Cardiovascular Considerations During Cancer Therapy

Abstract

The administration of certain cancer therapies can be associated with the development of cardiovascular toxicity or complications. This spectrum of toxicities is broad and requires nuanced approaches for prevention, identification, and management. This expert panel summarizes the consensus of opinions of diverse health care professionals in several key areas: 1) cardioprotection involves strategies aimed at the primary prevention of cancer therapy–related cardiovascular toxicity; 2) surveillance entails monitoring for cancer therapy–related cardiovascular toxicity during cancer therapy; 3) permissive cardiotoxicity is the informed continuation of cancer therapy in the presence of cardiovascular toxicity, along with the implementation of mitigating cardiovascular treatments; and 4) special considerations include the invasive management of severe cardiovascular disease in patients receiving treatments for advanced cancer and the exploration of drug-drug interactions in cardio-oncology. In this expert panel, we also highlight gaps in evidence in an effort to continue to advance science in the cardiovascular care of our patients undergoing cancer therapy.

Central Illustration

Highlights

• •There is a need to prevent, detect and manage CTR-CVT and CV events in cancer patients.
• •This panel provides recommendations to address this need based on current evidence.
• •Collaboration between oncology and cardiology is key to optimize patient care.

Between 2010 and 2019, global cancer incidence increased by 26%, with at least 17 million new cases reported in 2019 alone.¹ This trend is expected to continue, with projections suggesting a 53% increase in patients receiving first-line chemotherapy from 2018 levels to 15 million by 2050.² Moreover, patients with cancer often undergo additional treatments such as radiotherapy (RT), immunotherapy, targeted therapies, and hormonal therapies, many of which are associated with adverse cardiovascular effects.³ Consequently, there is an urgent need to develop strategies for the early identification and mitigation of cancer therapy–related cardiovascular toxicity (CTR-CVT).

These strategies may include the implementation of evidence-based approaches to prevent CTR-CVT (cardioprotection) and surveillance strategies aimed at the early identification of CTR-CVT. When CTR-CVT is present, the risks and benefits of ongoing cancer therapy must be carefully considered. This decision involves discussions with the patient, their caregivers, and treating health care providers. If the risk-benefit relationship is favorable, a strategy of permissive CTR-CVT may be adopted. This approach allows the continuation of cardiotoxic treatment under close surveillance, accompanied by appropriate cardiovascular therapies, with the goal of optimizing cancer treatment delivery.⁴

Finally, given the higher risk for cardiovascular disease in patients with cancer compared with those without cancer, and the increased likelihood of cancer in patients with established cardiovascular disease,⁵ specific management approaches for severe cardiovascular disease in patients receiving cancer therapy are essential.

The European Society of Cardiology has endorsed broad guidelines for cardio-oncology.⁶ Although most of these guidelines are based on limited evidence and predominantly reflect expert opinion, the purpose of this paper is to offer expert consensus recommendations that are firmly supported by research. We also aim to highlight gaps in knowledge regarding CTR-CVT cardioprotection (Table 1), surveillance (Table 2), and permissive CTR-CVT (Table 3) in adults receiving cancer treatment (Central Illustration).

Table 1.

Recommendations for Cardioprotection in Patients Receiving Cardiotoxic Cancer Therapies

Therapy	Recommended Cardioprotective Strategy	Gaps in Knowledge
Anthracycline	•ACEIs/ARBs and/or beta-blockers should be considered in patients with breast cancer undergoing anthracycline treatment to prevent LVEF decline. These are preferred antihypertensive agents for patients with hypertension indicated for anthracycline therapy. •Statin use should be considered in patients with lymphoma treated with anthracycline to prevent LVEF decline. •Dexrazoxane or liposomal doxorubicin should be considered for adults at high risk for heart failure when anthracycline treatment is strongly indicated.	•It remains unclear whether ACEIs/ARBs, beta-blockers, and statins reduce the risk of heart failure in patients with preserved systolic LV function receiving anthracycline therapy. •The specific patient population that would benefit most from dexrazoxane or liposomal doxorubicin has not been clearly defined.
HER2-targeted therapies	•ACEIs/ARBs and/or beta-blockers should be considered for patients with breast cancer undergoing HER2-targeted therapies to prevent LVEF decline.	•It remains unclear whether ACEIs/ARBs and beta-blockers reduce the risk of heart failure in patients with preserved systolic LV function receiving HER2-targeted therapies.
Radiotherapy	•To minimize cardiac exposure to radiation, optimize patient positioning, manage respiratory motion, and delineate target volumes. Advanced planning techniques and/or proton therapy should be considered.	•Although emerging data support purposeful sparing of radiation dose to specific cardiac substructures (eg, coronary arteries), optimal dose limits are not well established.

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; HER2 = human epidermal growth factor receptor 2; LV = left ventricular; LVEF = left ventricular ejection fraction.

Table 2.

Recommendations in Cancer Therapy–Related Cardiovascular Toxicity Surveillance

Therapy	Recommended Surveillance	Gaps in Knowledge
Anthracycline	• Echocardiography ○ Recommended routinely at baseline. ○ Should be considered during follow-up only based on clinical features or for those at high risk.a	The yield and ideal frequency of surveillance tests are uncertain, and it is unknown whether cardiovascular interventions predicated on these tests improve clinical outcomes.
HER2-targeted therapy	•Adjuvant or neoadjuvant therapy: measure LVEF every 3 mo, preferably by echocardiography. •Metastatic setting: measure LVEF every 6 months. •Echocardiography: preferred method for measuring LVEF.	It is uncertain whether less frequent surveillance or the use of blood biomarkers can effectively identify those at risk for heart failure.
ADT	•Cardiovascular symptoms, established cardiovascular disease, smoking, blood pressure, and weight should be recorded at baseline for all recipients. •Primary care physicians should be made aware of the cardiometabolic adverse effects of ADT to optimize cardiovascular risk factor management. •It is reasonable to refer patients receiving ADT who do not regularly see a cardiologist or internist to one if they have cardiovascular symptoms, established cardiovascular disease (including incidental arterial calcification on diagnostic imaging), or blood pressure >140/90 mm Hg.	•The optimal strategy to minimize the risk of adverse cardiovascular outcomes in ADT recipients is not well established. •The generalizability of cardiovascular risk scores developed for the general population to patients with prostate cancer remains unknown.
VEGFIs	•Blood pressure: monitor frequently during the first cycle of treatment and after any dose changes; subsequently, every 2-3 wk. •Perform baseline TTE in all patients. Repeat TTE may be considered 6-8 wk after starting treatment in high-risk patients.	Optimal approach to identify those who will develop LV dysfunction related to VEGFI use.
Bruton tyrosine kinase inhibitors	•Check blood pressure and heart rate with or without ECG at each clinic visit in all recipients of ibrutinib.	Frequency and intensity of cardiac rhythm monitoring strategies.
ALKIs	•Check heart rate and blood pressure at baseline and at subsequent clinic visits. •Lorlatinib: check lipid levels at baseline, then with each cycle of therapy until lipids are stable, followed by every 3 mo.	•Optimal frequency of lipid surveillance in patients receiving lorlatinib. •The optimal management of patients who develop severe bradycardia on ALKIs has not been defined.
Osimertinib	•Recommend conducting baseline ECG and echocardiography. •Avoid QT interval–prolonging drugs and electrolyte abnormalities. •Consider monitoring the QT interval and, for those at high risk, conducting echocardiographic surveillance.	•The role of echocardiographic surveillance remains uncertain. •The optimal dosing of osimertinib and corrected QT intervals in patients who exhibit QT interval prolongation remain unknown.
ICIs	•Conduct troponin and ECG at baseline. •Most patients with suspected ICI myocarditis should be hospitalized. For patients diagnosed with ICI myocarditis or those with suspected ICI myocarditis presenting with major cardiac events, initiate high-dose corticosteroids rapidly.	•A surveillance strategy for myocarditis with acceptable sensitivity and specificity for clinical use has not been defined. •The optimal adjunctive therapy to high-dose corticosteroids for the treatment of ICI myocarditis is uncertain.

ADT = androgen-deprivation therapy; ALKI = anaplastic lymphoma kinase inhibitor; ECG = electrocardiography; ICI = immune checkpoint inhibitor; TTE = transthoracic echocardiography; VEGFI = vascular endothelial growth factor inhibitor; other abbreviations as in Table 1.

