Cancer and aging

Arti Hurria, MD Hyman B. Muss, MD Harvey J. Cohen, MD

Overview

Cancer is a disease of aging. Approximately sixty percent of all cancers and seventy percent of cancer mortality occurs in people >/= age 65. The number of older adults with cancer is on the rise as the US population is aging. However, there is great heterogeneity in the health status of older adults which may impact cancer treatment decisions and outcomes. This chapter will review the principles of geriatric assessment and frailty, the biology of cancer and aging, as well as the unique issues and considerations in caring for older patients with cancer during treatment and into the survivorship years.

Cancer is a disease that disproportionately affects older patients. Almost 60% of all cancers occur in people ≥age 65. People aged 65 and older have a ninefold increase in the incidence of cancer and an 18-fold increase in cancer mortality in comparison to people younger than age 65 (Table 1).² The number of older people with cancer is continuously growing as the population is aging. In the United States, in 1900, 3.1 million people were of age 65 and older. Over the century, this number increased approximately 10-fold, so that in the year 2000 there were 35 million people aged 65 and older. This number is expected to double yet again, thus in 2030, it is projected that there will be 71.5 million people over the age of 65, accounting for 20% of the population^{3, 4} (Table 2).

Table 1 Ninefold increase in cancer incidence and 18-fold increase in cancer mortality with age < 65

	Incidence	Mortality
Age	(per 100,000)	(per 100,000)
<age 65	223.8	56.1
≥age 65	2095.8	1008.4

Source: Data derived from SEER for 1975–2011 Incidence and 1975–2010 for Mortality.¹

Table 2 The growing US population aged 65 and older 1.2

Year	Million	Percentage of population
1900	3.1	4.1
2000	35.0	12.4
2030	71.5	19.7

Among those over the age 65, there has been an age shift over time, leading to an increase in the older segment of the population. For example, during the 1990s the number aged 85 and older increased by 38%, the number aged 75 to 84 increased by 23%, and the number aged 65 to 74 increased by less than 2%. By 2030, the number ≥ age 85 is expected to double.³ Those who live to age 100 and beyond, the “centenarians,” are the fastest growing segment of the older population. On the basis of these statistics, oncologists inevitably care for a large number of older patients. There is no standard chronological age at which a person is considered “older.” Historically, aged ≥ 65 was used for two reasons:

1. this was the traditional age for retirement and
2. people in the United States become eligible for entitlement programs (Social Security, Medicare).

As our population ages, we see much heterogeneity in the aged ≥ 65 population, with many individuals continuing to work and function similarly to younger counterparts. Therefore, this chapter focuses on defining characteristics to understand “functional age,” rather than “chronological age” to distinguish the “older” patient. This chapter is also dedicated to discussing the unique issues and considerations in caring for an older patient with cancer.

Life expectancy and aging

Statistics regarding average life expectancy are useful to consider when caring for an older patient. The average life expectancy at birth is 76.5 years. As an individual ages, the average projected life expectancy increases. For example, a person who lives to 65 years of age has an average life expectancy of 19.1 years, placing their projected age of death at 84.1 years. A person who lives to 80 years of age has an average projected life expectancy of 9.1 years, placing the projected age of death at 89.1 years. Even the 100-year-old person has an average life expectancy of 2.3 years, placing their average projected age of death at 102.3 years. One may think of this as a “survival of the fittest” phenomenon, in which the absolute life expectancy increases as one ages (Table 3).⁵

Table 3 Average life expectancy

Age now	Life expectancy	Age of death
65	19.1	84.1
70	15.5	85.5
75	12.1	87.1
80	9.1	89.1
85	6.6	91.6
90	4.7	94.7
95	3.3	98.3
100	2.3	102.3

The biology of cancer and aging

Aging can be defined as “the process that converts healthy adults into frail ones with diminished reserves in most physiologic systems and an exponentially increasing vulnerability to disease and death”.⁶ Despite the universality of this definition, aging is clearly a heterogeneous process. Each individual ages at a unique pace and demonstrates varying manifestations of vulnerability. Although much progress has been made, the mechanisms of both aging and neoplasia are incompletely understood and therefore theories about the association of these two processes are an area of active research.^{7, 8} It has been suggested that cancer and aging are two sides of the same coin with the control of tissue renewal and repair being a pivotal point with excess proliferation leading to neoplasia and decline in cell growth and function resulting in senescence.^{9, 10} P16^INK expression may play a key role in this branch point as may metabolic stress resistance pathways and waste management controls via autophagy pathways.^{11, 12}

