HFA-ICOS cardio-oncology baseline risk assessment for anthracycline chemotherapy

Clinical background

Anthracyclines are a cornerstone of the treatment of haematological malignancies and solid tumours, but dose-dependent cardiotoxicity remains one of the commonest dose-limiting problems. The mechanism is above all oxidative damage to cardiomyocytes through iron-mediated lipid peroxidation, which can lead to progressive left ventricular dysfunction and heart failure, sometimes only years after treatment has finished [1].

The decision the instrument serves is not whether an anthracycline should be given, but how intensively cardiac function should be monitored during and after treatment, and whether the patient should be referred to cardio-oncology before starting. Without a structured risk assessment, monitoring tends either to be too lax in patients who are genuinely at high risk, or unnecessarily resource-intensive in patients at low risk. The HFA-ICOS baseline cardiovascular risk assessment was developed precisely to standardise this assessment and make it feasible in everyday oncology practice, not only at specialist clinics [1].

Applying the HFA-ICOS baseline cardiovascular risk assessment

The instrument was published in 2020 as a position statement from the Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the European Society of Cardiology, in collaboration with the International Cardio-Oncology Society (ICOS) [1]. It is not a statistically derived risk model from a defined cohort, but an expert consensus tool produced at a workshop with subsequent review by more than 50 co-authors. It is presented as a structured proforma for seven classes of cardiotoxic cancer therapy; the variant described here applies to anthracycline chemotherapy.

The assessment is hierarchical and rests on three levels of risk factors:

Very high risk criteria (any single criterion classifies the patient as very high risk regardless of the other scoring):

• Existing heart failure or cardiomyopathy
• Severe valvular heart disease
• Previous myocardial infarction or coronary revascularisation
• Stable angina
• Left ventricular ejection fraction (LVEF) <50% at baseline
• Age ≥80 years
• Previous anthracycline exposure
• Previous radiotherapy to the left chest or mediastinum

High risk criteria (any single criterion classifies the patient as high risk if no very high risk criterion is present):

• Borderline LVEF 50–54%
• Age 65–79 years

These two factors also feature in the medium-risk score with a weight of 2.

Medium risk factors that are scored and summed:

The total medium-risk score is denoted $P_{\text{medium}}$ and classification follows this logic:

$$\text{Risk} = \begin{cases} \text{Very high} & \text{if any very high risk criterion is present} \ \text{High} & \text{if any high risk criterion is present or } P_{\text{medium}} \geq 5 \ \text{Moderate} & \text{if } 2 \leq P_{\text{medium}} \leq 4 \ \text{Low} & \text{if } P_{\text{medium}} \leq 1 \end{cases}$$

A single very high risk criterion overrides all other scoring. This reflects the fact that these conditions in themselves constitute a cardiological problem in which anthracycline exposure may worsen an already unstable situation, and in which the decision about cancer therapy should be made in multidisciplinary discussion between oncologist and cardiologist [1].

Interpretation in practice

The risk category determines the intensity of monitoring and the referral pathway, not whether cancer treatment should be given. The 2022 ESC cardio-oncology guidelines build on the HFA-ICOS framework and recommend that the baseline assessment be performed in all patients before cardiotoxic therapy is started [3].

The original position statement emphasises that the decision to withhold effective cancer treatment should be made only at high or very high risk, and after multidisciplinary discussion in which the patient is informed and participates [1]. The ESC quality indicators for cardio-oncology further underline that patient participation in decision-making is a quality marker [2].

Validation and performance

Since the instrument is consensus-based and not statistically derived, external validation has been particularly important. The largest validation study to date is an analysis of the CARDIOTOX registry (NCT02039622) published in 2025 by Rivero-Santana et al. [4]. The study comprised 1,066 patients treated with an anthracycline, mean age 54 years, 82% women, 25% aged ≥65 years. Median follow-up was 55 months.

The distribution by HFA-ICOS was: low risk 54%, moderate 31%, high 14%, very high 1%. The primary endpoint was symptomatic or moderate to severe asymptomatic cancer therapy-related cardiac dysfunction (CTRCD). Its incidence rose stepwise with risk category, and for very high risk the hazard ratio was 28.7 (95% CI 9.3–88.5) compared with low risk. For all-cause mortality the hazard ratio was 7.4 (95% CI 3.2–17.2) in the same comparison.