^aHigh risk is conferred by prior therapies and cardiovascular risk factors as described in the text.

Table 3.

Recommendations in Permissive Cardiotoxicity

Therapy	Recommended Strategy	Gaps in Knowledge
Anthracycline	•The risks and benefits of continuing anthracycline in patients with LV dysfunction should be evaluated by a multidisciplinary team, considering the use of dexrazoxane, liposomal doxorubicin, and alternative cancer treatments.	•The acute and long-term risk for heart failure in patients with LV dysfunction treated with anthracycline, including liposomal doxorubicin, are unknown.
HER2-targeted therapy	•HER2-targeted therapy may continue in patients with mild, minimally symptomatic LV dysfunction, but there is a 5%-10% incidence of heart failure.	The benefits of continuing HER2-targeted therapy in patients with mild LV dysfunction are poorly defined.
5-fluorouracil, capecitabine	•Consider nitrates and/or calcium channel blockers if rechallenging with 5-fluorouracil/capecitabine after suspected coronary vasospasm, but ensure that the setting is closely monitored.	The risk for recurrent coronary vasospasm on rechallenge with 5-fluorouracil or capecitabine is unknown.
Other cancer therapies	•Decision making should be individualized, understanding the patient’s goals of care and involving cancer specialists and cardiologists.	The risks and benefits of permissive cardiotoxicity for other cancer therapies have not been systematically studied.

Abbreviations as in Table 1.

Central Illustration.

Recommendations for Cardioprotection, Surveillance for Cancer Therapy–Related Cardiovascular Toxicity, and Permissive Cardiotoxicity

This figure illustrates the comprehensive approach to cardio-oncology care during the administration of potentially cardiotoxic cancer therapies, adhering to evidence-based recommendations from the expert panel. Cardioprotection includes strategies to minimize cardiovascular toxicity from cancer treatments. Surveillance involves ongoing monitoring strategies during therapy. Permissive cardiotoxicity refers to the management strategies that allow the continuation of cancer treatments known to cause cardiovascular effects. 5-FU = 5-fluorouracil; ACEI = angiotensin-converting enzyme inhibitor; ALKi = anaplastic lymphoma kinase inhibitor; ARB = angiotensin receptor blockers; BTKi = Bruton tyrosine kinase inhibitor; ECG = electrocardiography; HER-2 = human epidermal growth factor receptor 2; ICI = immune checkpoint inhibitor; LV = left ventricular; LVEF = left ventricular ejection fraction; VEGFi = vascular endothelial growth factor inhibitor.

Cardioprotective Strategies

The management of cardiovascular risk factors in patients receiving potentially cardiotoxic cancer therapies should be optimized in accordance with current the American College of Cardiology and American Heart Association guidelines. In this section, we review the potential cardioprotective strategies on the basis of the respective cancer therapies.

Anthracyclines

Recommendations

• •It is recommended to consider the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and/or beta-blockers in patients with breast cancer undergoing anthracycline-based chemotherapy to prevent a decline in left ventricular ejection fraction (LVEF). They are also recommended as the antihypertensive agents of choice in patients with hypertension who require anthracycline treatment.
• •The use of statins may be considered in patients with lymphoma treated with anthracycline to prevent a decline in LVEF.
• •For adults at high risk for heart failure (HF) and in whom anthracycline is strongly indicated, dexrazoxane or liposomal doxorubicin is recommended.

Gaps in knowledge

• •It remains unclear whether ACEIs or ARBs, beta-blockers, or statins can prevent the development of HF in anthracycline recipients without left ventricular (LV) dysfunction.
• •The specific patient population that would derive the greatest benefit from dexrazoxane or liposomal doxorubicin has not been clearly defined.

There is substantial interest in repurposing cardiac medications for the prevention of anthracycline-related CTR-CVT. Some of these medications that were relevant to baseline assessment (prior to cancer therapy) were also discussed in the expert panel paper by Raisi-Estabragh et al.⁷ We briefly review some of these strategies in this statement, focusing on the time during therapy. Although neurohormonal blockade using a renin-angiotensin system antagonist or a beta-blocker may offer a small protective effect on LVEF, there are no data demonstrating a reduction in the incidence of clinical HF.8, 9, 10, 11 The primary prevention use of these medications must be carefully considered, weighing the potential beneficial effects against adverse effects. They may be most strongly indicated in patients with hypertension and those with established indications for their use.

A randomized trial comparing atorvastatin 40 mg/d with placebo in patients predominantly diagnosed with breast cancer receiving a median doxorubicin dose of 240 mg/m² showed no difference in absolute LVEF between the groups at 24 months.¹² A more recent trial involving patients with lymphoma treated with a median dose of 300 mg/m² doxorubicin or equivalent showed that a lower proportion of patients in the atorvastatin group experienced declines in LVEF at 1 year when taking atorvastatin 40 mg/d vs those on placebo.¹³ HF developed in 3% of the atorvastatin group and 6% of the placebo group (P = 0.26). Another trial involving a heterogeneous group of patients with cancer treated with anthracycline showed no post-treatment difference in LVEF between those atorvastatin 40 mg/d and those on placebo.¹⁴ On the basis of these findings, the use of atorvastatin 40 mg/d may be considered for patients with lymphoma receiving anthracycline treatment.

Consistent data support the use of dexrazoxane in the primary prevention of anthracycline-related CTR-CVT in patients who receive >250 mg/m² doxorubicin equivalent and those with pre-existing HF or reduced LVEF.^10,15 Among patients with breast cancer receiving anthracycline, compared with control subjects, dexrazoxane reduces the occurrence of HF, with a pooled RR of 0.19 (95% CI: 0.09-0.40).¹⁶ However, the reliability of these findings may be compromised by biases in one-half of the relevant studies due to the absence of masking and possible incomplete outcome data.

Dexrazoxane is approved for use in women with metastatic breast cancer who have received 300 mg/m² doxorubicin and require ongoing anthracycline for disease control. Nonetheless, the quality of evidence supporting this use is considered low, and additional trials are recommended before its systematic implementation.¹⁶ Although concerns have been raised about an increased risk for subsequent cancers in children treated with dexrazoxane, such associations have not been demonstrated in adults.¹⁷ Additionally, dexrazoxane may cause myelosuppression, potentially leading to undesirable delays if chemotherapy needs to be withheld until recovery of white cell counts. A meta-analysis of 2 randomized trials suggested a relative risk for grade 3 or 4 white cell count abnormalities of 1.16 (95% CI: 1.05-1.29),¹⁸ which could potentiate hematologic toxicities from RT or chemotherapy.

Liposomal doxorubicin may serve as an alternative for patients in whom anthracycline treatment is warranted but who are at high risk for HF. The evaluation of HF risk prior to anthracycline administration, as discussed in the expert panel paper by Raisi-Estabragh et al,⁷ emphasizes strong risk factors such as high cumulative doxorubicin doses (≥300 mg/m² or equivalent) and pre-existing systolic LV dysfunction. The pharmacokinetics of liposomal doxorubicin are designed to alter drug tissue distribution, reducing cardiac exposure while maintaining antitumor efficacy. A meta-analysis of 4 randomized trials demonstrated that liposomal doxorubicin significantly reduces the risk for HF compared with doxorubicin, with a pooled OR of 0.18 (95% CI: 0.08-0.38).¹⁵

In contrast, a more recent systematic review, focusing exclusively on grade 3 adverse cardiovascular events, did not show a statistically significant advantage to using liposomal doxorubicin, with a pooled OR of 0.60 (95% CI: 0.34-1.07).¹⁹ Notably, both systematic reviews found limited evidence in the lymphoma population. A more recent randomized trial involving 88 treatment-naive patients with diffuse large B cell lymphoma, who lacked cardiovascular risk factors, demonstrated that substituting nonpegylated liposomal doxorubicin for doxorubicin in the R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) regimen resulted in fewer individuals with LVEFs <50% (4.6% vs 15.8%).²⁰ However, another randomized trial involving 90 treatment-naive patients ≥60 years of age with diffuse large B cell lymphoma and baseline LVEFs ≥55% showed no benefit on LVEF.²¹

Human epidermal growth factor receptor 2–targeted therapies

Recommendations

• •It is recommended to consider the use of ACEIs or ARBs and/or beta-blockers in patients with breast cancer undergoing human epidermal growth factor receptor 2 (HER2)–targeted therapies to prevent a decline in LVEF.

