The Role of Frailty in Cardio-oncology and its Challenges

Cardiovascular disease (CVD) and cancer are among the leading causes of mortality, particularly in older populations.¹ Cardio-oncology is a dynamic and interdisciplinary field that brings together a diverse team of specialists, including oncologists, cardiologists, and other dedicated healthcare providers, to identify and address cardiovascular complications that can arise as a result of cancer and its treatments, particularly for patients exposed to potentially cardiotoxic therapies.^2–4 Cancer therapies, such as anthracyclines, tyrosine kinase inhibitors, or immune checkpoint inhibitors, are associated with cardiotoxic effects, such as heart failure, arrhythmias, and hypertension.² The establishment of comprehensive cardio-oncology services is crucial for implementing guideline-based evidence aimed at reducing the risk of adverse cardiovascular events in patients living with cancer and in survivorship.

Frailty is a multidimensional syndrome characterised by decreased physiological reserve and increased vulnerability to stressors.^5,6 It is a prevalent condition among older adults and has received considerable scientific attention over the past decades.⁷ The prevalence of frailty is highly varied, dependent on the study populations, the frailty definitions used, and the clinical settings (community-based, primary care, geriatric clinics, hospitals, long-term care institutions, etc.).⁸ In the general population, the prevalence of frailty ranged between 12 and 24%, according to findings from a systematic review of 240 population-based studies from 62 countries.⁹ In adults with cancer, the prevalence of frailty is even higher. For instance, a systematic review of 20 observational studies indicated that the mean prevalence of frailty was 42% (range 6–86%) and the prevalence of pre-frailty was 43% (range 13–79%).¹⁰ Factors such as age, comorbidities, and cancer-related symptoms (such as anorexia, fatigue, weight loss) may explain this elevated prevalence of frailty among older adults with cancer.

Frailty is a strong predictor of adverse outcomes in both cancer and cardiovascular disease.⁶ For example, Pearce et al.¹¹ conducted a meta-analysis of 58 studies in adults with solid-organ malignancy undergoing systemic anti-cancer treatment and found that frailty was associated with an increased risk of mortality (HR 1.68, 95% CI [1.41–2.00]), toxicity (OR 1.83, 95% CI [1.24–2.68]), treatment intolerance (OR 1.68, 95% CI 1.32–2.12) and hospitalisation (OR 1.94, 95% CI [1.32–2.83]). In another meta-analysis, frailty was independently associated with increased all-cause mortality (5-year HR 1.87, 95% CI [1.36–2.57]), postoperative mortality (30-day HR 2.67, 95% CI [1.08–6.62]), chemotherapy intolerance (OR 4.86, 95% CI 2.19–10.78), and postoperative complications (30-day HR 3.19, 95% CI [1.68–6.04]).¹⁰

Notwithstanding these results, there is a lack of evidence on how frailty impacts the risk of developing cardiotoxicity in patients receiving cancer therapies.¹² An assessment of the role of frailty on cardiotoxicity among cancer patients can better inform clinicians and patients about prognosis throughout the continuum of cancer care, especially among older adults.¹³ Therefore, understanding and addressing frailty in cardio-oncology is essential for optimising patient outcomes, personalising treatment plans, and improving quality of life. However, to our knowledge, there has been no comprehensive review addressing frailty in cardio-oncology.

Thus, in this review, we aim to discuss:

1. The pathophysiology of frailty in the context of cardio-oncology;
2. The common frailty definitions used in observational studies and in clinical drug trials among patients with cancer;
3. The challenges of frailty assessments in cardio-oncology;
4. The need to incorporate frailty into cardiovascular risk assessment tools in older patients with cancer.

