The world’s population is aging at an unprecedented rate with the number of older people growing at a faster rate than all other age groups. By 2050, one in six people will be over the age of 65 (16%), accounting for 1.6 billion worldwide. The global population aged 80 years and over is expected to more than triple between 2015 and 2050, growing from 126.5 million to 446.6 million.
As the population ages, there will be increasing numbers of older people with cancer. Age is the most important risk factor for developing cancer, and age is also associated with the poorest cancer survival. Sixty percent of all cancers and 70% of cancer mortality occur in people above 65 years of age. In addition, those above 65 years have an 11-fold increase in cancer incidence and a 16-fold increase in cancer mortality compared with their younger counterparts. In the UK, between 2014 and 2016, more than half (53%) of all new cancer cases were in adults aged between 50 and 74 years while more than a third (36%) were in those aged 75 years and over. Furthermore, cancer incidence rates are the highest in the 85–89 years age group regardless of sex (see Fig. 35.1 ). Despite its growth, the aging cancer population remains under-represented in clinical trials.
Surgery is an important treatment modality of cancer; oncologists and surgeons will see a growing population of older cancer patients undergoing surgery. Given that older cancer patients are such a heterogeneous group with varying degrees of frailty, decisions regarding the most beneficial oncology treatment are complex. Understanding the role of frailty in older cancer patients is paramount in making individualized treatment decisions and to minimize adverse outcomes.
This chapter will explore the concept of frailty, how it is measured, its prevalence in cancer patients, and its relevance in cancer care. It will then discuss geriatric syndromes, consider the importance of nutrition, and conclude with the principles of providing individualized care for older cancer patients in the perioperative period. Different models and pathways of perioperative care for older patients undergoing cancer surgery will be covered in another chapter.
Frailty in Cancer Patients
Chronologic age alone is a poor guide to tolerance of cancer treatment. An 80-year-old person who runs marathons and who is fully independent with his activities of daily living is likely to be a better candidate for cancer surgery than a 70-year-old person who is malnourished, cognitively impaired, has difficulty walking for more than 10 m, and who needs assistance for personal hygiene cares. The concept of frailty, in addition to age, has become an increasingly popular tool for assessing whether an older person has the reserve and resilience to benefit from aggressive therapies and surgery. Frailty is typically associated with advancing age; however, young people can also become frail.
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.
|Cancer Type||Author; Sample Size||Adverse Outcomes Associated With Frailty|
|Long-Term Mortalitya||Short-Term Mortalityb||Postop Complications||Prolonged Hospital Stay||Readmission||Institutionalization||Postop Functional Status|
|Breast||Clough-Gorr 2012; 660||√|
|Mandelblatt 2017; 1280||√|
|Colorectal||Chen 2018; 1928||√|
|Kristjansson 2010; 178||√|
|Kristjansson 2012; 176||√||√|
|Neuman 2013; 12,979||√||√|
|Ommundsen 2014; 178||√|
|Reisinger 2015; 310||√|
|Robinson 2011; 60||√ (30 days)||√|
|Rønning 2014; 93||X (non sig)|
|Souwer 2018; 139||√||√||√||√ (30 days)|
|Tan 2012; 83||√|
|Gastric||Choe 2017; 223||√ (1 year)|
|Lu 2017; 165||√||√|
|Tegels 2014; 180||√|
|Gastrointestinal||Bateni 2018; 1928||√||√|
|Buettner 2016; 1326||√|
|Kenig 2015; 75||√|
|Vermillion 2017; 41,455||√||√||√|
|Glioblastoma||Cloney 2016; 243||√||√|
|Gynaecologic||Courtney-Brooks 2012; 37||√|
|Driver 2017; 88||√|
|George 2016; 66,105||√||√|
|Uppal 2015; 6551||√||√|
|Head and neck||Abt 2016; 1193||√|
|Adams 2013; 6727||√||√|
|Nieman 2017; 159,301||√||√||√|
|Goldstein 2019; 274||√||√|
|Intracranial neoplasm||Youngerman 2018; 9149||√||√||√||√|
|Liver||Gani 2017; 2714||√||√||√|
|Ovarian||Ferrero 2017; 78||√|
|Kaibori 2016; 71||√|
|Kumar 2017; 535||√||√|
|Yao 2019; 535||√|
|Pancreas||Mogal 2017; 9986||√|
|Dale 2014; 76||√||√||√|
|Renal||Hoffen 2016; 11,755||√|
|Silvestri 2018; 162||√|
|Urologic||Burg 2019; 123||√|
|Chappidi 2016; 2679||√||√|
|Lascano 2015; 41,681||√|
|Matsushita 2018; 41||√|
|Various||Brown 2015; 416||√|
|Lascano 2015; 41,681||√|
|Shahrokni 2019; 1137||√||√|
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.