Gaps in knowledge

• •It remains unclear whether ACEIs or ARBs and/or beta-blockers can prevent HF in patients with breast cancer treated with HER2-targeted therapies.

In a systematic review of trials comparing ACEIs or ARBs or beta-blockers with placebo in patients with breast cancer undergoing trastuzumab-based therapy, these medications led to a modest attenuation of LVEF decline.¹¹ Among 1,362 participants in 9 randomized trials, individuals allocated to receiving ACEIs or ARBs or beta-blockers had a pooled mean LVEF that was 2.3% (95% CI: 0.0%-4.6%) higher than those in the control group. However, the follow-up duration in these studies was short, and it is not clear if this small difference in LVEF confers a clinical benefit. In addition, most of these trials were not blinded, and the risk for bias was considered high. Currently, no data are available on the use of ACEIs or ARBs or beta-blockers to prevent LVEF decline in patients treated with dual HER2 blockade (eg, trastuzumab and pertuzumab) or antibody-drug conjugates (eg, trastuzumab emtansine).

Radiation therapy

Recommendations

• •It is recommended to prioritize the optimization of patient positioning, management of respiratory motion, and target volume delineation to minimize cardiac exposure to radiation. Additionally, consideration for advanced planning techniques and/or proton therapy is advised.

Gaps in knowledge

• •Although emerging data support the purposeful sparing of radiation dose to specific cardiac substructures (eg, coronary arteries), optimal dose limits have not been well established.

Reducing cardiac dose exposure

Deep-inspiration breath hold

Deep-inspiration breath hold (DIBH) leverages the natural physiology of the respiratory cycle to distance the heart from the chest wall or breast, thereby minimizing cardiac dose exposure. DIBH has proved effective in reducing the dose to the heart and the left anterior descending coronary artery during treatment for left-sided breast cancer, compared with free-breathing treatment. Interestingly, patients with right-sided disease may also benefit from DIBH, particularly when treated with regional nodal irradiation.²² Additionally, DIBH has demonstrated cardiac dosimetric advantages in the treatment of gastric lymphoma.²³

Prone positioning

Prone positioning uses gravity to pull the breast away from the chest wall, which allows more shallow tangent beams and consistently reduces the ipsilateral lung dose across different laterality. However, this prone positioning may cause the heart to move anteriorly toward the chest wall. Data on whether this results in consistently higher or lower cardiac doses are mixed, particularly compared with supine DIBH.

Tumor motion management, margin shrinkage, and target volume reduction

Additional strategies to optimize RT planning include the reduction of planning target volume. This can be achieved by minimizing or accounting for tumor motion amplitude using 4-dimensional computed tomography, breath hold, forced shallow breathing through abdominal compression, real-time tumor tracking and/or gating, adaptive RT techniques, and/or daily image guidance. Respiratory gating techniques use a monitoring system to deliver RT during specific phases of the respiratory cycle, whereas motion-encompassing techniques generate a target volume that includes the tumor’s location at any point during the respiratory cycle.

Advanced RT planning techniques

Photon RT

Modern photon techniques, such as inverse planned intensity-modulated RT or volumetric modulated arc therapy, optimize high-dose conformality and aid organ-at-risk sparing, superior to traditional 3-dimensional conformal RT. However, these advances come at the expense of increased low-dose scatter. For breast RT, the benefits of these techniques are observed primarily in cases of challenging anatomy, such as synchronous bilateral breast cancer or regional nodal irradiation. For locally advanced lung and esophageal cancers, these approaches consistently improve cardiopulmonary dosimetry and are associated with improved survival outcomes in retrospective analyses.²⁴

Proton radiation therapy

Proton RT, which uses particle radiation, eliminates exit dose, thus minimizing low-dose bath. In breast cancer, intensity-modulated proton therapy may provide significant cardiac dosimetric advantages over photon-based methods, especially in scenarios involving regional nodal irradiation or bilateral breast cancer, particularly beneficial for younger patients facing the highest lifetime cumulative toxicity risks. Similarly, for locally advanced lung and esophageal cancers, intensity-modulated proton therapy has shown promise in improving cardiopulmonary dose sparing and reducing the overall total toxicity burden,²⁵ though it remains investigational. It is important to note, however, that the availability of proton RT resources is limited given their substantial capital and operational costs.

Cardiac implantable electronic devices

Ionizing radiation can damage cardiac implantable electronic devices (CIEDs), making multidisciplinary communication among radiation oncology, cardiology, and/or electrophysiology essential to ensure effective and safe RT. Damage to CIEDs during RT may result from electromagnetic interference, cumulative dose effects, and secondary neutron production.

Risk assessment

RT damage to implantable cardioverter-defibrillators can lead to oversensing and inappropriate shocks. The total (maximum) absorbed dose should be minimized, with a goal of ≤5 Gy and ideally <2 Gy, which is typically achievable with an RT field positioned more than 5 cm from the CIED.^26,27 Secondary neutron contamination, which can occur independently of the absorbed dose or distance from the CIED, is produced when protons, high-energy photons (>10 MV) or electrons (>20 MeV) interact with material in the treatment device head.

Risk-based management

Risk classification schemes have been described.^28,29 High-risk individuals, such as those receiving a cumulative dose of >5 Gy, may require risk mitigation strategies. These strategies include high neutron contamination, pacer dependency, or the presence of an implantable cardioverter-defibrillator. Risk management may involve considering CIED relocation and conducting CIED interrogations before RT, weekly during RT, and 1 and 6 months after RT. Additionally, measures such as pulse oximetry, heart monitoring, access to external pacing, and magnet use should be considered in consultation with electrophysiologists.

CTR-CVT Surveillance During Cancer Therapy

Surveillance for CTR-CVT during cancer treatment may be considered when the: 1) toxicity can be reliably detected at the time of the treatment; 2) the specific CTR-CVT is important in that it is common or potentially serious and is actionable; and 3) the cost of surveillance is acceptable.^30,31 We discuss the role of CTR-CVT surveillance across major classes of cancer therapy on the basis of these principles (Table 2). Notably, with few exceptions, evidence to support CTR-CVT surveillance in most settings is limited.

Anthracyclines

Recommendations

• •It is reasonable to perform surveillance echocardiography during anthracycline therapy to detect declines in LVEF in select asymptomatic high-risk individuals.

Gaps in knowledge

• •The benefits and optimal timing of routine echocardiography or blood biomarker surveillance for anthracycline CTR-CVT have not been consistently demonstrated.

Anthracyclines continue to be a cornerstone of chemotherapy for various malignancies, including lymphoma, acute myeloid leukemia, sarcoma, and some breast cancers.^32,33 The associated risk for CTR-CVT, namely, LV dysfunction and HF, is dose dependent, though instances of HF at low doses have been reported.³⁴ The highest risk for HF occurs in individuals receiving >250 mg/m² doxorubicin or >600 mg/m² epirubicin.¹⁹ This risk is also heightened for those receiving moderate doses in conjunction with chest irradiation that includes the heart, as well as those with pre-existing cardiovascular risk factors, age >60 years, borderline or decreased LVEFs, and histories of cardiovascular disease. The risk associated with lower doses of anthracyclines (≤250 mg/m² doxorubicin) is less pronounced in the absence of cardiac risk factors.

Echocardiography

It is generally recommended to perform baseline echocardiography before exposure to anthracyclines, ideally incorporating 3-dimensional LVEF³⁵ and global longitudinal strain,³⁶ to establish a baseline measurement in case of subsequent cancer therapy–related LV dysfunction. Echocardiography, preferred for its lack of ionizing radiation, greater accessibility, and lower cost compared with alternative imaging modalities, is explored in more detail in the expert panel paper by Raisi-Estabragh et al.⁷

During anthracycline therapy, LVEF typically decreases by approximately 3%.³⁷ However, the correlation between such a decrease and the subsequent development of HF remains understudied. In a prospective cohort study involving 2,625 patients receiving moderate doses of anthracyclines, with echocardiography conducted every 3 months, 226 (9%) developed CTR-CVT, defined as a reduction in LVEF of more than 10% from baseline to an absolute value <50%.³⁸ Among these 226 individuals, 15 (7%) experienced cardiac death or HF, all of whom had been prescribed ACEIs and/or beta-blockers. The effectiveness of these medications in reducing the risk for cardiac death or HF in this population, as well as the cost-effectiveness of this strategy, remains unproven. Therefore, routine measurement of LVEF during anthracycline administration is not recommended except for research purposes. However, it may be reasonable to monitor cardiac function in select high-risk individuals, including those with hypertension, diabetes, obesity,³⁹ or established structural or functional heart disease, as well as individuals at the extremes of age or receiving high doses of anthracycline (>250 mg/m² doxorubicin or equivalent).

