Cancer represents a significant societal, public health and economic burden in the 21st century, with an estimated 20 million new cancer cases diagnosed worldwide each year.1 Over the past decades, there has been a significant improvement in survival rates for several types of cancer, leading to a growing number of cancer survivors. However, anticancer treatments are associated with various types of cardiovascular toxicities, leading to the development of cardio-oncology, a multidisciplinary field that requires close collaboration between oncologists, haematologists and cardiologists to ensure optimal care for these patients.2,3
Frailty is a complex clinical syndrome characterised by a state of increased vulnerability and reduced physiological reserve. It is strongly linked to negative outcomes, such as hospitalisation, falls, functional decline, disability and increased mortality.4 Moreover, prospective studies have shown that frailty is closely associated with a higher risk of cardiovascular disease (CVD) across various age groups.5
Compared with younger subjects, older adults with cancer are more vulnerable to adverse health events throughout the disease course, and in the cardio-oncology setting, they experience higher rates of treatment-related cardiotoxic events.6,7 Given the strong impact of frailty on patient outcomes, particularly among older adults, the evaluation of functional status has played a key role in decisions related to chemotherapy initiation. Accordingly, current guidelines emphasise the inclusion of geriatric or frailty scales as part of the pre-chemotherapy oncological assessment.8 However, to our knowledge, few studies have specifically investigated the relationship between frailty and cancer therapy-related cardiovascular events in oncology patients.
In this review, we will provide an overview of the current understanding of the mechanisms driving frailty syndrome and its connections to cancer and CVD. Additionally, we will discuss recent studies that have explored the link between frailty and cardiotoxicity, with a focus on the potential role of frailty assessment and management in improving patient care within the field of cardio-oncology.
Frailty Assessment in Cancer Patients: Epidemiological Insights
Cancer predominantly affects older individuals. In the US, cancer incidence is relatively low among individuals aged <50 years, with <500 cases per 100,000 people. However, this rate increases significantly for individuals aged ≥70, with an incidence approximately fourfold higher.9
Frailty is often regarded as a clinical consequence of physiological ageing. The estimated prevalence of frailty in the older adult population varies widely, ranging from 4 to 59%, depending on the assessment method used. However, cancer and its treatments can negatively impact patients’ physiological reserve, accelerating the ageing process and leading to an earlier onset of frailty syndrome.10
Frailty prevalence varies by cancer type and is consistently associated with poorer clinical outcomes, including reduced overall survival and increased mortality.11 Among patients with breast cancer, frailty prevalence has been reported to range widely, from 5 to 71%, and is associated with a markedly increased risk of all-cause mortality compared with non-frail patients.12,13 In lung cancer patients, frailty prevalence is estimated at 45%, with a marked negative impact on patient survival.14
Cancer survivors, compared with individuals without a history of cancer, face a substantially increased risk of CVD, and have significantly lower long-term overall survival rates compared with those without CVD.15 In a prospective cohort study involving 6,101 breast and colorectal cancer survivors, frailty was found to be significantly associated with an increased risk of developing CVD and type 2 diabetes. These findings highlight the potential value of frailty assessment in identifying cancer survivors at increased risk for CVD and type 2 diabetes, supporting the importance of risk stratification in guiding early preventive and therapeutic interventions.16
In another study involving breast cancer patients undergoing adjuvant chemotherapy and targeted therapy, 20.2% experienced nonfatal cardiovascular events potentially related to cardiotoxicity. Multivariable analysis showed that higher frailty levels, as measured by the electronic health record frailty index, were significantly associated with an increased risk of these events. Moreover, both frail and pre-frail individuals were more likely to experience adverse cardiovascular outcomes compared with robust patients, particularly within the non-Hispanic white and non-Hispanic black subgroups.17
In contrast to previous studies, a single-centre retrospective analysis of 312 patients who received anthracycline chemotherapy found that frailty was present in approximately one-quarter of patients. However, after risk adjustment, frailty was not independently associated with heart failure or mortality.18
Frailty increases the risk of cardiovascular complications in cancer patients, significantly affecting survival and quality of life, especially among older adults. However, data on older cancer patients remain scarce, unlike the well-studied paediatric population. This lack of evidence often results in undertreatment, early therapy discontinuation and poorer outcomes, emphasising the need for more inclusive, age-adapted research and care strategies.19 Recognising these high-risk subpopulations is essential to guide targeted interventions and support clinical decision-making aimed at improving long-term outcomes.20