Agreement was made between the first author and the senior author on the selected topics. For each topic, we conducted a literature search on MEDLINE and Embase, using the keywords “frailty” and relevant conditions. For Aim 1, a search was conducted using the keywords “frailty,” “pathophysiology,” “cancer,” “oncology,” “cardiotoxicity,” “cardiovascular toxicity.” For Aim 2, we searched for systematic reviews on this subject and summarised the findings from these reviews. For Aim 3, a search was conducted using the keywords “frailty,” “challenges,” “cancer,” “oncology,” “cardiotoxicity,” “cardiovascular toxicity.” For Aim 4, a search was conducted using the keywords “Heart Failure Association-International Cardio-Oncology Society,” and “Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS).” The abstracts obtained through the literature search were then screened to select relevant papers.

The Pathophysiology of Frailty in the Context of Cardio-oncology

In cardio-oncology, frailty is particularly relevant because both cancer and its treatments (e.g. chemotherapy, radiation, immunotherapy) can exacerbate cardiovascular risks and diminish physiological reserves.¹⁴ Frailty in cancer patients with cardiovascular toxicity is a result of multiple factors, including inflammation, oxidative stress, metabolic dysregulation, cardiovascular complications and multi-organ dysfunction, each of which are intensified by cancer and its treatments.^6,15–17

Inflammatory Pathway

Frailty has been linked to significantly higher levels of serum inflammatory parameters, particularly C-reactive protein (CRP) and interleukin-6 (IL-6).¹⁸ Additionally, cancer and cardiotoxic treatments can exacerbate systemic inflammatory processes by increasing the levels of pro-inflammatory cytokines, accelerating frailty and cardiovascular dysfunction.^19,20 This heightened inflammation may lead to muscle wasting, fatigue and reduced functional capacity.

Neuroendocrine and Metabolic Pathways

Cancer induces a catabolic state through the release of cytokines and tumour-derived factors, leading to sarcopenia and weakness.^21,22 Neuroendocrine dysregulation occurs as stress from cancer and its treatment can activate the hypothalamic-pituitary-adrenal axis, leading to increased cortisol levels, promoting muscle catabolism and insulin resistance.^21,23 Chemotherapy has been shown to be linked to oxidative stress and mitochondrial dysfunction, creating a harmful cycle that contributes to both metabolic and muscular decline.²⁴

Musculoskeletal Pathway

Chemotherapy and radiotherapy can generate reactive oxygen species that damage mitochondria, leading to cellular dysfunction in skeletal muscle, cardiac tissue, and other organs.^25,26 In addition, anorexia and fatigue, which are very common in patients with cancer, can contribute to the development of frailty.^27,28 Research indicates that nutritional status plays a key role in reducing the risk of frailty, and that proper nutrition may enhance the functional outcomes of frail and older patients.^29–31 Weight loss, malnutrition, and decreased physical activity can lead to muscle atrophy, reduce resilience and increase the risk of developing frailty.^17,28 Cancer-induced cachexia, characterised by muscle loss and impaired metabolism, further exacerbates frailty.^32,33

Cardiovascular Pathway

The effects of cancer therapies (such as anthracyclines, HER2-targeted agents) may directly result in cardiac damage and lead to left ventricular dysfunction, heart failure, hypertension, arrhythmias, reducing cardiac output and exercise capacity, which are the key components of frailty.^34,35 Vascular dysfunction, caused by radiation and certain cancer therapies (such as cisplatin), damages endothelial cells, impairing blood flow and oxygen delivery to tissues, which exacerbates muscle fatigue and frailty.^36,37

The combination of cancer and cardiotoxicity can impair the cardiovascular system, leading to reduced physiological reserve. In patients with cancer and cancer therapy-related cardiotoxicity, microvascular injury and endothelial dysfunction can negatively impact tissue perfusion. Heart failure induced by cardiotoxicity also leads to impaired tissue perfusion and increased sympathetic tone, contributing to muscle wasting and fatigue.³⁸ The combined effects of cancer cachexia and cardiotoxicity-related fatigue accelerate muscle loss, reducing muscle strength and mobility.