Global longitudinal strain is regarded as a more sensitive marker of CTR-CVT than LVEF. A decline in global longitudinal strain (>15% relative change) may prompt the initiation of cardioprotective medications. However, the initiation of therapy on the basis of global longitudinal strain measurements has not been proved to prevent reductions in LVEF at 1 year⁴⁰ or 3 years.⁴¹

Blood biomarkers

A systematic review evaluated the relationship between elevated levels of cardiac troponin or natriuretic peptides (defined according to the reference values of each study) and CTR-CVT.⁴² Among 2,163 patients who had cardiac troponin measured after exposure to cancer treatments, often including anthracycline, 22% had elevated cardiac troponin levels. This elevation was associated with higher odds of impaired LVEF, with an OR of 12 (95% CI: 4-32). Additionally, elevated cardiac troponin had a positive predictive value of 52% and a negative predictive value of 93% for LV dysfunction, which occurred in 17% of patients. However, the review did not provide information on the association between elevated cardiac troponin levels and the risk for HF or cardiovascular death, nor did it differentiate results by the generation of cardiac troponin assay used. A more recent study demonstrates that measuring cardiac troponin during anthracycline-based therapy does not effectively predict which patients will develop reduced LVEF.⁴³

The adoption of high-sensitivity assays is expected to increase the rate of troponin positivity, leading to workflow challenges and the identification of individuals with minor myocardial injuries whose significance is unclear. Moreover, there is heterogeneity in the timing of blood tests and a conflation of biomarker measurements concurrent with LVEF assessments. In some instances, biomarkers may identify decreased LVEF, whereas in others, they are evaluated as predictors of future LVEF deterioration.

Given these limitations, along with the high frequency of cardiac troponin elevation after anthracycline exposure and the modest positive predictive value of this test, routine surveillance of cardiac troponin during anthracycline administration may not be an efficient way to improve clinical outcomes. However, measuring cardiac troponin at baseline to provide a benchmark is considered reasonable. In comparison, data on the predictive ability of natriuretic peptide levels for CTR-CVT are sparse. Currently, there is insufficient evidence to recommend routine measurement of natriuretic peptides during anthracycline therapy.

HER2-targeted therapies

Recommendations

• •LVEF should be measured every 3 to 4 months during therapy for early-stage cancer.
• •It is reasonable to consider measurement of LVEF every 6 months during therapy for metastatic disease or as clinically indicated.
• •Echocardiography is the preferred method modality for measuring LVEF.

Gaps in knowledge

• •It is not known whether it is safe to monitor LVEF less frequently in specific groups of HER2-targeted therapy recipients.

Overexpression of HER2 occurs in 10% to 30% of primary invasive breast cancers,^44,45 as well as in several gastrointestinal and genitourinary malignancies, and is associated with more aggressive disease. HER2-targeted therapy, when combined with chemotherapy, improves survival rates in breast cancer, metastatic gastric cancer, and gastroesophageal junction adenocarcinoma that overexpress HER2. Dual HER2-targeted therapy (eg, trastuzumab and pertuzumab) combined with chemotherapy has been shown to improve clinical outcomes in patients with breast cancer across neoadjuvant, adjuvant, and advanced settings. Furthermore, HER2 antibody-drug conjugates, such as trastuzumab emtansine and trastuzumab deruxtecan, are used in patients with residual breast cancer after neoadjuvant therapy and in advanced settings. HER2-targeted tyrosine kinase inhibitors (TKIs), such as lapatinib and tucatinib, are approved for use in advanced breast cancer after progression following an antibody-drug treatment. Furthermore, the combination of trastuzumab and tucatinib has been approved for treating advanced renin-angiotensin system wild-type colorectal cancer from the second line of treatment onward.

Trastuzumab-related CTR-CVT manifests as LV dysfunction in 15% to 20% of recipients and less frequently as HF in 3% to 4%. These complications are seen primarily in patients who have also received anthracyclines. A systematic review indicates that dual HER2-targeted therapy (eg, trastuzumab and pertuzumab) may increase the risk for clinical HF compared with single-agent trastuzumab, with a pooled relative risk of 1.97 (95% CI: 1.05-3.71).⁴⁶ The incidence of CTR-CVT reported in clinical trials for antibody-drug conjugates and HER2 TKIs has been relatively low (0.4%-7%). However, this finding is based on short-term follow-up and may result partly from the exclusion of patients who previously developed CTR-CVT from other HER2-targeted therapies, suggesting that those treated with newer agents may be self-selected as less susceptible to HER2-associated CTR-CVT.

In registration trials in which regular surveillance of LVEF was required per protocol, few patients developed clinical HF. LVEF was measured approximately every 3 months in these trials. In line with these protocols, we recommend assessing LVEF every 3 to 4 months during HER2-targeted therapy. However, for patients with metastatic disease, in whom the threshold for discontinuing HER2-targeted therapy in the presence of asymptomatic LV dysfunction may be higher, less frequent LVEF monitoring may be reasonable. In this group, decision making should be individualized, considering factors such as the duration of treatment, alternative therapies, disease extent, and patient preferences.

Androgen deprivation therapy

Recommendations

• •It is reasonable for patients receiving androgen deprivation therapy (ADT) to consult a cardiologist if they experience cardiovascular symptoms, have cardiovascular disease (which may include arterial calcification incidentally identified on diagnostic imaging), or have blood pressure > 140/90 mm Hg.

Gaps in knowledge

• •The generalizability of cardiovascular risk scores, originally developed for the general populations, to patients with prostate cancer is unknown.
• •There is no clearly defined optimal strategy to minimizing cardiovascular risk in patients receiving ADT, including the role of gonadotropin hormone–releasing hormone (GnRH) antagonists.

ADT significantly prolongs survival across multiple disease states in prostate cancer, including metastatic prostate cancer, as adjuvant therapy with RT for localized prostate cancer, and for patients with high-risk biochemical recurrence after definitive prostate cancer therapy. It is prescribed for nearly one-half of all patients with prostate cancer during the disease course.⁴⁷

ADT leads to an increased burden of cardiovascular risk factors such as weight gain, hypertension, diabetes, and sarcopenia, potentially increasing the risk for cardiovascular disease.^48,49 Consequently, surveillance for cardiovascular risk factors in ADT recipients is generally advocated. However, these risk factors are poorly managed in many individuals undergoing ADT, highlighting a significant treatment gap.^50,51 This gap is difficult to bridge because the management of cardiovascular risks typically falls outside the scope of expertise of many prostate cancer physicians, and current strategies for managing these risks are generally inadequate.

Efforts to bridge this treatment gap include proposed strategies that involve engaging with primary care physicians and cardiologists. These strategies, among other approaches, are currently under investigation. Until more definitive data are available, it is reasonable for physicians who prescribe ADT to screen for established cardiovascular diseases, cardiovascular symptoms, hypertension, and obesity. They should also discuss smoking cessation and the benefits of diet and exercise. Furthermore, diagnostic imaging often used in this patient population may incidentally reveal arterial calcification, a finding that doubles the risk for adverse cardiovascular events compared with its absence.⁵²

Although there is evidence to hypothesize that GnRH antagonists may be associated with lower cardiovascular risk compared with GnRH agonists,⁵³ the quality of this evidence is insufficient to recommend GnRH antagonists for reducing cardiovascular risks.

Other Therapies That Can Affect Cardiovascular Risk Factors, Cardiac Function, or Rhythm

Vascular endothelial growth factor inhibitors

Recommendations

• •Daily home blood pressure monitoring is recommended during the first cycle of vascular endothelial growth factor inhibitor (VEGFI) treatment and after any change in VEGFI dose. After this initial period, monitoring should be performed at regular intervals, such as every 2 to 3 weeks.
• •Baseline echocardiography is recommended for all recipients beginning VEGFI therapy. For high-risk individuals, consider follow-up echocardiography 8 weeks after the initiation of VEGFIs.

Gaps in knowledge

• •The benefits and optimal timing of routine echocardiogram surveillance for CTR-CVT in unselected patients receiving VEGFIs remain unproven.