Shared Pathophysiological Mechanisms Between Frailty and Cancer Therapy-related Cardiovascular Toxicity
Frailty represents an extreme manifestation of physiological ageing, in which the normal, gradual decline in physiological reserve seen in senescence is markedly accelerated, ultimately leading to a progressive failure of homeostatic mechanisms.21
Central to this decline is the dysfunction of key physiological systems, such as the metabolic, musculoskeletal and stress response systems, which are essential for maintaining internal stability and have been shown to operate abnormally in physically frail individuals.20
Metabolic impairments include disruptions in glucose–insulin homeostasis, such as glucose intolerance, insulin resistance and alterations in key energy-regulating hormones, including leptin, ghrelin and adiponectin, which contribute to the loss of muscle mass, accumulation of fat mass and reduced muscle strength.20,22
Additionally, this energy imbalance in frail patients is further exacerbated by dysfunction of the musculoskeletal system, characterised by reduced efficiency in energy usage and impaired mitochondrial function, including decreased mitochondrial biogenesis and copy number.23
Moreover, in frailty, the stress response system and its regulatory subsystems are dysregulated, with chronic low-grade inflammation characterised by elevated levels of pro-inflammatory markers, such as C-reactive protein and interleukin-6, as well as increased activity of immune cells, including macrophages and neutrophils. These alterations collectively accelerate muscle fibre breakdown and impair the body’s regenerative capacity.24
Dysfunction of the autonomic nervous system is also implicated, as demonstrated by reduced heart rate variability, and impaired orthostatic and cardiac regulation.25 Furthermore, hypothalamic–pituitary–adrenal axis dysregulation is frequently observed in frail individuals, characterised by elevated and flattened diurnal salivary cortisol profiles, as well as reduced circulating levels of dehydroepiandrosterone sulphate.26,27
The high prevalence of frailty among cancer patients can be attributed, at least in part, to an accelerated process of functional ageing. This phenomenon may result from the long-term effects of cancer-related treatments, such as the cytotoxic and genotoxic impact of chemotherapy and radiotherapy on healthy tissues, as well as from shared biological mechanisms between cancer and ageing, including genomic instability, impaired DNA repair and epigenetic alterations.28
Cancer therapy-related cardiovascular toxicity is a multifactorial process involving several mechanisms of cardiac cell death, most notably apoptosis, autophagy and necrosis. In recent years, additional regulated forms of cell death (such as necroptosis, pyroptosis and ferroptosis) have also been implicated, particularly in the context of anthracycline-induced toxicity. A central feature of these mechanisms is cardiomyocyte loss, which leads to progressive impairment of cardiac function.29
The heart is particularly vulnerable to anthracycline-induced toxicity due to both its high mitochondrial content, which can accumulate anthracyclines and lead to excessive reactive oxygen species production, and its relatively low antioxidant defences, which are further depleted by anthracyclines, resulting in oxidative stress and cellular damage.30
Older individuals already experience a progressive loss of cardiomyocytes and a reduction in myocardial volume, which is associated with an increased risk of cardiovascular events.31 Moreover, ageing is characterised by the accumulation of senescent cells, which show markers, such as DNA damage, telomere shortening and elevated expression of cell cycle inhibitors, such as p16INK4a and p53.32,33
Finally, senescent cardiomyocytes secrete pro-inflammatory cytokines and contribute to chronic low-grade inflammation, a phenomenon known as the senescence-associated secretory phenotype, which creates an inflammatory environment that can exacerbate chemotherapy-induced damage.33
Although the precise biological pathways linking frailty and chemotherapy-induced cardiotoxicity remain not completely understood, emerging evidence suggests the involvement of shared underlying mechanisms, particularly mitochondrial dysfunction, oxidative stress and chronic low-grade inflammation. These processes are central to the development of treatment-related cardiac damage, suggesting a strong connection between frailty, cancer and the progression of cardiovascular deterioration (Figure 1).34,35
Assessment of Frailty in Cancer Patients
Frailty in cancer patients has been associated with a heightened vulnerability to stressors and a diminished capacity to recover from medical interventions, leading to an increased risk of postoperative complications, chemotherapy intolerance, disease progression and mortality. For this reason, routine frailty screening should be considered a critical component of oncological assessment, as it plays a key role in guide individualised treatment strategies and optimising patients’ care, particularly in older adults.36
Over the past two decades, considerable efforts have been devoted to improving the detection and quantification of frailty in cancer patients, to help guiding decisions on treatment suitability and intensity.