Discrimination for predicting symptomatic or moderate to severe asymptomatic CTRCD at 12 months was an AUC of 0.78 (95% CI 0.70–0.82) and Uno's C-statistic 0.78 (95% CI 0.71–0.84). Calibration was good, with a Brier score of 0.04 (95% CI 0.03–0.05) [4].

A smaller prospective multicentre study from Italy by Di Lisi et al. included 109 breast cancer patients treated with an anthracycline with or without trastuzumab [5]. The distribution was 61 low, 37 moderate, 9 high and 2 very high risk patients. The incidence of CTRCD was 100% in the very high risk group, 55% in the high, 29% in the moderate and 13% in the low group. The difference between groups was statistically significant for high ($p = 0{.}006$) and very high risk ($p < 0{.}0001$). The study therefore confirms the instrument's ability to separate risk groups, but the cohort is small, particularly in the higher risk categories.

In summary, the available validation literature shows that HFA-ICOS works well for identifying patients at increased risk, with good discrimination and calibration in the largest study. The very small proportion of patients in the very high risk group (below 1% in CARDIOTOX) does, however, make the estimates for that category uncertain despite the high hazard ratios.

Limitations

The instrument was produced by expert consensus, not by statistical modelling in a cohort. The scoring of individual factors (1 or 2 points) and the threshold of ≥5 for high risk via the medium-risk score are not optimised against outcome data but rest on expert judgement of relative importance. This is an important difference from statistically derived risk models and should be borne in mind when comparing it with other instruments.

The following patient groups are not covered, or are covered only with considerable uncertainty:

• Paediatric patients: the instrument is validated in adults. Children have a different risk profile and different long-term cardiotoxicity.
• Patients receiving other cardiotoxic drugs at the same time: HFA-ICOS has separate proformas for HER2-targeted therapies, VEGF inhibitors and other classes. Combination treatment, particularly an anthracycline followed by trastuzumab, carries a cumulative risk that the anthracycline proforma alone does not fully capture.
• Patients with a previous heart transplant or mechanical circulatory support: these cases are not represented in the underlying material.

The instrument furthermore applies specifically to anthracycline chemotherapy. For other treatment modalities, such as immune checkpoint inhibitors or CAR-T cell therapy, there is no evidence on which parameters predict risk, and HFA-ICOS should not be used for these [1].

A common error is to interpret a low risk score as a decision to forgo follow-up echocardiography. Even low-risk patients can develop cardiotoxicity, and the baseline examination also has value as a reference for future comparison if symptoms arise.

Implementation in practice

Cardio-oncology is still a developing field, and access to structured cardio-oncology services varies between hospitals. The 2022 ESC guidelines [3] and the HFA-ICOS framework have, however, begun to be implemented at the larger oncology centres. In the absence of national guidelines that differ from the ESC, it is recommended that the instrument be used in accordance with the ESC guidelines, with local adaptation of referral pathways and monitoring frequency according to available resources.

References

1. Lyon AR, Dent S, Stanway S, et al. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the ESC in collaboration with the International Cardio-Oncology Society. Eur J Heart Fail. 2020;22(11):1945–1960. PMID: 32463967
2. Lee GA, Aktaa S, Baker E, et al. European Society of Cardiology quality indicators for the prevention and management of cancer therapy-related cardiovascular toxicity in cancer treatment. Eur Heart J Qual Care Clin Outcomes. 2022;9(1):1–12. PMID: 36316010
3. Lyon AR, López-Fernández T, Couch LS, 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(41):4229–4361. PMID: 36017568
4. Rivero-Santana B, Saldaña-García J, Caro-Codón J, et al. Anthracycline-induced cardiovascular toxicity: validation of the Heart Failure Association and International Cardio-Oncology Society risk score. Eur Heart J. 2025;46(3):273–284. PMID: 39106857
5. Di Lisi D, Madaudo C, Faro DC, et al. The added value of the HFA/ICOS score in the prediction of chemotherapy-related cardiac dysfunction in breast cancer. J Cardiovasc Med. 2024;25(3):218–224. PMID: 38305134