VEGFIs are used in treatment for various malignancies, including renal, thyroid, and colorectal cancers, sarcomas, neuroendocrine tumors, and gastrointestinal stromal tumors. Because VEGFIs function primarily by inhibiting the growth of tumor blood vessels, they can also interfere with cardiovascular homeostasis. Notably, up to 80% of patients treated with VEGFIs develop hypertension,⁵⁴ which can be severe. Consequently, it is recommended to monitor blood pressure at home daily during the first cycle of treatment and after any change in VEGFI dose. After this period, monitoring should be continued every 2 to 3 weeks. Blood pressure targets and treatment thresholds vary depending on the clinical context and cancer prognosis. The treatment of VEGFI-associated hypertension typically involves the use of standard agents; however, verapamil and diltiazem are generally avoided because of their potential for cytochrome P450 (CYP) 3A4 drug-drug interactions (DDIs) with VEGFIs.⁵⁴

LV dysfunction is observed in 10% to 28% of patients treated with VEGFIs.^55,56 Although hypertension and elevated LV afterload may contribute to LV dysfunction, direct cardiomyocyte toxicity and coronary microvascular dysfunction are also implicated.⁵⁷ VEGFI-associated LV dysfunction may be reversible; therefore, prompt recognition and treatment are vital to avoid symptomatic HF and to maximize the potential to continue or resume the safe administration of VEGFIs. Given the poorly defined risk factors for VEGFI-associated LV dysfunction, we recommend performing baseline echocardiography in all patients starting VEGFI therapy. Furthermore, for those at higher risk, echocardiography is advised 6 to 8 weeks after starting treatment, as cardiotoxic effects associated with VEGFIs are frequently observed early.^55,58

TKIs for chronic myeloid leukemia

Recommendations

• •Echocardiography is recommended for patients on dasatinib experiencing dyspnea to screen for pulmonary arterial hypertension.
• •The corrected QT interval should be reassessed in patients on chronic myeloid leukemia (CML) TKIs who are prescribed other QT interval–prolonging medications.

Gaps in knowledge

• •The role of screening for peripheral arterial disease by ankle-brachial index or imaging in patients treated with TKIs for CML remains uncertain.

TKIs used in the treatment of CML are associated with the development of pericardial effusions. Post hoc analyses of randomized trials suggest that second- and third-generation TKIs, compared with imatinib, may increase the risk for vascular occlusive adverse events.⁵⁹ Notably, with nilotinib, rates of myocardial infarction, cerebrovascular disease, or peripheral arterial disease requiring hospitalization are reported at 31 (17-45) per 1,000 person-years.⁶⁰ Similarly, ponatinib has been linked to serious adverse cardiovascular, cerebrovascular, and peripheral vascular events, observed in 5.1%, 2.4%, and 2.0% of patients, respectively, over a median of 15 months.⁶¹ Additionally, dasatinib is specifically implicated in the occurrence of precapillary pulmonary hypertension⁶² and pleural effusions in the absence of pulmonary hypertension. Both nilotinib and dasatinib are associated with QT interval prolongation.⁶³

Data to inform surveillance strategies for cardiovascular complications associated with TKI therapy in CML are limited. It may be reasonable to perform baseline echocardiography before starting dasatinib to evaluate pulmonary arterial pressure when feasible and electrocardiography to measure the corrected QT interval before initiating nilotinib treatment. However, the value of surveillance of asymptomatic individuals for cardiovascular complications during CML treatment remains uncertain.

Bruton TKIs

Recommendations

• •Blood pressure and heart rate, with or without electrocardiography, should be checked at each clinic visit for all recipients of Bruton TKIs.

Gaps in knowledge

• •The role of ambulatory heart rhythm monitoring in Bruton TKI recipients is uncertain.

Bruton TKIs are used in treating chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, and mantle cell and marginal zone lymphoma. The first-generation Bruton TKI ibrutinib notably increases the risk for atrial fibrillation,^64,65 primarily within 6 months of initiating treatment,⁶⁶ and increases the risk for hypertension, which typically emerges within the same time frame.^67,68 Observational studies suggest a potentially higher risk for HF and ventricular arrhythmias with ibrutinib use.^26,27,69 Prompt control of hypertension is crucial for preventing adverse cardiovascular events associated with ibrutinib.^67,70

The reliance on ibrutinib has been somewhat reduced by alternatives that present a lower risk for CTR-CVT; these alternatives include second-generation Bruton TKIs (acalabrutinib and zanubrutinib) and venetoclax.^71,72 Alternatives, either in the same class or from a different drug class, should be considered for patients with atrial fibrillation or HF or those at high cardiovascular risk.

Studies show differences in atrial fibrillation rates favoring acalabrutinib and zanubrutinib over ibrutinib and less hypertension with acalabrutinib than ibrutinib. However, indirect evidence suggests that atrial fibrillation and hypertension rates among those treated with second-generation Bruton TKIs may still exceed those of untreated adults in this demographic. Direct comparisons with placebo or nonibrutinib control subjects, providing high-level evidence, are lacking.

Bruton TKIs are known to increase bleeding risks.⁷³ Most patients have CHA₂DS₂-VASc scores >2,^74,75 indicating a potential need for anticoagulation if atrial fibrillation develops. Bruton TKIs may interact with direct oral anticoagulant agents, verapamil, diltiazem, digoxin, and amiodarone. When using apixaban or rivaroxaban concomitantly with a Bruton TKI, dose reductions should be considered. Alternatively, edoxaban, a direct oral anticoagulant agent less affected by CYP3A4 clearance, may be prescribed instead.

Anaplastic lymphoma kinase inhibitors

Recommendations

• •Patients starting anaplastic lymphoma kinase inhibitors (ALKIs) should have their heart rate and electrocardiogram recorded at baseline, with heart rate rechecked at each clinic visit during follow-up.
• •For patients receiving brigatinib or lorlatinib, blood pressure should be assessed at baseline and at each subsequent clinic visit.
• •Patients receiving lorlatinib should have their lipids checked at baseline, initially every 1 to 2 months until stable, and then every 3 to 6 months.

Gaps in knowledge

• •The optimal management strategy for patients who develop severe bradycardia while on ALKIs remains undefined.

ALKIs are used primarily in the treatment of anaplastic lymphoma kinase fusion–positive metastatic non–small cell lung cancer, which accounts for approximately 5% of cases of metastatic non–small cell lung cancer. The most common cardiac complication associated with ALKI therapy is bradycardia.^76,77 The incidence of bradycardia with crizotinib is significantly higher than with platinum-based chemotherapy (19% vs 0.5%),⁷⁷ though most cases are mild. A meta-analysis of randomized ALKI trials reported a pooled incidence of bradycardia of 8%, with a relative risk of 24.7 (95% CI: 7.1-85.7).⁷⁸ Notably, next-generation ALKIs, such as alectinib and lorlatinib, currently first-line therapies for anaplastic lymphoma kinase–positive metastatic non–small cell lung cancer, show similar bradycardia rates comparable with that of crizotinib. It is crucial to screen patients initiating ALKIs for bradycardia at baseline and to monitor them clinically during therapy.

Hypertension has also been observed in patients receiving brigatinib (23% vs 7% for crizotinib) and lorlatinib (18% vs 2% for crizotinib).^79,80 More than one-half of these adverse effects are classified as grade 3 or higher according to the Common Terminology Criteria for Adverse Events, necessitating medical intervention. Therefore, it is essential to assess blood pressure at baseline and during subsequent clinic visits for patients receiving brigatinib or lorlatinib. Additionally, in patients who develop hypertension during therapy, the use of antihypertensive agents that could cause bradycardia should be avoided when possible.

Hypercholesterolemia and hypertriglyceridemia are common adverse effects in patients receiving lorlatinib.⁸⁰ In the CROWN (A Study of Lorlatinib Versus Crizotinib in First Line Treatment of Patients With ALK-Positive NSCLC) trial, these conditions were reported in 70% and 64% of lorlatinib-treated patients, respectively, compared with 4% and 6% in those treated with crizotinib.⁸⁰ Although the long-term risks associated with these lipid abnormalities are unknown, therapy with lipid-lowering agents is frequently required. It is recommended that lipid profiles be assessed at baseline, then every 1 to 2 months until stabilized, followed by assessments every 3 to 6 months.