Recognising the clinical importance of frailty assessment, international and national medical societies, such as the International Society of Geriatric Oncology and the American Society of Clinical Oncology, have issued comprehensive guidelines recommending the evaluation of frailty in older adults prior to the initiation of cancer treatment. The goal is to identify vulnerabilities, including functional status, comorbidities, cognition, nutrition, psychosocial status and polypharmacy, that may not be evident through routine oncological evaluation alone. Incorporating frailty assessments into the treatment planning process enables clinicians to stratify patients according to risk, avoid overtreatment or undertreatment, and implement supportive interventions aimed at maintaining functional independence and improving overall outcomes.37,38
Two models are generally recognised as the gold standard to identify frailty in older people: the phenotype model by Fried and the cumulative deficit model by Rockwood.39
The Fried frailty criteria is a phenotype model, in which the presence of at least three of the following five criteria in a patient indicate frailty: low physical activity, poor endurance (self-reported exhaustion), weakness (reduced grip strength), slowness (decreased walking speed) and unintentional weight loss. Those with 3–5 points are deemed frail, those with 1–2 points are pre-frail and those with 0 are deemed robust.40
The Rockwood frailty index is based on a deficit accumulation model. The index is calculated by dividing the number of deficits diagnosed by the total number of 70 pre-defined deficits.41 In contrast to the phenotype model, the deficit accumulation model does not only allow the clinician to determine whether frailty is present or not (categorical variable), but it also quantifies the extent of frailty in a patient (continuous variable).
Although most frailty assessment tools are based on these two models, numerous additional instruments have been developed, incorporating broader domains, such as cognitive impairment, functional disability and comorbidities, as integral components of frailty evaluation.42 Among the wide range of available frailty assessment tools, the choice should be guided by feasibility, intended use in clinical or research settings and specific objectives, while also acknowledging limitations in comparative data. Phenotype-based tools are generally brief and suitable for initial screening, whereas deficit accumulation models require extensive clinical and functional data, making them less practical for primary screening.43
In the oncological setting, it is recommended to begin frailty assessment in older adults with cancer using a rapid screening to identify those who are potentially vulnerable and may benefit from a subsequent Comprehensive Geriatric Assessment (CGA), which is regarded as the gold standard for identifying vulnerable and frail patients. The CGA evaluates multiple domains (medical, functional, psychological, cognitive and social) to identify modifiable risk factors and improve outcomes, such as independence, cognition and quality of life. Moreover, it predicts surgical and overall mortality, and can enhance surgical outcomes when performed preoperatively.
Although the CGA provides valuable insights, it is not routinely used in oncology care due to its demanding nature in terms of time, resources and the requirement for specialised personnel. Therefore, a brief screening test is recommended as an initial step to identify patients who are potentially vulnerable and may benefit from a full CGA.44
For the initial evaluation, the most frequently applied tools are the so-called Geriatric 8 (G8) and Vulnerable Elders Survey-13 screening tools (Table 1).45,46 Multiple studies involving older cancer patients have shown that abnormal G8 scores are associated with adverse frailty-related outcomes, including reduced survival, greater treatment-related toxicity and increased postoperative complications.47
It is important to note that abnormal results from the G8 or other frailty screenings, such as Vulnerable Elders Survey-13, should not be used alone to classify a patient as ‘frail’ because false positives can occur. While the G8 test has higher sensitivity and lower specificity, the Vulnerable Elders Survey-13 has lower sensitivity, but higher specificity. Moreover, it should be emphasised that frailty should not be viewed as an absolute measure, but rather, assessed in relation to the degree of stress imposed on the patient by the proposed cancer treatment.48
The guidelines consistently emphasise that the CGA should encompass key geriatric domains, at least including physical function (such as instrumental activities of daily living and activities of daily living), mobility, nutritional status, cognitive function, mood, comorbidities and concurrent medications.37,38
Randomised controlled trials have demonstrated that CGA-guided management of patient vulnerabilities can significantly reduce the risk of treatment-related toxicity and early discontinuation of systemic cancer therapies. In the two largest trials to date (GAP70+ and the GAIN study), each enrolling >600 older adults with cancer, the incidences of grade 3–5 toxicities were reduced by 20 and 10%, respectively.49,50 Similarly, the smaller INTEGERATE trial showed a lower rate of chemotherapy discontinuation with integrated CGA-guided onco-geriatric care compared with usual care (33 versus 53%; OR 0.38; p=0.010).51 Consistent with these findings, the GERICO study, which evaluated tumour surgery followed by chemotherapy, reported that 45% of patients in the onco-geriatric intervention arm completed the planned chemotherapy regimen, compared with only 28% in the control group, resulting in 66 additional patients completing treatment.52