Principles of Frailty and Geriatric Syndromes
Geriatric syndromes contribute to frailty, and frailty also increases the risk of developing geriatric syndromes. Frailty screening may facilitate the detection of geriatric syndromes that can be optimized in cancer patients to prevent adverse outcomes. The mean number of geriatric syndromes per community-dwelling person above the age of 65 years has been found to be 2.9. In the oncology population, the prevalence of geriatric syndromes is as high as 78%, and 43% have suffered three or more geriatric syndromes. The presence of geriatric syndromes makes cancer treatment complex; cancer itself and the treatment required can also precipitate or exacerbate geriatric syndromes. Managing geriatric syndromes is important in cancer patients undergoing surgery because they are associated with increased complications, in-hospital mortality, prolonged hospital stay, high health care cost, and increased functional dependence on discharge from hospital. Geriatric syndromes negatively impact on a cancer patient’s fitness for surgery and their recovery from surgery. Comprehensive geriatric assessment (CGA) is the best way to identify and manage geriatric syndromes.
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 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 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 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.
Frailty Screening and Measurement Tools
Having established that frailty predicts adverse outcomes, we need to consider how it can be detected, whether screening for frailty is sufficient, and if frailty should be quantified to guide management. There are a multitude of tools developed for measuring frailty in general medical and surgical patients; many of these have been applied in cancer patients. There is currently no consensus on which tool is the best for use in routine practice. Each tool has its own strengths and weaknesses, and the tools vary in the time taken to perform, training required, and their predictability of adverse outcomes. Some clinicians argue that each oncology and surgical unit needs to find the tools that are practical and applicable for their patient population, as different tools may be more suited for different surgical settings (acute versus elective) and different cancer types. On the other hand, the use of multiple instruments limits the ability of specialists to communicate risks across different cancer types and precludes the development of definitive Clinical Practice Guidelines.
Traditionally, frailty was diagnosed and detected using the “eye-ball” method. However, for clinicians without geriatric knowledge and training, the “eye-ball” method can be subjective and unreliable. Systematic geriatric assessment using validated measurement tools is superior to the oncologist’s opinion in detecting frailty and prognosticating survival.
Most frailty measurement tools evaluate the various domains of CGA discussed above and include a combination of self-reported measures and performance-based measures. However, some studies use single tests as markers of frailty, such as gait speed, grip strength, Timed Up and Go, albumin, or C-reactive protein (CRP) alone. The sensitivity and specificity of a more comprehensive tool need to be balanced with its feasibility and practicality, as the time taken to detect frailty will be longer than for single markers of frailty. CGA is considered the gold standard for identifying frail patients; however, each assessment can take up to 60 min and requires a specialist geriatrician and a gerontology nurse. The goal of CGA is to detect geriatric syndromes for which interventions may be offered, while brief frailty screening tools such as G8 and VES-13 aim to select patients who are vulnerable and who may benefit from the entire CGA, making more efficient use of resources.
In the next section, we will discuss in more detail six frailty measurement tools that have been validated in two or more studies evaluating older patients undergoing cancer surgery. Table 35.2 shows the different components of the six frailty measurement tools, and Table 35.3 summarizes the clinical utility of these tools. For more information on all frailty measurement tools trialed in cancer patients and their sensitivity and specificity, refer to a systematic review by Hamaker et al.