Epidermal growth factor receptor inhibitors

Recommendations

• •It is recommended that patients receiving osimertinib undergo baseline electrocardiography, with subsequent electrocardiographic surveillance considered. Additionally, monitoring electrolytes and avoiding other QT interval–prolonging drugs are recommended.
• •Baseline echocardiography is advised for those treated with osimertinib, with surveillance considered for those at high risk.

Gaps in knowledge

• •The optimal dosing of osimertinib and management of corrected QT intervals in patients who exhibit QT interval prolongation are not known.

Osimertinib, a third-generation epidermal growth factor receptor inhibitor, is associated with a decline in LVEF and QT interval prolongation. Post hoc analyses detected a 3.1% to 5.5% incidence of LVEF decline of ≥10% to an absolute value <50%.⁸¹ Risk factors for LVEF decline include atrial fibrillation, hypertension, diabetes, and hypothyroidism. Osimertinib also shows 2 to 6 times higher odds of HF being reported to pharmacovigilance databases compared with other treatments.⁸²

All patients receiving epidermal growth factor receptor inhibitors should have cardiovascular risk factors assessed and undergo baseline echocardiography, with echocardiographic surveillance considered for those with risk factors for cardiomyopathy.

Osimertinib is additionally associated with QT interval prolongation.^83,84 The risk in patients with baseline heart rate–corrected QT interval prolongation is unknown because of trial exclusion criteria. All patients require baseline electrocardiography, and consideration should be given to ongoing electrocardiographic surveillance and electrolyte monitoring. Concurrent QT interval–prolonging medications should generally be avoided.

Immune checkpoint inhibitors

Recommendations

• •Baseline assessments for immune checkpoint inhibitor (ICI) recipients should include measurement of cardiac troponin levels and electrocardiography.
• •Hospitalization is recommended for most patients with suspected ICI myocarditis. For those diagnosed with ICI myocarditis or presenting with major cardiac events suspected to be myocarditis, rapid initiation of high-dose corticosteroids is recommended.

Gaps in knowledge

• •The role of using blood biomarkers, such as cardiac troponin, for ongoing surveillance of ICI myocarditis remains unclear.
• •There is uncertainty regarding the optimal adjunctive therapies to high-dose corticosteroids in the management of ICI myocarditis.

ICIs are associated with a broad range of cardiovascular toxicities. Although myocarditis is the most frequently described cardiovascular immune–related adverse event, other conditions, such as pericardial diseases, vasculitis, arrhythmias, atherosclerotic and thromboembolic events, and declines in LVEF without evidence of myocarditis, have also been reported. The overall combined incidence of cardiovascular immune–related adverse events is approximately 3.1% with monotherapy and 6% with dual therapy.⁸⁵

The cardiovascular immune–related adverse event most frequently described in the literature is myocarditis, with incidences ranging from 0.7% to 1.7%. Myocarditis typically manifests between 30 and 50 days from the first ICI dose, with the majority of cases detected within the first 3 months.85, 86, 87, 88, 89 ICI-associated myocarditis historically carries a poor prognosis, with mortality rates ranging from 17% to 30%, which is higher than non-ICI myocarditis, and is often due to fatal arrhythmias and HF.⁸⁹ The primary risk factor for myocarditis is the use of combination ICI therapy.⁸⁹

Baseline assessments of cardiac troponin and electrocardiography should be conducted to serve as comparators in the event of subsequent suspected myocarditis. However, the utility of ongoing surveillance for ICI-associated myocarditis has not been established. A prospective study monitoring cardiac troponin during up to 10 doses of ICI treatment showed that >10% of patients exhibited elevated cardiac troponin levels, yet only 1.4% were ultimately diagnosed with myocarditis.⁸⁶ Although biomarker surveillance could potentially identify asymptomatic, smoldering myocarditis, it also carries the risk of unnecessary delays in ICI treatment.

Most patients with suspected myocarditis require inpatient evaluation. The gold standard for diagnosis involves an endomyocardial biopsy, which detects infiltration of macrophages and T lymphocytes and evidence of myocyte necrosis. A risk for sampling error exists because of the patchy distribution of these histopathologic findings. In the absence of histopathologic data, diagnosis may rely on elevated cardiac troponin levels and cardiac magnetic resonance imaging. Although cardiac magnetic resonance imaging has limited sensitivity, it offers high specificity and may show late gadolinium enhancement, T2 hyperintensity, or increase in native T1 or T2 values. Additionally, echocardiography may reveal a decline in LVEF or regional wall motion abnormalities or decreased global longitudinal strain, and abnormal electrocardiographic findings may be present.

Other important considerations include the presence of other immune-related adverse events, particularly myositis and myasthenia-like syndromes, as well as the timing of these events. Corticosteroids should be administered early once a diagnosis is confirmed, as observational data indicate that initiation within 24 hours of admission and higher initial corticosteroid doses are associated with a reduced risk for major adverse cardiac events.⁹⁰ Many patients may be resistant to corticosteroids and require second-line immunosuppressants, with options including abatacept, mycophenolate, JAK-STAT inhibitors, and intravenous immunoglobulin. However, the optimal approach remains undefined and warrants further research. Effective management and diagnosis of ICI-associated cardiovascular toxicities require close collaboration between cardiologists and oncologists.

Permissive CTR-CVT

Recommendations

• •Permissive CTR-CVT should be individualized on the basis of the patient’s type of cancer, the specific cancer therapy involved, and patient preferences.

Gaps in knowledge

• •The balance of relative risks and benefits associated with permissive CTR-CVT is still unclear for all cancer therapies.

The rationale of permissive cardiotoxicity in cancer therapies is that mild CTR-CVT may be considered acceptable if it is manageable and the therapeutic benefits of the cancer treatment are clear. However, the nuances of different CTR-CVTs mean that strategies for permissive cardiotoxicity must be tailored to both the cancer therapy and the individual patient.

Anthracyclines

Recommendations

• •The risks and benefits of continuing ongoing anthracycline therapy in patients with LV dysfunction should be evaluated in a multidisciplinary setting. Consideration should include the use of dexrazoxane, liposomal doxorubicin, and alternate cancer treatments.

Gaps in knowledge

• •The acute and long-term risk for HF in patients with LV dysfunction treated with anthracycline, including liposomal doxorubicin, remains unclear.

The management of anthracycline-induced CTR-CVT aligns with that for LV systolic dysfunction of any etiology.⁹¹ In cases in which CTR-CVT develops during anthracycline administration, it is crucial to rule out other causes of LV dysfunction and adopt a multidisciplinary approach to determine the safety of continuing or resuming anthracycline therapy. For patients with mild CTR-CVT, continuing anthracycline treatment under close collaboration with a cardio-oncology specialist may be reasonable. However, for those with moderate or severe CTR-CVT, permanent discontinuation of anthracyclines is recommended. Exploring alternatives such as dexrazoxane, liposomal doxorubicin, and other effective cancer therapies with a lower risk for CTR-CVT should also be considered.

If abnormal cardiac troponin levels, indicative of subclinical myocardial injury, are identified during anthracycline administration, the effectiveness of cardioprotective treatments remains uncertain. In a study involving 56 patients who experienced increases in cardiac troponin levels shortly after high-dose cancer therapy (including anthracycline in some instances), ACEIs were shown to prevent a decline in LVEF compared with an open-label control group, and they also reduced the risk for developing overt HF.⁹² However, it is unclear if these results apply to high-sensitivity cardiac troponin tests, which detect smaller myocardial injuries.

Additionally, the rates of HF observed in the control arm of this open-label study were substantially higher at 24%, and LVEFs were markedly lower, compared with the expected HF rates of 6% and typical LVEF in this population.¹³ In a more recent trial using an open-label, blinded endpoint design, candesartan and carvedilol vs control were tested in patients receiving ≥300 mg/m² doxorubicin who exhibited elevations in high-sensitivity cardiac troponin I. This study revealed no difference in LVEF between the groups,⁹³ Therefore, further research is needed to validate cardiac troponin as a marker for subclinical CTR-CVT and to guide the use of ACEIs in mitigating anthracycline-induced CTR-CVT.

HER2-targeted therapies

Recommendations

• •It is feasible to continue HER2-targeted therapy in individuals with mild, minimally symptomatic LV dysfunction.

Gaps in knowledge

• •The risks and benefits of permissive cardiotoxicity for HER2-targeted CTR-CVT are not fully understood in large populations.