Psychosocial Pathway

Previous studies in community-dwelling older adults show that social isolation and depression significantly increased the risk of frailty.^39,40 Psychosocial and social factors such as pain, depression, anxiety, and social isolation, which are common in cancer patients undergoing treatment, further compound frailty by reducing motivation and physical activity.⁴¹ Furthermore, psychosocial stress further increases inflammation and neuroendocrine dysregulation, accelerating the dysfunction described in the inflammatory and neuroendocrine pathways above.

Figure 1 presents the key elements involved in the pathophysiology of frailty in the context of cardio-oncology.

Frailty Definitions used in Observational Studies and Clinical Drug Trials in Patients with Cancer

There has been a growing interest in frailty research in the past two decades. Considering variability in the formal definition of frailty, more than 70 different frailty assessment tools have been developed to define this condition.^12,42,43 However, there is still no agreement on the gold standard for a frailty diagnosis. The two most commonly used definitions of frailty are the physical frailty phenotype (also known as Fried’s frailty criteria), and Rockwood’s deficit accumulation model (also known as the Frailty Index).^44,45 Fried’s frailty criteria focus upon the physical aspects of frailty identified through five specific criteria: unintentional weight loss, low hand grip strength, self-reported exhaustion, slow walking speed, and low physical activity.⁴⁶ Individuals with three or more of these criteria are considered to have frailty, while one or two criteria indicates pre-frailty. Rockwood’s model focuses on the accumulation of deficits, including chronic health conditions, physical impairments, cognitive impairment, and socio-economic factors to formulate the Frailty Index as the ratio of present deficits in an individual to the total number of age-related health variables considered.^47–49 A cut-off value of the Frailty Index between 0.21 and 0.25 is usually used to distinguish between frail and non-frail individuals.^48–50

The International Society of Geriatric Oncology (SIOG) and the American Society of Clinical Oncology (ASCO) have developed detailed recommendations for the assessment of frailty in older adults prior to the initiation of cancer therapy.^51,52 The ASCO recommended that for patients aged 65 and above undergoing chemotherapy, a geriatric assessment (which evaluates functional capabilities, physical performance, risk of falls, comorbidities, depression, cognitive function, social support and nutritional health) should be conducted to identify vulnerabilities or geriatric impairments that are not routinely captured in standard oncology evaluations.⁵² The 2022 ESC guidelines on cardio-oncology highlighted the need for further research on the impact of early diagnosis and treatment of cancer therapy-related cardiovascular toxicity on frailty, but provided no specific recommendation on the assessment of frailty or the integration of frailty into the management of cardiotoxicity.²

Frailty Assessment Tools Used in Observational Studies in Patients with Cancer

In a 2015 systematic review of frailty in patients with cancer, 16 of the 22 included observational studies that used the comprehensive geriatric assessment (CGA) as the reference standard for frailty diagnosis, five used Fried’s frailty phenotype model, and one study used both CGA and the phenotype model.¹⁰ The 16 studies that used CGA assessed a variety of domains, including cognition, physical function, nutrition, mood, fatigue, polypharmacy, social support and comorbidity.

A 2025 systematic review on frailty and outcomes in adults undergoing systemic anticancer treatment showed that, among the 58 studies included, the most commonly used frailty assessment tool was Geriatric-8 (applied in 28 studies, covering eight domains: nutrition, weight loss, mobility, cognition, depression, polypharmacy, age, and self-rated health).¹¹ Other frailty assessment tools, applied in the included studies of this review, were the Clinical Frailty Scale, Edmonton Frail Scale, Flemish Triage Risk Screening Tool, Frailty Index, Fried’s frailty criteria, FRAIL criteria, geriatric assessment, Groningen Frailty Indicator and the Vulnerable Elders Survey-13.. Most frailty assessment tools reported frailty as a binary measure (frail/non-frail).