Other theories of the association with aging and neoplasia^{13, 14} include longer duration of exposure (time) and possibly increased susceptibility to oxidative stress and carcinogens; age-induced increase in DNA instability resulting in higher mutation potential that could result in both oncogene activation or amplification or tumor suppressor gene defects; a decrease in DNA repair with age, which might enhance the predisposition to the genetic defects; age-related telomere shortening, which might increase the above-mentioned DNA instability; immune dysregulation, which may decrease immune surveillance and allow the emergence of malignant clones but may also create a pro-inflammatory environment favoring the growth of malignant cells; and finally an altered microenvironment, including the presence of senescent cells that may secrete proinflammatory and carcinogenic cytokines.^14–16 These theories do not explain why there is a decrease in cancer incidence in the older segment of the population. In a autopsy study of 507 patients over 75 years of age, the prevalence of cancer at the time of autopsy decreased with increasing age (35% age 75 to 79, 20% age 95 to 99, and 16% in centenarians). This has been confirmed in a detailed demographic study and suggests that research into the cause of this phenomenon may be enlightening regarding the overall relationship of aging and cancer.¹⁷

Source: Data derived from the National Vital Statistics Report 5.

Physiologic changes with aging

Physiologic changes occur in each organ system with aging, independent of disease. Most organ systems show a linear physiological decline beginning at 30 years of age. This decline occurs at variable rates between individuals and across organ systems. The consequence of these changes during normal activity is minimal; however, during times of stress the decreased reserve becomes more apparent.¹⁸

As the cardiovascular system ages, there is a decrease in cardiac output, decrease in maximal heart rate, and prolonged recovery following exertion. During times of stress, there is a decreased response to catecholamines. As the pulmonary system ages, there is a decreased response to hypoxemia or hypercapnia, decreased elasticity in the lung tissue, increased ventilation–perfusion mismatch, and decreased forced expiratory volume. Endocrine changes with aging include a decrease in certain hormone levels and an increase in others. For example, there is a decrease in insulin-like growth factor, growth hormone, renin, aldosterone, dehydroepiandrosterone, and sex steroids and increase in insulin, norepinephrine, parathyroid hormone, vasopressin, and atrial natriuretic peptide. Changes to the neurological system with aging include neuronal loss, decrease in brain weight, decreased vision, loss in high frequency and low frequency hearing, and alterations in both taste and smell. Changes in the immune system manifest as decrease in thymic mass, decreased production of thymic hormones, decrease in naive lymphocytes, and a decrease in antibody response.¹⁸

There is a decrease in hepatic and renal mass with aging. Autopsy studies demonstrate a decrease in liver volume with aging by approximately 25% to 50%. In addition, there is decreased hepatic blood flow, estimated at a 10% to 15% decrease in liver perfusion, even after taking into account the decrease in liver volume.^19–21 Renal mass decreases by 25% to 30% over the lifespan, leading to a decreased number of functional nephrons. Renal blood flow decreases by 1% per year after 50 years of age and glomerular filtration decreases by 1 mL/min/year after the age of 40.^{19, 21}

Hematopoietic changes with aging include a decrease in bone marrow mass and increase in bone marrow fat. Despite this, peripheral blood cell concentrations in healthy older patients are similar to those of younger patients.²²

The frail older patient

The term “frail” is used to describe a subset of older patients with a critically reduced functional reserve that places them at risk for dependency, institutionalization, illness, hospitalization, and mortality.²³ A proposed definition of frailty is “a state of age-related physiologic vulnerability resulting from impaired homeostatic reserve and reduced capacity of the organism to withstand stress.” Therefore, the clinical syndrome of frailty is proposed to be a dynamic consequence of a negative energy balance; for example, starting with undernutrition that leads to loss of muscle and bone mass and contributes to further decline in activity level and strength. This, in combination with decreased reserve, contributes to the increased vulnerability of the frail patient. The end result is failure to thrive, which is a syndrome of unexplained weight loss, decreased muscle mass, and metabolic abnormalities including a decrease in albumin, creatinine, cholesterol, and hemoglobin. Immune dysfunction and chronic inflammation may play a role in frailty. Markers of inflammation are associated with aging and frailty including the cytokine interleukin 6 (IL 6) and the acute phase reactant, C-reactive protein (CRP).^24–26 In addition, elevations in plasma D dimer have been associated with age. Both IL 6 and D dimer have been predictive of mortality and functional decline.^{23, 27, 28}