Randomized control trials have demonstrated that shorter courses of HER2-targeted therapy (<1 year) in early-stage breast cancer can lead to worse disease-free and overall survival.⁹⁴ Observational data suggest that any interruptions in HER2-targeted therapy may be associated with poorer outcomes.⁹⁵ These findings prompted 2 prospective single-arm trials to evaluate the management of reduced LVEF in patients receiving HER2-targeted therapies.^96,97 In both studies, all participants were closely observed with serial echocardiography, and ACEIs and beta-blockers were administered at the highest tolerated doses. HER2-targeted therapy was discontinued only if the LVEF dropped to <35% to 40% or if moderate HF symptoms developed. Although the approach was deemed feasible, a 5% to 10% incidence of moderate to severe HF or LV impairment necessitating the discontinuation of HER2 therapy was observed with permissive CTR-CVT.⁹⁸ The risk-benefit relationship of this approach has not been fully evaluated, and the net clinical benefit regarding cancer-free survival remains uncertain. Up to 14% of patients treated with permissive CTR-CVT exhibited evidence of LV impairment at 18-month follow-up, though this rate may be confounded by prior anthracycline exposure and could plausibly be lower in those not treated with anthracyclines.⁹⁸ Further research is needed to define the role of permissive CTR-CVT with HER2-targeted therapy.

Fluoropyrimidines

Recommendations

• •Chest pain syndromes suspected to be caused by 5-fluorouracil (5-FU)–induced or capecitabine-induced coronary vasospasm should be acutely treated with nitrates and/or calcium-channel blockers.
• •After suspected coronary vasospasm, nitrates and/or calcium-channel blockers should be considered. If rechallenging with 5-FU or capecitabine is planned, it should be conducted in a closely monitored setting.

Gaps in knowledge

• •The risks and benefits of fluoropyrimidine permissive CTR-CVT are unknown.

5-FU is used in treating adenocarcinomas of the breast, as well as adenocarcinomas and squamous cell carcinomas of the bladder, gastrointestinal tract, and head and neck. Annually, more than 150,000 patients in the United States are treated with 5-FU or capecitabine, making 5-FU the third most common drug used for solid malignancies.⁹⁹

The most common manifestation of 5-FU-associated CTR-CVT is chest pain,¹⁰⁰ which can vary from atypical chest pain to typical angina, acute coronary syndrome, and myocardial infarction.¹⁰⁰ The principal mechanism behind this chest pain in the setting of 5-FU is thought to be coronary vasospasm. Typically, vasospasm occurs within the first few cycles of 5-FU treatment, with nearly 90% of cases presenting during their initial 3 doses (>70% during the first cycle).¹⁰¹ More than 95% of these cases present with chest pain, and >70% show ST/T-wave changes on admission electrocardiography.¹⁰¹ Other less common effects include arrhythmias, pericarditis, myocarditis, HF, and even death.⁹⁹ The reported incidence of these complications varies very widely in the literature, from 1% to >30%,¹⁰⁰ depending on the population studied, outcome definitions, and the drug’s formulations or administration protocols.

There is currently no clear consensus on the incidence, risk factors, and prognosis of 5-FU-associated coronary vasospasm.^101,102 Patients exhibiting suspected 5-FU-associated vasospasm should be referred to an emergency department, where 5-FU administration is paused, and nitrates are administered acutely. Discontinuing 5-FU administration typically resolves the chest pain. Many health care centers also recommend work-up for obstructive coronary disease; in the acute cases, many patients undergo coronary angiography because of electrocardiographic changes and the presence of chest pain.¹⁰³

There are no definitive data on the optimal management of patients experiencing 5-FU vasospasm. However, some studies suggest benefits from prophylactic use of nitrates^103,104 or calcium-channel blockers¹⁰⁴ or switching from infusional to bolus-only 5-FU¹⁰⁵ to reduce the likelihood of recurrent vasospasm. When considering a rechallenge, it is often advised to use a combination of the aforementioned cardioprotective medications. If a permissive CTR-CVT approach is desired, rechallenging the patient in an inpatient setting should be considered,¹⁰⁴ especially when there is clear evidence of myocardial ischemia or infarction. Alternatively, for patients who exhibit early-onset, severe, or life-threatening toxicity occurring within 96 hours after the administration of 5-FU or capecitabine, uridine triacetate is approved by the U.S. Food and Drug Administration for emergency use.¹⁰⁶

Other therapies

Rechallenging patients with other cancer therapies, such as various TKIs, VEGFIs, and ICIs after the development of CTR-CVT may be considered. However, the support for the efficacy and safety of permissive cardiotoxicity with these agents is currently limited, with evidence drawn only from case reports and small case series. Consequently, there are insufficient data to form evidence-informed recommendations. Clinical decision making should be individualized on a case-by-case basis, taking into account the patient’s goals of care and involving cancer specialists and cardiologists in the process.

Management of Severe Cardiovascular Disease

Recommendations

• •It is recommended that the decision to use invasive cardiovascular interventions in patients with advanced malignancies be guided by a multidisciplinary team.

Gaps in knowledge

• •The net clinical benefit of invasive cardiovascular interventions in patients with advanced malignancies is unknown.

There are limited data from randomized controlled trials or comprehensive prospective cohort studies to inform the role of invasive cardiovascular interventions in patients with severe cardiovascular disease who also have metastatic cancer with a guarded cancer-specific prognosis.¹⁰⁷ Therefore, decision making for these patients should be highly individualized and inclusive of all relevant stakeholders. Key factors to consider in this decision-making process should include 1) the expected magnitude and immediacy of benefits from the invasive cardiovascular procedure; 2) potential risks associated with the procedure; 3) the prognosis of the malignancy; 4) the patient goals of care and comorbidities (including thrombocytopenia); and 5) the consequences of interruptions during cancer treatments.

Specific Considerations

DDIs

Recommendations

• •It is recommended to consider the possibility of DDIs whenever prescribing new cancer or cardiovascular medications.

Gaps in knowledge

• •Direct knowledge about the consequences of coprescribing drugs with potential DDIs is limited.

The pharmacodynamic DDIs most relevant to cardio-oncology include QT interval prolongation and bleeding. Bleeding risks can arise from cancer therapies that induce thrombocytopenia, such as myelosuppressive chemotherapy regimens, stem cell transplantation, and JAK2 inhibitors such as ruxolitinib and fedratinib used in treating myeloproliferative neoplasms. Additionally, antiplatelet activity from therapies such as Bruton TKIs may also contribute to bleeding. This propensity for bleeding can lead to significant pharmacodynamic DDIs when patients are concurrently treated with antithrombotic medications for conditions such as coronary artery disease and atrial fibrillation.

QT interval prolongation, which increases the risk for torsades de pointes, is often seen with pharmacodynamic interactions between QT interval–prolonging medications, used in both treatment (eg, ribociclib, doxorubicin, sunitinib) and supportive (eg, ondansetron, citalopram, methadone) contexts. Additionally, in cancer treatment settings, symptoms such as vomiting, diarrhea, and poor oral intake can exacerbate this risk through electrolyte abnormalities. It is crucial to recognize these cancer-related factors when prescribing cardiovascular medications that also prolong the QT interval, such as sotalol, amiodarone, and class I antiarrhythmic drugs. The benefits and risks of using concomitant QT interval–prolonging drugs should be considered, with close monitoring of the corrected QT interval.

Pharmacokinetic interactions are frequently associated with drug metabolism, particularly involving CYP enzymes. The CYP enzymes most commonly implicated include CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Table 4). A drug may inhibit and be metabolized by the same enzyme, or it can act as both an inhibitor and an inducer for different enzymes. When 2 drugs competitively inhibit each other or inhibit the same enzyme, the effects can be competitive or synergistic. Additionally, a medication that is a substrate for multiple CYP enzymes may exhibit variable clinical significance in its interactions. Other pathways such as P-glycoprotein and UGT also play important roles in the clearance of medications and are significant in pharmacokinetic DDIs.

Table 4.