Frailty Assessment Tools Used in Clinical Drug Trials in Patients with Cancer

In a recent review on the assessment of frailty in 17 clinical drug trials, four cancer trials were included.⁵³ All four involved patients with multiple myeloma, and frailty was measured prospectively in two trials and retrospectively in the other two. Three trials applied the same approach of using age, the Charlson Comorbidity Index (CCI), and the Eastern Cooperative Oncology Group Performance Status (ECOG PS) to define frailty (the BOSTON, ALCYONE and MAIA trials).^54–56 In these trials, frailty was assessed based on age (≤75 years = 0 points; 76−80 years = 1 point, >80 years = 2 points), CCI (≤1 = 0 points; >1 = 1 point), and the ECOG PS (0 = 0 points; 1 = 1 point; ≥2 = 2 points). The sum of scores was used to classify patients as fit (0), intermediate (1) or frail (≥2).

A similar approach was also applied in the EMN01 study, using a frailty scoring system developed by the International Myeloma Working Group.⁵⁷ This scoring system also relied on age and the CCI (≤1 versus >1), but the Katz Activities of Daily Living Scale (>4 versus ≤4), and Lawton Instrumental Activities of Daily Living Scale (>5 versus ≤5) were added to the model instead of the ECOG PS. This frailty score also classified patients into three groups: fit (total score 0), intermediate-fit (total score 1), and frail (total score ≥2).⁵⁷

The Challenges of Frailty Assessments in Cardio-oncology

There are several challenges to the implementation of frailty assessment in cardio-oncology care. Time and resource constraints are among the top challenges. Implementing frailty assessment in clinical settings requires time, expertise, training and resources.⁵⁸ Many healthcare professionals find themselves stretched thin, facing high patient loads and limited resources, which makes it particularly difficult to conduct thorough and comprehensive frailty assessments during routine patient evaluations.

Lack of awareness about frailty is another common reason. An international survey on frailty assessment in patients with cancer found that, among the oncology healthcare professional participants, there was a worldwide lack of knowledge, and usage, of frailty screening tools.⁵⁹ Among the 737 participants from 91 countries (81% physicians, 13% nurses, and 5% other healthcare professionals), 73% reported using frailty screening tools for older patients with cancer, and 43% were aware of the Eastern Cooperative Oncology Group performance status scores only. Among the participants who have never applied a frailty screening tools, the top reasons were lack of awareness and time constraints.⁵⁹

One of the significant challenges faced by healthcare professionals is the concern surrounding patients’ acceptance of frailty assessments. Cancer patients, especially those who are older, may feel uncomfortable or resistant to undergoing these evaluations, which could affect their overall willingness to participate in frailty assessment. There is also a concern about the potential for unintentional harm to patients during frailty assessments, including causing anxiety about their health status. The physical assessment of older patients can sometimes result in unintentional injuries due to physiological changes caused by cancer, cardiotoxicity and other underlying conditions.⁶⁰ Therefore, clinicians must carefully balance conducting thorough assessments with ensuring that their patients feel respected and empowered throughout the process. A qualitative study conducted by Warnock et al. in 2024, involving 10 patients with lung cancer and 11 clinicians, indicated that assessing frailty could aid in decision-making, balancing the desire to deliver optimal treatment with the risks to patients who may be unable to tolerate it.⁶¹ Healthcare professionals face the challenges of integrating frailty assessments into clinical practice in a manner that is acceptable to patients and minimises the risk of any potential unintended harms.

A lack of consensus on a gold standard of frailty definition presents a significant practical challenge. Frailty assessment methods vary, and some approaches are time-consuming, limiting their use in busy oncology settings. In addition, there are limited studies validating the use of certain frailty assessment tools in the field of cardio-oncology. To ensure consistency across various healthcare settings, standardised frailty assessment tools need to be developed. More prospective studies are essential to validate frailty assessment tools tailored to cancer patients, as current evidence mostly comes from retrospective analyses.

The lack of specific recommendations for frailty in current cardio-oncology and oncology guidelines is an important challenge. Clinicians need to determine the appropriate treatment for patients with frailty compared to those who are non-frail. Clinicians may face difficulties in treatment decision-making, as balancing cancer treatment benefits with frailty-related risks is complex. Frail patients may be undertreated due to concerns about toxicity, or they may be overtreated without adequate consideration of their frailty status. In addition, addressing frailty requires managing multiple factors, such as polypharmacy, nutritional deficits, and psychosocial needs, which demands coordinated care across various specialties. Therefore, there is an urgent need for frailty-specific recommendations in cardio-oncology and oncology guidelines.