A phenotype for frailty was developed in a prospective observational study of 5317 community-dwelling men and women age ≥ 65. The “frailty phenotype” was defined as a clinical syndrome in which three or more of the following criteria are present: (1) unintentional weight loss ≥ 10 lbs in past year, (2) self-reported exhaustion, (3) weakness defined as the lowest twentieth percentile in grip strength adjusted for gender and body mass index, (4) slow walking speed defined as the lowest twentieth percentile on a timed walk of 15 feet, and (5) low physical activity defined as the lowest quintile of kilocalories per week. Individuals with one or two of the criteria were categorized as an “intermediate or prefrail phenotype.” Patients defined as frail or prefrail, compared with nonfrail, had a higher incidence of 3- and 7-year mortality, hospitalization, incident falls, progressive decline in ability to complete activities of daily living (ADL), and decreased mobility. On the basis of these criteria, 7% of community-dwelling individuals age 65 and older were frail and 47% were prefrail. The prevalence of frailty and prefrailty was greater in women than men and increased with age.²⁹ Frailty is also associated with an increased risk of recurrent falls, hip fracture, and any nonspine fractures.³⁰

Another method of measuring frailty was developed by Rockwood and colleagues in which frailty is viewed as an accumulation of deficits.³¹ This frailty index is based on the premise that while individual deficit may not have a discernible threat to mortality (or other outcomes), the accumulation of these individual deficits will add up to poorer outcomes in the geriatric population. For example, in general populations of older people, the accumulation of deficits has been demonstrated to predict hospitalization, institutionalization, and death.^{32, 33} In comparison to the phenotype model developed by Fried and colleagues, which requires the knowledge of specific parameters, the deficits accumulation method can be used for virtually any data set which captures geriatric assessment variables if enough variables are collected. Future research is needed to identify the utility of these different methods of measuring frailty in predicting outcomes in older adults with cancer.

Frail older patients with cancer represent a unique subset of patients that pose challenging therapeutic decisions. The aforementioned geriatric measures of frailty have not been widely studied in older adults with cancer, where there may be additional outcomes of interest. For example, a consensus statement on research recommendations for older adults with cancer proposed that an oncologic definition of frailty should assess the risk for toxicity to cancer treatment.³⁴ An important initial step in evaluation of the frail patient is to determine whether the cancer is likely to decrease the patient’s life expectancy. In a model proposed by Balducci and Stanta,³⁵ one would consider treatment of the cancer if it was impacting the patient’s life expectancy or if it was causing a compromise in quality of life. The goal of treatment must be determined: life prolonging versus palliation. Treatment decisions involve weighing the risks and benefits with the patient and caregiver. As the nation is aging, there will be a rise in the number of frail older patients with cancer. Clinical trials focusing on efficacy and tolerability of treatment within this patient population are needed.³⁶

Evaluation of the older patient: geriatric assessment

The term “geriatric assessment” was defined at a consensus conference in 1989 as “a multi-dimensional inter-disciplinary patient evaluation that leads to the identification of patient’s problems.”³⁷ The assessment includes an evaluation of the older person’s functional status (ability to live independently at home and in the community), comorbid medical conditions, cognition, psychological status, social functioning and support, medication review, and nutritional status (Table 4). This comprehensive assessment allows for identification of areas of vulnerability and a multidisciplinary plan to address these areas. In addition, geriatric assessment provides valuable information regarding prognostic factors for morbidity and mortality in the older patient.³⁸ Each domain of a geriatric assessment is reviewed in the following section.

Table 4 Key components of a comprehensive geriatric assessment

Functional status

Comorbid (co-existing) medical conditions

Cognition

Psychological status

Social functioning and support

Socioeconomic issues

Medication review

Nutritional status

Functional status

Assessment of functional status includes an evaluation of an individual’s ability to live independently at home and in the community. Traditional assessment measures are “ADL” and “instrumental activities of daily living” (IADL) (Table 5). ADL are basic self-care skills, such as ability to bathe, dress, toilet, transfer, maintain continence, and feed oneself. These activities are essential in order for one to maintain independence in the home. The need for assistance with ADL has been predictive of cognitive impairment and greater resource requirement,³⁹ nursing home placement,⁴⁰ prolonged hospital stay, and worsening of function in the hospital.⁴¹

Table 5 Functional status assessment

Activities of daily living	Instrumental activities of daily living
Bathing	Telephone
Dressing	Traveling
Toileting	Shopping
Transfer	Preparing meals
Continence	Housework
Eating	Medication management Money management

IADL include those self-care skills that allow one to live independently in the community. These include ability to telephone, shop, travel, prepare meals, do housework, take medications, and manage one’s finances. In a study by Reuben and colleagues of 282 patients aged 64 and older, dependence in IADL (such as housework, shopping, and driving, scored as a continuous variables) was an independent predictor of mortality (p < 0.0001).⁴² The need for assistance with IADL is predictive of risk of cognitive impairment.⁴³ Individuals who require assistance with IADL often need assistance to maintain independence in the community.