After the initial frailty assessment at the onset of cancer treatment, both the overall frailty status and individual vulnerabilities may change significantly over the course of therapy.18
Although studies on progression of frailty over time in older cancer patients are limited, clinical experience indicates that worsening frailty in older cancer patients may be driven by progressive tumour disease, treatment-related toxicity, or the exacerbation and progression of chronic conditions or acute intercurrent illnesses unrelated to the cancer. Conversely, improvements in frailty status may be observed following tumour remission or as a result of targeted interventions addressing specific vulnerabilities.47
Cancer Therapy-related Cardiovascular Toxicity in Frail Cancer Patients: A Clinical Challenge
The complex management of frail cancer patients, in particular those with cancer therapy-related cardiac dysfunction, requires an integrated and multidisciplinary approach tailored to their unique vulnerabilities.
Current literature provides limited evidence on the association between frailty and the onset of cardiotoxicity in cancer patients. The 2022 European Society of Cardiology guidelines on cardio-oncology acknowledge a significant gap in the evidence regarding frailty in relation to the diagnosis and treatment of cancer therapy-related cardiovascular toxicity.53 Moreover, the limited evidence available in the literature is contradictory. While some studies suggest that pretreatment frailty status may serve as a useful marker for cardiotoxicity risk in patients undergoing adjuvant systemic treatments for early-stage breast cancer, other findings do not support this association.54 In a single-centre retrospective cohort study involving 312 older cancer patients treated with anthracyclines, frailty was not significantly associated with the development of anthracycline-related heart failure.18
A possible pathophysiological explanation for this association is that cardiotoxic therapies may accelerate biological ageing. Moreover, several mechanisms underlying frailty are also implicated in anthracycline-induced cardiotoxicity, including oxidative stress, chronic inflammation, mitochondrial dysfunction and impaired cellular repair pathways, making frail patients more susceptible to age-related adverse effects, including an earlier onset and faster progression of cardiotoxicity.55,56
Given the limited data in the literature regarding management of frailty in the context of cancer therapy-related cardiac dysfunction, current insights are largely extrapolated from the management of frailty in heart failure (HF), which represents one of the main clinical manifestations of cardiotoxicity (Figure 2).
The relationship between frailty and HF is bidirectional, with both conditions exacerbating the other. In the clinical context of HF, frailty is a crucial feature that must be considered, as it is associated with a significant worsening of prognosis, carrying a 1.5- to twofold increased risk of all-cause mortality and hospitalisations compared with non-frail individuals.57
The treatment of HF related to cardiotoxic therapies is based on diuretic therapy in addition to the so-called ‘four pillars’: b-blockers, renin–angiotensin–aldosterone system inhibitors (RAASi), mineralocorticoid receptor antagonists and sodium–glucose cotransporter-2 inhibitors (SGLT2-I).58
Despite the proven benefits of guidelines-based pharmacotherapy, frail and older patients, especially those aged >80 years with HF with reduced ejection fraction, are often undertreated, partly due to their underrepresentation in clinical trials. HF pharmacotherapy in older patients should be started at low doses with cautious uptitration to targets.59,60
The prevalence of chronic kidney disease (CKD) in frail patients is high, and the treatment of HF and cardiotoxicity in this population remains challenging, as most HF therapies have significant limitations in the context of CKD.61
Although they play a role in nephroprotection in CKD, RAASi and mineralocorticoid receptor antagonists can lead to a transient reduction in glomerular filtration rate. Moreover, RAASi have side-effects, including hyperkalaemia and rising creatinine, which can be a barrier to their use in patients with HF and CKD. However, an increase of up to 30% in serum creatinine can be viewed as a direct haemodynamic consequence of RAASi therapy and is generally considered to be benign, with no long-term negative effects.62
This highlights the importance of tailored dosing and careful monitoring of renal function and electrolyte imbalance in these patients. SGLT2-I are not associated with hyperkalaemia. However, they are contraindicated in patients with advanced renal failure, as data on their efficacy and safety in this population are lacking, given that such patients were excluded from clinical trials. Glycosuria, as the consequence of SGLT2-I action, may predispose to fungal genitourinary infections, dehydration, hypotension and prerenal renal failure, particularly among older and frail patients.63 An overview of key limitations of these drugs in CKD is provided in Table 2.
