Cancer is the second leading cause of death in the United States, and the incidence of cancer increases with increasing age. From 1980 to 2003, the proportion of cancer deaths has increased, while deaths from heart disease and stroke has trended down, reflecting our aging population. In addition, data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program from 1998 to 2002 indicate that 56% of newly diagnosed cancer patients and 71% of cancer deaths occur in individuals greater than age 65. The number of older adults with a cancer diagnosis will continue to increase as the population ages and life expectancies increase. In the United States, it is estimated that by 2030 70% of cancer patients will be over the age of 65.
Breast cancer is a disease of aging, and its incidence increases with age (Figure 1). Approximately 1 in 125 women between the ages of 65 and 85 will develop breast cancer each year, as compared to 1 out of 390 women between the ages if 45 and 55. Given the increasing incidence of breast cancer with age and an increasing proportion of the US population over age 65, oncologists will be caring for an ever-larger number of elderly patients.
Breast cancer mortality also increases with increasing age (Figure 1). However, SEER data suggest that stage at diagnosis is higher only for patients over age 85. Clearly, other factors play a role in the increased breast cancer mortality with aging. Possible explanations include lower rates of screening mammography, less aggressive therapy after diagnosis, and the presence of comorbidity and frailty among older women.
As the proportion of adults over 65 increases, a growing number of frail elders will develop breast cancer. Oncology interventions for frail elders with breast cancer pose a particular challenge, as non–breast cancer-related illnesses are likely to be the major causes of mortality, minimizing the potential benefits of breast cancer therapy. The attendant toxicity of therapy must be carefully considered. This review will examine domains of frailty and explore assessment tools to help identify patients at risk of negative outcomes with breast cancer therapy. Appropriate therapeutic interventions for frail breast cancer patients and possible interventions to prevent progression to frailty will also be discussed.
Characteristics of Frailty
Frailty has no standardized definition, although as health-care professionals we may feel we can intuitively recognize frail patients. The American Geriatric Society has defined frailty as a "physiological syndrome, characterized by decreased reserve and diminished resistance to stressors, resulting from cumulative decline across multiple physiological systems, and causing vulnerability to adverse outcomes." Disease, inactivity, and physiologic changes with aging exhaust the inherent redundancy of muscular and neurologic backup systems and prevent a frail person from compensating in times of stress.
Frailty is a chronic condition, although an acute event such as stroke can contribute to its severity. Adverse outcomes from frailty include falls, injuries, susceptibility to illness, dependence, and institutionalization. Frailty increases the risk of death. Several factors contribute to frailty, including physiologic changes related to aging, chronic disease, decreased physical strength, and low levels of physical activity.[9,10]
Frailty can be independent of age or comorbidity.[10,11] Older adults show wide variations in physical function and disease, and chronologic age alone is an inadequate indicator of frailty. However, frailty is more common with increasing age, and the American Medical Association estimates that 40% of adults over age 80 are frail. Many clinicians consider individuals over 85 as inherently frail due to the physiologic changes that occur with aging.[13,14] Others consider age over 70 to be a trigger to further investigate for the presence of frailty.
Although the aging process is heterogeneous, universal physiologic changes described in Table 1 occur and can lead in time to decreased physiologic reserve in cardiac, respiratory, and renal function. Several neurologic changes also occur with aging, including decreased vision and neuropathy. Decrease in hematopoietic reserve and impaired immunosurveillance with aging may also influence tolerance of systemic cancer therapy. As a whole, these changes contribute to an increased risk for chemotherapy-associated side effects and death in older patients.[17,18]
Diminished muscle mass and strength are associated with decreased mobility, decreased ability to perform activities of daily living (ADLs, Table 2), and a higher risk of hospitalization and nursing home admission. Contributing to age-associated sarcopenia are genetics; a reduced production of growth hormone, testosterone, and insulin-like growth factor type 1 (IGF-1); an increase in inflammatory cytokines; increased protein degradation; and decreased protein synthesis. In addition to age-related changes in mobility, other contributors to sarcopenia include lack of exercise and increased oxygen free radical production. Sarcopenia is not necessarily associated with a reduced body mass indexsarcopenic obesity may occur in up to 6 % of the elderly and can carry an even greater risk of adverse outcomes, especially in those who are less active.[22,23]
Progressive inflammation, a consistent finding with aging, has also been proposed as a mechanism for the development of frailty. C-reactive protein and interleukin-6 (IL-6) levels increase with age. An increase in IL-6 and D-dimer predict functional decline and mortality in community-dwelling elders over age 70. Individuals among the Cardiovascular Health Study cohort meeting the criteria for frailty had increased levels of C-reactive protein, factor VIII(Drug information on factor viii), and D-dimer compared to nonfrail individuals. The association of an increase in inflammatory markers with age and functional decline has led to the possibility of using biomarkers as indicators of frailty.
