End of cancer therapy and long-term follow-up risk assessment Part 1: End of therapy risk assessment and management

Keywords

chemotherapy, radiotherapy, toxicity, follow-up, cardio-oncology

Abbreviation list

CPET - cardiopulmonary exercise test

CS - cancer survivors

cTn - cardiac troponins

CTR-CVT - cancer treatment-related cardiovascular toxicity

CVD - cardiovascular disease

ESC -European Society of Cardiology

GLS - global longitudinal strain

HFA - Heart Failure Association of the ESC

LVEF - left ventricular ejection fraction

ICOS - International Cardio-Oncology Society

MDT - multidisciplinary team

NP - natriuretic peptide

NMR - nuclear magnetic resonance

PAD - peripheral artery disease

RT - radiotherapy

Take-home messages

• Every CS at end of therapy should receive a careful evaluation of the risk of future CTR-CVT development.
• The risk factors for the development of future CRT-CVT at the end of therapy are related to the patient’s basal risk level, to the toxicity of the cancer therapy, to the development of a CTR-CVT during treatment and to the results of the clinical and instrumental findings at the end of therapy and should periodically evaluated with a clinical assessment, ECG, echocardiography, and biomarkers.
• Specific recommendations apply for the management of patients at the end of therapy according to their risk level.

Patient-oriented messages

• Some cancer treatments may negatively, albeit infrequently, affect the heart and circulation. These rare side effects can be prevented if correctly diagnosed and treated.
• You should understand the importance of a careful CV assessment at the end of treatment and eventually, at one year and long-term follow-up.
• This evaluation consists of simple cardiac consultations and sometimes of echocardiography and blood exams to evaluate your risk of developing a CTR-CVT.
• If you are considered at low risk and your cancer treatment was potentially cardiotoxic, you may need one heart check in the first year after the end of therapy.
• If you are considered at moderate risk and your cancer treatment was potentially cardiotoxic you need closer monitoring of your heart health with more frequent tests after treatment.
• If you are considered at high risk and your cancer treatment was potentially cardiotoxic you will need a more articulated one year and long-term follow-up. The ESC Guidelines provide information to your physicians on which protective treatments to consider and which tests to carry out during the first year after treatment and the long-term.

Impact on practice statement

Every physician taking care of a patient at the end of cancer treatment should know how to identify patients who will need further cardiology assessments to identify future CVD. On the other hand, it helps to avoid useless screening of cancer populations without any CV risk.

The risk assessment includes:

• the HFA-ICOS assessment tools [2] (Table 1)
• the kind of cancer therapy and its specific risk of long-term CRT-CVT
• the development during treatment of a moderate or severe CRT-CVT
• the development of new symptoms or cardiac abnormalities evaluated by echocardiography or serum biomarkers (at 3 months in high-risk patients) and at 1 year in any risk categories.

This evaluation also allows decision on continuing or weaning off CV protective treatments.

Figure 1. End of therapy and follow-up.

CTR-CVT: cancer treatment-related cardiovascular toxicity; CV: cardiovascular; CVD: cardiovascular disease; CS: cancer survivor; LV: left ventricular; MDT: multidisciplinary team

1. CTR-CVT risk evaluation at the end of therapy

1.1 Defining the “end of therapy”

End of cancer therapy begins immediately after the last cardiotoxic cancer therapy dose administration. It is not possible to define the ‘end of therapy’ in cases of discontinuation of therapy for any reason, cancer progression, poor prognosis or end of life care.

Moreover, in some conditions, patients may receive complex neoadjuvant therapies associated with radiotherapy (RT) at the beginning of cancer therapy and continue the adjuvant therapies for very long periods (e.g., trastuzumab and long-term antioestrogen therapy in breast cancer: the end of therapy coincides here with the last trastuzumab dose).

1.2 Tools for CTR-CVT risk evaluation at the end of therapy

The first step in the evaluation at the end of therapy consists of a careful clinical history and physical examination that should be undertaken by oncology specialists or any kind of medical professional who has a CS in their charge. The CS population may be divided in two groups: normal patients and patients with a pre-existing CVD or with a pre-existing CTR-CVT leading to a prevention strategy with specific interventions during therapy and also at the end of therapy.

This evaluation includes a re-evaluation every 12 months (and at 3 months for high-risk patients) for common cardiovascular (CV) risk factors and preventive measures.

