increased incident cancers in patients with heart failure leading to suggestions of a possible bidirectional relationship.64–68 This has been hypothesised to relate to shared aetiologies, biology and genetics with preclinical studies suggesting heart failure itself may promote tumourigenesis.69 70 In addition to impacts on inflammation and oxidative stress, implicated pathophysiological pathways include cardiac and other circulating factors, immune dysfunction and neurohormonal activation.68 In mouse models, heart failure after large anterior myocardial infarction was associated with enhanced colonic tumour growth, possibly related to elevated cardiac mediators including serpinA3 which increases tumour growth in vitro.71 In a further study using transverse aortic constriction, a model for pressure overload induced heart failure, injection of cancer cells resulted in larger tumours with higher proliferation indexes and increased numbers of metastases compared with controls.72

Compensatory activation of the renin–angiotensin–aldosterone system occurs in heart failure to maintain blood pressure and cardiac output; however, detrimental consequences occur with chronic stimulation.68 In preclinical models, renin–angiotensin overactivation has been associated with increased tumour cell survival, proliferation, migration, and angiogenesis and enhanced sympathetic nervous system activity with reduced antitumoural immunity.73 74 In mouse models, myocardial infarction accelerated breast cancer growth with an immunosuppressive intratumoural immune landscape, suggesting altered innate immune responses in acute myocardial infarction could impact tumour development.75

CV toxicities of oncological treatments

The survival benefits associated with advancing cancer therapeutics have also increased the potential for treatment-related toxicity. CV toxicities of cancer therapies include myocardial dysfunction, heart failure, ischaemic and valvular heart disease, arrhythmias, thromboembolic disease, arterial and pulmonary hypertension, and pericardial disease.76 Indirect CV consequences can occur due to physiological or haemodynamic effects of therapy including fluid retention and increased blood pressure.77 Underlying CV risk factors such as hypertension and diabetes mellitus increase the risk of treatment-related cardiotoxicity and are of particular concern in ageing populations with cancer.10 78–81

Chemotherapy related myocardial dysfunction is seen most prominently with anthracyclines and heart failure may develop several years after treatment. In a study of 2625 patients treated with anthracycline chemotherapy, 9% developed cardiac impairment, of which 98% had detectable declines in left ventricular ejection fraction of >10% within the first year post-treatment.79 Anthracycline-induced cardiac damage is generally irreversible but early detection is associated with improved outcomes underlining the importance of monitoring for subclinical toxicity.79 81 Other examples of chemotherapy-induced CV toxicity include acute myocardial ischaemia, either due to vasospasm such as with fluoropyrimidines or arterial thrombus best described with platinum agents, and conduction abnormalities.

In addition to acute toxicity, chemotherapy exposure has been associated with late consequences, with accelerated vascular ageing described in clinical cohorts following exposure to cisplatin and anthracyclines.82 83 Long-term studies of men treated for testicular cancer with cisplatin-based chemotherapy report a 1.4-fold to 7.1-fold increase in CV risk thought to be due to both direct vascular consequences of cisplatin exposure and metabolic risk factors including diabetes, hypertension and dyslipidaemia due to hypogonadism.83–85

In men receiving androgen deprivation therapy (ADT) for prostate cancer, observational studies highlight the increased risk of metabolic consequences, CV risk and mortality.86 In a population-based cohort study of over 73 196 men with locoregional prostate cancer, ADT with a luteinising hormone-releasing hormone agonist was associated with increased risk of coronary heart disease (HR 1.16; 95% CI: 1.10 to 1.21; p<0.001), myocardial infarction (HR 1.11; 95% CI: 1.01 to 1.21; p=0.03), sudden cardiac death (HR 1.16; 95% CI: 1.05 to 1.27; p=0.004) and incident diabetes (HR 1.44; 95% CI: 1.34 to 1.55; p<0.001).87 Excess risk of diabetes was also observed with androgen deprivation achieved through orchidectomy (HR 1.34; 95% CI: 1.20 to 1.50; p<0.001) but without significant differences in cardiac outcomes.87 Use of novel antiandrogen agents, such as abiraterone or enzalutamide, used in combination with ADT, also increases the risk of hypertension and CV adverse events in phase III trials.86 In breast cancer survivors, aromatase inhibitor (AI) use has been associated with increased risk of dyslipidaemia, hypertension, ischaemic heart disease and heart failure, compared with the selective oestrogen receptor modulator tamoxifen.88 89 In a meta-analysis of RCTs comparing adjuvant AIs with tamoxifen, there was a 30% increase in risk of ischaemic heart disease with AI use (RR: 1.30, 95% CI: 1.11 to 1.53).90 However, lower rates of myocardial infarction have been observed with tamoxifen versus placebo so whether this is due to a protective effect from tamoxifen remains uncertain.89 90 Consistent data highlight elevated risk of VTE with tamoxifen use, with some evidence it may increase body fat, triglycerides and risk of diabetes.89

