How to utilize current guidelines to manage patients with cancer at high risk for heart failure

Abstract

Heart failure (HF) in patients with cancer is associated with high morbidity and mortality. The success of cancer therapy has resulted in an exponential rise in the population of cancer survivors, however cardiovascular disease (CVD) is now a major life limiting condition more than 5 years after cancer diagnosis [Sturgeon, Deng, Bluethmann, et al 40(48):3889-3897, 2019]. Prevention and early detection of CVD, including cardiomyopathy (CM) and HF is of paramount importance. The European Society of Cardiology (ESC) published guidelines on Cardio-Oncology (CO) [Lyon, López-Fernández, Couch, et al 43(41):4229-4361, 2022] detailing cardiovascular (CV) risk stratification, prevention, monitoring, diagnosis, and treatment throughout the course and following completion of cancer therapy. Here we utilize a case to summarize aspects of the ESC guideline relevant to HF clinicians, with a focus on risk stratification, early detection, prevention of CM and HF, and the role for guideline directed medical therapy in patients with cancer.

Clinical case

A 38-year-old pre-menopausal woman presents to HF clinic prior to initiating treatment for triple negative (ER-/PR-/HER2-) breast cancer. She has a history of Hodgkin’s Lymphoma 20 years ago, treated with chemotherapy including doxorubicin (total dose of 300 mg/m2) and mediastinal radiation therapy (RT). CV risk factors (RF) include obesity (BMI 30 kg/m2), hypertension (HTN), diabetes mellitus (DM), and “social” smoking history. Her blood pressure (BP) is 132/80 mm Hg (on hydrochlorothiazide and diltiazem), pulse is 78 beats/min, electrocardiogram (ECG) reveals sinus rhythm and is otherwise unremarkable. Her planned treatment includes weekly paclitaxel and carboplatin × 12 followed by 4 cycles of doxorubicin (total dose 240 mg/m2) and cyclophosphamide with pembrolizumab prior to and following breast surgery (Keynote 522 protocol) [1]. Her baseline 3-dimensional transthoracic echocardiogram (TTE) with global longitudinal strain (GLS) reveals LVEF 52%, GLS – 15% (normal: -18% to -22%), with borderline dilated left ventricle, and cardiac biomarkers reveal NT-pro BNP at 225 pg/ml (normal > 125 pg/ml < 75-year-old) and high sensitivity troponin I within normal limits (Fig. 1).

Fig. 1

The case of a 38 year old survivor of childhood cancer (Hodgkin’s Lymphoma) diagnosed with breast cancer and planned for additional potential cardiotoxic cancer therapy to highlight the ESC Guideline approach to risk quantification and opportunities for risk mitigation throughout and folloing the course of therapy

How to approach risk stratification before cancer treatment

Traditional CV risk calculators such as the Atherosclerotic Cardiovascular Disease (ASCVD) Risk Estimator [2] underestimate the risk of CV toxicity in patients with cancer and should be used with caution. Other scoring systems specific for survivors of childhood cancers can be considered (http://survivorshipguidelines.org/pdf/2018/COG_LTFU_Guidelines_v5.pdf ). Adult survivors of childhood cancer are at a uniquely higher risk of CV toxicity compared to age matched controls, primarily due to prior anthracycline and mediastinal radiation therapy (RT). Cancer therapy-related cardiac dysfunction (CTRCD) [3], including HF, is a late effect of treatment that results in tremendous morbidity and early mortality [4]. Traditional CVD RFs are multiplicative in raising risk of CTRCD and must be recognized and aggressively managed [4].

In 2020, the Heart Failure Association of the ESC developed a baseline risk stratification tool for patients with cancer, for use prior to starting cancer therapy [5]. This tool considers traditional CV RFs, lifestyle factors (e.g., smoking), age and cancer therapy related factors. Patients are classified as low, medium, high (H) or very high (VH) risk of CV toxicity depending on their total score [5] Our patient is considered at VH risk due to: borderline LVEF 50–54%, elevated NT-proBNP, HTN, obesity, prior exposure to anthracycline, and mediastinal RT. Patients considered H or VH risk for CTCRD at baseline should be referred to a cardiologist with expertise in CO or HF. Coronary artery disease as a cause or contributor to LVD should be considered, in alignment with HF guidelines [6]. Multiple consensus statements and guidelines have been published, with variations in recommendation for ischemic evaluation in patients who have received mediastinal RT, especially with concomitant anthracycline exposure (http://survivorshipguidelines.org/pdf/2018/COG_LTFU_Guidelines_v5.pdf ) [7,8,9,10].

How to approach prevention of cardiac dysfunction during cancer therapy

Cancer and CVD share both modifiable and non-modifiable RFs that must be recognized and addressed to optimize clinical outcomes. Primary prevention strategies include:

• Counseling and optimization of modifiable RF (e.g., smoking cessation)

• Avoidance of polypharmacy and/or alteration of drugs that might exacerbate CTRCD (e.g., diltiazem)

• Alteration or avoidance of potentially cardiotoxic agents when possible:

  • Adjustment of anthracycline dose and/or infusion time or use of a non- anthracycline containing regimen.