Although not specific to cancer patients, the SCORE2 and SCORE2-OP [3] are suggested for risk evaluation and consequent optimisation in CS >40 years of age. Relevant risk factors are a family history of premature cardiovascular disease (CVD), lifestyle factors (smoking, alcohol consumption, sedentary habits, exposure to pollution), and frailty; and moreover, a prior treatment history and history of doses of cardiotoxic drugs.

Typical cardiac symptoms and signs like dyspnoea, chest pain, valvular murmurs and signs of congestion suggesting the presence of an unknown CVD, require specific investigations. .

A prior history of CVD or of CTR-CVT requires a more comprehensive evaluation for the possible development and evolution of new future CVD or CTR-CVT.

1.2.2 Imaging

​ An echocardiographic assessment of left and right ventricular function may identify the level of risk of patients at the end of therapy. Echocardiography may be done by the traditional 2D method, and more recently, by 3D echo and speckle tracking, allowing for the evaluation of the global longitudinal strain (GLS) of both ventricles [3]. In case of technical problems such as poor image quality, other imaging techniques may be used. Nuclear magnetic resonance (NMR) is the most promising although relatively unavailable and costly.

Figure 2 shows the parameters which may be obtained by echo and NMR.

Figure 2. Imaging role in Cardio-Oncology.

FAC: fractional area change: GLS: global longitudinal strain; IVC: inferior vena cava : LA: left atrium; LV: left ventricular; LVEF: left ventricular ejection fraction; PSAP: pulmonary systolic artery pressure: RA: right atrium; RV: right ventricular; RVEF: right ventricular ejection fraction; s’: TAPSE: TTE: transthoracic echocardiography;

The measurement at the end of therapy and at one year of natriuretic peptides (NPs) and cardiac troponins (cTn) [4] has a high negative predictive value for future CTR-CVT end events. In a large study, the incidence of cardiotoxicity after anthracycline was 9% and about 98% of cases were diagnosed at a median time of 3.5 months [5]. Each 1% decrease of the left ventricular ejection fraction (LVEF) predicted CTR-CVT with a hazard ratio (HR) 1.37, 95% confidence interval (CI): 1.33–1.42.

The risk of future events may also be detected by the determination of cTn at the end of cancer therapy, e.g., after anthracycline chemotherapy an increase in cTnI level identifies CS at risk for developing LV dysfunction and which patients should receive angiotensin-converting enzyme inhibitors (ACE-I) and/or betablocker protection.

1.3 Risk factors for future cardiovascular diseases at the end of cancer therapy

• Baseline risk (assessed by Heart Failure Association of the ESC (HFA)- International Cardio-Oncology Society (ICOS) risk assessment tools) [2]

This risk assessment is based on CV risk factors, on previous CVD history, on the cancer story and on previous cancer treatments. This assessment implies a clinical assessment, an electrocardiogram (ECG), and in the case of pre-existing CVD or cancer treatments entailing a high-risk of CTR-CVT, the determination of cTn, NPs and of LVEF and GLS with echocardiogram.

• Type (and dosage) of cancer therapy

Each chemotherapy agent may entail a specific risk of CTR-CVT, from no risk to very high risk, generally related to the doses administered, both single doses and cumulative doses (e.g. cumulative doses of anthracyclines), and to the contemporary or in-sequence administration of other cancer treatments (e.g. anthracyclines plus trastuzumab plus RT).

• CRT-CVT occurring during therapy administration

Includes almost every kind of CV damage at any CV level, of different pathophysiological meaning and of different clinical relevance.

• Clinical conditions, echocardiography, and biomarkers assessment

This reappraisal should be undertaken in all CS at 12 months and at 3 and 12 months in patients classified at high and very high risk at baseline. The echocardiography should include a complete evaluation of left and right ventricle function and, when possible, the evaluation of the GLS compared with baseline data. The clinical evaluation should include CV risk factors according to the ESC Guidelines on Prevention [6].

Table 1 shows the baseline risk stratification according to previous CVD, imaging findings, biomarkers, age and CV risk factors, lifestyle risk factors, current or previous exposure to anthracyclines and RT, in relationship with five of the most common treatments.

Table 1. Baseline CV toxicity risk stratification.

With permission from [1]. Lyon AR, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43:4229-361.