Radiotherapy (RT)-associated CVD includes accelerated atherosclerosis, valvular and pericardial diseases, cardiomyopathy, conduction disease and autonomic dysfunction. Typically, this occurs late (>10 years after treatment) making estimations of the burden of RT-induced CVD difficult to quantify.91 92 As a locoregional therapy, CV toxicity is limited to where the radiation field includes the heart or major blood vessels, including treatment of breast, lung and oesophageal cancers, and lymphoma. In a case–control study of 2168 women who received RT for breast cancer, a linear relationship was observed between mean RT heart dose and subsequent major coronary events.93 Risk increased by 7.4%/Gy without an apparent threshold (95% CI: 2.9% to 14.5%; p<0.001), and remained elevated at 20 years.93 Recognition of these adverse consequences and advancing RT techniques has led to the development of dose/volume limits.94 Using data from historical studies may therefore overestimate the risk of current practice.

Recent decades have seen substantial and rapid progress in anticancer therapeutics, with targeted therapies and immunotherapies. Many of these are associated with CV toxicities and are increasingly used in potentially curative settings. Initial high rates of cardiac dysfunction were observed with the human epidermal growth factor receptor-2 (HER-2) monoclonal antibody trastuzumab when co-administered with anthracyclines in breast cancer management. Rates of CV toxicity were subsequently lowered with use of sequential regimes.95 In a pooled analysis of 7445 patients enrolled in three adjuvant clinical trials, asymptomatic or mildly symptomatic myocardial dysfunction with trastuzumab occurred in 8.7% and severe congestive cardiac failure in a further 2.3%.96 However, this may underestimate the true incidence of cardiac dysfunction, with higher rates of myocardial dysfunction and heart failure reported in real-world cohort studies which include more representative populations with cancer.97 Novel HER-2 targeted agents have also been developed including monoclonal antibodies, antibody–drug conjugates and tyrosine kinase inhibitors (TKIs), with safety data to date not showing additional CV risk.95

The vascular endothelial growth factor (VEGF) signalling pathway plays a critical role in regulation of angiogenesis. Several anticancer agents have been developed to target this pathway, including monoclonal antibodies and TKIs.98 Acute and dose-dependent arterial hypertension is the best characterised vascular toxicity of anti-angiogenics, with additional excess rates of arterial thromboembolism, cardiac dysfunction and ischaemia.99 100 In a meta-analysis of 77 phase III trials evaluating drugs targeting the VEGF pathway, hypertension occurred in 22%, severe hypertension in 7.4%, arterial thromboembolism in 1.8%, cardiac dysfunction in 2.7% and cardiac ischaemia in 1.7%, although fatal CV events were rare.99

TKIs of the BCR-ABL mutation are also associated with significant CV adverse events and produce off-target toxicity due to multikinase inhibition.101 Substantial variability exists in type and frequency of CV toxicity, ranging from the low-risk profile seen with the first-generation inhibitor imatinib, to high rates of arterial occlusive events with the third-generation TKI ponatinib.101 102 In a phase II trial of ponatinib, the cumulative incidence of arterial occlusive events was 25% at 5 years, 10% of which were cardiovascular, 7% cerebrovascular and 8% peripheral vascular events.102 Combination TKI therapy targeting BRAF and MEK pathways is also associated with significant CVD. In clinical trials, toxicities included hypertension (6–26%), left ventricular systolic dysfunction (2–12%), VTE (1–4%), QT prolongation (1–5%) and atrial fibrillation (1–4%).103

