Frailty in the Perioperative Setting for Cancer Patients

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.

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.