The key challenges in the implementation of frailty in cardio-oncology are summarised in Figure 2.

The Need to Incorporate Frailty into Cardiovascular Risk Assessment Tools for Patients Scheduled to Receive Cardiotoxic Cancer Therapies

Conducting a baseline cardiovascular risk assessment prior to cancer treatment is a vital step in providing comprehensive care for patients with cancer. This assessment is important for recognising individuals who may have an increased likelihood of developing cardiovascular complications during or following their cancer treatment. Existing cardiovascular risk assessment tools are designed for general populations free of existing CVD, and do not address the unique challenges faced by cancer patients. For example, the US PREVENT and European SCORE2 CVD risk scores emphasise traditional risk factors but overlook cancer-specific stressors, such as chemotherapy-induced inflammation or the impact of frailty on the cardiovascular system.^62,63 The 2022 ESC guidelines on cardio-oncology recommended baseline cardiovascular risk stratification before starting anticancer drugs, using the Heart Failure Association–International Cardio-Oncology Society (HFA-ICOS) risk assessment tool.² This tool, introduced in 2020, takes into account multiple factors, including demographic factors, cardiovascular risk factors, lifestyle risk factors, history of cardiovascular disease, cardiac biomarkers, current cancer treatment regimen, and prior exposure to cardiotoxic cancer treatment, to classify patients into categories of low-, medium-, high- or very high-risk (Table 1).⁶⁴ However, it is important to note that this recommendation is based on expert opinion, and it is associated with a level of evidence B or C.² While expert opinion can offer valuable guidance, it may not be supported by the highest tier of empirical research. Consequently, there is an imperative to conduct further studies to validate the HFA-ICOS risk assessment tool in a variety of demographic groups. This includes a focused examination of its effectiveness and applicability in older adults and those who are considered frail, as these populations may present unique health challenges and risk factors that differ from younger, more robust individuals. This validation effort will ensure that the tool is reliable and effective across diverse patient profiles, enhancing its utility in cardio-oncology settings.

Supplementary Table 1 provides a summary of the eight studies that have validated the HFA-ICOS risk assessment tool since its introduction in 2020.^65–72 The findings suggest that the predictive ability of the HFA-ICOS tool is still limited, with five out of eight studies reporting a c-statistic below 0.7. Furthermore, none of the studies validated this tool exclusively in patients with frailty. Frailty assessment at baseline was conducted in only two studies using ECOG PS.^67,72 However, frailty was not included in the outcome analysis. This evidence gap highlights that further studies are needed to validate the HFA-ICOS risk assessment tool in cancer patients with frailty.

Future cardiovascular risk assessment tools should, thus, consider incorporating frailty to improve the precision of risk stratification for cancer patients. Furthermore, frailty assessments can also help identify patients who would benefit from targeted interventions before cancer treatment, such as physical therapy, nutritional support, cognitive training, or social support, to enhance resilience. This proactive approach aligns with the principles of patient-centred care and has the potential to improve treatment tolerability during cancer treatment. This approach is particularly vital in cardio-oncology, where balancing cancer control with cardiovascular safety is a priority. By recognising and addressing frailty, healthcare professionals can better tailor treatment plans that optimise both cancer outcomes and cardiovascular health. Assessing frailty may help identify cancer patients who are at a higher risk of cardiotoxicity and may benefit from interventions to mitigate this risk.⁷³

Further research is needed to better understand the underlying mechanisms linking frailty to cardiotoxicity and to explore potential interventions that may mitigate these risks in cancer patients.

Discussion

There is a pressing need to address the unmet needs related to frailty in cardio-oncology. It is important to incorporate frailty into the research designs of studies in cardio-oncology populations, including a prespecified analysis plan by frailty status. Greater effort should be made to include frailty assessments in prospective registries, as well as to integrate frailty assessment into ongoing cardio-oncology trials.

