Definition, Conceptualization, and Prevalence of Frailty

Frailty is a state of increased vulnerability leading to adverse health outcomes. It describes a diminished physiologic reserve that results in reduced resilience and adaptive capacity to respond to stressors and maintain homeostasis. Frailty is the result of a complex interplay between aging-related physiologic changes (such as inflammation and immune activation, sarcopenia, decrease in sex hormones, higher levels of cortisol, and vitamin D deficiency), genetic and epigenetic factors, environmental and lifestyle stressors, as well as acute and chronic diseases. Frailty is distinct from disability and chronic diseases although they overlap and share similarities.

Adverse health consequences can be viewed as a balance between frailty status or reserve and external insults to the body, such as a new disease, infection, cancer, or a change in medication. A fit individual with large physiologic reserves will require a major insult such as major surgery or intensive care admission to render them functionally dependent. However, a frail individual with little reserves may suffer significant decline in their physical and functional abilities after even minor insults, such as a urinary tract infection or a medication change. It is also important to remember that chronologic age still has a critical role. Consider a 75-year-old frail man: he will have a greater risk of adverse outcomes than a 75-year-old man with lower frailty but will have lower risks of adverse outcomes than a 95-year-old man with the same frailty status. Whether health assets (such as a positive health attitude and supportive caregivers) can mitigate the effect of frailty is an area of ongoing research. Fig. 35.2 depicts our current conceptualization of frailty, incorporating the impact of age, health assets, health deficits, and a health insult on three distinct types of people: (A) a healthy younger person with high assets and low deficits; (B) a healthy older person with high assets and low deficits; and (C) an older person with low assets and high deficits.

Conceptualization of frailty.

Although the prevalence of frailty in the general community-dwelling older population is estimated to be 10%, in a systematic review of 20 studies the median prevalence of frailty in older adults with cancer was up to 42%. The prevalence of prefrail older adults with cancer is reported to be 43%, with the minority being fit. In older people with cancer, both the disease process and its intense treatment are important contributors to the high prevalence of frailty, making these patients particularly susceptible to adverse outcomes.

Sex Differences in Frailty

Previous cross-sectional evidence has proposed a male-female health-survival paradox, whereby females are found to be frailer yet live longer. To this effect, a recent meta-analysis confirmed a consistent relationship between sex, frailty, and mortality. The review synthesized seven studies using frailty index to assess frailty and found that in every age group, females had higher frailty than males yet tolerated this frailty better, evidenced by a lower mortality rate.

A number of biological, behavioral, and psychosocial factors in the pathophysiology of sex differences in frailty, morbidity, and mortality have been proposed. ^, Perhaps most interestingly is the influence of chronic inflammation, which has been identified as a key driver of the development of frailty. It has been suggested that male-female variation in diet, the gut microbiome, and central adiposity all contribute to the more critical role of inflammation in the development of frailty in females compared to males. In addition, estrogen and testosterone may contribute to sex differences in frailty by modulating inflammation, as well as having direct effects on other tissues.

While females tend to be frailer than males, they may also cultivate more health assets to help them maintain function and independence for longer. To date, no studies have investigated the association of sex with frailty in cancer patients. It is an important area for future research given the emerging evidence showing that sex influences the pathophysiology, clinical signs, treatment outcomes, and responses to cancer.

Frailty in Predicting Cancer and Surgical Outcomes

Frailty in general medical and surgical patients is associated with increased mortality and morbidity, and this is also observed in older cancer patients. Over the past decade, there has been a surge of research and publications evaluating the impact of frailty on adverse outcomes in cancer patients. In a meta-analysis by Handforth et al. frailty increased the risk of all-cause mortality at 5, 7, and 10 years of follow up by 1.8-, 2.3-, and 1.7-fold, respectively. Multiple studies have also confirmed that frailty is predictive of chemotherapy, toxicity, and intolerance. Similarly, in cancer patients who have undergone surgery, frailty is associated with increased postoperative major complications (Clavien-Dindo grade ≥II), non-home discharge, increased hospital cost, and higher 30-day mortality and hospital readmission. Table 35.1 summarizes the adverse outcomes associated with frailty in cancer surgery in key papers published since 2010. The most frequently assessed adverse outcome in these 44 studies was major postoperative complications: frailty was a significant predictor in all 29 studies that evaluated this outcome, regardless of the types of cancer surgery and tools of frailty measurement. Short-term mortality, including in-hospital mortality, was the next frequently assessed adverse outcome linked to frailty. Several studies found that frailty was a superior predictor of mortality and morbidity than chronologic age and American Society of Anaesthesiology (ASA) classification.

As frailty is a strong predictor of poor outcomes in older cancer patients, frailty assessment is important for risk stratification before surgery and chemoradiotherapy. Detecting frail patients preoperatively has the potential to inform risk of postoperative complications and adverse outcomes, thus enabling treatment planning, prompting early detection of complications, and enhancing communication with family and patients regarding expected treatment outcome. Although there is no current consensus on how to incorporate frailty assessment into cancer treatment planning or perioperative care, screening for frailty may be a good starting point for detecting those who are the most vulnerable.