Recovery from myocarditis

ABPI: ankle-brachial pressure index; BCR-Abl: breakpoint cluster region-abelson oncogene locus; BMI: body mass index; CABG: coronary artery bypass graft; cTn: cardiac troponin; CTRCD: cancer therapy-related cardiac dysfunction; CV: cardiovascular; CVD: cardiovascular disease; DVT: deep vein thrombosis; HER2: human epidermal receptor 2; HF: heart failure; IMID: immunomodulatory drugs; LV: left ventricular ejection fraction; MEK: mitogen-activated protein kinase; MI: myocardial infarction; NP: natriuretic peptide; PCI: percutaneous coronary intervention; PE: pulmonary embolism; PI: proteasome inhibitors; QTc: QT interval; RAF: proto-oncogene B-RAF; RT: radiotherapy; TKI: tyrosine kinase inhibitor; VEGF: vascular endothelial growth factor inhibitors

Risk level: Low risk = no risk factors OR one moderate1 risk factor; moderate risk (M) = moderate risk factors with a total of 2–4 points (Moderate 1 [M1] = 1 point; Moderate [M2] = 2 points); high risk (H) = moderate risk factors with a total of ≥5 points OR any high-risk factor; very-high risk (VH) = any very-high risk factor.

a AF, atrial flutter, ventricular tachycardia, or ventricular fibrillation.

b Elevated above the ULN of the local laboratory reference range.

c Systolic BP > 140 mmHg or diastolic BP > 90 mmHg, or on treatment.

d eGFR < 60 mL/min/1.73 m².

e HbA1c > 7.0% or >53 mmol/mol, or on treatment.

f Non-high density lipoprotein cholesterol >3.8 mmol/L (>145 mg/dL) or on treatment.

g High risk if anthracycline chemotherapy and trastuzumab delivered concurrently.

h Previous malignancy (not current treatment protocol).

Table 2 shows the toxicity definition of some of the most common cancer treatments.

Table 2. Cancer therapy-related cardiovascular toxicity definitions.

With permission from [1]. Lyon AR, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43:4229-361.

CMR: cardiovascular magnetic resonance; GLS: global longitudinal strain; HF: heart failure; LVEF: left ventricular ejection fraction; NMR: nuclear magnetic resonance

1.4 Which cancer survivors require long-term cardiovascular surveillance?

The timing of the first cardiology re-evaluation after any cardiotoxic cancer treatment should take into account the level of risk at baseline according to the risk criteria shown in section 1.3.

This assessment at 12 months (and at 3 months in the subjects identified before and during treatment as being at high and very high risk) allows the identification of high-risk patients when they show these characteristics:

• Baseline high risk or very high risk after the evaluation at pre-treatment based on HFA-ICOS criteria
• Cancer therapy with:

• Doxorubicin ≥250 mg/m²
• RT >15 Gy MHD
• Both doxorubicin ≥100 mg/m² and RT ≥ 5–15Gy MHD
• Haematopoietic stem-cell transplantation
• Moderate or severe CTR-CVT during cancer treatment, especially LV dysfunction, immune checkpoint inhibitor (ICI)-related myocarditis, arrhythmias or severe vascular toxicities.
• New asymptomatic abnormalities in echocardiography and biomarkers, or new CV symptoms at the end of therapy evaluation.

2. Recommendations for the patients and the clinicians at end of cancer therapy

Beyond the risk evaluation of future CTR-CVT, at the end of cancer therapy should be considered other relevant recommendations for all physicians who have in care CS.

In patients with moderate or severe symptomatic or severe asymptomatic CTR-CVT during cancer treatment, HF protective drugs should be continued lifelong.

Selected patients with asymptomatic mild or moderate CTR-CVT, who are taking cardioprotective medications initiated during cancer therapy and who have fully recovered with normal echocardiography and cardiac biomarkers may be eligible to be weaned off CV therapy.

The end of therapy evaluation may also include the execution of a cardiopulmonary exercise test (CPET) for those CS experiencing exertional limitations and who may benefit from cardiac rehabilitation. Notably, patients submitted to higher doses of anthracycline or RT, with high CV risk at baseline or with abnormalities in LV function during or at the end of therapy, should undergo a CPET as this may identify CV versus non-CV causes of symptoms.

Other recommendations may be summarised as follows:

• Education and support of CS to adopt appropriate healthy lifestyle measures
• Periodical assessment of common CV risk factors
• Education of CS regarding recognition for early signs and symptoms of CTR-CVT
• Prompt cardiology referral of CS with new symptoms or new asymptomatic abnormalities in echocardiography and cardiac biomarkers
• Appropriate cardiac rehabilitation in CS with high CV risk

Moreover, specific categories of patients require specific interventions:

• The development of hypertension during cancer therapy with TKI requires a CV follow-up and treatment optimisation
• Patients who develop vascular toxicities during cancer therapy need specific management measures
• The occurrence of a prolongation of the QT or true long QT syndrome (LQTS) after certain chemotherapy agents indicates a regular ECG follow-up