Comorbidity also contributes to frailty, and in general the more medical problems that exist, the more likely a patient is to be frail. Comorbid conditions that cause functional limitations and are expected to progress, such as cardiovascular disease, pulmonary disease, or diabetes, limit survival and are more likely to contribute to frailty. Elders with comorbidity are at increased risk for treatment-related complications and mortality.[28,29] Satariano and Ragland evaluated the effect of comorbidity on 3-year survival among women with primary breast cancer. Those with three or more comorbid conditions had a 20-fold higher rate of mortality from a cause other than breast cancer and a 4 times higher rate of all-cause mortality compared to women with no comorbid conditions.
Other contributors to frailty are the geriatric syndromes. Geriatric syndromes are considered easily recognized clinical presentations that have multifactorial etiologies and are associated with an increased risk for adverse outcomes.[30,31] They include dementia, polypharmacy, falls, incontinence, pressure ulcers, sensory impairment, and malnutrition. Cognition and dementia are critical issues in cancer management; individuals undergoing therapy need to have the cognitive capacity to take medications correctly and report side effects.
It is difficult to separate impaired physical function and disability from frailty as they are both contributors to and consequences of frailty. Frail individuals often have immobility, gait abnormalities, muscle weakness, minimal exercise tolerance, and poor balance. They may have difficulty performing ADLs and instrumental activities of daily living (IADLs), which are thought to be critical in the ability of elderly individuals to maintain function (Table 2). Tasks for independent living including those for self-care are important for quality of life. Conditions associated with frailty are listed in Table 3.
Tools for Geriatric and Frailty Assessment
Ideally, oncologists treating the elderly should be able to differentiate between a high-functioning elder, a patient who is currently functioning but is at risk for treatment complications, and those too frail to receive aggressive therapy. However, correctly identifying individuals who belong to these three groups is difficult. The importance of performance status has long been appreciated in oncology with development of the Karnofsky performance status scale over 50 years ago. Karnofsky and Eastern Cooperative Oncology Group (ECOG)performance status may be insufficient to identify risk, and assessment tools to identify at-risk and frail elders are needed in oncology.
Criteria for defining frailty among the general population have been developed. Clinical criteria for frailty were adapted by the National Institute of Aging and the American Geriatric Society Expert Consensus in 2004. Using data from the Cardiovascular Health Study, a phenotype of frailty was operationalized. Individuals with 3 or more criteria were determined to be frail, and those with 1 to 2 criteria were considered prefrail (Table 4). At 3 years, the mortality rate was 18% for frail patients and 3% for the nonfrail. The prevalence of frailty increased with age and was greater in women than men. Compared to fit older subjects, those who were moderately or severely frail had an eightfold higher risk of institutionalization (relative risk [RR] = 8.6) and a sevenfold increased risk of death (RR = 7.3). Individuals defined as frail had a higher incidence of hospitalization and falls, progressive decline in the ability to complete ADLs, and decreased mobility. Those considered prefrail were at increased risk of becoming frail.
The Comprehensive Geriatric Assessment (CGA) is a multidimensional, often interdisciplinary diagnostic approach used by geriatricians to care for the elderly. It measures several domains including comorbid medical conditions, use of medication, social support, functional status, cognition and nutritional states, and generally includes an assessment of ADLs and IADLs. Once assessments are made, the CGA is interpreted with a multidisciplinary approach, and interventions are implemented. Reviews of CGA have shown benefit in elderly individuals.
A CGA scale for elderly cancer patients has been developed by the Italian Group for Geriatric Oncology.[36,37] Repetto et al evaluated ECOG performance status and CGA in 363 elderly patients with cancer. Of patients felt to have a good performance status, 13% had two or more comorbidities, 9.3% had ADL impairment, and 37% had IADL limitations. Performance status alone missed impairment that was identified with CGA. Balducci and others evaluated a CGA in elderly patients and identified 18% as having dependence in one or more ADLs, 72% with dependence in one or more IADLs, 41% with polypharmacy, and 19% with malnutrition.[35,38]
A limitation of the CGA is the length of time it takes to complete, prompting researchers to develop shorter self-administered comprehensive assessments. The Cancer and Leukemia Group B (CALGB) is currently testing a cancer-specific geriatric assessment that includes self-assessment and health-care–directed components. In a pilot study, it was determined to take less than 30 minutes to complete.
The Vulnerable Elders Survey (VES-13) is a tool developed to identify community-living older adults at risk of functional decline and death. It includes one question for age and 12 items that assess self-reported health. The VES-13 has been pilot-tested as a screening tool in older adults with prostate cancer. Using the CGA as the gold standard, the VES-13 had 72.7% sensitivity and 85.7% specificity for CGA-detected deficits.