  • Consideration for liposomal doxorubicin [11] (when available) or dexrazoxane [12,13,14], both currently recommended by the ESC guidelines [15] for patients at H or VH risk for CTRCD or in those who have previously received high dose anthracyclines [16,17,18].

How to approach monitoring for cardiovascular complications during cancer therapy

Natriuretic peptides (NP) and cardiac troponins (cTn) may help guide risk stratification, diagnosis, and therapy. The ESC guidelines note that clinically relevant cutoff values have not been studied in the CO population.

Cardiac imaging including TTE [with 3D-LVEF and GLS when available] and cardiac MRI (CMR) are the mainstay of surveillance in CO patients and crucial to early identification and management of toxicity [19]. In patients who are H or VH risk, frequency of imaging and biomarker evaluation is dependent on the type of cancer therapy planned and baseline risk.

All patients receiving anthracycline-based chemotherapy should have a baseline assessment including ECG, TTE (3D, GLS) and cardiac biomarkers, repeated at minimum 12 months post treatment.

In patients at VH risk, the ESC additionally recommends [20]:

• biomarker evaluation before each cycle of anthracycline and 3- and 12-months post

• Imaging to be repeated at alternating anthracycline cycles and 3 months post. Of note, CMR can be used in patients where TTE is unavailable or nondiagnostic.

GLS is helpful in patients with low normal LVEF. Relative change in GLS of > 15% has been shown to be useful in the identification of asymptomatic CTRCD, although different thresholds for % change have been proposed [19].

Immune Checkpoint Inhibitor (ICI) therapy (e.g. pembrolizumab) has been associated with adverse CV events including progression of atherosclerosis [21] and ICI-associated myocarditis, particularly early after therapy initiation and with combination ICI therapy [22]. Late toxicities are not well understood, but non-inflammatory HF and higher mortality have been described [23].

Per ESC guidelines, all patients receiving ICI therapy should have baseline ECG, NP and cTn prior to ICI initiation. In VH risk patients, baseline imaging is recommended with consideration for repeat ECG, NP, and cTn before doses 2, 3, and 4, with decreased frequency thereafter assuming normal values. CV assessment in H and VH risk patients should be performed every 6–12 months when treatment with ICI will extends past 12 months.

Case continued

Prior to initiating breast cancer therapy, thiazide and diltiazem are discontinued and carvedilol/losartan started. Statin therapy is initiated [24]. She completes weekly paclitaxel and carboplatin × 12, and doxorubicin and cyclophosphamide are planned. After discussion with the oncology team, concomitant dexrazoxane (10:1 dexrazoxane: doxorubicin) is started prior to each doxorubicin infusion [12,13,14] with concurrent pembrolizumab. On repeat 3D TTE (post cycle 4 of doxorubicin and cyclophosphamide) she is noted to have an asymptomatic drop in LVEF (now LVEF 40%, GLS -12%). Repeat labs include NT-pro BNP 450 pg/ml, and cTnI of 45 pg/ml (normal < 25 pg/ml). Electrocardiogram (ECG) is unchanged.

How to approach diagnosis and treatment of cardiovascular complications during cancer therapy

Our patient remains asymptomatic but has developed moderate asymptomatic CTRCD (new LVEF reduction of ≥ 10% to EF 40–49%) [23] after receiving 4 cycles of doxorubicin and cyclophosphamide (and in the context of prior exposure to high dose anthracyclines). Although our patient meets criteria for anthracycline induced CTRCD, she has completed all planned anthracycline dosing currently. In this complex case, the patient received concomitant pembrolizumab with her chemotherapy, and the plan is to proceed with additional adjuvant pembrolizumab after her breast cancer surgery.

In addition to consideration of anthracycline toxicity, ICI-related cardiac dysfunction should be considered due to a significant reduction in LVEF and a corresponding rise in cardiac biomarkers. ICI-related myocarditis generally develops within the first 3 months of therapy [25]. The diagnosis is challenging but can be confirmed by a combination of clinical presentation, ECG findings, troponin elevation, CMR characteristics, presence of other immune related complications (i.e. thyroiditis, myositis) and/or endomyocardial biopsy (EMB) [3]. Importantly, preserved, or unchanged LVEF on echocardiogram does not exclude ICI-related myocarditis and, if clinical suspicion remains, CMR or EMB should be performed. Diagnostic CMR (i.e., meeting modified Lake Louise criteria with abnormal late gadolinium enhancement/abnormal T1 imaging and abnormal T2 imaging) in a patient with positive troponin and clinical symptoms is sufficient to establish the diagnosis of ICI myocarditis. However, findings of negative or equivocal CMR in a patient with suggestive clinical symptoms would require an EMB to establish the diagnosis. In cases of high concern or confirmed myocarditis, the ESC guidelines and others recommend treatment with high dose steroids initially. Additionally, an ongoing clinical trial is examining the incremental value of abatacept in addition to corticosteroids in high-risk ICI myocarditis patients (NCT05335928). Interruption of ICI therapy is recommended in all cases of suspected myocarditis with rechallenge individualized.