Prolongation of the QT interval is a risk of multiple anticancer therapies and supportive agents; thus, the assessment of baseline risk, concurrent prescribing and consideration of the required monitoring are important considerations.104 QT prolongation is seen with cyclin-dependent kinase 4 and 6 inhibitors used to treat breast cancer, most notably with ribociclib.104 In phase III trials, risk of QT prolongation with ribociclib was especially high when co-administered with tamoxifen compared with an AI.105 Inhibitors of the epidermal growth factor receptor are also associated with QT prolongation, with the highest risk seen with osimertinib which has additionally been linked with elevated risk of supraventricular tachyarrhythmias and heart failure.106

Immune checkpoint inhibitors (ICIs) have revolutionised oncological outcomes in several tumour types over the last decade. Blockage of negative co-stimulatory T cell receptors, such as PD-1 and CTLA-4, can rejuvenate antitumour T cell responses but risks immune-mediated toxicity. CV immune-mediated toxicity includes myocarditis, myocardial dysfunction, conduction disorders and acute coronary syndromes.81 92 While myocarditis is uncommon, with incidence estimates of between 0.04% and 1.14%, significant mortality of up to 50% of those affected has been reported.107–109 A matched cohort study of 2842 patients receiving ICI therapy found a threefold increased risk of CV events compared with matched controls (HR 3.3, 95% CI, 2.0–5.5; P<0.001) and a greater than threefold increase in aortic atherosclerotic plaque progression.110 In mouse models, ICIs accelerated atherosclerotic plaque development and destabilisation, characterised by increased infiltrate of cytotoxic CD8+ T cells.111 112 Preclinical models have also demonstrated short-term exposure to ICIs increased vascular and myocardial inflammation.113 The potential implications of such an impact on atherosclerosis could be significant as ICIs gain increasing indications including in curative settings.114 Other immunotherapy approaches, such as T cell therapies, also carry a risk of CV toxicity. Chimeric antigen receptor T cell therapy is already used to treat B cell lymphomas with trials ongoing in other tumour types. CV toxicity may occur either as direct toxic events or because of cytokine release syndrome, causing arrhythmias, VTE, myocardial ischaemia and dysfunction.115 116

The rapid output of novel therapeutics underscores the importance of robust long-term pharmacovigilance strategies to detect toxicity not seen or underestimated during initial clinical trials, either due to their infrequency, late occurrence or population differences, for example, in performance status or comorbid conditions.117

CV health in cancer survivorship

Treatment-related CV toxicity and the safe delivery of cancer treatment to patients with CVD have been the focus of long-standing collaborations between cardiologists and oncologists ultimately evolving into the subspecialty of cardio-oncology. In addition to acute toxicity, the long-term consequences of cancer treatment on CV health are recognised. This is reflected in the guidelines (table 1) produced by oncological societies including the ESMO and the ASCO which include recommendations for post-treatment survivorship.118 119 Survivorship guidelines produced by the National Comprehensive Cancer Network also recommend all cancer survivors receive CV risk assessment, management and counselling.120 Whether these guidelines are implemented in practice is less clear and evidence suggests CV risk factors may be underdiagnosed and undertreated in cancer survivors.121 122 The ESC has recently released its first consensus guidelines for cardio-oncology, which in addition to guidance on prevention and management of treatment-related CV toxicity, addresses long-term follow-up and chronic CV complications.81 Post-treatment CV guidelines are particularly relevant in good prognosis tumours where CV mortality may exceed that of the primary cancer and thus the potential impact of risk-reducing strategies may be greatest.12 Furthermore, development of comorbid CVD may impair the quality of life of cancer survivors, which studies of patient priorities suggest is often valued equally to length of life.123