Potential Cardio-Oncology Drug-Drug Interactions Related to Moderate or Strong CYP or P-gp Interactions

Drug Type	Drug	Substrate						Inhibitor						Inducer
		2C9	2C8	2C19	2D6	3A4	P-gp	2C9	2C8	2C19	2D6	3A4	P-gp	2C9	2C19	2D6	3A4	P-gp
Antithrombotic	Warfarin	X
	Apixaban					X	Xa
	Rivaroxaban					X	Xa
	Edoxaban						X
	Dabigatran						X
	Clopidogrel			X					X
	Ticagrelor					X
Lipid lowering	Atorvastatin					X
	Gemfibrozil								X
Antiarrhythmic/atrial fibrillation	Flecainide				X
	Dronedarone					X						X	X
	Amiodarone					X							X
	Verapamil					X						X	X
	Diltiazem					X						X
Pulmonary hypertension	Sildenafil					X
CLL/SLL/mantle cell lymphoma	Ibrutinib					X
	Acalabrutinib					X
GI/liver cancer	Regorafenib					X
Lung cancer	Osimertinib					X
Prostate cancer	Abiraterone					X					X
	Enzalutamide		X			X							X	X	X		X
	Apalutamide		X												X		X	X
Breast cancer	Tamoxifen				X	X
	Exemestane					X
	Ribociclib					X						X
	Tucatinib		X			X						X	X
AML	Midostaurin					X
	Ivosidenib					X
CML	Imatinib					X						X
MM, AL amyloidosis	Bortezomib					X
Melanoma	Dabrafenib		X			X											X
Breast, GU	Olaparib					X
Cytotoxic chemotherapy	Doxorubicin				X	X	X
	Paclitaxel		X			X

Only moderate or strong CYP inducers or inhibitors are included.

AL = amyloid light chain; AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; CML = chronic myeloid leukemia; CYP = cytochrome P450; GI = gastrointestinal; GU = genitourinary; MM = multiple myeloma; P-gp = P-glycoprotein; SLL = small lymphocytic lymphoma.

^aMinor P-gp substrates may generally pose less risk, but if a drug acts as both a CYP3A4 and a P-gp inhibitor or inducer, it may result in a more clinically significant interaction. Sources: UpToDate, Lexicomp, product monograph pharmacokinetic information, and Beavers et al.¹⁰⁸

Empirical data to inform the effects of cardio-oncologic DDIs are limited. Generally, DDIs are predicted on the basis of analogous observations of interactions between other drugs metabolized by the same CYP enzymes. The decision to avoid or accept anticipated DDIs should be tailored on the basis of the clinical importance of the respective drugs involved. A comprehensive review of drug interactions has been published.¹⁰⁸ Specific cardiovascular DDIs that are frequently encountered include interactions with diltiazem, verapamil, and amiodarone, which inhibit several CYP enzymes. Among oral anticoagulant agents, apixaban is a substrate of CYP3A4 and CYP3A5; dabigatran etexilate and edoxaban are substrates of P-glycoprotein; and rivaroxaban is a substrate of CYP3A4, CYP3A5, and P-glycoprotein.

Once a DDI is identified, management strategies may include close monitoring, dose modification, transitioning to an alternative therapy, or discontinuation. Involving a multidisciplinary team, including a clinical oncology or cardiology pharmacist, can be instrumental in identifying and addressing DDIs in the cardio-oncology patient population.

Newer immunotherapies

Recommendations

• •It is recommended to consider baseline cardiac troponin, electrocardiography, and echocardiography before initiating immunotherapy.

Gaps in knowledge

• •The optimal surveillance strategy for CTR-CVT after immunotherapy is not known.

Chimeric antigen receptor T cell therapy modifies T lymphocytes to target specific antigens, thereby redirecting immune effector cells against those antigens, such as CD19 in lymphomas and BCMA in multiple myeloma.

Although chimeric antigen receptor T cell therapies have drastically improved outcomes for hematologic cancers, they are associated with unique toxicities, such as cytokine release syndrome (CRS). CRS is an acute inflammatory reaction that can range from mild symptoms such as isolated fever (grade 1) to severe complications such as multiorgan failure (grade 4).109, 110, 111 Cardiovascular toxicities are most frequently observed during CRS episodes. The underlying mechanism is not entirely understood but is thought to be related to an acute inflammatory response, particularly affecting individuals with pre-existing cardiovascular conditions or risk factors. The reported overall incidence of cardiovascular toxicities varies, with rates ranging between 12% and 21%, including HF (4%-13%), myocardial infarction (5%), cardiogenic shock (2%), and arrhythmias (4%).112, 113, 114, 115 In clinical trials with carefully selected patients, a lower incidence of cardiovascular toxicities is reported, such as a 0.5% to 1% incidence of reduced LVEF and a 0.5% incidence of cardiac arrest.^116,117 Retrospective studies report higher rates, with wide variations depending on the definition used, cohort studied, and type of study.

The optimal strategy for surveillance strategy for cardiovascular toxicities after Chimeric antigen receptor T cell therapy is unknown, including the roles of biomarkers and serial echocardiography. In the absence of robust data, we recommend a baseline assessment of comorbidities and consideration of initial tests such as baseline cardiac troponin, N-terminal pro–B-type natriuretic peptide, electrocardiography, and echocardiography for patients being evaluated for this therapy. Special attention and proactive optimization of treatment should be directed at patients with pre-existing cardiovascular conditions, particularly those related to previous treatments such as anthracyclines. Prompt treatment of CRS with agents such as tocilizumab is crucial to mitigate the effects of CRS and potentially prevent the onset of subsequent cardiovascular toxicities. As these therapies become more prevalent in oncology, ongoing collaboration between cardiologists and oncologists is essential to optimize patient outcomes and minimize the risk for cardiovascular toxicity in real-world settings.

Bispecific antibodies are an emerging class of immunotherapeutic agents used in hematologic malignancies such as leukemia, multiple myeloma, and lymphoma. These antibodies function by binding to 2 targets: one on tumor cells and one on T cells, which activates the T cells and leads to the destruction of cancer cells. Bispecific antibodies can cause grade 3 CRS in 1% to 7% of patients, characterized by fever, hypotension requiring vasopressors, and/or hypoxia.¹¹⁸ Because clinical trials often excluded patients with underlying or recent cardiac toxicity, effective management of these patients should include the identification of any cardiac comorbidities and the prompt management of CRS to prevent any cardiovascular decompensation.

Summary

The European Society of Cardiology has published detailed cardio-oncology clinical guidelines.⁶ The present expert panel report focuses on providing practical recommendations during cancer therapy supported by high-quality evidence that can be applied across diverse settings while also highlighting the significant knowledge gaps in the field of cardio-oncology. The identification, prevention, and management of CTR-CVT should be driven by outcomes-based data. In areas in which such data are lacking, management should be tailored to the individual needs of each patient.

Funding Support and Author Disclosures

Dr Leong has received consulting fees or honoraria from AbbVie, Ferring, Ipsen, Jazz, Myovant Sciences, Novartis, Pfizer, Sanofi, Tolmar, Antev, AstraZeneca, and Boston Scientific; and has received research grants from Novartis and Tolmar. Dr Waliany has received consulting fees from AstraZeneca. Dr Abdel-Qadir has received speaker honoraria from Jazz Pharmaceuticals and AstraZeneca. Dr Atkins has received honoraria from OncLive. Dr Neilan has received consulting fees from Bristol Myers Squibb, RACE Oncology, Roche, Genentech, Roivant, and Sanofi; and has received grant fees from Bristol Myers Squibb, AstraZeneca, and Abbott. Dr Lang has received research grants from Roche Diagnostics, Astra Zeneca, and Boehringer Ingelheim; and has received consulting fees and honoraria from Roche Diagnostics, Myokardia, Pharmacosmos, Akero Therapeutics, CV6 Therapeutics, Jazz Pharmaceuticals, and Novartis. Dr Moore has received consulting fees from AstraZeneca, Daiichi-Sankyo, Eli Lilly, Novartis, RACE Oncology, and Pfizer. Dr Mian has received research support from Janssen; and has received honoraria and consulting fees from Janssen, Pfizer, Sanofi, Bristol Myers Squibb, Takeda, Amgen, and FORUS. Dr Morgans has received consulting fees from Astellas, AstraZeneca, AAA, Bayer, Janssen, Exelixis, Lantheus, Myovant Sciences, Merck, Pfizer, Novartis, Sanofi, and Telix. Dr Ellis has received honoraria from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Jazz Pharmaceuticals, Merck, Novartis, Roche, Sanofi, and Pfizer. Dr Dent has received honoraria from Pfizer, AstraZeneca, Gilead Sciences, Novartis, Bristol Myers Squibb, and Myocardial Solutions. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.