A multidisciplinary discussion between the HF clinician and oncology team is essential to determine the most appropriate course of action. Although clinical opinion varies, temporary disruption of ICI therapy should be strongly considered in patients who develop either moderate or severe asymptomatic CTRCD and is recommended by ESC guidelines in patients with clinical suspicion for ICI myocarditis.

Irrespective of etiology, guideline directed medical therapy (GDMT) for Stage B Heart Failure with reduced ejection fraction (HFrEF) should be optimized according to established HF guidelines [6], and in this clinical case, in agreement with ESC guidelines that recommend a GDMT approach in patients with asymptomatic CTRCD while continuing cancer therapy [6, 15] Decisions on appropriateness and type of GDMT in patients with cancer receiving cardiotoxic cancer therapies bears further discussion, as evidence for use in such cases is limited. Patients with active or suspected malignancy or with history of recent malignancy were excluded in pivotal trials of patients across the spectrum of ejection fraction [26]. Therefore, use of GDMT in patients with Stage B and Stage C HF actively receiving cancer therapies is generally extrapolated from more robust patient subsets.

In our Stage B patient (TTE LVEF 40%, elevated cardiac biomarkers), carvedilol and angiotensin receptor blocker were initiated, with plans to up titrate to target doses as tolerated. Sodium glucose transport inhibitor therapy can be considered, as there is limited evidence for their role in primary prevention in cancer patients with diabetes [27, 28] as well as in Stage A HF patients with type 2 DM and established CVD or at high CV risk [29,30,31]. The patient should be encouraged to continue daily aerobic exercise as this has been shown to be beneficial throughout and following anthracycline therapy [32]. If the decision is made to halt cancer therapy, a multidisciplinary discussion is necessary before restarting therapy, considering cancer therapy adjustment or non-cardiotoxic alternatives.

It should be noted that GDMT optimization must be considered in the context of issues unique to patients receiving cancer therapies including fluid shifts, nausea, vomiting, dehydration and hypotension and attention must be paid to the use of these cardiac medications in such patients.

Lastly, multidisciplinary discussion, especially in asymptomatic patients should include risk/benefit discussion on the impact of interruption in cancer therapy on overall cancer outcome. In this case, triple negative breast cancer portends worse oncologic prognosis and should be factored into clinical decision making of withholding cancer therapy [33]. The concept of permissive cardiotoxicity has recently been described and should be explored in asymptomatic patients in the appropriate clinical context [34], with the recognition that this is a rapidly evolving field of study.

Case further continued

Although chemotherapy has been completed, the decision is made to temporarily halt ICI therapy while further evaluating the asymptomatic drop in LVEF in the context of concern for ICI-myocarditis. The patient undergoes cardiac MRI with findings including LVEF 40%, normal LV size, RVEF within normal limits, without evidence of delayed gadolinium enhancement or edema to suggest myocarditis. The patient’s pembrolizumab is held for two cycles while awaiting cardiac MRI and optimizing GDMT. Repeat TTE roughly 6 weeks later reveals LVEF 50%. BP is 120/80. ECG is unremarkable. She reinitiates and completes the Keynote-522 protocol [1] while continuing GDMT. A plan is made to continue long-term GDMT (with BB and ARB) given history of CTRCD and overall high risk for progression to symptomatic HF. If she were to develop symptomatic HF regardless of EF, consideration will be made to initiate GDMT with angiotensin receptor-neprolysin inhibitor (ARNI), SGLT-2 inhibitor, and mineralocorticoid antagonist therapy [6].

How to approach long term management of cardiovascular complications during cancer therapy

Even in the scenario of complete LV recovery, HF guidelines support continuation of maximally tolerated GDMT [6], as withdrawal is associated with a high rate of relapse [35]. The ESC guidelines do briefly address this topic, suggesting multidisciplinary discussion regarding the weaning of CV therapy at the end of cancer therapy, acknowledging that GDMT should be continued in asymptomatic patients with exposure to anthracyclines [15].

At the completion of cancer therapy, patients considered H or VH risk should have long term cardiac surveillance and monitoring. TTE and cardiac biomarkers are checked at 3- and 12-months post completion of anthracycline chemotherapy. Modifiable RF should be continually addressed and aggressively treated. Patients should be active participants in their care including adherence to medical therapy, regular exercise, and a healthy diet. All patients should be educated about long term risk and need for lifelong cardiovascular surveillance [15].