Timing of CV prevention strategies is important; pretreatment risk assessment and optimisation may help to reduce treatment-related CV events and a further planned assessment after completion of therapy offers the opportunity to address individualised long-term risk and prevention strategies.81 Surveillance with serum cardiac biomarkers and/or cardiac imaging, usually transthoracic echocardiography, aims to detect subclinical toxicity and allow early cardiac intervention. In addition to surveillance during cardiotoxic cancer therapy, guidelines from ESMO, ASCO and the ESC provide recommendations for post-treatment surveillance for asymptomatic cancer survivors who remain at elevated risk of cardiac dysfunction (summarised in table 1). The ESC guidelines also provide recommendations for risk stratification based on clinical and treatment characteristics to guide the level of required surveillance, both in the first year post-treatment and then with repeat risk stratification after 12 months to arrange longer-term follow-up.81

Pretreatment CV risk factor assessment and control is a consistent recommendation within guidelines produced by oncology and cardiology societies. Several tools exist for predicting long-term risk of CVD; however, none of these tools take account of the specific risks associated with a cancer diagnosis and treatment. In an attempt to standardise CV risk stratification for high-risk therapies, the Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the ESC, in collaboration with the International Cardio-Oncology Society (ICOS), have developed risk stratification proformas for those planned to undergo treatment with anthracycline chemotherapy, HER-2 targeted therapy, VEGF inhibitors, second and third-generation BCR-ABL inhibitors, multiple myeloma therapies (proteosome inhibitors and immunomodulators) and combination BRAF and MEK inhibitors.124 These estimate the risk of treatment-related CV complications by measuring patient and treatment-related factors including the presence of CVD, medical and lifestyle CV risk factors, cardiac biomarkers and previous cardiotoxic anticancer treatment.124 Pretreatment risk stratification allows early identification of patients who require further investigations or cardio-oncology input from the outset.81 Repeat risk stratification in the 12 months following completion of high-risk anticancer therapy is recommended to organise long-term follow-up.81 The HFA-ICOS proformas were developed based on evidence and expert consensus but require validation. Several studies have already provided initial corroboration, but further validation studies are required to inform and refine use of these tools in clinical practice.125–128

Several long-term risk assessment tools are available to estimate the 10-year risk of fatal and non-fatal CVD in primary prevention populations, for example, the Systematic Coronary Risk Estimation 2 (SCORE2) and SCORE2-Older Persons (OP) derived and validated in European populations, and QRISK3 in an English population. The ESC guidelines recommended risk stratification using SCORE2 or SCORE2-OP, for patients without a diagnosis of CVD or other high-risk features, prior to certain anticancer therapies which are associated with an increased risk of myocardial infarction, such as ADT, endocrine therapy for breast cancer, fluoropyrimidines and RT where a volume includes the heart.81 While these scores are derived from large populations and play an important role in a primary prevention setting, they have not been specifically validated in patients with cancer. A recent cohort study of cancer as a predictor in CV risk scores in 81 420 English cancer survivors, compared with 413 547 non-cancer controls, found adding a 1-year cancer survivorship variable into a QRISK3-based model met the threshold for inclusion in risk derivation for males and females with haematological cancers and males with solid organ cancers, but not females.129 These findings support the need for further research into the performance of CV risk assessment tools in cancer survivors, including drivers of elevated CV risk, and evaluation of cancer survivorship status in future CV risk prediction derivations.

Optimisation of medical and lifestyle CV risk factors is recommended both prior to anticancer treatment and in the post-treatment survivorship phase. Several epidemiological studies report associations between elevated baseline CV risk, cancer treatment-related cardiac toxicity and late CV outcomes in cancer survivors.10 130 In a study using the CARDIOTOX registry (NCT02039622) of 1324 patients who underwent medium to high-risk cardiotoxic anticancer treatment, a higher baseline CV risk estimated using SCORE was significantly associated with increased rates of cardiotoxicity and all-cause mortality.131 Individual risk factors were common with at least one present in 67.5% including a new diagnosis of hypertension, diabetes and hypercholesterolaemia detected in 2.1%, 5.0% and 24.4% of the cohort, respectively, at baseline. A further 13.9%, 10.3% and 9.8% had a subsequent diagnosis of hypertension, dyslipidaemia and diabetes during the 2-year follow-up period.131 Risk factor control declined during cancer treatment, despite management in a dedicated cardio-oncology service.131 Similarly, studies show declines in adherence to medication for hypertension, dyslipidaemia and diabetes mellitus during cancer treatment, and high levels of non-adherence in cancer survivors are associated with increased CV events.132 133 Re-evaluation at the end of cancer treatment offers the opportunity to reassess and optimise risk factors, including evaluation for non-adherence and patient education of the benefits of risk factor control.