A very important issue to consider in frail cancer patients is polypharmacy. This not only represents a risk factor for the development of frailty, but is much more common in both cancer and HF patients, and is associated with an increased risk of cancer therapy-related toxic effects.64 Strategies to reduce polypharmacy, such as deprescribing unnecessary medications or using polypill treatment, have shown to improve outcomes by minimising drug-related risks and addressing the specific needs of frail cancer patients.65
Another important factor to consider is the presence of depression and social isolation, which are common both in cancer patients and in frail patients with HF. Those patients often require psychosocial interventions, such as counselling and social support, helping to mitigate the effects of social isolation and depression on frailty.65,66
It is important to emphasise that frailty is a dynamic and potentially reversible condition. Effective frailty management in HF requires a multidisciplinary approach with input from cardiologists, geriatricians, dietitians, physical therapists and social workers.
By addressing key modifiable risk factors, such as obesity, tobacco use, heavy alcohol consumption, physical inactivity, low educational attainment, polypharmacy, social isolation and depression, it is possible to delay or reduce the progression of frailty, particularly in the context of CVD.67,68
Physical, pharmacological, cognitive, nutritional and psychosocial interventions, or a combination of these, have the potential to prevent the onset of frailty, reverse its progression or enhance the quality of life in older adults already living with frailty (Figure 3).69
Frailty is often marked by significant physical and functional limitations. In 2020, as many as 35.5% of the cancer survivors aged ≥18 years reported physical inactivity.70 Several studies have demonstrated that cardiac rehabilitation improves mobility, independence and physical performance. Studies, such as HF-ACTION and REHAB-HF, show that aerobic exercise enhances quality of life and physical function in HF patients.71,72
Moreover, in breast cancer patients, aerobic exercise has been shown to be a nonpharmacological therapy that attenuates anthracycline-induced cardiotoxicity, without compromising anthracycline’s antitumour effects.73 Growing evidence suggests that aerobic exercise improves systolic and diastolic cardiac function, and mitigates pathological cardiac remodelling through reducing oxidative stress, pro-apoptotic mediators and mitochondrial dysfunction, and enhancing myofilament protein synthesis.74,75
Several pharmacological interventions have been studied to address frailty, mainly targeting sarcopenia as a key physical contributor. Among the various interventions are vitamin D3 supplementation, testosterone replacement therapy and nutritional approaches, such as whey protein supplementation, with the aim to improve frailty-related outcomes by enhancing muscle strength.
Considering the central pathogenic role of oxidative stress in the development of both frailty and cancer therapy-related cardiac dysfunction, particularly in the context of anthracyclines, the emerging role of therapies targeting mitochondrial dysfunction and oxidative stress reduction is of great interest. Among the drugs already in clinical use in HF treatment, SGLT2-I have demonstrated antioxidative properties; thus, their potential usefulness in the treatment of frailty can be hypothesised, although further research in this area would be necessary.76,77 Among the drugs currently under investigation, are interleukin-1β inhibitors, which have shown potential in modulating inflammation associated with frailty and HF.65,78 Additionally, a systematic review and meta-analysis of four large prospective cohort studies found that greater adherence to a Mediterranean diet is significantly associated with a lower incidence of frailty, likely due to its high antioxidant contents, such as β-carotene equivalents, vitamin C and vitamin E, which exert protective effects through anti-inflammatory mechanisms.76
Conclusion
The relationship between HF, cancer and frailty is mutually reinforcing. Both HF and cancer contribute to reduced physiological reserve, decreased exercise tolerance and physical deconditioning, all of which accelerate the onset and progression of frailty. Although frail patients are often considered at increased risk for adverse outcomes associated with the full implementation of medical and device-based therapies, emerging evidence suggests that they may, paradoxically, benefit the most from these interventions.79
Further studies are needed to evaluate the prognostic impact of frailty on the development of cancer therapy-related cardiovascular toxicity, to implement measures that optimise the management of these patients.