Incorporate Frailty Assessment into Prospective Registries

Frailty assessment should be routinely applied in prospective clinical registries. Prospective registries involve the systematic collection of longitudinal data from a large cohort of patients with cancer in real-world settings, allowing for the tracking of frailty status alongside cardio-oncology outcomes such as cardiovascular events and survival. Patients should be enrolled at the time of their cancer diagnosis or when they begin cardiotoxic treatments. They should receive baseline frailty assessments followed by periodic follow-ups. These registry designs are particularly useful for identifying the progression of frailty, and impact of frailty on treatment tolerance in diverse populations, including older patients. This approach also provides opportunities for international collaboration to build large clinical datasets.

Integration of Frailty Assessment into Ongoing Cardio-Oncology Trials

Frailty should be assessed using validated frailty tools at the time of enrolment and at key points throughout the trial. This approach enables researchers to evaluate how frailty may affect treatment efficacy and safety. Additionally, frailty can be evaluated as a secondary trial endpoint. There are several advantages of this approach, including the use of existing trial infrastructure and funding. It also improves the generalisability of trial results into frail populations, facilitates risk stratification for personalised medicine, and supports the development of evidence-based guidelines. However, there are potential downsides, such as the added burden on trial participants, the need for amendments to the trial protocols, ethical concerns related to frail populations, high costs and challenges in recruitment.

Potential Unintended Consequences of Labelling Patients as ‘Frail’

Despite the clinical usefulness of assessing frailty for risk stratification and care planning, labelling patients as ‘frail’ can have unintended consequences. Clinicians and researchers should be mindful of the potential negative impacts of labelling someone as frail. This label can lead to the stereotyping of older individuals as failing to age well, which can be internalised by them and result in unnecessary suffering.⁷⁴ While labelling patients as “frail” in clinical settings can serve as a useful tool for identifying vulnerability and guiding care, it also poses risks to patients’ psychological, social, and physical well-being. Patients may internalise the label, resulting in anxiety, diminished self-esteem, fear of falling, or a worsened quality of life, which can accelerate functional decline.

Research has indicated that the public’s and patients’ views of frailty may be quite different compared to the medical view of frailty.^75,76 Older adults usually perceived the term “frail” as negative, and often described frailty as something they could recognise in others but would never use to describe themselves.⁷⁵

The potential for stigma, altered perceptions, and biased decision-making can lead to negative outcomes. In clinical contexts, the label could sometimes lead clinicians to make biased treatment decisions. This includes both undertreatment, which may result in extended hospital stays, reduced independence, or increased care needs upon discharge, and overtreatment, with unnecessary interventions or opportunity cost from resource misallocation.

To address these issues, strategies should focus on person-centred care, clear communication, and the integration of shared decision-making to empower patients, rather than defining them by a label. The goal should be to reframe frailty as a manageable condition by involving patients in discussions. Training programmes for healthcare providers, along with public health campaigns, can raise awareness of frailty as a condition influenced by life-course factors, reducing stigma and promoting positive perceptions.

Conclusion

As cancer survival rates improve and the population ages, the relationship between frailty, cancer, and cardiovascular health is becoming increasingly important. Frailty is a critical factor in cardio-oncology, influencing treatment tolerance and prognosis. Further studies and initiatives are needed to raise awareness and education for clinicians about incorporating frailty assessment into the management of patients with cancer. Despite the challenges in standardisation and implementation, the growing evidence of frailty’s prognostic value, along with technological innovations, makes its integration more feasible. By systematically assessing and managing frailty, clinicians can optimise cancer and cardiovascular outcomes, personalise treatment plans, and enhance patient-centred care. Further research is essential to gain a better understanding of the underlying mechanisms linking frailty to cardiotoxicity. This understanding should help develop guidelines that integrate frailty recommendations into cardio-oncology care. Additionally, there should be a clear call to action for research focused on potential interventions that address frailty in patients with cardio-oncologic conditions.

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