Cancer in an older patient is associated with an increased need for assistance in daily activities. In a large study of older patients, individuals with cancer had more limitations in ADL and IADL than individuals without cancer and required more healthcare use.^{44, 45} The need for assistance with IADLs has been associated with poorer overall survival^{46, 47} and increased risk of chemotherapy toxicity in older adults with cancer.^48–50 For example, the need for assistance with IADL and poorer quality of life are associated with poorer overall survival among older adults with lung cancer.⁴⁷ In a study of older adults with ovarian cancer, predictors of chemotherapy toxicity included a poor performance status (Eastern Cooperative Oncology Group performance status of <2) and functional dependence (defined as living at home with assistance or living with assistance in a specialized institution).⁵¹

Comorbid medical conditions

Comorbidity is defined as a concurrent medical problem that is a competing source of morbidity or mortality. In a study by Yancik and colleagues, summary data on comorbidity were collected on 7600 patients aged ≥ 55 years. The most common concurrent medical problems included hypertension (42.9%), heart-related conditions (39.1%), and arthritis (34.9%). The number of comorbid conditions increased with age. Patients aged 55 to 64 had an average of 2.9 comorbid conditions, patients aged 65 to 74 had 3.6 comorbid conditions, and those 75 and older had 4.2 medical conditions (Table 6).³ The association between comorbidity and survival in patients with cancer is independent of a patient’s functional status.⁵² Therefore, each is an important domain to assess. The potential impact of a new disease as a competing cause of mortality decreases with increasing age secondary to the decrease in absolute projected life expectancy.⁵³ For example, consider the impact of a disease with a projected 50% mortality over 5 years in a 65-year-old person in comparison to an 85-year-old person. This disease will decrease the 65-year-old person’s average life expectancy by approximately 10 years, whereas because the absolute projected life expectancy of an 85-year-old person is less than that of a 65-year-old person, it will decrease an 85-year-old person’s average life expectancy by only about 2 years.⁵³ A study by Piccirillo et al.⁵⁴ with evaluative data of over 27,000 patients demonstrated that among individuals with cancer, the mean number of comorbid conditions and the severity of the comorbid conditions increase with age.

Table 6 Rank order of major condition, >10% of study sample

Condition	Percent
Hypertension	42.9
Heart-related conditions	39.1
Arthritis	34.9
Gastrointestinal problems	31.0
Anemia	22.6
Eye problems	19.0
Urinary tract	18.0
Previous cancers	15.4
Gallbladder problems	14.9
Chronic obstructive pulmonary disease	14.5
Diabetes	12.8
Fracture	10.8
Gland disorders	10.6

Source: Yancik 1997.³ Reproduced with permission from John Wiley & Sons.

The level of comorbidity has been shown to affect functional recovery following surgical treatment for breast cancer. In a study of older women with breast cancer, women with >2 comorbid conditions were less likely following surgery to become independent in completing IADL and more likely to experience difficulty completing tasks requiring upper body strength.⁵⁵

Comorbid medical conditions also impact the likelihood of receipt and tolerance of chemotherapy. Data from the Surveillance, Epidemiology, and End Results-Medicare database demonstrates that older patients with colon cancer who have a history of heart failure, diabetes, or chronic obstructive pulmonary disease are less likely to receive adjuvant chemotherapy.⁵⁶ In a clinical trial of older adults with lung cancer, patients with higher levels of comorbidity were more likely to discontinue chemotherapy.⁵⁷

Nutrition

Poor nutritional status is an independent predictor of functional dependency and survival. In a prospective cohort study of 214 older community-dwelling adults, a low body mass index defined as a body mass index < 22 kg/m² was associated with dependency in ADL [odds ratio 1.21; 95% confidence interval (CI) 1.01–1.45]. After adjusting for potential confounding factors including age, gender, mental status, comorbidity, and functional dependency, body mass index < 22 kg/m² was associated with decreased 1-year survival [relative risk (RR) 0.85, 95% CI 0.74–0.97].⁵⁸ However, conflicting data has shown that among hospitalized old adults, a BMI ≥ 30 was associated with better 4-year all-cause mortality, while lower BMI was not associated with increased risk of mortality.⁵⁹

Weight change over a 3-year period was recorded in a study of 4714 community-dwelling adults, aged 65 and older. Weight change, defined as a 5% or greater loss or gain in weight over a 3-year period, occurred in 34.6% of women and 27.3% of men. A higher proportion of participants lost weight than gained weight. Weight loss, and not weight gain, was associated with an increased risk of mortality (Hazard ratio = 1.67, 95% CI = 1.29–2.15).⁶⁰

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