The benefits of a healthy lifestyle should be discussed including smoking cessation, weight management, diet and regular physical activity. In the general population, the role of a healthy lifestyle in prevention of diseases including cancer and CVD is well established.134 A recent study using the UK biobank found a healthy lifestyle was associated with slower development of CVD and type two diabetes including in cancer survivors with similar levels of risk reduction to those seen in people without cancer.135 Furthermore, in a study of 992 stage III colon cancer survivors after a median follow-up of 7 years, higher healthy living scores (comprising BMI, physical activity and diet) were associated with lower overall mortality (HR 0.58; 95% CI: 0.34 to 0.99; p=0.01 for trend) and increased disease-free survival (HR 0.69; 95% CI: 0.45 to 1.06; p=0.03 for trend).136 Studies of patient preferences in survivorship demonstrate high levels of interest in health promotion including on nutrition, weight management and exercise.137 Recommendations regarding diet, exercise and healthy body weight maintenance are included in numerous post-treatment survivorship guidelines, largely extrapolated from disease prevention guidance.118–120 138 139 Diet and physical activity approaches advocated for CVD prevention are also recommended.81 118 140 Key recommendations include maintenance of a healthy body weight through nutrient-rich foods including varied fresh fruits, vegetables and whole grains, while limiting intake of refined grains, processed foods, sugar-sweetened beverages, salt, alcohol, processed and red meat.118–120 136 138 139 Regular physical activity is also advised, aiming for a minimum of 150–300 min of moderate-intensity physical activity, or 75–150 min of vigorous-intensity physical activity, or an equivalent combination per week; strength training and limiting time spent sedentary.120 138 139 141

While patient education and counselling is recommended, eliciting impactful behavioural change remains a challenge. Given the potential benefits, including in addressing lifestyle contributions to health disparity with social deprivation in both CVD and cancer, research and adoption of effective health promotion strategies should be a priority. This is also important given detrimental impacts of cancer treatment on CRF which is a modifiable target and independently associated with survival.44 49

Exercised-based interventions have been proposed and are supported by high levels of patient interest, and a growing body of literature supports their safety and benefits.142–145 The positive impact of regular physical activity on CV events and mortality is well known, and studies in cancer survivors similarly demonstrate significant reductions in CV events and mortality.146–148 Meta-analyses of observational studies have found reduced all-cause and cancer-specific mortality in association with higher levels of physical activity.149 150 Meta-analyses of randomised exercise-based interventions also demonstrate benefits to CRF, muscle strength, health-related quality of life, cancer-related fatigue, anxiety and depression.142 144 Dedicated cardio-oncology rehabilitation approaches are currently under development.81 151 This approach is recommended by the American Heart Association, modelled on cardiac rehabilitation for those with coronary artery disease where it reduces hospital admissions, CV mortality and all-cause hospitalisation, and improves health-related quality of life.139 151 152

Search strategy

Searches were performed up to February 2023 using PubMed and Medline databases, with various iterations of key search terms “cancer survivors”, “neoplasms”, “cardiovascular disease”, “cardiotoxicity”, “heart disease risk factors” with subheadings and subcategories relating to epidemiology, aetiology, genetics, pathophysiology, survival, cardiovascular risk assessment, risk factor modification, health promotion, quality of life and patient preferences. We also searched relevant clinical guidelines produced by the European Society for Medical Oncologists (ESMO), American Society of Clinical Oncology (ASCO), European Society of Cardiology (ESC), and National Comprehensive Cancer Network. The reference lists of retrieved articles were also searched. Peer -reviewed systematic reviews and meta-analyses, large epidemiological studies and randomised control trials (RCTs) were prioritised where available.