Dementia and Delirium

Dementia is a neurodegenerative condition that causes multidomain decline in cognitive function, which may manifest as memory loss, disorientation, impaired judgment and insight, impaired planning, impaired visual spatial awareness, impaired language, personality change, or behavioral disturbances. The biggest risk factor for dementia is age. Delirium is an acute onset fluctuating course of altered level of consciousness and inattention, usually precipitated by a medical illness or a change of environment. Dementia is a risk factor for delirium, and delirium is associated with high mortality and morbidity. Dementia is more prevalent in older cancer patients compared with their younger counterparts simply due to age. Cognitive impairment has implications for cancer treatments.

Cognitive impairment may affect a person’s ability to understand in full the consequences of cancer treatments and the ability to weigh up benefits and risks when embarking on intensive therapies; hence the capacity to provide informed consent to a complex treatment regimen may be impaired. Dementia and delirium are associated with functional impairments and the need for prompting and supervision to carry out activities of daily living, such as driving, remember appointments, and taking regular medications. This means that cancer patients with cognitive impairment will likely need more help to adhere to medication regimes, frequent blood tests required when undergoing chemotherapy, and help with transportion to and from health appointments.

Falls

Falls are common in the older population and their causes are often multifactorial. Falls may be intrinsic in nature, for example, secondary to postural hypotension, dehydration, infections, blood dyscrasia, cardiac arrhythmias, seizures, strokes, Parkinson’s disease, dyspraxia from dementia, sciatica, peripheral neuropathy, or lower limb muscle weakness due to frailty. Falls may also be extrinsic in nature, secondary to an external trigger; for example, wet floors, loose-fitting footwear, uneven walking surfaces, or loose carpet edges. The consequences of falls range from mild, such as soft tissue injury, to severe, such as intracranial bleed and fractures, or even death. In addition, the psychologic sequelae from falls can pathologically heighten anxiety level with a fear of falls, leading to fear of mobilizing and immobility.

Screening for falls in older cancer patients is important as falls may trigger investigations for underlying causes leading to treatment of previously undiagnosed medical problems, optimization of medications, a review of a person’s home environment to prevent future falls, and physiotherapy to improve gait and balance. Falls may be an indicator of a person’s underlying frailty, hence affecting the tolerability of intensive cancer treatments.

Depression and Anxiety

Older adults are particularly at risk of mood and anxiety disorders. Many psychosocial precipitants to depression and anxiety are associated with aging: functional impairments leading to increased dependence on their spouse, children, friends, or carers; sensory impairments affecting quality of life; physical slowing and falls; symptoms from medical comorbidities; social isolation due to being outside of the workforce; and loneliness as their peers and friends pass away from advancing age. Some older adults may experience existential crisis, losing the meaning of life and feeling they have lived longer than they wished. Depression in older people can present atypically where self-reported low mood may be absent, but psychomotor retardation, apathy, and reduced appetite are also prominent features that should not be overlooked. Reduced appetite from low mood can compound the malnutrition associated with cancer.

Cancer patients are particularly susceptible to depression and anxiety, not only due to physical symptoms that cancers cause, for example pain, nausea, general lethargy, and weakness, but also due to the uncertainty of future, in terms of survival, treatment plans, and potential side effects from cancer treatment. Depression and anxiety significantly impact on quality of life and are risk factors for adverse health outcomes as apathy can lead to functional decline and poor self-care.

Polypharmacy

Polypharmacy is commonly defined as taking five or more regular medications; however, other definitions exist, including taking unnecessary medications. Polypharmacy is common in older adults due to their multiple comorbidities and chronic pain from degenerative joint diseases. Cancer and chemotherapy treatment can also add to pill burden. For example, a patient undergoing chemotherapy can suddenly have five extra medications to take for pain, constipation, and nausea. Increased number of medications in a patient is associated with greater risks of drug interactions and side effects. In addition, psychotropic medications, such as benzodiazepines, antipsychotics, and antidepressants, increase the anticholinergic load in the body, predisposing an older adult to falls and cognitive impairment.

Malnutrition

Malnutrition is another syndrome common in the older population and overlaps with cancer cachexia. Malnutrition will be explored in more detail in a later section entitled Nutrition and How It Impacts on Surgical Journey.

Comprehensive Geriatric Assessment

Comprehensive geriatric assessment (CGA) is a way of identifying and managing geriatric syndromes. It is usually conducted by a multidisciplinary team with a geriatrician and/or a gerontology nurse taking the main roles. CGA gives a holistic view of an older person’s physiologic and functional status and assesses multiple domains of health, including medical comorbidities, medications, nutrition, cognition, activities of daily living, continence, mobility, psychologic status, and social support. A CGA typically involves administering some or all of the following tools: a scale for personal and instrumental activities of daily living (such as Barthel’s index or the Nottingham Extended Activities of Daily Living Scale), Mini-Nutritional Assessment (MNA), the Mini-Mental Status Exam (MMSE), or the Mini-Cog and Geriatric Depression Scale (GDS), a social support scale, each with set cutoff points to denote abnormality. A CGA also includes a review of comorbidities, medications, and physical-based tests, such as grip strength, Timed Up and Go Test, and balance test. CGA is versatile and the number of items can be modified to as few as three components depending on the size of the multidisciplinary team and time constraint. Abbreviated-CGA (aCGA) is a validated tool using shortened forms of GDS, MMSE, and number of impaired activities of daily living items.